Biology subjects

Wang, D.

Publications and source records attributed to Wang, D..

At least 289 records · Page 16Linked to original sources

bioRxiv2024

A 3D endometrium-on-a-chip reveals the role of conceptus-derived factors CAPG and PDI in conceptus-endometrial communication

Early embryo loss affects all mammalian species, including humans and agriculturally important food-producing mammals such as cattle. The developing conceptus (embryo and extra-embryonic membranes) secretes factors which modify the endometrium and can be critical for early pregnancy processes such maternal recognition of pregnancy (MRP) and enhancing uterine receptivity to implantation. For example, a competent bovine conceptus secretes IFNT to initiate MRP. The bovine conceptus also secretes other proteins at the time of MRP, including CAPG and PDI, which are highly conserved among placental mammals. We have previously shown that these proteins act upon the endometrium to modulate receptivity, embryo development, and implantation in species with different implantation strategies (humans and cattle). We hypothesise that developing a novel 3D bovine endometrium on a chip system will enhance our understanding of the role of conceptus-derived factors in altering the endometrium and/or ULF secretion. Here we have developed a 3D bovine endometrium on a chip system, comprising both stromal and epithelial cell culture combined with culture medium flow better mimics the in vivo endometrium and exposure to conceptus-derived factors than conventional 2D endometrial cell culture. We have demonstrated that the conceptus-derived proteins CAPG and PDI modulate the endometrial transcriptome and secretory response to promote pathways associated with early pregnancy and alter ULF composition. This work highlights the critical need for more robust and in vivo -like culture systems to study endometrial-conceptus interactions in vitro to further investigate the role of conceptus derived factors for pregnancy success. SIGNIFICANCE STATEMENTWe have developed an in vitro 3D bovine endometrium-on-a-chip system comprising both primary stromal cells under static conditions and epithelial cells under flow conditions to mimic the in vivo endometrial environment from the conceptuses perspective. The secretome of the 3D endometrium-on-a-chip was characterised, was found to contain proteins associated with cell adhesion and tissue development, and contained proteins previously identified in in vivo uterine luminal fluid. PDI and CAPG (previously identified conceptus-derived factors) altered the transcriptome and secretome of cells within the system. Exposure to CAPG or PDI altered the secretome of proteins previously identified in pregnant uterine luminal fluid or associated with early pregnancy, and exposure to CAPG or PDI also altered the transcriptome to support processes such as immune response, secretion, proliferation, and adhesion related pathways. This data supports previously published works and highlights the need for the use of more in vivo-like in vitro models to study conceptus-endometrial interactions.

molecular biology↗

bioRxiv2024

A Deep Dive into Statistical Modeling of RNA Splicing QTLs Reveals New Variants that Explain Neurodegenerative Disease

Genome-wide association studies (GWAS) have identified thousands of putative disease causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a new pipeline for sQTL discovery. MAJIQTL includes two new statistical methods: a weighted multiple testing approach for sGene discovery and a model for sQTL effect size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the novel variant rs582283 in Alzheimers disease. Using antisense oligonucleotides, we validate this variants effect by blocking the implicated YBX3 binding site, leading to exon skipping in the gene MS4A3.

genomics↗

bioRxiv2024

Fornix and Uncinate Fasciculus Support Metacognition-Driven Cognitive Offloading

People often use external tools to offload cognitive demands associated with remembering future intentions. While previous research has established a causal role of metacognition in cognitive offloading, the neural mechanisms supporting this metacognitive control process remain unclear. To address this, we conducted a study with 34 participants using diffusion tensor imaging (DTI) to examine how white matter connectivity supports metacognition-driven cognitive offloading. Behaviorally, we replicated prior findings showing that under-confidence in internal memory predicts a bias toward using external reminders. At the neural level, we used diffusion tensor imaging to quantify fractional anisotropy (FA), a measure of microstructural integrity in white matter. We found the microstructural integrity of the superior longitudinal fasciculus (SLF) and cingulum bundle (CB) negatively predicted deviations from the optimal use of reminders. The microstructural integrity of the fornix negatively predicted participants confidence in performing the task when restricted to internal memory. Our findings reveal the microstructural organization of these fronto-temporal-parietal white-matter tracts are related to metacognition driven cognitive offloading. We discuss several aspects of metacognition driven cognitive offloading from a white matter microstructural perspective.

neuroscience↗

bioRxiv2024

Multimodal Protein-Ligand Contrastive Pretraining for Effective and Efficient Drug Discovery

Recent advancements in genomics and proteomics have identified numerous clinically significant protein targets, with notably 85% categorized as undruggable. These targets present widespread challenges due to their complex structures and dynamics, rendering conventional drug design strategies not always effective. In this study, we introduce Uni-Clip, a contrastive learning framework that incorporates multi-modal features of proteins (structure and residue) and ligands (conformation and graph). Optimized with a specifically designed CF-InfoNCE loss, Uni-Clip enhances the modeling of protein-ligand interactions for both undruggable and druggable proteins. Uni-Clip demonstrates superior performance in benchmark evaluations on widely acknowledged datasets, LIT-PCBA and DUD-E, achieving a 147% and 218% improvements in enrichment factors at 1% compared to baselines. Furthermore, Uni-Clip proves to be a practical tool for various drug discovery applications. In virtual screening for the challenging protein target GPX4 with flat surface, it identified non-covalent inhibitors with an IC50 of 4.17 M, in contrast to the predominantly covalent inhibitors currently known. Through target fishing for benzbromarone, Uni-Clip identified the intrinsically disordered protein c-Myc as a potential target, highlighting benzbromarones potential for repurposing in cancer therapy. Explainable analyses effectively identified binding sites consistent with molecular dynamics and experimental results, even for challenging undruggable targets.

bioinformatics↗

bioRxiv2024

The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21

Obesity is a debilitating disease with increasing worldwide prevalence. Despite its high prevalence, specific pharmacologic intervention for obesity is challenging. Here, we report that halofuginone, an FDA-approved anti-scleroderma and anti-protozoal drug, is a promising anti-obesity agent in rodent models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in preclinical diet-induced obese mouse models, while also decreasing insulin resistance and hepatic steatosis. By combining genetic and pharmacological tools with transcriptomics, we identified that halofuginone increases FGF21 and GDF15 levels via ATF4. Using knockout mice, we show these hormones are both necessary for its anti-obesity effects. Thus, our study first reports the beneficial metabolic effects of halofuginone and underscores its utility to treat obesity and its associated metabolic complications.

pharmacology and toxicology↗

bioRxiv2024

Paraptosome: A Novel Pathological Feature in Paraptotic Cell Death

Paraptosis is a novel form of programmed cell death characterized by distinct morphological features such as swelling of the endoplasmic reticulum and mitochondria, and cytoplasmic vacuolation. Unlike apoptosis, paraptosis does not involve the activation of caspases or DNA fragmentation. These unique features make paraptosis an intriguing target for cancer therapy, particularly against apoptosis-resistant cells. Here, we report a novel morphological feature of paraptosis: the formation of high-density spherical structure, which we tentatively term "paraptosome." We found that these putative paraptosomes originate from the Golgi apparatus, appearing as high-density formations under light microscopy and colocalizing with the trans-Golgi marker {beta}4GALT1-RFP. Time-lapse confocal microscopy and immunostaining demonstrated that putative paraptosomes form due to Golgi stress or disintegration, leading to severe disruption of Golgi function. Furthermore, we show that paraptosis inducers such as glabridin, morusin, and honokiol can cause significant alterations in the endoplasmic reticulum, mitochondria, autophagosomes, and lysosomes in U251MG glioblastoma cells; however, the formation of putative paraptosomes is not induced by isolated stress inducers. Collectively, these findings suggest that the putative paraptosome may be a novel characteristic structure of paraptosis. The discovery of paraptosomes provides a unique marker for defining paraptotic cell death and offers new insights into the characteristic pathological phenomena associated with multiple organelle dysfunction. This finding broadens the scope of cell biology research by introducing a new structural paradigm linked to paraptosis and may have implications for developing targeted therapies against apoptosis-resistant cancers.

cell biology↗

bioRxiv2024

3D Reconstruction of Neuronal Allometry and Neuromuscular Projections in Asexual Planarians Using Expansion Tiling Light Sheet Microscopy

The intricate coordination of the neural network in planarian growth and regeneration has remained largely unrevealed, partly due to the challenges of imaging the central nervous system (CNS) in three dimensions (3D) with high resolution and within a reasonable timeframe. To address this gap in systematic imaging of the CNS in planarians, we adopted high-resolution, nanoscale imaging by combining tissue expansion and tiling light-sheet microscopy, achieving up to 4-fold linear expansion. Using an automatic 3D cell segmentation pipeline, we quantitatively profiled neurons and muscle fibers at the single-cell level in over 400 wild-type planarians during homeostasis and regeneration. We validated previous observations of neuronal cell number changes and muscle fiber distribution. We found that the increase in neuron cell number tends to lag behind the rapid expansion of somatic cells during the later phase of homeostasis. By imaging the planarian with up to 120 nm resolution, we also observed distinct muscle distribution patterns at the anterior and posterior poles. Furthermore, we investigated the effects of {beta}-catenin RNAi on muscle fiber distribution at the posterior pole, consistent with changes in anterior-posterior polarity. The glial cells were observed to be close in contact with dorsal-ventral muscle fibers. Finally, we observed disruptions in neural-muscular networks in inr-1 RNAi planarians. These findings provide insights into the detailed structure and potential functions of the neural-muscular system in planarians and highlight the accessibility of our imaging tool in unraveling the biological functions underlying their diverse phenotypes and behaviors.

developmental biology↗

bioRxiv2024

Thermophilic Fungus Uses Anthraquinones to Modulate Ferrous Excretion, Sterol-Mediated Endocytosis and Iron Storage in Response to Cold Stress

To date, there is no real physiological mechanisms for iron excretion in eukaryote, and no physiological "actuator" that can control all the three fundamental biologic processes of absorption, storage and excretion. Here we observed that the accumulation of anthraquinones by Thermomyces dupontii under cold stress can achieve this process. Through mutation analysis, we found that mutant {Delta}An deficiency in anthraquinones accumulated ferrous and total free iron due to adopting a rare lifestyle with no endocytosis but accumulation of membrane-derived vesicles. Anthraquinone complement indicated that the vesicles in {Delta}An could coat the extrinsic anthraquinone-induced granules to prevent contact with the fungal interiors. Detailed chemical investigation on {Delta}An led to characterization of a rare oxygen-free ergosterene with unstable nature in air as the major membrane steroid in {Delta}An, suggesting hypoxia inner in {Delta}An cells, consistent with dramatically low oxygen-consuming rates in {Delta}An. A series of physiological and metabolic analysis indicated anthraquinones were involved in exporting ferrous and promoting formation of oxygen-containing metabolites, including ergosterols for endocytosis and iron chelators for iron storage. Moreover, we found that both the anticancer agent mitoxantrone with well know-cardiotoxicity side effect and the major terpenoid-derived polycyclic aromatics from Danshen for treating cardiovascular disease showed potent ferrous transporting capabilities in human cancer cells. Our findings provide a novel insight into the underlying mechanisms of polycyclic aromatics in nature and pharmacology, and offer new strategy for developing potential therapeutics and agents for membrane transport, iron homestasis and anticold. Graphical AbstractUp to now, regulation of iron homeostasis by metabolites have rarely been characterized. Moreover, no excretory mechanisms for iron in fungi have been reported. In this study, we found that Thermomyces dupontii can accumulate a large amount of anthraquinones under cold stress. The anthraquinones can release free ferric ion, reduce ferric to ferrous ions, and export ferrous ions, greatly enhancing thermophilic fungus to survive in the bio-system environment. Furthermore, lack of the anthraquinones can inhibit oxygen-dependent ergosterol mediated endocytosis, leading to an self-imposed isolation via oxygen-free ergosterene-mediated cell membranes. Importantly, the well known anthraquinone compound Mitoxantraquinone for anticancer and the main terpenoid polycyclic aromatic metabolites in traditional Chinese medicine Danshen for the treatment of cardiovascular diseases both exhibit strong ferrous ions transport capabilities. Our findings provided new insights for developing potential therapies and drugs for iron homeostasis and drug delivery. O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/605589v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@114551eorg.highwire.dtl.DTLVardef@1e03589org.highwire.dtl.DTLVardef@dad51borg.highwire.dtl.DTLVardef@dd0601_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Harnessing in vivo Synthesis of Bioactive Multiarylmethanes in Escherichia coli via Oxygen-Mediated Free Radical Reaction Induced by Simple Phenols

BackgroundXanthenes and multi-aryl carbon core containing compounds represent different types of complex and condensed architectures that have impressive wide range of pharmacological, industrial and synthetic applications. Moreover, indoles as building blocks were only found in naturally occurring metabolites with di-aryl carbon cores and in chemically synthesized tri-aryl carbon core containing compounds. Up to date, rare xanthenes with indole bearing multicaryl carbon core have been reported in natural or synthetic products. The underlying mechanism of fluores-cein-like arthrocolins with tetra-arylmethyl core were synthesized in an engineered Escherichia coli fed with toluquinol remained unclear. ResultsIn this study, the Keio collection of single gene knockout strains of 3901 mutants of E. coli BW25113, together with 14 distinct E. coli strains, was applied to explore the origins of endoge-nous building blocks and the biogenesis for arthrocolin assemblage. Deficiency in bacterial res-piratory and aromatic compound degradation genes ubiX, cydB, sucA and ssuE inhibited the mu-tant growth fed with toluquinol. Metabolomics of the cultures of 3897 mutants revealed that only disruption of tnaA involving in transforming tryptophan to indole, resulted in absence of arthro-colins. Further media optimization, thermal cell killing and cell free analysis indicated that a non-enzyme reaction was involved in the arthrocolin biosynthesis in E. coli. Evaluation of redox potentials and free radicals suggested that an oxygen-mediated free radical reaction was respon-sible for arthrocolins formation in E. coli. Regulation of oxygen combined with distinct phenol derivatives as inducer, 31 arylmethyl core containing metabolites including 13 new and 8 biolog-ical active, were isolated and characterized. Among them, novel arthrocolins with p-hydroxylbenzene ring from tyrosine were achieved through large scale of aerobic fermentation and elucidated x-ray diffraction analysis. Moreover, most of the known compounds in this study were for the first time synthesized in a microbe instead of chemical synthesis. Through feeding the rat with toluquinol after colonizing the intestines of rat with E. coli, arthrocolins also ap-peared in the rat blood. ConclusionOur findings provide a mechanistic insight into in vivo synthesis of complex and condensed ar-throcolins induced by simple phenols and exploits a quinol based method to generate endoge-nous aromatic building blocks, as well as a methylidene unit, for the bacteria-facilitated synthesis of multiarylmethanes.

biochemistry↗

bioRxiv2024

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag- RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

neuroscience↗

bioRxiv2024

Trapping Devices of Carnivorous Fungus Arthrobotrys oligospora Can Isolate Heat-Triggered Excess Irons

Under low-nutrient conditions, Arthrobotrys oligospora and other NTFs can differentiate their mycelia into specialized trapping devices for capturing prey as their nutritional source. Using energy-dispersive X-ray spectroscopy (EDX) in conjunction with transmission electron microscopy (TEM), we identified that the characteristic electron-dense bodies in trapping devices contained more iron than vacuoles and mitochondria. Meanwhile, fungal mycelial cells used effective desferriferrichromes for iron chelation and storage. Complex bioassays showed that electron-dense bodies represent a novel type of microbial iron storage particle and trapping devices in A. oligospora function as an unprecedented phenotypic system for iron storage. Unexpectedly, all NTFs lack a crucial Ccc1-mediated vacuolar iron detoxification mechanism, which is conserved in most fungi. Inserting the Ccc1 gene cloned from yeast into A. oligospora significantly reduced formation of trapping devices and inhibited nematicidal activity. Notably, Bayesian relaxed molecular clock analysis indicated that the loss of Ccc1-mediated vacuolar iron storage occurred during the Late Paleozoic Ice Age, while the origin of the trapping devices and the acquisition of desferriferrichrome biosynthesis were strongly associated with significantly elevated temperatures. Temperature bioassays demonstrated that the formation of trapping devices is highly temperature-dependent, with free iron content in mycelial cells being inversely proportional to temperature, consistent with that A. oligospora is sensitive to high temperatures and fails to grow above 30{degrees}C. Our findings revealed that global temperature fluctuations are a crucial driver of the genetic evolution of NTFs, as a catalyst for the origin of trapping devices, which are a novel phenotypic indicator of eukaryotic iron overload. Author summaryWe found that a unique group of carnivorous fungi has evolved specialized trapping devices to sequester excess iron, compensating for the absence of the crucial Ccc1-mediated vacuolar iron detoxification pathway, which is conserved in most fungi. Furthermore, we report for the first time that elevated temperature is a non-trophic factor that induces iron overload in eukaryotes, as iron content and composition in fungal mycelia are negatively correlated with temperature. Our findings suggest that nematode-trapping fungi could serve as a potential eukaryotic model for investigating the dynamic regulation mechanisms of iron homeostasis, which could contribute to the development of therapies for iron overload-related diseases in humans. In humans, iron overload leads to tissue damage, particularly in the cardiovascular system. It has long been assumed that iron overload occurs when iron intake is increased over an extended period, either through repeated red blood cell transfusions or enhanced absorption from the gastrointestinal tract. Caucasians are particularly susceptible to iron overload and the complications of hemochromatosis due to a higher incidence of mutations in the homeostatic iron regulation gene within this population. The discovery of eukaryotes exhibiting an iron overload phenotype when exposed to heat holds significant implications for developing treatments and strategies for human iron overload disorders.

evolutionary biology↗

bioRxiv2024

A second X chromosome improves cognition in aging male and female mice

Women show resilience to cognitive aging, in the absence of dementia, in many populations. To dissect sex differences, we utilized the FCG and XY*mouse models. Female gonads and sex chromosomes improved cognition in aging mice of both sexes. Further, presence of a second X in male and female mice conferred cognitive resilience while its absence in females blocked it. In the hippocampal proteome of aging female mice, the second X increased proteins involved in synaptogenesis signaling - a potential pathway to improved cognition.

neuroscience↗

bioRxiv2024

The Impact of SARS-CoV-2 nsp14 Proofreading on Nucleoside Antiviral Activity: Insights from Genetic and Pharmacological Investigations

Nucleoside analogues are a class of well-established antiviral agents that act by being directly incorporated into the viral genome during the replication process, resulting in chain termination or the induction of lethal mutations. While many nucleoside analogues have exhibited broad-spectrum activity against a wide range of viruses, their effectiveness against SARS-CoV-2 is limited. The lack of activity is hypothesized to be attributed to the proofreading function of viral nsp14 exonuclease. In this study, the role of the nsp14 proofreading in modulating nucleoside antiviral activity was investigated using genetic and pharmacological approaches. Introduction of exonuclease attenuation or disabling mutations to nsp14 led to either severe replication defect or increased sensitivity of SARS-CoV-2 and SARS-CoV replicons to specific nucleoside analogues. In contrast, repurposing of HCV NS5A inhibitors to suppress nsp14 exonuclease activity is insufficient to enhance the potency of nucleoside analogues. These findings provided further support for nsp14 as a target for SARS-CoV-2 antiviral development and highlighted the complex interplay between nsp14 proofreading and RNA replication.

molecular biology↗

bioRxiv2024

FLASH radiotherapy using high-energy X-rays: validation of the FLASH effect triggered by a compact single high-energy X-ray source device

PurposeThis preclinical study aimed to verify the FLASH effect of compact single high-energy X-ray source (CHEXs) and to explore whether three irradiations with single-gantry rotation two 30 s pauses can generate FLASH effect in mice. Materials and methodsThe absolute dose and pulsed beam of the CHEXs were measured using an EBTXD radiochromic film and fast current transformer. Healthy C57BL/6J female mice and a subcutaneous tumor model were irradiated under different conditions: sham (control), FLASH-RT (FLASH1: delivering the total dose in 1 fraction; FLASH3: delivering the total dose with two 30 second pauses to simulate a three-field delivery where the gantry rotation is occurring within 30 seconds), and conventional dose rate radiotherapy (CONV-RT). Various total doses were administered to the corresponding normal tissues (whole thorax, 30 Gy; whole abdomen, 12 Gy; and skin, 36 Gy) and tumors (CT26, 16.5 Gy; and LLC, 18 Gy). Survival status, normal tissue damage, and tumor growth suppression were recorded in each group. ResultsThe average dose rate of the CHEXs exceeded 40 Gy/s. For whole-thorax and skin irradiation, both FLASH1 and FLASH3 demonstrated protective effects. For whole-abdomen irradiation, FLASH1 exhibited a superior protective effect. No significant differences in tumor growth responses were observed between the FLASH1, FLASH3, and CONV-RT groups (P>0.05). ConclusionThis study confirmed that the FLASH effect could be triggered using CHEXs FLASH radiotherapy, and demonstrated that three irradiations with single gantry rotation two 30 s pauses can trigger the FLASH effect, indicating the potential benefit of CHEXs 3D conformal radiotherapy. Our findings indicate that further clinical trials on CHEXs are warranted.

cancer biology↗

bioRxiv2024

Visual analysis of spatial transcriptomics data with RedeViz

Spatial transcriptomics (ST) technologies are powerful tools to illustrate the spatial hierarchy and heterogeneity of tissues with the lens of multiplexed gene readouts. However, ST technologies generate sequence data rather than images, preventing intuitive examination of the cellular contexture of tissues. Moreover, the inherent sparsity of ST data caused by molecular crowdedness and sequencing dropouts poses great challenges to accurate and clear visualization. In this study, we introduce RedeViz, a toolkit crafted for enhancing and visualizing subcellular-resolution ST data. RedeViz applies a pixel-level enhancement strategy, visualizes ST data in automatic or customized manners, and can display the cellular and genic spatial patterns with effects akin to HE staining. Strict evaluations confirm that RedeViz fits a wide range of ST platforms, including Xenium, Visium HD, MERFISH, CosMx, Stereoseq, as well as spatial proteomic platforms like CODEX. The impressive performance of RedeViz across various scales from cell-, tissue-, organ-, to organism-levels brings us a universal "What You See Is What You Get" framework for visual analysis of ST data.

bioinformatics↗

bioRxiv2024

Basal Cambrian soft-bodied segmented bilaterians preserved as microbial pseudomorphs

Before Cambrian Stage 3, unambiguous body fossils of segmented bilaterians were rare, severely hampering our understanding of the early history of such important animals. Here we report a variety of microfossils with quintessential features such as paired appendages, dorsoventral and anteroposterior differentiations from the basal Cambrian Fortunian of South China, representing the earliest known three-dimensional body fossils of segmented bilaterians. These fossils were all microbial pseudomorphs built up by secondarily phosphatized bacteria aggregations, testifying microbial pseudomorph could serve as a novel and important pathway to preserve tiny, fragile bilaterian progenitors. This finding unveils a diversified segmented bilaterian world at the very beginning of Cambrian and would arouse a more comprehensive perspective on the early evolution of bilaterian body plans.

paleontology↗

bioRxiv2024

Polymerization of Tspan7 into Helical Transmembrane Skeletons for Membrane Tether Stabilization

Tubular cell membrane protrusions, such as filopodia1, dendrites2, tunneling nanotubes (TNTs)3 and retraction fibers4, are prevalent on the cell surface. They play crucial roles in various physiological processes and disease states, including angiogenesis, wound healing, and cancer metastasis5-7. The shaping and stabilization of these protrusions are crucial for their function, and the molecular machineries involved have long been an active area of investigation. Here we employed an integrative approach combining live-cell imaging, in vitro reconstitution, and in situ cryo-EM analysis to reveal that the transmembrane protein tetraspanin 7 (TSPAN7) senses membrane curvature and polymerizes into a helical configuration on highly curved tubular membranes. These spirals act as a "transmembrane skeleton", effectively maintaining the structural integrity of membrane protrusions under mechanical stress. Our findings reveal a previously unreported assembly strategy for transmembrane proteins and a mechanism for maintaining tubular membrane protrusions.

cell biology↗

bioRxiv2024

Nanopore Direct RNA Sequencing Reveals Virus-Induced Changes in the Transcriptional Landscape in Human Bronchial Epithelial Cells

Direct RNA nanopore sequencing data reveals changes in gene expression, polyadenylation, splicing, m6A methylation, and pseudouridylation in response to influenza virus exposure of primary human bronchial epithelial cells. This study focuses on the epitranscriptomic profile of genes in the host immune response. In addition to polyadenylated noncoding RNA, we purified and sequenced nonpolyadenylated noncoding RNA and observed changes in expression, N6-methyl-adenosine (m6A), and pseudouridylation ({Psi}) in these novel RNA. Two recently discovered lincRNA with roles in immune response, Chaserr and LEADR, are predicted in the analysis of the sequencing data to be highly methylated in response to influenza exposure. Several H/ACA type snoRNAs that guide pseudouridylation are decreased in expression in response to influenza, and there is a corresponding predicted decrease in the pseudouridylation of two novel lncRNA. Thus, novel epitranscriptomic changes revealed by direct RNA sequencing with nanopore technology provide unique insights into the host epitranscriptomic changes in epithelial gene networks that respond to influenza virus exposure.

bioinformatics↗