Induction of Fas mediated caspase-8 independent apoptosis in immune cells by <i>Armigeres subalbatus</i> saliva

Background It is widely recognized that the introduction of saliva of bloodsucking arthropods at the site of pathogen transmission might play a central role in vector-borne infections. However, how the interaction between salivary components and the host immune system takes place and which physiological processes this leads to has yet to be investigated. Armigeres subalbatus is one of the prominent types of mosquitoes involved in the transmission of parasitic and viral diseases in humans and animals. Methodology/Principal Findings Using murine peritoneal macrophages and lymphocytes, and human peripheral mononuclear cells (PBMCs), this study shows that saliva of the female Ar. subalbatus induces apoptosis via interaction with the Fas receptor within a few hours but without activating caspase-8. The process further activates downstream p38 MAPK signaling, a cascade that leads to the induction of apoptosis in capase-3 dependent manner. We further illustrate that Ar. subalbatus saliva suppresses proinflammatory cytokines without changing IL-10 levels, which might happen as a result of apoptosis. Conclusions Our study shows for the first time that saliva-induced apoptosis is the leading phenomenon exerted by Ar. subalbatus that impede immune cells leading to the suppression of their effecter mechanism.</br

Competition of nuclear factor-erythroid 2 factors related transcription factor isoforms, Nrf1 and Nrf2, in antioxidant enzyme induction

AbstractAlthough the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) regulated expression of multiple antioxidant and cytoprotective genes through the electrophile responsive element (EpRE) is well established, interaction of Nrf2/EpRE with Nrf1, a closely-related transcription factor, is less well understood. Due to either proteolysis or alternative translation, Nrf1 has been found as proteins of varying size, p120, p95, and p65, which have been described as either activators of EpRE or competitive inhibitors of Nrf2. We investigated the effect of Nrf1 on EpRE-regulated gene expression using the catalytic and modifier subunits of glutamate cysteine ligase (GCLC and GCLM) as models and explored the potential role of Nrf1 in altering their expression in aging and upon chronic exposure to airborne nano-sized particulate matter (nPM). Nrf1 knockout resulted in the increased expression of GCLC and GCLM in human bronchial epithelial (HBE1) cells. Overexpression Nrf2 in combination with either p120 or p65 diminished or failed to further increase the GCLC- and GLCM-EpRE luciferase activity. All known forms of Nrf1 protein, remained unchanged in the lungs of mice with age or in response to nPM. Our study shows that Nrf1 could inhibit EpRE activity in vitro, whereas the precise role of Nrf1 in vivo requires further investigations. We conclude that Nrf1 may not be directly responsible for the loss of Nrf2-dependent inducibility of antioxidant and cytoprotective genes observed in aged animals

The evolution of synaptic and cognitive capacity: insights from the nervous system transcriptome of Aplysia

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Orvis, J., Albertin, C., Shrestha, P., Chen, S., Zheng, M., Rodriguez, C., Tallon, L., Mahurkar, A., Zimin, A., Kim, M., Liu, K., Kandel, E., Fraser, C., Sossin, W., & Abrams, T. The evolution of synaptic and cognitive capacity: insights from the nervous system transcriptome of Aplysia. Proceedings of the National Academy of Sciences of the United States of America, 119(28), (2022): e2122301119, https://doi.org/10.1073/pnas.2122301119.The gastropod mollusk Aplysia is an important model for cellular and molecular neurobiological studies, particularly for investigations of molecular mechanisms of learning and memory. We developed an optimized assembly pipeline to generate an improved Aplysia nervous system transcriptome. This improved transcriptome enabled us to explore the evolution of cognitive capacity at the molecular level. Were there evolutionary expansions of neuronal genes between this relatively simple gastropod Aplysia (20,000 neurons) and Octopus (500 million neurons), the invertebrate with the most elaborate neuronal circuitry and greatest behavioral complexity? Are the tremendous advances in cognitive power in vertebrates explained by expansion of the synaptic proteome that resulted from multiple rounds of whole genome duplication in this clade? Overall, the complement of genes linked to neuronal function is similar between Octopus and Aplysia. As expected, a number of synaptic scaffold proteins have more isoforms in humans than in Aplysia or Octopus. However, several scaffold families present in mollusks and other protostomes are absent in vertebrates, including the Fifes, Lev10s, SOLs, and a NETO family. Thus, whereas vertebrates have more scaffold isoforms from select families, invertebrates have additional scaffold protein families not found in vertebrates. This analysis provides insights into the evolution of the synaptic proteome. Both synaptic proteins and synaptic plasticity evolved gradually, yet the last deuterostome-protostome common ancestor already possessed an elaborate suite of genes associated with synaptic function, and critical for synaptic plasticity.This work was supported by NSF EAGER Award IOS-1255695 and NIH grant R01 MH 55880 grant to T.W.A.; by a Natural Sciences and Engineering Research Council of Canada Discovery grant and Canadian Institutes of Health Research project grant 340328 to W.S.; by funding from the HHMI to E.R.K.; and by a Hibbitt Early Career Fellowship to C.A. W.S. is James McGill Professor at McGill University

Small-scale proxies for large-scale Transformer training instabilities

Teams that have trained large Transformer-based models have reported training instabilities at large scale that did not appear when training with the same hyperparameters at smaller scales. Although the causes of such instabilities are of scientific interest, the amount of resources required to reproduce them has made investigation difficult. In this work, we seek ways to reproduce and study training stability and instability at smaller scales. First, we focus on two sources of training instability described in previous work: the growth of logits in attention layers (Dehghani et al., 2023) and divergence of the output logits from the log probabilities (Chowdhery et al., 2022). By measuring the relationship between learning rate and loss across scales, we show that these instabilities also appear in small models when training at high learning rates, and that mitigations previously employed at large scales are equally effective in this regime. This prompts us to investigate the extent to which other known optimizer and model interventions influence the sensitivity of the final loss to changes in the learning rate. To this end, we study methods such as warm-up, weight decay, and the $\mu$Param (Yang et al., 2022), and combine techniques to train small models that achieve similar losses across orders of magnitude of learning rate variation. Finally, to conclude our exploration we study two cases where instabilities can be predicted before they emerge by examining the scaling behavior of model activation and gradient norms

Damping of tropical instability waves caused by the action of surface currents on stress

Ocean eddies and fronts affect surface stress via two mechanisms: (1) ocean surface currents altering the relative motion between air and sea and, hence, the stress fields and (2) ocean sea surface temperature (SST) gradients forcing changes in stability and near-surface winds. In this paper, we quantify the first effect and how it impacts Tropical Instability Waves (TIW) in the eastern Pacific. High-resolution satellite data and a regional coupled model are used to distinguish between stress changes due to the surface currents and those due to the changes in stability and near-surface winds. It is found that both mechanisms affect the surface stress curl, but they do so at different latitudes, allowing for their effect on Ekman pumping to be distinguished. The Ekman pumping due to the surface current effect alone, leads to significant damping of the TIWs. In terms of the eddy kinetic energy, the inclusion of surface current in the stress leads to decay with an e-folding time comparable with the period of the TIWs. It is, thus, an important damping mechanism to be included in ocean and coupled ocean-atmosphere models

Acute Respiratory Distress Syndrome Induced by a Swine 2009 H1N1 Variant in Mice

Background: Acute respiratory distress syndrome (ARDS) induced by pandemic 2009 H1N1 influenza virus has been widely reported and was considered the main cause of death in critically ill patients with 2009 H1N1 infection. However, no animal model has been developed for ARDS caused by infection with 2009 H1N1 virus. Here, we present a mouse model of ARDS induced by 2009 H1N1 virus. Methodology Principal Findings: Mice were inoculated with A/swine/Shandong/731/2009 (SD/09), which was a 2009 H1N1 influenza variant with a G222D mutation in the hemagglutinin. Clinical symptoms were recorded every day. Lung injury was assessed by lung water content and histopathological observation. Arterial blood gas, leukocyte count in the bronchial alveolar lavage fluid and blood, virus titers, and cytokine levels in the lung were measured at various times post-inoculation. Mice infected with SD/09 virus showed typical ARDS symptoms characterized by 60 % lethality on days 8–10 postinoculation, highly edematous lungs, inflammatory cellular infiltration, alveolar and interstitial edema, lung hemorrhage, progressive and severe hypoxemia, and elevated levels of proinflammatory cytokines and chemokines. Conclusions/Significance: These results suggested that we successfully established an ARDS mouse model induced by a virulent 2009 H1N1 variant without previous adaptation, which may be of benefit for evaluating the pathogenesis or therapy of human ARDS caused by 2009 H1N1 virus

PDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and Metabolism

The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease

RNA-Seq Analyses Generate Comprehensive Transcriptomic Landscape and Reveal Complex Transcript Patterns in Hepatocellular Carcinoma

RNA-seq is a powerful tool for comprehensive characterization of whole transcriptome at both gene and exon levels and with a unique ability of identifying novel splicing variants. To date, RNA-seq analysis of HBV-related hepatocellular carcinoma (HCC) has not been reported. In this study, we performed transcriptome analyses for 10 matched pairs of cancer and non-cancerous tissues from HCC patients on Solexa/Illumina GAII platform. On average, about 21.6 million sequencing reads and 10.6 million aligned reads were obtained for samples sequenced on each lane, which was able to identify >50% of all the annotated genes for each sample. Furthermore, we identified 1,378 significantly differently expressed genes (DEGs) and 24, 338 differentially expressed exons (DEEs). Comprehensive function analyses indicated that cell growth-related, metabolism-related and immune-related pathways were most significantly enriched by DEGs, pointing to a complex mechanism for HCC carcinogenesis. Positional gene enrichment analysis showed that DEGs were most significantly enriched at chromosome 8q21.3–24.3. The most interesting findings were from the analysis at exon levels where we characterized three major patterns of expression changes between gene and exon levels, implying a much complex landscape of transcript-specific differential expressions in HCC. Finally, we identified a novel highly up-regulated exon-exon junction in ATAD2 gene in HCC tissues. Overall, to our best knowledge, our study represents the most comprehensive characterization of HBV-related HCC transcriptome including exon level expression changes and novel splicing variants, which illustrated the power of RNA-seq and provided important clues for understanding the molecular mechanisms of HCC pathogenesis at system-wide levels