SummaryGene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post‐transcription, and post‐translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear. Here, we report on N6‐methyladenosine (m6A) RNA modification profiles of human peripheral blood mononuclear cells (PBMCs) from young and old cohorts. An m6A RNA profile identified a decrease in overall RNA methylation during the aging process as well as the predominant modification on proteincoding mRNAs. The m6A‐modified transcripts tend to be more highly expressed than nonmodified ones. Among the many methylated mRNAs, those of DROSHA and AGO2 were heavily methylated in young PBMCs which coincided with a decreased steady‐state level of AGO2 mRNA in the old PBMC cohort. Similarly, downregulation of AGO2 in proliferating human diploid fibroblasts (HDFs) also correlated with a decrease in AGO2 mRNA modifications and steady‐state levels. In addition, the overexpression of RNA methyltransferases stabilized AGO2 mRNA but not DROSHA and DICER1 mRNA in HDFs. Moreover, the abundance of miRNAs also changed in the young and old PBMCs which are possibly due to a correlation with AGO2 expression as observed in AGO2‐depleted HDFs. Taken together, we uncovered the role of mRNA methylation on the abundance of AGO2 mRNA resulting in the repression of miRNA expression during the process of human aging.

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Eukaryotic mRNA metabolism regulates its stability, localization, and translation using complementarity with counter-part RNAs. To modulate their stability, small and long noncoding RNAs can establish complementarity with their target mRNAs. Although complementarity of small interfering RNAs and microRNAs with target mRNAs has been studied thoroughly, partial complementarity of long noncoding RNAs (lncRNAs) with their target mRNAs has not been investigated clearly. To address that research gap, our lab investigated whether the sequence complementarity of two lncRNAs, lincRNA-p21 and OIP5-AS1, influenced the quantity of target RNA expression. We predicted a positive correlation between lncRNA complementarity and target mRNA quantity. We confirmed this prediction using RNA affinity pull down, microarray, and RNA-sequencing analysis. In addition, we utilized the information from this analysis to compare the quantity of target mRNAs when two lncRNAs, lincRNA-p21 and OIP5-AS1, are depleted by siRNAs. We observed that human and mouse lincRNA-p21 regulated target mRNA abundance in complementarity-dependent and independent manners. In contrast, affinity pull down of OIP5-AS1 revealed that changes in OIP5-AS1 expression influenced the amount of some OIP5-AS1 target mRNAs and miRNAs, as we predicted from our sequence complementarity assay. Altogether, the current study demonstrates that partial complementarity of lncRNAs and mRNAs (even miRNAs) assist in determining target RNA expression and quantity.

Salt-sensitive (SS) hypertension is accompanied with an early onset of proteinuria, which results from the loss of glomerular podocytes. Here, we hypothesized that glomerular damage in the SS hypertension occurs in part due to mitochondria dysfunction, and we used a unique model of freshly isolated glomeruli to test this hypothesis. In order to mimic SS hypertension, we used Dahl SS rats, an established animal model. Animals were fed a 0.4% NaCl (normal salt, NS) diet or challenged with a high salt (HS) 4% NaCl diet for 21 days to induce an increase in blood pressure (BP). Similar to previous studies, we found that HS diet caused renal hypertrophy, increased BP, glomerulosclerosis, and renal lesions such as fibrosis and protein casts. We did not observe changes in mitochondrial biogenesis in the renal cortex or isolated glomeruli fractions. However, Seahorse assay performed on freshly isolated glomeruli revealed that basal mitochondrial respiration, maximal respiration, and spare respiratory capacity were lower in the HS compared to the NS group. Using confocal imaging and staining for mitochondrial H 2 O 2 using mitoPY1, we detected an intensified response to an acute H 2 O 2 application in the podocytes of the glomeruli isolated from the HS diet fed group. TEM analysis showed that glomerular mitochondria from the HS diet fed group have structural abnormalities (swelling, enlargement, less defined cristae). Therefore, we report that glomerular mitochondria in SS hypertension are functionally and structurally defective, and this impairment could eventually lead to loss of podocytes and proteinuria. Thus, the glomerular-mitochondria axis can be targeted in novel treatment strategies for hypertensive glomerulosclerosis.

1 Кардиохирургическое отделение аорты и коронарных артерий ФГУ «Новосибирский научно-исследовательский институт патологии кровообращения имени академика Е.Н. Мешалкина» Минздрава России, Новосибирск, Российская Федерация 2 Институт теоретической и прикладной механики им. С.А. Христиановича СО РАН, Новосибирск, Российская Федерация Цель: экспериментальная оценка производительности дискового насоса вязкого трения, изучение взаи мосвязи междискового зазора и размеров входных и выходных отверстий и параметров производитель ности насоса. Материалы и методы. Для изучения характеристик и оптимизации конструкции дисково го насоса трения, предназначенного для перекачивания крови, был изготовлен макет насоса и стенд для его испытания. Габариты насоса задавались, исходя из медикобиологических требований для систем механической поддержки сердца и с учетом экспериментальных исследований наших коллег из Пен сильвании. Объемный расход рабочей жидкости измерялся поплавковым ротаметром Krohne VA40 c по грешностью измерений не более 1%. Значения давления в гидродинамическом контуре измерялись при помощи монитора производства фирмы «БиософтМ». Дросселирующее устройство позволяло менять гидравлическое сопротивление системы, имитируя общее периферическое сопротивление сердечносо судистой системы человека. Результаты. В ходе эксперимента получена линейная прямая зависимость между производительностью насоса и создаваемым им перепадом давления жидкости на входе и выхо де на насосе. Требуемые значения расхода (5-7 л/мин) и давления (90-100 мм рт. ст.) достигаются при частоте вращения ротора в диапазоне 2500-3000 об/мин. Показано, что увеличение входного диаметра до 15 мм не привело к значимому увеличению производительности насоса, а наибольшие значения про изводительности можно получить для величины междискового зазора 0,4-0,5 мм. Заключение. Спроек тированный и изготовленный экспериментальный макет дискового насоса для перекачивания жидкости показал принципиальную возможность использовать такую модель в качестве системы для механиче ской поддержки сердца.