ПОЛИПЕПТИД (ВАРИАНТЫ), ДЕЙСТВУЮЩИЙ В КОМПЛЕКСЕ С РЕЦЕПТОРОМ АНДРОГЕНА, НУКЛЕИНОВАЯ КИСЛОТА (ВАРИАНТЫ), ВЕКТОР (ВАРИАНТЫ) И КЛЕТКА-ХОЗЯИН (ВАРИАНТЫ)

Изобретение относится к биотехнологии и генной инженерии. Полипептид с последовательностью SEQ ID NO:3 связывается с рецептором андрогенов и увеличивает способность рецептора андрогенов трансактивировать андроген-чувствительный ген. Предложены также нуклеиновая кислота, кодирующая такой полипептид, и вектор, содержащий такую нуклеиновую кислоту. Группа изобретений может быть использована для создания трансгенных животных, экспрессирующих ген белка, действующего в комплексе с рецептором андрогена, служащих моделями для разработки лекарственных средств для лечения рака. 12 н. и 12 з.п. ф-лы.

НОВЫЕ ФЛУОРЕСЦИРУЮЩИЕ БЕЛКИ Aequorea coerulscens И СПОСОБЫ ИХ ПРИМЕНЕНИЯ

Изобретение относится к области генной инженерии и биотехнологии и может быть использовано для мечения белков, клеток и организмов. Путем введения замен в нуклеиновую кислоту Aequorea coerulescens, кодирующую бесцветный GFP-подобный белок acGFP, получена нуклеиновая кислота, кодирующая флуоресцентный белок. Кассета экспрессии, содержащая данную нуклеиновую кислоту под контролем регуляторных элементов, обеспечивает биосинтез флуоресцентного белка в клетке. С помощью данной генетической конструкции получены трансгенный организм и клетка, продуцирующие флуоресцентный белок, кодируемый указанной нуклеиновой кислотой. Данный флуоресцентный белок используют в способах мечения клетки, внутриклеточной структуры и белка, а также для регистрации транскрипционной активности промотора. Применение изобретения позволяет расширить арсенал маркировочных средств, используемых в биохимии, молекулярной биологии и медицинской диагностике. 10 н. и 1 з.п. ф-лы, 25 ил.

ОПОСРЕДОВАННЫЙ ВИРУСОМ УСИЛЕННЫЙ ПЕРЕНОС ДНК

Изобретение относится к медицине и касается опосредованного вирусом усиленного переноса ДНК и способа повышения эффективности трансдукции кроветворных и других клеток под действием ретровируса. Способ включает инфицирование клеток в присутствии фибронектина или его фрагментов. Фибронектин и его фрагменты значительно усиливают опосредованный ретровирусом перенос генов в клетки, в частности кроветворные клетки, включая коммитированные клетки-предшественники и первичные кроветворные стволовые клетки. Настоящим изобретением предусматриваются также усовершенствованные способы соматической генотерапии на основе усиленного переноса генов, популяции кроветворных клеток и новые конструкции, предназначенные для усиления опосредованного ретровирусом переноса ДНК в клетки, и их использование. Преимущество изобретения заключается в разработке эффективного переноса генетического материала в клетки млекопитающих без опасных последствий и ограничений. 18 с. и 70 з.п. ф-лы, 4 табл., 11 ил.

ПОЛУЧЕНИЕ АНТИТЕЛ ИЗ ОДНИХ ТЯЖЕЛЫХ ЦЕПЕЙ В ТРАНСГЕННЫХ ЖИВОТНЫХ

Настоящее изобретение относится к биотехнологии. Описан способ получения VH антител, включающий стадии обеспечения более одного гетерологического VH локуса тяжелых цепей на разных хромосомах в данном млекопитающем. Причем каждый VH локус тяжелых цепей содержит один или более сегментов V-гена, один или более сегментов D-гена, один или более сегментов J-гена и сегмент гена, кодирующий постоянную область тяжелых цепей, которая при экспрессии не включает участок Сн1. В результате антигенной стимуляции только один локус продуктивно рекомбинируется в В-клетке, что приводит к получению VH антитела из одних тяжелых цепей и экспрессии указанного VH антитела из указанного продуктивно рекомбинировавшегося локуса. Изобретение позволяет расшить репертуар ответа антител. 4 н. и 28 з.п. ф-лы, 12 ил., 1 табл.

ТРАНСКРИПЦИОННАЯ РЕГУЛЯТОРНАЯ ДНК ГЕНА ХОМЯКА EF-1α

Изобретение относится к генной инженерии, конкретно к очищению и выделению полинуклеотидов, регулирующих транскрипцию генов млекопитающих, и может быть использовано для регуляции экспрессии гетерологичных полинуклеотидов, получения трансгенных животных и для идентификации родственных регуляторных последовательностей ДНК. ДНК, содержащую транскрипционную регуляторную ДНК гена хомяка EF-1α, выделяли путем скрининга геномной библиотеки к ДНК яичника китайского хомячка (СНО-К1). Конструируют химерный полинуклеотид, включающий выделенную регуляторную ДНК гена хомяка EF-1α, оперативно связанную с генной последовательностью, кодирующей целевой белковый продукт, отличный от белка, кодируемого геном хомяка EF-1α. Полученный химерный полинуклеотид используют в составе экспрессионной плазмиды для трансформирования или трансфицирования клетки-хозяина. Для увеличения транскрипции целевого гена в клетке-хозяине интегрируют ДНК, содержащую регуляторную ДНК гена хомяка EF-1α, в геномную ДНК клетки-хозяина ...

СПОСОБ ЛЕЧЕНИЯ ОСТРОГО ПОВРЕЖДЕНИЯ ЛЕГКИХ И СПОСОБ ЛЕЧЕНИЯ ФИБРОЗА, МОНОКЛОНАЛЬНОЕ АНТИТЕЛО, ГИБРИДОМА АТСС НВ12382

Изобретение относится к медицине, в частности к терапии и пульмонологии, и касается лечения острого повреждения легких и фиброза. Для этого предлагают вводить пациенту терапевтическую дозу антитела, специфически связывающего αvβ6. Предложена также гибридома - продуцент указанного антитела. Способ обеспечивает подавление интегринового рецептора αvβ6, что приводит к купированию процессов фиброза и также явлений острого повреждения легких. 4 с. и 8 з.п.ф-лы, 3 ил.

НОВЫЙ КЛАСС ФЕРМЕНТОВ В БИОСИНТЕТИЧЕСКОМ ПУТИ ПОЛУЧЕНИЯ ТРИАЦИЛГЛИЦЕРИНА И РЕКОМБИНАНТНЫЕ МОЛЕКУЛЫ ДНК, КОДИРУЮЩИЕ ЭТИ ФЕРМЕНТЫ

Изобретение относится к биотехнологии. Предложено использование фермента фосфолипид: диацилглицерин ацилтрансферазы в качестве катализатора в ацил-СоА-независимой реакции переноса жирных кислот из фосфолипидов в диацилглицерин в процессе биосинтетического получения триацилглицерина. Заявленное изобретение позволяет получать триацилглицерин с высокой степенью эффективности. 8 ил., 2 табл.

СИНТЕТИЧЕСКИЙ МУТАНТНЫЙ ГЕН Rb (ВАРИАНТЫ), СИНТЕТИЧЕСКИЙ МУТАНТНЫЙ ГЕН p53, ПЛАЗМИДА (ВАРИАНТЫ), СПОСОБ ИНГИБИРОВАНИЯ КЛЕТОЧНОЙ ПРОЛИФЕРАЦИИ (ВАРИАНТЫ)

Изобретение относится к биотехнологии и медицине и может быть использовано для ингибирования клеточной пролиферации. Ген Rb, кодирующий функционально активный ретинобластомный белок, мутируют путем изменения в консервативной области гомологии Р5 или ген Rb мутируют путем изменения нуклеотидной последовательности, кодирующей аминокислоту, расположенную в сайте фосфорилирования белка. Мутантный ген р53 получают путем изменения в консервативной области гомологии Р5. Плазмиды, содержащие мутантный ген Rb или р53, экспрессируют активный мутантный белок, способный подавлять клеточную пролиферацию. Изобретение позволяет разрабатывать способы лечения нераковых клеточно-пролиферативных заболеваний. 7 с. и 5 з.п. ф-лы, 9 ил., 2 табл.

СЛИТЫЙ ПОЛИПЕПТИД ИЛИ ЕГО СОЛЬ, ЭКСПРЕССИРУЮЩИЙ ВЕКТОР И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ПРЕДНАЗНАЧЕННАЯ ДЛЯ ЛЕЧЕНИЯ IGE-ОПОСРЕДОВАННЫХ БОЛЕЗНЕЙ

Изобретение относится к генетической инженерии. Слитый полипептид или его соль включает, по крайней мере, один IgЕ-связывающий домен с, по крайней мере, одним компонентом сывороточного альбумина (HSA). IgE-связывающий домен является IgЕR или пре-IgЕR. Аминокислотная последовательность приведена в описании. Экспрессирующий вектор содержит нуклеотидную последовательность, кодирующую слитый полипептид. Фармацевтическая композиция содержит слитый полипептид или его соль в эффективном количестве и фармацевтически приемлемые носители или разбавители. Изобретение позволяет получить фармкомпозицию для лечения опосредованных IgE аллергических заболеваний и связанных с ними нарушений, таких как атопический дерматит, атопическая астма и хроническая крапивница. 3 с. и 3 з.п.ф-лы, 15 ил.

СПОСОБ ИДЕНТИФИКАЦИИ МОДУЛЯТОРА СВЯЗЫВАНИЯ МЕЖДУ ПОЛИПЕПТИДОМ αd И VCAM-1 (ВАРИАНТЫ)

Изобретение относится к биотехнологии и может быть использовано для поиска модулятора биологической активности β2-интегрина человека. Модулятор связывания между полипептидом αd(α-субъединица β2-интегрина) и VCAM-1 идентифицируют путем контактирования полипептида αd с последовательностью аминокислот SEQ ID N2, 53, 55 или 103 и VCAM-1 и детектированием связывания. Полипептид αd или VCAM-1 иммобилизуют на твердом носителе, неиммобилизованный партнер связывания метят детектируемым агентом, в частности флуоресцентным агентом. Детектирование связывания осуществляют по эмиссии света из флуоресцентного агента. Изобретение позволяет разрабатывать практические средства для терапевтического вмешательства в связанные с β2-интегрином иммунные и воспалительные реакции. 2 с и 2 з.п.ф-лы, 4 ил., 2 табл.

СПОСОБ СКРИНИНГА НЕВРОПАТОЛОГИИ

Изобретение предназначено для диагностики невропатологических состояний, например церебральной ишемии, эпилепсии. Способ скрининга для невропатологии включает в себя несколько стадий. Получают образец жидкости от первого индивидуума. Соединяют его с антителом, специфически иммунореактивным с IСАМ-4. Проводят количественный анализ связывания IСАМ-4/антитело в образце. Сравнивают связывание IСАМ/антитело в указанном образце с таким же связыванием в образце от второго индивидуума, не имеющего неврологических заболеваний. Очищенная и выделенная ДНК содержит промотор для IСАМ-4 млекопитающих. Химерный полинуклеотид содержит промотор для гена человеческого IСАМ-4. Вектор экспрессии содержит указанную ДНК. Клетка-хозяин трансформирована указанным вектором экспрессии. Полипептид, обозначенный как "IСАМ-4", относится к факторам клеточной адгезии. Он обладает структурным родством с факторами межклеточной адгезии IСАМ-1, IСАМ-2 и IСАМ-R. Изобретение позволит определить уровни растворимого IСАМ-4 в ...

ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, АКТИВНАЯ В ОТНОШЕНИИ РЕЦЕПТОРА КАЛЬЦИЯ, СПОСОБ ЛЕЧЕНИЯ ПАЦИЕНТА, СПОСОБ АНАЛИЗА СОЕДИНЕНИЯ ОКАЗЫВАТЬ ВЛИЯНИЕ НА АКТИВНОСТЬ РЕЦЕПТОРА НЕОРГАНИЧЕСКОГО ИОНА, НУКЛЕИНОВАЯ КИСЛОТА, КОДИРУЮЩАЯ РЕЦЕПТОР, РЕЦЕПТОР КАЛЬЦИЯ

Изобретение относится к медицине, точнее препаратам и способам лечения и исследования, связанным с рецепторами кальция и др. неорганических ионов. Предпочтительно молекула способна воздействовать как селективный агонист или антагонист на Са+2-рецептор одной или более, но не всех клеток, выбранных из группы, состоящей из паратироидных клеток, костных остеокластов, окологломерулярных почечных клеток, проксимальных канальцевых почечных клеток, периферических канальцевых почечных клеток, клеток толстой восходящей ветви петли Хенля и/или собирающей протоки, кератиноцита в эпидермисе, парафолликулярной клетки в тироиде (С-клеток), интестинальных клеток, трофобласта в плаценте, тромбоцита, клетки сосудов гладкой мышцы, клетки сердечного предсердия, клеток, секретирующих гастрин и глюкагон, почечной, мезангиальной клетки и клетки грудной железы. Изобретение расширяет арсенал средств, способных блокировать активность внеклеточных ионов кальция, при различных патологиях. 6 с. и. 50 з.п. ф-лы, 47 ...

ПРИМЕНЕНИЕ РЕЦЕПТОРА EDG2 НА МОДЕЛИ СЕРДЕЧНО-СОСУДИСТОЙ НЕДОСТАТОЧНОСТИ У ЖИВОТНЫХ

... 1. Миокардиальные клетки млекопитающего, которые содержат вектор с аденовирусной последовательностью для одновременной экспрессии рецептора, сопряженного с G-белком, EDG2 и GFP. 2. Миокардиальные клетки млекопитающего по п.1, где эта аденовирусная векторная последовательность состоит из рекомбинантного аденовируса, дефектного по Е1/Е3-области, который экспрессирует рецептор, сопряженный с G-белком, EDG2 и GFP под контролем двух независимых промоторов. 3. Миокардиальные клетки млекопитающего по п.2, где этими двумя независимыми промоторами являются два промотора CMV. 4. Миокардиальные клетки млекопитающего по одному из пп.1-3, которые содержат белок рецептора, сопряженного с G-белком, EDG2 и белок GFP. 5. Миокардиальные клетки млекопитающего по п.1, где этим млекопитающим является кролик, мышь или крыса. 6. Способ получения миокардиальной клетки, охарактеризованной в п.1, где а) сердце млекопитающего удаляют оперативными способами ветеринарии, b) сердце обрабатывают и подвергают расщеплению ...

НОВЫЙ ЛИГАНД РЕЦЕПТОРА ЦИТОКИНА ZCYTOR17

... 1. Выделенный полипептид, содержащий последовательность аминокислотных остатков, которая по меньшей мере на 90% идентична последовательности аминокислотных остатков, выбранных из следующей группы: (а) полипептид, содержащий остатки с 38 (Val) по 152 (Leu), показанные в SEQ ID NO:2; (b) полипептид, содержащий остатки с 27 (Leu) по 164 (Thr), показанные в SEQ ID NO:2; (с) полипептид, содержащий остатки с 24 (Thr) по 164 (Thr), показанные в SEQ ID NO:2; и (d) полипептид, содержащий остатки с 1 (Met) по 164 (Thr), показанные в SEQ ID NO:2. 2. Выделенный полипептид по п.1, где аминокислотные остатки 73, 133 и 147 являются цистеином. 3. Выделенный полипептид по п.1, который связывается с рецептором zcytor17, показанным в SEQ ID NO:5 или SEQ ID NO:71. 4. Выделенный полипептид, содержащий по меньшей мере 14 смежных аминокислотных остатков SEQ ID NO:2 или SEQ ID NO:11. 5. Выделенный полипептид по п.4, где аминокислотные остатки выбраны из следующей группы: (а) аминокислотные остатки 38-52 SEQ ID ...

НОВАЯ АЛЬФА-СУБЪЕДИНИЦА БЕТА2-ИНТЕГРИНА ЧЕЛОВЕКА

... 1. Антитело, способное специфически связываться с полипептидом α4. 2. Способ лечения воспаления, включающий в себя этап введения эффективного количества антитела по п.1. 3. Способ по п.2, отличающийся тем, что воспаление представляет собой острое воспаление. 4. Способ по п.2, отличающийся тем, что воспаление представляет собой хроническое воспаление. 5. Способ по п.2, отличающийся тем, что воспаление выбрано из группы, состоящей из астмы, атеросклероза, ревматоидного артрита, рассеянного склероза, острого воспаления легких, острого респираторного дистресс-синдрома, псориаза, лейкоза с крупными гранулярными лимфоцитами (LGL), диабета типа I и воспалительной болезни кишечника. 6. Способ по п.5, отличающийся тем, что острое воспаление легких представляет собой альвеолит. 7. Способ по п.5, отличающийся тем, что лекарственное средство ингибирует инфильтрацию макрофагов к месту воспаления. 8. Способ по п.5, отличающийся тем, что лекарственное средство уменьшает количество ксантомных клеток при ...

СПОСОБ ПЕРЕПРОГРАММИРОВАНИЯ СОМАТИЧЕСКИХ КЛЕТОК

... 1. Очищенный препарат выделенных плюрипотентных клеток млекопитающего, отличающийся тем, что клетки (а) экспрессируют эндогенные Oct4 и Nanog; (б) будучи инъецированы SCID мышам, дифференцируются в клетки тканей, имеющих характеристики эндодермы, мезодермы и эктодермы; (в) не экспрессируют введенный экзогенно ген плюрипотентности или селективный маркер, функционально связанный с эндогенным геном плюрипотентности, (г) являются перепрограммированными соматическими клетками млекопитающего. ! 2. Очищенный препарат клеток по п.1, отличающийся тем, что по меньшей мере 50% клеток резистентны к деметилированию ДНК. ! 3. Очищенный препарат клеток по п.1, отличающийся тем, что клетки выживают в условиях, в которых экспрессия ДНК-метилтрансферазы I снижается по меньшей мере на 50%. ! 4. Очищенный препарат клеток по п.1, отличающийся тем, что клетки не являются генетически модифицированными. ! 5. Очищенный препарат клеток по п.1, отличающийся тем, что клетки содержат по меньшей мере одну генную модификацию ...

ПРИМЕНЕНИЕ SGK И NEDD В КАЧЕСТВЕ МИШЕНЕЙ ДЛЯ ДИАГНОСТИЧЕСКИХ И ТЕРАПЕВТИЧЕСКИХ ЦЕЛЕЙ

... 1. Применение по меньшей мере одного вещества для обнаружения экспрессии и/или функции активированной и/или неактивной Sgk, прежде всего Sgk1 и/или Sgk3, и/или РКВ, и/или Nedd, прежде всего Nedd4-2, для диагностики заболеваний, связанных с нарушением транспорта глюкозы. 2. Применение по п.1, отличающееся тем, что субстанция представляет собой по меньшей мере одно вещества из группы антител и нуклеотидов. 3. Применение по п.2, отличающееся тем, что применяют антитела к фосфорилированным и/или нефосфорилированным последовательностям в Sgk, прежде всего Sgk1 и/или Sgk3, и/или в РКВ, и/или Nedd, прежде всего Nedd4-2. 4. Применение по п.3, отличающееся тем, что применяют антитела к по меньшей мере одной фосфорилированной и/или нефосфорилированной киназной консенсусной последовательности, прежде всего консенсусной последовательности Sgk1 в протеине Nedd, прежде всего в протеине Nedd4-2. 5. Применение по п.1, отличающееся тем, что выявляют по меньшей мере одну мутацию в Nedd, прежде всего инактивирующую ...

ЛЮМИНЕСЦЕНТНОЕ ТРАНСГЕННОЕ ЖИВОТНОЕ, НЕ ОТНОСЯЩЕЕСЯ К ЧЕЛОВЕЧЕСКОМУ РОДУ, ПОТОМСТВО, ПРОИЗВОДНЫЕ КЛЕТОК И ИХ ПРИМЕНЕНИЕ

... 1. Трансгенное животное, не принадлежащее к человеческому роду, потомство и производные клеток, способные экспрессировать ген апофотопротеина и продуцировать биолюминесцентный сигнал в ответ на изменения внутриклеточной концентрации кальция. ! 2. Трансгенное животное, не принадлежащее к человеческому роду, потомство и производные клеток по п.1, в котором экспрессия гена апофотопротеина и/или продукция люминесцентного сигнала в ответ на изменения внутриклеточной концентрации кальция являются универсальными. ! 3. Трансгенное животное, не принадлежащее к человеческому роду, потомство и производные клеток по п.1, в котором экспрессия гена апофотопротеина и/или продукция люминесцентного сигнала в ответ на изменения внутриклеточной концентрации кальция являются индуцируемыми и/или специфичными для органа, ткани, типа клеток или стадии развития. ! 4. Трансгенное животное, не принадлежащее к человеческому роду, потомство и производные клеток по любому из предшествующих пунктов, где животное является ...

ЖИВОТНАЯ МОДЕЛЬ ДЛЯ ЗАБОЛЕВАНИЯ, ИНДУЦИРОВАННОГО HIV

... 1. Способ получения животной модели для HIV, включающий этапы, на которых: ! a. создают и вводят белки, родственные HIV, необходимые HIV для прикрепления, проникновения и воспроизведения в живом животном путем кодирования указанных белков в организмах-комменсалах, происходящих из лимфоидной ткани, связанной с кишкой, с помощью технологии рекомбинирования; ! b. создают и вводят белки, родственные HIV, необходимые HIV, чтобы избежать иммунного ответа указанного животного, путем кодирования указанных белков, родственных HIV, в организмах-комменсалах, происходящих из лимфоидной ткани, связанной с кишкой, с помощью технологии рекомбинирования; и ! c. инфицируют указанное животное живым, репликационно компетентным HIV. ! 2. Способ по п.1, где концентрации указанного белка, родственного HIV, вводимые указанному животному, представлены в транс-форме и отражают концентрации, определенные в нормальной иммунологической среде человека. ! 3. Способ по п.1, где указанный способ дополнительно включает ...

МЫШИ, ЭКСПРЕССИРУЮЩИЕ ЛЕГКУЮ ЦЕПЬ С ВАРИАБЕЛЬНОЙ ОБЛАСТЬЮ λ ЧЕЛОВЕКА И КОНСТАНТНОЙ ОБЛАСТЬЮ МЫШИ

СВИНЬИ, СОДЕРЖАЩИЕ МОДИФИЦИРОВАННЫЙ БЕЛОК CD163, И СВЯЗАННЫЕ С ЭТИМ СПОСОБЫ

ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА ЖИВОТНЫЕ С ГУМАНИЗИРОВАННЫМ ГЕНОМ СИГНАЛЬНОГО РЕГУЛЯТОРНОГО БЕЛКА

СПОСОБЫ ПОЛУЧЕНИЯ ЦЕЛЕВОЙ МОЛЕКУЛЫ В ТРАНСГЕННОМ ЖИВОТНОМ И ВЫДЕЛЕНИЯ ЦЕЛЕВОЙ МОЛЕКУЛЫ

... 1. Трансгенная система для выделения целевого полипептида, обладающего связываемым эпитопом, система, включающая трансгенное животное, имеющее в своем геноме нуклеиновую кислоту, кодирующую поливалентный связывающий полипептид под контролем промотора, который направляет экспрессию в эпителиальных клетках молочной железы, где поливалентный связывающий полипептид включает первую связывающую группу, которая специфически связывает связываемый эпитоп целевого полипептида, и вторую связывающую группу, которая специфически связывает матрикс, посредством чего такой трансгенный поливалентный связывающий полипептид экспрессируется в высоких концентрациях в молоко трансгенного животного, и матрикс, с которым вторая связывающая группа поливалентного связывающего полипептида специфически связывается. 2. Система по п.1, в которой связываемый эпитоп целевого полипептида является удаляемым. 3. Система по п.2, в которой связывающая группа поливалентного связывающего полипептида удаляет связываемый эпитоп ...

ИЗОЦИТРАТДЕГИДРОГЕНАЗА, ЕЕ ГЕН И ИХ ПРИМЕНЕНИЕ В ЛЕЧЕНИИ ОЖИРЕНИЯ, ГИПЕРЛИПИДЕМИИ И ЖИРОВОЙ ИНФИЛЬТРАЦИИ ПЕЧЕНИ ПРИ БИОСИНТЕЗЕ ЛИПИДОВ

... 1. Способ увеличения активности активируемого пролифератором пероксисом рецептора γ (PPARγ), при котором вводят цитозольную НАДФ+-зависимую изоцитратдегидрогеназу (IDPc), ген IDPc или НАДФН, где НАДФН является продуктом ферментативной реакции с участием IDPc. 2. Способ увеличения биосинтеза липидов, таких как триглицериды, холестерин или сквален, при котором вводят IDPc или ген IDPc. 3. Способ увеличения биосинтеза липидов, таких как триглицериды, холестерин или сквален, in vivo, при котором прибавляют НАДФН, который является продуктом ферментативной реакции с участием IDPc. 4. Способ отбора ингибитора, который ингибирует отложение жиров или продуцирование триглицеридов и холестерина, при котором используют IDPc, где этот ингибитор взаимодействует с IDPc, снижая активность этого фермента, а затем снижая в клетках уровень НАДФН, который является продуктом ферментативной реакции с участием IDPc. 5. Способ отбора ингибитора, который ингибирует отложение жиров или продуцирование триглицеридов ...

IN PROSTATA AKTIVER GEWEBESPEZIFISCHER ENHANCER

VERFAHREN UND ZUSAMMENSETZUNGEN ZUR BEOBACHTUNG DER ZELLULÄREN VERARBEITUNG VON BETA-AMYLOID-VORLÄUFERPROTEINEN

MENSCHLICHES MUTATOR-GEN NMSH2 UND SEINE VERBINDUNG ZUM HEREDITAREN, NICHTPOLYPÖSEN KOLORREKTALEN KARZINOM

POLYAMINOSÄURE-TRÄGER FÜR OLIGONUKLEOTID

POLYPEPTIDE VON DER SEMAPHORIN-GENFAMILIE

POLYMORPHISMUS IM HUMANEN MDR-1 GEN UND DESSEN VERWENDUNG

GEN BETEILIGT AN V(D)J REKOMBINATION UND/ODER DNA REPARATUR

DIAGNOSTISCHE UND THERAPEUTISCHE VERWENDUNG VON ENSADIN-0581 GEN UND PROTEIN FÜR NEURODEGENERATIVE ERKRANKUNGEN

MODIFIZIERTES BIOLOGISCHES MATERIAL

REGULIERENDE SEQUENZEN DES VILLIN-GENS AUS DER MAUS UND VERWENDUNG ZUR HERSTELLUNG VON TRANSGENEN TIEREN

MUTATIONEN IM MYOSTATINGEN STEIGERN MUSKELMASSE IN SÄUGETIEREN

FLUORESZIERENDES PROTEIN AUS AEQUOREA COERULESCENS UND IHRE VERWENDUNGEN

VERWENDUNG VON LEZITHIN-CHOLESTERIN-AZETYLTRANSFERASE FÜR DIE BEHANDLUNG VON ATHEROSKLEROSE

NUKLEINSÄURESEQUENZEN FÜR ATP-BINDUNGS CASSETTE-TRANSPORTER

MATERIALIEN UND METHODEN MIT BEZUG ZUR IDENTIFIZIERUNG UND SEQUENZIERUNG DES KREBS-SUSZEPTILITAETSGENS BRCA2 UND DESSEN ANWENDUNGEN

MATERIALIEN UND METHODEN MIT BEZUG ZUR IDENTIFIZIERUNG UND SEQUENZIERUNG DES KREBS-SUSZEPTILITAETSGENS BRCA2 UND DESSEN ANWENDUNGEN

A mammal with inducible in situ ductal carcinoma useful as a model for research and identification of therapeutics

A mammal with an inducible in situ ductal carcinoma (DCIS), where the mammal contains an oncogene activatible through a lactotropic hormone, is new. An Independent claim is also included for a method for preparing a mammal as above comprising: (a) introducing a DNA coding for an oncogene in fertilized oocytes of a mammal, where the DNA under the control of a promoter is specific for a lactotropic hormone; (b) implantation of the oocyte in a pseudopregnant mammal; and (c) selection of progeny of containing the DCIS.

VERFAHREN ZUR HERSTELLUNG VON SÄUGETIEREN MIT DEFINIERTEN GENETISCHEN EIGENSCHAFTEN

BAFF, DESSEN INHIBITOREN UND DESSEN VERWENDUNG ZUR MODULIERUNG DER B-ZELL-ANTWORT

HEMMUNG DER EXPRESSION VON GENEN MITTELS DSRNA

EINEN NMDA REZEPTOR ENTHALTENDE MULTIPROTEIN-KOMPLEXE UND DEREN VERWENDUNG

Stress-gekoppelte, Kalzium-abhängige Protein Kinase Proteine sowie deren Verwendung in Pflanzen

METHODEN ZUR IDENTIFIZIERUNG VON ZUSAMMENSETZUNGEN, DIE FÜR DIE BEHANDLUNG VON FETTLEIBIGKEIT NÜTZLICH SIND, UNTER VERWENDUNG VON FOXC2

NUKLEOTIDSEQUENZ, DIE FÜR EINE FLAVINMONOOXYGENASE KODIERT, DAS KORRESPONDIERENDE PROTEIN, SOWIE DEREN VERWENDUNGEN IN DIAGNOSTIK UND THERAPIE

ERYTHROPOIETIN-ANALOG-MENSCHLICHES SERUM-ALBUMIN FUSIONSPROTEIN

FUSIONSPOLYPEPTIDE DIE EINE IGE-BINDUNGSDOMÄNE UND EINE HSA-KOMPONENTE ENTHALTEN UND DEREN DIAGNOSTISCHE UND THERAPEUTISCHE VERWENDUNG

PROTEOM-ANALYSE ZUM CHARAKTERISIEREN VON AUF- UND ABGEREGELTEN PROTEINEN IN BIOLOGISCHEN PROBEN

FAS LIGAND ÄHNLICHES PROTEIN, SEINE HERSTELLUNG UND VERWENDUNG

VERFAHREN ZUR DIFFERENZIERUNG MESENCHYMALER STAMMZELLEN ZU STEROIDPRODUZIERENDEN ZELLEN

VASKULÄRER ENDOTHELIALER WACHSTUMSFAKTOR X

IM IRAK-GEN MODIFIZIERTE TRANSGENE MÄUSE

VERFAHREN ZUR DETEKTION DER GAMMA-SEKRETASE-AKTIVITÄT

TRANSGENE AMPHIBISCHE TIERMODELLE FÜR LYMPHANGIOGENESE

VERWENDUNG VON LÖSLICHEM CD14 ZUR BEHANDLUNG VON ERKRANKUNGEN

Suppression of xenotransplant rejection

Selection method

Protein expression

Cell mediated transgenesis

Nuclear transfer with selected donor cells

Human genome-derived single exon nucleic acid probes useful for analysis of gene expression in human hela cells or other human cervical epithelial cells

Reduced xenoantigen transfer following human donor tissue hosting in non-human mammal

Drosophila melanogaster GABA B receptors and their use in identifying insecticides

Human serine/threonine/tyrosine protein kinase

Nucleic acid sequences (SEQ ID NO: 1 and 2) encoding a human serine/threonine/tyrosine protein kinase (STTK) of SEQ ID NO: 3 are claimed. Also claimed are vectors and host cells that express STTK, protein fragments and fusion proteins of STTK and antibodies thereto. The invention also claims transgenic cells and non-human organisms comprising STTK. Pharmaceutical compositions comprising the STTK polynucleotide, polypeptide or antibody are also claimed, as are diagnostic methods and assays for antagonists or agonists of STTK activity. Possible roles for STTK in diseases, including Alzheimer's and hemochromatosis are disclosed.

Regulation of endogenous gene expression in cells using zinc finger proteins

Human genome-derived single exon nucleic acid probes useful for analysis of gene expression in human breast and HBL 100 cells

A single exon nucleic acid microarray comprising a plurality of single exon nucleic acid probes for measuring gene expression in a sample derived from human HBL 100 cells is described. Also described are single exon nucleic acid probes expressed in the HBL 100 cells and their use in methods for detecting gene expression.

Excretable reporter systems

Human N-methyl-D-aspartate receptor subunits,nucleic acids encoding same and uses therefor

Sex reversal enzyme

Nucleic acid sequences for the production of transgenic animals prone to thrombi,dilated cardiomyopathy or the like

A nucleic acid consists of DNA comprising a gene sequence coding for an Epstein-Barr virus nuclear antigen leader protein or homologue or derivative preferably fused to an upstream segment containing a mouse metallothionein-I gene sequence providing promoter and control sequences and fused to a downstream segment containing a human growth hormone gene sequence (hGH). Transgenic animals such as mice produced by incorporating this DNA into the genome thereof have a substantially increased probability of spontaneously developing blood clotting or thrombi in their circulatory system, especially in the left atrium of the heart, and/or symptoms of dilated cardiomyopathy or similar heart dysfunction. Such animals can be useful for screening and identifying or testing drugs or other substances for antithrombotic or thrombolytic activity or for cardiotherapeutic activity for use in human medicine.

Human genome-derived single exon nucleic acid probes useful for anlaysis of gene expression in human hela cells or other human cervical epithelial cells

Control of gene expression

Control of gene expression

Conditional mutants of influenza virus M2 protein

Human genome-derived single exon nucleic acid probes useful for analysis of gene expression in human breast and BT 474 cells

Methods for producing antibodies

A method for producing immortalised antibody-secreting cells, comprising:

Proteins

Detection of cellular stress

Protein

Targeted gene modification by parvoviral vectors

Materials and methods relating to improved vaccination strategies

Ires

Sodium channel regulators and modulators

Transgenic mice

The invention relates to nucleic acid constructs for expression in mice for the production of heavy chain only antibodies and VH domains, transgenic mice, related methods and uses.

Polypeptide

Methods

Regulation of endogenous gene expression in cells using zinc finger proteins

Four human zinc-finger-containing proteins: mdz3,mdz4,mdz7 and mdz12

Recombinant vectors

Immunosupression

Recombinant DNA

Gene control

Novel compounds

Pole top support for aerial electric power lines

Novel modified msp-1 nucleic acid sequences and methods for increasing mrna levels and protein expression in cell systems

Animal model for parkinson's disease

Disclosed are methods and compositions for an animal model of Parkinson's disease. In particular, disclosed is the use of antisense compounds to inhibit the expression of ALDH1A1 in the substantia nigra of an animal brain for the purpose of creating an animal that will displays the symptoms of a human with Parkinson's Disease, including various biochemical, histological, and behavioral characteristics. Also disclosed are methods for using the animal model for Parkinson's disease to test potential therapeutic agents for Parkinson's disease.

Novel uses of vegfxxxb

The invention provides VEGF xxx b, or an agent which selectively promotes the expression of VEGF xxx b in preference to VEGF xxx in cells of a subject or in vitro, or an expression vector system which causes the expression of the VEGF xxx b in a host organism, for use in treating or preventing microvascular hyperpermeability disorders, or in regulating the pro-angiogenic pro-permeability properties of VEGF xxx isoforms, or in supporting epithelial cell survival without increased permeability, or in reducing the nature (for example the number density and/or size) of fenestrations of epithelial filtration membranes in vivo or in vitro.

Human monoclonal antibody against a costimulatory signal transduction molecule ailim and pharmaceutical use thereof

Immunization of human antibody-producing transgenic mice, which have been created using genetic engineering techniques, with AILIM molecule as an antigen resulted in various human monoclonal antibodies capable of binding to AILIM and capable of controlling a variety of biological reactions (for example, cell proliferation, cytokine production, immune cytolysis, cell death, induction of ADCC, etc.) associated with AILIM-mediated costimulatory signal (secondary signal) transduction. Furthermore, it has been revealed that the human monoclonal antibody is effective to treat and prevent various diseases associated with AILIM-mediated costimulatory signal transduction, being capable of inhibiting the onset and/or advancement of the diseases.

Anti- integrin antibodies, compositions, methods and uses

The present invention relates to at least one novel anti-alpha-V subunit antibodies, including isolated nucleic acids that encode at least one anti-alpha-V subunit antibody, alpha-V subunit, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, including therapeutic compositions, methods and devices.

Psca: prostate stem cell antigen and uses thereof

The invention provides a novel prostate cell-surface antigen, designated Prostate Stem Cell Antigen (PSCA), which is widely over-expressed across all stages of prostate cancer, including high grade prostatic intraepithelial neoplasia (PIN), androgen-dependent and androgen-independent prostate tumors.

Methods of Diagnosing Hypophosphatemic Disorders

The present invention relates to methods of diagnosing hypophosphatemic disorders.

Prevention and treatment of blood coagulation-related disases

Provided herein is an animal having a persistent hypercoagulable state by implanting a cell, for example a tumor cell, in which the gene of human tissue factor is implanted to an experimental animal such as a mouse and then growing the cell, thereby persistently supplying human tissue factor to the experimental animal. This animal model is useful for research and development of therapeutic agents for diseases having a persistent hypercoagulable state. Also provided are preventive or therapeutic agents for diseases having a persistent hypercoagulable state, a hypercoagulable state resulting from infections, venous thrombosis, arterial thrombosis, and diseases resulting from the hypertrophy of vascular media, the agent comprising an antibody against human tissue factor (human TF) as an active ingredient.

Sex-determination and methods of specifying same

The present invention relates generally to the field of sex determination of animals. Provided are methods and agents to manipulate sex determination, particularly in avian animals such as chickens, through a male chromosome-linked testis (sex) regulatory gene. Expression or activity of the DMRT1 gene or protein is modulated to produce animals with displaying a phenotype sex that differs from their genotype.

Compositions comprising female germline stem cells and methods of use thereof

The present invention relates to female germline stem cells and their progenitors, methods of isolation thereof, and methods of use thereof.

Immunocompromised Ungulates

Porcine animals, tissue and organs as well as cells and cell lines derived from such animals are provided that lack functional endogenous immunoglobulin loci and are deficient in immunoglobulin expression and B-cells. These animals are useful as model systems for research and for development of new pharmaceutical and biological agents. In addition, methods are provided to prepare such animals.

Class ii human histone deacetylases, and uses related thereto

The invention provides histone deacetylase class II nucleic acids and polypeptides, methods and reagents for their use, and related compounds including small molecule libraries containing class II histone deacetylase inhibitors.

Human antibodies derived from immunized xenomice

Fully human antibodies against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Characterization of granulocytic ehrlichia and methods of use

The present invention relates, in general, to granulocytic ehrlichia (GE) proteins. In particular, the present invention relates to nucleic acid molecules coding for GE S2, S7, S22, S23, C6.1, C6.2, S11, E8, E46#1, and E46#2 proteins; purified GE S2, S7, S22, S23, C6.1, C6.2, S1, E8, E46#1, and E46#2 proteins and polypeptides; recombinant nucleic acid molecules; cells containing the recombinant nucleic acid molecules; antibodies having binding affinity specifically to GE S2, S7, S22, S23, C6.1, C6.2, S1, E8, E46#1, and E46#2 proteins and polypeptides; hybridomas containing the antibodies; nucleic acid probes for the detection of nucleic acids encoding GE S2, S7, S22, S23, C6.1, C6.2, S11, E8, E46#1, and E46#2 proteins; a method of detecting nucleic acids encoding GE S2, S7, S22, S23, C6.1, C6.2, S11, E8, E46#1, and E46#2 proteins or polypeptides in a sample; kits containing nucleic acid probes or antibodies; bioassays using the nucleic acid sequence, protein or antibodies of this invention to diagnose, assess, or prognose a mammal afflicted with ehrlichiosis; therapeutic uses, specifically vaccines comprising S2, S7, S22, S23, C6.1, C6.2, S11, E8, E46#1, and E46#2 proteins or polypeptides or nucleic acids; and methods of preventing or inhibiting ehrlichiosis in an animal.

Double mutant mouse and cell lines

A mutant transgenic mouse and cell line derived from the mouse are disclosed. The mutant transgenic mouse was developed from a cross between a mutant mouse which carries mutant genes that express a phenotype similar to human Hermansky-Pudlak Syndrome, and a mouse strain containing a transgene encoding a temperature sensitive protein that is inactive at physiological temperatures. The resulting mutant mouse is characterized by the presence of the HPS mutations as well as the transgene. The mutant mouse and cell lines derived from the lung tissue of the mouse are useful models for lung pathology associated with human HPS, lung fibrosis and inflammation. Methods and assays utilizing the cell lines also are disclosed.

Pnmt as a novel marker for progenitor cells

In certain aspects, the present invention provides methods and compositions relating to a Pnmt-positive progenitor cell. In certain aspects, the present invention relates to methods for isolating and transplanting the subject progenitor cells, and methods for treating diseases such as myocardiac injuries and neurodegenerative disorders.

Drg11-responsive (dragon) gene family

This invention features methods and compositions useful for treating and diagnosing diseases of the nervous system, retina, skin, muscle, joint, and cartilage using a Dragon family protein. Protein and nucleic acid sequences of human, murine, zebrafish, and C. elegans Dragon family members are also disclosed.

Methods for protecting dopaminergic neurons from stress and promoting proliferation and differentiation of oligodendrocyte progenitors by nrg-2

The invention features methods of treatment and diagnosis using NRG-2 polypeptides, nucleic acid molecules, and antibodies. The invention also provides novel NRG-2 polypeptides and nucleic acid molecules.

Method for preparing a transgenic animal of simultaneous multiple-gene expression

A method for preparing a transgenic animal of simultaneous multiple-gene expression is provided. Additionally, a method for preparing a transgenic embryo, which introduces both phytase gene and human myxovirus resistant gene A into a target embryo, to obtain a transgenic embryo is provided. The transgenic animal of simultaneous multiple-gene expression can be achieved by transplanting the transgenic embryo into the body of a female target animal. A significant advantage of the foregoing methods, among many others, exists in that the simultaneous expression of multiple genes can be achieved in one transgenosis, which provides a convenient mean for the preparation of combined-gene transferred animals etc.

Inducible small rna expression constructs for targeted gene silencing

The invention relates to vectors for the inducible expression of RNA molecules in eukaryotic, particularly mam

Expression of secreted human alpha-fetoprotein in transgenic animals

The invention features a process of expressing secreted recombinant human alpha-fetoprotein (rHuAFP) in the milk or urine of transgenic mammals.

Method for constructing chimeric rat using rat embryonic stem cells

The present invention provides a preparation method of a chimeric embryo and a chimeric rat, which is characterized by contacting a rat pluripotent stem cell and a host embryo in the presence of an ES cell differentiation inhibitor. The method includes (a) a step for contacting a fertilized host embryo collected from a female rat and a rat pluripotent stem cell in the presence of an ES cell differentiation suppressant, and (b) a step for culturing the host embryo in contact with the rat pluripotent stem cell to form a chimeric embryo.

Transgenic animal overexpressing luciferase and preparation method thereof

The present disclosure provides a vector comprising a promoter and a luciferase gene having a nucleic acid sequence as disclosed in SEQ ID NO: 1; a fertilized egg transformed with the present vector; and a transgenic non-human animal overexpressing a luciferase gene from the vector and a method for preparing it. The vector and the animal of the present disclosure have a high expression rate for the luciferase gene, which confers high sensitivity for detection and thus useful for imaging analysis in a variety of research areas.

Regulation of t cell-mediated immunity by tryptophan

A mechanism of macrophage-induced T cell suppression is the selective elimination of tryptophan and/or increase in one or more tryptophan metabolites within the local macrophage microenvironment Expression of IDO can serve as a marker of suppression of T cell activation, and may play a significant role in allogeneic pregnancy and other types of transplantation. Inhibitors of IDO can be used to activate T cells. Inhibiting tryptophan degradation, or supplementing tryptophan concentration, can be used in addition to, or in place of, inhibitors of IDO. Increasing tryptophan degradation (thereby, decreasing tryptophan concentration and increasing tryptophan metabolite concentration), for example, by increasing IDO concentration or IDO activity, can suppress T cells. One can manipulate local tryptophan concentrations, and/or modulate the activity of the high affinity tryptophan transporter, and/or administer tryptophan degrading enzymes. Regulation can be further manipulated using cytokines such as MCSF, IFNγ, alone or in combination with antigen or other cytokines.

Use of meganucleases for inducing homologous recombination ex vivo and in toto in vertebrate somatic tissues and application thereof

A monomer of an I-CreI meganuclease variant wherein said monomer when in dimeric form binds and cleaves DNA.

Methods and compositions for modulating the activity of the interleukin-35 receptor complex

The receptor for Interleukin 35 (IL-35) is provided. The Interleukin 35 Receptor (IL-35R) comprises a heterodimeric complex of the Interluekin12Rβ2 receptor and the gp130 receptor. Various compositions comprising the IL-35R complex, along with polynucleotides encoding the same and kits and methods for the detection of the same the same are provided. Methods of modulating the activity of IL-35R or modulating effector T cell functions are also provided. Such methods employ various IL-35R antagonists and agonists that modulate the activity of the IL-35R complex and, in some embodiments, modulate effector T cell function. Further provided are methods for screening for IL-35R binding agents and for IL-35R modulating agents. Various methods of treatment are further provided.

Transgenic non-human animals

The invention provides a non-human transgenic animal comprising a transgene encoding angiogenin and food products comprising or obtained from the non-human transgenic animal and uses thereof.

Pathogen Restriction Factors

The use of interferon induced transmembrane protein 1, 2, or 3 (IFITM1, 2, or 3) as a viral restriction factor, and methods of using the same to produce virus, transgenic animals expressing exogenous IFITM1, 2, or 3, and methods of treating or inhibiting viral infections by targeting a gene identified herein

Methods of Modulating Thrombocytopenia and Modified Transgenic Pigs

The application provides methods of modulating platelet uptake by liver sinusoidal endothelial cells and of modulating thrombocytopenia. Transgenic pigs modified to bind fewer platelets are provided.

Treatment of Pompe's Disease

The invention provides methods of treating Pompe's disease using human acid alpha glucosidase. A preferred treatment regime comprises administering greater than 10 mg/kg body weight per week to a patient.

Modulating production traits in avians

The present invention relates to methods of modulating traits, particularly production traits, in avians such as chickens. In particular, the invention relates to the in ovo delivery of a dsRNA molecule, especially siRNAs, to modify production traits in commercially important birds.

Tiki1 and Tiki2, Wnt Inhibitors

This invention relates to Tiki1 and Tiki2 proteins and nucleic acids, cells expressing the same, and methods for identifying compounds that modulate Tiki1/2 activity for use in the treatment of osteoporosis or cellular proliferative disorders.

GDE Compositions and Methods

The present invention relates to compositions to treat glycerophosphodiester phosphodiesterase (GDE) related disorders. The invention also relates to methods treating GDE related disorders. The invention further relates to kits for treating GDE related disorders in a subject. The invention further relates to methods of identifying novel treatments for treating GDE related disorders in a subject.

Zcytor17 heterodimeric cytokine receptor polynucleotides

Novel polypeptide combinations, polynucleotides encoding the polypeptides, and related compositions and methods are disclosed for zcytor17-containing multimeric or heterodimer cytokine receptors that may be used as novel cytokine antagonists, and within methods for detecting ligands that stimulate the proliferation and/or development of hematopoietic, lymphoid and myeloid cells in vitro and in vivo. The present invention also includes methods for producing the multimeric or heterodimeric cytokine receptor, uses therefor and antibodies thereto.

Therapeutic compositions

This application relates to therapeutic siRNA agents and methods of making and using the agents.

Novel regulatory proteins and inhibitors

The invention provides a previously uncharacterized protein (gamma secretase activating protein or gSAP) that activates γ-secretase to produce β-amyloid protein (Aβ). Deposition of Aβ has been associated with Alzheimer's disease and other pathologies. The invention thus additionally provides, e.g., screening methods and novel research tools, inhibitors of this novel protein, and methods of diagnosis, treatment and control of Alzheimer's disease and other neurodegenerative conditions associated with deposition of Aβ.

Methods and Compositions for the Diagnosis of Cancer Susceptibilities and Defective DNA Repair Mechanisms and Treatment Thereof

Methods and compositions for the diagnosis of cancer susceptibilities, defective DNA repair mechanisms and treatments thereof are provided. Among sequences provided here, the FANCD2 gene has been identified, and probes and primers are provided for screening patients in genetic-based tests and for diagnosing Fanconi Anemia and cancer. The FANCD2 gene can be targeted in vivo for preparing experimental mouse models for use in screening new therapeutic agents for treating conditions involving defective DNA repair. The FANCD2 polypeptide has been sequenced and has been shown to exist in two isoforms identified as FANCD2-S and the monoubiquinated FANCD-L form. Antibodies including polyclonal and monoclonal antibodies have been prepared that distinguish the two isoforms and have been used in diagnostic tests to determine whether a subject has an intact Fanconi Anemia/BRCA pathway.

Light-Activated Cation Channel and Uses Thereof

The present invention provides compositions and methods for light-activated cation channel proteins and their uses within cell membranes and subcellular regions. The invention provides for proteins, nucleic acids, vectors and methods for genetically targeted expression of light-activated cation channels to specific cells or defined cell populations. In particular the invention provides millisecond-timescale temporal control of cation channels using moderate light intensities in cells, cell lines, transgenic animals, and humans. The invention provides for optically generating electrical spikes in nerve cells and other excitable cells useful for driving neuronal networks, drug screening, and therapy.

Use of meganucleases for inducing homologous recombination ex vivo and in toto in vertebrate somatic tissues and application thereof

A single chain homing endonuclease, comprising a first variant of I-CreI having the amino acid sequence of accession number pdb 1g9y and a second variant of I-CreI variant having the amino acid sequence of accession number pdb 1g9y in a single polypeptide.

Transgenic animals with customizable traits

Disclosed are materials and methods for creating customizable traits in animals. In the demonstration of the principle of the subject invention, a keratin-14 specific promoter is used with red fluorescent protein in the loxp cassette, dominant black (ΔG23) beta defensin 103 in the pigment cassette, and an SV40 (with intron) polyadenylation sequence. When Cre recombinase (or HTNCre) is applied to the animal's skin in a carrier base (e.g., lipid bilayers), fur is permanently genetically modified to turn black in the shape in which the HTNCre was applied.

Humanized transgenic mouse model

Provided is a transgenic animal model for testing immunogenicity and protective efficacy of human vaccines and the method for generating such a multitransgenic animal. Also disclosed are methods for screening compositions for human vaccine development. More specifically, a mouse model capable of expressing human leukocyte antigen DR4, and human costimulatory molecules (CD80) upon infusion of human HLA-matched hematopoietic stem cells, which can develop into a functional man immune system is provided.

Polynucleotide for use in treatment of influenza a virus induced diseases, encoding modified mx protein, said modified mx protein, and a transgenic animal expressing gene encoding modified mx protein

A method can be used for treating or reducing likelihood of an influenza A virus-induced disease in a mammal. The method includes administering a polynucleotide to the mammal. Theis polynucleotide includes a gene encoding Mx protein having a TRAF2 and/or a TRAF6 binding domain. The TRAF2 and/or TRAF6 binding domain can be represented by the sequences P-X-Q/E-E, P-X-Q/E-X-X-D, or P-X-E-E-X-E. The TRAF2 and/or TRAF6 binding domain can also be located in the Mx protein in a position which corresponds to the position of the hexapeptide PEEESE in the bovine Mx1 protein or in a position which is up to 20 amino acid residues upstream or downstream of that position.

Albumin Fusion Proteins

The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

Production of Transgenic Avians Using Improved Retroviral Vectors

A transgenic avian containing in its genome an exogenous nucleotide sequence which includes a promoter component and a vector with reduced promoter interference wherein the exogenous nucleotide sequence is integrated into the genome and the avian.

Nucleic acid construct for expression of oxidative stress indicator and use thereof

The present invention provides a nucleic acid construct for expressing an oxidative stress indicator comprising: a nucleic acid sequence encoding an Nrf2 protein-derived partial protein that comprises at least an Neh2 domain sequence and substantially lacks or is functionally deficient in an Neh1 domain sequence or an Neh1-Neh3 domain sequence; a stress-inducible promoter sequence positioned upstream of the nucleic acid sequence encoding an Nrf2 protein-derived partial protein; and a nucleic acid sequence encoding a protein capable of generating a detectable signal, the nucleic acid sequence being positioned downstream of the nucleic acid sequence encoding an Nrf2 protein-derived partial protein. The present invention also provides a method for measuring oxidative stress and a method for screening for an anti-oxidative stress agent, using the nucleic acid construct.

Biological control

The invention relates to a non-human multicellular organism carrying a dominant lethal genetic system, the lethal effect of which is conditional, wherein the lethal effect of the lethal system occurs in the natural environment of the organism.

Compositions and methods relating to non-human animals modified to promote production of selected gametes

Methods and compositions for producing selected non-human mammalian germ cells and gametes and for making non-human animals using the produced germ cells and gametes are provided by the present invention. Methods of generating a non-human embryo and/or animal derived from donor stem cells, methods of generating chimeric non-human animals having substantially all gametes and/or germ cells derived from the donor stem cells, methods of producing a non-human host embryo lacking functional endogenous germ cells and non-human host embryos incapable of developing endogenous gametes of the present invention are described herein.

Chimeric gene constructs for generation of fluorescent transgenic ornamental fish

Four zebrafish gene promoters, which are skin specific, muscle specific, skeletal muscle specific and ubiquitously expressed respectively, were isolated and ligated to the 5′ end of the EGFP gene. When the resulting chimeric gene constructs were introduced into zebrafish, the transgenic zebrafish emit green fluorescence under a blue light or ultraviolet light according to the specificity of the promoters used. Thus, new varieties of ornamental fish of different fluorescence patterns, e.g., skin fluorescence, muscle fluorescence, skeletal muscle-specific and/or ubiquitous fluorescence, are developed.

Antitumor vaccination using allogeneic tumor cells expressing alpha (1,3)-galactosyltransferase

The invention relates to methods and compositions for causing the selective targeting and killing of tumor cells. Through ex vivo gene therapy protocols tumor cells are engineered to express an α(1,3)galactosyl epitope. The cells are then irradiated or otherwise killed and administered to a patient. The α galactosyl epitope causes opsonization of the tumor cell enhancing uptake of the opsonized tumor cell by antigen presenting cells which results in enhanced tumor specific antigen presentation. The animal's immune system thus is stimulated to produce tumor specific cytotoxic cells and antibodies which will attack and kill tumor cells present in the animal.

Recombinant or transgenic factor vii composition, each factor vii molecule having two n-glycosylation sites with defined glycan units

The invention is related to a composition of recombinant or transgenic Factor VII, each molecule of Factor VII of the composition exhibiting two N-glycosylation sites, wherein, among all the molecules of FVII of the composition, the rate of Galα1,3G al glycan moieties is comprised between 0 and 4%. The invention is also related to a process for preparing such a composition of FVII.

Delivery of biological materials into cellular organelles

Systems, devices, and methods for delivering a biological material into an organelle of a cell are provided. In one aspect, for example, a method for introducing biological material into an organelle of a cell includes bringing into proximity a lance and a preselected biological material outside of a cell and charging the lance with a polarity and a charge sufficient to electrically associate the preselected biological material with a tip portion of the lance. The method also includes penetrating an outer portion of the cell with the lance and directing and inserting the lance into an organelle, discharging the lance to release at least a portion of the biological material into the organelle, and withdrawing the lance from the cell.

SIGLEC TRANSGENIC MICE AND METHODS OF USE THEREOF

Provided herein are transgenic non-human animals whose genomes comprise two or more human genes selected from CD33, Siglec-5, Siglec-7, Siglec-9, Siglec-11, Siglec-14, and Siglec-16, to methods of screening candidate agents that bind to and/or modulate the function and/or activity of at least one of the human genes in the transgenic non-human animals, and to methods of screening candidate agents to determine their effect on one or more activities and/or functions associated with expression of at least one of the human genes in the transgenic non-human animals. Further provided herein are methods of recapitulating a human Siglec immune system in a non-human animal, and methods of generating a non-human animal disease model comprising a human Siglec repertoire. 147.-. (canceled)48. A method of screening candidate agents , the method comprisingi) administering one or more candidate agents to a transgenic non-human animal, wherein the genome of the transgenic non-human animal comprises two or more human genes, wherein the two or more human genes are selected from the group consisting of CD33, Siglec-5, Siglec-7, Siglec-9, Siglec-11, Siglec-14, and Siglec-16, wherein the two or more human genes are expressed in one or more cells of the transgenic non-human animal, and wherein the one of more cells selected from the group consisting of myeloid cells, natural killer (NK) cells, T cells, microglia, and any combination thereof; andii) determining whether the one or more candidate agents bind to and/or modulates the function and/or activity of at least one of the two or more human genes in the transgenic non-human animal.49. A method of screening candidate agents , the method comprisingi) administering one or more candidate agents to a transgenic non-human animal, wherein the genome of the transgenic non-human animal comprises two or more human genes, wherein the two or more human genes are selected from the group consisting of CD33, Siglec-5, Siglec-7, Siglec-9, Siglec-11, ...

TRANSGENIC MAMMALS AND METHODS OF USE THEREOF

Transgenic mammals that express canine-based immunoglobulins are described herein, including transgenic rodents that express canine-based immunoglobulins for the development of canine therapeutic antibodies. 1. A transgenic rodent or rodent cell comprising a genome comprising an engineered partly canine immunoglobulin light chain locus comprising canine immunoglobulin λ light chain variable region gene segments , wherein the engineered immunoglobulin locus is capable of expressing immunoglobulin comprising canine variable domains and wherein the transgenic rodent produces more , or is more likely to produce , immunoglobulin comprising λ light chain than immunoglobulin comprising κ light chain.2. The transgenic rodent according to claim 1 , wherein more λ light chain producing cells than κ light chain producing cells are likely to be isolated from said rodent.3. The transgenic rodent according to claim 1 , wherein the transgenic rodent produces at least about 25% claim 1 , 30% claim 1 , 35% claim 1 , 40% claim 1 , 45% claim 1 , 50% claim 1 , 55% claim 1 , 60% claim 1 , 65% claim 1 , 70% claim 1 , 75% claim 1 , 80% claim 1 , 85% claim 1 , 90% or 95% and up to about 100% immunoglobulin comprising λ light chain.4. The transgenic rodent cell according to claim 1 , wherein the transgenic rodent cell claim 1 , or its progeny claim 1 , has at least about a 25% claim 1 , 30% claim 1 , 35% claim 1 , 40% claim 1 , 45% claim 1 , 50% claim 1 , 55% claim 1 , 60% claim 1 , 65% claim 1 , 70% claim 1 , 75% claim 1 , 80% claim 1 , 85% claim 1 , 90% claim 1 , or 95% and up to about 100% claim 1 , probability of producing immunoglobulin comprising λ light chain.5. The transgenic rodent or rodent cell according to claim 1 , wherein the engineered immunoglobulin locus comprises canine V and J gene segment coding sequences embedded in rodent non-coding regulatory or scaffold sequences of a rodent immunoglobulin λ light chain variable region gene locus.6. The transgenic rodent or rodent ...

MALE ARTHROPOD KILLING FACTORS AND METHODS OF USE THEREOF

The present disclosure relates to genetically modified arthropods, genetically modified bacteria, and methods for controlling and/or reducing arthropod populations. 2. The arthropod of claim 1 , wherein the gene encoding the male arthropod killing factor is from a bacterium claim 1 , a prophage claim 1 , or a phage.3Wolbachia. The arthropod of claim 2 , wherein the gene encoding the male arthropod killing factor is from .4. The arthropod of claim 3 , wherein the male arthropod killing factor is wink (WD0626).5. The arthropod of claim 1 , wherein the male arthropod killing factor comprises the amino acid sequence SEQ ID NO:1 claim 1 , or a variant thereof.6. The arthropod of claim 1 , wherein the reduction in viable male offspring is greater than 10%.7. The arthropod of claim 1 , wherein the arthropod is an insect.8Aedes, CulexAnopheles.. The arthropod of claim 7 , wherein the insect is selected from the genera consisting of and9Aedes albopictus, Aedes aegyptiAedes polynesiensis.. The arthropod of claim 8 , wherein the insect is selected from the group consisting of and10Drosophila suzukii.. The arthropod of claim 7 , wherein the insect is11. A method for controlling a population of target arthropods claim 7 , comprising:providing a gene encoding a male arthropod killing factor, and a promoter operably linked to the gene encoding the male arthropod killing factor;transforming a population of arthropods with the gene encoding the male arthropod killing factor and the promoter operably linked to the gene encoding the male arthropod-killing factor; andreleasing the population of arthropods amongst a population of target arthropods, wherein the release of the arthropods reduces the population of target arthropods.12. The method of claim 11 , wherein the gene encoding the male arthropod killing factor is from a bacterium claim 11 , a prophage claim 11 , or a phage.13Wolbachia.. The method of claim 12 , wherein the gene encoding the male arthropod killing factor is from14. ...

CIRCOVIRUS SEQUENCES ASSOCIATED WITH PIGLET WEIGHT LOSS DISEASE (PWD)

The genome sequences and the nucleotide sequences coding for the PWD circovirus polypeptides, such as the circovirus structural and non-structural polypeptides, vectors including the sequences, and cells and animals transformed by the vectors are provided. Methods for detecting the nucleic acids or polypeptides, and kits for diagnosing infection by a PWD circovirus, also are provided. Method for selecting compounds capable of modulating the viral infection are further provided. Pharmaceutical, including vaccine, compositions for preventing and/or treating viral infections caused by PWD circovirus and the use of vectors for preventing and/or treating diseases also are provided. 114.-. (canceled)15. A vaccine for protecting a pig against infection by a piglet weight loss disease circovirus comprising: an isolated ORF′2 polypeptide of porcine circovirus Type B (PCVB); and a recombinant expression vector.16. The vaccine of claim 15 , wherein the recombinant expression vector is a baculovirus expression vector.17. The vaccine of claim 15 , further comprising an adjuvant.18. The vaccine of claim 15 , further comprising a pharmaceutically or veterinarily acceptable carrier.19. The vaccine of claim 15 , wherein the ORF′2 polypeptide has at least 90% identity to the sequence of SEQ ID NO:26.20. The vaccine of claim 15 , wherein the ORF′2 polypeptide has at least 95% identity to the sequence of SEQ ID NO:26.21. The vaccine of claim 15 , wherein the ORF′2 polypeptide is encoded by a nucleic acid having at least 90% identity to the sequence of SEQ ID NO:25.22. A method for protecting a pig against infection by a piglet weight loss disease circovirus comprising: administering to the pig the vaccine of .23. The method of claim 22 , wherein the vaccine is administered to a pig 3 weeks of age or older.24. The method of claim 22 , wherein the vaccine is administered as a single dose.25. The method of claim 22 , wherein the vaccine is administered via a route selected from the group ...

GENETIC ENGINEERING OF NON-HUMAN ANIMALS FOR THE PRODUCTION OF CHIMERIC ANTIBODIES

The invention provides non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing transgenic cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention. 1. (canceled)2. A mouse whose genome comprises a transgene encoding a polypeptide comprising an immunoglobulin light chain variable region , wherein the transgene comprises (1) a plurality of immunoglobulin light chain variable (V) exons encoding feline immunoglobulin light chain variable (V) polypeptides; (2) non-coding sequences between the V exons; (3) a plurality of immunoglobulin light chain joining (J) coding sequences encoding feline immunoglobulin light chain joining (J) polypeptides; and (4) non-coding sequences between the J coding sequences; wherein the non-coding sequences between the V exons and the non-coding sequences between the J coding sequences are derived from mouse immunoglobulin light chain non-coding sequences and wherein the transgene is capable of undergoing gene arrangement and thereby upon expression to produce a polypeptide comprising the immunoglobulin light chain variable region.3. The mouse according to claim 2 , wherein the non-coding sequences between the V exons and the non-coding sequences between the J coding sequences are selected from the group consisting of intronic sequences and cis regulatory sequences.4. The mouse according to claim 3 , wherein the cis regulatory sequences are selected from promoters claim 3 , enhancers claim 3 , recombination signal sequences claim 3 , splice acceptor sequences claim 3 , and splice donor sequences.5. The mouse according to claim 2 , wherein the V exons encode kappa light chain V (Vκ) polypeptides or lambda light chain V (Vλ) polypeptides.6. The mouse according to claim 2 , wherein the V exons encode kappa ...

WISE/SOST NUCLEIC ACID SEQUENCES AND AMINO ACID SEQUENCES

The present invention relates to nucleic acid sequences and amino acid sequences which influence bone deposition, the Wnt pathway, ocular development, tooth development, and may bind to LRP. The nucleic acid sequence and polypeptides include Wise and Sost as well as a family of molecules which express a cysteine knot polypeptide. Additionally, the present invention relates to various molecular tools derived from the nucleic acids and polypeptides including vectors, transfected host cells, monochronal antibodies, Fab fragments, and methods for impacting the pathways. 1. A method for modulating bone deposition comprising contacting a host cell with an antibody to Sost , wherein the antibody prevents wild-type Sost from binding with a Sost binding partner , wherein the Sost binding partner is an LRP having an amino acid sequence selected from the group consisting of SEQ ID NOS: 68 , 73 , 76 , 79 , 84 , and 86.2. The method according to claim 1 , wherein the antibody is a monoclonal antibody.3. The method according to claim 1 , wherein the Sost binding partner is an LRP having an amino acid sequence selected from the group consisting of SEQ ID NOS: 68 claim 1 , 72 claim 1 , and 84.4. The method according to claim 1 , wherein the Sost binding partner is an LRP having an amino acid sequence according to SEQ ID NO: 68.5. The method according to claim 1 , wherein the Sost binding partner is an LRP having an amino acid sequence according to SEQ ID NO: 72.6. The method according to claim 1 , wherein the Sost binding partner is an LRP having an amino acid sequence according to SEQ ID NO: 84.7. A composition for modulating bone deposition comprising an antibody to Sost claim 1 , wherein the antibody prevents wild-type Sost from binding with a Sost binding partner claim 1 , wherein the Sost binding partner is an LRP having an amino acid sequence selected from the group consisting of SEQ ID NOS: 68 claim 1 , 73 claim 1 , 76 claim 1 , 79 claim 1 , 84 claim 1 , and 86.8. The ...

RECOMBINANT CONSTRUCTS AND TRANSGENIC FLUORESCENT ORNAMENTAL FISH THEREFROM

The present invention relates to the method and use of reef coral fluorescent proteins in making transgenic red, green and yellow fluorescent zebrafish. Preferably, such fluorescent zebrafish are fertile and used to establish a population of transgenic zebrafish and to provide to the ornamental fish industry for the purpose of marketing. Thus, new varieties of ornamental fish of different fluorescence colors from a novel source are developed. 171.-. (canceled)73. The transgenic fish of claim 72 , wherein the first and second fluorescent proteins are ZsGreen1 claim 72 , ZsYellow1 claim 72 , DsRed2 claim 72 , GFP claim 72 , eGFP claim 72 , YFP claim 72 , eYFP claim 72 , BFP claim 72 , eBFP claim 72 , CFP claim 72 , eCFP claim 72 , FP claim 72 , AmCyan1 claim 72 , DsRed-Express claim 72 , AsRed2 claim 72 , HcRed1 claim 72 , mPlum claim 72 , mCherry claim 72 , tdTomato claim 72 , mStrawberry claim 72 , J-Red claim 72 , DsRed-monomer claim 72 , mOrange claim 72 , mKO claim 72 , MCitrine claim 72 , Venus claim 72 , Ypet claim 72 , EYFP claim 72 , Emerald claim 72 , CyPet claim 72 , mCFPm claim 72 , Cerulean claim 72 , or T-Sapphire.74. The transgenic fish of claim 73 , wherein the first and second fluorescent proteins are ZsGreen1.75. The transgenic fish of claim 73 , wherein the first and second fluorescent proteins are DsRed 2.76. The transgenic fish of claim 72 , wherein said fish β-actin promoter is a carp β-actin promoter.77. The transgenic fish of claim 72 , wherein said fish myosin light chain promoter is a zebrafish fast skeletal myosin light chain promoter.78. The transgenic fluorescent fish of claim 72 , wherein each of said genes comprise at least two polyadenylation signals positioned in tandem.79. The transgenic fluorescent fish of claim 78 , wherein said polyadenylation signals are viral polyadenylation signals.80. The transgenic fluorescent fish of claim 79 , wherein said viral polyadenylation signals are SV40 polyadenylation sequences.81. The transgenic ...

Synthesis of High Molecular Weight Proteins Using Inteins

This disclosure is directed to split intein protein production systems using transgenic target organisms such as . A vector set for transforming a target organism includes: a first vector having a first donor sequence that encodes (i) a first non-native protein and (ii) at least one split intein domain; a second vector having a second donor sequence that encodes (i) a second non-native protein and (ii) at least one split intein domain. The respective split intein domains encoded by the first and second vectors are configured to associate with one another and ligate the first and second non-native proteins to thereby form a fused protein. 1Bombyx mori. A method of producing transgenic , the method comprising:providing a first vector having a first donor sequence that encodes a first non-native protein and at least one split intein domain;providing a second vector having a second donor sequence that encodes a second non-native protein and at least one split intein domain;{'i': 'Bombyx mori', 'incorporating the first vector into one or more cells; and'}{'i': 'Bombyx mori', 'incorporating the second vector into one or more cells,'}wherein the split intein domains encoded by the first and second vectors are configured to associate with one another and ligate the first and second non-native proteins to thereby form a fused protein.2Bombyx mori.. The method of claim 1 , further comprising providing a gene editing assembly that includes a nuclease configured to target one or more locations within a silk protein gene of the3. The method of claim 2 , wherein the gene editing assembly targets the FibH gene.4. The method of claim 1 , wherein the first donor sequence claim 1 , the second donor sequence claim 1 , or both encode for a spider silk protein.5. The method of claim 4 , wherein the spider silk protein comprises an AS28 protein claim 4 , a MaSp1 protein claim 4 , a MaSp4 protein claim 4 , or combination thereof.6. The method of claim 4 , wherein the spider silk protein ...

Animal Models of Cancer

The present invention provides transgenic, large non-human animal models of cancer, as well as methods of using such animal models in the identification and characterization of therapies for cancer. 1185-. (canceled)186. A transgenic animal that models a human disease or condition , comprising a large , non-human transgenic animal comprising a p53 mutation wherein the p53 mutation comprises a mutation of an endogenous p53 gene and wherein the p53 mutation results in an altered expression of a p53 translation product and/or in expression of a non-functional p53 protein that corresponds to an alteration in a human p53 gene associated with a human disease or condition.187. The transgenic animal of claim 186 , wherein said transgenic animal is an ungulate.188. The transgenic animal of claim 187 , wherein said ungulate is selected from the group consisting of a swine claim 187 , a cows claim 187 , a sheep claim 187 , and a goats.189. The transgenic animal of claim 188 , wherein said ungulate is a swine that models a human cancer.190. The transgenic animal of claim 186 , wherein said mutation is in exon 5 of the endogenous p53 gene.191. The transgenic animal of claim 186 , wherein said p53 mutation is a gain of function mutation.192. The transgenic animal of claim 190 , wherein said p53 mutation results in an R167H substitution.193. The transgenic animal of claim 186 , wherein said p53 mutation is present in both alleles of the p53 gene.194. The transgenic animal of claim 186 , wherein said p53 mutation is a missense mutation resulting in a substitution of an amino acid in the endogenous p53 selected from Y220 claim 186 , G245 claim 186 , R248 claim 186 , and R273.195. The transgenic animal of claim 186 , wherein said p53 mutation is a deletion claim 186 , a disruption claim 186 , or an activation of both alleles of the endogenous p53 gene.196. The transgenic animal of claim 186 , wherein the transgenic animal further comprises a KRAS mutation claim 186 , wherein said ...

Humanized il-6 and il-6 receptor

Mice that comprise a replacement of endogenous mouse IL-6 and/or IL-6 receptor genes are described, and methods for making and using the mice. Mice comprising a replacement at an endogenous IL-6Rα locus of mouse ectodomain-encoding sequence with human ectodomain-encoding sequence is provided. Mice comprising a human IL-6 gene under control of mouse IL-6 regulatory elements is also provided, including mice that have a replacement of mouse IL-6-encoding sequence with human IL-6-encoding sequence at an endogenous mouse IL-6 locus.

NUCLEIC ACID MOLECULES AND APPLICATIONS THEREOF IN HUMAN ANTIBODY

Nucleic acid molecules include immunoglobulin genes or parts of immunoglobulin genes. The nucleic acid molecules includes the IgM gene (IgHCμ) and IgM switch region (Sμ). The sequences of the Sμ and the IgHCμ are both derived from a transgenic host animal. In this invention, human antibodies are directly generated and no humanization process is required, and the human antibody druggability is increased. The transgenic human antibody mouse has normal early Bcell development, maturation and the Bcell number in comparison with that of wild type animal, thereby facilitating the differentiation of the Bcells. The specificity and diversity of the produced antibody are improved; and the efficiency for screening the therapeutic antibody is improved. 1. Nucleic acid molecules comprising immunoglobulin genes or parts of the immunoglobulin genes , wherein , the nucleic acid molecules comprises an IgM gene (IgHCμ) and an IgM switch region (Sμ) , and sequences of the Sμ and the IgHCμ are both derived from a transgenic host animal.2. The nucleic acid molecules according to claim 1 , wherein the IgHCμ comprises a CH1 exon claim 1 , a CH2 exon claim 1 , a CH3 exon claim 1 , a CH4 exon claim 1 , and intron sequences between the CH1 exon and the CH2 exon claim 1 , the CH2 exon and the CH3 exon claim 1 , and between the CH3 exon and the CH4 exon claim 1 , a TM1 claim 1 , a TM2 claim 1 , and PolyA signal sequences.3. The nucleic acid molecules according to claim 1 , wherein a nucleotide sequence of the Sμ is listed as positions ranging from (2550) to (4451) in SEQ ID NO:1.4. The nucleic acid molecules according to claim 1 , further comprising an IgH heavy chain 5′-enhancer of the transgenic host animal.5. The nucleic acid molecules according to claim 4 , wherein a nucleotide sequence of the IgH heavy chain 5′-enhancer is listed as positions ranging from (433) to (1444) in SEQ ID NO:1.6. (canceled)7. The nucleic acid molecules according to claim 1 , further comprising IgG genes (Igγ).8. ...

FLY AVATARS FOR CANCER AND USES THEREOF

The invention relates to improved methods for treating a human subject diagnosed with cancer using combination drug regimens tailored to the genome/proteome/phenome of the subject's turn or/cancer. The treatment regimens are selected and/or their efficacy is confirmed using an animal model “avatar,” preferably a transgenic avatar, of the genome/proteome/phenome of the subject. In certain embodiments, “avatar armies” representing the genomes/proteomes/phenomes of a population of patients diagnosed with a disease or disorder can be used to screen and select therapeutic regimens for treatment and/or to screen for new lead compounds and identify new therapeutics for the disease or disorder. 1. A method for treating a subject diagnosed with cancer , comprising: (c) cancer cells from the subject exhibit increased activity of one or more oncogenes and/or reduced activity of one or more tumor suppressors, and', {'i': Drosophila', 'Drosophila', 'Drosophila', 'Drosophila, "(d) the drug or combination of drugs, when fed to a culture of a larva avatar, allows the larva avatar to survive to pupation, wherein the larva avatar is genetically modified such that upon induction through an external factor there is an increase in the activity of one or more orthologs of the subject's one or more oncogenes and/or inhibition one or more orthologs of the subject's one or more tumor suppressors in a larval tissue that is necessary for survival to pupation, which increase in activity and/or inhibition prevents an untreated larva avatar from surviving to pupation."}], 'administering a therapeutic regimen to a subject diagnosed with cancer, wherein the therapeutic regimen comprises a drug or a combination of drugs, wherein'}2. The method of claim 1 , wherein the cancer is a solid tumor.3. The method of claim 2 , wherein the cancer is selected from the group consisting of bladder cancer claim 2 , bone cancer claim 2 , breast cancer claim 2 , cervical cancer claim 2 , colorectal cancer claim 2 ...

Novel Animal Model For Laing Distal Myopathy (Mpd1) And Methods of Use Thereof

The inventive technology is directed to the generation of a novel transgenic mammalian model for the study of Laing distal myopathy. The novel animal model of the invention may include a transgenic animal, and preferably a transgenic mouse, expressing the β-myosin R1500P mutation transgene that produces one or more phenotypes associated with MPD1. The β-myosin R1500P mutation transgene may further be selectively expressed in fast muscle tissue of the transgenic animal. 1. A Laing distal myopathy (MPD1) model animal expressing a β-myosin R1500P mutant transgene wherein the arginine (R) residue at amino acid position 1500 is substituted with a proline (P) residue , and wherein said transgene causes at least one pathological phenotype associated with MPD1.2. The MPD1 model animal of claim 1 , wherein said animal is selected from the group consisting of: a rodent claim 1 , and a mouse.3. The MPD1 model animal of claim 1 , and further comprising wherein the wild-type β-myosin has been knocked-out or its expression disrupted.4. The MPD1 model animal of claim 1 , wherein said β-myosin R1500P mutant transgene comprises the nucleotide sequence encoding the amino acid sequence according to SEQ ID NO. 1 claim 1 , or a fragment or variant thereof.5. The MPD1 model animal of claim 1 , wherein said β-myosin R1500P mutant transgene is operably linked to a promoter selected from the group consisting of: an inducible promoter claim 1 , a tissue-specific promoter claim 1 , and a muscle creatine kinase (MCK) promoter.6. The MPD1 model animal of claim 1 , further comprising a tag coupled with said β-myosin R1500P mutant transgene.7. The MPD1 model animal of claim 6 , wherein said tag comprises a myc-tag.8. The MPD1 model animal of claim 1 , wherein the pathological phenotype associated with MPD1 is selected from the group consisting of:abnormal muscle tissue or muscle atrophy;decreased the muscle/body weight ratio;muscle tissue had a higher proportion of smaller muscle fibers; ...

ADENO-ASSOCIATED VIRUS ANTIBODIES AND FRAGMENTS THEREOF

The present disclosure relates to an isolated anti-AAV (adeno-associated virus) antibody or an antigen-binding fragment thereof capable of specifically binding an epitope of AAVrh74 capsid protein and uses thereof. 160-. (canceled)61. An isolated antibody or antigen-binding fragment thereof that comprises a heavy chain variable region comprising VH CDR1 , VH CDR2 , and VH CDR3 domains , and a light chain variable region comprising VL CDR1 , VL CDR2 , and VL CDR3 domains , wherein:a. the VH CDR1 domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 33, SEQ ID NO: 39, SEQ ID NO: 46, SEQ ID NO: 52, and SEQ ID NO: 58;b. the VH CDR2 domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 40, SEQ ID NO: 47, SEQ ID NO: 53, and SEQ ID NO: 59;c. the VH CDR3 domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 35, SEQ ID NO: 41, SEQ ID NO: 48, SEQ ID NO: 54, and SEQ ID NO: 60;d. the VL CDR1 domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 42, SEQ ID NO: 49, SEQ ID NO: 55, and SEQ ID NO: 61;e. the VL CDR2 domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 37, SEQ ID NO: 43, SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO: 62; orf. the VL CDR3 domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 38, SEQ ID NO: 44, SEQ ID NO: 51, SEQ ID NO: 57, and SEQ ID NO: 63.62. The isolated antibody or antigen binding fragment thereof of claim 61 , wherein the heavy chain variable region comprises a VH CDR3 selected from the group consisting of GVAHYSDSRFAFDY (SEQ ID NO: 35) claim 61 , GNAHPGGSAFVY (SEQ ID NO: 41) claim 61 , RGSYYYDSSPAWFAY (SEQ ID NO: 48) claim 61 , RGVDSSGYGAFAY (SEQ ID NO: 54) claim 61 , and TRGTSTMISTFAFVY (SEQ ID NO: 60).63. The isolated antibody or antigen binding fragment thereof of claim 62 , wherein the heavy chain variable ...

NON-HUMAN ANIMALS EXPRESSING HUMANIZED C1Q COMPLEX

Disclosed herein are nucleic acids encoding for and proteins expressing chimeric C1q polypeptides, non-human animals comprising said nucleic acids, and methods of making or using said non-human animals. 1. A genetically modified non-human animal comprising in its genome a nucleic acid encoding a chimeric C1q polypeptide , wherein the nucleic acid comprises a non-human nucleic acid sequence and a human nucleic acid sequence , wherein the chimeric C1q polypeptide is selected from the group consisting of a chimeric C1qa polypeptide , a chimeric C1qb polypeptide , and a chimeric C1qc polypeptide , and wherein the chimeric C1q polypeptide comprises a globular head domain that is substantially human and an N-terminal stalk-stem region that is substantially non-human.2. The genetically modified non-human animal of claim 1 , wherein the non-human animal expresses a chimeric C1qa polypeptide claim 1 , a chimeric C1qb polypeptide claim 1 , a chimeric C1qc polypeptide claim 1 , or a combination thereof.3. The genetically modified non-human animal of or claim 1 , wherein the non-human animal is a mammal.4. The genetically modified non-human animal of or claim 1 , wherein the non-human animal is a rodent.5. The genetically modified non-human animal of or claim 1 , wherein the non-human animal is a rat or a mouse.6. The genetically modified non-human animal of any one of - claim 1 , wherein the chimeric C1q polypeptide is a chimeric C1qa polypeptide.7. The genetically modified non-human animal of claim 6 , wherein the chimeric C1qa polypeptide comprises a globular head domain that is substantially identical to the globular head domain of a human C1qa polypeptide claim 6 , and an N-terminal stalk-stem region that is substantially identical to the N-terminal stalk-stem region of a non-human C1qa polypeptide.8. The genetically modified non-human animal of claim 7 , wherein the globular head domain of a human C1qa polypeptide comprises 108-245 of SEQ ID NO: 4.9. The genetically ...

OPTOGENETIC CONTROL OF ENDOTHELIAL CELLS

The invention features methods for regulating vascular properties by controlling the membrane properties of endothelial cells using optogenetics and light. The invention features methods to transport therapeutics across the vascular barrier into tissues such as the brain and the lung, with high spatial and temporal precision, and for controlling vascular properties such as vascular tone, arterial diameter, and vascular growth. 12-. (canceled)3. A method to deliver a therapeutic across the vascular endothelial barrier comprising endothelial cells expressing an optogenetic reagent in a subject , said method comprising the steps of: a) introducing said therapeutic into the blood stream of said subject; and b) contacting said endothelial cells with light , wherein said light activates said optogenetic reagent and thereby changes permeability of said endothelial cells and opens the vascular endothelial barrier such that said therapeutic in the blood stream crosses the vascular endothelial barrier.4. The method of claim 3 , wherein said optogenetic reagent is selected from the group consisting of ChR1 claim 3 , ChR2 claim 3 , VChR1 claim 3 , ChR2 C128A claim 3 , ChR2 C128S claim 3 , ChR2 C128T claim 3 , ChD claim 3 , ChEF claim 3 , ChF claim 3 , ChIEF claim 3 , NpHR claim 3 , eNpHR claim 3 , Arch 3.0 claim 3 , Arch T 3.0 claim 3 , Mac 3.0 claim 3 , melanopsin claim 3 , chimeras of these proteins and natural and engineered variants thereof.5. The method of claim 3 , wherein said optogenetic reagent are expressed in the endothelial cells by introducing a recombinant nucleic acid encoding the optogenetic reagent into said cells or precursors thereof.6. The method of claim 5 , wherein said recombinant nucleic acid is introduced into said cells by using any one or more of a virus claim 5 , an electroporation device claim 5 , a transfection method claim 5 , and a transgenic method.7. The method of claim 6 , wherein said recombinant nucleic acid is encapsidated within a ...

ARTIFICIAL RECOMBINANT CHROMOSOME AND USE THEREOF

The disclosure in the specification relates to an artificial recombinant chromosome and the use thereof, and more particularly to an artificial recombinant chromosome generated by the recombination of two or more chromosomes and a production of a transgenic animal using a cell including the same. Especially, in the disclosure in the specification, an interchromosomal exchange between the recipient chromosome and the donor chromosome has many merits to produce the artificial recombinant chromosome for producing the transgenic animal. 1. A method for producing a transgenic mouse expressing a gene originating from a non-mouse subject , the method comprising: wherein the donor chromosome comprises a non-mouse centromere, a non-mouse telomere, and a non-mouse target gene interposed between the non-mouse centromere and the non-mouse telomere;', 'wherein the donor chromosome further comprises a first recombinase recognition sequence (a first RRS) and a second recombinase recognition sequence (a second RRS) inserted between the non-mouse centromere and the non-mouse telomere such that a non-mouse gene segment comprising the non-mouse target gene is interposed between the first RRS and the second RRS;, 'providing a donor cell that is an engineered cell of the non-mouse subject and comprises a donor chromosome that is engineered from a non-mouse chromosome of the non-mouse subject;'}processing the donor cell to produce a plurality of microcells comprising the donor chromosome; wherein the recipient chromosome comprises a mouse centromere, a mouse telomere, and a mouse orthologous gene that is orthologous to the non-mouse target gene and interposed between the mouse centromere and the mouse telomere;', 'wherein the recipient chromosome further comprises a third recombinase recognition sequence (a third RRS) and a fourth recombinase recognition sequence (a fourth RRS) inserted between the mouse centromere and the mouse telomere such that a mouse gene segment comprising the ...

NEURON-SPECIFIC HuR-DEFICIENT OR INDUCIBLE HuR-DEFICIENT ANIMAL MODELS

Provided herein non-human transgenic animals comprising a genome that: i) under-expresses, or is inducible to under-express, Hu Antigen R (HuR) in at least some neurons of said transgenic animal; ii) does not express HuR, or is inducible to not express HuR, in at least some neurons of said transgenic animal; or iii) does not express functional HuR, or is inducible to not express functional HuR in at least some neurons of said transgenic animal, as well as methods of screening drugs and therapies (e.g., useful in treating ALS) using such animals. 1. A non-human transgenic animal comprising a genome that:i) under-expresses compared to wild-type, or is inducible to under-express compared to wild-type, Hu Antigen R (HuR) in at least some neurons of said transgenic animal;ii) does not express HuR, or is inducible to not express HuR, in at least some neurons of said transgenic animal; oriii) does not express functional HuR, or is inducible to not express functional HuR in at least some neurons of said transgenic animal.2. The non-human transgenic animal of claim 1 , wherein said genome comprises a heterologous genetic construct.3. The non-human transgenic animal of claim 2 , wherein said genetic construct comprises a neuron-specific promoter.4. The non-human transgenic animal of claim 3 , wherein said genetic construct further comprises at least one recombinase sequence inducible by an exogenous agent claim 3 , wherein said recombinase sequence claim 3 , once induced claim 3 , mediates the deletion of the HuR gene in said transgenic animal.5. The transgenic animal of claim 1 , wherein said animal is selected from the group consisting of a mouse claim 1 , a rat claim 1 , a dog claim 1 , and a rabbit.6. The transgenic animal of claim 1 , wherein said at least some neuron cells are in said transgenic animal's brain or spinal cord.7. The transgenic animal of claim 1 , wherein said animal displays symptoms of claim 1 , or similar to claim 1 , amyotrophic lateral sclerosis (ALS ...

NOVEL BT TOXIN RECEPTORS AND METHODS OF USE

The disclosure relates to Bt toxin resistance management. One embodiment relates to the isolation and characterization of polynucleotides and polypeptides corresponding to novel Bt toxin receptors. The polynucleotides and polypeptides are useful in identifying or designing novel Bt toxin receptor ligands including novel insecticidal toxins. 1. A heterologous polynucleotide comprising:a) the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9;b) a nucleotide sequence encoding the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, or 10;c) a nucleotide sequence having at least about 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9, wherein said nucleotide sequence having at least about 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9 encodes a polypeptide having Bt toxin binding activity;d) a nucleotide sequence that hybridizes to the complement of the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9 under stringent conditions, wherein said nucleotide sequence that hybridizes to the complement of the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9 under stringent conditions encodes a polypeptide having Bt toxin binding activity; ore) a nucleotide sequence complementary to at least one nucleotide sequence set forth in a), b), c), and d).2. The heterologous polynucleotide of claim 1 , wherein said heterologous polynucleotide comprises a nucleotide sequence encoding a polypeptide having Cry toxin binding activity.3. The heterologous polynucleotide of claim 2 , wherein said heterologous polynucleotide comprises a nucleotide sequence encoding a polypeptide having Cry2A binding activity.4. A heterologous polypeptide having the amino acid sequence comprising:a) the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, or 10; or b) a variant of the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, or 10, wherein said sequence variant has Bt toxin ...

ENDOPLASMIC RETICULUM LOCALIZATION SIGNALS

The invention relates to cellular localization signals. In particular, the invention relates to endoplasmic reticulum localization signals in monomeric or multimeric form. The localization signals are utilized as research tools or are linked to therapeutics. Disclosed are methods of making and using polypeptides and modified polypeptides as signals to localize therapeutics, experimental compounds, peptides, proteins and/or other macromolecules to the endoplasmic reticulum of eukaryotic cells. The polypeptides of the invention optionally include linkage to reporters, epitopes and/or other experimental or therapeutic molecules. The invention also encompasses polynucleotides encoding the localization signals and vectors comprising these polynucleotides. 114.-. (canceled)15. An isolated polypeptide localization signal comprising an amino acid sequence of SEQ ID NO:39 and an amino acid sequence at least 80% identical to SEQ ID NO:70.16. The isolated polypeptide localization signal of comprising an amino acid sequence at least 85% identical to SEQ ID NO:70.17. The isolated polypeptide localization signal of comprising an amino acid sequence at least 90% identical to SEQ ID NO:70.18. The isolated polypeptide localization signal of comprising an amino acid sequence at least 95% identical to SEQ ID NO:70.19. The isolated polypeptide localization signal of comprising an amino acid sequence of SEQ ID NO:70.20. The isolated polypeptide localization signal of linked to an epitope tag claim 15 , reporter claim 15 , polypeptide of interest claim 15 , macromolecule claim 15 , or therapeutic molecule.21. The isolated polypeptide localization signal of linked to an epitope tag claim 16 , reporter claim 16 , polypeptide of interest claim 16 , macromolecule claim 16 , or therapeutic molecule.22. The isolated polypeptide localization signal of linked to an epitope tag claim 17 , reporter claim 17 , polypeptide of interest claim 17 , macromolecule claim 17 , or therapeutic molecule.23. ...

ENHANCED EXPRESSION OF HUMAN OR HUMANIZED IMMUNOGLOBULIN IN NON-HUMAN TRANSGENIC ANIMALS

The present invention describes transgenic animals with human(ized) immunoglobulin loci and transgenes encoding human(ized) Igα and/or Igβ sequences. Of particular interest are animals with transgenic heavy and light chain immunoglobulin loci capable of producing a diversified human(ized) antibody repertoire that have their endogenous production of Ig and/or endogenous Igα and/or Igβ sequences suppressed. Simultaneous expression of human(ized) immunoglobulin and human(ized) Igα and/or Igβ results in normal B-cell development, affinity maturation and efficient expression of human(ized) antibodies. 16-. (canceled)7. A method for producing human or humanized antibodies in a non-human animal , comprising the steps of:(a) introducing and expressing a transgene construct encoding either a native human Igα subunit or a chimeric Igα subunit, and/or a transgene construct encoding either a native human Igβ subunit or a chimeric Igβ subunit into the non-human animal;(b) introducing and expressing a transgene construct encoding a human or humanized immunoglobulin locus into the non-human animal;(c) subjecting the animal to an antigenic stimulus; and(d) isolating human or humanized antibodies from the animal.8. The method according to claim 7 , wherein the antibody is a monoclonal antibody.9. The method according to claim 7 , wherein the antibody is a fragment of a monoclonal antibody.10. The method according to claim 9 , wherein the antibody fragment is fused to a heterologous amino acid sequence.111. An isolated human or humanized antibody produced with the method according to claim . This is a non-provisional application filed under 37 CFR 1.53(b), claiming priority under U.S.C. Section 119(e) to U.S. Provisional Patent Application Ser. No. 60/841,980 filed Sep. 1, 2006.This invention relates to a method to improve the expression of human(ized) immunoglobulin in non-human transgenic animals by promoting normal B-cell development and by sustaining the expression of human(ized) ...

NUCLEIC ACID MOLECULES AND APPLICATIONS THEREOF IN PREPARING HUMAN SINGLE-DOMAIN ANTIBODY

Nucleic acid molecules and single-domain antibody applications are provided. The nucleic acid molecules include a transgenic host animal immunoglobulin genes or parts of immunoglobulin genes. Main characters are: it comprises the transgenic host animal IgH 5′-enhancer, IgM switch region (Sμ), and IgM sequences, specifically, all the IgM sequences are originated from the transgenic host animal, and the CH1 sequences of the IgM is deleted (IgM-dCH1). The regulatory control sequences of IgG are also derived from the transgenic host animal including Sγ, TM1, TM2, PolyA sequences, etc., and IgG Cγ sequences (Hinge, CH2 and CH3) are human sequence (Igγ-dCH1). The present invention ensures normal B-cell development in transgenic animal, and the transgenic animal expresses human single-domain antibodies, reducing the subsequent antibody humanization process and improving the druggability of the antibodies. 1. Nucleic acid molecules comprising immunoglobulin genes or parts of the immunoglobulin genes , wherein , the nucleic acid molecules comprises an IgG gene (Igγ) , an IgG switch region (Sγ) and an IgM gene (IgHCμ) and an IgM switch region (Sμ) , wherein , the IgM gene and the IgG gene do not have a CH1 function.2. The nucleic acid molecules according to claim 1 , wherein the Sμ claim 1 , the Sγ and the IgHCμ are derived from a transgenic host animal.3. The nucleic acid molecules according to claim 1 , wherein the IgHCμ comprises an IgM CH2 exon claim 1 , an IgM CH3 exon claim 1 , an IgM CH4 exon claim 1 , intron sequences between the IgM CH2 exon and the IgM CH3 exon claim 1 , and between the IgM CH3 exon and the IgM CH4 exon claim 1 , a TM1 claim 1 , a TM2 and PolyA signal sequences of the transgenic host animal.4. (canceled)5. The nucleic acid molecules according to claim 3 , wherein the Igγ comprises a Hinge exon claim 3 , a CH2 exon claim 3 , a CH3 exon and intron sequences between the Hinge exon and the CH2 exon claim 3 , and between the CH2 exon and the CH3 exon a ...

Pharmaceutical composition for preventing or treating heart failure

A pharmaceutical composition can be provide for treating or preventing heart failure. Additionally, siRNA and a vector expressing said siRNA can be provided that can be used in the pharmaceutical composition for treating or preventing heart failure. For example, a pharmaceutical composition can be provided for treating or preventing heart failure that contains a DNA sequence encoding RNA containing a sense strand sequence of consecutive 18 to 29 nucleotides from angiopoietin-like protein 2 (ANGPTL2) mRNA or the alternative splicing type RNA thereof and an antisense strand sequence complementary to the sense strand sequence under control of a promoter, and a pharmaceutically acceptable carrier.

RECOMBINANT AAV VARIANTS AND USES THEREOF

The disclosure in some aspects relates to recombinant adeno-associated viruses having distinct tissue targeting capabilities. In some aspects, the disclosure relates to gene transfer methods using the recombinant adeno-associated viruses. In some aspects, the disclosure relates to isolated AAV capsid proteins and isolated nucleic acids encoding the same. 1. A recombinant expression vector comprising a sequence selected from the group consisting of: SEQ ID NO: 1 to 47 , or a fragment thereof that does not encode a peptide that is identical to a sequence of any one of SEQ ID NOs: 98 to 100.2. An isolated AAV capsid protein comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs: 51 to 97.3. An isolated AAV capsid protein comprising a sequence selected from the group consisting of: SEQ ID NOs: 51 to 61 , wherein an amino acid of the sequence that is not identical to a corresponding amino acid of the sequence set forth as SEQ ID NO: 98 is replaced with a conservative substitution.4. An isolated AAV capsid protein comprising a sequence selected from the group consisting of: SEQ ID NOs: 62 to 67 , wherein an amino acid of the sequence that is not identical to a corresponding amino acid of the sequence set forth as SEQ ID NO: 99 is replaced with a conservative substitution.5. An isolated AAV capsid protein comprising a sequence selected from the group consisting of: SEQ ID NOs: 68 to 97 , wherein an amino acid of the sequence that is not identical to a corresponding amino acid of the sequence set forth as SEQ ID NO: 100 is replaced with a conservative substitution.6. A peptide fragment of the isolated AAV capsid protein of any one of to that is not identical to a sequence of any one of SEQ ID NOs: 98 to 100.7. An isolated AAV capsid protein comprising the peptide fragment of .8. An recombinant expression vector comprising a nucleic acid sequence encoding the isolated AAV capsid protein of any one of to .9. A composition comprising the isolated ...

A GENETICALLY MODIFIED MOUSE EXPRESSING HUMAN APOE4 AND MOUSE TREM2 P.R47H AND METHODS OF USE THEREOF

Genetically modified mice characterized by one or more symptoms or signs associated with expression of human APOE4p and mouse Trem2p and relevant to non-familial late-onset Alzheimer's disease are provided wherein the genome of the mouse includes: 1) a DNA sequence encoding a human APOE4 protein (APOE4p) operably linked to a promoter; and 2) a DNA sequence encoding a mouse Trem2 protein having a mutation p,R47H (Trem2p) operably linked to a promoter, such that the mouse expresses human APOE4p and mouse Trem2p. Methods ace provided for screening for a compound for use in the treatment of Alzheimer's disease using such genetically modified mice. 1. A genetically modified mouse characterized by one or more symptoms or signs associated with expression of human APOE4p and mouse Trem2p and relevant to non-familial late-onset Alzheimer's disease , the genome of the mouse comprising: 1) a DNA sequence encoding a human APOE4 protein (APOE4p) operably linked to a promoter; and 2) a DNA sequence encoding a mouse Trem2 protein having a mutation p.R47H (Trem2p) operably linked to a promoter , wherein the mouse expresses human APOE4p and mouse Trem2p.2. The genetically modified mouse of claim 1 , therein the APOE4p comprises an amino acid sequence of: SEQ ID NO: 1 claim 1 , or the APOE4p is encoded by the complement of a nucleic acid which hybridizes to SEQ ID NO:2 under highly stringent hybridization conditions.3. The genetically modified mouse of claim 1 , wherein the mouse Trem2p comprises an amino acid sequence of: SEQ ID NO:3 claim 1 , or the mouse Trem2p is encoded by the complement of a nucleic acid which hybridizes to SEQ ID NO:4 under highly stringent hybridization conditions.4. The genetically modified mouse of claim 1 , wherein the genetically modified mouse is a B6(SJL)-ApoeTrem2/J mouse whose genome comprises: 1) a DNA sequence encoding human APOE4 protein (APOE4p) operably linked to a promoter;and 2) a DNA sequence encoding mouse Trem2 protein having a mutation p. ...

METHODS FOR IMPROVING THE HEALTH OF PORCINE SPECIES BY TARGETED INACTIVATION OF CD163

The present disclosure relates methods and compositions useful for prevention of porcine reproductive and respiratory syndrome virus (PRRSv) in animals, including animals of the species . The present teachings relate to swine wherein at least one allele of a CD163 gene has been inactivated, and to specific methods and nucleic acid sequences used in gene editing to inactivate the CD163 gene. Swine wherein both alleles of the CD163 gene are inactivated are resistant to porcine reproductive and respiratory syndrome virus (PRRSv). Elite lines comprising homozygous CD163 edited genes retain their superior properties 1Sus scrofa. A method of making a progeny having a genome containing a non-wild-type , edited CD163 gene comprising sequence SEQ ID NO: 453 , the method comprising the steps of:{'i': 'Sus scrofa;', 'obtaining a genetic sample of a first'}{'i': 'Sus scrofa;', 'determining the presence or absence of SEQ ID NO: 453 in the genome of the first'}{'i': Sus scrofa', 'Sus scrofa, 'selecting the first for breeding if SEQ ID NO: 453 is present in the genome of the first ; and'}{'i': Sus scrofa', 'Sus scrofa', 'Sus scrofa, 'breeding the first with a second of the opposite sex to generate the progeny having a genome containing a non-wild-type, edited CD163 gene comprising sequence SEQ ID NO: 453.'}2. The method of claim 1 , wherein the determining comprises annealing of a probe to SEQ ID NO: 453.3. The method of claim 1 , wherein the determining comprises at least one real time PCR (rtPCR) reaction comprising a probe that anneals to SEQ ID NO: 453.4. The method of claim 1 , wherein the determining comprises two real time PCR (rtPCR) reactions claim 1 , each reaction using a differently labelled probe; wherein a first probe anneals to SEQ ID NO: 453 and a second probe anneals to SEQ ID NO: 249 claim 1 , wherein:a) detecting signal from the label of the first probe and not the label of the second probe indicates a homozygous edit;b) detecting signals from the labels of the ...

Use of interleukin-4 antagonists and compositions thereof

Methods for treating medical conditions induced by interleukin-4 involve administering an IL-4 antagonist to a patient afflicted with such a condition. Suitable IL-4 antagonists include, but are not limited to, IL-4 receptors (such as a soluble human IL-4 receptor), antibodies that bind IL-4, antibodies that bind IL-4R, IL-4 muteins that bind to IL-4R but do not induce a biological response, molecules that inhibit IL-4-induced signal transduction, and other compounds that inhibit a biological effect that results from the binding of IL-4 to a cell surface IL-4R. Particular antibodies provided herein include human monoclonal antibodies generated by procedures involving immunization of transgenic mice. Such human antibodies may be raised against human IL-4 receptor. Certain of the antibodies inhibit both IL-4-induced and IL-13-induced biological activities.

METHODS AND COMPOSITIONS FOR MODULATING GENE EXPRESSION

The present disclosure provides compositions with a modulating gene expression and methods for modulating transcription. 1. A chimeric protein , comprising:a targeting element comprising a sequence targeting polypeptide; andan effector domain comprising all or a biologically active portion of an epigenetic modifying agent,wherein the chimeric protein modifies an anchor sequence associated with a target anchor sequence-mediated conjunction.2. The chimeric protein of claim 1 , wherein the targeting element comprises a sequence targeting polypeptide that specifically binds a sequence in or around an anchor sequence associated with an anchor sequence-mediated conjunction.3. The chimeric protein of claim 1 , which epigenetically modifies the anchor sequence.4. The chimeric protein of claim 1 , which increases methylation of the anchor sequence.5. The chimeric protein of claim 4 , wherein the increase in methylation of the anchor sequence decreases binding of a nucleating protein to the anchor sequence.6. The chimeric protein of claim 1 , wherein the chimeric protein decreases methylation of the anchor sequence.7. The chimeric protein of claim 6 , wherein the decrease in methylation of the anchor sequence increases binding of a nucleating protein to the anchor sequence.8. The chimeric protein of claim 1 , which modulates the activity and/or expression of one or more target nucleic acid sequences.9. The chimeric protein of claim 1 , wherein the anchor sequence is a CTCF binding site.10. The chimeric protein of claim 1 , wherein the nucleating protein is CTCF.11. The chimeric protein of claim 1 , wherein the epigenetic modifying agent comprises an agent that affects DNA methylation claim 1 , histone acetylation claim 1 , histone methylation claim 1 , or RNA-associated silencing.12. The chimeric protein of claim 1 , wherein the epigenetic modifying agent comprises a DNA methylase.13. The chimeric protein of claim 12 , wherein the epigenetic modifying agent comprises DNMT3a ...

Rat embryonic stem cell

The present invention provides a rat embryonic stem cell characterized by having the following properties of (a) expressing Oct3/4 gene and Nanog gene, (b) positive for alkaline phosphatase activity, (c) having an embryoid body forming ability, (d) expressing SSEA (Stage-Specific Embryonic Antigen)-1 and SSEA-4, (e) having the same number of chromosomes as does a normal rat cell, (f) capable of being subcultured and holding the undifferentiated state, (g) having in vitro pluripotency, (h) having a potential to differentiate for cells of three embryonic germ lineages, (i) having teratoma formation ability, and (j) having an ability to produce a chimeric rat, a method of establishing the aforementioned rat embryonic stem cell and the like.

Transgenic pig which simultaneously expresses ho-1 gene and tnfr1-fc gene, and comprises knocked-out ggta1 gene, and use thereof

The present invention relates to a transgenic pig in which an immune rejection response is suppressed during xenotransplantation, wherein a gene coding for heme oxygenase-1 (HO-1) and a gene coding for tumor necrosis factor receptor 1-Fc (TNFR1-Fc) are simultaneously expressed and a gene coding for α-1,3-galactosyltransferase (GGTA1) is knocked out; and a method for producing the same. The transgenic pig of the present invention, in which the genes coding for human HO-1 and TNFR1-Fc fusion protein are simultaneously expressed and the gene coding for GGTA1 is knocked out, may reduce oxidative stress during organ isolation and in vitro culture by antioxidative reaction, cytoprotective function, etc., and may also reduce a TNF-α-mediated inflammatory response in early transplantation by TNFR1-Fc expression. In addition, the transgenic pig may inhibit the maturation of dendritic cells and regulate the activation and proliferation of T-cells, thereby reducing an acute vascular rejection response to promote early engraftment of a transplanted organ. In addition, the transgenic pig can increase the viability of a transplanted organ by suppressing a hyper-acute immune rejection reaction caused by GGTA1. Accordingly, an organ, in which an immune rejection response is suppressed during xenotransplantation, can be produced using the transgenic pig.

RECOMBINANT AAV VARIANTS AND USES THEREOF

The disclosure in some aspects relates to recombinant adeno-associated viruses having distinct tissue targeting capabilities. In some aspects, the disclosure relates to gene transfer methods using the recombinant adeno-associated viruses. In some aspects, the disclosure relates to isolated AAV capsid proteins and isolated nucleic acids encoding the same. 142.-. (canceled)43. A recombinant adeno-associated viral (rAAV) particle comprising an AAV capsid and at least one transgene , wherein the AAV capsid comprises a protein comprising an amino acid sequence selected from any one of SEQ ID NOs: 79 to 87.44. A composition comprising the rAAV particle of claim 43 , and a pharmaceutically acceptable carrier.45. A method for delivering a transgene to a subject comprising administering the rAAV particle of to the subject claim 43 , wherein the rAAV particle infects cells of a target tissue of the subject.46. The method of claim 45 , wherein the at least one transgene is a protein coding gene.47. The method of claim 45 , wherein the at least one transgene encodes a small interfering nucleic acid selected from a miRNA or an shRNA.48. The method of claim 45 , wherein the target tissue is skeletal muscle claim 45 , heart claim 45 , liver claim 45 , pancreas claim 45 , spleen claim 45 , brain claim 45 , or lung.49. The method of claim 45 , wherein the target tissue is heart tissue.50. The method of claim 45 , wherein the rAAV particle is administered intravenously claim 45 , transdermally claim 45 , intraocularly claim 45 , intrathecally claim 45 , orally claim 45 , intramuscularly claim 45 , subcutaneously claim 45 , intranasally claim 45 , or by inhalation.51. A method for generating a somatic transgenic non-human animal model comprising administering the rAAV particle of to a non-human animal claim 43 , wherein the rAAV particle infects cells of a target tissue of the non-human animal.52. A somatic transgenic non-human animal model produced by the method of .53. A recombinant ...

COMPOSITIONS AND METHODS FOR DETERMINING GENETIC POLYMORPHISMS IN THE TMEM216 GENE

In alternative embodiments, the invention provides nucleic acid sequences that are genetic polymorphic variations of the human TMEM216 gene, and TMEM216 polypeptide encoded by these variant alleles. In alternative embodiments, the invention provides methods of determining or predicting a predisposition to, or the presence of, a ciliopathy (or any genetic disorder of a. cellular cilia or cilia anchoring structure, basal body or ciliary function) in an individual, such as a Joubert Syndrome (JS), a Joubert Syndrome Related Disorder (JSRD) or a Meckel Syndrome (MKS). In alternative embodiments, the invention provides compositions and methods for the identification of genetic polymorphic variations in the human TMEM216 gene, and methods of using the identified genetic polymorphisms and the proteins they encode, e.g., to screen for compounds that can modulate the human TMEM216 gene product, and possibly treat JS, JSRD or MKS. an alternative embodiments, the invention provides cells, cell lines and/or non-human transgenic animals that can be used as screening or model systems for studying ciliopathies and testing various therapeutic approaches in treating ciliopathies, e.g., JS, JSRD or MKS. 120-. (canceled)21. A method of identifying or predicting a predisposition to , or the presence of , a ciliopathy or any genetic disorder of a cellular cilia or cilia anchoring structure , basal body or ciliary function in an individual , comprising: (i) analyzing a sample from the individual to detect the presence of at least one Transmembrane Protein 216 (TMEM216) genetic variant in the individual , wherein the at least one TMEM216 genetic variant encodes an amino acid variation from wild type selected from the group consisting of R73L , R73H , R73C , L3X , L114R , G77A and R85X , and (ii) identifying or predicting a predisposition to , or the presence of , the ciliopathy or the genetic disorder of a cellular cilia or cilia anchoring structure , basal body or ciliary function , if ...

ANIMAL MODELS OF AGE-RELATED DISORDERS AND AGE-SENSITIVE TRAITS ASSOCIATED WITH SENESCENCE-INDUCING STIMULI AND USES THEREOF

This disclosure provides non-human animal models for age-related disorders and age-sensitive traits, particularly those caused by senescence-inducing stimuli, wherein the models comprise transgenes selectively expressed by senescent cells. The disclosure further provides methods for identifying therapeutic agents effective for treating or preventing age-related disorders and age-sensitive traits using the animal models, therapeutic agents identified using such methods, pharmaceutical compositions comprising the identified therapeutic agents, and methods of treating or preventing age-related disorders and age-sensitive traits. 1. A non-human animal model for aging comprising a non-human animal that (a) exhibits an age-related disorder or age-sensitive trait , and (b) comprises a transgene selectively expressed by senescent cells , wherein the animal is exposed to or treated with a senescence-inducing stimulus.2. The animal model of claim 1 , wherein the transgene comprises a senescent cell-specific promoter.3. The animal model of claim 2 , wherein the senescent cell-specific promoter is derived from p16.4. The animal model of claim 1 , wherein the transgene expresses at least one detectable label claim 1 , a cytotoxic agent claim 1 , a cytotoxicity-activating molecule claim 1 , an RNA claim 1 , or a combination thereof.5. The animal model of claim 4 , wherein the detectable label is selected from the group consisting of (a) luciferase; (b) a red fluorescent protein; (c) a green fluorescent protein; and (d) a luciferase and a red fluorescent protein.6. The animal model of claim 4 , wherein the cytotoxicity-activating molecule is a truncated herpes simplex virus thymidine kinase or a FK506-binding protein (FKBP)-caspase fusion polypeptide.7. (canceled)8. The animal model of claim 1 , wherein the transgene comprises (a) a p16promoter operatively linked to a polynucleotide sequence encoding a FKBP-caspase fusion polypeptide (p16-FKBP-caspase transgene) claim 1 , and to a ...

Human SIRPa Transgenic Animals and Their Methods of Use

The invention relates generally to compositions and methods of using transgenic non-human animals expressing human SIRPα that are engrafted with a human hematopoietic system. In various embodiments, the human hematopoietic system engrafted, human SIRPα transgenic non-human animals of the invention are useful as systems for the in vivo evaluation of the growth and differentiation of hematopoietic and immune cells, for the in vivo assessment of an immune response, for the in vivo evaluation of vaccines and vaccination regimens, for in vivo production and collection of immune mediators, including human antibodies, and for use in testing the effect of agents that modulate hematopoietic and immune cell function.

FIBRILLIN-1 MUTATIONS FOR MODELING NEONATAL PROGEROID SYNDROME WITH CONGENITAL LIPODYSTROPHY

Provided are non-human animals comprising a mutation in the Fbn1 gene to model neonatal progeroid syndrome with congenital lipodystrophy (NPSCL). Also provided are methods of making such non-human animal models. The non-human animal models can be used for screening compounds for activity in inhibiting or reducing NPSCL or ameliorating NPSCL-like symptoms or screening compounds for activity potentially harmful in promoting or exacerbating NPSCL as well as to provide insights in to the mechanism of NPSCL and potentially new therapeutic and diagnostic targets. 1. A non-human mammal whose genome comprises a fibrillin-1 (Fbn1) gene comprising a mutation , whereby expression of the gene results in a C-terminally truncated Fbn1 protein disposing the non-human mammal to develop one or more congenital lipodystrophy-like symptoms of neonatal progeroid syndrome.2. The non-human mammal of claim 1 , wherein the non-human mammal is heterozygous for the mutation.3. The non-human mammal of claim 1 , wherein the Fbn1 gene includes an Fbn1 promoter endogenous to the non-human mammal.4. The non-human mammal of claim 1 , wherein the mutation is a frameshift mutation.5. The non-human mammal of claim 1 , wherein the mutation results in a premature termination codon.6. The non-human mammal of claim 5 , wherein the premature termination codon is in the penultimate or the final exon of the Fbn1 gene.7. The non-human mammal of claim 6 , wherein the premature termination codon is in the final exon or is less than about 55 base pairs upstream of the last exon-exon junction in the Fbn1 gene.8. The non-human mammal of claim 1 , wherein the mutation is a splice site mutation resulting in the penultimate exon being skipped.9. The non-human mammal of claim 1 , wherein the mutation results in a premature termination codon in the last coding exon.10. The non-human mammal of claim 1 , wherein the mutation disrupts a basic amino acid recognition sequence for proprotein convertases of the furin family. ...

Methods and compositions for modulating regulatory t cell function

Pharmaceutical compositions comprising a compound selected from the group consisting of Compound Nos. 1, 2, 3, 4, 5, 6, 7, 13, 22, 23, 24 and 25, as described in Table 1, and a pharmaceutically acceptable excipient. The pharmaceutical composition of the invention may further comprise an antigen, and/or an adjuvant. Also provided are methods of inhibiting a regulatory T (Treg) cell-mediated immune suppression, or more generally a method for enhancing immune response using a pharmaceutical composition comprising a ligand for human Toll-like receptor (TLR) 8 which activates the MyD88-IRAK4 signalling pathway. The present invention further provides a method of screening for an inhibitor of Treg cells' suppressive activity of host immune response using CD4 + Treg cells which express CD25, GITR and FoxP3; secrete IL-10, and are able to suppress the activation of CD4 + T cells.

Compositions and methods for diagnosis and treatment of neurological disease

Provided herein are methods, assays and compositions relating to the treatment of neurological diseases and disorders, particularly by modulating expression and/or activity of Bif-1.

STRAIN OF DEFORMED WING VIRUS (DWV)

The invention is in the field of virology and relates to the deformed wing virus (DWV). A new strain of deformed wing virus (DWV) has been identified that is predominant in bees infested with mites. This particular strain of DWV can be used in diagnostics to identify at risk colonies. Also, inhibitors of the particular strain may be used in the treatment and/or prevention of DWV. 1. A polynucleotide comprising a sequence having at least 98% homology to SEQ ID NO: 1 , 2 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 or 62 based on nucleotide identity over its entire length.2. An oligonucleotide which specifically hybridises to a part of a polynucleotide according to .34-. (canceled)5. An oligonucleotide according to claim 2 , which is a ribonucleic acid (RNA).68-. (canceled)9varroa destructor. An isolated strain of deformed wing virus (DWV) which comprises the virus 1 (VDV-1) capsid proteins (CP) and the DWV non-structural proteins (NS).10. (canceled)11. An antibody which specifically binds to an isolated strain of DWV according to .1213-. (canceled)14. A vector comprising-an oligonucleotide according to claim 2 , wherein said oligonucleotide is operably linked to a promoter.15. A vector according to claim 14 , wherein said promoter is the honeybee heatshock protein 70 (hsp70) promoter.16. A vector according to claim 15 , wherein said promoter comprises the sequence of SEQ ID NO: 8.17. A vector according to claim 14 , which further comprises retroviral RNA which facilitates integration into the bee genome.18. (canceled)19. A composition comprising an oligonucleotide according to claim 14 , an antibody according to or a vector according to claim 14 , and a delivery vehicle.2021-. (canceled)22Varroa. A method of treating or preventing deformed wing disease in a mite-infested bee or bee colony claim 9 , comprising contacting the bee or bee colony with an inhibitor of an isolated strain of DWV according to .23. A method according to claim 22 , wherein the inhibitor is ...

Identification of a 5-Gene Expression Signature Predicting Clinical Outcome of Patients with Brain Tumors

High-grade gliomas are the most common brain tumors in humans and are essentially incurable. The defining hallmark of these high-grade gliomas is the presence within the tumor mass of highly tumorigenic cellular subpopulations that fuel tumor aggressiveness. Identification of the molecular mechanisms remains elusive. Therefore, there is a need for diagnostic markers to accurately determine the type of glioma and appropriate treatment. Gene delivery vehicles are provided that comprise an oncogene, IRES-Cre-ER cassette and a gene encoding an oligonucleotide that inhibits p53 including shp53. Methods are also provided for determining a diagnosis and for treatment of non-aggressive and aggressive gliomas. 1. A method , comprising(a) obtaining a sample of a glioma from a subject,(b) determining a level of expression of each protein selected from the group consisting of TCF12/HEB, RAP1GAP, CDKN1C, ID2 and ID3 in the subject glioma sample, and(c) comparing the level of expression of each protein in the subject glioma sample to a known median level of expression of each of the corresponding proteins TCF12/HEB, RAP1GAP, CDKN1C, ID2 and ID3 in a standard glioma population, and(d) if the level of expression of TCF12/HEB, RAP1GAP and CDKN1C is significantly lower in the subject glioma sample compared to the known median for each corresponding protein in the standard glioma population, and the level of each of ID2 and ID3 expression is significantly higher in the subject glioma sample than the standard glioma population, then determining that subject glioma is an aggressive glioma carrying a very poor prognosis.2. The method of claim 1 , further comprising(e) treating the aggressive glioma in a subject in need thereof.3. The method of claim 1 , wherein the level of expression of each of the proteins TCF12/HEB claim 1 , RAP1GAP claim 1 , CDKN1C claim 1 , ID2 and ID3 in the glioma is determined by a method selected from the group consisting of determining the level of each of the ...

PHARMACOKINETIC ANIMAL MODEL

The present invention relates to a method of assessing pharmacokinetic properties of a variant of human serum albumin using a non-primate animal species where the native albumin of the animal provides minimal competition for HSA binding to the FcRn receptor in said animal. In the non-primate animal species, the binding affinity of wild type HSA to the native FcRn of said animal is the same as or higher than the binding affinity of the native albumin of said animal to the native FcRn. The present invention also relate to animal models which are particularly suitable for assessing pharmacokinetics of human serum albumin variants. 1. A method for assessing one or more (several) pharmacokinetic properties of a variant HSA compared to wild type HSA comprisinga. Selecting a non-primate animal species where the binding affinity at pH 6 of wild type HSA to the native FcRn of said animal is the same as or higher than the binding affinity of the native albumin of said animal to said FcRn;b. Administering the variant HSA to one animal and the wild type HSA to another animal of the non-primate animal species selected in a); andc. Measuring the one or more (several) pharmacokinetic properties of the variant HSA and the wild type HSA.2. The method according to claim 1 , wherein the binding affinity of wild type HSA to the native FcRn of said animal is between 0.8 and 3.5 fold when compared with the binding affinity of the native albumin of said animal.3. The method according to claim 1 , wherein the native FcRn has a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16.4. The method according to claim 1 , wherein the native FcRn has a valine in the position corresponding to position 52 when aligned to SEQ ID NO: 16.5. The method according to claim 1 , wherein the non-primate animal species is a wild type animal or a transgenic animal.6. The method according to claim 5 , wherein the wild type animal is a pig.7. The method according to claim 5 , ...

NON-HUMAN ANIMALS HAVING AN ENGINEERED IMMUNOGLOBULIN LAMBDA LIGHT CHAIN LOCUS

Non-human animals (and/or non-human cells) and methods of using and making the same are provided, which non-human animals (and/or non-human cells) have a genome comprising human antibody-encoding sequences (i.e., immunoglobulin genes). Non-human animals described herein express antibodies that contain human Igλ light chains, in whole or in part. In particular, non-human animals provided herein are, in some embodiments, characterized by expression of antibodies that contain human Igλ light chains, in whole or in part, that are encoded by human Igλ light chain-encoding sequences inserted into an endogenous Igλ light chain locus of said non-human animals. Methods for producing antibodies from non-human animals are also provided. 129-. (canceled)31. The method of claim 30 , wherein the engineered endogenous immunoglobulin λ light chain locus comprises two mouse Eλs.32. The method of claim 31 , wherein the two mouse Eλs are a mouse Eλ and a mouse Eλ3-1.33. The method of claim 30 , wherein the engineered endogenous immunoglobulin λ light chain locus comprises three human Eλs.34. The method of claim 30 , wherein the germline genome of the genetically modified mouse further comprises:{'sub': H', 'H', 'H', 'H', 'H', 'H, '(i) an engineered endogenous immunoglobulin heavy chain locus comprising insertion of one or more human Vgene segments, one or more human Dgene segments, and one or more human Jgene segments, which human V, Dand Jgene segments are operably linked to a mouse immunoglobulin heavy chain constant region; or'}{'sub': H', 'H', 'H', 'H', 'H', 'H, '(ii) an engineered endogenous immunoglobulin heavy chain locus comprising insertion of one or more human Vgene segments, one or more human Dgene segments, and one or more human Jgene segments, which human V, Dand Jgene segments are operably linked to a mouse immunoglobulin heavy chain constant region, and an engineered endogenous immunoglobulin κ light chain locus comprising insertion of one or more human Vκ gene segments ...

Non-human gene-edited mammal, protein crude extract separated from connective tissue of non-human gene-edited mammal, method for protein crude extract and uses of protein crude extract

A non-human gene-edited mammal, a protein crude extract isolated from a connective tissue of the non-human gene-edited mammal, a method for preparing the protein crude extract, and uses of the protein crude extract are provided. The method includes: microinjecting a deoxyribonucleic acid sequence construct (DNA construct) containing SEQ ID NO: 4 or SEQ ID NO: 5 into a rat embryo, transplanting the rat embryo into a female rat of the same species to develop into a mature rat, and isolating a protein crude extract from a connective tissue of the mature rat. The protein crude extract includes human type I collagen and a non-native chimeric protein peptide chain.

MUTATIONS IN RHODOPSIN GENE IN ZEBRAFISH AND USES THEREOF

Disclosed are non-naturally occurring zebrafish, such as transgenic zebrafish, which comprise a mutation in the rhodopsin (rho) gene. Also disclosed are methods of identifying compounds useful in treating retinal-specific defects and disorders, such as degeneration. Further disclosed are methods of identifying mutations in the rhodopsin gene that can cause retinal-specific defects. 1Xenopus. A non-naturally occurring zebrafish comprising one or more mutations in rhodopsin (rho) locus , wherein said one or more mutations leads to rod degeneration , and further wherein said zebrafish comprises an exogenous nucleic acid encoding a reporter protein that is operably linked to a opsin (Xops) promoter: wherein the zebrafish exhibits a photoreceptor degeneration phenotype analogous to humans.2. The zebrafish of claim 1 , wherein the mutation or mutations disrupts sites essential for protein-protein interaction or trafficking.3. The zebrafish of claim 1 , wherein the mutation or mutations leads to altered protein folding.4. The zebrafish of claim 1 , wherein the mutation or mutations disrupts a consensus sequence for protein glycosylation.5. The zebrafish of claim 1 , wherein the mutation comprises SEQ ID NO: 2 claim 1 , 3 claim 1 , 8 claim 1 , 9 claim 1 , 10 claim 1 , or 11.6. The zebrafish of claim 1 , wherein the zebrafish further comprises a nucleic acid sequence encoding a fluorescent reporter polypeptide.7. The zebrafish of claim 1 , wherein the zebrafish further comprises the mutation pde6c.8. The zebrafish of claim 7 , wherein the zebrafish are homozygous for pde6c.9. The zebrafish of claim 1 , wherein the zebrafish are embryos larvae claim 1 , juveniles and adults.1020-. (canceled) This application claims is a divisional application of U.S. application Ser. No. 15/972,761, filed on May 7, 2018, which claims priority to and benefit of U.S. Provisional Application No. 62/501,934, filed May 5, 2017, all of which are hereby incorporated herein by reference in their ...

T2R Taste Receptors and Genes Encoding Same

Newly identified mammalian taste-cell-specific G Protein-Coupled Receptors and the genes encoding said receptors are described. Specifically, T2R taste G Protein-Coupled Receptors that are believed to be involved in bitter taste sensation, and the genes encoding the same, are described, along with methods for isolating such genes and for isolating and expressing such receptors. Methods for representing taste perception of a particular tastant in a mammal are also described, as are methods for generating a novel molecules or combinations of molecules that elicit a predetermined taste perception in a mammal, and methods for simulating one or more tastes. 1137-. (canceled)138. A composition comprising a recombinant cell , which expresses at least one polypeptide having at least 90% sequence identity to the bitter taste receptor polypeptide of SEQ ID NO: 2 , 6 , 8 , 10 , 12 , 14 , 16 , 18 , 20 , or 24 , wherein the composition further comprises an agent that facilitates the detection of compounds that modulate the signal transduction activity of the at least one polypeptide.139. The composition of claim 138 , wherein the at least one polypeptide has at least 95% sequence identity to the bitter taste receptor polypeptide of SEQ ID NO: 2 claim 138 , 6 claim 138 , 8 claim 138 , 10 claim 138 , 12 claim 138 , 14 claim 138 , 16 claim 138 , 18 claim 138 , 20 claim 138 , or 24.140. The composition of claim 138 , wherein the at least one polypeptide has at least 98% sequence identity to the bitter taste receptor polypeptide of SEQ ID NO: 2 claim 138 , 6 claim 138 , 8 claim 138 , 10 claim 138 , 12 claim 138 , 14 claim 138 , 16 claim 138 , 18 claim 138 , 20 claim 138 , or 24.141. The composition of claim 138 , wherein the at least one polypeptide has at least 99% sequence identity to the bitter taste receptor polypeptide of SEQ ID NO: 2 claim 138 , 6 claim 138 , 8 claim 138 , 10 claim 138 , 12 claim 138 , 14 claim 138 , 16 claim 138 , 18 claim 138 , 20 claim 138 , or 24.142. The ...

Humanized il-6 and il-6 receptor

Mice that comprise a replacement of endogenous mouse IL-6 and/or IL-6 receptor genes are described, and methods for making and using the mice. Mice comprising a replacement at an endogenous IL-6Rα locus of mouse ectodomain-encoding sequence with human ectodomain-encoding sequence is provided. Mice comprising a human IL-6 gene under control of mouse IL-6 regulatory elements is also provided, including mice that have a replacement of mouse IL-6-encoding sequence with human IL-6-encoding sequence at an endogenous mouse IL-6 locus.

Spontaneous Autoimmune Diabetes in Humanized Mice Carrying Human Type 1 Diabetes Susceptibility and Uses Therefor

A mouse model that develops type 1 diabetes spontaneously and used thereof are described. In some embodiments, the mouse model expresses a combination of HLA-DQ8 and GAD65 in a C57BL/6-BTBR congenic background, where the GAD65 is expressed under the rat insulin promoter. 1. A mouse model that develops type 1 diabetes spontaneously.2. The mouse model of claim 1 , wherein the mouse model expresses a diabetes-susceptibility human MHC class II molecule in antigen presenting cells claim 1 , and expresses a human β-cell autoantigen in mouse β-cells.3. The mouse model of claim 2 , wherein the diabetes-susceptibility human MHC class II molecule comprises DQ8.4. The mouse model of claim 2 , wherein the human β-cell autoantigen comprises human Glutamic Acid Decarboxylase (hGAD65).5. The mouse model of claim 4 , wherein the mouse model expresses hGAD65 from the rat insulin promoter (RIP).6. The mouse model of claim 2 , wherein the mouse model has compromised β-cell neogenesis and/or proliferation.7. The mouse model of claim 2 , wherein the mouse model comprises a C57BL/6-BTBR background.8. A mouse model expressing a combination of HLA-DQ8 and GAD65 with a C57BL/6-BTBR background.9. The mouse model of claim 8 , wherein the mouse model expresses GAD65 from the rat insulin promoter (RIP).10. The mouse model of claim 1 , wherein the mouse model which expresses high levels of hGAD65 in β-cells claim 1 , and comprises endogenous mouse MHC-class II antigens replaced by a human HLA-DQ8 diabetes susceptibility locus claim 1 , wherein the mouse model has a genetic background providing for compromised β-cell neogenesis and/or proliferation.11. The mouse model of claim 10 , wherein the genetic background comprises a C57BL/6-BTBR background.12. The mouse model of claim 10 , wherein the mouse model develops diabetic retinopathy.13. The mouse model of claim 10 , wherein the mouse model develops diabetic nephropathy.14. The mouse model of claim 10 , wherein the mouse model demonstrates focal ...

Pancreatic Islets of Transgenic LEA29Y Animals for Treating Diabetes

The present invention relates to methods of treating diabetes in a human subject comprising the use of pancreatic islets or of embryonic pancreatic tissue of a transgenic animal, wherein said transgenic animal contains a polynucleotide sequence encoding a CTLA4 peptide-immunoglobulin fusion, preferably LEA29Y, and expresses said CTLA4 peptide-immunoglobulin fusion in a tissue-specific manner in pancreatic islets. 1. A method of treating diabetes in a human subject , comprising the steps of:isolating pancreatic islets of a transgenic animal and administering said isolated pancreatic islets of the transgenic animal into a human subject in need thereof, wherein said isolated pancreatic islets of the transgenic animal have the ability to normalize blood glucose levels in the human subject into which the islets are administered, wherein said transgenic animal is a transgenic animal whose genome comprises a recombinant nucleic acid comprising a polynucleotide sequence encoding a CTLA4 peptide fused to an immunoglobulin (“CTLA4 peptide-immunoglobulin fusion”) wherein said polynucleotide sequence is operably linked to an insulin promoter that results in expression of the CTLA4 peptide-immunoglobulin fusion, wherein said animal expresses the CTLA4 peptide-immunoglobulin fusion, wherein said expression is stable in offspring of said transgenic animal, wherein said animal exhibits, as a result of the expression of said CTLA4 peptide-immunoglobulin fusion, tissue-specific expression of the CTLA4 peptide-immunoglobulin fusion in pancreatic islets; andwherein after xenotransplantation of said transgenic pancreatic islets of said animal into a human subject, said transgenic pancreatic islets are protected from rejection by mature human immune system cells, normalize blood glucose levels in the human subject, and prevent re-occurrence of hyperglycemia.2. The method of claim 1 , wherein the transgenic animal does not exhibit an immunodeficient phenotype.3. The method of claim 1 , ...

METHOD FOR GENERATING ANTIBODIES WITH IMPROVED SPECIFICITY AND/OR AFFINITY

The present disclosure relates to methods of generating antibodies with improved specificity and/or affinity for a target antigen, as well as B-cells and hybridomas expressing the antibodies and compositions comprising antibodies with improved specificity and/or affinity for the target antigen. 1. A method for generating an antibody having improved specificity and/or affinity for a target antigen , the method comprising:i) introducing the target antigen in an animal, wherein the animal expresses a variant antigen that is structurally related to the target antigen, and the animal further comprises B-cells encoding an antibody with a basic specificity and/or affinity for the target antigen, whereby the B-cells express a B-cell receptor comprising the antibody;ii) allowing the B-cells to undergo affinity maturation in the animal; andiii) isolating B-cells that have undergone affinity maturation in the animal;whereby the B-cells isolated in iii) express antibodies with improved specificity and/or affinity for the target antigen compared to antibodies expressed by the B-cells prior to affinity maturation.2. A method for generating an antibody having improved specificity and/or affinity for a target antigen , the method comprising:i) introducing into an animal a B-cell, the B-cell encoding an antibody with a basic specificity and/or affinity for the target antigen, whereby the B-cell expresses a B-cell receptor comprising the antibody, and wherein the animal expresses a variant antigen that is structurally related to the target antigen;ii) introducing the target antigen in the animal;iii) allowing the B-cells to undergo affinity maturation in the animal; andiv) isolating the B-cells that have undergone affinity maturation in the animal;whereby the B-cells isolated in iv) express antibodies with improved specificity and/or affinity for the target antigen compared to antibodies expressed by the B-cells prior to affinity maturation.3. The method of or , wherein the B-cells ...

REPRODUCIBLE METHOD FOR TESTIS-MEDIATED GENETIC MODIFICATION (TGM) AND SPERM-MEDIATED GENETIC MODIFICATION (SGM)

The present invention provides a method of direct germline mutagenesis of a non-human animal. 1. A method of integrating an exogenous nucleic acid into the genome of at least one cell of an animal comprising administering a composition directly to the testis of the animal , wherein the composition comprisesa) a transposon comprising an exogenous nucleic acid, wherein the exogenous nucleic acid is flanked by a first inverted repeat sequence comprising a sequence at least about 90% sequence identity to one ITR of a transposase disclosed herein and/or a second inverted repeat sequence comprising a sequence at least about 90% sequence identity to a known ITR of a transposase disclosed herein; andb) a nucleic acid encoding any transposase disclosed herein, according to any one to excise the exogenous nucleic acid from a plasmid, episome, or transgene and integrate the exogenous nucleic acid into the genome of the animal.2. The method according to wherein the transposon and nucleic acid encoding the transposase of b) are present on separate vectors.3. The method according to wherein the transposon and nucleic acid encoding the transposase of b) are present on the same vector.4. The method according to claim 1 , wherein the animal is a vertebrate.5. The method according to wherein the vertebrate animal is a mammal.6. The method according to claim 1 , wherein the step of administering is administering via injection with a composition comprising the nucleic acid sequence (a) and (b) claim 1 , and wherein the composition is sterile and pyrogen-free.7. The method according to claim 1 , wherein the exogenous nucleic acid comprises a gene expressible in a mammal.8. A method of generating a non-human claim 1 , transgenic animal comprising a germline mutation comprising administering directly to the testis of the animal:a composition comprising:a) a nucleic acid comprising an exogenous nucleic acid; andb) a nucleic acid encoding a genetic modification enzyme selected from: a ...

MINIMALLY-INVASIVE AND ACTIVITY-DEPENDENT CONTROL OF EXCITABLE CELLS

The present invention provides a method of bioluminescence-driven optogenetic control of excitable cells. The excitable cell expresses a light-gated ion channel, and a luminescent protein can be expressed either in the excitable cell or in another cell proximal to the excitable cell. The methods of the invention can be used to desynchronize local activity of excitable cells in a mammalian tissue. The methods of the invention can be used to treat a disease or condition in a mammal, the disease or condition being related to bursting. The disease or condition can be Parkinson's disease, epilepsy, a sleep disorder, or a sensory-related disease or condition (e.g., attention deficit disorder or pain). The invention also provides a conjugate of containing a voltage-gated ion channel and a luminescent protein. 1. A method of modulating activity of an excitable cell expressing a luminescent protein and a conjugate of a light-gated ion channel and a subcellular element in a tissue in a mammal , the method comprising contacting a luciferin with the cell , wherein the luciferin undergoes an oxidation reaction mediated by the luminescent protein to produce light , thereby modulating the activity of the excitable cell.2. The method of claim 1 , wherein the excitable cell is a neuron claim 1 , a muscle cell claim 1 , or an endocrine cell.3. The method of claim 2 , wherein the endocrine cell is a pituitary cell claim 2 , a β-cell in an islet of Langerhans claim 2 , or an adrenal medullar cell.4. The method of any one of to claim 2 , wherein the subcellular element is a voltage-gated ion channel.5. A method of desynchronizing the activity of excitable cells in a tissue claim 2 , the method comprising expressing a light-gated ion channel in a first population of excitable cells in the tissue claim 2 , expressing a luminescent protein in a second population of excitable cells in the tissue claim 2 , and contacting the tissue with a luciferin claim 2 , wherein the luciferin reacts with ...