Biology subjects

Tu, Y.

Publications and source records attributed to Tu, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

A molecularly defined brain circuit module for regulating the panic-like defensive state

Panic is an episode of strong defensive state, characterized by intense fear and severe physical symptoms such as elevated cardiorespiratory activities. How the brain generates panic state remains poorly understood. Here, we developed a robot-based experimental paradigm to evoke panic-like defensive state in mice. When stimulated by the robot, the mice exhibited jumping escapes and elevated cardiorespiratory activities. With this paradigm, we identified Cbln2-expressing (Cbln2+) neurons in the posterior hypothalamic nucleus (PHN) as a key neuronal population essential for the induction of panic-like defensive state. Activation of Cbln2+ PHN neurons induced behavioral and physical symptoms of panic-like defensive state. These neurons were strongly activated by noxious mechanical stimuli and encode jumping escape vigor. They were synaptically innervated by anxiety-associated brain areas and provoked panic-like defensive state via their projection to the periaqueductal gray. Together, our results reveal a molecularly defined circuit module that regulates the panic-like defensive state in mice.

neuroscience↗

bioRxiv2024

The Accumulation of Progerin Underlies the Loss of Aortic Smooth Muscle Cells in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid disorder characterized by multiple aging-like phenotypes, including disease in large arteries. HGPS is caused by an internally truncated prelamin A (progerin) that cannot undergo the ZMPSTE24-mediated processing step that converts farnesyl-prelamin A to mature lamin A; consequently, progerin retains a carboxyl-terminal farnesyl lipid anchor. In cultured cells, progerin and full-length farnesyl-prelamin A (produced in Zmpste24-/- cells) form an abnormal nuclear lamin meshwork accompanied by nuclear membrane ruptures and cell death; however, these proteins differ in their capacity to cause arterial disease. In a mouse model of HGPS (LmnaG609G), progerin causes loss of aortic smooth muscle cells (SMCs) by [~]12 weeks of age. In contrast, farnesyl-prelamin A in Zmpste24-/- mice does not cause SMC loss--even at 21 weeks of age. In young mice, aortic levels of farnesyl-prelamin A in Zmpste24-/- mice and aortic levels of progerin in LmnaG609G/+ mice are the same. However, the levels of progerin and other A-type lamins increase with age in LmnaG609G/+ mice, whereas farnesyl-prelamin A and lamin C levels in Zmpste24-/- mice remain stable. Lmna transcript levels are similar, implying that progerin influences nuclear lamin turnover. We identified a likely mechanism. In cultured SMCs, the phosphorylation of Ser-404 by AKT (which triggers prelamin A degradation) is reduced in progerin. In mice, AKT activity is significantly lower in LmnaG609G/+ aortas than in wild-type or Zmpste24-/- aortas. Our studies identify that the accumulation of progerin in LmnaG609G aortas underlies the hallmark arterial pathology in HGPS. One Sentence SummaryThe age-related accumulation of progerin in smooth muscle cells (SMCs) explains the loss of arterial SMCs in Hutchinson-Gilford progeria syndrome.

cell biology↗

bioRxiv2024

Phthalate exposure influences mating behavior and sperm morphology in an aquatic ecotoxicology model system

Phthalates are a group of chemicals used to make plastics more durable, found in applications from cosmetics, lubricating oils, and flooring to soap, shampoo, and hairspray (CDC, 2021). Phthalates are also now known to be endocrine disruptors with connections to adverse reproductive outcomes in animals, including humans. Here, we evaluate the potential effects of a widely used phthalate ester, dimethyl phthalate (DMP), on male reproduction in a freshwater snail. DMP is found in industrial applications like solid rocket propellant as well as consumer products such as insect repellents and plastics. While there is some evidence that DMP negatively affects reproduction, especially in females, we still know very little about potential DMP effects on males. We addressed this important knowledge gap by testing the effects of DMP on Potamopyrgus antipodarum, a prosobranch snail native to New Zealand. These snails are very sensitive to water conditions and environmental chemicals, including endocrine-disrupting compounds, and are thus rising in prominence as water-quality sentinels and ecotoxicology models. We exposed experimental groups of male P. antipodarum to one of three different concentrations of DMP and characterized mating behavior and sperm morphology as a function of DMP exposure. Differences in these traits were primarily observed between the males in the control versus the High (10-6 M) DMP concentration group. As DMP exposure levels increased, we found that mating frequency ultimately decreased by more than 69% and that sperm morphology was increasingly altered relative to control males. Altogether, study outcomes suggest DMP exposure in male animals could have negative effects on reproduction, with particular relevance in aquatic and marine environments that are especially likely to harbor leached endocrine-disrupting chemicals.

ecology↗

bioRxiv2024

Programmable Editing of Primary MicroRNA Switches Stem Cell Differentiation and Improves Tissue Regeneration

Programmable RNA editing is harnessed for modifying mRNA. Besides mRNA, miRNA also regulates numerous biological activities, but current RNA editors have yet to be exploited for miRNA manipulation. To engineer primary miRNA (pri-miRNA), the miRNA precursor, we present a customizable editor REPRESS (RNA Editing of Pri-miRNA for Efficient Suppression of miRNA) and characterize critical parameters. The optimized REPRESS is distinct from other mRNA editing tools in design rationale, hence enabling editing of pri-miRNAs that are not editable by other RNA editing systems. We edited various pri-miRNAs in different cells including adipose-derived stem cells (ASCs), hence attenuating mature miRNA levels without disturbing host gene expression. We further developed an improved REPRESS (iREPRESS) that enhances and prolongs pri-miR-21 editing for at least 10 days, with minimal perturbation of transcriptome and miRNAome. iREPRESS reprograms ASCs differentiation, promotes in vitro cartilage formation and augments calvarial bone regeneration in rats, thus implicating its potentials for engineering miRNA for many applications such as stem cell engineering and tissue regeneration.

bioengineering↗

bioRxiv2024

Bacterial motility depends on a critical flagellum length and energy-optimised assembly

The flagellum is the most complex macromolecular structure known in bacteria and comprised of around two dozen distinct proteins. The main building block of the long, external flagellar filament, flagellin, is secreted through the flagellar type-III secretion system at a remarkable rate of several tens of thousands amino acids per second, significantly surpassing the rates achieved by other pore-based protein secretion systems. The evolutionary implications and potential benefits of this high secretion rate for flagellum assembly and function, however, have remained elusive. In this study, we provide both experimental and theoretical evidence that the flagellar secretion rate has been evolutionarily optimized to facilitate rapid and efficient construction of a functional flagellum. By synchronizing flagellar assembly, we found that a minimal filament length of 2.5 {micro}m was required for swimming motility. Biophysical modelling revealed that this minimal filament length threshold resulted from an elasto-hydrodynamic instability of the whole swimming cell, dependent on the filament length. Furthermore, we developed a stepwise filament labeling method combined with electron microscopy visualization to validate predicted flagellin secretion rates of up to 10,000 amino acids per second. A biophysical model of flagellum growth demonstrates that the observed high flagellin secretion rate efficiently balances filament elongation and energy consumption, thereby enabling motility in the shortest amount of time. Taken together, these insights underscore the evolutionary pressures that have shaped the development and optimization of the flagellum and type-III secretion system, illuminating the intricate interplay between functionality and efficiency in assembly of large macromolecular structures. Significance statementOur study demonstrates how protein secretion of the bacterial flagellum is finely tuned to optimize filament assembly rate and flagellum function while minimizing energy consumption. By measuring flagellar filament lengths and bacterial swimming after initiation of flag-ellum assembly, we were able to establish the minimal filament length necessary for swimming motility, which we rationalized physically as resulting from an elasto-hydrodynamic instability of the swimming cell. Our bio-physical model of flagellum growth further illustrates how the physiological flagellin secretion rate is optimized to maximize filament elongation while conserving energy. These findings illuminate the evolutionary pressures that have shaped the function of the bacterial flagellum and type-III secretion system, driving improvements in bacterial motility and overall fitness.

microbiology↗

bioRxiv2024

A replicable and generalizable neuroimaging-based indicator of pain sensitivity across individuals

Developing neural indicators of pain sensitivity is crucial for revealing the neural basis of individual differences in pain and advancing individualized pain treatment. To identify reliable neural indicators of pain sensitivity, we leveraged six large and diverse functional magnetic resonance imaging (fMRI) datasets (total N=1046). We found replicable and generalizable correlations between nociceptive-evoked fMRI responses and pain sensitivity for laser heat, contact heat, and mechanical pains. These fMRI responses correlated more strongly with pain sensitivity than with tactile, auditory, and visual sensitivity. Moreover, we developed a machine learning model that accurately predicted not only pain sensitivity but also pain reduction from different interventions in healthy individuals. Notably, these findings were influenced considerably by sample sizes, requiring >200 for univariate correlation analysis and >150 for multivariate machine learning modelling. Altogether, we demonstrate the validity of decoding pain sensitivity from fMRI responses, thus facilitating interpretations of subjective pain reports and promoting more mechanistically informed investigation of pain physiology.

neuroscience↗

bioRxiv2024

Identification of a Conserved B-Cell Epitope on the Capsid Protein of Porcine Circovirus Type 4

Porcine circovirus type 4 (PCV4), a recently identified circovirus, is prevalent in numerous provinces in China, as well as in South Korea, Thailand, and Europe. PCV4 virus rescued from an infectious clone showed pathogenicity, suggesting the economic impact of PCV4. However, there remains a lack of understanding regarding the immunogenicity and epitopes of PCV4. This study generated a monoclonal antibody (MAb) 1D8 by immunizing mice with PCV4 virus-like particles (VLPs). Subsequently, the epitope recognized by the MAb 1D8 was identified by truncated protein expression and alanine scanning mutagenesis analysis. Results showed that the 225PKQG228 located at the C-terminus of the PCV4 Cap protein is the minimal motif binding to the MAb. Homology modeling analysis and immunoelectron microscopy revealed that the epitope extends beyond the outer surface of the PCV4 VLP. Moreover, the epitope is highly conserved among PCV4 strains and does not react with other PCVs. Together, the MAb 1D8 recognized epitope shows potential for detecting PCV4. These findings significantly contribute to the design of antigens for PCV4 detection and control strategies. IMPORTANCEPorcine circovirus type 4 (PCV4) is a novel circovirus. Although PCV4 has been identified in several countries, including China, Korea, Thailand, and Spain, no vaccine is available. Given the potential pathogenic effects of PCV4 on pigs, PCV4 could threaten the global pig farming industry, highlighting the urgency for further investigation. Thus, epitopes of PCV4 remain to be determined. Our finding of a conserved epitope significantly advances vaccine development and pathogen detection.

microbiology↗

bioRxiv2024

The stability of lower genital tract microbiota correlates with reproductive system function and in vitro fertilization and frozen embryo transfer outcomes in women with polycystic ovarian syndrome

We previously found that the lower genital tract (LGT) microbiota of polycystic ovarian syndrome (PCOS) women has altered when compared to healthy reproductive-aged women, however whether this alternation will have an impact on the reproductive system function and pregnancy outcomes of PCOS patients have not yet been identified. Between 2018 and 2021, we totally enrolled 191 reproductive-aged women in three independent case-control studies, 209 vaginal and 209 cervical swabs, and 9 cervical epithelial cells samples were collected from the study subjects. Firstly, we analyzed the correlation between LGT flora and clinical characteristics of 97 women (containing 47 PCOS patients and 50 control reproductive-aged women), canonical correspondence analysis (CCA) showed that LH/FSH ratio was the most relevant factor that was related to the dominant genera in women with PCOS (r2=0.233, p=0.001), and menstrual cycle frequency was also strongly related to the LGT organisms (r2=0.116, p=0.005). Next, through analysis of 72 PCOS patients who were underwent IVF-FET therapy, the FET outcome in PNB group (PCOS with relative abundance of Lactobacillus [≥]50%, n=57) was significant better than PDB group(PCOS patients with relative abundance of Lactobacillus<50%, n=15). Further, we randomly selected nine reproductive-aged PCOS patients (approximately half of them had altered LGT microbiota: Lactobacillus spp. [≤]50%, n=5) and simultaneously collected both LGT swabs and cervical epithelial cells from them. By synchronization analysis of RNA sequencing of the cervical epithelial cells and 16S rRNA sequencing of the microbes, we found that the gene expression profiles of the cells significantly differed between the PDB (PCOS patients with relative abundance of Lactobacillus<50%, n=4) and PNB (PCOS with relative abundance of Lactobacillus [≥]50%, n=5) groups. Above all, we systematically elucidate the potential relationship between LGT microbiota with the reproductive system function and IVF-FET outcomes in PCOS patients. Importancepolycystic ovarian syndrome (PCOS) women always suffered from poor pregnancy outcome: high incidence of abortion, preterm-birth, and premature rupture of membranes. Although some patients have improved their reproductive outcomes through assisted reproductive technology, the risk of early clinical pregnancy loss for PCOS patients after IVF treatment still ranges from 12% to 48%. As we previously found that the LGT flora of PCOS women had significant altered when compared with healthy parallel group, and more evidence showed that the genital tract microbiota may have a critical role in the process of embryo implantation and development, here we used multiple study groups to explore the potential relationship between LGT microbiota with reproductive system function and FET outcome in PCOS patients in this study. Our findings provide a new perspective for exploring novel therapy to improve the reproductive outcomes of PCOS patients.

physiology↗

bioRxiv2023

Pain hypersensitivity is dependent on autophagy protein Beclin 1 in males but not females

Chronic pain is a pervasive health, social, and economic problem affecting 1 in 5 individuals around the world. Increasingly, it is understood that alterations in fundamental cell biological processes are critical for chronic pain. A prominent cellular process is autophagy but whether it plays a role in pain is unknown. To investigate whether autophagy is involved in pain processing and is targetable for pain relief, we focused on Beclin 1, a component of the class III phosphatidylinositol 3-kinase (PI3K) complex necessary for initiating autophagy. Here, we found that inflammatory pain hypersensitivity in male mice lacking one allele of Becn1 is significantly greater than that in wild type mice. By contrast, in female mice, loss of Becn1 did not affect inflammation-induced pain hypersensitivity. Further, intrathecal delivery of an activator of Beclin 1, tat-beclin 1, reversed mechanical hypersensitivity induced by peripheral inflammation or peripheral nerve injury in males. Tat-beclin 1 also prevented mechanical hypersensitivity induced by exogenous brain-derived neurotrophic factor (BDNF), a core mediator of inflammatory and neuropathic pain in the spinal dorsal horn in males. Pain signaling pathways converge on enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. We found that loss of Beclin 1 increases expression of the pain-critical NMDAR subunit, GluN2B, in the dorsal horn and upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. From our converging lines of evidence, we conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males. Our findings provide the basis for sex-specific therapeutic approaches targeting pain with a new class of analgesics - activators of Beclin 1.

neuroscience↗

bioRxiv2023

Tunable photoinitiated hydrogel microspheres for direct quantification of cell-generated forces in complex three-dimensional environments

We present a high-throughput method using standard laboratory equipment and microfluidics to produce cellular force microscopy probes with controlled size and elastic modulus. Mechanical forces play crucial roles in cell biology but quantifying these forces in physiologically relevant systems remains challenging due to the complexity of the native cell environment. Polymerized hydrogel microspheres offer great promise for interrogating the mechanics of processes inaccessible to classic force microscopy methods. However, despite significant recent advances, their small size and large surface-to-volume ratio impede the high-yield production of probes with tunable, monodisperse distributions of size and mechanical properties. To overcome these limitations, we use a flow-focusing microfluidic device to generate large quantities of droplets with highly reproducible, adjustable radii. These droplets contain acrylamide gel precursor and the photoinitiator Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as a source of free radicals. LAP provides fine control over microsphere polymerization due to its high molar absorptivity at UV wavelengths and moderate water solubility. The polymerized microspheres can be functionalized with different conjugated extracellular matrix proteins and embedded with fluorescent nanobeads to promote cell attachment and track microsphere deformation. As proof of concept, we measure the mechanical forces generated by a monolayer of vascular endothelial cells engulfing functionalized microspheres. Individual nanobead motions are tracked in 3D and analyzed to determine the 3D traction forces within seconds and without the need for solving an ill-posed inverse problem. These results reveal that the cell monolayer collectively exerts strong radial compression and subtle lateral distortions on the encapsulated probe.

biophysics↗

bioRxiv2022

Single-cell Sequencing Highlights Heterogeneity and Malignant Progression in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors (TFs) along AK to cSCC progression. Immunohistochemistry (IHC) / immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.

cancer biology↗

bioRxiv2022

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Chronic pain is a devastating problem affecting 1 in 5 individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics and data mining have contributed to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Here, with the goal of identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species and imputed commonalities, as well as differences in cellular pathways and gene regulation. We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signaling nodes. We interrogated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase Syk, which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties. One sentence summaryUnbiased approach to predicting safe therapies for neuropathic pain

neuroscience↗

bioRxiv2022

A cooperative switch within the KaiC hexamer revealed by cryo-EM

The circadian clock of cyanobacteria is based on an approximately 24h rhythm in the phosphorylation level of KaiC, a hexameric ATPase. This oscillation can be reconstituted in vitro by incubating three proteins together with ATP. Like all chemical oscillators, this system must include a nonlinear, or switch-like, feedback loop, whose nature has been unclear. Here, by using single particle cryo-EM at near-atomic resolution we identified two major conformational states of KaiC subunits, denoted as the exposed state and the buried state, which may provide a structural basis of how the KaiC hexamer changes its conformation during the (day-night) phosphorylation-dephosphorylation cycle. We classify the abundance and pattern of exposed and buried states within hexamers for more than 160,000 KaiC particles. The statistics of the spatial arrangement of the two states in hexamers can be quantitatively fit by a simple statistical physics model with an interaction energy between neighboring subunits and a local field that depends on phosphorylation state. Our study shows that phosphorylation shifts the probability of each conformation and reveals that there is substantial cooperativity between neighboring subunits, which can allow a KaiC hexamer to respond in an ultrasensitive, switch-like manner to changes in the phosphorylation level.

biophysics↗

bioRxiv2021

A multi-state dynamical process underpins mechano-adaptation in the bacterial flagellar motor

Adaptation is a defining feature of living systems. The bacterial flagellar motor adapts to changes in the external mechanical environment by adding or removing torque-generating stator units. However, the molecular mechanism for mechanosensitive motor remodeling remains unclear. Here, we induced stator disassembly using electrorotation, followed by the time-dependent assembly of the individual stator units into the motor after electrorotation was terminated. From these experiments, we extracted detailed statistics of the dwell times that comprise the stochastic dynamics of the binding and unbinding of stator units. Dwell times reveal multiple timescales, indicating the existence of multiple binding states of the stator units. Based on these results, we propose a minimal model in which the stator unit can occupy four different states - two bound states with very different rates of unbinding, a diffusive unbound state, and a transiently detached state. Our minimal model quantitatively explains multiple features of the experimental data and allows us to determine the transition rates among all four states. Our experiments and modeling suggest a mechanism of mechano-adaptive remodeling of the bacterial flagellar motor in which torque generated by bound stator units controls their effective unbinding rate by modulating the transition between the two bound states. Furthermore, the binding rate of stator units with the motor has a non-monotonic dependence on the number of bound units, likely because of two counteracting effects of motor rotation on the binding process.

biophysics↗

bioRxiv2021

Dynamic Instability of Dendrite Tips Generates the Highly Branched Morphologies of Sensory Neurons

The highly ramified arbors of neuronal dendrites provide the substrate for the high connectivity and computational power of the brain. Altered dendritic morphology is associated with neuronal diseases. Many molecules have been shown to play crucial roles in shaping and maintaining dendrite morphology. Yet, the underlying principles by which molecular interactions generate branched morphologies are not understood. To elucidate these principles, we visualized the growth of dendrites throughout larval development of Drosophila sensory neurons and discovered that the tips of dendrites undergo dynamic instability, transitioning rapidly and stochastically between growing, shrinking, and paused states. By incorporating these measured dynamics into a novel, agent-based computational model, we showed that the complex and highly variable dendritic morphologies of these cells are a consequence of the stochastic dynamics of their dendrite tips. These principles may generalize to branching of other neuronal cell-types, as well as to branching at the subcellular and tissue levels.

biophysics↗

bioRxiv2021

Effects of short-term plasticity in early olfactory information processing in Drosophila

In Drosophila, olfactory information received by the olfactory receptor neurons (ORNs) is first processed by an incoherent feed forward neural circuit in the antennal lobe (AL) that consists of ORNs (input), the inhibitory local neurons (LNs), and projection neurons (PNs). This "early" olfactory information process has two important characteristics. First, response of a PN to its cognate ORN is normalized by the overall activity of other ORNs, a phenomenon termed "divisive normalization". Second, PNs respond strongly to the onset of ORN activities, but they adapt to prolonged or continuously increasing inputs. Despite the importance of these characteristics for learning and memory, their underlying mechanism remains not fully understood. Here, we develop a circuit model for describing the ORN-LN-PN dynamics by including key features of neuron-neuron interactions, in particular short-term plasticity (STP) and presynaptic inhibition (PI). Our model shows that STP is critical in shaping PNs steady-state response properties. By fitting our model to experimental data quantitatively, we found that strong and balanced short-term facilitation (STF) and short-term depression (STD) in STP is crucial for the observed nonlinear divisive normalization in Drosophila. By comparing our model with the observed adaptive response to time-varying signals quantitatively, we find that both STP and PI contribute to the highly adaptive response with the latter being the dominant factor for a better fit with experimental data. Our model not only helps reveal the mechanisms underlying two main characteristics of the early olfactory process, it can also be used to predict the PN responses to arbitrary time-dependent signals and to infer microscopic properties of the circuit (such as the strengths of STF and STD) from the measured input-output relation.

neuroscience↗

bioRxiv2021

Mechanosensitive remodeling of the bacterial flagellar motor is independent of direction of rotation

Motility is critical for the survival and dispersal of bacteria, and it plays an important role during infection. How bacteria regulate motility is thus a question of broad interest. Regulation of bacterial motility by chemical stimuli is well studied, but recent work has added a new dimension to the problem of motility control. The bidirectional flagellar motor of the bacterium Escherichia coli recruits or releases torque-generating units (stator units) in response to changes in load. Here, we show that this mechanosensitive remodeling of the flagellar motor is independent of direction of rotation. Remodeling rate constants in clockwise rotating motors and in counterclockwise rotating motors, measured previously, fall on the same curve if plotted against torque. Increased torque decreases the off rate of stator units from the motor, thereby increasing the number of active stator units at steady state. A simple mathematical model based on observed dynamics provides quantitative insight into the underlying molecular interactions. The torque-dependent remodeling mechanism represents a robust strategy to quickly regulate output (torque) in response to changes in demand (load). SignificanceMacromolecular machines carry out most of the biological functions in living organisms. Despite their significance, we do not yet understand the rules that govern the self-assembly of large multi-protein complexes. The bacterial flagellar motor tunes the assembly of its torque-generating stator complex with changes in external load. Here, we report that clockwise and counterclockwise rotating motors have identical remodeling response to changes in the external load, suggesting a purely mechanical mechanism for this regulation. Autonomous control of self-assembly may be a general strategy for tuning the functional output of protein complexes. The flagellar motor is a prime example of a macromolecular machine in which the functional regulation of assembly can be rigorously studied.

biophysics↗

bioRxiv2020

Peramivir, an anti-influenza virus drug, exhibits potential anti-cytokine storm effects

Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF- by partly intervention of NF-{kappa}B activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/201806v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@667e34org.highwire.dtl.DTLVardef@e7bf85org.highwire.dtl.DTLVardef@ced400org.highwire.dtl.DTLVardef@c055a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗