Biology subjects

He, Y.

Publications and source records attributed to He, Y..

At least 523 records · Page 29Linked to original sources

bioRxiv2021

A chloride efflux transporter OsBIRG1 regulates grain size and salt tolerance in rice

Grain size is determined by the number of cells and cell size of the grain. Regulation of grain size is crucial for improving crop yield. However, the genes and underlying molecular mechanisms controlling grain size remain elusive. Here we report a member of Detoxification efflux carrier (DTX)/Multidrug and Toxic Compound Extrusion (MATE) family transporter, BIG RICE GRAIN 1 (BIRG1), negatively regulates the grain size in rice. BIRG1 is highly expressed in reproductive organs and roots. In birg1 grain, the size of the outer parenchyma layer cells of spikelet hulls is noticeably larger but the cell number is not altered compared with that in the wild-type (WT) grain. When expressed in Xenopus oocytes, BIRG1 exhibits chloride efflux activity. In line with the role of BIRG1 in mediating chloride efflux, the birg1 mutant shows reduced tolerance to salt stress under which the chloride level is toxic. Moreover, the birg1 grains contain higher level of chloride compared to WT grains when grown under normal paddy field. The birg1 roots accumulate more chloride than those of WT under saline condition. Collectively, our findings suggest that BIRG1 functions as a chloride efflux transporter regulating grain size and salt tolerance via controlling chloride homeostasis in rice.

plant biology↗

bioRxiv2021

Hypothalamic perineuronal nets are regulated by sex and dietary interventions

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons, and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus plays an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

neuroscience↗

bioRxiv2021

Ameliorating Emotional Attention through Modulation of Neural Oscillations with Transcranial Alternating Current Stimulation

BackgroundNumerous clinical reports suggest that psychopathy like schizophrenia, anxiety and depressive disorder is accompanied by early attentional abnormalities in emotional information processing. In the past decade, the efficacy of transcranial alternating current stimulation (tACS) in changing emotional functioning has been repeatedly observed and has demonstrated a causal relationship between endogenous oscillations and emotional processing. However, tACS effects on emotional attention have not yet been tested. MethodsA total of 53 healthy participants were randomized to 2 groups, and they were subjected to active or sham tACS at individual alpha frequency (IAF) in the bilaterally dorsolateral prefrontal cortex (dlPFC). Participants and received this treatment for 20 min durations daily for 7 consecutive days. On days 1 and 7, electroencephalogram (EEG) recording of 8 minute resting with eyes open and closed. Responses to a facial emotion identification task were also recorded to measure alpha changes and event-related potential (ERP) alterations. ResultsOn day 7 after tACS, the active group showed a more clear elevation in alpha power at rest, especially in open state around stimulation area, compared to the sham group. ERPs revealed a significant larger P200 amplitude after active stimulation (p < 0.05), indicating attentional improvement in facial emotion processing. Additionally, a notable positive correlation (p < 0.05) between alpha power and P200 amplitude was found, providing an electrophysiological interpretation regarding the role of tACS in emotional attention modulation. In addition, the IAF-tACS showed an obvious advantage in alpha entrainment compared to an additional 10 Hz-tACS. ConclusionsThese results support a seminal outcome for the effect of IAF-tACS on emotional attention modulation, demonstrating a feasible and individual-specific therapy for neuropsychiatric disorders related to emotion processing, especially regarding oscillatory disturbances.

bioengineering↗

bioRxiv2021

Development of Large-Scale Brain Network Dynamics in Children

Functional brain networks require dynamic reconfiguration to support flexible cognitive function. However, the developmental principles shaping brain network dynamics remain poorly understood. Here, we report the longitudinal development of large-scale brain network dynamics during childhood and adolescence, and its connection with gene expression profiles. Using a multilayer network model, we show the temporally varying modular architecture of child brain networks, with higher network switching primarily in the association cortex and lower switching in the primary regions. This topographical profile exhibits progressive maturation, which manifests as reduced modular dynamics, particularly in the transmodal (e.g., default-mode and frontoparietal) and sensorimotor regions. These developmental refinements mediate age-related enhancements of global network segregation and are linked with the expression profiles of genes associated with the enrichment of ion transport and nucleobase-containing compound transport. These results highlight a progressive stabilization of brain dynamics, which expand our understanding of the neural mechanisms that underlie cognitive development.

neuroscience↗

bioRxiv2021

ClusterMap: multi-scale clustering analysis of spatial gene expression

Quantifying RNAs in their spatial context is crucial to understanding gene expression and regulation in complex tissues. In situ transcriptomic methods generate spatially resolved RNA profiles in intact tissues. However, there is a lack of a unified computational framework for integrative analysis of in situ transcriptomic data. Here, we present an unsupervised and annotation-free framework, termed ClusterMap, which incorporates physical proximity and gene identity of RNAs, formulates the task as a point pattern analysis problem, and thus defines biologically meaningful structures and groups. Specifically, ClusterMap precisely clusters RNAs into subcellular structures, cell bodies, and tissue regions in both two- and three-dimensional space, and consistently performs on diverse tissue types, including mouse brain, placenta, gut, and human cardiac organoids. We demonstrate ClusterMap to be broadly applicable to various in situ transcriptomic measurements to uncover gene expression patterns, cell-cell interactions, and tissue organization principles from high-dimensional transcriptomic images.

genomics↗

bioRxiv2021

Engineering the Immune Adaptor Protein STING as a Biologic

Activation of the stimulator of interferon genes (STING) pathway through cyclic dinucleotides (CDNs) has been explored extensively as potent vaccine adjuvants against infectious diseases as well as to increase tumor immunogenicity towards cancer immunotherapy in solid tumors. Over the last decade, a myriad of synthetic vehicles, including liposomes, polymers, and other nanoparticle platforms, have been developed to improve the bioavailability and therapeutic efficacy of STING agonists in preclinical mouse models. In comparison to synthetic materials, protein-based carriers represent an attractive delivery platform owing to their biocompatibility, amenability to genetic engineering, and intrinsic capacity to form well-defined structures. In the present work, we have engineered the immune adaptor STING as a protein-based delivery system for efficient encapsulation and intracellular delivery of CDNs. Through genetic fusion with a protein transduction domain, the recombinant STING can spontaneously penetrate cells to markedly enhance the delivery of CDNs in a mouse vaccination model and a syngeneic mouse melanoma model. Moreover, motivated by recent findings that certain tumor cells can evade immune surveillance via loss of STING expression, we further unveiled that our STING platform can serve as a functional vehicle to restore the STING signaling in a panel of lung and melanoma cell lines with impaired STING expression. Taken together, our STING-based protein delivery platform may offer a unique direction towards targeting STING-silenced tumors as well as augmenting the efficacy of STING-based vaccine adjuvants.

bioengineering↗

bioRxiv2021

Tracing Human Amygdala across School Age

The developmental pattern of the amygdala throughout childhood and adolescence has been inconsistently reported in previous neuroimaging studies. Given the relatively small size of the amygdala on full brain MRI scans, discrepancies may be partly due to methodological differences in amygdalar segmentation. To investigate the impact of volume extraction methods on amygdala volume, we compared FreeSurfer, FSL and volBrain segmentation measurements with those obtained by manual tracing. The manual tracing method, which we used as the gold standard, exhibited almost perfect intra- and inter-rater reliability. We observed systematic differences in amygdala volumes between automatic (FreeSurfer and volBrain) and manual methods. Specifically, compared with the manual tracing, FreeSurfer estimated larger amygdalae, and volBrain produced smaller amygdalae while FSL demonstrated a mixed pattern. The tracing bias was not uniform, but higher for smaller amygdalae. We further modeled amygdalar growth curves using accelerated longitudinal cohort data from the Chinese Color Nest Project. Trajectory modeling and statistical assessments of the manually traced amygdalae revealed linearly increasing and parallel developmental patterns for both girls and boys, although the amygdalae of boys were larger than those of girls. Compared to these trajectories, the shapes of developmental curves were similar when using the volBrain derived volumes. FreeSurfer derived trajectories had more nonlinearities and appeared flatter. FSL derived trajectories demonstrated an inverted U shape and were significantly different from those derived from manual tracing method. The use of amygdala volumes adjusted for total gray-matter volumes, but not intracranial volumes, resolved the shape discrepancies and led to reproducible growth curves curves between manual tracing and the automatic methods (except FSL). Our findings revealed steady growth of the human amygdala, mirroring its functional development across the school age. Methodological improvements are warranted for current automatic tools to achieve more accurate tracing of the amygdala at school age, calling for next generation tools.

neuroscience↗

bioRxiv2021

Pre-mutagenic and mutagenic changes imprinted on the genomes of mammalian cells after irradiation with a nail polish dryer

Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of mammalian cells. These results have far-reaching implications in regard to public health and to preventing skin cancer due to consumer-based exposure to ultraviolet light from artificial sources.

cancer biology↗

bioRxiv2021

Landscape of glioblastoma niches reveals the prognostic effects of tumor-infiltrating cells

A comprehensive characterization of non-tumor cells in the niches of primary glioblastoma is not fully established yet. This study aims to present an overview of tumor-infiltrating non-malignant cells in the complex microenvironment of glioblastoma with detailed characterizations of their prognostic effects. We curate 540 gene signatures covering a total of 64 non-tumor cell types. Cell type-specific expression patterns are interrogated by normalized enrichment score (NES) across four large gene expression profiling cohorts of glioblastoma with a total number of 967 cases. The GBMs in each cohort are hierarchically clustered into negative or positive immune response classes with significantly different overall survival. Our results show that astrocytes, macrophages, monocytes, NKTs, preadipocytes, smooth muscle cells, and MSC are risk factors, while CD8 T cells, CD8+ T cells, and plasma cells are protective factors. Moreover, we find that the immune system and organogenesis are uniformly enriched in negative immune response clusters, in contrast to the enrichment of nervous system in positive immune response clusters. Mesenchymal differentiation is also observed in the negative immune response clusters. High enrichment status of macrophages in negative immune response clusters are independently validated by analyzing scRNA-seq data from eight high-grade gliomas, revealing that negative immune response samples comprised 46.63% to 55.12% of macrophages, whereas positive immune response samples comprised only 1.70% to 8.12%, with IHC staining of samples from six short-term and six long-term survivors of GBMs confirming the results. Simple SummaryThe landscape of infiltrating non-tumor cells in glioblastoma niches remains unclear. In this study, we explore the enrichment status of a total of 64 non-tumor cell types predicted by applying 540 gene signatures curated from literature and normalized enrichment score (NES) across four large gene expression profiling cohorts of glioblastoma with 967 cases. Based on non-tumor cell type-based enrichment status, GBMs in each cohort are classified into positive or negative immune response clusters, showing a statistically significant different overall survival. Astrocytes, macrophages, monocytes, NKTs, preadipocytes, smooth muscle cells, and MSC are identified as risk factors, as well as protector factors of CD8 T cells, CD8+ T cells, and plasma cells. Our results also find that immune system- and organogenesis-related GO terms are uniformly enriched in negative immune response clusters, whereas positive immune response clusters are enriched with GO terms concerning the nervous system. The mesenchymal differentiation is observed in the negative immune response clusters. Particularly, the high presence of macrophages in the negative immune response clusters is further validated using scRNA-seq analysis and IHC staining of GBMs from independent cohorts.

cancer biology↗

bioRxiv2020

The size of helical pitch is important for microtubule plus end dynamic instability

Microtubule (MT) dynamic instability is a conserved phenomenon underlying essential cellular functions such as cell division, cell migration and intracellular transport, and is a key target of many chemotherapeutic agents. However, it remains unclear how the organization of tubulin dimers at the nanometer scale translates into dynamic instability as an emergent property at the micrometer scale. Tubulin dimers are organized into left-handed helical MT lattice, and most present-day MTs converge at a 1.5 dimer helical pitch that causes a seam in an otherwise symmetric helix. Because presently there are no experimental methods that can precisely manipulate tubulin subunit with sub-dimer resolution, the impact of helical pitch on dynamic instability remains unknown. Here by using stochastic simulations of microtubule assembly dynamics we demonstrate that helical pitch plays essential roles in MT plus end dynamic instability. By systematically altering helical pitch size, one half-dimer at a time, we found that a helical pitch as small as one half-dimer is sufficient to inhibit short-term MT length plateaus associated with diminishing GTP-tubulin cap. Notably, MT plus end dynamics quantitatively scale with the size of helical pitch, rather than being clustered by the presence or absence of helical symmetry. Microtubules with a 1.5 dimer helical pitch exhibit growth and shrinkage phases and undergo catastrophe and rescue similar to experimentally observed microtubules. Reducing helical pitch to 0 promotes rapid disassembly, while increasing it causes microtubules to undergo persistent growth, and it is the 1.5 dimer helical pitch that yields the highest percentage of MTs that undergo alternating growth and shrinkage without being totally disassembled. Finally, although the 1.5 dimer helical pitch is conserved among most present-day MTs, we find that other parameters, such as GTP hydrolysis rate, can partially compensate for changes in helical pitch. Together our results indicate that helical pitch is a determinant of MT plus end dynamic instability and that the evolutionarily conserved 1.5 dimer helical pitch promotes dynamic instability required for microtubule-dependent cellular functions.

cell biology↗

bioRxiv2020

neoDL: A novel neoantigen intrinsic feature-based deep learning model identifies IDH wild-type glioblastomas with the longest survival

BackgroundIDH wild-type glioblastoma (GBM) is the most aggressive tumor in the central nervous system in spite of extensive therapies. Neoantigen based personalized immune therapies achieve promising results in melanoma and lung cancer, but few neoantigen based models perform well in IDH wild-type GBM. Unlike the neoantigen load and occurrence that are well studied and often found useless, the association between neoantigen intrinsic features and prognosis remain unclear in IDH wild-type GBM. ResultsWe presented a novel neoantigen intrinsic feature-based deep learning model (neoDL) to stratify IDH wild-type GBMs into subgroups with different survivals. We first calculated a total of 2928 intrinsic features for each neoantigen and filtered out those not associated with survival, followed by applying neoDL in the TCGA data cohort. Leave one out cross validation (LOOCV) in the TCGA demonstrated that neoDL successfully classified IDH wild-type GBMs into different prognostic subgroups, which was further validated in an independent data cohorts from Asian population. Long-term survival IDH wild-type GBMs identified by neoDL were found characterized by 12 protective neoantigen intrinsic features and enriched in development and cell cycle. ConclusionsOur results provide a novel model, neoDL, that can be therapeutically exploited to identify IDH wild-type GBM with good prognosis who will most likely benefit from neoantigen based personalized immunetherapy.

bioinformatics↗

bioRxiv2020

Intra-Ramanome Correlation Analysis Unveils Metabolite Conversion Network from an Isogenic Cellular Population

Revealing dynamic features of cellular systems, such as links among metabolic phenotypes, typically requires a time- or condition-series set of samples. Here Intra-Ramanome Correlation analysis (IRCA) was proposed to achieve this goal from just one snapshot of an isogenic population, by pairwise correlating among cells all the thousands of Raman bands from Single-cell Raman Spectra (SCRS), i.e., based on the intrinsic inter-cellular metabolic heterogeneity. IRCA of Chlamydomonas reinhardtii under nitrogen depletion revealed a metabolite conversion network at each time point and its temporal dynamics that feature protein-to-starch conversion followed by starch-to-TAG conversion (plus conversion of membrane lipids to TAG). Such correlation patterns in IRCA were abrased by knocking out the starch-biosynthesis pathway yet fully restored by genetic complementation. Extension to 64 ramanomes from microalgae, fungi and bacteria under various conditions suggests IRCA-derived metabolite conversion network as an intrinsic, reliable, species-resolved and state-sensitive metabolic signature of isogenic cellular population. The high throughput, low cost, excellent scalability and broad extendibility of IRCA suggest its broad application in cellular systems.

microbiology↗

bioRxiv2020

Identification of four linear B-cell epitopes on the SARS-CoV-2 spike protein able to elicit neutralizing antibodies

SARS-CoV-2 unprecedentedly threatens the public health at worldwide level. There is an urgent need to develop an effective vaccine within a highly accelerated time. Here, we present the most comprehensive S-protein-based linear B-cell epitope candidate list by combining epitopes predicted by eight widely-used immune-informatics methods with the epitopes curated from literature published between Feb 6, 2020 and July 10, 2020. We find four top prioritized linear B-cell epitopes in the hotspot regions of S protein can specifically bind with serum antibodies from horse, mouse, and monkey inoculated with different SARS-CoV-2 vaccine candidates or a patient recovering from COVID-19. The four linear B-cell epitopes can induce neutralizing antibodies against both pseudo and live SARS-CoV-2 virus in immunized wild-type BALB/c mice. This study suggests that the four linear B-cell epitopes are potentially important candidates for serological assay or vaccine development.

microbiology↗

bioRxiv2020

Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor

Mutational signature analysis is commonly performed in genomic studies surveying cancer and normal somatic tissues. Here we present SigProfilerExtractor, an automated tool for accurate de novo extraction of mutational signatures for all types of somatic mutations. Benchmarking with a total of 34 distinct scenarios encompassing 2,500 simulated signatures operative in more than 60,000 unique synthetic genomes and 20,000 synthetic exomes demonstrates that SigProfilerExtractor outperforms thirteen other tools across all datasets with and without noise. For genome simulations with 5% noise, reflecting high-quality genomic datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true positive signatures while yielding more than 5-fold less false positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome sequenced and 19,184 whole-exome sequenced cancers reveals four previously missed mutational signatures. Two of the signatures are confirmed in independent cohorts with one of these signatures associating with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting mutational signatures, and several novel mutational signatures including a signature putatively attributed to direct tobacco smoking mutagenesis in bladder cancer and in normal bladder epithelium.

bioinformatics↗

bioRxiv2020

The biophysical basis of protein domain compatibility in ion channels

Understanding the biophysical mechanisms that govern the combination of protein domains into viable proteins is essential for advancing synthetic biology and biomedical engineering. Here, we use massively parallel genotype/phenotype assays to determine cell surface expression of over 300,000 variants of the inward rectifier K+ channel Kir2.1 recombined with hundreds of protein motifs. We use machine learning to derive a quantitative biophysical model and practical rules for domain recombination. Insertional fitness depends on nonlinear interactions between the biophysical properties of inserted motifs and the recipient protein, which adds a new dimension to the rational design of fusion proteins. Insertion maps reveal a generalizable hierarchical organization of Kir2.1 and several other ion channels that balances stability needed for folding and dynamics required for function. SummaryMassively parallel assays reveal interactions between donor domains and recipient proteins govern domain compatibility

biophysics↗

bioRxiv2020

Characterization of a novel endopeptidase Cwl0971 that hydrolyzes peptidoglycan of Clostridioides difficile involved in pleiotropic cellular processes

Clostridioides difficile is a Gram-positive, spore-forming, toxin-producing anaerobe that can cause nosocomial antibiotic-associated intestinal disease. Although the production of toxin A (TcdA) and toxin B (TcdB) contribute to the main pathogenesis of C. difficile, the mechanism of TcdA and TcdB release from cell remains unclear. In this study, we identified and characterized a new cell wall hydrolase Cwl0971 (CDR20291_0971) from C. difficile R20291, which is involved in bacterial autolysis. The gene 0971 deletion mutant (R20291{Delta}0971) generated with CRISPR-AsCpfI exhibited significantly delayed cell autolysis and increased cell viability compared to R20291, and the purified Cwl0971 exhibited hydrolase activity for Bacillus subtilis cell wall. Meanwhile, 0971 gene deletion impaired TcdA and TcdB release due to the decreased cell autolysis in the stationary / late phase of cell growth. Moreover, sporulation of the mutant strain decreased significantly compared to the wild type strain. In vivo, the defect of Cwl0971 decreased fitness over the parent strain in a mouse infection model. Collectively, Cwl0971 is involved in cell wall lysis and cell viability, which affects toxin release, sporulation, germination, and pathogenicity of R20291, indicating that Cwl0971 could be an attractive target for C. difficile infection therapeutics and prophylactics.

microbiology↗

bioRxiv2020

A Large-Scale Structural and Functional Connectome of Social Mentalizing

Humans have a remarkable ability to infer the mind of others. This mentalizing skill relies on a distributed network of brain regions but how these regions connect and interact is not well understood. Here we leveraged large-scale multimodal neuroimaging data to elucidate the connectome-level organization and brain-wide mechanisms of mentalizing processing. Key features of the mentalizing connectome have been delineated in exquisite detail and its relationship with the default mode network has been extensively scrutinized. Our study demonstrates that mentalizing processing unfolds across functionally heterogeneous regions with highly structured fiber tracts and unique hierarchical functional architecture, which make it distinguishable from the default mode network and other social brain networks.

neuroscience↗

bioRxiv2020

Drosophila larval light avoidance is negatively regulated by temperature through two pairs of central brain neurons

Animals innate avoidance behavior is crucial for its survival. It subjects to modulation by environmental conditions in addition to the commanding sensorimotor transformation pathway. Although much has been known about the commanding neural basis, relatively less is known about how innate avoidance behavior is shaped by external conditions. Here in this paper, we report that Drosophila larvae showed stronger light avoidance at lower temperatures than at higher temperatures. Such negative regulation of light avoidance by temperature was abolished by blocking two pairs of central brain neurons, ACLPR60F09 neurons, that were responsive to both light and temperature change, including cooling and warming. ACLPR60F09 neurons could be excited by pdf-LaN neurons in the visual pathway. On the downstream side, they could inhibit the CLPNR82B09 neurons that command light induced reorientation behavior. Compared with at warm temperature, ACLPR60F09 neurons response to light was decreased at cool temperature so that the inhibition on CLPNR82B09 neurons was relieved and the light induced avoidance was enhanced. Our result proposed a neural mechanism underlying cross-modal modulation of animal innate avoidance behavior.

neuroscience↗