Biology subjects

Jiang, M.

Publications and source records attributed to Jiang, M..

At least 127 records · Page 7Linked to original sources

bioRxiv2021

Anterior Cingulate Cortex Signals the Need to Control Intrusive Thoughts During Motivated Forgetting

How do people limit awareness of unwanted memories? Evidence suggests that when unwelcome memories intrude, a retrieval stopping process engages the right dorsolateral prefrontal cortex (rDLPFC; Anderson et al., 2004) to inhibit hippocampal activity (Benoit and Anderson, 2012; Benoit et al., 2015; Gagnepain et al., 2017) and disrupt retrieval. It remains unknown how and when the need to engage prefrontal control is detected, and whether control operates proactively to prevent an unwelcome memory from being retrieved, or must respond reactively, to counteract its intrusion. We hypothesized that dorsal anterior cingulate cortex (dACC) achieves this function by detecting signals indicating that an unwanted trace is emerging in awareness, and transmitting the need for inhibitory control to right DLPFC (Alexander and Brown, 2011; Botvinick et al., 2001). During a memory suppression task, we measured trial-by-trial variations in dACCs theta power and N2 amplitude, two electroencephalographic (EEG) markers of the need for enhanced control (Cavanagh and Frank, 2014). With simultaneous EEG-fMRI recordings, we tracked dynamic interactions between the dACC, rDLPFC and hippocampus during suppression. EEG analyses revealed a clear role of dACC in detecting the need for memory control, and in upregulating prefrontal inhibition. Importantly, we identified dACC contributions before episodic retrieval could have occurred (500 ms) and afterwards, indicating distinct proactive and reactive control signalling. Stronger proactive control by the dACC led to reduced hippocampal activity and diminished overall blood-oxygen-level-dependent (BOLD) signal in dACC and rDLPFC, suggesting that pre-empting retrieval early reduced overall control demands. However, when dACC activity followed the likely onset of recollection, retrieval was cancelled reactively: effective connectivity analyses revealed robust communication from dACC to rDLPFC and from rDLPFC to hippocampus, tied to successful forgetting. Together, our findings support a model in which dACC detects the emergence of unwanted content, triggering top-down inhibitory control, and in which rDLPFC countermands intruding thoughts that penetrate awareness.

neuroscience↗

bioRxiv2021

Early life exposure to high fructose diet induces metabolic dysregulation associated with sex-specific cognitive impairment in adolescent rats.

BackgroundThe incidence of adolescent mental health disorders is on the rise. Epidemiological studies suggest that poor nutrition is a significant contributor to this public health crisis, specifically through exposure to high level of dietary sugar, including fructose, during critical periods of development. Previous studies have shown that elevated fructose exposure during adolescence disrupts mental health. Further, it seems that infants display the highest level of exposure to fructose based on nutritional surveys. Despite these data, it is currently unknown how fructose exposure, specifically during infancy, may impact adolescent mental health. MethodsWe developed an experimental protocol in rats to investigate the effects of fructose exposure during infancy on behavioral, cognitive and metabolic endpoints in adolescence. Specifically, rat pups were exposed to fructose from birth until weaning through maternal diet. Metabolic assays, quantitative PCR and behavioral protocols such as open field, elevated O maze and a Go/ No-Go operant task, were used to determine whether high fructose exposure during infancy may set the stage for behavioral and metabolic dysfunction in adolescence. ResultsWe found that exposing rats to high fructose from birth to weaning resulted in higher circulating glucose, insulin and leptin levels in adolescence. High fructose during infancy also increased bodyweight, disrupted metabolic homeostasis in the basolateral amygdala (BLA) as indicated by decreased activity of the cellular energy sensor AMPK, and impaired attention and impulsivity in a male-specific manner. This impaired attention observed in adolescent male rats following neonatal fructose exposure was partially rescued by viral-mediated, in vivo expression of a constitutively active form of AMPK in principal neurons of the BLA. ConclusionOur results suggest that exposure to high level of fructose during infancy may impact adolescent mental health in a male-specific manner and that manipulation of AMPK activity may mitigate this impact.

animal behavior and cognition↗

bioRxiv2021

Analysis of rhizosphere bacterial diversity of Angelica dahurica var. formosana based on different experimental sites and varieties (strains)

Only with good producing areas and good germplasm can good medicinal materials be produced. In this study, in order to explore the effects of soil environment and germplasm on yield and quality of Angelica dahurica var. formosana from microorganism level, Illumina MiSeq was used to study the rhizosphere bacterial diversity of A. dahurica var. formosana based on different origin and varieties (strains). The results showed that the bacterial community of A. dahurica var. formosana was stable and conserved to a certain extent, and the bacteria of Proteobacteria and Firmicutes might play an important role in improving the yield and quality of A. dahurica var. formosana. Soil variables were the key factors affecting the rhizosphere bacterial community composition of A. dahurica var. formosana. These results are of great significance for further understanding the growth promotion mechanism of beneficial rhizosphere bacteria, reducing fertilizer application, expanding planting area, improving soil environment, and improving yield and quality. ImportanceRhizosphere microorganisms play an important role in plant growth and accumulation of secondary metabolites. In this study, it was found for the first time that the rhizosphere bacterial community of A. dahurica var. formosana was relatively stable and conserved which could adapt to different environmental changes and resist the interference of external factors to a certain extent, providing a theoretical basis for distant planting and promotion of planting. The bacterial taxa of Proteobacteria and Firmicutes might play an important role in improving the yield and quality of A. dahurica var. formosana. This provided a theoretical basis for the exploitation and utilization of rhizosphere microbial resources of A. dahurica var. formosana to artificially control the soil environment and provided a new idea for increasing yield and quality of A. dahurica var. formosana.

microbiology↗

bioRxiv2021

Calsyntenin-3, an atypical cadherin, suppresses inhibitory basket- and stellate-cell synapses but boosts excitatory parallel-fiber synapses in cerebellum

Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic adaptors for kinesin-mediated vesicular transport. Here, we show that acute CRISPR-mediated deletion of calsyntenin-3 in cerebellar Purkinje cells in vivo causes a large decrease in inhibitory synapses, but a surprisingly robust increase in excitatory parallel-fiber synapses. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Thus, by promoting formation of an excitatory type of synapses and decreasing formation of an inhibitory type of synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells. No similarly opposing function of a synaptic adhesion molecule was previously observed, suggesting a new paradigm of synaptic regulation.

neuroscience↗

bioRxiv2021

Deep Learning-Based Approaches for Decoding Motor Intent from Peripheral Nerve Signals

The ultimate goal of an upper-limb neuroprosthesis is to achieve dexterous and intuitive control of individual fingers. Previous literature shows that deep learning (DL) is an effective tool to decode the motor intent from neural signals obtained from different parts of the nervous system. However, it still requires complicated deep neural networks that are inefficient and not feasible to work in real-time. Here we investigate different approaches to enhance the efficiency of the DL-based motor decoding paradigm. First, a comprehensive collection of feature extraction techniques is applied to reduce the input data dimensionality. Next, we investigate two different strategies for deploying DL models: a one-step (1S) approach when big input data are available and a two-step (2S) when input data are limited. With the 1S approach, a single regression stage predicts the trajectories of all fingers. With the 2S approach, a classification stage identifies the fingers in motion, followed by a regression stage that predicts those active digits trajectories. The addition of feature extraction substantially lowers the motor decoders complexity, making it feasible for translation to a real-time paradigm. The 1S approach using a recurrent neural network (RNN) generally gives better prediction results than all the ML algorithms with mean squared error (MSE) ranges from 10-3 to 10-4 for all finger while variance accounted for (VAF) scores are above 0.8 for the most degree of freedom (DOF). This result reaffirms that DL is more advantageous than classic ML methods for handling a large dataset. However, when training on a smaller input data set as in the 2S approach, ML techniques offers a simpler implementation while ensuring comparably good decoding outcome to the DL ones. In the classification step, either machine-learning (ML) or DL models achieve the accuracy and F1 score of 0.99. Thanks to the classification step, in the regression step, both types of models result in comparable MSE and VAF scores as those of the 1S approach. Our study outlines the trade-offs to inform the implementation of real-time, low-latency, and high accuracy DL-based motor decoder for clinical applications.

bioengineering↗

bioRxiv2021

Comparative genome analysis revealed gene inversions, boundary expansion and contraction, and gene loss in Stemona sessilifolia (Miq.) Miq. chloroplast genome

Stemona sessilifolia (Miq.) Miq., commonly known as Baibu, is one of the most popular herbal medicines in Asia. In Chinese Pharmacopoeia, Baibu has multiple authentic sources, and there are many homonym herbs sold as Baibu in the herbal medicine market. The existence of the counterfeits of Baibu brings challenges to its identification. To assist the accurate identification of Baibu, we sequenced and analyzed the complete chloroplast genome of Stemona sessilifolia using next-generation sequencing technology. The genome was 154,039 bp in length, possessing a typical quadripartite structure consisting of a pair of inverted repeats (IRs: 27,094 bp) separating by a large single copy (LSC: 81,950 bp) and a small single copy (SSC: 17,901 bp). A total of 112 unique genes were identified, including 80 protein-coding, 28 transfer RNA, and four ribosomal RNA genes. Besides, 45 tandem, 27 forward, 23 palindromic, and 72 simple sequence repeats were detected in the genome by repeat analysis. Compared with its counterfeits (Asparagus officinalis and Carludovica palmate), we found that IR expansion and SSC contraction events of Stemona sessilifolia resulted in two copies of the rpl22 gene in the IR regions and partial duplication of the ndhF gene in the SSC region. Secondly, an approximately 3-kb-long inversion was identified in the LSC region, leading to the petA and cemA gene presented in the complementary strand of the chloroplast DNA molecule. Comparative analysis revealed some highly variable regions, including trnF-GAA_ndhJ, atpB_rbcL, rps15_ycf1, trnG-UCC_trnR-UCU, ndhF_rpl32. Finally, gene loss events were investigated in the context of phylogenetic relationships. In summary, the complete plastome of Stemona sessilifolia will provide valuable information for the molecular identification of Baibu and assist in elucidating the evolution of Stemona sessilifolia.

genomics↗

bioRxiv2020

Methylation of Dual Specificity Phosphatase 4 Controls Cell Differentiation

A collection of signaling and epigenetic events needs to be orchestrated for normal development of hematopoietic lineages. While mitogen-activated protein (MAP) kinases (MAPKs) and multiple epigenetic modulators have been implicated in the megakaryocytic (Mk) cell differentiation, the underlying molecular mechanisms of signaling-epigenetic crosstalk remain unclear. MAPKs are in general inactivated by dual specificity phosphatases (DUSPs), whose activities are tightly regulated by various posttranslational modifications. Using knockdown screening and single-cell transcriptional analysis, we determined that DUSP4 is the phosphatase that inactivates p38 MAPK in hematopoietic cells and serves as a key regulator to promote Mk differentiation. With the nextgeneration Bioorthogonal Profiling of Protein Methylation technology for live cells, we identified DUSP4 as a PRMT1 substrate. Mechanistically, PRMT1-mediated Arg351 methylation of DUSP4 triggers its ubiquitinylation by HUWE1 (an E3 ligase) and then degradation, which results in p38 MAPK activation and inhibition of Mk differentiation in vitro and in vivo. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation and thus argues immunological roles of Mk cells. Collectively, these results demonstrate a critical role of PRMT1-mediated posttranslational modification of DUSP4 in regulation of Mk differentiation and maturation. In the context of thrombocytopenia observed in myelodysplastic syndromes (MDS), we demonstrated that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis in MDS samples. These findings provide novel mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a targeting strategy for treatment of thrombocytopenia associated with myeloid malignancies such as MDS.

cell biology↗

bioRxiv2020

High-throughput Single-cell CNV Detection Reveals Clonal Evolution During Hepatocellular Carcinoma Recurrence

Single-cell genomics provides substantial resources for dissecting cellular heterogeneity and cancer evolution, but classical DNA amplification-based methods are low-throughput and introduce coverage bias during sample preamplification. We developed a single-cell DNA library preparation method without preamplification in nanolitre scale (scDPN). The method has a throughput of up to 1,800 cells per run for copy number variation (CNV) detection. Also, it has a lower level of amplification bias and noise than the multiple displacement amplification (MDA) method and showed high sensitivity and accuracy based on evaluation in cell lines and tumour tissues. We used this approach to profile the tumour clones in paired primary and relapsed tumour samples of hepatocellular carcinoma (HCC). We identified 3 clonal subpopulations with a multitude of aneuploid alterations across the genome. Furthermore, we observed that a minor clone of the primary tumour containing additional alterations in chromosomes 1q, 10q, and 14q developed into the dominant clone in the recurrent tumour, indicating clonal selection during recurrence in HCC. Overall, this approach provides a comprehensive and scalable solution to understand genome heterogeneity and evolution.

cell biology↗

bioRxiv2020

Rice Calcium/Calmodulin-Dependent Protein Kinase Directly Phosphorylates a Mitogen-Activated Protein Kinase Kinase to Regulate Abscisic Acid Responses

Ca2+/calmodulin (CaM)-dependent protein kinase (CCaMK) is an important positive regulator of abscisic acid (ABA) and abiotic stress signaling in plants and is believed to act upstream of mitogen-activated protein kinase (MAPK) in ABA signaling. However, it is unclear how CCaMK activates MAPK in ABA signaling. Here, we show that OsDMI3, a rice (Oryza sativa) CCaMK, directly interacts with and phosphorylates OsMKK1, a MAPK kinase (MKK) in rice, in vitro and in vivo. OsDMI3 was found to directly phosphorylate Thr-25 in the N-terminus of OsMKK1, and this Thr-25 phosphorylation is OsDMI3-specific in ABA signaling. The activation of OsMKK1 and its downstream kinase OsMPK1 is dependent on Thr-25 phosphorylation of OsMKK1 in ABA signaling. Moreover, ABA treatment also induces the phosphorylation in the activation loop of OsMKK1, and the two phosphorylations in the N-terminus and in the activation loop are independent. Further analyses revealed that OsDMI3-mediated phosphorylation of OsMKK1 positively regulates ABA responses in seed germination, root growth, and tolerance to both water stress and oxidative stress. Our results indicate that OsMKK1 is a direct target of OsDMI3, and OsDMI3-mediated phosphorylation of OsMKK1 plays an important role in the activation of MAPK cascade and ABA signaling. One-sentence summaryOsMKK1 is a direct target of OsDMI3, and OsDMI3-mediated phosphorylation of OsMKK1 plays an important role in the activation of MAPK cascade and ABA signaling. The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) is: Mingyi Jiang (myjiang@njau.edu.cn)

plant biology↗

bioRxiv2020

Global Profiling of the Lysine Crotonylome in Different Pluripotent States

Pluripotent stem cells (PSCs) can be expanded in vitro in different culture conditions, resulting in a spectrum of cell states with distinct properties. Understanding how PSCs transition from one state to another, ultimately leading to lineage-specific differentiation, is important for developmental biology and regenerative medicine. Although there is significant information regarding gene expression changes controlling these transitions, less is known about post-translational modifications of proteins. Protein crotonylation is a newly discovered post-translational modification where lysine residues are modified with a crotonyl group. Here, we employed affinity purification of crotonylated peptides and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to systematically profile protein crotonylation in mouse PSCs in different states including ground, metastable and primed state, as well as metastable PSCs undergoing early pluripotency exit. We successfully identified 3628 high-confidence sites in 1426 proteins. These crotonylated proteins are enriched for factors involved in functions related to pluripotency such as RNA biogenesis, central carbon metabolism and proteasome function. Moreover, we found that increasing the cellular levels of crotonyl-CoA through crotonic acid treatment promotes proteasome activity in metastable PSCs and delays their differentiation, consistent with previous observations showing that enhanced proteasomal activity helps to sustain pluripotency. Our atlas of protein crotonylation will be valuable for further studies of pluripotency regulation and may also provide insights into the role of metabolism in other cell fate transitions.

cell biology↗

bioRxiv2020

A Bioelectric Neural Interface Towards Intuitive Prosthetic Control For Amputees

ObjectiveWhile prosthetic hands with independently actuated digits have become commercially available, state-of-the-art human-machine interfaces (HMI) only permit control over a limited set of grasp patterns, which does not enable amputees to experience sufficient improvement in their daily activities to make an active prosthesis useful. ApproachHere we present a technology platform combining fully-integrated bioelectronics, implantable intrafascicular microelectrodes and deep learning-based artificial intelligence (AI) to facilitate this missing bridge by tapping into the intricate motor control signals of peripheral nerves. The bioelectric neural interface includes an ultra-low-noise neural recording system to sense electroneurography (ENG) signals from microelectrode arrays implanted in the residual nerves, and AI models employing the recurrent neural network (RNN) architecture to decode the subjects motor intention. Main resultsA pilot human study has been carried out on a transradial amputee. We demonstrate that the information channel established by the proposed neural interface is sufficient to provide high accuracy control of a prosthetic hand up to 15 degrees of freedom (DOF). The interface is intuitive as it directly maps complex prosthesis movements to the patients true intention. SignificanceOur study layouts the foundation towards not only a robust and dexterous control strategy for modern neuroprostheses at a near-natural level approaching that of the able hand, but also an intuitive conduit for connecting human minds and machines through the peripheral neural pathways. Clinical trialDExterous Hand Control Through Fascicular Targeting (DEFT). Identifier: NCT02994160.

bioengineering↗

bioRxiv2020

Limbal Niche Cells in Three-Dimensional Matrigel Induced Dedifferentiation of Mature Corneal Epithelial Cells toward a Progenitor State

PurposeTo investigate the possibility and the key factors of stably committed mature corneal epithelial cells dedifferentiate into corneal epithelial stem cells in vitro. MethodsMature cornea epithelia cell (MCEC) sheets or limbal epithelial progenitor cell (LEPC) sheets were isolated from central corneas or limbal segments by Dispase II and further digested with 0.25% trypsin/1 mM EDTA (T/E) to yield single cells. Limbal niche cells (LNC) were isolated from the limbal stroma by collagenase A and expanded on 5% Matrigel coated plastic. Single MCECs were seeded on 50% Matrigel with or without LNC culturing for 10 days, regarding as three-dimensional MCEC (3D-MCEC) group or three-dimensional MCEC+LNC (3D-MCEC+LNC) group. Expression of CK12, p63, PCK, Vimentin were analyzed with immunofluorescence staining. ResultsThe expression of mature cornea epithelial marker (CK12) in MCEC was higher than that in LEPC (P=0.020) but epithelial stem cell marker (p63) was lower than that in LEPC (P=0.000). When seeded in 3D Matrigel, single MCEC cells could form spheres within 72 hours, and the expression of CK12 reduced (P=0.005) and the expression of p63 also reduced to zero (P=0.000) compared to MCEC. Serial passages of LNC which were expanded in coated Matrigel could form spheres in 3D Matrigel. After mixing MCECs with LNC, rounder spheres emerged within 24 hours which consisted of both epithelia cells (PCK+/Vim-) and LNC (PCK-/Vim+). Moreover, epithelia cells in 3D-MCEC+LNC group expressed less CK12 and more p63 than those in MCEC group (P=0.043, 0.000). Besides, the diameter of spheres in 3D-MCEC+LNC group were larger than that in 3D-MCEC group (P=0.000). ConclusionHuman LNC and three-dimensional Matrigel could induce the dedifferentiation of mature corneal epithelial cells into corneal epithelial stem cells.

bioengineering↗

bioRxiv2020

Foundation species across a latitudinal gradient in China

AbstractFoundation species play important roles in structuring forest communities and ecosystems. Foundation species are difficult to identify without long-term observations or experiments and their foundational roles rarely are identified before they are declining or threatened. We used new statistical criteria based on size-frequency distributions, species diversity, and spatial codispersion among woody plants to identify potential ("candidate") foundation species in 12 large forest dynamics plots spanning 26 degrees of latitude in China. We used these data to identify a suite of candidate foundation species in Chinese forests; test the hypothesis that foundation woody plant species are more frequent in the temperate zone than in the tropics; and compare these results with comparable data from the Americas to suggest candidate foundation genera in Northern Hemisphere forests. We identified more candidate foundation species in temperate plots than in subtropical or tropical plots, and this relationship was independent of the latitudinal gradient in overall species richness. Two species of Acer, the canopy tree Acer ukurunduense and the shrubby treelet Acer barbinerve were the only two species that met both criteria in full to be considered as candidate foundation species. When we relaxed the diversity criteria, Acer, Tilia, and Juglans spp., and Corlyus mandshurica were frequently identified as candidate foundation species. In tropical plots, the tree Mezzettiopsis creaghii and the shrubs or treelets Aporusa yunnanensis and Ficus hispida had some characteristics associated with foundation species. Species diversity of co-occurring woody species was negatively associated with basal area of candidate foundation species more frequently at 5- and 10-m spatial grains (scale) than at a 20-m grain. Conversely, Bray-Curtis dissimilarity was positively associated with basal area of candidate foundation species more frequently at 5-m than at 10- or 20-m grains. Our data support the hypothesis that foundation species should be more common in temperate than in tropical or boreal forests, and suggest that in the Northern Hemisphere that Acer be investigated further as a foundation tree genus.

ecology↗

bioRxiv2020

Bio-upcycling of polyethylene terephthalate

Over 359 million tons of plastics were produced worldwide in 2018, with significant growth expected in the near future, resulting in the global challenge of end-of-life management. The recent identification of enzymes that degrade plastics previously considered non-biodegradable opens up opportunities to steer the plastic recycling industry into the realm of biotechnology. Here, we present the sequential conversion of polyethylene terephthalate (PET) into two types of bioplastics: a medium chain-length polyhydroxyalkanoate (PHA) and a novel bio-based poly(amide urethane) (bio-PU). PET films were hydrolyzed by a thermostable polyester hydrolase yielding 100% terephthalate and ethylene glycol. A terephthalate-degrading Pseudomonas was evolved to also metabolize ethylene glycol and subsequently produced PHA. The strain was further modified to secrete hydroxyalkanoyloxy-alkanoates (HAAs), which were used as monomers for the chemo-catalytic synthesis of bio-PU. In short, we present a novel value-chain for PET upcycling, adding technological flexibility to the global challenge of end-of-life management of plastics. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/993592v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1433e0dorg.highwire.dtl.DTLVardef@19efc71org.highwire.dtl.DTLVardef@cf97f7org.highwire.dtl.DTLVardef@101f123_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

Genetic structure, function and evolution of capsule biosynthesis loci in Vibrio parahaemolyticus

Capsule-forming extracellular polysaccharides are crucial to bacterial host colonization, invasion, immune evasion and ultimately pathogenicity. Due to warming ocean waters and human encroachment of coastal ecosystems, Vibrio parahaemolyticus has emerged as a globally important food-borne enteropathogen implicated in acute gastroenteritis, wound infections, and septic shock. Conventionally, the antigenic properties of lipopolysaccharide (LPS, O antigen) and capsular polysaccharide (CPS, K antigen) have provided a basis for serotyping V. parahaemolyticus, while disclosure of genetic elements encoding 13 O-serogroups have allowed molecular serotyping methods to be developed. However, the genetic structure of CPS loci for 71 K-serogroups has remained unidentified, limiting progress in understanding its roles in V. parahaemolyticus pathophysiology. In this study, we identified and characterized the genetic structure and their evolutionary relationship of CPS loci of 40 K-serogroups through whole genome sequencing of 443 V. parahaemolyticus strains. We found a distinct pattern of CPS gene cluster across different K-serogroups, and expanded its new right-border by identifying glpX as a key gene conserved across all serotypes. A total of 217 genes involved in CPS biosynthesis were annotated. Functional contents and genetic structure of the 40 K-serogroups were analyzed. Based on inferences from species trees and gene trees, we proposed an evolution model of the CPS gene clusters of 40 K-serogroups. Horizontal gene transfer by recombination from other Vibrio species, gene duplication and nonsense mutations are likely to play instrumental roles in the evolution of CPS in V. parahaemolyticus. It is the first time, to the best of our knowledge, that a large-scale of CPS gene clusters of different K-serogroups in V. parahaemolyticus have been identified and characterized in evolutionary contexts. This work should help advance understanding on the variation of CPS in V. parahaemolyticus, and provide a framework for developing diagnostically relevant serotyping methods. Author summaryDue to warming ocean waters and human encroachment of coastal ecosystems, Vibrio parahaemolyticus has emerged as a globally important food-borne enteropathogen. However, the genetic structure of CPS loci for 71 K-serogroups V. parahaemolyticus have remained unidentified, limiting progress in understanding its roles in V. parahaemolyticus pathophysiology. In this study, we identified and characterized the genetic structure of CPS loci of 40 K-serogroups through whole genome sequencing of 443 V. parahaemolyticus strains. We expanded and identified its new right-border by identifying glpX as a key gene conserved across all serotypes. We proposed an evolution model of the CPS gene clusters of 40 K-serogroups. We also found horizontal gene transfer by recombination from other Vibrio species, gene duplication and nonsense mutations are likely to play instrumental roles in the evolution of CPS in V. parahaemolyticus. It is the first time, to the best of our knowledge, that a large-scale of CPS loci of different K-serogroups in V. parahaemolyticus have been identified and characterized in evolutionary contexts. This work should help advance understanding on the variation of CPS in V. parahaemolyticus, and provide a framework for developing diagnostically relevant serotyping methods.

microbiology↗

bioRxiv2019

Patient stratification of clear cell renal cell carcinoma using the global transcription factor activity landscape derived from RNA-seq data

Clear cell renal cell carcinoma represents the most common type of kidney cancer. Precision medicine approach to ccRCC requires an accurate stratification of patients that can predict prognosis and guide therapeutic decision. Transcription factors are implicated in the initiation and progression of human carcinogenesis. However, no comprehensive analysis of transcription factor activity has been proposed so far to realize patient stratification. Here we propose a novel approach to determine the subtypes of ccRCC patients based on global transcription factor activity landscape. Using the TCGA cohort dataset, we identified different subtypes that have distinct upregulated biomarkers and altered biological pathways. More important, this subtype information can be used to predict the overall survival of ccRCC patients. Our results suggest that transcription factor activity can be harnessed to perform patient stratification.

systems biology↗

bioRxiv2019

In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

Stroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.

neuroscience↗

bioRxiv2019

A general quantitative relation linking bacterial cell growth and the cell cycle

The foundation of bacterial cell cycle studies has long resided in two interconnected dogmas between biomass growth, DNA replication, and cell division during exponential growth: the SMK growth law that relates cell mass (a measure of cell size) to growth rate1, and Donachies hypothesis of a growth-rate-independent initiation mass2. These dogmas have spurred many efforts to understand their molecular bases and physiological consequences3-12. Most of these studies focused on fast-growing cells, with doubling times shorter than 60 min. Here, we systematically studied the cell cycle of E. coli for a broad range of doubling times (24 min to over 10 hr), with particular attention on steady-state growth. Surprisingly, we observed that neither dogma held across the range of growth rates examined. In their stead, a new linear relation unifying the slow- and fast-growth regimes was revealed between the cell mass and the number of cell divisions it takes to replicate and segregate a newly initiated pair of replication origins. This and other findings in this study suggest a single-cell division model, which not only reproduces the bulk relations observed but also recapitulates the adder phenomenon established recently for stochastically dividing cells13-15. These results allowed us to develop quantitative insight into the bacterial cell cycle, providing a firm new foundation for the study of bacterial growth physiology.

microbiology↗