Biology subjects

Liang, B.

Publications and source records attributed to Liang, B..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

A Causal Role of Human Laryngeal Motor Cortex in Speech Lexical Tone and Voicing Perception

Speech perception is believed to recruit the left motor cortex. However, the exact role of the laryngeal subregion and its right counterpart in speech perception, as well as their temporal patterns of involvement remain unclear. To address these questions, we conducted a hypothesis-driven study, utilizing transcranial magnetic stimulation on the left or right dorsal laryngeal motor cortex (dLMC) when participants performed perceptual decision on Mandarin lexical tone or consonant (voicing contrast) presented with or without noise. We used psychometric function and hierarchical drift-diffusion model to disentangle perceptual sensitivity and dynamic decision-making parameters. Results showed that bilateral dLMCs were engaged with effector specificity, and this engagement was left-lateralized with right upregulation in noise. Furthermore, the dLMC contributed to various decision stages depending on the hemisphere and task difficulty. These findings substantially advance our understanding of the hemispherical lateralization and temporal dynamics of bilateral dLMC in sensorimotor integration during speech perceptual decision-making.

neuroscience↗

bioRxiv2022

SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinsons disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation utilising a model of human monocyte-derived microglia. We identified that SARS-CoV-2 isolates can bind and enter microglia, triggering inflammasome activation in the absence of viral replication. Mechanistically, microglial NLRP3 could be both primed and activated with SARS-CoV-2 spike glycoprotein in a NF-{kappa}B and ACE2-dependent manner. Notably, virus- and spike protein-mediated inflammasome activation in microglia was significantly enhanced in the presence of -synuclein fibrils, which was entirely ablated by NLRP3-inhibition. These results support a possible mechanism of microglia activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinsons disease in certain COVID-19 infected individuals, and a potential therapeutic avenue for intervention. SIGNIFICANCE STATEMENTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) principally affects the lungs, however there is evidence that the virus can also reach the brain and lead to chronic neurological symptoms. In this study, we examined the interaction SARS-CoV-2 with brain immune cells, by using an ex-vivo model of human monocyte-derived microglia. We identified robust activation of the innate immune sensor complex, NLRP3 inflammasome, in cells exposed to SARS-CoV-2. This was dependent on spike protein-ACE2 receptor interaction and was potentiated in the presence of -synuclein. We therefore identify a possible mechanism for SARS-CoV-2 and increased vulnerability to developing neurological dysfunction. These findings support a potential therapeutic avenue for treatment of SARS-CoV-2 driven neurological manifestations, through use of NLRP3 inflammasome or ACE2 inhibitors.

neuroscience↗

bioRxiv2021

Stratum Lacunosum-moleculare Interneurons of the Hippocampus Coordinate Memory Encoding and Retrieval

Encoding and retrieval of memory are two processes serving distinct biological purposes but operating in highly overlapping brain circuits. It is unclear how the two processes are coordinated in the same brain regions, especially in the hippocampal CA1 region where the two processes converge at the cellular level. Here we find that the neuron-derived neurotrophic factor (NDNF)-positive interneurons at stratum lacunosum-moleculare (SLM) in CA1 play opposite roles in memory encoding and retrieval. These interneurons show high activities in learning and low activities in recall. Increasing their activity facilitates learning but impairs recall. They inhibit the entorhinal- but dis-inhibit the CA3- inputs to CA1 pyramidal cells and thereby either suppress or elevate CA1 pyramidal cells activity depending on animals behavioral states. Thus, by coordinating entorhinal- and CA3- dual inputs to CA1, these SLM interneurons are key to switching the hippocampus between encoding and retrieval modes.

neuroscience↗

bioRxiv2021

Complete protection by a single dose skin patch delivered SARS-CoV-2 spike vaccine

SARS-CoV-2 has infected over 160 million people and resulted in more than 3.3 million deaths, and we still face many challenges in the rollout of vaccines. Here, we use the high-density microarray patch to deliver a SARS-CoV-2 spike subunit vaccine directly to the skin. We show the vaccine, dry-coated on the patch is thermostable, and delivery of spike via HD-MAP induced greater cellular and antibody immune responses, with serum able to potently neutralize clinically relevant isolates including those from the B.1.1.7 and B.1.351 lineages. Finally, a single dose of HD-MAP-delivered spike provided complete protection from a lethal virus challenge, demonstrating that HD-MAP delivery of a SARS-CoV-2 vaccine is superior to traditional needle-and-syringe vaccination and has the potential to greatly impact the ongoing COVID-19 pandemic.

microbiology↗

bioRxiv2021

Human genome integration of SARS-CoV-2 contradicted by long-read sequencing

A recent study proposed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate into the DNA of infected cells. If confirmed, this finding could have significant clinical implications. Here, we applied deep (>50x) long-read Oxford Nanopore Technologies (ONT) sequencing to HEK293T cells infected with SARS-CoV-2, and did not find the virus integrated into the genome. By examining ONT data from separate HEK293T cultivars, we completely resolved 78 L1 insertions arising in vitro in the absence of L1 overexpression systems. ONT sequencing applied to hepatitis B virus (HBV) positive liver cancer tissues located a single HBV insertion. These experiments demonstrate reliable resolution of retrotransposon and exogenous virus insertions via ONT sequencing. That we found no evidence of SARS-CoV-2 integration suggests such events are, at most, extremely rare in vivo, and therefore are unlikely to drive oncogenesis or explain post-recovery detection of the virus.

genomics↗

bioRxiv2021

Categorical edge-based analyses of phylogenomic data reveal conflicting signals for difficult relationships in the avian tree

Phylogenetic analyses fail to yield a satisfactory resolution of some relationships in the tree of life even with genome-scale datasets, so the failure is unlikely to reflect limitations in the amount of data. Gene tree conflicts are particularly notable in studies focused on these contentious nodes, and taxon sampling, different analytical methods, and/or data type effects can further confound analyses. Although many efforts have been made to incorporate biological conflicts, few studies have curated individual genes for their efficiency in phylogenomic studies. Here, we conduct an edge-based analysis of Neoavian evolution, examining the phylogenetic efficacy of two recent phylogenomic bird datasets and three datatypes (ultraconserved elements [UCEs], introns, and coding regions). We assess the potential causes for biases in signal-resolution for three difficult nodes: the earliest divergence of Neoaves, the position of the enigmatic Hoatzin (Opisthocomus hoazin), and the position of owls (Strigiformes). We observed extensive conflict among genes for all data types and datasets even after meticulous curation. Edge-based analyses (EBA) increased congruence and provided information about the impact of data type, GC content variation (GCCV), and outlier genes on each of nodes we examined. First, outlier gene signals appeared to drive different patterns of support for the relationships among the earliest diverging Neoaves. Second, the placement of Hoatzin was highly variable, although our EBA did reveal a previously unappreciated data type effect with an impact on its position. It also revealed that the resolution with the most support here was Hoatzin + shorebirds. Finally, GCCV, rather than data type (i.e., coding vs non-coding)per se, was correlated with a signal that supports monophyly of owls + Accipitriformes (hawks, eagles, and New World vultures). Eliminating high GCCV loci increased the signal for owls + mousebirds. Categorical EBA was able to reveal the nature of each edge and provide a way to highlight especially problematic branches that warrant a further examination. The current study increases our understanding about the contentious parts of the avian tree, which show even greater conflicts than appreciated previously.

evolutionary biology↗

bioRxiv2021

A high-continuity and annotated tomato reference genome

Genetic and functional genomics studies require a high-quality genome assembly. Tomato (Solanum lycopersicum), an important horticultural crop, is an ideal model species for the study of fruit development. Here, we assembled an updated reference genome of S. lycopersicum cv. Heinz 1706 that was 799.09 Mb in length, containing 34,384 predicted protein-coding genes and 65.66% repetitive sequences. By comparing the genomes of S. lycopersicum and S. pimpinellifolium LA2093, we found a large number of genomic fragments probably associated with human selection, which may have had crucial roles in the domestication of tomato. Our results offer opportunities for understanding the evolution of the tomato genome and will facilitate the study of genetic mechanisms in tomato biology. Information for the assembled genome SLT1.0 was deposited both into the Genome Warehouse (GWH) database (https://bigd.big.ac.cn/gwh/) in the BIG Data Center under Accession Number GWHBAUD00000000.

genomics↗

bioRxiv2021

Occurrence of COVID-19 symptoms during SARS-CoV-2 infection defines waning of humoral immunity

Approximately half of the SARS-CoV-2 infections occur without apparent symptoms, raising questions regarding long-term humoral immunity in asymptomatic individuals. Plasma levels of immunoglobulin G (IgG) and M (IgM) against the viral spike or nucleoprotein were determined for 25,091 individuals enrolled in a surveillance program in Wuhan, China. We compared 405 asymptomatic individuals with 459 symptomatic COVID-19 patients. The well-defined duration of the SARS-CoV-2 endemic in Wuhan allowed a side-by-side comparison of antibody responses following symptomatic and asymptomatic infections without subsequent antigen re-exposure. IgM responses rapidly declined in both groups. However, both the prevalence and durability of IgG responses and neutralizing capacities correlated positively with symptoms. Regardless of sex, age, and body weight, asymptomatic individuals lost their SARS-CoV-2-specific IgG antibodies more often and rapidly than symptomatic patients. These findings have important implications for immunity and favour immunization programs including individuals after asymptomatic infections. One-Sentence SummaryPrevalence and durability of SARS-CoV-2-specific IgG responses and neutralizing capacities correlate with COVID-19 symptoms.

immunology↗

bioRxiv2021

Talaromyces marneffei promotes M2 polarization of human macrophages by downregulating SOCS3 expression and activating TLR9 pathway

Little is known about how Talaromyces marneffei, a thermally dimorphic fungus that causes substantial morbidity and mortality in Southeast Asia, evades the human immune system. Polarization of macrophages into fungal-inhibiting M1 and fungal-promoting M2 types has been shown to play an important role in the innate immune response against fungal pathogens. This mechanism has not been defined for T. marneffei. Here, we demonstrated that T. marneffei promotes its survival in human macrophages by inducing them towards M2 polarization. Our investigations of the mechanism revealed that T. marneffei infection led to SOCS3 protein degradation by inducing tyrosine phosphorylation, thereby relieving the inhibitory effect of SOCS3 on p-STAT6, a key factor for M2 polarization. Our SOCS3-overexpression experiments showed that SOCS3 is a positive regulator of M1 polarization and plays an important role in limiting M2 polarization. Furthermore, we found that inhibition of TLR9 pathway partially blocked T. marneffei-induced M2 polarization and significantly enhanced the killing activity of macrophages against T. marneffei. Collectively, these results reveal a novel mechanism by which T. marneffei evades the immune response of human macrophages.

microbiology↗

bioRxiv2021

The basis of a more contagious 501Y.V1 variant of SARS-COV-2

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing a world-wide pandemic. A variant of SARS-COV-2 (20I/501Y.V1) recently discovered in the United Kingdom has a single mutation from N501 to Y501 within the receptor binding domain (Y501-RBD), of the Spike protein of the virus. This variant is much more contagious than the original version (N501-RBD). We found that this mutated version of RBD binds to human Angiotensin Converting Enzyme 2 (ACE2) a ~10 times more tightly than the native version (N501-RBD). Modeling analysis showed that the N501Y mutation would allow a potential aromatic ring-ring interaction and an additional hydrogen bond between the RBD and ACE2. However, sera from individuals immunized with the Pfizer-BioNTech vaccine still efficiently block the binding of Y501-RBD to ACE2 though with a slight compromised manner by comparison with their ability to inhibit binding to ACE2 of N501-RBD. This may raise the concern whether therapeutic anti-RBD antibodies used to treat COVID-19 patients are still efficacious. Nevertheless, a therapeutic antibody, Bamlanivimab, still binds to the Y501-RBD as efficiently as its binds to N501-RBD.

biochemistry↗

bioRxiv2020

Transcriptome analysis of an albino mutant in Haworthia cooperi var. pilifera

Photosynthetic organisms appear green due to the accumulation of chlorophyll (Chl) pigments in their chloroplasts. Although the genes encoding key enzymes related to Chl biosynthesis have been well characterized in herbaceous plants, such as rice, Arabidopsis and maize, white leaf mutants have not yet been fully studied in succulent plants. In this work, we explored the molecular mechanism of leaf color formation in an albino mutant (HUA) of Haworthia cooperi var. pilifera. We investigated the differentially expressed genes (DEGs) between HUA and control plants (wild type, LV) by transcriptome sequencing. Approximately 2,586 genes (1,996 downregulated and 590 upregulated) were found to be differentially expressed in HUA compared with LV using a threshold of ratio change [≥] 2 and false discovery rate (FDR) [≤]0.05. GO analysis predicted that these DEGs participate in 12 cellular component, 20 biological process and 13 molecular function terms. Among the DEGs were well-recognized genes associated with chloroplast division and the biosynthesis of plant pigments, including chlorophyll, carotenoids and anthocyanin, as well as various transcription factor families. Overall, these results can help confirm the molecular regulatory mechanisms controlling leaf pigmentation and provide a comprehensive resource for breeding colorful leaf phenotypes in succulent plants.

genetics↗

bioRxiv2020

Mechanical Efficiency Investigation of an ankle-assisted robot for human walking with a backpack-load

Lower limb assistive robots have a wide range of applications in medical rehabilitation, hiking, and the military. The purpose of this work is to investigate the efficiency of wearable assistive devices under different weight-bearing walking conditions. We designed an experimental platform, with a lightweight ankle-assisted robot weighing 5.2 kg and carried mainly on the back. Eight subjects were tested in three experimental conditions: free walk with load (FWL), power-off with load (POFL), and power-on with load (PONF) for different levels of force at a walking speed of 3.6 km/h. We recorded the metabolic expenditure and kinematics of the subjects under three levels of weight-bearing (equal to 10%, 20%, and 30% of body mass). The critical forces from the fit of the assistive force and metabolic depletion curves were 130 N, 160 N and 215 N at three different load levels. The intrinsic weight of our device increases mechanical work at the ankle as the load weight rises, with 2.08 J, 2.43 J, 2.73 J for one leg during a gait cycle. The ratio of the mechanical work input by the robot to the mechanical work output by the weight of the device decreases (0.904, 0.717, and 0.513 with different load carriages), verifying that the walking assistance efficiency of such devices decreases as the weight rises. In terms of mechanical work in the ankle joint, our results confirm that the efficiency of the ankle-assisted walking robot decreases as weight bearing increases, which provides important guidance for the lightweight design of portable weight-bearing walking robots.

biophysics↗

bioRxiv2020

Longitudinal characterization of phenotypic profile of T cells in chronic hepatitis B identifies immune markers predicting HBsAg loss

The current desirable endpoint of treatment against chronic hepatitis B virus infection (cHBV) is to achieve a functional cure, which is defined as HBsAg loss (sAg-L) with or without anti-HBs seroconversion. However, the immunological features that are associated with functional cure have not been studied in detail. Here, a total of 172 cHBV patients including 31 sAg-L patients, and 24 healthy individuals were examined for their T cell phenotypic profile and HBV-specific T cell responses by flow cytometry. sAg-L patients showed distinct CD4 and CD8 T cell phenotype fingerprints compared to those of HBsAg-positive patients, as indicated by the upregulation of CD25, CD40L and CTLA-4 expression on CD4 T cells; HLA-DR, CD95 and PD-1 on both CD4 and CD8 T cells; as well as a potent HBcAg-specific CD8 T cell response. The changes in the T cell phenotype in sAg-L patients began during rapid HBsAg decrease upon treatment onset, were maintained after sAg-L. HLA-DR expression on T cells was positively correlated with the level of HBsAg reduction and the magnitude of the HBcAg-specific T cell responses in cHBV patients. Importantly, increased HLA-DR and CTLA-4 expression on CD4, as well as HLA-DR and TIM-3 expression on CD8 T cells were identified as predictive factors for HBsAg loss within 48 weeks of therapy in cHBV patients. The onset of HBsAg decrease and subsequent loss in cHBV patients on treatment is associated with significant alterations of both CD4 and CD8 T cell phenotypes. Characterization of the T cell phenotype in cHBV patients possessed greater predicative value for sAg-L.

microbiology↗

bioRxiv2020

De novo design of transmembrane beta-barrels

The ability of naturally occurring transmembrane {beta}-barrel proteins (TMBs) to spontaneously insert into lipid bilayers and form stable transmembrane pores is a remarkable feat of protein evolution and has been exploited in biotechnology for applications ranging from single molecule DNA and protein sequencing to biomimetic filtration membranes. Because it has not been possible to design TMBs from first principles, these efforts have relied on re-engineering of naturally occurring TMBs that generally have a biological function very different from that desired. Here we leverage the power of de novo computational design coupled with a "hypothesis, design and test" approach to determine principles underlying TMB structure and folding, and find that, unlike almost all other classes of protein, locally destabilizing sequences in both the {beta}-turns and {beta}-strands facilitate TMB expression and global folding by modulating the kinetics of folding and the competition between soluble misfolding and proper folding into the lipid bilayer. We use these principles to design new eight stranded TMBs with sequences unrelated to any known TMB and show that they insert and fold into detergent micelles and synthetic lipid membranes. The designed proteins fold more rapidly and reversibly in lipid membranes than the TMB domain of the model native protein OmpA, and high resolution NMR and X-ray crystal structures of one of the designs are very close to the computational model. The ability to design TMBs from first principles opens the door to custom design of TMBs for biotechnology and demonstrates the value of de novo design to investigate basic protein folding problems that are otherwise hidden by evolutionary history. One sentence summarySuccess in de novo design of transmembrane {beta}-barrels reveals geometric and sequence constraints on the fold and paves the way to design of custom pores for sequencing and other single-molecule analytical applications.

synthetic biology↗

bioRxiv2020

Conserved Arginine Residues in Synaptotagmin 1 Regulate Fusion Pore Expansion Through Membrane Contact

Synaptotagmin 1 is a vesicle-anchored membrane protein that functions as the Ca2+ sensor for synchronous neurotransmitter release. In this work, an arginine containing region in the second C2 domain of synaptotagmin 1 (C2B) is shown to control the expansion of the fusion pore and thereby the concentration of neurotransmitter released. This arginine apex, which is opposite the Ca2+ binding sites, interacts with membranes or membrane reconstituted SNAREs; however, only the membrane interactions occur under the conditions in which fusion takes place. Other regions of C2B influence the probably and kinetics of fusion but do not control the expansion of the fusion pore. These data indicate that the C2B domain has at least two distinct molecular roles in the fusion event, and the data are consistent with a novel model where the arginine apex of C2B positions the domain at the curved membrane surface of the expanding fusion pore.

neuroscience↗

bioRxiv2020

Tomato Protein Phosphatase 2C (SlPP2C3) negatively regulates fruit ripening onset and fruit gloss

Abscisic acid (ABA) plays a vital role in coordinating physiological processes during fresh fruit ripening. ABA can bind to ABA receptors which interacts and inhibits their co-receptors type 2C phosphatases (PP2Cs). However, the dissected mechanism of PP2C during fruit ripening is unclear. In this study, we identify the role of SlPP2C3, a tomato type 2C phosphatase, as a negative regulator of ABA signaling and fruit ripening. SlPP2C3 selectively interacted with monomeric ABA receptors and SlSnRK2.8 kinase in both yeast and tobacco epidermal cells. Expressions of SlPP2C3 were observed in all tissues, and it negatively correlated with the fruit ripening which was induced by exogenous ABA. Tomato plants with suppressed SlPP2C3 expression exhibited enhanced sensitivity to ABA, while SlPP2C3 over-expressed plants were less sensitive to ABA. Meaningfully, lack of SlPP2C3 expression causes the acceleration of fruit ripening onset via the alternation of ABA signaling activity, and the fruit gloss is affected by the changes of outer epidermis structure. RNA-seq analysis found significant different expression of cuticle-related genes in pericarp between wild-type and SlPP2C3 suppressed lines. Taken together, our finding demonstrate that SlPP2C3 plays an important role in the regulation of fruit ripening and fruit appearance quality in tomato.

developmental biology↗

bioRxiv2020

In-Vivo Toxicity Studies and In-Vitro Inactivation of SARS-CoV-2 by Povidone-iodine In-situ Gel Forming Formulations

To curb the spread of SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, we characterize the virucidal activity of long-acting Povidone Iodine (PVP-I) compositions developed using an in-situ gel forming technology. The PVP-I gel forming nasal spray (IVIEW-1503) and PVP-I gel forming ophthalmic eye drop (IVIEW-1201) rapidly inactivated SARS-CoV-2, inhibiting the viral infection of VERO76 cells. No toxicity was observed for the PVP-I formulations. Significant inactivation was noted with preincubation of the virus with these PVP-I formulations at the lowest concentrations tested. It has been demonstrated that both PVP-I formulations can inactivate SARS-CoV-2 virus efficiently in both a dose-dependent and a time-dependent manner. These results suggest IVIEW-1503 and IVIEW-1201 could be potential agents to reduce or prevent the transmission of the virus through the nasal cavity and the eye, respectively. Further studies are needed to clinically evaluate these formulations in early-stage COVID-19 patients.

microbiology↗

bioRxiv2020

Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy

The v{beta}8 integrin is a key activator of transforming growth factor {beta} (TGF {beta}), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that v{beta}8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against v{beta}8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. v{beta}8 is expressed on tumor cells in some of these models, but tumor cell expression of v{beta}8 is not essential for the beneficial effects of ADWA-11 therapy. v{beta}8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGF{beta} and are involved in tumor cell killing, including Granzyme B and Interferon-{gamma}. These findings solidify v{beta}8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.

cancer biology↗