Biology subjects

Xu, C.

Publications and source records attributed to Xu, C..

At least 253 records · Page 14Linked to original sources

bioRxiv2022

Speech-In-Noise Comprehension is Improved When Viewing a Deep-Neural-Network-Generated Talking Face

Listening in a noisy environment is challenging, but many previous studies have demonstrated that comprehension of speech can be substantially improved by looking at the talkers face. We recently developed a deep neural network (DNN) based system that generates movies of a talking face from speech audio and a single face image. In this study, we aimed to quantify the benefits that such a system can bring to speech comprehension, especially in noise. The target speech audio was masked with signal to noise ratios of -9, -6, -3, and 0 dB and was presented to subjects in three audio-visual (AV) stimulus conditions: 1) synthesized AV: audio with the synthesized talking face movie; 2) natural AV: audio with the original movie from the corpus; and 3) audio-only: audio with a static image of the talker. Subjects were asked to type the sentences they heard in each trial and keyword recognition was quantified for each condition. Overall, performance in the synthesized AV condition fell approximately halfway between the other two conditions, showing a marked improvement over the audio-only control but still falling short of the natural AV condition. Every subject showed some benefit from the synthetic AV stimulus. The results of this study support the idea that a DNN-based model that generates a talking face from speech audio can meaningfully enhance comprehension in noisy environments, and has the potential to be used as a "visual hearing aid."

neuroscience↗

bioRxiv2022

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimers Disease

Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

neuroscience↗

bioRxiv2022

Structural insights into AT-rich DNA recognition by SALL family proteins

Spalt-like 4 (SALL4) plays an essential role in controlling the pluripotent property of embryonic stem cells (ESCs) via binding to AT-rich regions of genomic DNA. Here we present crystal structures of the the zinc finger cluster 4 (ZFC4) domain of SALL4 (SALL4ZFC4) bound with different double stranded DNAs containing a conserved AT-rich motif. In the structures, two zinc fingers of SALL4ZFC4 coordinatively recognize an AATA tetranucleotide. We also solved the DNA-bound structures of SALL3ZFC4 and SALL4ZFC1. These structures illuminate a common recognition mode for AT-rich DNA by the SALL family proteins. The DNA binding activity is essential for SALL4 function as DNA-binding defective mutants of mouse Sall4 failed to repress aberrant gene expression in Sall4-/- mESCs. Thus, these analyses provide new insights into the mechanisms of action underlying SALL family in controlling cell fate via preferentially targeted to AT-rich sites within genomic DNAs during cell differentiation.

biochemistry↗

bioRxiv2022

Quantifying the Human Cost of Global Warming

The costs of climate change are often estimated in monetary terms1,2 but this raises ethical issues3. Here we express them in terms of numbers of people left outside the human climate niche4 - defined as the historically highly-conserved distribution of relative human population density with respect to mean annual temperature (MAT). We show that climate change has already put [~]8% of people (>500 million) outside this niche. By end-of-century (2080-2100), current policies leading to around 2.7 {degrees}C global warming5-9 could leave one third (21-42% or 2-4 billion) of a future 9.5 billion population outside the niche. Limiting global warming to 1.5 {degrees}C could halve this exposure, reducing it by [~]1.5 billion people. For the two countries with the most people affected - India and Nigeria - reducing global warming from 2.7 to 1.5 {degrees}C results in a >6-fold decrease in the population exposed to unprecedented temperatures, MAT [≥]29 {degrees}C. The lifetime emissions of [~]3.5 global average citizens today (or [~]1.2 average US citizens) expose 1 future person to MAT [≥]29 {degrees}C by end-of-century. That person comes from a place where emissions today are around half of the global average. These results highlight the need for more decisive policy action to limit the human costs and inequities of climate change.

ecology↗

bioRxiv2022

Parallel analysis of RNA ends reveals global microRNA-mediated target RNA cleavage in maize

MicroRNAs (miRNAs) are endogenous 20-to 24-nucleotide (nt) noncoding RNAs that play important regulatory roles in many biological processes in eukaryotes. miRNAs modulate the expression of target genes at the post-transcriptional level by transcript cleavage or translational inhibition. Identification of miRNA target genes have been extensively investigated in Arabidopsis and rice, but an in-depth global analysis of miRNA-mediated target regulation is still lacking in maize. Here, we report a transcriptome-wide identification of miRNA targets by analyzing Parallel Analysis of RNA Ends (PARE) datasets derived from nine different tissues at five developmental stages of the maize (Zea mays L.) B73 cultivar. 246 targets corresponding to 60 miRNAs from 25 families were identified, including transcription factors and other genes. In addition, PARE analysis revealed that miRNAs guide specific target transcript cleavage in a tissue-preferential manner. Interestingly, primary transcripts of MIR159c and MIR169e were found to be cleaved by mature miR159 and miR169, respectively, indicating a positive-feedback regulatory mechanism in miRNA biogenesis. Moreover, several new miRNA-target gene pairs involved in seed germination were identified and experimentally validated. Our PARE analyses generated a wide and detailed miRNA-target interaction atlas, which provides a valuable resource for investigating the roles of miRNAs and their targets in maize.

plant biology↗

bioRxiv2022

Respiratory mucosal vaccination of peptide-poloxamine-DNA nanoparticles provides complete protection against lethal SARS-CoV-2 challenge

The ongoing SARS-CoV-2 pandemic represents a brutal reminder of the continual threat of mucosal infectious diseases. Mucosal immunity may provide robust protection at the predominant sites of SARS-CoV-2 infection. However, it remains unclear whether respiratory mucosal administration of DNA vaccines could confer protective immune responses against SARS-CoV-2 challenge due to the insurmountable barriers posed by the airway. Here, we applied self-assembled peptide-poloxamine nanoparticles with mucus-penetrating properties for pulmonary inoculation of a COVID-19 DNA vaccine (pSpike/PP-sNp). Not only displays the pSpike/PP-sNp superior gene-transfection and favorable biocompatibility in the mouse airway, but pSpike/PP-sNp promotes a tripartite immunity consisting of systemic, cellular and mucosal immune responses that are characterized by mucosal IgA secretion, high levels of neutralizing antibodies, and resident memory phenotype T-cell responses in the lungs of mice. Most importantly, pSpike/PP-sNp completely eliminates SARS-CoV-2 infection in both upper and lower respiratory tracts and enables 100% survival rate of mice following lethal SARS-CoV-2 challenge. Our findings indicate PP-sNp might be a promising platform in mediating DNA vaccines to elicit all-around mucosal immunity against SARS-CoV-2.

immunology↗

bioRxiv2022

APOE Expression and Secretion are Modulated by Copper-Dependent and -Independent Mitochondrial Dysfunction

Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimers disease risk factor apolipoprotein E (APOE) and other secretome components. This upregulation of secretory proteins was of a similar extent as modifications to the mitochondrial annotated proteome. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain, elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.

cell biology↗

bioRxiv2022

Adipokine C1q/Tumor necrosis factor-related protein 3 (CTRP3) Attenuates Intestinal Inflammation via Histone Deacetylase Sirtuin 1 (SIRT1)/NF-κB Signaling

BACKGROUND & AIMSThe adipokine C1q/tumor necrosis factor-related protein 3 (CTRP3) has anti-inflammatory effects in several non-intestinal disorders. Although CTRP3 is reduced in the serum of patients with inflammatory bowel disease (IBD), its function in IBD has not been established. We aimed to elucidate the function of CTRP3 and related molecular mechanisms in intestinal inflammation using a colitis model of genetically-modified CTRP3 mice and intestinal epithelial tissue from patients with Crohns disease (CD), one of the two main forms of IBD. METHODSCTRP3 knockout (KO) and overexpressing transgenic (Tg) mice along with their corresponding wild-type (WT) littermates were subjected to drinking water containing dextran sulfate sodium (DSS) for 6-10 days to induce acute colitis. Mouse colitis symptoms and histological data were analyzed. CTRP3-mediated signaling was examined in the intestinal tissue of mice and patients with CD. RESULTSCTRP3 mRNA and protein were detected in murine and human intestinal epithelial cells, as well as in murine intestinal smooth muscle cells and mesenteric fat. In DSS-induced acute colitis models, CTRP3 KO mice developed more severe colitis than their WT littermates, while CTRP3 overexpressing Tg mice developed less severe colitis than their WT littermates. In both water- and DSS-treated CTRP3 KO mice, reduced CTRP3 levels correlated with decreased levels of Sirtuin 1 (SIRT1), a histone deacetylase, increased levels of phosphorylated nuclear factor kappa B (NF-{kappa}B) subunit p65, resulting in increased expression of pro-inflammatory cytokines tumor necrosis factor- (TNF-) and interleukin 6 (IL-6). The results from CTRP3 Tg mice mirrored those from CTRP3 KO mice in most respects. This CTRP3/SIRT1/NF-{kappa}B relationship was also observed in the intestinal epithelial tissue of patients with active and inactive CD. CONCLUSIONSCTRP3 expression levels correlate negatively with intestinal inflammation in mouse colitis models and CD patients. CTRP3 attenuates intestinal inflammation via SIRT1/NF-{kappa}B signaling to suppress pro-inflammatory cytokines in mouse colitis models and patients with IBD. The manipulation of CTRP3 signaling, including through the use of SIRT1 agonists, may offer translational potential in the treatment of IBD. WHAT YOU NEED TO KNOWO_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSAdipokine C1q/tumor necrosis factor-related protein 3 (CTRP3) is a novel adipokine with known non-intestinal anti-inflammatory effects. CTRP3 is reduced in the serum of patients with inflammatory bowel disease (IBD). However, little is known about whether and how CTRP3 influences intestinal inflammation in IBD. NEW FINDINGSCTRP3 mRNA and protein were detected in murine and human intestinal epithelial cells, as well as in murine intestinal smooth muscle cells and mesenteric fat. CTRP3 deletion was associated with more severe acute dextran sulfate sodium (DSS)-induced colitis, while CTRP3 overexpression was associated with less severe colitis. In both mice and humans, reduced CTRP3 levels correlated with reduced levels of the histone deacetylase Sirtuin 1 (SIRT1), resulting in the up-regulation of phosphorylated nuclear factor-kappa B (NF-{kappa}B) p65 and pro-inflammatory cytokine synthesis. LIMITATIONSThis study was performed using genetically modified mice and human tissue samples. An acute DSS-induced colitis model was used; additional mouse colitis models designed to mimic other aspects of IBD will be examined in future studies. The specific source of the secreted CTRP3 protein which influences intestinal inflammation is yet to be identified. The use of recombinant CTRP3 protein supplementation and SIRT1 agonists to mitigate intestinal inflammation also requires further study. IMPACTCTRP3 is a novel anti-inflammatory adipokine that attenuates intestinal inflammation in colitis mouse models and intestinal epithelial tissue of patients with IBD. CTRP3 attenuates intestinal inflammation by activating SIRT1, which suppresses the pro-inflammatory transcriptional activity of phosphorylated NF-{kappa}B p65. CTRP3 and SIRT1 agonists have potential as novel IBD drug targets.

pathology↗

bioRxiv2022

Induction of a CD8 T cell intrinsic DNA damage and repair response is associated with clinical response to PD-1 blockade in uterine cancer.

Despite the success of immune checkpoint blockade (ICB), many patients fail to achieve durable clinical benefit, and the underlying immunological mechanisms remain poorly understood. Here, we investigated immune reinvigoration by ICB in advanced or recurrent hypermutated or microsatellite instability-high, mismatch repair deficient (MSI-H/MMRd) uterine cancer patients treated with anti-PD-1 (nivolumab). CD8 T cells underwent rapid pharmacodynamic proliferation 2-4 weeks after initiating PD-1 blockade. This immunological response, however, did not correlate with clinical response. We hypothesized that the T cell-intrinsic response to proliferative and genotoxic stress might contribute to the disparity between immunological and clinical response. We developed a high-dimensional single cell cytometric platform to simultaneously analyze T cell differentiation with changes in DNA damage and repair (DDR) pathways. This DDR-Immune platform revealed T cell subset-specific patterns of DDR, and distinct DDR pathways induced by different types of DNA damage. Applying this platform to MSI-H/MMRd or hypermutated uterine cancer patients revealed a signature of DDR exemplified by rapid increase in phosphorylated-ATM (pATM) intrinsic to CD8 T cells proliferating in response to PD-1 blockade that distinguished clinical responders and non-responders. ATM regulated transcriptional circuits in T cells were associated with better clinical response to PD-1 blockade. These findings highlight a previously unrecognized role for CD8 T cell-intrinsic DDR as a potential determinant of immune fitness and clinical outcome of PD-1 blockade therapy. STATEMENT OF SIGNIFICANCEUsing high-dimensional immune and DNA damage response (DDR) profiling in T cell subsets we identified distinct signatures in anti-PD-1 treated MSI-H/hypermutated uterine cancer patients associated with clinical response versus non-response. Thus, T cell-intrinsic DDR is a potential determinant of immune responsiveness and clinical outcome to PD-1 blockade therapy in cancer.

immunology↗

bioRxiv2022

A genetic model for in vivo proximity labeling of the mammalian secretome

Organ functions are highly specialized and interdependent. Secreted factors regulate organ development and mediate homeostasis through serum trafficking and inter-organ communication. Enzyme-catalyzed proximity labeling enables the identification of proteins within a specific cellular compartment. Here, we report a BirA*G3 mouse strain that enables CRE-dependent promiscuous biotinylation of proteins trafficking through the endoplasmic reticulum. When broadly activated throughout the mouse, widespread labeling of proteins was observed within the secretory pathway. Streptavidin affinity purification and peptide mapping by quantitative mass spectrometry (MS) proteomics revealed organ-specific secretory profiles and serum trafficking. As expected, secretory proteomes were highly enriched for signal peptide-containing proteins, highlighting both conventional and non-conventional secretory processes, and ectodomain shedding. Lower-abundance proteins with hormone-like properties were recovered and validated using orthogonal approaches. Hepatocyte-specific activation of BirA*G3 highlighted liver-specific biotinylated secretome profiles. The BirA*G3 mouse model demonstrates enhanced labeling efficiency and tissue specificity over viral transduction approaches and will facilitate a deeper understanding of secretory protein interplay in development, and healthy and diseased adult states.

cell biology↗

bioRxiv2022

Strong and consistent associations of waterbird community composition with HPAI H5 occurrence in European wild birds

Since 2014, highly pathogenic avian influenza (HPAI) H5 viruses of clade 2.3.4.4 have been dominating the outbreaks across Europe, causing massive deaths among poultry and wild birds. However, the factors shaping its broad-scale outbreak patterns remain unclear. With extensive waterbird survey datasets of about 7,000 sites across Europe, we here demonstrated that H5N8 occurrence in wild birds in the 2016/17 and 2020/21 epidemics as well as H5N1 occurrence in 2005/06 epidemic were strongly associated with very similar waterbird community attributes, pointing to the possibility of similar interspecific transmission processes between different epidemics. A simple extrapolation of the model constructed from the 2016/17 epidemic can well predict the H5N8 pattern in wild birds in 2020/21 epidemic. We also found a dilution effect of phylogenetic diversity that was always negatively correlated with H5 occurrence in wild birds. In contrast, H5N8 occurrence in poultry was subject to different risk factors between the two epidemics. In general, waterbird community composition play a much more important role in determining the spatial pattern of H5N8 in wild birds than in poultry. Our work contributes to reveal the factors driving H5N8 patterns, and highlights the value of waterbird community factors in future HPAI surveillance and prediction.

ecology↗

bioRxiv2022

PanGu Drug Model: Learn a Molecule Like a Human

Recent achievements in large-scale pre-trained models like GPT-3 and PanGu- showed amazing performances in many downstream tasks, which makes AI friendlier toward industrial users. Deep learning has been recognized as the most promising technology for pharmaceuticals, a powerful molecule pre-trained model could save researchers tons of time. In chemistry classes, the students learn two molecule representations, the molecular formula and the structure formula, and learn to translate them from one way to the other. Inspired by this, we developed a novel deep learning architecture using a graph-to-sequence asymmetric conditional variational autoencoders, called PanGu Drug Model, which can appropriately characterize the molecule from both representations and improve the performance of downstream drug discovery tasks. After pretrained with 1.7 billion small molecules, our proposed model achieved the state-of-the-art results in 20 drug discovery tasks, such as molecule property prediction (predict ADMET properties, compound-target interactions, drug-drug interactions and chemical reaction productivity), molecule generation and molecule optimization. A new drug screening library of 100 million drug-like small molecules with 99.68% novelty was generated by PanGu molecule generator, which could efficiently produce novel compounds with similar physiochemical properties to given distribution, this library could be used to supplement existing compound databases. In addition, PanGu molecule optimizer could optimize the chemical structures of starting molecule with improved molecular property of interest. An automatic multi-objective optimization web application implemented by PanGu Drug Model is available at http://www.pangu-drug.com/.

biochemistry↗

bioRxiv2022

Different astrocyte-to-neuron conversion tracing reporters affect results in mouse striatum under Ptbp1 knockdown

Conversion of astrocytes to neurons (AtN) is a promising potential strategy for the treatment of neurodegenerative diseases. Recent studies have reported that shRNA-, CasRx-, or ASO-mediated Ptbp1 suppression could reprogram resident astrocytes to neurons1-3. However, some groups have disputed the data interpretation of the reported AtN conversion events4-7. These controversies surrounding AtN conversion may due to differences in the astrocyte fate-mapping systems they applied from that in the original study, i.e., recombinant mouse strains with astrocyte specific reporter constructs versus AAV-based labeling systems. Here, we applied AAV-based tracing systems to label astrocytes with GFAP-driven HA-tagged Cas13X (AAV-GFAP::Cas13X-NLS-HA-sgPtbp1). Compared to GFAP-driven tdTomato reporter (AAV-GFAP::tdTomato) system in previous studies, we found no AtN conversion in mouse striatum. Furthermore, no intermediate neurons and no neuron density increase suggested no AtN conversion. Our findings indicated that inconsistent AtN outcomes may arise from different fate-mapping systems between AAV and transgenic mice, as well as through use of different reporter proteins. Thus, the complexity of astrocyte labeling systems warrants careful attention when drawing conclusions about whether AtN conversion occurs.

neuroscience↗

bioRxiv2022

An integrated cell atlas of the human lung in health and disease

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.

cell biology↗

bioRxiv2022

Rational evolution of a recombinant DNA polymerase for efficient incorporation of unnatural nucleotides by dual-site boosting

Machine learning modelling assisting function-oriented enzyme engineering is normally built on predefined protein sequence space. However, efficient defining the determinant amino acid positions upon which the combinatorial mutation library is constructed is still a challenge in protein science. Herein, we present a comprehensive investigation of modifying a recombinant DNA polymerase for efficient incorporating one unnatural nucleotide, including the identification of key sites/regions, machine learning-assisted mutants screening, and the underlying mechanism of kinetics boosting. By using hundreds of training points and only dozens of testing samples, we found that one highly engineered enzymes catalytic efficiency can be further improved by one order of magnitude by specific mutation on two sites, 485I and 451L. Compared to the position 485 which is known to dominate local conformation of B-family DNA polymerases, 451 is a split-new active site discovered by our approach. A novel allosteric regulation mechanism is underlying the apparent synergy of 485I and 451L on the kinetics boosting. As a result, a "half-closed" conformation of the binding pocket and a cooperative binding of both primer and template DNA strands on the protein accelerated the processes of substrates incorporation, molecular recognition, and releasing of incorrect nucleotides. These findings have implications in guiding the function-tuning of DNA polymerases for a broad range of biotechnological applications.

biochemistry↗

bioRxiv2022

Intergenerational transfer and sex differences of DNA methylation patterns in the Pacific oyster (Crassostrea gigas)

Apart from DNA-sequence-based inheritance, inheritance of epigenetic marks such as DNA methylation is controversial across the tree of life. In mammals, post-fertilization and primordial germ cell reprogramming processes erased most parental DNA methylation information. In nonmammalian vertebrates and insects, it has been proposed that DNA methylation is an essential hereditary carrier. However, how and to what extent general DNA methylation reprogramming affects intergenerational inheritance in molluscs remains unclear. Here, we investigated genome-wide DNA methylation in a mollusc model, the Pacific oyster (Crassostrea gigas), to test how epigenetic information transfers from parents to offspring. Analysis of global methylome revealed that the DNA methylation patterns are highly conserved within families. Almost half of the differentially methylated CpG dinucleotides (DMCs) between families in parents could transfer to offspring. These results provided the direct evidence for the hypothesis that the Pacific oyster DNA methylation patterns are inherited in generations. Moreover, distinct DNA methylation differences between male and female somatic tissues in C. gigas are revealed in this study. These sex-differential methylated genes significantly enriched in the regulation of Rho protein signal transduction process, which indicated that DNA methylation might have an essential role in the sexual differentiation of somatic tissues in C. gigas. Author SummaryTransgenerational inheritance of DNA methylation marks varies across the tree of life. In mammals, post-fertilization and primordial germ cell reprogramming processes obstructed the DNA methylation transmission from parents to child, and only some CpG dinucleotides retain gamete-inherited methylation. However, the DNA methylation inheritance seems apparent in nonmammalian vertebrates and insects. As one of the essential mollusc models, the Pacific oyster Crassostrea gigas have received the most substantial epigenetic studies, mainly focusing on the DNA methylation profiles. While a previous study suggested the existence of paternal inheritance of DNA methylation patterns in C. gigas, more data are needed to confirm this hypothesis. In this study, genome-wide DNA methylation analysis was performed to investigate the epigenetic inheritance in C. gigas. Almost half of the DNA methylation differences between families in parents were found to be transferred to children, indicating the absence of global DNA methylation reprogramming in C. gigas. Besides, extensive hypomethylation in C. gigas females compared with males were also unveiled. These hypomethylated genes were significantly enriched in the regulation of Rho protein signal transduction process. For example, guanine nucleotide exchange factors, including KALRN, FGD1, and FGD6, were hypomethylated in C. gigas females, and the corresponding transcriptions were significantly upregulated. Our findings provided insights into the evolution of DNA methylation patterns, transgenerational epigenetic inheritance, and sexual differentiation in molluscs.

evolutionary biology↗

bioRxiv2022

Structural Basis of HIV-1 Maturation Inhibitor Binding and Activity

HIV-1 maturation inhibitors (MIs) interfere with the final step in the viral lifecycle by disrupting the ordered proteolytic processing of the viral Gag polyprotein into its individual domains. Bevirimat (BVM) and its analogs interfere with the final catalytic cleavage of spacer peptide 1 (SP1) from the capsid protein (CA) C-terminal domain (CACTD), by binding to and stabilizing the CACTD-SP1 region. MIs are under development as alternative drugs to augment current antiretroviral therapies. Although promising, their mechanism of action and associated virus resistance pathways remain poorly understood at the molecular, biochemical, and structural levels. Here, we report atomic-resolution magic angle spinning (MAS) NMR structures of microcrystalline assemblies of CACTD-SP1 complexed with BVM and/or the assembly cofactor inositol hexakisphosphate (IP6). BVM and IP6 can bind simultaneously to SP1, with BVM positioned in the center of its 6-helix bundle in a unique conformation. Importantly, the NMR-observed structural effects of BVM on IP6 binding suggest that the inhibitor stabilizes the 6-helix bundle in multiple ways. In addition, BVM-resistant SP1-A1V and SP1-V7A variants exhibit distinct conformational and binding characteristics. Taken together, our results reveal a novel allosteric mechanism by which BVM disrupts maturation and provide a structural explanation for BVM resistance as well as important guidance for the design of new MIs.

biophysics↗

bioRxiv2022

Right atrial mechanism contributes to atrial fibrillation in a canine model of pulmonary arterial hypertension

ObjectivesThe aim of this study was to investigate proarrhythmic substrates of atrial fibrillation (AF) in a canine model of dehydromonophylline (DMCT)-induced pulmonary arterial hypertension (PAH). MethodsAll cannines (n=12) underwent baseline echocardiographic and hemodynamic examinations, 7 of which were injected with DMCT (3.0mg/kg) to induce PAH via jugular vein cannulation. The control beagles (n=5) were given the same dose of normal saline. Then, both groups were monitored by insertable cardiac monitors. Hemodynamic, echocardiographic, electrophysiological and histological examinations were performed 8 weeks later. ResultsIn PAH group, 2 died after the injection (mortality 28.6%). Thus, 10 beagles (PAH group: 5, control group: 5) underwent all the examinations. The pulmonary artery pressure increased significantly while the right atrium (RA) and right ventricle expanded slightly. Spontaneous AF episodes were recorded in all PAH canines 1 week after the injection. The AF burden increased rapidly from 1 week (7.6{+/-}1.8%) and remained high after 2-3 weeks (32.0{+/-}4.9% at 8 weeks). Compared with the control group, the PAH group had abbreviated effective refractory periods (ERPs), increased atrial ERP dispersion, and slower conduction velocities. Notably, AF susceptibility and atrial remodeling in RA was more significant those in LA, such as increased WOV(39.0{+/-}6.5ms vs. 28.0{+/-}5.7ms, P=0.022), enlarged low voltage regions (7.66{+/-}0.46% vs. 4.40{+/-}0.55%, P<0.0001) and fibrosis (8.22{+/-}0.61% vs. 4.93{+/-}0.60%, P <0.0001). ConclusionsDMCT-induced canine PAH model increased the incidence of spontaneous and induced AF. The electrophysiological and structural remodeling of the RA facilitated the AF genesis.

physiology↗