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Ma, K.

Publications and source records attributed to Ma, K..

At least 91 records · Page 5Linked to original sources

Undersampling correction methods to control γ-dependence for comparing β-diversity between regions

Measures of {beta}-diversity are known to be highly constrained by the variation in {gamma}-diversity across regions (i.e., {gamma}-dependence), making it challenging to infer underlying ecological processes. Undersampling correction methods have attempted to estimate the actual {beta}-diversity in order to minimize the effects of {gamma}-dependence arising from the problem of incomplete sampling. However, no study has systematically tested their effectiveness in removing {gamma}-dependence, and examined how well undersampling-corrected {beta}-metrics reflect true {beta}-diversity patterns that respond to ecological gradients. Here, we conduct these tests by comparing two undersampling correction methods with the widely used individual-based null model approach, using both empirical data and simulated communities along a known ecological gradient across a wide range of {gamma}-diversity and sample sizes. We found that undersampling correction methods using diversity accumulation curves were generally more effective than the null model approach in removing {gamma}-dependence. In particular, the undersampling-corrected {beta}-Shannon diversity index was most independent on {gamma}-diversity and was the most reflective of the true {beta}-diversity pattern along the ecological gradient. Moreover, the null model-corrected Jaccard-Chao index removed {gamma}-dependence more effectively than either approach alone. Our validation of undersampling correction methods as effective tools for accommodating {gamma}-dependence greatly facilitates the comparison of {beta}-diversity across regions.

ecology↗

Large field of view-spatially resolved transcriptomics at nanoscale resolution

Spatially resolved transcriptomic technologies are promising tools to study cell fate decisions in a physical microenvironment, which is fundamental for enhancing our knowledge of mammalian development. However, the imbalance between resolution, transcript capture and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation mammalian embryos. Here, we combined DNA nanoball (DNB) patterned arrays and tissue RNA capture to create SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq). This approach allows transcriptomic profiling of large histological sections with high resolution and sensitivity. We have applied Stereo-seq to study the kinetics and directionality of transcriptional variation in a time course of mouse organogenesis. We used this information to gain insight into the molecular basis of regional specification, neuronal migration and differentiation in the developing brain. Furthermore, we mapped the expression of a panel of developmental disease-related loci on our global transcriptomic maps to define the spatiotemporal windows of tissue vulnerability. Our panoramic atlas constitutes an essential resource to investigate longstanding questions concerning normal and abnormal mammalian development.

cell biology↗

Hydraulic diversity stabilizes productivity in a large-scale subtropical tree biodiversity experiment

Extreme climatic events threaten forests and their climate mitigation potential globally. Understanding the drivers promoting ecosystem stability is therefore considered crucial to mitigate adverse climate change effects on forests. Here, we use structural equation models to explain how tree species richness, asynchronous species dynamics and diversity in hydraulic traits affect the stability of forest productivity along an experimentally manipulated biodiversity gradient ranging from 1 to 24 tree species. Tree species richness improved stability by increasing species asynchrony. That is, at higher species richness, inter-annual variation in productivity among tree species buffered the community against stress-related productivity declines. This effect was mediated by the diversity of species hydraulic traits regarding drought tolerance and stomatal control, but not by the community-weighted means of these traits. The identified mechanisms by which tree species richness stabilizes forest productivity emphasize the importance of hydraulically diverse, mixed-species forests to adapt to climate change.

ecology↗

Sequencing of clinical samples reveals that adaptation keeps establishing during H7N9 virus infection in humans

The H7 subtype avian influenza viruses (AIV) have a much longer history and their adaptation through evolution pose continuous threat to humans 1. Since 2013 March, the novel reasserted H7N9 subtype have transmitted to humans through their repeated assertion in the poultry market. Through repeated transmission, H7N9 gradually became the second AIV subtype posing greater public health risk after H5N1 2,3. After infection, how the virus tunes its genome to adapt and evolve in humans remains unknown. Through direct amplification of H7N9 and high throughput (HT) sequencing of full genomes from the swabs and lower respiratory tract samples collected from infected patients in Shenzhen, China, we have analyzed the in vivo H7N9 mutations at the level of whole genomes and have compared with the genomes derived by in vitro cultures. These comparisons and frequency analysis against the H7N9 genomes in the public database, 40 amino acids were identified that play potential roles in virus adaptation during H7N9 infection in humans. Various synonymous mutations were also identified that might be crucial to H7N9 adaptation in humans. The mechanism of these mutations occurred in a single infection are discussed in this study.

microbiology↗

Bromodomain protein inhibition protects β-cells from cytokine-induced death and dysfunction via antagonism of NF-κB pathway.

Cytokine induced {beta}-cell apoptosis is the major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding underlying mechanisms, few drugs have been translated to protect {beta}-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (Bromo- and Extra-Terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in NOD (non-obese diabetes) mouse model of T1D. However, the role of BET proteins in {beta}-cell function in response to cytokines is unknown. Here we demonstrate that I-BET, a BET protein inhibitor, protected {beta}-cells from cytokine induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced {beta}-cell apoptosis and preserved {beta}-cell mass, suggesting a cytoprotective function of I-BET. Furthermore, human islets treated with I-BET displayed better glucose stimulated insulin secretion compared to controls, when exposed to cytokines. Mechanistically, RNA-Seq analysis revealed I-BET treatment suppressed pathways involved in apoptosis, including NF-kB signaling, while maintaining the expression of genes critical for {beta}-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting {beta}-cells from cytokine-induced dysfunction and apoptosis, and may have potential therapeutic values in T1D.

molecular biology↗

A valid protective immune response elicited in rhesus macaques by an inactivated vaccine is capable of defending against SARS-CoV-2 infection

With the relatively serious global epidemic outbreak of SARS-CoV-2 infection, public concerns focus on not only clinical therapeutic measures and public quarantine for this disease but also the development of vaccines. The technical design of our SARS-CoV-2 inactivated vaccine provides a viral antigen that enables the exposure of more than one structural protein based upon the antibody composition of COVID-19 patients convalescent serum. This design led to valid immunity with increasing neutralizing antibody titers and a CTL response detected post-immunization of this vaccine by two injections in rhesus macaques. Further, this elicited immunoprotection in macaques enables not only to restrain completely viral replication in tissues of immunized animals, compared to the adjuvant control and those immunized by an RBD peptide vaccine, but also to significantly alleviate inflammatory lesion in lung tissues in histo-pathologic detection, compared to the adjuvant control with developed interstitial pneumonia. The data obtained from these macaques immunized with the inactivated vaccine or RBD peptide vaccine suggest that immunity with a clinically protective effect against SARS-CoV-2 infection should include not only specific neutralizing antibodies but also specific CTL responses against at least the S and N antigens.

immunology↗

Species packing and the latitudinal gradient in local beta-diversity

The decline in species richness at higher latitudes is among the most fundamental patterns in ecology. Whether changes in species composition across space (beta-diversity) contribute to this gradient of overall species richness (gamma-diversity) remains hotly debated. Previous studies that failed to resolve the issue suffered from a well-known tendency for small samples in areas with high gamma-diversity to have inflated measures of beta-diversity. Here, we provide here a novel analytical test, using beta-diversity metrics that correct the gamma-diversity and sampling biases, to compare beta-diversity and species packing across a latitudinal gradient in tree species richness of 21 large forest plots along a large environmental gradient in East Asia. We demonstrate that after accounting for topography and correcting the gamma-diversity bias, tropical forests still have higher beta-diversity than temperate analogs. This suggests that beta-diversity contributes to the latitudinal species richness gradient as a component of gamma-diversity. Moreover, both niche specialization and niche marginality (a measure of niche spacing along an environmental gradient) also increase towards the equator, after controlling for the effect of topographic heterogeneity. This supports the joint importance of tighter species packing and larger niche space in tropical forests while also demonstrating the importance of local processes in controlling beta-diversity.

ecology↗

Single-cell regulatory landscape and disease vulnerability map of adult Macaque cortex

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell chromatin accessibility (single-cell ATAC) and transcriptomic data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult cynomolgus monkey brain, and integrated this dataset with Stereo-seq (Spatio-Temporal Enhanced REsolution Omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity. We reveal calcium ion transport and axon guidance genes related to specialized functions of PFC and M1, identified the similarities and differences between adult macaque and human oligodendrocyte trajectories, and mapped the genetic variants and gene perturbations of human diseases to NHP cortical cells. This resource establishes a transcriptomic and chromatin accessibility combinatory regulatory landscape at a single-cell and spatially resolved resolution in NHP cortex.

neuroscience↗

Accurate Diagnosis of Colorectal Cancer Based on Histopathology Images Using Artificial Intelligence

BackgroundAccurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on their daily image analyses. MethodsBased on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC prediction/diagnosis using weakly labeled pathological whole slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, >14,680 WSIs, from >9,631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, U.S., and Germany. ResultsOur innovative AI tool was consistently nearly perfectly agreed with (average Kappa-statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multi-centers. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.981 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. ConclusionsThis first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. Hence, it will drastically alleviate the heavy clinical burden of daily pathology diagnosis, and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

pathology↗

Tead1 reciprocally regulates adult β-cell proliferation and function

Proliferative quiescence in {beta}-cells is required to maintain functional competence. While this presents a significant hurdle in regenerative therapy for diabetes, the molecular underpinnings of this reciprocal relationship remain unclear. Here, we demonstrate that TEAD1, the transcription effector of the mammalian-Hippo pathway, drives developmental stage-specific {beta}-cell proliferative capacity in conjunction with its functional maturation. TEAD1 promotes adult {beta}-cell mature identity by direct transcriptional control of a network of critical {beta}-cell transcription factors, including, Pdx1, Nkx6.1, and MafA, while its regulation of Cdkn2a maintains proliferative quiescence. Consequently, mice with either constitutive or inducible genetic deletion of TEAD1 in {beta}-cells developed overt diabetes due to a severe loss of secretory function despite induction of proliferation. Furthermore, we show that TEAD1 has a similar regulatory role in human {beta}-cells. Consistent with this function in {beta}-cells, variants in TEAD1 have been associated with c-HOMA-B in American Indians. We propose that TEAD1 is an essential intrinsic molecular switch coordinating adult {beta}-cell proliferative quiescence with mature identity and its differential modulation may be necessary to overcome the challenge of inducing proliferation with functional competence in human beta cells.

molecular biology↗

Tyrosine phosphorylation of ACLY regulates lipid metabolism and oncogenesis in ALK positive Anaplastic Large Cell Lymphoma

A fundamental requirement for growth of rapidly proliferating cells is metabolic adaptation to promote synthesis of biomass1. ATP citrate lyase (ACLY) is a critical enzyme responsible for synthesis of cytosolic acetyl-CoA, the key building component for de novo fatty acid synthesis and links vital pathways such as carbohydrate and lipid metabolism2. The mechanisms of ACLY regulation are not completely understood and the regulation of ACLY function by tyrosine phosphorylation is unknown. Here we show using mass-spectrometry-driven phosphoproteomics and metabolomics that ACLY is phosphorylated and functionally regulated at an evolutionary conserved residue, Y682. Physiologic signals promoting rapid cell growth such as epidermal growth factor stimulation in epithelial cells and T-cell receptor activation in primary human T-cells result in rapid phosphorylation of ACLY at Y682. In vitro kinase assays demonstrate that Y682 is directly phosphorylated by multiple tyrosine kinases, including ALK, ROS1, SRC, JAK2 and LTK. Oncogenically activating structural alterations such as gene-fusions, amplification or point mutations of ALK tyrosine kinase result in constitutive phosphorylation of ACLY in diverse forms of primary human cancer such as lung cancer, anaplastic large cell lymphoma (ALCL) and neuroblastoma. Expression of a phosphorylation-defective ACLY-Y682F mutant in NPM-ALK+ ALCL decreases ACLY activity and attenuates lipid synthesis. Metabolomic analyses reveal that ACLY-Y682F expression results in increased {beta}-oxidation of 13C-oleic acid-labeled fatty acid with increased labeling of +2-citrate (p<0.01) and +18-oleyol carnitine (p<0.001). Similarly, oxygen consumption rate (OCR) is significantly increased in cells expressing ACLY-Y682F (p<0.001). Moreover, expression of ACLY-Y682F dramatically decreases cell proliferation, impairs clonogenicity and abrogates tumor growth in vivo. Our results reveal a novel mechanism for direct ACLY regulation that is subverted by multiple oncogenically-activated tyrosine kinases in diverse human cancers. These findings have significant implications for novel therapies targeting ACLY in cancer and metabolism.

cancer biology↗

Learning immune cell differentiation

The mammalian genome contains several million cis-regulatory elements, whose differential activity marked by open chromatin determines organogenesis and differentiation. This activity is itself embedded in the DNA sequence, decoded by sequence-specific transcription factors. Leveraging a granular ATAC-seq atlas of chromatin activity across 81 immune cell-types we show that a convolutional neural network ("AI-TAC") can learn to infer cell-type-specific chromatin activity solely from the DNA sequence. AI-TAC does so by rediscovering, with astonishing precision, binding motifs for known regulators, and some unknown ones, mapping them with high concordance to positions validated by ChIP-seq data. AI-TAC also uncovers combinatorial influences, establishing a hierarchy of transcription factors (TFs) and their interactions involved in immunocyte specification, with intriguingly different strategies between lineages. Mouse-trained AI-TAC can parse human DNA, revealing a strikingly similar ranking of influential TFs. Thus, Deep Learning can reveal the regulatory syntax that drives the full differentiative complexity of the immune system.

genomics↗

Identification of 12 cancer types through genome deep learning

MotivationCancer is a major cause of death worldwide, and an early diagnosis is required for a favorable prognosis. Histological examination is the gold standard for cancer identification; however, there is a large amount of inter-observer variability in histological diagnosis. Numerous studies have shown that cancer genesis is accompanied by an accumulation of harmful mutations within patients genome, potentiating the identification of cancer based on genomic information. We have proposed a method, GDL (genome deep learning), to study the relationship between genomic variations and traits based on deep neural networks with multiple hidden layers and nonlinear transformations. ResultWe analyzed 6,083 samples from 12 cancer types obtained from the TCGA (The Cancer Genome Atlas) and 1,991 healthy samples from the 1000 Genomes project(Genomes Project, et al., 2010). We constructed 12 specific models to distinguish between certain types of cancers and healthy tissues, a specific model that can identify healthy vs diseased tissues, and a mixture model to distinguish between all 12 types of cancer based on GDL. We present the success obtained with GDL when applied to the challenging problem of cancer based on genomic variations and demonstrate state-of-the-art results (97%, 70.08% and 94.70%) for cancer identification. The mixture model achieved a comparable performance. With the development of new molecular and sequencing technologies, we can now collect circulating tumor DNA (ctDNA) from blood and monitor the cancer risk in real time, and using our model, we can also target cancerous tissue that may develop in the future. We developed a new and efficient method for the identification of cancer based on genomic information that offers a new direction for disease diagnosis while providing a new method to predict traits based on that information. Contactchenwenbin@genomics.cn

bioinformatics↗

Intra-familial phenotypic heterogeneity and telomere abnormality in von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p=0.834) and between first-born patients and the other siblings (p=0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

genetics↗

3D Chromatin Architecture Remodeling during Human Cardiomyocyte Differentiation Reveals A Novel Role of HERV-H In Demarcating Chromatin Domains

Dynamic restructuring of chromatin architecture has been implicated in cell-type specific gene regulatory programs; yet, how chromatin remodels during lineage specification remains to be elucidated. Through interrogating chromatin reorganization during human cardiomyocyte differentiation, we uncover dynamic chromatin interactions between genes and distal regulatory elements harboring noncoding variants associated with adult and congenital heart diseases. Unexpectedly, we also discover a new class of human pluripotent stem cell (PSC)-specific topologically associating domains (TAD) that are created by the actively transcribed endogenous retrotransposon HERV-H. Deletion or silencing of specific HERV-H elements eliminates corresponding TAD boundaries, while de novo insertion of HERV-H can introduce new chromatin domain boundaries in human PSCs. Furthermore, comparative analysis of chromatin architecture in other species that lack HERV-H sequences supports a role for actively transcribed HERV-H in demarcating human PSC-specific TADs. The biological role of HERV-H is further underscored by the observation that deletion of a specific HERV-H reduces transcription of genes upstream and facilitates cell differentiation. Overall, our results highlight a previously unrecognized role for retrotransposons in restructuring genome architecture in the human genome and delineate dynamic gene regulatory networks during cardiomyocyte development that inform how non-coding genetic variants contribute to human heart diseases.

genomics↗

Generation of Cynomolgus Monkeys (Macaca fascicularis) Embryos with ICSI Based on the MII-Stage Oocytes Acquired by Personalized Superovulation Protocol

The use of cynomolgus monkeys (Macaca fascicularis) has facilitated the establishment of gene-modified animal models, and the appropriate number of high-quality mature oocytes (MII-stage oocytes) are crucial in assisted reproductive technologies (ART) of cynomolgus macaques. In this study we performed 3 different superovulation protocols on 24 female cynomolgus monkeys aimed to improve the proportion of MII-stage oocyte retrieval. The results suggested some differences in the proportion of MII-stage oocytes between the personalized superovulation protocol and the superovulation protocols I and II. Afterwards, we performed Intracytoplasmic sperm injection (ICSI) on 22 MII-stage oocytes derived from one animal with personalized superovulation protocol, obtained 15 embryos of 2-4-cells, 2 cases of successful pregnancy after transferring to 4 surrogate female, and obtained 3 aborted fetuses. These results suggested that personalized superovulation protocol incorporated the menstrual cycle length of each cynomolgus monkey, and the timing of oocytes retrieval based on the equation: menstrual cycle length/2 {+/-} 1, which increased the rate of MII-stage oocytes acquired and generation of cynomolgus monkeys embryos with ICSI based on these oocytes, and finally could successfully develop into fetus under conditions that effectively guarantee the synchronization of the surrogate mothers.\n\nSUMMARY STATEMENTThe personalized superovulation protocol based on the menstrual cycle length of each cynomolgus monkey can increase the rate of MII-stage oocytes acquired, and finally could successfully develop into fetus under conditions that minimize damage to the surrogate mothers and effectively guarantee the synchronization of the surrogate mothers.

developmental biology↗

Behavioral Analysis of Substrate Texture Preference in a Leech, Helobdella austinensis

Leeches in the wild are often found on smooth surfaces, such as vegetation, smooth rocks or human artifacts such as bottles and cans, thus exhibiting what appears to be a \"substrate texture preference behavior\". Here, we have reproduced this behavior under controlled circumstances, by allowing leeches to step about freely on a range of silicon carbide sandpaper substrates. To begin to understand the neural mechanisms underlying this texture preference behavior, we have determined relevant parameters of leech behavior both on uniform substrates of varying textures, and in a behavior choice paradigm in which the leech is confronted with a choice between rougher and smoother substrate textures at each step. We tested two non-exclusive mechanisms which could produce substrate texture preference: 1) a Diffusion Trap mechanism, in which a leech is more likely to stop moving on a smooth surface than on a rough one, and; 2) an Anterior Choice mechanism, in which a leech is more likely to attach its front sucker (prerequisite for taking a step) to a smooth surface than to a rough one. We propose that both mechanisms contribute to the texture preference exhibited by leeches.

animal behavior and cognition↗

Sequencing of Panax notoginseng genome reveals genes involved in disease resistance and ginsenoside biosynthesis

Panax notoginseng is a traditional Chinese herb with high medicinal and economic value. There has been considerable research on the pharmacological activities of ginsenosides contained in Panax spp.; however, very little is known about the ginsenoside biosynthetic pathway. We reported the first de novo genome of 2.36 Gb of sequences from P. notoginseng with 35,451 protein-encoding genes. Compared to other plants, we found notable gene family contraction of disease-resistance genes in P. notoginseng, but notable expansion for several ATP-binding cassette (ABC) transporter subfamilies, such as the Gpdr subfamily, indicating that ABCs might be an additional mechanism for the plant to cope with biotic stress. Combining eight transcriptomes of roots and aerial parts, we identified several key genes, their transcription factor binding sites and all their family members involved in the synthesis pathway of ginsenosides in P. notoginseng, including dammarenediol synthase, CYP716 and UGT71. The complete genome analysis of P. notoginseng, the first in genus Panax, will serve as an important reference sequence for improving breeding and cultivation of this important nutraceutical and medicinal but vulnerable plant species.

genomics↗