Biology subjects

Ma, S.

Publications and source records attributed to Ma, S..

At least 235 records · Page 13Linked to original sources

bioRxiv2020

H2O2/ABA signal pathway participates in the regulation of stomata opening of cucumber leaves under salt stress by putrescine

The stomatal-aperture is imperative for plant physiological metabolism. The function of polyamines (PAs) in stomatal regulation under stress environment largely remains elucidate. Herein, we investigated the regulatory mechanism of exogenous putrescine (Put) on the stomatal opening of cucumber leaves under salt stress. The results revealed that Put relieved the salt-induced photosynthetic inhibition of cucumber leaves by regulating stomatal-apertures. Put application increased hydrogen peroxide (H2O2) and decreased abscisic acid (ABA) content in leaves under salt stress. The inhibitors of diamine oxidase (DAO), polyamine oxidase (PAO), nicotinamide adenine dinucleotide phosphate oxidase (NADPH) are AG, 1,8-DO and DPI, respectively and pre-treatment with these inhibitors up-regulated key gene NCED of ABA synthase and down-regulated key gene GSHS of reduced glutathione (GSH) synthase. The content of H2O2 and GSH were decreased and ABA content was increased and its influenced trend is AG>1,8-DO>DPI. Moreover, the Put induced down-regulation of ABA content under salt stress blocked by treatment with H2O2 scavenger (DMTU) and GSH scavenger (CNDB). Additionally, the application of DMTU also blocked the increase of GSH content. Collectively, these results suggest that Put can regulate GSH content by promoting H2O2 generation through polyamine metabolic pathway, which inhibits ABA accumulation to achieve stomatal regulation under salt stress. HighlightExogenous putrescine alleviates photosynthesis inhibition in salt-stressed cucumber seedlings by regulating stomatal-aperture.

physiology↗

bioRxiv2020

Temporally-Divergent Regulatory Mechanisms Govern Neuronal Development and Diversification in the Neocortex

Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling these early and late stages diverge: early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation, while programs active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. The data uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.

neuroscience↗

bioRxiv2020

St. Jude Cloud a Pediatric Cancer Genomic Data Sharing Ecosystem

Effective data sharing is key to accelerating research that will improve the precision of diagnoses, efficacy of treatments and long-term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem developed via collaboration between St. Jude Childrens Research Hospital, DNAnexus, and Microsoft, for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients, long-term survivors of pediatric cancer and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabyes on St. Jude Cloud include 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes, which are freely available to researchers worldwide. The resource is expanding rapidly with regular data uploads from St. Judes prospective clinical genomics programs, providing public access as soon as possible rather than holding data back until publication. Three interconnected apps within the St. Jude Cloud ecosystem--Genomics Platform, Pediatric Cancer Knowledgebase (PeCan) and Visualization Community--provide a unique experience for simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the St. Jude Cloud ecosystem through use cases that classify 48 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 subtypes of pediatric cancer.

cancer biology↗

bioRxiv2020

Cell-type-specific epigenomic variations associated with BRCA1 mutation in pre-cancer human breast tissues

BRCA1 germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here we report cell-type-specific profiling of genome-wide histone modifications including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal, and stromal cells extracted from pre-cancer BRCA1 mutation carriers and non-carriers, conducted using a low-input technology that we developed. We discover that basal and stromal cells present the most extensive epigenomic differences between mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+) while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due to BRCA1 mutation appear to facilitate their transformation into luminal progenitor cells. Our findings shed light on the pre-cancer epigenomic dynamics due to BRCA1 mutation and how they may contribute to eventual development of predominantly basal-like breast cancer.

genomics↗

bioRxiv2020

Rapid and efficient in vivo astrocyte-to-neuron conversion with regional identity and connectivity?

In vivo reprogramming of glia into functional neurons emerges as potential regeneration-based therapeutics for neural injuries or neurological diseases. Recent studies show that AAV-based manipulation of certain factors can rapidly and highly efficiently convert resident glia into functional neurons with brain region-specificity and precise connectivity. Using NEUROD1 as an example, we here show that the presumed astrocytes-converted neurons are essentially endogenous neurons in the adult mouse brain. AAV-mediated co-expression of NEUROD1 and a reporter indeed specifically, rapidly, and efficiently induces numerous reporter-labeled neurons. However, these neurons cannot be traced back to quiescent or reactive astrocytes by using stringent lineage-mapping strategies. Conversely, reporter-labeled neurons cannot be detected when NEUROD1 is strictly expressed in adult brain astrocytes. Through a retrograde labeling approach, our results rather reveal that endogenous neurons are the cell source for NEUROD1-induced reporter-labeled neurons. These results underline the indispensable value of stringent lineage-tracing strategies and beg for cautious interpretation of the in vivo reprogramming phenomena.

neuroscience↗

bioRxiv2020

Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia

DYT1 dystonia is a hereditary neurological disease caused by a heterozygous mutation in torsin A (TOR1A). While animal models provide insights into disease mechanisms, significant species-dependent differences exist since mice with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-derived motor neurons. These neurons with the heterozygous TOR1A mutation show markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport, whereas they lack the perinuclear "blebs" that are often observed in animal models. Importantly, we further uncover that the nuclear lamina protein LMNB1 is specifically dysregulated in expression and subcellular localization. LMNB1 downregulation can largely ameliorate all the cellular defects in DYT1 motor neurons. These results reveal the value of disease modeling with human neurons and provide novel molecular mechanisms underlying DYT1 dystonia and potentially other neurological diseases with impaired nucleocytoplasmic transport.

neuroscience↗

bioRxiv2020

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole. MethodsWe tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI. ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole, in combination with either Fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growth in vitro. Single-agent Riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures. ConclusionsRiluzole, alone or combined with endocrine therapy, may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.

cancer biology↗

bioRxiv2020

Chromatin potential identified by shared single cell profiling of RNA and chromatin

Cell differentiation and function are regulated across multiple layers of gene regulation, including the modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of the regulatory events leading to cell fate commitment. Here, we developed SHARE-seq, a highly scalable approach for measurement of chromatin accessibility and gene expression within the same single cell. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define Domains of Regulatory Chromatin (DORCs), which significantly overlap with super-enhancers. We show that during lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting changes in chromatin accessibility may prime cells for lineage commitment. We therefore develop a computational strategy (chromatin potential) to quantify chromatin lineage-priming and predict cell fate outcomes. Together, SHARE-seq provides an extensible platform to study regulatory circuitry across diverse cells within tissues.

genomics↗

bioRxiv2020

Coupling between slow-waves and sharp-wave ripples organizes distributed neural activity during sleep in humans

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80-150 Hz) and subcortical/cortical slow-waves (0.5-4 Hz). However, the precise role of SWR-slow-wave interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, temporal and frontal cortices, to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high frequency activity (HFA; 70-200 Hz) a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical slow-waves. Finally, local cortical slow-wave phase offsets during SWRs predicted functional connectivity between the frontal and temporal cortex. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

neuroscience↗

bioRxiv2020

Proteasome activator PA200 maintains stability of histone marks during transcription and aging

The epigenetic inheritance relies on stability of histone marks, but various diseases, including aging-related diseases, are usually associated with alterations of histone marks. How the stability of histone marks is maintained still remains unclear. The core histones can be degraded by the atypical proteasome, which contains the proteasome activator PA200, in an acetylation-dependent manner during somatic DNA damage response and spermiogenesis. Here we show that PA200 promotes the transcription-coupled degradation of the core histones, and plays an important role in maintaining the stability of histone marks. Degradation of the histone variant H3.3, which is incorporated into chromatin during transcription, was much faster than that of its canonical form H3.1, which is incorporated during DNA replication. This degradation of the core histones could be suppressed by the transcription inhibitor, the proteasome inhibitor or deletion of PA200. The histone deacetylase inhibitor accelerated the degradation rates of H3 in general, especially its variant H3.3, while the mutations of the putative acetyl-lysine-binding region of PA200 abolished histone degradation in the G1-arrested cells, supporting that acetylation is involved in the degradation of the core histones. Deletion of PA200 dramatically altered deposition of the active transcriptional hallmarks (H3K4me3 and H3K56ac) and transcription, especially during cellular aging. Furthermore, deletion of PA200 or its yeast ortholog Blm10 accelerated cellular aging. Notably, the PA200-deficient mice displayed a range of aging-related deteriorations, including immune malfunction, anxiety-like behaviors and shorter lifespan. Thus, the proteasome activator PA200 is critical to the maintenance of the stability of histone marks during transcription and aging.

cell biology↗

bioRxiv2020

An Arabidopsis gene expression predictor enables inference of transcriptional regulators

Gene expression regulation by transcription factors (TF) has long been studied, but no model exists yet that can accurately predict transcriptome profiles based on TF activities. We have constructed a universal predictor for Arabidopsis to predict the expression of 28192 non-TF genes using 1678 TFs. Applied to bulk RNA-Seq samples from diverse tissues, the predictor produced accurate predicted transcriptomes correlating well with actual expression, with average correlation coefficient of 0.986. Having recapitulated the quantitative relationships between TFs and target genes, the predictor further enabled downstream inference of TF regulators for genes and pathways, i.e. those involved in suberin, flavonoid, glucosinolate metabolism, lateral root, xylem, secondary cell wall development, and endoplasmic reticulum stress response. Our predictor provides an innovative approach to study transcriptional regulation.

systems biology↗

bioRxiv2020

Decoding transcriptional regulation via a human gene expression predictor

Transcription factors (TF) regulate cellular activities via controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes was lacking. We constructed a universal human gene expression predictor and utilized it to decode transcriptional regulation. Using 1613 TFs expression, the predictor reconstituted highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The predictors broad applicability indicated it had recapitulated the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs were then extracted from the predictor and enabled downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. Thus, we present a novel approach to study human transcriptional regulation following the "understanding by modeling" principle.

systems biology↗

bioRxiv2020

Chromatin-Bound PARP1 Correlates with Upregulation of Inflammatory Genes in Response to Long-Term Treatment with Veliparib

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat human HCC1937 BRCA1 mutant and isogenic BRCA1-complemented cells for three weeks with veliparib, a PARP inhibitor. We show that long-term treatment with veliparib results in chromatin-bound PARP1 in the BRCA1 mutant cells, and that this correlates with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/ signalling effector stimulator of interferon genes (STING) pathway. In contrast, long-term treatment of isogenic BRCA1-complemented cells with veliparib does not result in chromatin-associated PARP or significant upregulation of the inflammatory response. Our results suggest that long-term veliparib treatment may prime BRCA1 mutant tumors for positive responses to immune checkpoint blockade.

cancer biology↗

bioRxiv2020

Deep learning-based adaptive detection of fetal nucleated red blood cells

Aimthis study, we established an artificial intelligence system for rapid identification of fetal nucleated red blood cells (fNRBCs). MethodDensity gradient centrifugation and magnetic-activated cell sorting were used for the separation of fNRBCs from umbilical cord blood. The cell block technique was used for fixation. We proposed a novel preprocessing method based on imaging characteristics of fNRBCs for region of interest (ROI) extraction, which automatically segmented individual cells in peripheral blood cell smears. The discriminant information from ROIs was encoded into a feature vector and pathological diagnosis were provided by the prediction network. ResultsFour umbilical cord blood samples were collected and validated based on a large dataset containing 260 samples. Finally, the dataset was classified into 3,720 and 1,040 slides for training and testing, respectively. In the test set, classifier obtained 98.5% accuracy and 96.5% sensitivity. ConclusionTherefore, this study offers an effective and accurate method for fNRBCs preservation and identification.

pathology↗

bioRxiv2020

Polyploidization enhancing genetic recombination of the ancestral diploid genome in the evolution of hexaploid wheat

Allopolyploidy increases its evolutionary potential by fixing heterosis and the advantage of gene redundancy. Allelic combinations generated from genetic recombination potentially provide many variations to the selection pools for evolution. May there be any relationship between allopolyploidization and genetic recombination? To study the impact of polyploidy on genetic recombination, we selected wheat as a model and simulated its evolution pathway of allopolyploidy by developing synthetic hexaploid wheat. The change of homologous chromosome recombination were investigated on their diploid DD and tetraploid AABB genomes after their allohexaploidization, respectively. The genetic recombination of the ancestral diploid genome of Aegilops tauschii was enhanced significantly more than 2 folds after their hexaploidization. Hexaploidization enhancing genetic recombination of the ancestral diploid D genome was firstly reported to be a new way to increase evolutionary potential of wheat, which is beneficial for wheat to conquer their narrow origination of D genome, quickly spread and make it a major crop of the world. Finally, re-synthetizing hexaploid wheat using diverse Ae. tauschii species with tetraploid wheat can be considered as a pleiotropic strategy to speed adaptive evolution of bread wheat in breeding processes by increasing both gene allele types and genetic recombination variations.

evolutionary biology↗

bioRxiv2020

A Cretaceous bug indicates that exaggerated antennae may be a double-edged sword in evolution

In the competition for the opposite sex, sexual selection can favor production of exaggerated features, but the high cost of such features in terms of energy consumption and enemy avoidance makes them go to extinction under the influence of natural selection. However, to our knowledge, fossil on exaggerated traits that are conducive to attracting opposite sex are very rare. Here, we report the exaggerated leaf-like expansion antennae of Magnusantenna wuae Du & Chen gen. et sp. nov. (Hemiptera: Coreidae) with more abundant sensory hairs from a new nymph coreid preserved in a Cretaceous Myanmar amber. The antennae are the largest among species of coreid and one of the largest known insects. Such bizarre antennae indicate that sensitive and delicate sensory system and magnificent appearance in Hemiptera have been already well established in mid-Cretaceous. Our findings provide evidence for Darwins view that sensory organs play an important role in sexual selection. This nymph with the leaf-like antennae may also represents a new camouflage pattern for defense. However, the oversized antennae are costly to develop and maintain, increasing the risks from predators. Such unparalleled expanded antennae might be the key factor for the evolutionary fate of this Myanmar amber coreid species. SignificanceDarwin proposed the importance of sensory organs in sexual selection, but it was greatly ignored compared with weapons and other common ornaments. Here, we report a new type of insect antennae, the multiple segments leaf-like expansion antennae from a new nymph coreid preserved in a Cretaceous Myanmar amber. Our finding provides evidence for the prominent role of sensory organs in sexual selection and thus supports Darwins viewpoint. This discovery demonstrates that high-efficiency antennae were present in Coreidae 99 million years ago. In addition, the exaggerated antennae might represent a new evolutionary innovation for defensive behavior. This is a case in which the high benefits and high costs brought by the exaggerated antennae jointly determine the direction of species evolution.

paleontology↗

bioRxiv2020

Schisandrin B for treatment of male infertility

The decline of male fertility and its consequences on human populations are important public-health issues. However, there are limited choices for treatment of male infertility. In an attempt to identify a compound that could promote male fertility, we identified and characterized a library of small molecules from an ancient formulation Wuzi Yanzong-Pill, which was used as a folk medicine since the Tang dynasty of China. We found that SB enabled evident repairs in oligoasthenospermia-associated testicular tissue abnormality and in spermatogenesis disruption, resulting in significant improvements of sperm count, mobility, and reproductive ability in oligoasthenospermia mice. Furthermore, SB could alter substantial testicular genes (2033), among which, upregulation of Fst while downregulation of Inhba involved in reproductive signaling pathway could explain its role in enhancing spermatogenesis. The encouraging preclinical data with pharmacokinetics warranted a rapid development of this new class of therapeutic agent. Our finding provides a strong potent drug for treatment of male infertility.

pharmacology and toxicology↗

bioRxiv2020

Molecular Diversity Among Adult Hippocampal and Entorhinal Cells

The hippocampal-entorhinal system is comprised of functionally distinct subregions collectively critical for cognition, and selectively vulnerable to aging and pathological processes. To gain insights into neuronal and non-neuronal populations within this system, we performed single-nucleus transcriptional profiling from five human hippocampal-entorhinal subregions. We found that transcriptomic diversity of excitatory neurons across these subregions reflected the molecular transition from three-layered archicortex to six-layered neocortex. Additionally, mRNA and protein for DCX, an immature neuron marker, were clearly detected in some cells, but not in dentate granule cells, the cell-type predicted to be generated in adult neurogenesis. We also found that previously functionally uncharacterized METTL7B was enriched in human and non-human primate neuronal subtypes less vulnerable to initial Alzheimers disease pathology. Proteomic and biochemical assays revealed METTL7B interacts with Alzheimers disease-related proteins, including APP, and its overexpression reduced amyloid-beta generation. These results reveal cell type-specific molecular properties relevant for hippocampal-entorhinal physiology and dysfunction.

neuroscience↗