Rab11a and Rab8 work in conjunction with myosin5B to promote discoidal/fusiform vesicle exocytosis at the apical surface of umbrella cells. It is predicted that similar Rab cascades will be common to other regulated secretory pathways.

During early development, midbrain dopaminergic (mDA) neuronal progenitors (NPs) arise from the ventral mesencephalic area by the combined actions of secreted factors and their downstream transcription factors. These mDA NPs proliferate, migrate to their final destinations, and develop into mature mDA neurons in the substantia nigra and the ventral tegmental area. Here, we show that such authentic mDA NPs can be efficiently isolated from differentiated ES cells (ESCs) using a FACS method combining two markers, Otx2 and Corin. Purified Otx2 + Corin + cells coexpressed other mDA NP markers, including FoxA2, Lmx1b, and Glast. Using optimized culture conditions, these mDA NPs continuously proliferated up to 4 wk with almost 1,000-fold expansion without significant changes in their phenotype. Furthermore, upon differentiation, Otx2 + Corin + cells efficiently generated mDA neurons, as evidenced by coexpression of mDA neuronal markers (e.g., TH, Pitx3, Nurr1, and Lmx1b) and physiological functions (e.g., efficient DA secretion and uptake). Notably, these mDA NPs differentiated into a relatively homogenous DA population with few serotonergic neurons. When transplanted into PD model animals, aphakia mice, and 6-OHDA-lesioned rats, mDA NPs differentiated into mDA neurons in vivo and generated well-integrated DA grafts, resulting in significant improvement in motor dysfunctions without tumor formation. Furthermore, grafted Otx2 + Corin + cells exhibited significant migratory function in the host striatum, reaching >3.3 mm length in the entire striatum. We propose that functional and expandable mDA NPs can be efficiently isolated by this unique strategy and will serve as useful tools in regenerative medicine, bioassay, and drug screening.neural precursors | dopaminergic neurons | transplantation

Uroplakin (UP)3a is critical for urinary tract development and function; however, its role in these processes is unknown. We examined the function of the UP3a-like protein Upk3l, which was expressed at the apical surfaces of the epithelial cells that line the pronephric tubules (PTs) of the zebrafish pronephros. Embryos treated with upk3l-targeted morpholinos showed decreased pronephros function, which was attributed to defects in PT epithelial cell morphogenesis and polarization including: loss of an apical brush border and associated phospho-ERM proteins, apical redistribution of the basolateral Na+/K+–ATPase, and altered or diminished expression of the apical polarity complex proteins Prkcz (atypical protein kinase C zeta) and Pard3 (Par3). Upk3l missing its C-terminal cytoplasmic domain or containing mutations in conserved tyrosine or proline residues did not rescue, or only partially rescued the effects of Upk3l depletion. Our studies indicate that Upk3l promotes epithelial polarization and morphogenesis, likely by forming or stimulating interactions with cytoplasmic signaling or polarity proteins, and that defects in this process may underlie the pathology observed in UP3a knockout mice or patients with renal abnormalities that result from altered UP3a expression.

MIT SPR spoke with three researchers in public health to understand their perspectives on how public health crises (COVID-19, for example) affect innovation in methods and practices across government, academia, and industry.

Ðèòóêñèìàá -õèìåðíîå ìîíîêëîíàëüíîå àíòèòåëî, âêëþ÷àþùåå êàïïà (k)-êîíñòàí-òíûå ðåãèîíû Fc-ôðàãìåíòà èììóíîãëîáóëèíà IgG1 ÷åëîâåêà è âàðèàáåëüíûå ôðàã-ìåíòû èììóíîãëîáóëèíà IgG1 ìûøè. Òàêàÿ ìîäèôèöèðîâàííàÿ ñòðóêòóðà èììóíîãëî-áóëèíà íàäåëÿåò ðèòóêñèìàá ñïîñîáíîñòüþ ñïåöèôè÷åñêè ðàñïîçíàâàòü àíòèãåí CD20, ýêñïîíèðóåìûé, ãëàâíûì îáðàçîì, íà Â-ëèìôîöèòàõ.  îáçîðå îáñóaeäàþòñÿ 4 îñíîâíûõ ìåõàíèçìà äåéñòâèÿ ðèòóêñèìàáà, ïðèâîäÿùèå ê ñíèaeåíèþ ïîïóëÿöèè Â-ëèìôîöèòîâ ó ïàöèåíòîâ ñ ëèìôîïðîëèôåðàòèâíûìè ïðîöåññàìè. Îòíîñèòåëüíûé âêëàä ïðèâåäåííûõ ìåõàíèçìîâ äåéñòâèÿ â êëèíè÷åñêèé ýôôåêò ðèòóêñèìàáà äî êîíöà íå îïðåäåëåí.Êëþ÷åâûå ñëîâà: ðèòóêñèìàá; äîêëèíè÷åñêèå èññëåäîâàíèÿ; ýêñïåðèìåíòû in vitro ÂÂÅÄÅÍÈÅ Ðèòóêñèìàá -èììóíîãëîáóëèí (Ig) G-1k õèìåðíûé èëè õèìåðíîå àíòè-CD20 ìîíîêëîíàëüíîå àíòèòåëî, êîòîðîå, ïîäîáíî íàòóðàëüíîìó IgG è äðóãèì àíòèòå-ëàì ÷åëîâåêà, ïðåäñòàâëåíî 2 ëåãêèìè (êàïïà) è 2 òÿ-aeåëûìè (ãàììà) ïîëèïåïòèäíûìè öåïÿìè, ñîåäèíåí-íûìè ìåaeäó ñîáîé äèñóëüôèäíûìè ìîñòèêàìè [4,23,16]. Âàðèàáåëüíûå ðåãèîíû (ïåðâè÷íûå àìèíî-êèñëîòíûå ïîñëåäîâàòåëüíîñòè) ëåãêèõ è òÿaeåëûõ öå-ïåé ïîëó÷åíû èç IgG ìûøåé, êîíñòàíòíûå ðåãèîíû -èç IgG ÷åëîâåêà. Àíòè-CD20 àíòèòåëî ðèòóêñèìàá ïî-ëó÷àþò ìåòîäîì ãåííîé èíaeåíåðèè. Êëþ÷åâûìè ïîêà-çàíèÿìè ê ïðèìåíåíèþ ðèòóêñèìàáà (òîðãîâûå íàèìå-íîâàíèÿ Rituxan ® , MabThera ® , Zytux ® , Àöåëëáèÿ ® ) ÿâ-ëÿþòñÿ: B-êëåòî÷íûå íåõîäaeêèíñêèå ëèìôîìû (ÍÕË) (ðåöèäèâèðóþùèå èëè õèìèîóñòîé÷èâûå ñ íèçêîé ñòå-ïåíüþ çëîêà÷åñòâåííîñòè èëè ôîëëèêóëÿðíûå) ó âçðîñëûõ ïàöèåíòîâ, ðåâìàòîèäíûé àðòðèò, à òàêaeå òÿaeåëûå ôîðìû àêòèâíîãî ãðàíóëåìàòîçà ñ ïîëèàíãèè-òîì (ãðàíóëåìàòîç Âåãåíåðà) è ìèêðîñêîïè÷åñêîãî ïî-ëèàíãèèòà (êîìáèíèðîâàííàÿ òåðàïèÿ ñ ãëþêîêîðòèêî-ñòåðîèäàìè).Ðèòóêñèìàá ñïåöèôè÷åñêè ñâÿçûâàåòñÿ ñ òðàíñìåì-áðàííûì áåëêîì -Â-ëèìôîöèòàðíûì àíòèãåíîì CD20, ïðåäñòàâëåííûì ïðåèìóùåñòâåííî íà ïîâåðõ-íîñòè ïðå-Â-ëèìôîöèòîâ è çðåëûõ Â-ëèìôîöèòîâ. Ïî-ñëå ñâÿçûâàíèÿ ðèòóêñèìàáà ñ CD20 èíèöèèðóþòñÿ èììóíîëîãè÷åñêèå ðåàêöèè, âêëþ÷àþùèå, â ÷àñòíî-ñòè, ìåõàíèçìû êîìïëåìåíò-çàâèñèìîé öèòîòîêñè÷íî-ñòè, àíòèòåëîçàâèñèìîé êëåòî÷íîé öèòîòîêñè÷íîñòè è àïîïòîçà, îïîñðåäóþùèå, â êîíå÷íîì èòîãå, ëèçèñ Â-êëåòîê è òîòàëüíîå ïðîäîëaeèòåëüíîå ñíèaeåíèå èõ ïóëà. Êðîìå òîãî, ðèòóêñèìàá in vitro ïîâûøàåò ÷óâñò-âèòåëüíîñòü êëåòîê Â-ëèìôîì ÷åëîâåêà ê íåêîòîðûì õèìèîòåðàïåâòè÷åñêèì ïðåïàðàòàì, â ÷àñòíîñòè ýòî-ïîçèäó, âèíêðèñòèíó, öèñïëàòèíó, ÷òî áûëî ýêñïåðè-ìåíòàëüíî ïîêàçàíî íà êëåòî÷íûõ ìîäåëÿõ ñ èñïîëüçî-âàíèåì ëèíèé Raji, RL è SUDHL-4 [20].Íàêîïëåí âíóøèòåëüíûé îáúåì ýêñïåðèìåíòàëü-íûõ èññëåäîâàíèé ôàðìàêîëîãè÷åñêèõ ýôôåêòîâ ðè-òóêñèìàáà in vitro è in vivo íà ìîäåëÿõ ñ êñåíîòðàíñ-ïëàíòàòàìè ðàçëè÷íûõ òèïîâ ëèìôîì ÷åëîâåêà.Èññëåäîâàíû ìåõàíèçìû äåéñòâèÿ ðèòóêñèìàáà íà 4 êëåòî÷íûõ ëèíèÿõ ôîëëèêóëÿðíîé ëèìôîìû, 1 ëè-íèè êëåòîê ëèìôîìû Áåðêèòòà, 3 îáðàçöàõ ôîëëèêó-ëÿðíîé ëèìôîìû ïàöèåíòîâ è íîðìàëüíûõ Â-êëåòêàõ in vitro. Òàê, ðèòóêñèìàá ýôôåêòèâíî áëîêèðîâàë ïðî-ëèôåðàöèþ íîðìàëüíûõ Â-ëèìôîöèòîâ, íî íå êëåòîê ëèìôîìû. Èññëåäîâàòåëè íå çàôèêñèðîâàëè çíà÷èìûõ èçìåíåíèé àïîïòîçà êëåòîê â êóëüòóðàõ â îòâåò íà îá-ðàáîòêó ðèòóêñèìà...