Biology subjects

Ma, L.

Publications and source records attributed to Ma, L..

At least 217 records · Page 12Linked to original sources

bioRxiv2022

A computational framework linking synaptic adaptation to circuit behaviors in the early visual system

Retina ribbon synapses are the first synapses in the visual system. Unlike the conventional synapses in the central nervous system triggered by action potentials, ribbon synapses are uniquely driven by graded membrane potentials and are thought to transfer early sensory information faithfully. However, how ribbon synapses compress the visual signals and contribute to visual adaptation in retina circuits is less understood. To this end, we introduce a physiologically constrained module for the ribbon synapse, termed Ribbon Adaptive Block (RAB), and an extended "hierarchical Linear-Nonlinear-Synapse" (hLNS) framework for the retina circuit. Our models can elegantly reproduce a wide range of experimental recordings on synaptic and circuit-level adaptive behaviors across different cell types and species. In particular, it shows strong robustness to unseen stimulus protocols. Intriguingly, when using the hLNS framework to fit intra-cellular recordings from the retina circuit under stimuli similar to natural conditions, we revealed rich and diverse adaptive time constants of ribbon synapses. Furthermore, we predicted a frequency-sensitive gain-control strategy for the synapse between the photoreceptor and the CX bipolar cell, which differ from the classic contrast-based strategy in retina circuits. Overall, our framework provides a powerful analytical tool for exploring synaptic adaptation mechanisms in early sensory coding.

neuroscience↗

bioRxiv2022

Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme

The successful generation of endodermal, ectodermal, and most mesodermal lineages from pluripotent stem cells has resulted in basic discoveries and regenerative medicine clinical trials of cell-based therapies. In contrast, the derivation of tissue-specific mesenchyme via directed differentiation in vitro has markedly lagged, due in part to a limited understanding of the signaling pathways regulating in vivo mesenchymal development and a lack of specific markers or reporters able to purify such lineages. The derivation of lung-specific mesenchyme is a particularly important goal since this tissue plays important roles in lung development and respiratory disease pathogenesis. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer facilitating the tracking and purification of engineered lung-specific mesenchyme. We identify the key signaling pathways (RA and Shh) necessary to specify lung mesenchyme from lateral plate mesodermal precursors and find that mouse iPSC-derived lung mesenchyme (iLM) expresses the molecular and functional phenotypes of primary developing lung mesenchyme. Purified iLM can be recombined with separately engineered lung epithelial progenitors, self-organizing into 3-dimensional organoids featuring significantly augmented structural complexity and lineage purity, including interacting juxtaposed layers of epithelium and mesenchyme. Co-culture with iLM increases the yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional epithelial-mesenchymal crosstalk. Our iPSC-derived population thus expresses key features of developing lung mesenchyme, providing an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.

developmental biology↗

bioRxiv2022

Identify non-mutational p53 loss of function in human cancers

An accurate assessment of TP53s functional status is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivations that are not detectable through DNA sequencing. These undetected cases are often misclassified as p53-normal, leading to inaccurate prognosis and downstream association analyses. To address this issue, we build the support vector machine (SVM) models to systematically reassess p53s functional status in TP53 wild-type (TP53WT) tumors from multiple TCGA cohorts. Cross-validation demonstrates the excellent performance of the SVM models with a mean AUC of 0.9822, precision of 0.9747, and recall of 0.9784. Our study reveals that a significant proportion (87-99%) of TP53WT tumors actually have compromised p53 function. Additional analyses uncovered that these genetically intact but functionally impaired (termed as predictively reduced function of p53 or TP53WT-pRF) tumors exhibit genomic and pathophysiologic features akin to p53 mutant tumors: heightened genomic instability and elevated levels of hypoxia. Clinically, patients with TP53WT-pRF tumors experience significantly shortened overall survival or progression-free survival compared to those with TP53WT-pN (predictive normal function of p53) tumors, and these patients also display increased sensitivity to platinum-based chemotherapy and radiation therapy.

bioinformatics↗

bioRxiv2022

Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice

Durable reconstitution of the injured distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising potential therapy for diseases that result from alveolar damage. Here we differentiate murine PSCs in vitro into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. Emulating the roadmap of the developing embryo, we generate transplantable PSC-derived Nkx2-1+/Sox9+ lung epithelial progenitors that are highly similar to cultured primary embryonic distal lung bud tip progenitors. These cells display a stable phenotype after frozen archiving or extensive expansion in culture, providing a nearly inexhaustible source of cells that can be engrafted into syngeneic injured mouse lungs without the need for immunosuppression. After transplantation PSC-derived tip-like progenitors downregulate Sox9 and mature in the distal lung, upregulating alveolar type 2 cell markers or assuming the flat morphology and molecular phenotype of terminally differentiated alveolar type 1 cells. After months in vivo, donor-derived cells retain their alveolar epithelial type 2-like and type 1-like phenotypes, as characterized by single cell RNA sequencing, ultrastructural analyses, in vivo histologic profiling, and ex vivo organoid assays that demonstrate continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lungs facultative progenitor and differentiated epithelial cell compartments in vivo with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy which can be utilized to better understand the mechanisms and utility of engraftment prior to future clinical studies.

cell biology↗

bioRxiv2022

FHL5 controls vascular disease-associated gene programs in smooth muscle cells

BackgroundGenome-wide association studies (GWAS) have identified hundreds of loci associated with common vascular diseases such as coronary artery disease (CAD), myocardial infarction (MI), and hypertension. However, the lack of mechanistic insights for a majority of these loci limits translation of these findings into the clinic. Among these loci with unknown functions is UFL1-FHL5 (chr6q16.1), a locus that reached genome-wide significance in a recent CAD/MI GWAS meta-analysis. In addition to CAD/MI, UFL1-FHL5 is also implicated to coronary calcium, intracranial aneurysm, and migraine risk, consistent with the widespread pleiotropy observed among other GWAS loci. MethodsWe apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and imaging of human coronary artery tissues to implicate Four-and-a-half LIM domain 5 (FHL5) as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments. ResultsWe prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through eQTL colocalization methods. FHL5 gene expression was enriched in the SMC and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating SMC contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream CAD/MI loci, such as FOXL1 and FN1 that have roles in vascular remodeling. ConclusionTaken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling loci. These trans-acting mechanisms may account for a portion of the heritable risk for complex vascular diseases.

genomics↗

bioRxiv2022

Inhibitory effects of GT0918 on acute lung injury and the molecular mechanisms of anti-inflammatory response

Coronavirus disease 2019 (COVID-19) has caused the public health crisis in the whole world. Anti-androgens block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and protect against severe clinical COVID-19 outcomes. GT0918, a novel androgen receptor antagonist, accelerated viral clearance and increased recovery rate in outpatients by blocking SARS-CoV-2 infection though down-regulating ACE2 and TMPRSS2 expression. Further clinical study showed that GT0918 reduced mortality rate and shortened hospital stay in hospitalized COVID-19 patients. GT0918 also exhibits protective efficacy in severe COVID-19 patient in critical care. However, the mechanism of GT0918 treatment for severe COVID-19 disease is unknown. Here, we found GT0918 decreased the expression and secretion of proinflammatory cytokines through NF-{kappa}B signaling pathway. The acute lung injury induced by LPS or Poly(I:C) was also attenuated in GT0918-treated mice, compared with vehicle control group. Moreover, GT0918 elevated the NRF2 protein level but not mRNA transcription activity. GT0918 induced proinflammatory cytokines downregulation was partially dependent on NRF2. In conclusion, our data demonstrate that GT0918 reduced cytokine release and suppressed inflammatory responses through inhibiting NF-{kappa}B signaling and activating NRF2. GT0918 is not only effective for treatment of mild to moderate COVID-19 patients, but also a potential therapeutic drug for severe COVID-19 patients by reducing the risk of cytokine storm and acute respiratory distress syndrome.

cell biology↗

bioRxiv2022

A GPU-based computational framework that bridges Neuron simulation and Artificial Intelligence

Biophysically detailed multi-compartment models are powerful tools to explore computational principles of the brain and also serve as a theoretical framework to generate algorithms for artificial intelligence (AI) systems. However, the expensive computational cost severely limits the applications in both the neuroscience and AI fields. The major bottleneck during simulating detailed compartment models is the ability of a simulator to solve large systems of linear equations. Here, we present a novel Dendritic Hierarchical Scheduling (DHS) method to markedly accelerate such process. We theoretically prove that the DHS implementation is computationally optimal and accurate. This GPU-based method performs at 2-3 orders of magnitude higher speed than that of the classic serial Hines method in the conventional CPU platform. We build a DeepDendrite framework, which integrates the DHS method and the GPU computing engine of the NEURON simulator and demonstrate applications of DeepDendrite in neuroscience and AI tasks. We investigated how spatial patterns of spine inputs affect neuronal excitability in a detailed human pyramidal neuron model with 25,000 spines; and examined how dendrites protect morphologically detailed neural networks against adversarial attacks in typical image classification tasks.

neuroscience↗

bioRxiv2022

Retina Gap Junction Networks Facilitate Blind Denoising in Visual Hierarchy

Gap junctions in the retina are electrical synapses, which strength is regulated byambient light conditions. Such tunable synapses are crucial for the denoising function of the early visual system. However, it is unclear that how the plastic gap junction network processes unknown noise, specifically how this process works synergistically with the brains higher visual centers. Inspired by the electrically coupled photoreceptors, we develop a computational model of the gap junction filter (G-filter). We show that G-filter is an effective blind denoiser that converts different noise distributions into a similar form. Next, since deep convolutional neural networks (DCNNs) functionally reflect some intrinsic features of the visual cortex, we combine G-filter with DCNNs as retina and ventral visual pathways to investigate the relationship between retinal denoising processing and the brains high-level functions. In the image denoising and reconstruction task, G-filter dramatically improve the classic deep denoising convolutional neural network (DnCNN)s ability to process blind noise. Further, we find that the gap junction strength of the G-filter modulates the receptive field of DnCNNs output neurons by the Integrated Gradients method. At last, in the image classification task, G-filter strengthens the defense of state-of-the-arts DCNNs (ResNet50, VGG19 and InceptionV3) against blind noise attacks, far exceeding human performance when noise is large. Our results indicate G-filter significantly enhance DCNNs ability on various blind denoising tasks, implying an essential role for retina gap junction networks in high-level visual processing.

neuroscience↗

bioRxiv2022

Cell detoxification of secondary metabolites by P4-ATPase mediated vesicle transport

Mechanisms for cellular detoxification of drug compounds are of significant interest in human health. Cyclosporine A (CsA) and tacrolimus (FK506) are widely known antifungal and immunosuppressive microbial natural products. However, both compounds can result in significant side effects when used as immunosuppressants. The insect pathogenic fungus Beauveria bassiana shows resistance to CsA and FK506. However, the mechanisms underlying the resistance have remained unknown. Here, we identify a P4-ATPase gene, BbCRPA, from the fungus, which confers resistance via a unique vesicle mediated transport pathway that targets the compounds into detoxifying vacuoles. Interestingly, the expression of BbCRPA in plants promotes resistance to the phytopathogenic fungus Verticillium dahliae via detoxification of the mycotoxin cinnamyl acetate using a similar pathway. Our data reveal a new function for a subclass of P4-ATPases in cell detoxification. The P4-ATPases conferred cross-species resistance can be exploited for plant disease control and human health protection.

microbiology↗

bioRxiv2022

Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation

Metabolic syndrome (MetSyn) is a cluster of dysregulated metabolic conditions that occur together to increase the risk for cardiometabolic disorders such as type 2 diabetes (T2D). One key condition associated with MetSyn, abdominal obesity, is measured by computing the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI). WHRadjBMI and T2D are complex traits with genetic and environmental components, which has enabled genome-wide association studies (GWAS) to identify hundreds of loci associated with both. Statistical genetics analyses of these GWAS have predicted that WHRadjBMI is a strong causal risk factor of T2D and that these traits share genetic architecture at many loci. To date, no variants have been described that are simultaneously associated with protection from T2D but with increased abdominal obesity. Here, we used colocalization analysis to identify genetic variants with a shared association for T2D and abdominal obesity. This analysis revealed the presence of five loci associated with discordant effects on T2D and abdominal obesity. The alleles of the lead genetic variants in these loci that were protective against T2D were also associated with increased abdominal obesity. We further used publicly available expression, epigenomic, and genetic regulatory data to predict the effector genes (eGenes) and functional tissues at the 2p21, 5q21.1, and 19q13.11 loci. We also computed the correlation between the subcutaneous adipose tissue (SAT) expression of predicted effector genes (eGenes) with metabolic phenotypes and adipogenesis. We proposed a model to resolve the discordant effects at the 5q21.1 locus. We find that eGenes gypsy retrotransposon integrase 1 (GIN1), diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2), and peptidylglycine alpha-amidating monooxygenase (PAM) represent the likely causal eGenes at the 5q21.1 locus. Taken together, these results are the first to describe a potential mechanism through which a genetic variant can confer increased abdominal obesity but protection from T2D risk. Understanding precisely how and which genetic variants confer increased risk for MetSyn will develop the basic science needed to design novel therapeutics for metabolic syndrome.

genomics↗

bioRxiv2022

A Lysozyme Murein Hydrolase with Broad-spectrum Antibacterial Activity from Enterobacter Phage myPSH1140

Bacteriophages and bacteriophage-derived peptidoglycan hydrolases (endolysins) present promising alternatives for the treatment of infections caused by multi-drug resistant Gram-negative and Gram-positive pathogens. In this study, Gp105, a putative lysozyme murein hydrolase from Enterobacter phage myPSH1140 was characterized in silico, in vitro as well as in vivo using the purified protein. Gp105 contains a T4-type lysozyme-like domain (IPR001165) and belongs to Glycoside hydrolase family 24 (IPR002196). The putative endolysin indeed had strong antibacterial activity against Gram-negative pathogens including E. cloacae, K. pneumoniae, P. aeruginosa, S. marcescens, Citrobacter sp. and A. baumannii. Also, an in vitro peptidoglycan hydrolysis assay showed strong activity against purified peptidoglycans. This study demonstrates the potential of Gp105 to be used as an antibacterial protein to combat Gram-negative pathogens.

microbiology↗

bioRxiv2022

Controlling taxa abundance improves metatranscriptomics differential analysis

A common task in analyzing metatranscriptomics data is to identify microbial metabolic pathways with differential RNA abundances across multiple sample groups. With information from paired metagenomics data, current differential methods control for either DNA or taxa abundances to address their strong correlation with RNA abundance. We discovered that when either DNA or taxa abundance is controlled for, RNA abundance still has a strong partial correlation with the other factor. Thus, both factors need to be controlled for in the differential model. In both simulation studies and a real data analysis, we demonstrated that controlling for both DNA and taxa abundances leads to superior performance compared to only controlling for one factor.

microbiology↗

bioRxiv2022

Molecular Control of Circuit Plasticity and the Permanence of Imprinted Odor Memory

Behavioral imprinting is a distinct form of learning that has a lifelong impact on social interactions and affectional behaviors1-4. Unlike other forms of memory, imprinting does not require conspicuous association of stimuli; exposure per se appears sufficient to induce memories that neither undergo extinction nor are altered by experience later in life. The site of storage of imprinted memory and the mechanisms that control its formation and permanence are unknown. Here we uncover a molecular mechanism that controls olfactory imprinting, which underlies behaviors including kin and nest recognition, maternal attachment, and homing5-10. We show that odor exposure during the perinatal period converts an innately aversive odor into a homing signal. The behavioral change is associated with odor-induced changes in the projection patterns of olfactory sensory neuron (OSN) expressing the cognate receptors for the exposed odor. We show that the Wnt signaling receptor Frizzled1 (Fzd1) acts as a master regulator of the critical period of OSN development and is responsible for closing the critical period to prevent further changes in the neural circuit. In Fzd1 knockout mice axon projection patterns are continually modified by sensory experience. As Fzd1 knockout abolishes the developmental critical period, it also abolishes odor imprinting. Specific knockout of Fzd1 in the OSNs have the same effect. Mechanistically, Fzd1 controls the critical period through an autoregulated shutdown and by controlling an activity-driven regulon in the OSNs. The transient expression and the subsequent downregulation of Fzd1 leads to the irreversible closure of the critical period to lock in circuits established during the critical period. The evidence suggests that imprinted odor memory is stored in the patterns of connectivity at the first synapse in the olfactory bulb. Early odor experience induces changes in the OSN projection to alter connectivity with innate circuits to establish a life-long memory.

neuroscience↗

bioRxiv2022

Alternative 3' UTRs contributes to post-transcriptional gene expression regulation under high salt stress

High salt stress continually challenges growth and survival of many plants, but the underlying molecular basis is not fully explored. Alternative polyadenylation (APA) produces mRNAs with different 3'UTRs (alternative 3'UTRs) to regulate gene expression at post-transcriptional level. However, the roles of such process in response to salt stress remain elusive. Here, we reported that alternative 3'UTRs responded to high salt stress in the halophyte-Spartina alterniflora, which tolerant to hash salt environment. High salt stress induced the global APA and increased the prevalence of APA events. Strikingly, high salt stress significantly led to 3' UTR lengthening of 207 transcripts through increasing the usage of distal poly(A) sites. Transcripts with alternative 3' UTRs were mainly enriched in salt stress related ion transporters. Alternative 3' UTRs of SaHKT1 increased RNA stability and protein synthesis in vivo. Regulatory AU-rich elements were identified in the alternative 3' UTRs and alternative 3' UTRs increased protein level of SaHKT1 in an AU-rich element dependent manner. Finally, 3' UTR lengthening might result from variations in poly(A) signals and poly(A) factors. Overall, these results suggest that APA is a potential novel high salt stress responsive mechanism by modulating mRNA 3' UTR length. These results also reveal complex regulator roles of alternative 3' UTRs coupling alternative polyadenylation and regulatory elements at post-transcriptional level in plants. One sentence summaryAlternative 3' UTRs acts as a potential novel mechanism in gene expression regulation of high salt tolerant genes

plant biology↗

bioRxiv2022

Anatomical connectivity profile development constrains medial-lateral topography in the dorsal prefrontal cortex

The prefrontal cortex (PFC) is a highly variable, evolutionarily expanded brain region that is engaged in multiple cognitive processes. The subregions of the PFC mature relatively late compared with other brain regions, and the maturation times vary between these subregions. Among these, the dorsomedial and dorsolateral prefrontal cortex (dmPFC and dlPFC) share a parallel topographic pattern of functional connectivity, while participating in different types of complex behaviors. However, the developmental trajectories of the two areas remain obscure. In this study, we uncovered differences in the developmental trends of the dmPFC and dlPFC. These differences were mainly caused by structural and functional changes in the medial area of the superior frontal gyrus (SFG). The developmentally different arealization patterns were verified using multiple parcellation approaches with multimodal data, including structural magnetic resonance imaging (sMRI), diffusion MRI (dMRI), resting state functional MRI (rfMRI), and a publicly available transcriptomic dataset. Human brain gene expression data was also used to perform downstream analyses, which could inform us about the potential biological mechanisms underlying the developmentally different arealizations. Furthermore, behavioral analyses hinted at the effects of regionalization on ontogeny. In brief, this study revealed a tendency toward a medial-lateral prefrontal division and can provide a fuller understanding of the potential underlying genetic underpinnings as well as of the potential effects on developmental behavior.

neuroscience↗

bioRxiv2022

Boosting with Omicron-matched or historical mRNA vaccines increases neutralizing antibody responses and protection against B.1.1.529 infection in mice

The B.1.1.529 Omicron variant jeopardizes vaccines designed with early pandemic spike antigens. Here, we evaluated in mice the protective activity of the Moderna mRNA-1273 vaccine against B.1.1.529 before or after boosting with preclinical mRNA-1273 or mRNA-1273.529, an Omicron-matched vaccine. Whereas two doses of mRNA-1273 vaccine induced high levels of serum neutralizing antibodies against historical WA1/2020 strains, levels were lower against B.1.1.529 and associated with infection and inflammation in the lung. A primary vaccination series with mRNA-1273.529 potently neutralized B.1.1.529 but showed limited inhibition of historical or other SARS-CoV-2 variants. However, boosting with mRNA-1273 or mRNA-1273.529 vaccines increased serum neutralizing titers and protection against B.1.1.529 infection. Nonetheless, the levels of inhibitory antibodies were higher, and viral burden and cytokines in the lung were slightly lower in mice given the Omicron-matched mRNA booster. Thus, in mice, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against B.1.1.529 infection with limited differences in efficacy measured.

microbiology↗

bioRxiv2022

Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

The complement component C3 is a fundamental plasma protein for host defense. However, recent work has demonstrated the critical importance of local C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice. Human lung transcriptome analysis showed secretory epithelial cells are a major source of C3. Mice with a C3 gene ablation from lung epithelial cells had worse pulmonary injury compared to wild type, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier. One Sentence SummaryLung-derived C3 mitigates severe bacterial pneumonia suggesting a novel cytoprotective role at mucosal barrier surfaces independent of circulating C3.

immunology↗

bioRxiv2022

Knockout of OsSWEET15 impaired rice embryo formation and seed-setting

we show that the knockout of a sugar transporter gene OsSWEET15 led to a significant drop in rice fertility because near half of the knockout mutant spikelets bore blighted or empty grains. The rest spikelets bore fertile grains with slightly reduced weight. Notably, the ovaries in the blighted grains of the ossweet15 mutants expanded after flowering but terminated development before the endosperm cellularization stage and aborted subsequently. GUS and GFP representing OsSWEET15 expression showed that the protein was strongly expressed in the embryo surrounding region (ESR) which was supposed to supply nutrients for the embryo development. These results joined with the proteins sucrose transport capacity and plasma membrane localization suggest that OsSWEET15 plays a prominent role during the caryopsis formation stage probably by releasing sucrose from the ESR to support the embryo development. By contrast, the empty grains were probably caused by the reduced pollen viability of the ossweet15 mutants. Investigation of the makeup of ossweet11 mutant grains revealed similar phenotypes that were observed in the ossweet15 mutants. These results indicate that both OsSWETT15 and OsSWEET11 play important and similar roles during rice pollen development, caryopsis formation, and seed-setting in addition to their function in seed-filling that was demonstrated previously.

plant biology↗