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Biology subjects

Chen, S.

Publications and source records attributed to Chen, S..

At least 577 records · Page 32Linked to original sources

Network topology enables efficient response to environment in Physarum polycephalum

The network-shaped body plan distinguishes the unicellular slime mould Physarum polycephalum in body architecture from other unicellular organisms. Yet, network-shaped body plans dominate branches of multi-cellular life such as in fungi. What survival advantage does a network structure provide when facing a dynamic environment with adverse conditions? Here, we probe how network topology impacts P. polycephalums avoidance response to an adverse blue light. We stimulate either an elongated, I-shaped amoeboid or a Y-shaped networked specimen and subsequently quantify the evacuation process of the light-exposed body part. The result shows that Y-shaped specimen complete the avoidance retraction in a comparable time frame, even slightly faster than I-shaped organisms, yet, at a lower almost negligible increase in migration velocity. Contraction amplitude driving mass motion is further only locally increased in Y-shaped specimen compared to I-shaped providing further evidence that Y-shapeds avoidance reaction is energetically more efficient than in I-shaped amoeboid organisms. The difference in the retraction behaviour suggests that the complexity of network topology provides a key advantage when encountering adverse environments. Our findings could lead to a better understanding of the transition from unicellular to multicellularity.

biophysics↗

Serial dependence in timing at the perceptual level being modulated by working memory

Recent experiences bias the perception of following stimuli, as has been verified in various kinds of experiments in visual perception. This phenomenon, known as serial dependence, may reflect mechanisms to maintain perceptual stability. In the current study, we examined several key properties of serial dependence in temporal perception. Firstly, we examined the source of serial dependence effect in temporal perception. We found that perception without motor reproduction is sufficient to induce the sequential effect; the motor reproduction caused a stronger effect and it is achieved by biasing the perception of the future target duration rather than directly influences the subsequent movement. Secondly, we ask how the working memory influences serial dependence in the in a temporal reproduction task. By varying the delay time between standard duration and the reproduction, we showed that the strength of serial dependence enhanced as the delay increased. Those features of serial dependence are consistent with what has been observed in the visual perceptual tasks, for example, orientation perception or location perception. The similarities between the visual and the timing tasks may suggest a similar neural coding mechanism of magnitude between the visual stimuli and the duration.

neuroscience↗

Systematic characterization of brain cellular crosstalk signaling networks in Alzheimer's disease reveals a novel role for SEMA6D in TREM2-dependent microglial activation

Cellular crosstalk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimers disease (AD). To discover crosstalk dysregulations in AD, we reconstructed crosstalk networks from single-nucleus transcriptional profiles from 67 clinically and neuropathologically well-characterized controls and AD brain donors. We predicted a significant role for TREM2 and additional AD risk genes mediating neuron-microglia crosstalk in AD. The gene sub-network mediating SEMA6D-TREM2 crosstalk is activated near A{beta} plaques and SEMA6D-expressing cells and is disrupted in late AD stages. Using CRISPR-modified human induced pluripotent stem cell-derived microglia, we demonstrated that SEMA6D induces microglial activation in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular crosstalk networks can yield novel insights into AD biology. One Sentence SummaryWe investigate cell-to-cell communication in Alzheimers disease to characterize disease biology and suggest new avenues for therapeutic intervention.

neuroscience↗

Single-cell gene expression and chromatin accessibility profiling of human pancreatic islets at basal and stimulatory conditions nominates mechanisms of type 1 diabetes genetic risk

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by the loss of pancreatic islet beta cells. The mechanisms of T1D genetic risk remain poorly understood. Here, we present a multi-omic integrative study of single-cell/nucleus molecular profiles of gene expression and chromatin accessibility in the same biological samples from healthy and beta cell autoantibody+ (AAB+) human pancreatic islets to characterize mechanisms of islet-mediated T1D genetic risk. We additionally performed single-cell/nucleus multi-omic profiling of healthy islets under two stimulatory conditions used as in vitro models of T1D (cytokine cocktail and CVB4 infection) to evaluate how environmental exposures recapitulate multi-omic signatures of T1D. In total, we analyzed 121,272 cells/nuclei across 34 libraries, identifying 10 distinct cell types. We identified cell-type-specific and disease-associated cis-regulatory elements and nominated likely target genes. We provide evidence that T1D genetic risk is mediated through multiple pancreatic cell populations, including islet endocrine cells (beta, alpha, gamma, and delta), exocrine acinar and ductal cells, and immune cells. Finally, we identified three independent T1D risk variants acting through pancreatic islet endocrine cells at the TOX, RASGRP1, and DLK1/MEG3 loci. Together, this work improves our understanding of how non-coding genetic variants encode T1D risk through a complex interplay of different cell types in the pancreas.

genomics↗

PAST: latent feature extraction with a Prior-based self-Attention framework for Spatial Transcriptomics

Rapid advances in spatial transcriptomics (ST) have revolutionized the interrogation of spatial heterogeneity and increased the demand for comprehensive methods to effectively characterize spatial domains. As a prerequisite for ST data analysis, spatial domain characterization is a crucial step for downstream analyses and biological implications. Here we propose PAST, a variational graph convolutional auto-encoder for ST, which effectively integrates prior information via a Bayesian neural network, captures spatial patterns via a self-attention mechanism, and enables scalable application via a ripple walk sampler strategy. Through comprehensive experiments on datasets generated by different technologies, we demonstrated that PAST could effectively characterize spatial domains and facilitate various downstream analyses, including ST visualization, spatial trajectory inference and pseudo-time analysis, by integrating spatial information and reference from various sources. Besides, we also show the advantages of PAST for accurate annotation of spatial domains in newly sequenced ST data and biological implications in the annotated domains.

bioinformatics↗

Mechanically manipulate glymphatic transportation by ultrasound combined with microbubbles

The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transportation is believed to be driven by the perivascular pumping effect generated by arterial wall pulsation induced by the cardiac cycle. Ultrasound sonication of circulating microbubbles in the cerebral vasculature induces volumetric expansion and contraction of microbubbles that push and pull on the vessel wall to generate a microbubble pumping effect. The objective of this study was to evaluate whether glymphatic transportation can be mechanically manipulated by focused ultrasound (FUS) sonication of microbubbles. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as a fluid tracer followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected microbubbles. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the perivascular space into the interstitial space. This study revealed that ultrasound combined with circulating microbubbles could noninvasively enhance glymphatic transportation in the brain. Significance StatementThe glymphatic system is a waste clearance system in the brain analogous to the lymphatic system in peripheral organs. Glymphatic system impairment might contribute to brain disease pathologies, including those in neurodegenerative diseases, traumatic brain injury, and stroke. This study revealed that ultrasound could mechanically enhance glymphatic transportation. This result opens opportunities for using ultrasound to probe the role of the glymphatic system in brain function and brain diseases. Findings from this study suggest that ultrasound can be utilized as a noninvasive/nonpharmacological approach to mitigate brain diseases caused by impaired glymphatic function.

bioengineering↗

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase

{beta}-lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of {beta}-lactamases among pathogenic bacteria limits the efficacy of {beta}-lactam antibiotics. This has created a major public health crisis. The use of {beta}-lactamase inhibitors has proven useful in restoring the activity of {beta}-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-{beta}-lactamases (MBLs) are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia, is a significant contributor to the {beta}-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, 3-{beta}7 and {beta}12-5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics (MD) simulations were performed, Markov State Models (MSM) were built, and convolutional variational autoencoder (CVAE)-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, R236) were mutated and the activity of the generated L1 variants was evaluated in cell-based experiments. The results demonstrate that there are extremely significant gating interactions between 3-{beta}7 and {beta}12-5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions.

biophysics↗

GPR84-Mediated Signal Transduction Promotes Brown Adipocyte Function

G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, may be involved in various metabolic conditions but the mechanism remains unclear. We found that GPR84 is highly expressed and functions in brown adipose tissue (BAT). GPR84 knockout mice exhibited increased adiposity and vulnerability to cold exposure after aging, along with an increased BAT lipid content and decreased BAT activation compared to wild-type control mice. In vitro, primary brown adipocytes from GPR84 knockout mice showed reduced expression of thermogenic genes and lower O2 consumption. The GPR84 agonist 6-OAU reversed these effects and restored brown adipocyte activation. In vivo and in vitro results showed that BAT defects in GPR84 knockout mice were attributed to mitochondrial dysfunction. GPR84 activation greatly affected intracellular calcium efflux, further influencing mitochondrial respiration. GPR84 activates BAT by controlling the mitochondrial calcium content and respiration, suggesting a therapeutic target for activating BAT and treating metabolic diseases. HIGHLIGHTSO_LIHigh expression of GPR84 in brown adipocytes is induced by cold stimulation. C_LIO_LIAged GPR84 knockout mice exhibit brown adipose tissue defects under cold exposure. C_LIO_LIGPR84 knockout mice show reduced mitochondrial function of brown adipocytes. C_LIO_LIGPR84 activation improves brown adipocyte functions. C_LI

physiology↗

SurvivalML: an integrative platform for the discovery and exploration of prognostic models in multi-center cancer cohorts

Advances in multi-omics and big-data technologies have led to numerous prognostic signatures aimed at improving current clinicopathological staging systems. Due to the lack of reproducibility and independent confirmation, few signatures have been translated into clinical routine. As high-quality datasets accumulate, identifying robust signatures across multiple independent cohorts becomes possible. Nonetheless, inaccurate data retrieval, different versions of genome annotations, disparate expression distributions, difficult data cleaning, inconsistent clinical information, algorithm selection, and parameter tuning have impeded model development and validation in multi-center datasets. Hence, for the first time, we introduced SurvivalML (https://rookieutopia.com/app_direct/SurvivalML/), a web application for helping develop and validate prognostic models across multi-center datasets. SurvivalML included 37,325 samples (253 eligible datasets) with both transcriptome data and survival information from 21 cancer types, which were renewedly and uniformly re-annotated, normalized, and cleaned. This application provided 10 survival machine-learning algorithms for flexibly training models via tuning essential parameters online and delivered four aspects for model evaluation, including Kaplan-Meier survival analysis, time-dependent ROC, calibration curve, and decision curve analysis. Overall, we believe that SurvivalML can serve as an attractive platform for model discovery from multi-center datasets.

bioinformatics↗

FGFR1 governs iron metabolism via regulating post-translational modification of IRP2 in prostate cancer cells

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. However, how FGFR1 facilitates PCa progression is not fully revealed, although it is known to confer tumor growth advantage and metastasis. Here we report that FGFR1 deletion in DU145 human PCa cells retards the iron metabolism and reduces transferrin receptor 1 (TFR1), which synergistically enhances the anti-cancer effect of iron chelator. FGFR1 and TFR1 are highly expressed in PCa, and FGFR1 overexpression increased TFR1 in PCa cell lines. Furthermore, we first time demonstrate that FGFR1 deletion boosts and shifts the degradation of iron regulatory proteins 2 (IRP2) to downregulate TFR1. Detailed characterization revealed that based on FGFR1 deletion the stability of IRP2 is broken, whose degradation is accelerated, which can be not observed without FGFR1 deletion. In addition, IRP2 overexpression rescue the malignancy degree of DU145 cells. Our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by upregulating iron metabolism, and that the FGFR1/IRP2/TFR1 axis can be a potential target for managing PCa progression.

cancer biology↗

Differential expression of RSK4 transcript isoforms in cancer and its clinical relevance

RSK4 belongs to the p90 Ribosomal S6 Kinase family which lies downstream of the MAPK pathway. While we previously revealed this kinase to be a therapeutic target in lung and bladder cancers, there is conflicting evidence for its wider role in other cancer types. Indeed, RSK4 was instead suggested to be a tumour suppressor in colorectal and gastric cancers, and reports of its role in breast malignancies are contradictory. One possible explanation for these discrepancies may be the expression of different RSK4 isoforms across cancers. Four RNAs are produced from the RSK4 gene with two being protein-coding. Here, we analysed the expression of the two RSK4 protein-coding mRNAs across 30 normal and 33 cancer tissue types from the combined GTEx/TCGA dataset and correlated it with associated clinical features. This analysis revealed the mRNA expression of RSK4 isoform 1 and 2 to be independent prognostic factors for patient survival, pathological stage, cancer metastasis, recurrence, and immune infiltration in brain, stomach, cervical, and kidney cancers. However, we found that the upregulation of either RSK4 isoform can equally be associated with good or bad prognosis depending on the cancer type considered, and changes in the expression ratio of isoforms fail to predict clinical outcome. Taken together, we show that differential isoform expression alone cannot explain the contradictory roles of RSK4 in cancers and that further research is needed to highlight the underlying mechanisms for the context-dependent function of this kinase.

bioinformatics↗

CorA gene rearrangement triggered the salinity-driven speciation of Poseidoniales

Land-ocean interactions greatly impacted the evolution of coastal life on Earth. However, the geological forces and genetic mechanisms that shaped evolutionary adaptations and allowed microorganisms to inhabit coastal brackish waters remain largely unexplored. Here, we infer the evolutionary trajectory of the ubiquitous heterotrophic archaea Poseidoniales (Marine Group II archaea) across global aquatic habitats. Our results show that their brackish subgroups have evolved through the rearrangement of the magnesium transport gene corA that conferred osmotic-stress tolerance dated to over 600 million years ago. The coastal family of Poseidoniales showed a rapid increase in the evolutionary rate during and in the aftermath of the Cryogenian Snowball Earth (~700 million years ago), possibly in response to the enhanced phosphorus supply and the rise of algae. Our study highlights the close interplay between genetic changes and ecosystem transformations that boosted microbial diversification in the Neoproterozoic continental margins.

evolutionary biology↗

A scalable implementation of the recursive least-squares algorithm for training spiking neural networks

Training spiking recurrent neural networks on neuronal recordings or behavioral tasks has become a popular way to study computations performed by the nervous system. As the size and complexity of neural recordings increase, there is a need for efficient algorithms that can train models in a short period of time using minimal resources. We present optimized CPU and GPU implementations of the recursive least-squares algorithm in spiking neural networks. The GPU implementation can train networks of one million neurons, with 100 million plastic synapses and a billion static synapses, about 1000 times faster than an unoptimized reference CPU implementation. We demonstrate the codes utility by training a network, in less than an hour, to reproduce the activity of > 66, 000 recorded neurons of a mouse performing a decision-making task. The fast implementation enables a more interactive in-silico study of the dynamics and connectivity underlying multi-area computations. It also admits the possibility to train models as in-vivo experiments are being conducted, thus closing the loop between modeling and experiments.

neuroscience↗

Polylactide Degradation Activates Immune Cells by Metabolic Reprogramming

Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet methods to neutralize the pH have not significantly reduced adverse responses. Using a bioenergetic model, we observed delayed cellular changes that were not apparent in the short-term. Amorphous and semi-crystalline PLA degradation products, including monomeric L-lactic acid, mechanistically remodel metabolism in cells leading to a reactive immune microenvironment characterized by elevated proinflammatory cytokines. Selective inhibition of metabolic reprogramming and altered bioenergetics both reduce these undesirable high cytokine levels and stimulate anti-inflammatory signals. Our results present a new biocompatibility paradigm by identifying metabolism as a target for immunomodulation to increase tolerance to biomaterials, ensuring safe clinical application of PLA-based implants for soft- and hard-tissue regeneration, and advancing nanomedicine and drug delivery.

bioengineering↗

Molecular and morphological analyses of the genus Episoriculus with the description of a new subgenus

Shrews in the genus Episoriculus are among the least known mammals in China. It occurs mainly in the Himalayas and the Hengduan Mountains. We report the sequencing and analyses of one mitochondrial gene (Cyt b) and three nuclear genes (Apob, Brca1, and Rag2) for 77 specimens, and analyses of morphological measurements for 56 specimens. Phylogenetic and morphological studies answer three longstanding questions. First, Episoriculus sacratus and E. umbrinus are valid species, and not subspecies of E. caudatus. Second, Pseudosoriculus fumidus is a valid taxon that does not belong to the genus Episoriculus. Third, the genus Episoriculus has eight valid species: E. baileyi, E. caudatus, E. leucops, E. macrurus, E. sacratus, E. soluensis, Episoriculus sp., and E. umbrinus. Ultimately, we erected subgenus Longacauda subgen. nov. for morphologically distinct E. macrurus, which leaves the nominate subgenus Episoriculus with the remaining seven congeners.

synthetic biology↗

Plant and prokaryotic TIR domains generate distinct cyclic ADPR NADase products

Toll/interleukin-1 receptor (TIR) domain proteins function in cell death and immunity. In plants and bacteria, TIR domains are enzymes that produce isomers of cyclic ADPR (cADPR) as putative immune signaling molecules. The identity and functional conservation of cADPR isomer signals is unclear. A previous report found that a plant TIR could cross-activate the prokaryotic Thoeris TIR-immune system, suggesting the conservation of plant and prokaryotic TIR-immune signals. Here, we generate auto-active Thoeris TIRs and test the converse hypothesis: do prokaryotic Thoeris TIRs also cross-activate plant TIR-immunity? Using in planta and in vitro assays, we find that Thoeris and plant TIRs generate overlapping sets of cADPR isomers, and further clarify how plant and Thoeris TIRs activate the Thoeris system via producing 3cADPR. This study demonstrates that the TIR-signaling requirements for plant and prokaryotic immune systems are distinct and that TIRs across kingdoms generate a diversity of small molecule products.

plant biology↗

Cellular Heterogeneity of Pluripotent Stem Cell Derived Cardiomyocyte Grafts is Mechanistically Linked to Treatable Arrhythmias

BackgroundExciting pre-clinical data have confirmed that human pluripotent stem cell derived cardiomyocytes (PSC-CMs) can remuscularise the injured or diseased heart, with several clinical trials now in planning or recruitment stages worldwide. However, ventricular arrhythmias are a predictable complication following engraftment of intramyocardially injected PSC-CMs. Therefore, there is an urgent unmet need to gain mechanistic insights and treatment strategies to control or prevent these engraftment arrhythmias (EAs). MethodsWe used a porcine model of myocardial infarction and PSC-CM transplantation to investigate efficacy of pharmacologic and catheter based anti-arrhythmic strategies in mitigating EAs. Furthermore, cell doses were robustly phenotyped using single cell ribonucleic acid sequencing and high parameter flow cytometry to identify cellular characteristics predictive of arrhythmogenesis. ResultsCombination therapy with amiodarone and ivabradine significantly reduced EA rate and burden following PSC-CM transplantation. Catheter ablation was also a feasible and effective treatment strategy which could be considered in the case of pharmacologically refractory arrhythmias. In addition, we show that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. We further describe two unique surface marker signatures, SIRPA+/CD90-/CD200+ and SIRPA+/CD90-/CD200-, which identify arrhythmogenic and non-arrhythmogenic cardiomyocytes respectively. ConclusionOur data deepens mechanistic understanding of EAs and suggests that modifications to current PSC-CM production and/or selection protocols could ameliorate this problem. We further show that current clinical pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias, an important safety consideration given several impending clinical trials.

cell biology↗

Amyloidogenic Propensity of Self-Assembling Peptides and their Adjuvant Potential for use as DNA Vaccines

De novo designed peptides that self-assemble into cross-{beta} rich fibrillar biomaterials have been pursued as an innovative platform for the development of adjuvant- and inflammation-free vaccines. However, they share structural properties similar to amyloid species implicated in neurodegenerative diseases, which has been a long-standing concern for their translation. Here, we comprehensively characterize the amyloidogenic character of the amphipathic self-assembling cross-{beta} peptide KFE8, compared to pathological amyloid and amyloid-like proteins -synuclein (-syn) and TDP-43. Further, we developed plasmid-based DNA vaccines with the KFE8 backbone serving as a fibrillizing scaffold for delivery of a GFP model antigen. We find that expression of tandem repeats of KFE8 is non-toxic and can be efficiently cleared by autophagy. We also demonstrate that synthetic KFE8 nanofibers do not cross-seed amyloid formation of -syn in mammalian cells compared to -syn preformed fibrils. In mice, vaccination with plasmids encoding the KFE32-GFP fusion protein elicited robust immune responses, inducing production of significantly higher levels of anti-GFP antibodies compared to soluble GFP or -syn tagged GFP. Antigen-specific CD8+T cells were also detected in the spleens of vaccinated mice and cytokine profiles from antigen recall assays indicate a balanced Th1/Th2 response. These findings illustrate that cross-{beta}-rich peptide nanofibers have distinct properties from those of pathological amyloidogenic proteins, and are an attractive platform for the development of DNA vaccines with self-adjuvanting properties and improved safety profiles.

bioengineering↗