Developmental patterning function of GNOM ARF-GEF mediated from the plasma membrane

The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study redefine the current notions of GN function. We show that GN, but not GNL1, localizes to the PM at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that PM is the major place of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations. A study of GN-GNL1 chimeric ARF-GEFs indicate that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps towards the elucidation of the mechanism underlying unique cellular and development functions of GN.

Cre-Dependent Anterograde Transsynaptic Labeling and Functional Imaging in Zebrafish Using VSV With Reduced Cytotoxicity

The small size and translucency of larval zebrafish (Danio rerio) have made it a unique experimental system to investigate whole-brain neural circuit structure and function. Still, the connectivity patterns between most neuronal types remain mostly unknown. This gap in knowledge underscores the critical need for effective neural circuit mapping tools, especially ones that can integrate structural and functional analyses. To address this, we previously developed a vesicular stomatitis virus (VSV) based approach called Tracer with Restricted Anterograde Spread (TRAS). TRAS utilizes lentivirus to complement replication-incompetent VSV (VSVΔG) to allow restricted (monosynaptic) anterograde labeling from projection neurons to their target cells in the brain. Here, we report the second generation of TRAS (TRAS-M51R), which utilizes a mutant variant of VSVΔG [VSV(M51R)ΔG] with reduced cytotoxicity. Within the primary visual pathway, we found that TRAS-M51R significantly improved long-term viability of transsynaptic labeling (compared to TRAS) while maintaining anterograde spread activity. By using Cre-expressing VSV(M51R)ΔG, TRAS-M51R could selectively label excitatory (vglut2a positive) and inhibitory (gad1b positive) retinorecipient neurons. We further show that these labeled excitatory and inhibitory retinorecipient neurons retained neuronal excitability upon visual stimulation at 5–8 days post fertilization (2–5 days post-infection). Together, these findings show that TRAS-M51R is suitable for neural circuit studies that integrate structural connectivity, cell-type identity, and neurophysiology.

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer

Comprehensive sequencing of patient tumors reveals numerous genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative High Throughput differential Screening (qHT-dS) platform. Coupling of highly sensitive BRET biosensors with miniaturized co-expression in an ultra-HTS format allows large-scale monitoring of interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. Screening of 13,392 interactions with 1,474,560 data points revealed a landscape of gain-of-interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E-KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

Modeling of COVID-19 Transmission Dynamics on US Population: Inter-transfer Infection in Age Groups, Mutant Variants, and Vaccination Strategies

The in-depth understanding of the dynamics of COVID-19 transmission among different age groups is of great interest for governments and health authorities so that strategies can be devised to reduce the pandemic's detrimental effects. We developed the SIRDV-Virulence epidemiological model based on a population balance equation to study the effect of mutants of the virus and the effect of vaccination strategies on mitigating the transmission among the population in the United States. Based on the available data from the Centers for Disease Control and Prevention (CDC), we obtain the key parameters governing the dynamic evolution of the spread of the COVID-19 pandemic. In the context studied, the results show that a large fraction of infected cases comes from the adult and children populations in the presence of a mutant variant of COVID-19 with high infection rates. We further investigate the optimum vaccine distribution strategy among different age groups. Given the current situation in the United States, the results show that prioritizing children and adult vaccinations over that of seniors can contain the spread of the active cases, thereby preventing the healthcare system from being overwhelmed and minimizing subsequent deaths. The model suggests that the only option to curb the effects of this pandemic is to reduce the population of unvaccinated individuals. A higher fraction of 'Anti/Non-vaxxers' can lead to the resurgence of the pandemic.

Second wave of COVID-19 pandemic is depressing: is there any hope?

We read the article detailing the impact on the mental health amongst the residents of Assam during COVID-19 lockdown with a lot of anguish and concern. The rise of second wave of COVID-19 pandemic is more unforgiving due to the high infectivity of the double mutant variant. The deadly cost of ignorance has compounded the misery aggravating the mental imbalance.Hope seems elusive during the evolving crisis with highly constrained healthcare infrastructure, resources and high fatality.

Understanding the Psychological Issues in The Geriatric Population in The Times of COVID-19- A Critical Review from The Lens of a Psychologist

The first wave of the Covid-19 pandemic hit India in January 2020 when the first confirmed case was reported at a general hospital of Kerala. Since then, the number of reported cases kept on increasing at a steady pace, we saw deaths, rise, fall and stagnancy in the number of cases in India while the figures of deaths reported remained worrisome. While India is currently battling with the deadly double mutant variant of the virus, the present critical review is an attempt to study, analyse and understand the need of catering to the needs of geriatric population, especially in a collectivistic culture like India, where elderly issues, psychological difficulties, and coping mechanism takes a back seat while there is constant fear of leading a healthy life especially in the testing times of a national pandemic, COVID-19. This critical review is an attempt to highlight the various issues dealt by the average Indian elderly, their lifestyle after retirement, sustaining means of livelihood in times of uncertainty and keeping a positive mindset for a better quality of life. This paper also attempts to enumerate few strategies required to inculcate a sense of life satisfaction and improved quality of life among the elderly.

Role of N501Y Mutation in SARS-CoV-2 Spike Protein Structure

It has been more than a year since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found. This coronavirus has infected more than 110 million people worldwide by the end of February, 2021, and several virulent as well as more spreadable mutant forms of SARS-CoV-2 have emerged subsequently. In the latter group, three variants B.1.1.7, B.1.351, and P1 lineages, have been reported. Using computer simulation, the present paper investigates the structural differences between the wild type SARS-CoV-2 spike protein and its Asn501Tyr (N501Y) mutant variant. Time-based structural changes between the receptor binding domains of these two species are also examined. The N501Y mutation is common to all the three aforesaid mutant variants.

The Uncovered Function of the Drosophila GBA1a-Encoded Protein

Human GBA1 encodes lysosomal acid β-glucocerebrosidase (GCase), which hydrolyzes cleavage of the beta-glucosidic linkage of glucosylceramide (GlcCer). Mutations in this gene lead to reduced GCase activity, accumulation of glucosylceramide and glucosylsphingosine, and development of Gaucher disease (GD). Drosophila melanogaster has two GBA1 orthologs. Thus far, GBA1b was documented as a bone fide GCase-encoding gene, while the role of GBA1a encoded protein remained unclear. In the present study, we characterized a mutant variant of the fly GBA1a, which underwent ERAD and mildly activated the UPR machinery. RNA-seq analyses of homozygous mutant flies revealed upregulation of inflammation-associated as well as of cell-cycle related genes and reduction in programmed cell death (PCD)-associated genes, which was confirmed by qRT-PCR. We also observed compromised cell death in the midgut of homozygous larvae and a reduction in pupation. Our results strongly indicated that GBA1a-encoded protein plays a role in midgut maturation during larvae development.