Proteomic identification of phosphorylation dependent Septin 7 interactors that drive dendritic spine formation

Septins are a family of cytoskeletal proteins that regulate several important aspects of neuronal development. Septin 7 (Sept7) is enriched at the base of dendritic spines in excitatory neurons and mediates both spine formation and spine-synapse maturation. Phosphorylation at a conserved C-terminal tail residue of Sept7 mediates its translocation into the dendritic spine head to allow spine-synapse maturation. The mechanistic basis for postsynaptic stability and compartmentalization conferred by phosphorylated Sept7, however, is not known. We report herein the proteomic identification of Sept7 phosphorylation dependent neuronal interactors. Using Sept7 C-terminal phosphopeptide pulldown and biochemical assays, we show that the 14-3-3 family of proteins specifically interact with Sept7 when phosphorylated at the T426 residue. Biochemically, we validate the interaction between Sept7 and 14-3-3 isoform gamma, and show that 14-3-3 gamma is also enriched in mature dendritic spine head. Further, we demonstrate that interaction of phosphorylated Sept7 with 14-3-3 protects it from dephosphorylation, as expression of a 14-3-3 antagonist significantly decreases phosphorylated Sept7 in neurons. This study identifies 14-3-3 proteins as an important physiological regulator of Sept7 function in neuronal development.

Inhibition of CMP-sialic acid transport by endogenous 5-methyl CMP

Nucleotide-sugar transporters (NSTs) transport nucleotide-sugar conjugates into the Golgi lumen where they are then used in the synthesis of glycans. We previously reported crystal structures of a mammalian NST, the CMP-sialic acid transporter (CST) (Ahuja and Whorton 2019). These structures elucidated many aspects of substrate recognition, selectivity, and transport; however, one fundamental unaddressed question is how the transport activity of NSTs might be physiologically regulated as a means to produce the vast diversity of observed glycan structures. Here, we describe the discovery that an endogenous methylated form of cytidine monophosphate (m5CMP) binds and inhibits CST. The presence of m5CMP in cells results from the degradation of RNA that has had its cytosine bases post-transcriptionally methylated through epigenetic processes. Therefore, this work not only demonstrates that m5CMP represents a novel physiological regulator of CST, but it also establishes a link between epigenetic control of gene expression and regulation of glycosylation.

Insolation And Covid‑19: Protection From The Aggressor

The article reviews the importance of insolation as a factor of prevention and containment of infectious diseases and epidemics. The authors consider insolation not as a mean of curing the Сoronavirus Disease (WHO fairly calls such possibility “a myth”) but as a means to lower the risks of dissemination of the infection, to reduce viability of the virus in the environment, to support human protective immune mechanisms affecting susceptibility of the population as a whole, severity and recovery time, i.e. both sanitary and hygienic and prevention factors of the COVID‑19 epidemic containment. Apart from the germicidal and virucidal sanitising effects of solar rays, the article reviews anti-epidemic capabilities of insolation as a microclimate factor and a psychological and physiological regulator of human protective capabilities as well as the insolation standards as a mechanism of development density regulation. It is impossible to efficiently combat massive dissemination of highly contagious infections without concerted utilisation of all available means and measures: both medical and preventive and organisational. The unprecedented mobilisation of healthcare systems and large-scale restrictive quarantine measures are under special attention of the society. This article reviews the importance of insolation as a universal natural anti-epidemic factor which is undeservedly placed in the end of the list of effective infection combating measures.

Conservative route to genome compaction in a miniature annelid

The causes and consequences of genome reduction in animals are unclear because our understanding of this process mostly relies on lineages with often exceptionally high rates of evolution. Here, we decode the compact 73.8-megabase genome of Dimorphilus gyrociliatus, a meiobenthic segmented worm. The D. gyrociliatus genome retains traits classically associated with larger and slower-evolving genomes, such as an ordered, intact Hox cluster, a generally conserved developmental toolkit and traces of ancestral bilaterian linkage. Unlike some other animals with small genomes, the analysis of the D. gyrociliatus epigenome revealed canonical features of genome regulation, excluding the presence of operons and trans-splicing. Instead, the gene-dense D. gyrociliatus genome presents a divergent Myc pathway, a key physiological regulator of growth, proliferation and genome stability in animals. Altogether, our results uncover a conservative route to genome compaction in annelids, reminiscent of that observed in the vertebrate Takifugu rubripes.

Endothelin XVI

Although 31 years have passed since the discovery of endothelin, that pioneering report, and the subsequent flood of influential studies elucidating its molecular and clinical details, have since paved the way for thousands of publications. They showed the promise of endothelin and the vast amount of work that remains to be done to fully unleash the potential this peptide possesses, both as a key physiological regulator and as a therapeutic target. Endothelin conferences and their proceedings have served as a host for many of these breakthrough studies, and in keeping with this fine tradition, Endothelin XVI will host novel research articles presented at the Sixteenth International Conference on Endothelin (ET-16) as its proceedings. On September 22–25, 2019, ET-16 was held at Kobe Port Oasis, Kobe, Japan, where numerous important discoveries were presented to the scientific community for the first time, many of which are compiled and published in this special issue. As the Editors of this special issue that comprises in-depth reviews, insightful editorials, and numerous original research articles discussing findings from various biomedical fields, we are extremely proud to present Endothelin XVI. We sincerely hope for the continued growth of this field for the benefit of the patients and the advancement of biomedical science.

Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

Cardiolipin, an essential mitochondrial physiological regulator, is synthesized from phosphatidic acid (PA) in the inner mitochondrial membrane (IMM). PA is synthesized in the endoplasmic reticulum and transferred to the IMM via the outer mitochondrial membrane (OMM) under mediation by the Ups1/Mdm35 protein family. Despite the availability of numerous crystal structures, the detailed mechanism underlying PA transfer between mitochondrial membranes remains unclear. Here, a model of Ups1/Mdm35-membrane interaction is established using combined crystallographic data, all-atom molecular dynamics simulations, extensive structural comparisons, and biophysical assays. The α2-loop, L2-loop, and α3 helix of Ups1 mediate membrane interactions. Moreover, non-complexed Ups1 on membranes is found to be a key transition state for PA transfer. The membrane-bound non-complexed Ups1/ membrane-bound Ups1 ratio, which can be regulated by environmental pH, is inversely correlated with the PA transfer activity of Ups1/Mdm35. These results demonstrate a new model of the fine conformational changes of Ups1/Mdm35 during PA transfer.

Inhibition of CMP-sialic acid transport by endogenous 5-methyl CMP

Nucleotide-sugar transporters (NSTs) transport nucleotide-sugar conjugates into the Golgi lumen where they are then used in the synthesis of glycans. We previously reported crystal structures of a mammalian NST, the CMP-sialic acid transporter (CST) (Ahuja and Whorton 2019). These structures elucidated many aspects of substrate recognition, selectivity, and transport; however, one fundamental unaddressed question is how the transport activity of NSTs might be physiologically regulated as a means to produce the vast diversity of observed glycan structures. Here, we describe the discovery that an endogenous methylated form of cytidine monophosphate (m5CMP) binds and inhibits CST. The presence of m5CMP in cells results from the degradation of RNA that has had its cytosine bases post-transcriptionally methylated through epigenetic processes. Therefore, this work not only demonstrates that m5CMP represents a novel physiological regulator of CST, but it also establishes a link between epigenetic control of gene expression and regulation of glycosylation.

Conservative route to genome compaction in a miniature annelid

SummaryThe causes and consequences of genome reduction in animals are unclear, because our understanding of this process mostly relies on lineages with often exceptionally high rates of evolution. Here, we decode the compact 73.8 Mb genome of Dimorphilus gyrociliatus, a meiobenthic segmented worm. The D. gyrociliatus genome retains traits classically associated with larger and slower-evolving genomes, such as an ordered, intact Hox cluster, a generally conserved developmental toolkit, and traces of ancestral bilaterian linkage. Unlike some other animals with small genomes, the analysis of the D. gyrociliatus epigenome revealed canonical features of genome regulation, excluding the presence of operons and trans-splicing. Instead, the gene dense D. gyrociliatus genome presents a divergent Myc pathway, a key physiological regulator of growth, proliferation, and genome stability in animals. Altogether, our results uncover a conservative route to genome compaction in annelids, reminiscent of that observed in the vertebrate Takifugu rubripes.

Metabiotics: prospects, challenges and opportunities

In this review authors discuss modern condition of treatment and prophylaxis of human metabolic diseases associated with microecological imbalance of intestinal symbiotic microbiota. Now the most frequently for these aims various probiotic nutrient additives and functional fermented foods prepared on the basis of living bacteria have been used. Unfortunately such probiotics have not possessed the real effectiveness and are not completely safe. Instead of traditional commercially available living probiotics the authors suggest to use novel microecological means (metabiotics) that are structural components of probiotic bactrerial strains, and/or their metabolites and/or signaling molecules with known chemical structure. Metabiotics can optimize host‑specific physiological, regulator, metabolic and/or hormone/behavior functions and reactions. Metabiotics possess some advantages in future personalized medicine because they have exact chemical structure, well dosed, safe and long shelf‑life.