Biology subjects

Wu, X.

Publications and source records attributed to Wu, X..

At least 235 records · Page 13Linked to original sources

bioRxiv2024

Machine Learning Identifies Genes Linked to Neurological Disorders Induced by Equine Encephalitis viruses (EEV), Traumatic Brain Injuries (TBI), and Organophosphorus nerve agents (OPNA)

Venezuelan, eastern, and western equine encephalitis viruses (collectively referred to as equine encephalitis viruses---EEV) cause serious neurological diseases and are a significant threat to the civilian population and the warfighter. Likewise, organophosphorus nerve agents (OPNA) are highly toxic chemicals that pose serious health threats of neurological deficits to both military and civilian personnel around the world. Consequently, only a select few approved research groups are permitted to study these dangerous chemical and biological warfare agents. This has created a significant gap in our scientific understanding of the mechanisms underlying neurological diseases. Valuable insights may be gleaned by drawing parallels to other extensively researched neuropathologies, such as traumatic brain injuries (TBI). By examining combined gene expression profiles, common and unique molecular characteristics may be discovered, providing new insights into medical countermeasures (MCMs) for TBI, EEV infection and OPNA neuropathologies and sequelae. In this study, we collected transcriptomic datasets for neurological disorders caused by TBI, EEV, and OPNA injury, and implemented a framework to normalize and integrate gene expression datasets derived from various platforms. Effective machine learning approaches were developed to identify critical genes that are associated, either shared among the three neuropathologies or to either TBI, EEV, and OPNA. With the aid of deep neural networks, we were able to extract important association signals for accurate prediction of different neurological disorders by using integrated gene expression datasets of VEEV, OPNA, and TBI samples. Gene ontology and pathway analyses further identified neuropathologic features with specific gene product attributes and functions, shedding light on the fundamental biology of these neurological disorders. Collectively, we highlight a workflow to analyze published transcriptomic data using machine learning, which can be used for both identification of gene biomarkers that are unique to specific neurological conditions, as well as genes shared across multiple neuropathologies. These shared genes could serve as potential neuroprotective drug targets for conditions like EEV, TBI, and OPNA.

neuroscience↗

bioRxiv2024

Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation.

A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation, is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSA). In a mouse orthotopic lung transplantation model, impaired recipient complement regulation resulted in more severe obstructive airway lesions when compared to wildtype controls, despite only moderate differences in graft-infiltrating effector T cells. Impaired complement regulation promoted the intragraft accumulation of memory B cells and antibody-secreting cells, resulting in increased DSA levels. In summary, genetic predisposition to complement activation is associated with B cell activation and worse CLAD-free survival. BRIEF SUMMARYLung transplant recipients genetically predisposed to impaired complement regulation demonstrate worse chronic rejection-free survival. This phenotype is associated with intragraft B cell-activation and donor-specific antibodies.

immunology↗

bioRxiv2024

A genome-wide ATLAS of liver chromatin architecture reveals that sex dictates diet-induced nucleosome dynamics

The three-dimensional organization of the genome plays an important role in cellular function. Alterations between open and closed chromatin states contributes to DNA binding, collaborative transcriptional activities and informs post-transcriptional processing. The liver orchestrates systemic metabolic control and has the ability to mount a rapid adaptive response to environmental challenges. We interrogated the chromatin architecture in liver under different dietary cues. Using ATAC-seq, we mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements in response to diet revealed that sex is the dominant factor segregating changes in chromatin accessibility. A lipid-rich diet led to a more accessible chromatin confirmation at promoter regions in female mice along with enrichment of promoter binding CCAAT-binding domain proteins. Male liver exhibited stronger binding for nutrient sensing nuclear receptors. Integrative analysis with gene expression corroborated a role for chromatin states in informing functional differences in metabolic traits. We distinguished the impact of gonadal sex and chromosomal sex as determinants of chromatin modulation by diet using the Four Core Genotypes mouse model. Our data provide mechanistic evidence underlying the regulation for the critical sex-dimorphic GWAS gene, Pnpla3. In summary, we provide a comprehensive epigenetic resource in murine liver that uncovers the complexity of chromatin dynamics in response to diet and sex. HighlightsATAC-Seq, RNA-Seq, and FCG model-integrated analysis unravel sex differences in chromatin accessibility and transcriptome responses to dietary challenges. Lipid-rich diet led to sex-biased chromatin confirmation at promoter regions. Gonadal sex emerged as the most prevalent determinant of the sex bias hepatic chromatin modulation by lipid-rich diets. The critical sex-dimorphic GWAS gene Pnpla3 is suppressed by testosterone, which underlies hepatic differences in expression between the sexes.

molecular biology↗

bioRxiv2024

TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity

Due to the inevitable progression to castration-resistant prostate cancer (CRPC) following treatment with androgen deprivation therapy (ADT), it is essential to develop novel treatment approaches for managing CRPC. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-{beta}1 to activate TGF-{beta} signaling pathway. Moreover, LINC01179 interacted with Miz1 to attenuate TLL1 expression and LINC01179 impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-{beta} signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-{beta} signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+ T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+ T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.

cancer biology↗

bioRxiv2024

Neratinib, a clinical drug against breast cancer, protects against atherosclerosis via ASK1 inhibition

Atherosclerosis commences with endothelial dysfunction and the retention of cholesterol within the vessel wall, followed by a chronic inflammatory response. Cholesterol-lowering strategies (such as statins and PCSK9 inhibitors) are primarily used for treating patients with atherosclerotic cardiovascular diseases, but leaving the therapeutic dilemma of residual inflammatory risk. To address this challenge, we employed Connectivity Map (CMap) screening for inflammation mechanism-based anti-atherosclerotic compounds using perturbational datasets obtained from TNF and IL-1{beta}-stimulated human endothelial cells. This screening process allow us to identify Neratinib, a clinical drug against breast cancer, as the hit compound with potential anti-inflammatory actions in endothelial cells. Further studies reveal that Neratinib inhibited endothelial cell inflammation elicited by three different pro-inflammatory stimuli (TNF, IL-1{beta} and LPS). Intriguingly, the anti-inflammatory effect of Neratinib was independent of its classical target HER2/ERBB2 inhibition. Mechanistically, Neratinib directly binds ASK1 and suppresses ASK1 activation. In both male and female Ldlr-/- mice, treatment with Neratinib decreased the plaque area, reduced the necrotic core size and mitigated macrophage infiltration to stabilize plaques. Lastly, we observed that Neratinib, in conjunction with the use of Rosuvastatin (a standard lipid-lowering drug), led to a reduction in serum lipids, and produced synergistic anti-atherosclerotic effects. Olink proteomics study suggested that combination treatment alleviated inflammation-related cytokines/chemokines in the serum from Ldlr-/- mice. Taken together, these findings support the concept that Neratinib could be tested for its potential as a "repurposed" drug for vascular inflammation and atherosclerosis, thereby streamlining efforts to translate preclinical discoveries to clinical testing in humans. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/622073v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@78ef07org.highwire.dtl.DTLVardef@194f56forg.highwire.dtl.DTLVardef@7d65e4org.highwire.dtl.DTLVardef@ac7fe3_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryNeratinib protects against atherosclerosis by reducing endothelial inflammation via ASK1 inhibition

pharmacology and toxicology↗

bioRxiv2024

The Cryo-EM structure of TRPC1 and TRPC5 heterotetramer

Ion channel heteromers display distinct electrophysiological and ligand-binding properties, allowing precise modulation of cellular functions in specific tissues. Among the TRPC subtypes, the TRPC1/4/5 heteromers are the most abundant isoform in the human brain and represent a primary target for treating anxiety and depression. However, the structural organization of TRPC1/4/5 heteromers remain unclear, limiting the advancement of research on these channels. Here, we report the cryo-EM structure of TRPC1/5 heterotatramer at a resolution of 2.84 [A]. It consists of an asymmetric structure with three TRPC5 subunits and one TRPC1 subunit. Further structural and functional analysis revealed that the TRPC1 subunit contributes to an asymmetrical ion conduction pathway, a characteristic that differentiates it from TRPC5 homomers. The unique features of the TRPC1 pore loop and its interface interactions with TRPC5 were shown to play crucial roles in modulating the ion conduction properties and gating mechanisms of the heteromeric complex. In addition, we identified key residues within the gating regions that influence channel activation and ion permeability, elucidating the structural basis for the functional divergence between the TRPC1/C5 heterotetramer and TRPC5 homotetramer. Notably, TRPC5 residues were found to dominate gating mechanisms, underscoring the complex interplay between subunit composition and functional outcomes in TRPC channels. Our findings provide novel insights into the structural and functional dynamics of TRPC1/C5 heteromers, paving the way for targeted therapeutic strategies in TRPC5-related disorders.

biophysics↗

bioRxiv2024

Aerobic carbon metabolism modulates nitrite ammonifiers for inhibiting nitrogen loss as revealed by microcosm experiment of agricultural upland soil

Denitrification and dissimilatory nitrate reduction to ammonium (DNRA), two divergent nitrogen metabolism pathways, share nitrite as a common intermediate during anaerobic reduction. However, these pathways influence the environment and soil nutrients differently. Unlike denitrification, which involves nitrogen loss through gaseous nitrogen emission and nitrate leaching, DNRA is beneficial for the conservation of nitrogen. Nevertheless, the key mechanism underlying the joint regulation of aerobic carbon metabolism to nitrite ammonifiers in soil is still unclear, although previous studies have reported factors such as carbon and oxygen can independently affect DNRA. Here, microcosm experiments with agricultural upland soil were conducted under different aeration conditions supplemented with labile carbon to analyze the process of anaerobic nitrogen metabolism. The results indicated that denitrification exclusively dominated nitrite reduction when the soil was directly placed in an anaerobic environment. Nonetheless, a significant increase in DNRA activity and the attenuation of denitrification were detected when the soil was incubated aerobically with the addition of glucose prior to anaerobic incubation. Specifically, up to 55.8% of nitrite reduction switched to nitrogen conservation mainly via DNRA under high-carbon conditions. Quantitative assays of the nrfA gene and metagenomic data revealed a significant increase in DNRA-related genes after aerobic carbon metabolism. Furthermore, nrfA gene sequence analysis revealed a significant shift in the composition of nitrite ammonifiers community. These results indicate that nitrate/nitrite metabolic flux in the soil could be regulated to enhance DNRA by stimulating facultative anaerobic nitrite ammonifiers such as Sedimentibacter under alternating aerobic and anaerobic environments with carbon metabolism. IMPORTANCEThis study revealed that aerobic conditions with a carbon supply strongly influence the community assembly of nitrite ammonifiers. Nitrite ammonifiers such as Sedimentibacter enriched under sufficient carbon and aeration conditions promoted the subsequent DNRA process under anaerobic conditions. Therefore, regulating the competition between DNRA and denitrification by altering functional microbiota would be a promising approach for improving the efficiency of fertilizer application and for reducing greenhouse gas emissions from denitrification. These findings are essential for understanding the biological mechanism of nitrogen cycling in dryland agricultural soil. Based on these findings, we may design a strategy to increase the abundance of nitrite ammonifiers in agricultural soil, which might promote DNRA metabolism to improve nitrogen retention. This strategy would ultimately enhance fertilizer use efficiency and mitigate the detrimental environmental effects of nitrogen fertilizer abuse.

microbiology↗

bioRxiv2024

The C3-C3aR axis modulates trained immunity in alveolar macrophages

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that alveolar macrophage C3 and C3aR1 expression increased in humans after an intranasal exposure to a training stimulus. In vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus. Ex vivo, trained C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output as well as impaired phagocytosis and reactive oxygen species (ROS) production compared to wildtype AMs. Real-time confocal microscopy of live, intact mouse alveoli revealed that AMs internalize C3 rapidly after alveolar microinstillation, as compared to C3a. Correspondingly, the blunted cytokine output was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs - a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling and highlight a novel role for C3 in trained immunity.

immunology↗

bioRxiv2024

Denoising complex-valued diffusion MR images using a two-step non-local principal component analysis approach

Purposeto propose a two-step non-local principal component analysis (PCA) method and demonstrate its utility for denoising diffusion tensor MRI (DTI) with a few diffusion directions. MethodsA two-step denoising pipeline was implemented to ensure accurate patch selection even with high noise levels and was coupled with data preprocessing for g-factor normalization and phase stabilization before data denoising with a non-local PCA algorithm. At the heart of our proposed pipeline was the use of a data-driven optimal shrinkage algorithm to manipulate the singular values in a way that would optimally estimate the noise-free signal. Our approachs denoising performances were evaluated using simulation and in-vivo human data experiments. The results were compared to those obtained with existing local-PCA-based methods. ResultsIn both simulation and human data experiments, our approach substantially enhanced image quality relative to the noisy counterpart, yielding improved performances for estimation of relevant DTI metrics. It also outperformed existing local-PCA-based methods in reducing noise while preserving anatomic details. It also led to improved whole-brain tractography relative to the noisy counterpart. ConclusionThe proposed denoising method has the utility for improving image quality for DTI with reduced diffusion directions and is believed to benefit many applications especially those aiming to achieve quality parametric mapping using only a few image volumes.

neuroscience↗

bioRxiv2024

A tumor-secreted protein utilizes glucagon release to cause host wasting

Tumor-host interaction plays a critical role in malignant tumor-induced organ wasting across multiple species. Despite known regulation of regional wasting of individual peripheral organs by tumors, whether and how tumors utilize critical host catabolic hormone(s) to simultaneously induce systemic host wasting, however, is largely unknown. Using the conserved yki3SA-tumor model in Drosophila, we discovered that tumors increase the production of adipokinetic hormone (Akh), a glucagon-like catabolic hormone, to cause systemic host wasting, including muscle dysfunction, lipid loss, hyperglycemia, and ovary atrophy. We next integrated RNAi screening and Gal4-LexA dual expression system to identify that yki3SA-gut tumors secrete Pvf1 to remotely activate its receptor Pvr in Akh-producing cells (APCs), ultimately promoting Akh production. The underlying molecular mechanisms involved the Pvf1-Pvr axis that triggers Mmp2-dependent ECM remodeling of APCs and enhances innervation from the excitatory cholinergic neurons. Interestingly, we also confirmed the similar mechanisms governing tumor-induced glucagon release and organ wasting in mammals. Blockade of either glucagon or PDGFR (homolog of Pvr) action efficiently ameliorated organ wasting in the presence of malignant tumors. Therefore, our results demonstrate that tumors remotely promote neural-associated Akh/glucagon production via Pvf1-Pvr axis to cause systemic host wasting.

physiology↗

bioRxiv2024

Cross-Species Analysis Reveals No Universal Programmed Aging Mechanism: Insights from Single-Cell Transcriptomics in Zebrafish, Fruit Fly, and Nematode

The question of whether aging follows a universal programmed process has been a topic of debate for a long time. Previous arguments, either supporting or refuting programmed aging, were mainly based on different evolutionary biology theories. In this study, we analysed single-cell RNA sequencing data from zebrafish, fruit fly, and nematode at various stages of development to explore gene co-expression modules across these species. We successfully identified a co-expression module related to ribosomal protein genes that is shared across the early development stages in multiple tissues of all three species. However, we did not find any cross-species shared gene co-expression modules related to aging. Further analysis of gene regulatory networks (GRNs) demonstrated that although certain aging-related genes are conserved, their regulatory mechanisms vary significantly between species. These findings suggest that aging is not governed by a conserved universal program but rather by species-specific adaptations to damage and environmental conditions.

evolutionary biology↗

bioRxiv2024

Frem2 Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis

Fraser syndrome is a rare autosomal recessive disorder characterized by multiple congenital malformations, including cryptophthalmos, syndactyly, and renal agenesis, which can lead to severe complications beginning at the embryonic stage. Mutations in genes encoding extracellular matrix proteins such as FRAS1, FREM1, FREM2, and the associated trafficking protein GRIP1, are implicated in Fraser syndrome. These proteins are critical for maintaining epithelial integrity during embryogenesis, with deficiencies leading to tissue detachment and blistering phenotypes in mouse models. The FREM2 protein is a single-pass membrane protein of 3169 amino acids. While Frem2-deficient mouse models encoding missense variants found in patients, or a truncated FREM2 protein product were previously reported, it has not been studied in a constitutive knockout (KO) mouse model. Here, we developed constitutive Frem2-KO mice exhibiting neonatal lethality, mainly due to bilateral renal agenesis, along with blood-filled blisters, cryptophthalmos, and syndactyly. Only one mouse survived to adulthood exhibiting unilateral renal agenesis and Fraser syndrome-like phenotypes. These findings confirm FREM2s crucial role in the development of the kidneys, skin, and eyes and provide an animal model for further studies of FREM2-related developmental disorders.

developmental biology↗

bioRxiv2024

Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila

Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from Drosophila Mettl5 mutations. Rescue experiments revealed that Mettl5 functions predominantly within neurons and glia marked by Mettl5-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in Trmt112 mutation recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of Mettl51bp mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep and offer insights into the sleep phenotypes associated with ID.

genetics↗

bioRxiv2024

Construction of a macrophage-tropic subtype C HIV-1-mGreenLantern reporter virus for studies on HIV-1 rep-lication and the impact of methamphetamine

HIV-1 subtype C viruses are responsible for 50% of global HIV burden. However, nearly all currently available reporter viruses widely used in HIV research are based on subtype B. We constructed and characterized a replication competent HIV-1 subtype C reporter virus expressing mGreenLantern. mGreenLantern sequences were inserted in-frame with nef ATG in HIV-1IndieC1. As controls, we employed HIV-1IndieC1, HIV-1ADA, and HIV-1NLAD8-GFP-Nef viruses. HIV-1IndieC1-mGreenLantern (HIV-1IndieC1-mGL) exhibited characteristics of the parental HIV-1IndieC1 virus, including its infectivity in TZMbl reporter cells and replication competence in macrophages. To further characterize HIV-1IndieC1-mGL virus, we tested its responsiveness to CCL2 levels, a characteristic feature of subtype B HIV-1 that is missing in subtype C. CCL2 immunodepletion inhibited the production of HIV-1ADA and HIV-1NLAD8-GFP-Nef as expected, but not that of HIV-1IndieC1-mGL as previously reported. We also tested the effect of Methamphetamine, as its effect is mediated by NF-{kappa}B and since subtype C viruses carry an additional copy of NF{kappa}B. We found that methamphetamine increased the replication of all viruses tested in macrophages, however, its effect was much more robust for HIV-1IndieC1 and HIV-1IndieC1-mGL. Our studies established that HIV-1IndieC1-mGL retains all the characteristics of the parental HIV-1IndieC1 and can be a useful tool for HIV-1 subtype C investigations.

microbiology↗

bioRxiv2024

Peptide-Based Complex Coacervates Stabilized by Cation-π Interactions for Cell Engineering

Complex coacervation is a form of liquid-liquid phase separation (LLPS), whereby two types of macromolecules, usually bearing opposite net charges, self-assemble into dense microdroplets driven by weak molecular interactions. Peptide-based coacervates have recently emerged as promising carriers to deliver large macromolecules (nucleic acids, proteins and complex thereof) inside cells. Thus, it is essential to understand their assembly/disassembly mechanisms at the molecular level in order to tune the thermodynamics of coacervates formation and the kinetics of cargo release upon entering the cell. In this study, we design histidine-rich peptides consisting of modular sequences in which we systematically incorporate cationic, anionic, or aromatic residues at specific positions along the sequence in order to modulate intermolecular interactions and the resulting coacervation stability. We show that cation-{pi} interactions between arginine and aromatic side chains are particularly efficient in stabilizing complex coacervates, and these interactions can be disrupted in the protein-rich intracellular environment, triggering the disassembly of complex coacervates followed by cargo release. With the additional grafting of a disulfide-based self-immolative sidechain, these complex coacervates exhibit enhanced stability and can deliver proteins, mRNA, and CRISPR/Cas9 genome editing tools with tunable release kinetics into cells. This capability extends to challenging cell types, such as macrophages. Our study highlights the critical role of cation-{pi} interactions in the design of peptide-based coacervates, expanding the biomedical and biotechnology potential of this emerging innovative intracellular delivery platform. Table of ContentTandem peptides designed from histidine-rich beak proteins are modified with either negative, positive, or aromatic residues that can undergo complex coacervation through cation-{pi} rather than electrostatic interactions. These complex coacervates can effectively recruit various macromolecular cargos and deliver them intracellularly with controlled release kinetics, including in hard-to-transfect macrophages. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/619264v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1e92628org.highwire.dtl.DTLVardef@1c80e19org.highwire.dtl.DTLVardef@115ac05org.highwire.dtl.DTLVardef@1d0b122_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

A 128-channel receive array with enhanced SNR performance for 10.5 tesla brain imaging

PurposeTo develop and characterize the performance of a 128-channel head array for brain imaging at 10.5 tesla and evaluate the potential of brain imaging at this unique, >10 tesla magnetic field. MethodsThe coil is composed of a 16-channel self-decoupled loop transmit/receive array with a 112-loop receive-only (Rx) insert. Interactions between the outer transmitter and the inner 112Rx insert were mitigated using coaxial cable traps placed every 1/16 of a wavelength on each feed cable, locating most preamplifier boards outside the transmitter field and miniaturizing those placed directly on individual coils. ResultsThe 128-channel array described herein achieved 77% of ultimate intrinsic SNR in the center of the brain. Transmit field maps obtained experimentally on a phantom with and without the receive array were similar and matched EM simulations, leading to FDA approval for human imaging. Anatomical and functional data, including with power demanding sequences, were acquired successfully on human volunteers. ConclusionsCounterintuitive to expectations based on magnetic fields [≤]7T, the higher channel counts provided SNR gains centrally, capturing [~]80% uiSNR. Fraction of uiSNR achieved centrally in 64Rx, 80Rx, and 128Rx arrays suggested that a plateau was being reached at 80%. At this plateau, linear to approximately quadratic B0 dependent SNR gains for the periphery and the center, respectively, were observed for 10.5T relative 7T.

neuroscience↗

bioRxiv2024

Pathogenicity and intestinal barrier disruptive ability of Malassezia furfur in an alternative model host Caenorhabditis elegans is partially alleviated by Lacticaseibacillus rhamnosus

Malassezia furfur is associated with various diseases; however, the mechanisms underlying its pathogenicity remain largely unknown. In the present study, Caenorhabditis elegans was used as the model host to evaluate M. furfur pathogenicity. Additionally, effects of lactic acid bacteria against M. furfur pathogenicity were evaluated. Compared to Escherichia coli OP50 (OP, control), both live and heat-killed M. furfur reduced the lifespan and body size of C. elegans, although heat-killed M. furfur was less effective than live M. furfur in lifespan shortening. Furthermore, unlike heat-killed M. furfur, live M. furfur disrupted the nematode intestinal barrier. nsy-1 and sek-1 loss-of-function mutants were susceptible to M. furfur, suggesting their involvement in the defense against M. furfur infection. Expression of genes involved in host defense and of those coding for C-type lectin domain-containing proteins and antimicrobial peptides was upregulated in M. furfur-infected C. elegans. Lacticaseibacillus rhamnosus (LR) significantly ameliorated lifespan shortening and body size reduction in M. furfur-infected C. elegans and protected against intestinal barrier disruption, suggesting that LR protects nematodes from M. furfur virulence. This study highlights M. furfur pathogenicity and intestinal barrier disruptive ability in C. elegans and suggests that the M. furfur virulence is partially attenuated by LR. ImportanceInfection with Malassezia furfur shortens the lifespan and disrupts the intestinal barrier in the model host C. elegans. The probiotic Lacticaseibacillus rhamnosus (LR) attenuates M. furfur virulence, thus partially protecting the intestinal tract. Signaling of the innate immune response to M. furfur in C. elegans is mediated by nsy-1 and sek-1, suggesting that the expression of genes involved in the biological defense response may be regulated downstream of nsy-1 and sek-1. This study enhances our understanding of the diseases associated with M. furfur and offers insights into potential preventive and therapeutic methods using probiotics.

microbiology↗

bioRxiv2024

Initiation of ERAD by the bifunctional complex of Mnl1 mannosidase and protein disulfide isomerase

Misfolded glycoproteins in the endoplasmic reticulum (ER) lumen are translocated into the cytosol and degraded by the proteasome, a conserved process called ER-associated protein degradation (ERAD). In S. cerevisiae, the glycan of these proteins is trimmed by the luminal mannosidase Mnl1 (Htm1) to generate a signal that triggers degradation. Curiously, Mnl1 is permanently associated with protein disulfide isomerase (Pdi1). Here, we have used cryo- electron microscopy, biochemical, and in vivo experiments to clarify how this complex initiates ERAD. The Mnl1-Pdi1 complex first de-mannosylates misfolded, globular proteins that are recognized through a C-terminal domain (CTD) of Mnl1; Pdi1 causes the CTD to ignore completely unfolded polypeptides. The disulfides of these globular proteins are then reduced by the Pdi1 component of the complex, generating unfolded polypeptides that can be translocated across the membrane. Mnl1 blocks the canonical oxidative function of Pdi1, but allows it to function as the elusive disulfide reductase in ERAD.

cell biology↗