Biology subjects

Wang, B.

Publications and source records attributed to Wang, B..

At least 361 records · Page 20Linked to original sources

bioRxiv2023

A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis

Inflammation activates many blood cell types, driving aging and malignancy. Yet, hematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long blood production. To understand HSC adaptation to inflammation, we developed xenograft inflammation-recovery models and performed single cell multiomics on isolated human HSC. Two transcriptionally and epigenetically distinct HSC subsets expressing canonical HSC programs were identified. Only one showed sustained transcriptional and epigenetic changes after recovery from inflammatory treatments. This HSC inflammatory memory (HSC-iM) program is enriched in memory T cells and HSCs from recovered COVID-19 patients. Importantly, HSC-iM accumulates with age and with clonal hematopoiesis. Overall, heritable molecular alterations in a subset of human HSCs, an adaptation to long-term inflammatory stress, may predispose to heightened age-related risk of blood cancer and infection. One-Sentence SummaryInflammation across a lifetime rewires human HSCs to produce a distinct HSC subset with both beneficial and deleterious fitness consequences.

cell biology↗

bioRxiv2023

Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

genetics↗

bioRxiv2023

The entire brain, more or less is at work: 'Language regions' are artefacts of averaging

Models of the neurobiology of language suggest that a small number of anatomically fixed brain regions are responsible for language functioning. This derives from centuries of aphasia studies and decades of neuroimaging. The latter rely on thresholded measures of central tendency applied to activity patterns from heterogeneous stimuli. We hypothesised that these methods obscure the whole brain distribution of regions supporting language. Specifically, language regions are connectivity hubs, coordinating varying peripheral activity that averages out following thresholding. We tested this with neuroimaging meta-analyses and movie-fMRI. Results show that words localise to language regions when averaged but are distributed throughout the brain when examining specific linguistic representations. These language regions are partially connectivity hubs that are spatiotemporally dynamic, making connections with [~]40% of the brain periphery outside those regions, and only appearing in the aggregate over time. Hub-periphery connections encode linguistic representations, not the language regions alone. Results replicate with audiobook-fMRI. Finally, intracranial neuronal recordings support findings, showing language regions are hub-like, with linguistic representations decodable throughout the brain. Together, these four studies suggest that language regions are artefacts of averaging heterogeneous language representations. Instead, they are connectivity hubs coordinating whole-brain distributed network representations, suggesting why their damage results in aphasia.

neuroscience↗

bioRxiv2023

E-cigarette vapour induces cellular senescence in primary lung fibroblasts and may contribute to lung pathology

Cellular senescence has been recognized to play a role in COPD pathophysiology. Non-aerosolized E-liquid treatment of a lung fibroblast foetal cell line resulted in cellular senescence induction, but this has not been assessed using E-vapour exposure and using primary lung fibroblasts. Therefore, we investigated whether E-vapour exposure induces cellular senescence in primary human lung fibroblasts and whether this affects their tissue repair function. Primary human lung fibroblasts were stimulated with E-cigarette vapour extracts, and cigarette smoke extract (CSE) and Paraquat (PQ) as positive controls. IL-8 secretion was measured to confirm a stimulatory response. Multiple senescence markers (p16, p21, SA-{beta}-gal, and proliferation) were assessed and the tissue repair function was assessed using a scratch assay. Finally, we tried to validate our findings in an E-cigarette-exposed mouse model. Upon stimulation with CSE, PQ, and E-vapour extracts, cellular senescence was induced, which seemed dose-dependent and nicotine-independent. E-vapour-induced senescence resulted in an impaired tissue repair function. No significant difference was observed in the E-cigarette-exposed mouse model. In this study, we identify E-cigarette vapours potential to induce cellular senescence in primary human lung fibroblasts and that this affects their tissue repair function, which further adds to the identified risks of E-cigarette use.

cell biology↗

bioRxiv2023

Sm-like protein Rof inhibits transcription termination factor Rho by binding site obstruction and conformational insulation

Transcription termination factor {rho} is a hexameric, RNA-dependent NTPase that can adopt active closed-ring and inactive open-ring conformations. The Sm-like protein Rof, a homolog of the RNA chaperone Hfq, inhibits {rho}-dependent termination in vivo but recapitulation of this activity in vitro has proven difficult and the precise mode of Rof action is presently unknown. Our electron microscopic structures of {rho}-Rof and {rho}-RNA complexes show that Rof undergoes pronounced conformational changes to bind {rho} at the protomer interfaces, undercutting {rho} conformational dynamics associated with ring closure and occluding extended primary RNA-binding sites that are also part of interfaces between {rho} and RNA polymerase. Consistently, Rof impedes {rho} ring closure, {rho}-RNA interactions, and {rho} association with transcription elongation complexes. Structure-guided mutagenesis coupled with functional assays confirmed that the observed {rho}-Rof interface is required for Rof-mediated inhibition of cell growth and {rho}-termination in vitro. Bioinformatic analyses revealed that Rof is restricted to Pseudomonadota and that the {rho}-Rof interface is conserved. Genomic contexts of rof differ between Enterobacteriaceae and Vibrionaceae, suggesting distinct modes of Rof regulation. We hypothesize that Rof and other cellular anti-terminators silence {rho} under diverse, but yet to be identified, stress conditions when unrestrained transcription termination by {rho} would be lethal.

biochemistry↗

bioRxiv2023

Genomic insights into post-domestication expansion and selection of body size in ponies

Horses domestication revolutionized human civilization by changing transportation, farming, and warfare patterns. Despite extensive studies on modern domestic horse origins, the intricate demographic history and genetic signatures of pony size demand further exploration. Here, we present a high-quality genome of the Chinese Debao pony and extensively analyzed 385 individuals from 49 horse breeds. We reveal the conservation of ancient components in East Asian horses and close relationships between Asian horses and specific European pony lineages. Genetic analysis uncovers Asian paternal origin for European pony breeds, and these pony-sized horses share a close genetic affinity due to the presence of a potential ancestral ghost pony population. Additionally, we identify promising cis-regulatory elements influencing horse withers height by regulating genes like RFLNA and FOXO1. Overall, our study provides insightful perspectives into the development history and genetic determinants underlying body size in ponies and offers broader implications for horse population management and improvement. TeaserDecoding pony genetics: exploring origins and size determinants sheds light on their historical and biological impacts.

genomics↗

bioRxiv2023

Acquired stress resilience through bacteria-to-nematode horizontal gene transfer

Natural selection drives acquisition of organismal resilience traits to protect against adverse environments. Horizontal gene transfer (HGT) is an important evolutionary mechanism for the acquisition of novel traits, including metazoan acquisition of functions in immunity, metabolism, and reproduction via interdomain HGT (iHGT) from bacteria. We report that the nematode gene rml-3, which was acquired by iHGT from bacteria, enables exoskeleton resilience and protection against environmental toxins in C. elegans. Phylogenetic analysis reveals that diverse nematode RML-3 proteins form a single monophyletic clade most highly similar to bacterial enzymes that biosynthesize L-rhamnose to build cell wall polysaccharides. C. elegans rml-3 is regulated in developing seam cells by heat stress and stress-resistant dauer stage. Importantly, rml-3 deficiency impairs cuticle integrity, barrier functions and organismal stress resilience, phenotypes that are rescued by exogenous L-rhamnose. We propose that iHGT of an ancient bacterial rml-3 homolog enables L-rhamnose biosynthesis in nematodes that facilitates cuticle integrity and organismal resilience in adaptation to environmental stresses during evolution. These findings highlight the remarkable contribution of iHGT on metazoan evolution that is conferred by the domestication of bacterial genes.

genetics↗

bioRxiv2023

Transcription termination factor {rho} polymerizes under stress

Bacterial RNA helicase {rho} is a genome sentinel that terminates synthesis of damaged and junk RNAs that are not translated by the ribosome. Co-transcriptional RNA surveillance by {rho} is essential for quality control of the transcriptome during optimal growth. However, it is unclear how bacteria protect their RNAs from overzealous {rho} during dormancy or stress, conditions common in natural habitats. Here we used cryogenic electron microscopy, biochemical, and genetic approaches to show that residue substitutions, ADP, or ppGpp promote hyper-oligomerization of Escherichia coli {rho}. Our results demonstrate that nucleotides bound at subunit interfaces control {rho} switching from active hexamers to inactive higher-order oligomers and extended filaments. Polymers formed upon exposure to antibiotics or ppGpp disassemble when stress is relieved, thereby directly linking termination activity to cellular physiology. Inactivation of {rho} through hyper-oligomerization is a regulatory strategy shared by RNA polymerases, ribosomes, and metabolic enzymes across all life.

microbiology↗

bioRxiv2023

Percutaneous Intramyocardial Septal Cryoablation: A Canine Model with 6 months Follow-up

BACKGROUNDEchocardiography-guided percutaneous intramyocardial septal radiofrequency ablation (PIMSRA, Liwen procedure) is a novel treatment option for hypertrophic obstructive cardiomyopathy (HOCM). The safety and feasibility of using this procedure for cryoablation are unknown. OBJECTIVETo establish a canine model for echocardiography-guided percutaneous intramyocardial septal cryoablation (PIMSCA). METHODSEight canines underwent PIMSCA and had electrocardiography, echocardiography, myocardial contrast echocardiography (MCE), (ECG), serological and pathological examinations during the preoperative, immediate postoperative, and in 6-month follow-up. RESULTSAll eight canines underwent successful cryoablation and continued to be in sinus rhythm during ablation and without malignant arrhythmias. MCE showed that ablation area had decreased myocardial perfusion after procedure. Troponin I levels were significantly elevated [0.010 (0.005, 0.297) ng/mL vs. 3.122 (1.152,7.990) ng/mL, p < 0.05)]. At follow-up 6-months after procedure, all animals were alive, with thinning of the interventricular septum (7.26 {+/-} 0.52 mm vs. 3.86 {+/-} 0.29 mm, p < 0.05). Echocardiography showed no significant decrease in left ventricular ejection fractions (LVEF) (54.32 {+/-} 2.93 %vs. 54.70 {+/-} 2.47 %, p > 0.05) or changes by pulse-wave Doppler E/A (1.17 {+/-} 0.43 vs. 1.07 {+/-} 0.43, p > 0.05), E/e(8.09 {+/-} 1.49 vs. 10.05 {+/-}2.68, p > 0.05). Pathological findings proved effective cryoablation in myocardial tissues. We observed pericardial effusions and premature ventricular complexes (PVCs) associated with the procedure. CONCLUSIONOur findings provide preliminary evidence of the safety and feasibility of PIMSACA in interventricular septum reduction, which provides a potentially new treatment option for HOCM.

zoology↗

bioRxiv2023

Projection neurons are necessary for the maintenance, but not for the assembly, of the mouse olfactory circuit

The assembly and maintenance of neural circuits is crucial for proper brain function. Although the assembly of brain circuits has been extensively studied, much less is understood about the mechanisms controlling their maintenance as animals mature. In the olfactory system, the axons of olfactory sensory neurons (OSNs) expressing the same odor receptor converge into discrete synaptic structures of the olfactory bulb (OB) called glomeruli, forming a stereotypic odor map. The OB projection neurons, called mitral and tufted cells (M/Ts), have a single dendrite that branches into a single glomerulus, where they make synapses with OSNs. We used a genetic method to progressively eliminate the vast majority of M/T cells in early postnatal mice, and observed that the assembly of the OB bulb circuits proceeded normally. However, as the animals became adults the apical dendrite of remaining M/Ts grew multiple branches that innervated several glomeruli, and OSNs expressing single odor receptors projected their axons into multiple glomeruli, disrupting the olfactory sensory map. Moreover, ablating the M/Ts in adult animals also resulted in similar structural changes in the projections of remaining M/Ts and axons from OSNs. Interestingly, the ability of these mice to detect odors was relatively preserved despite only having 1-5% of projection neurons transmitting odorant information to the brain, and having highly disrupted circuits in the OB. These results indicate that a reduced number of projection neurons does not affect the normal assembly of the olfactory circuit, but induces structural instability of the olfactory circuitry of adult animals.

neuroscience↗

bioRxiv2023

Discovery of a multipotent cell type from the term human placenta

We identify a population of multipotent CDX2 cells from term human placentas with clonal expansion, migratory capacity, and immune-privileged transcriptional profiles. Isolated from 180 healthy pregnancies, these cells differentiate into cardiomyocyte and vascular lineages in vitro and in vivo. Single-cell RNA sequencing uncovers distinct cardiogenic and vasculogenic subpopulations, along with immune-modulatory and chemotactic programs, providing a blueprint for precision-guided cardiovascular cell therapy. In a NOD/SCID myocardial infarction model, CDX2 cells restore cardiac function, and clonal propagation preserves their cardiovascular differentiation potential. These findings position placental CDX2 cells as an ethically accessible, regenerative platform for targeted treatment of cardiovascular disease.

cell biology↗

bioRxiv2023

Differential substrate affinity and catabolite repression enable preferential use of urea by ammonia-oxidizing bacteria

Four distinct lineages of ammonia-oxidizing microorganisms (AOM) collectively contribute to one of the largest nitrogen fluxes in the global nitrogen budget. AOM possess widely different specific affinities for ammonia, thought to determine their niche differentiation. Nevertheless, ammonia-oxidizing archaea and bacteria (AOA, AOB), and complete ammonia oxidizers (comammox) co-occur in soils, freshwater sediments, and aquifers, suggesting that other factors must drive their coexistence. Here, we show that representatives of four AOM lineages employ distinct regulatory strategies for ammonia or urea utilization, thereby minimizing direct competition for either substrate. The tested AOA and comammox species preferentially used ammonia over urea, while beta-proteobacterial AOB favored urea utilization, repressed ammonia transport in the presence of urea, and showed higher affinity for urea than ammonia, whereas gamma-proteobacterial AOB co-utilized both substrates. Stable isotope tracing, kinetics, and transcriptomics experiments revealed that both assimilation and oxidation of ammonia are transport-dependent. These results reveal novel mechanisms of nitrogen metabolism regulation and transporter-based affinity underlying the contrasting niche adaptation and coexistence patterns among the major AOM lineages.

microbiology↗

bioRxiv2023

Modulation of prefrontal couplings by prior belief-related responses in ventromedial prefrontal cortex

Humans and animals can maintain constant payoffs in an uncertain environment by steadily re-evaluating and flexibly adjusting current strategy, which largely depends on the interactions between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). While the ventromedial PFC (vmPFC) represents the level of uncertainty (i.e., prior belief about external states), it remains unclear how the brain recruits the PFC-MD network to re-evaluate decision strategy based on the uncertainty. Here, we leverage nonlinear dynamic causal modeling on fMRI data to test how prior belief-dependent activity in vmPFC gates the information flow in the PFC-MD network when individuals switch their decision strategy. We show that the prior belief-related responses in vmPFC had a modulatory influence on the connections from dorsolateral PFC (dlPFC) to both, lateral orbitofrontal (lOFC) and MD. Bayesian parameter averaging revealed that only the connection from the dlPFC to lOFC surpassed the significant threshold, which indicates that the weaker the prior belief, the less was the inhibitory influence of the vmPFC on the strength of effective connections from dlPFC to lOFC. These findings suggest that the vmPFC acts as a gatekeeper for the recruitment of processing resources to re-evaluate the decision strategy in situations of high uncertainty. Author SummaryPrefrontal cortex (PFC) together with the mediodorsal thalamus (MD) jointly establish computations critical for behavioral adaptations. While the task uncertainty (i.e., prior belief) was represented by the ventromedial PFC (vmPFC), it remains unclear how the PFC-MD network reallocates the processing resources to re-evaluate decision strategy under uncertainty. Here we filled this gap by leveraging the Bayesian hierarchical modelling and nonlinear dynamic causal modelling in an associative learning task. We found that in situations of high uncertainty, the prior belief-related responses in vmPFC significantly strengthened effective connectivity from the dorsolateral PFC to the orbitofrontal cortex, but not to the MD. The findings provide evidence for the role of vmPFC in driving the re-evaluation of the decision strategy during behavioral adaptations in situations of uncertainty.

neuroscience↗

bioRxiv2023

3D electronic implants in subretinal space: long-term follow-up in rodents

Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 m pixel size. Since decreasing the pixel size below 75 m in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 m high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 m-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 m-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

neuroscience↗

bioRxiv2023

Modeling Human Spine-Spinal Cord Organogenesis by hPSC-Derived Neuromesodermal Progenitors

Human trunk development, including spine and spinal cord organogenesis, is a coordinated, orderly, and interdependent process with spatiotemporal tissue patterning. However, the underlying cellular and molecular mechanisms remain largely unclear due to the lack of an effective model that can simulate the early development of human body axis. Here, we reported the long-term patterning and dynamic morphogenesis of human trunk through the formation of spine-spinal cord organoids (SSCOs) self-organized from three-dimensional culture of human PSC-derived neuromesodermal progenitors (NMPs). The SSCOs resembled the morphogenetic features of spine and spinal cord along the anterior-posterior axis, and showed the chondro-osteogenic and neural trajectories consistent with developmental dynamics of spine and spinal cord in gestational embryo through single-cell RNA sequencing (scRNA-seq). In addition, we identified a new HMMR+ bipotent cell population with self-renewal ability and neural/mesodermal competence but distinct from NMPs, which may be involved in trunk development and represent an invaluable tool for disease modeling of spine- and spinal cord-related disorders. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/549829v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@14bfd30org.highwire.dtl.DTLVardef@1db7fe8org.highwire.dtl.DTLVardef@1aa66a1org.highwire.dtl.DTLVardef@380932_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

Single cell RNA analysis uncovers the cell differentiation trajectories and functionalization for air breathing of frog lung

The evolution and development of vertebrate lungs have received extensive concerns for the significance in terrestrial adaptation. Amphibians possess the most primitive lungs among tetrapods, underscoring the evolutionary importance of lungs in bridging the transition from aquatic to terrestrial life. However, the intricate process of cell differentiation during amphibian lung development is still lacking. Using single cell RNA-seq, we identified 21 cell types in the developing lung of a land-dwelling frog (Microhyla fissipes). We elucidated that single type of alveolar epithelial cells (AECs) existed in amphibian and the diversity of AECs may correspond to the capacity for terrestrial adaptation in tetrapods. Based on pseudotime trajectories analysis, we revealed previously unrecognized developmental-specific transition cell states of epithelial and endothelial cells supporting the rapid morphogenesis of lung during metamorphic climax. We illustrated the cellular and molecular processes during lung functionalization. These findings uncover the cell differentiation trajectories and functionalization for air breathing of frog lungs and highlight the evolutionary peculiarity of the primitive lungs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/549571v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d3188aorg.highwire.dtl.DTLVardef@f049feorg.highwire.dtl.DTLVardef@189f98borg.highwire.dtl.DTLVardef@15e3857_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Reusability Report: Few-shot learning creates predictive models of drug response that translate from high-throughput screens to individual patients

Machine learning (ML) and artificial intelligence (AI) methods are increasingly used in personalized medicine, including precision oncology. Ma et al. (Nature Cancer 2021) developed a new method c alled "Transfer of Cell Line Response Prediction" (TCRP) to train predictors of drug response in cancer cell lines and optimize their performance in higher complex cancer model systems via few-shot learning. TCRP was presented as a successful modeling approach in multiple case studies. Given the importance of this approach to assist clinicians in their treatment decision process, we sought to reproduce independently the authors findings and improve the reusability of TCRP in new case studies, including validation in clinical trial datasets, a high bar for drug response prediction. Our results support the superiority of TCRP over established statistical and machine learning approaches in preclinical and clinical settings. We developed new resources to increase the reusability of the TCRP model for future improvements and validation studies.

bioinformatics↗

bioRxiv2023

xTrimoPGLM: Unified 100B-Scale Pre-trained Transformer for Deciphering the Language of Protein

Protein language models have shown remarkable success in learning biological information from protein sequences. However, most existing models are limited by either autoencoding or autoregressive pre-training objectives, which makes them struggle to handle protein understanding and generation tasks concurrently. We propose a unified protein language model, xTrimoPGLM, to address these two types of tasks simultaneously through an innovative pre-training framework. Our key technical contribution is an exploration of the compatibility and the potential for joint optimization of the two types of objectives, which has led to a strategy for training xTrimoPGLM at an unprecedented scale of 100 billion parameters and 1 trillion training tokens. Our extensive experiments reveal that 1) xTrimoPGLM significantly outperforms other advanced baselines in 18 protein understanding benchmarks across four categories. The model also facilitates an atomic-resolution view of protein structures, leading to an advanced 3D structural prediction model that surpasses existing language model-based tools. 2) xTrimoPGLM not only can generate de novo protein sequences following the principles of natural ones, but also can perform programmable generation after supervised fine-tuning (SFT) on curated sequences. These results highlight the substantial capability and versatility of xTrimoPGLM in understanding and generating protein sequences, contributing to the evolving landscape of foundation models in protein science. Trained weight for the xTrimoPGLM model, and downstream datasets are available at https://huggingface.co/proteinglm.

synthetic biology↗