The Gut Microbiota and Epigenetics

The human gut microbiota presents a strong influence on health and disease development. Metagenomic analysis has revealed the importance of the interaction between the genomes of food, gut microbiota and the host. Also, the establishment of humanized mouse gut microbiota in appropriate animal models has further contributed to the understanding of its function. The composition of the gut microbiota presents a significant impact on the risk of disease development supported by findings of substantial individual variations. Many low molecular weight bacterial substances have been indicated to affect chromatin remodeling, regulation of apoptosis, cellular differentiation and inflammation. The gut microbiota has also been linked to the etiology of cancer because of how it can alter dietary exposures. Furthermore, microbial metabolites have been associated with epigenetic modifications, reversible heritable changes in gene expression without alterations in the primary DNA sequence, which may influence the risk of various cancers and other diseases. As many microbial metabolites are absorbed into systemic circulation, gene expression might also be affected in distal regions of the gut. Therefore, the interaction of dietary intake, gut microbiota and epigenetic modifications plays an important role in disease risk, development and preventio

Novel Semliki Forest virus vectors with reduced cytotoxicity and temperature sensitivity for long-term enhancement of transgene expression.

Alphaviral vectors inhibit host cell protein synthesis and are cytotoxic. To overcome these limitations, we modified the nonstructural protein-2 (nsP2) gene in the Semliki Forest virus (SFV) vector, pSFV1. Packaging of SFV replicons with two point mutations in nsP2 resulted in high-titer recombinant SFV(PD) particles. SFV(PD) led to more efficient host cell protein synthesis, exhibited reduced cytotoxicity and improved cell survival, and allowed greater and prolonged transgene expression than the original vector, SFV. In dissociated hippocampal neurons and organotypic rat hippocampal slices, SFV(PD) infection preserved neuronal morphology and synaptic function more efficiently than SFV. Combination of the two point mutations with a replication-persistent mutation in nsP2 resulted in a highly temperature-sensitive vector, SFV(PD713P), which efficiently transduced neurons in hippocampal slice cultures. At 31 °C, SFV(PD713P) allowed continuous transgene expression in BHK cells, at amounts comparable to SFV(PD). These new SFV mutants are expected to substantially broaden the application of alphaviral vectors in neurons and other mammalian cells

Radiometric validation of age, growth, and longevity for the blackgill rockfish (Sebastes melanostomus)

As nearshore fish populations decline, many commercial fishermen have shifted fishing effort to deeper continental slope habitats to target fishes for which biological information is limited. One such fishery that developed in the northeastern Pacific Ocean in the early 1980s was for the blackgill rockfish (Sebastes melanostomus), a deep-dwelling (300−800 m) species that congregates over rocky pinnacles, mainly from southern California to southern Oregon. Growth zone-derived age estimates from otolith thin sections were compared to ages obtained from the radioactive disequilibria of 210Pb, in relation to its parent, 226Ra, in otolith cores of blackgill rockfish. Age estimates were validated up to 41 years, and a strong pattern of agreement supported a longevity exceeding 90 years. Age and length data fitted to the von Bertalanffy growth function indicated that blackgill rockfish are slow-growing (k= 0.040 females, 0.068 males) and that females grow slower than males, but reach a greater length. Age at 50% maturity, derived from previously published length-at-maturity estimates, was 17 years for males and 21 years for females. The results of this study agree with general life history traits already recognized for many Sebastes species, such as long life, slow growth, and late age at maturation. These traits may undermine the sustainability of blackgill rockfish populations when heavy fishing pressure, such as that which occurred in the 1980s, is applied

Microbial U isotope fractionation depends on U(VI) reduction rate

U isotope fractionation may serve as an accurate proxy for U(VI) reduction in both modern and ancient environments, if the systematic controls on the magnitude of fractionation (ε) are known. We model the effect of U(VI) reduction kinetics on U isotopic fractionation during U(VI) reduction by a novel Shewanella isolate, Shewanella sp. (NR), in batch incubations. The measured ε values range from 0.96 ± 0.16 to 0.36 ± 0.07‰ and are strongly dependent on the U(VI) reduction rate. The ε decreases with increasing reduction rate constants normalized by cell density and initial U(VI). Reactive transport simulations suggest that the rate dependence of ε is due to a two-step process, where diffusive transport of U(VI) from the bulk solution across a boundary layer is followed by enzymatic reduction. Our results imply that the spatial decoupling of bulk U(VI) solution and enzymatic reduction should be taken into account for interpreting U isotope data from the environment

Predicting COVID-19—Comorbidity Pathway Crosstalk-Based Targets and Drugs: Towards Personalized COVID-19 Management

It is well established that pre-existing comorbid conditions such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), cancers, and chronic obstructive pulmonary disease (COPD) are associated with increased severity and fatality of COVID-19. The increased death from COVID-19 is due to the unavailability of a gold standard therapeutic and, more importantly, the lack of understanding of how the comorbid conditions and COVID-19 interact at the molecular level, so that personalized management strategies can be adopted. Here, using multi-omics data sets and bioinformatics strategy, we identified the pathway crosstalk between COVID-19 and diabetes, hypertension, CVDs, CKDs, and cancers. Further, shared pathways and hub gene-based targets for COVID-19 and its associated specific and combination of comorbid conditions are also predicted towards developing personalized management strategies. The approved drugs for most of these identified targets are also provided towards drug repurposing. Literature supports the involvement of our identified shared pathways in pathogenesis of COVID-19 and development of the specific comorbid condition of interest. Similarly, shared pathways- and hub gene-based targets are also found to have potential implementations in managing COVID-19 patients. However, the identified targets and drugs need further careful evaluation for their repurposing towards personalized treatment of COVID-19 cases having pre-existing specific comorbid conditions we have considered in this analysis. The method applied here may also be helpful in identifying common pathway components and targets in other disease-disease interactions too

Would New SARS-CoV-2 Variants Change the War against COVID-19?

The scientific, private, and industrial sectors use a wide variety of technological platforms available to achieve protection against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), including vaccines. However, the virus evolves continually into new highly virulent variants, which might overcome the protection provided by vaccines and may re-expose the population to infections. Mass vaccinations should be continued in combination with more or less mandatory non-pharmaceutical interventions. Therefore, the key questions to be answered are: (i) How to identify the primary and secondary infections of SARS-CoV-2? (ii) Why are neutralizing antibodies not long-lasting in both cases of natural infections and post-vaccinations? (iii) Which are the factors responsible for this decay in neutralizing antibodies? (iv) What strategy could be adapted to develop long-term herd immunity? (v) Is the Spike protein the only vaccine target or is a vaccine cocktail better

Associations and Disease-Disease Interactions of COVID-19 with Congenital and Genetic Disorders: A Comprehensive Review

Since December 2019, the COVID-19 pandemic, which originated in Wuhan, China, has resulted in over six million deaths worldwide. Millions of people who survived this SARS-CoV-2 infection show a number of post-COVID complications. Although, the comorbid conditions and post-COVID complexities are to some extent well reviewed and known, the impact of COVID-19 on pre-existing congenital anomalies and genetic diseases are only documented in isolated case reports and case series, so far. In the present review, we analyzed the PubMed indexed literature published between December 2019 and January 2022 to understand this relationship from various points of view, such as susceptibility, severity and heritability. Based on our knowledge, this is the first comprehensive review on COVID-19 and its associations with various congenital anomalies and genetic diseases. According to reported studies, some congenital disorders present high-risk for developing severe COVID-19 since these disorders already include some comorbidities related to the structure and function of the respiratory and cardiovascular systems, leading to severe pneumonia. Other congenital disorders rather cause psychological burdens to patients and are not considered high-risk for the development of severe COVID-19 infection

COVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity

The COVID-19 pandemic has been the focus of research the past two years. The major breakthrough was made by discovering pathways related to SARS-CoV-2 infection through cellular interaction by angiotensin-converting enzyme (ACE2) and cytokine storm. The presence of ACE2 in lungs, intestines, cardiovascular tissues, brain, kidneys, liver, and eyes shows that SARS-CoV-2 may have targeted these organs to further activate intracellular signalling pathways that lead to cytokine release syndrome. It has also been reported that SARS-CoV-2 can hijack coatomer protein-I (COPI) for S protein retrograde trafficking to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), which, in turn, acts as the assembly site for viral progeny. In infected cells, the newly synthesized S protein in endoplasmic reticulum (ER) is transported first to the Golgi body, and then from the Golgi body to the ERGIC compartment resulting in the formation of specific a motif at the C-terminal end. This review summarizes major events of SARS-CoV-2 infection route, immune response following host-cell infection as an important factor for disease outcome, as well as comorbidity issues of various tissues and organs arising due to COVID-19. Investigations on alterations of host-cell machinery and viral interactions with multiple intracellular signaling pathways could represent a major factor in more effective disease management

Can COVID-19 Vaccines Induce Premature Non-Communicable Diseases: Where Are We Heading to?

According to the WHO, as of January 2023, more than 850 million cases and over 6.6 million deaths from COVID-19 have been reported worldwide. Currently, the death rate has been reduced due to the decreased pathogenicity of new SARS-CoV-2 variants, but the major factor in the reduced death rates is the administration of more than 12.8 billion vaccine doses globally. While the COVID-19 vaccines are saving lives, serious side effects have been reported after vaccinations for several premature non-communicable diseases (NCDs). However, the reported adverse events are low in number. The scientific community must investigate the entire spectrum of COVID-19-vaccine-induced complications so that necessary safety measures can be taken, and current vaccines can be re-engineered to avoid or minimize their side effects. We describe in depth severe adverse events for premature metabolic, mental, and neurological disorders; cardiovascular, renal, and autoimmune diseases, and reproductive health issues detected after COVID-19 vaccinations and whether these are causal or incidental. In any case, it has become clear that the benefits of vaccinations outweigh the risks by a large margin. However, pre-existing conditions in vaccinated individuals need to be taken into account in the prevention and treatment of adverse events