Hbxip (Lamtor5) is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1

Hbxip, also named Lamtor5, has been well characterized as a transcriptional coactivator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5. Using Hbxip knockout embryonic stem cells (ESCs), we showed that depletion of Hbxip compromises the self-renewal of ESCs, with reduced expression of pluripotency genes, reduced cell proliferation, and decreased colony forming capacity. In addition, Hbxip-/- ESCs are defective in differentiation, particularly ectodermal and mesodermal differentiation. Consistently, Hbxip-/- epiblast fails to differentiate properly, indicated by sustained expression of Oct4 in E8.5 Hbxip-/- epiblast. Mechanistically, in ESCs, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, display differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/-, and p18-/- mice, lacking subunits of the Ragulator complex, also share similar phenotypes, embryonic lethality and retarded growth around E7-8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.

Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5′-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1–Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.

REGIONAL FEATURES OF INNOVATIVE DEVELOPMENT AND DIFFERENTIATION OF DIRECTIONS OF INNOVATION POLICY OF RUSSIA

In our manuscript we have made an attempt to study specific sides of Russian Federation’s innovative development, analyze its impact in economy growth and provide main ways of innovative policy realization in different types of regions. The method is based on partial abstraction from the unique properties of each region, thereby uniting them into homogeneous groups using k-means method. Further analysis of the determination of the main factor at the level of country was carried out using decision trees functions with the subsequent collection of OOB errors. Group analysis was carried out using regression analysis. As a result, the authors obtained five types of regions (with a high, above average, average, below average, low level of innovative development), provided an individual characteristic for each group regarding the innovation development and identified prerogative innovative factors that can be considered by the state as a criterion for differentiating state policy and regulation of the development of innovation policy.

Revisiting CFTR Interactions: Old Partners and New Players

Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key. With the availability of CFTR modulators, there is interest in comprehending which interactions are critical to rescue CFTR and which are altered by modulators or CFTR mutations. Here, the current knowledge on interactions that govern CFTR folding, processing, and stability is summarized. Furthermore, we describe protein complexes and signal pathways that modulate the CFTR function. Primary epithelial cells display a spatial control of the CFTR interactions and have become a common system for preclinical and personalized medicine studies. Strikingly, the novel roles of CFTR in development and differentiation have been recently uncovered and it has been revealed that specific CFTR gene interactions also play an important role in transcriptional regulation. For a comprehensive understanding of the molecular environment of CFTR, it is important to consider CFTR mutation-dependent interactions as well as factors affecting the CFTR interactome on the cell type, tissue-specific, and transcriptional levels.

Fruit and Vegetable Supplemented Diet Modulates the Pig Transcriptome and Microbiome after a Two-Week Feeding Intervention

A study was conducted to determine the effects of a diet supplemented with fruits and vegetables (FV) on the host whole blood cell (WBC) transcriptome and the composition and function of the intestinal microbiome. Nine six-week-old pigs were fed a pig grower diet alone or supplemented with lyophilized FV equivalent to half the daily recommended amount prescribed for humans by the Dietary Guideline for Americans (DGA) for two weeks. Host transcriptome changes in the WBC were evaluated by RNA sequencing. Isolated DNA from the fecal microbiome was used for 16S rDNA taxonomic analysis and prediction of metabolomic function. Feeding an FV-supplemented diet to pigs induced differential expression of several genes associated with an increase in B-cell development and differentiation and the regulation of cellular movement, inflammatory response, and cell-to-cell signaling. Linear discriminant analysis effect size (LEfSe) in fecal microbiome samples showed differential increases in genera from Lachnospiraceae and Ruminococcaceae families within the order Clostridiales and Erysipelotrichaceae family with a predicted reduction in rgpE-glucosyltransferase protein associated with lipopolysaccharide biosynthesis in pigs fed the FV-supplemented diet. These results suggest that feeding an FV-supplemented diet for two weeks modulated markers of cellular inflammatory and immune function in the WBC transcriptome and the composition of the intestinal microbiome by increasing the abundance of bacterial taxa that have been associated with improved intestinal health.

ATM- and ATR-Induced Primary Ciliogenesis Promotes Cisplatin Resistance in Pancreatic Ductal Adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. However, recent study showed that primary cilia regrowth contributes to the development of diverse kinase inhibitor resistance in lung cancer. We elucidated the role of regrowth primary ciliogenesis in PDAC chemoresistance and uncovered the underlying molecular mechanism.ResultsWe showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. ConclusionsCollectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

New gene markers involved in regulation of granulosa cells development and differentiation towards endodermal and epithelial tissues – a new insight into the stemness specificity of ovarian follicular cells

Maintaining of female fertility is strictly dependent on proper hormonal regulation. Granulosa cells (GCs) are components of ovarian follicles, and they are important in paracrine regulation of the ovary. Preovulatory follicle GCs are responsible for production of estrogens to the ovary microenvironment and lead to the LH surge. Proper functioning of GCs is necessary to ensure appropriate conditions for oocyte development, maturation, ovulation and its release to the oviduct. Long-term in vitro culture of GCs show significant stem-like characteristics. Understanding the molecular processes underlying GCs differentiation towards different cell lineages may reveal other possible stem cell markers. A transcriptomic analysis of short-term primary in vitro cultured GCs, which were isolated from porcine preovulatory follicles was the major focus of the study. The ontological groups herby considered are associated with endodermal and epithelial tissues. Results were and compare to freshly isolated GC cells. 6 the most reduced expression: HSD17B1, DAPL1, NEBL, MAL2, DAB1, ITM2A were chosen for analysis. These genes have been response for processes associated with GCs development and differentiation towards endodermal and epithelial tissues, which make them important for further consideration.

Insights into in vivo follicle formation: a review of in vitro systems

In vitro systems capable of reconstituting the process of mouse oogenesis are now being established to help develop further understanding of the mechanisms underlying oocyte/follicle development and differentiation. These systems could also help increase the production of useful livestock or genetically modified animals, and aid in identifying the causes of infertility in humans. Recently, we revealed, using an in vitro system for recapitulating oogenesis, that the activation of the estrogen signaling pathway induces abnormal follicle formation, that blocking estrogen-induced expression of anti-Müllerian hormone is crucial for normal follicle formation, and that the production of α-fetoprotein in fetal liver tissue is involved in normal in vivo follicle formation. In mouse fetuses, follicle formation is not carried out by factors within the ovaries but is instead orchestrated by distal endocrine factors. This review outlines findings from genetics, endocrinology, and in vitro studies regarding the factors that can affect the formation of primordial follicles in mammals.

Epigenetic Regulation during Primordial Germ Cell Development and Differentiation

Germline development varies significantly across metazoans. However, mammalian primordial germ cell (PGC) development has key conserved landmarks, including a critical period of epigenetic reprogramming that precedes sex-specific differentiation and gametogenesis. Epigenetic alterations in the germline are of unique importance due to their potential to impact the next generation. Therefore, regulation of, and by, the non-coding genome is of utmost importance during these epigenomic events. Here, we detail the key chromatin changes that occur during mammalian PGC development and how these interact with the expression of non-coding RNAs alongside broader epitranscriptomic changes. We identify gaps in our current knowledge, in particular regarding epigenetic regulation in the human germline, and we highlight important areas of future research.