Mammalian splicing divergence is shaped by drift, buffering in trans, and a scaling law

Alternative splicing is ubiquitous, but the mechanisms underlying its pattern of evolutionary divergence across mammalian tissues are still underexplored. Here, we investigated the cis-regulatory divergences and their relationship with tissue-dependent trans-regulation in multiple tissues of an F1 hybrid between two mouse species. Large splicing changes between tissues are highly conserved and likely reflect functional tissue-dependent regulation. In particular, micro-exons frequently exhibit this pattern with high inclusion levels in the brain. Cis-divergence of splicing appears to be largely non-adaptive. Although divergence is in general associated with higher densities of sequence variants in regulatory regions, events with high usage of the dominant isoform apparently tolerate more mutations, explaining why their exon sequences are highly conserved but their intronic splicing site flanking regions are not. Moreover, we demonstrate that non-adaptive mutations are often masked in tissues where accurate splicing likely is more important, and experimentally attribute such buffering effect to trans-regulatory splicing efficiency.

REMOVAL OF BERYLLIUM (Be2+) FROM WATER SAMPLES BY SORPTION PROCESS: A REVIEW

Beryllium (Be2+) is an important industrial metal because of its unusual material properties: it is lighter than aluminium and six times stronger than steel. Beryllium is a strategic metal due to its low density combined with its strength, low neutron absorption, high melting point and high modulus of elasticity. Beryllium is often alloyed with other metals such as copper and is an important component of materials used in the aerospace, automotive, energy, defense, medical, and electronics industries. However, beryllium and its compounds are very toxic, especially to the lungs, skin, and eyes. Beryllium compounds are known carcinogens based on sufficient evidence of carcinogenicity in humans from human studies. Toxic effects of beryllium include immunotoxic, allergic, mutagenic, and carcinogenic effects. Mammalian tissues do not excrete it, so the effects are cumulative and can lead to death at high concentrations. Therefore, removal of Be2+ is important. In this review, the removal of Be2+ from water samples by sorption processes using different sorbents was summarized. The effects of process parameters on the removal of Be2+ have been summarized. The work discussed showed that ion exchange resins, various modified biosorbents metal oxides can be used for the removal of Be2+. The results showed that the pH of the solution has an important effect on the removal rate. Sorption kinetics vary from 3 minutes to 48h. When the functional groups are on the surface of the sorbent, the sorption process is rapid. However, if the surface of the sorbent is covered with oxides such as magnetite, it takes longer to reach equilibrium. Published work shows that more than 99 % of Be2+ can be removed from solution.

H2S Donors and Their Use in Medicinal Chemistry

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.

Ionophore Ability of Carnosine and Its Trehalose Conjugate Assists Copper Signal in Triggering Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Activation In Vitro

l-carnosine (β-alanyl-l-histidine) (Car hereafter) is a natural dipeptide widely distributed in mammalian tissues and reaching high concentrations (0.7–2.0 mM) in the brain. The molecular features of the dipeptide underlie the antioxidant, anti-aggregating and metal chelating ability showed in a large number of physiological effects, while the biological mechanisms involved in the protective role found against several diseases cannot be explained on the basis of the above-mentioned properties alone, requiring further research efforts. It has been reported that l-carnosine increases the secretion and expression of various neurotrophic factors and affects copper homeostasis in nervous cells inducing Cu cellular uptake in keeping with the key metal-sensing system. Having in mind this l-carnosine ability, here we report the copper-binding and ionophore ability of l-carnosine to activate tyrosine kinase cascade pathways in PC12 cells and stimulate the expression of BDNF. Furthermore, the study was extended to verify the ability of the dipeptide to favor copper signaling inducing the expression of VEGF. Being aware that the potential protective action of l-carnosine is drastically hampered by its hydrolysis, we also report on the behavior of a conjugate of l-carnosine with trehalose that blocks the carnosinase degradative activity. Overall, our findings describe a copper tuning effect on the ability of l-carnosine and, particularly its conjugate, to activate tyrosine kinase cascade pathways.

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases

Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.

Universal DNA Methylation Age Across Mammalian Tissues

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated over 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and Cilia to Regulate Ciliogenesis and Ciliary Protein Traffic

ELMODs are a family of three mammalian paralogs that display GTPase activating protein (GAP) activity towards a uniquely broad array of ADP-ribosylation factor (ARF) family GTPases that includes ARF-like (ARL) proteins. ELMODs are ubiquitously expressed in mammalian tissues, highly conserved across eukaryotes, and ancient in origin, being present in the last eukaryotic common ancestor. We described functions of ELMOD2 in immortalized mouse embryonic fibroblasts (MEFs) in the regulation of cell division, microtubules, ciliogenesis, and mitochondrial fusion. Here, using similar strategies with the paralogs ELMOD1 and ELMOD3, we identify novel functions and locations of these cell regulators and compare them to those of ELMOD2, allowing determination of functional redundancy among the family members. We found strong similarities in phenotypes resulting from deletion of either Elmod1 or Elmod3 and marked differences from those arising in Elmod2 deletion lines. Deletion of either Elmod1 or Elmod3 results in the decreased ability of cells to form primary cilia, loss of a subset of proteins from cilia, and accumulation of some ciliary proteins at the Golgi, predicted to result from compromised traffic from the Golgi to cilia. These phenotypes are reversed upon activating mutant expression of either ARL3 or ARL16, linking their roles to ELMOD1/3 actions.

Macrophage network dynamics depend on haptokinesis for optimal local surveillance

Macrophages are key immune cells with important roles for tissue surveillance in almost all mammalian organs. Cellular networks made up of many individual macrophages allow for optimal removal of dead cell material and pathogens in tissues. However, the critical determinants that underlie these population responses have not been systematically studied. Here, we investigated how cell shape and the motility of individual cells influences macrophage network responses in 3D culture settings and in mouse tissues. We show that surveying macrophage populations can tolerate lowered actomyosin contractility, but cannot easily compensate for a lack of integrin-mediated adhesion. Although integrins were dispensable for macrophage chemotactic responses, they were crucial to control cell movement and protrusiveness for optimal surveillance by a macrophage population. Our study reveals that β1 integrins are important for maintaining macrophage shape and network sampling efficiency in mammalian tissues, and sets macrophage motility strategies apart from the integrin-independent 3D migration modes of many other immune cell subsets.

Glutathione Transferases as Efficient Ketosteroid Isomerases

In addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present in some, but not all, mammals. The alpha class enzyme GST A3-3 in humans and the horse shows the highest catalytic efficiency with kcat/Km values of approximately 107 M−1s−1, ranking close to the most active enzymes known. The expression of GST A3-3 in steroidogenic tissues suggests that the enzyme has evolved to support the activity of 3β-hydroxysteroid dehydrogenase, which catalyzes the formation of 5-androsten-3,17-dione and 5-pregnen-3,20-dione that are substrates for the double-bond isomerization catalyzed by GST A3-3. The dehydrogenase also catalyzes the isomerization, but its kcat of approximately 1 s−1 is 200-fold lower than the kcat values of human and equine GST A3-3. Inhibition of GST A3-3 in progesterone-producing human cells suppress the formation of the hormone. Glutathione serves as a coenzyme contributing a thiolate as a base in the isomerase mechanism, which also involves the active-site Tyr9 and Arg15. These conserved residues are necessary but not sufficient for the ketosteroid isomerase activity. A proper assortment of H-site residues is crucial to efficient catalysis by forming the cavity binding the hydrophobic substrate. It remains to elucidate why some mammals, such as rats and mice, lack GSTs with the prominent ketosteroid isomerase activity found in certain other species. Remarkably, the fruit fly Drosophila melanogaster, expresses a GSTE14 with notable steroid isomerase activity, even though Ser14 has evolved as the active-site residue corresponding to Tyr9 in the mammalian alpha class.

How does Heparan Sulfate and COVID-19 Work?: An Overview

Globally, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) had infected over 3 million individuals and claimed many lives producing a global epidemic that necessitates the rapid development of therapeutic solutions. The ideal technique for quickly deploying well-characterized medicines against novel infections is known as drug repurposing. Several repurposable medicines are currently being tested to see if they may be used to treat COVID-19. Heparin, which is commonly utilized to reduce thrombotic events associated with COVID-19-induced disease, is one such promising drug. Heparansulphate is prevalently expressed in mammalian tissues. CoV-2 requires the helping cofactor heparansulphate (HS) on the cell surface: knocking down genes related in HS formation or treating cells with an HS mimic both prevent spike-mediated viral entrance. Heparin/HS binds directly to spike and promotes viral entrance by facilitating the attachment of spike-bearing viral particles to the cell surface. As documented with cell surface-bound heparansulphate, heparin binding to the open conformation of the spike structurally supports the state and may enhance ACE2 binding. Thus, heparansulphate could potentially be utilised to prevent SARS-CoV-2 transmission, based on available datas also consumption of heparansulphate during SARS-CoV-2 cellular entrance may play a role in the thrombotic events associated with COVID-19 infection. Furthermore, this study provides the findings on the mechanism(s) by which heparansulphate could slow the progression of SARS-CoV-2 infection. Keywords: COVID-19, HeparanSulphate, Spike Protiens