Biology subjects

Wang, C.

Publications and source records attributed to Wang, C..

At least 937 records · Page 52Linked to original sources

bioRxiv2020

The role of CLV1, CLV2 and HPAT homologs in nitrogen-regulation of root development

Plants use a variety of hormonal and peptide signals to control root development, including in adapting root development to cope with nutrient stress. Nitrogen (N) is a major limiting factor in plant growth and in response to N stress plants dramatically modulate root development, including in legumes influencing the formation of N-fixing nodules in response to external N supply. Recently, specific CLE peptides and/or receptors important for their perception, including CLV1 and CLV2, have been found to play important roles in root development in a limited number of species, including in some cases the response to N. In the legume Medicago truncatula, this response also appears to be influenced by RDN1, a member of the hydroxyproline O-arabinosyltransferase (HPAT) family which can modify specific CLE peptides. However, it not known if this signalling pathway plays a central role in root development across species, in particular root responses to N. In this study, we sought to systematically examine the role of homologues of these genes in root development of the legume pea (Pisum sativum. L) and non-legume tomato (Solanum lycopersicum) using a mutant based approach. This included a detailed examination of root development in response to N in these mutant series in tomato. We found no evidence for a role of these genes in pea seedling root development. Furthermore, the CLV1-like FAB gene did not influence tomato root development, including N response. In contrast, both CLV2 and the HPAT FIN appear to positively influence root size in tomato but do not mediate root responses to N. These suggest a relatively species-specific role for these genes in root development, including N regulation of root architecture.

plant biology↗

bioRxiv2020

scGNN: a novel graph neural network framework for single-cell RNA-Seq analyses

Single-cell RNA-sequencing (scRNA-Seq) is widely used to reveal the heterogeneity and dynamics of tissues, organisms, and complex diseases, but its analyses still suffer from multiple grand challenges, including the sequencing sparsity and complex differential patterns in gene expression. We introduce the scGNN (single-cell graph neural network) to provide a hypothesis-free deep learning framework for scRNA-Seq analyses. This framework formulates and aggregates cell-cell relationships with graph neural networks and models heterogeneous gene expression patterns using a left-truncated mixture Gaussian model. scGNN integrates three iterative multi-modal autoencoders and outperforms existing tools for gene imputation and cell clustering on four benchmark scRNA-Seq datasets. In an Alzheimers disease study with 13,214 single nuclei from postmortem brain tissues, scGNN successfully illustrated disease-related neural development and the differential mechanism. scGNN provides an effective representation of gene expression and cell-cell relationships. It is also a novel and powerful framework that can be applied to scRNA-Seq analyses.

bioinformatics↗

bioRxiv2020

Quorum Sensing Regulates 'swim-or-stick' Lifestyle in the Phycosphere

Originality-significance statementMotility and biofilm formation are processes regulated by quorum sensing (QS) in bacteria. Both functions are believed to play an important role in interactions between bacteria and phytoplankton. Here, we show that two bacterial symbionts from the microbial community associated with a ubiquitous diatom switch their motile lifestyle to attached cells while an opportunist bacterium from the same community is incapable of attachment, despite possessing the genetic machinery to do so. Further work indicated that the opportunist lacks QS signal synthases while the symbionts produce three QS signals, one of which is mainly responsible for regulating symbiont colonization of the diatom microenvironment. These findings suggest that QS regulates colonization of diatom surfaces and further work on these model systems will inform our understanding of particle aggregation and bacterial attachment to marine snow and how these processes influence the global carbon cycle. SummaryInteractions between phytoplankton and bacteria play major roles in global biogeochemical cycles and oceanic nutrient fluxes. These interactions occur in the microenvironment surrounding phytoplankton cells, known as the phycosphere. Bacteria in the phycosphere use either chemotaxis or attachment to benefit from algal excretions. Both processes are regulated by quorum sensing (QS), a cell-cell signaling mechanism that uses small infochemicals to coordinate bacterial gene expression. However, the role of QS in regulating bacterial attachment in the phycosphere is not clear. Here, we isolated a Sulfitobacter pseudonitzschiae F5 and a Phaeobacter sp. F10 belonging to the marine Roseobacter group and an Alteromonas macleodii F12 belonging to Alteromonadaceae, from the microbial community of the ubiquitous diatom Asterionellopsis glacialis. We show that only the Roseobacter group isolates (diatom symbionts) can attach to diatom transparent exopolymeric particles. Despite all three bacteria possessing genes involved in motility, chemotaxis, and attachment, only S. pseudonitzschiae F5 and Phaeobacter sp. F10 possessed complete QS systems and could synthesize QS signals. Using UHPLC-MS/MS, we identified three QS molecules produced by both bacteria of which only 3-oxo-C16:1-HSL strongly inhibited bacterial motility and stimulated attachment in the phycosphere. These findings suggest that QS signals enable colonization of the phycosphere by algal symbionts.

ecology↗

bioRxiv2020

Single-cell Long Non-coding RNA Landscape of T Cells in Human Cancer Immunity

The development of new therapeutic targets for cancer immunotherapies and the development of new biomarkers require deep understanding of T cells. To date, the complete landscape and systematic characterization of long noncoding RNAs (lncRNAs) in T cells in cancer immunity are lacking. Here, by systematically analyzing full-length single-cell RNA sequencing (scRNA-seq) data of more than 20,000 T cell libraries across three cancer types, we provide the first comprehensive catalog and the functional repertoires of lncRNAs in human T cells. Specifically, we developed a custom pipeline for de novo transcriptome assembly obtaining 9,433 novel lncRNA genes that increased the number of current human lncRNA catalog by 16% and nearly doubled the number of lncRNAs expressed in T cells. We found that a portion of expressed genes in single T cells were lncRNAs which have been overlooked by the majority of previous studies. Based on metacell maps constructed by MetaCell algorithm that partition scRNA-seq datasets into disjointed and homogenous groups of cells (metacells), 154 signature lncRNAs associated with effector, exhausted, and regulatory T cell states are identified, 84 of which are functionally annotated based on co-expression network, indicating that lncRNAs might broadly participate in regulation of T cell functions. Our findings provide a new point of view and resource for investigating the mechanisms of T cell regulation in cancer immunity as well as for novel cancer-immune biomarker development and cancer immunotherapies.

bioinformatics↗

bioRxiv2020

Development of predictive QSAR models on the phosphopeptide binding affinity against 14-3-3 isoforms

AO_SCPLOWBSTRACTC_SCPLOW14-3-3s present in multiple isoforms in human cells and mediate signal transduction by binding to phosphoserine-containing proteins. Recent findings have demonstrated that 14-3-3s act as a key factor in promoting chemoresistance of cancer. Here, we aimed to develop the predictive models that can determine the binding affinity of phosphopeptide fragments against 14-3-3s. It is found that the hydrophobic property of residues in phosphopeptides has a significant contribution to the binding affinity for most of 14-3-3 isoforms. The conserved patterns of 14-3-3 biding motifs were verified by our predictions. A group of peptide sequences were predicted with high binding affinity and high sequence conservation, which had agreement with 14-3-3s ligands. Overall, our results demonstrate that how the residues are likely to function in 14-3-3s interaction and the computational methods we introduced may contribute to the further research.

bioinformatics↗

bioRxiv2020

Quantitative proteomics reveals the protective effects of ESD against osteoarthritis via attenuating inflammation and modulating immune response

Epimedium, Salvia miltiorrhiza, and Dioscorea nipponica Makino (ESD) have been combined to treat osteoarthritis (OA) for a long time. In this study we used quantitative proteomics to find the protective effects of ESD against OA and possible mechanism. After papain-induced rats OA model established ESD was intragastrically administrated to rats for four weeks. Label-free quantitative proteomics was used to screen the comprehensive protein profiling changes in both OA and ESD groups. After stringent filtering, 62 proteins were found to be significantly up-regulated and 208 proteins were down-regulated in OA model compared with sham-operated control. Functional analysis revealed that these OA up-regulated proteins were enriched in the activation of humoral immunity response, complement activation, leukocyte mediated immunity, acute inflammatory, endocytosis regulation, and proteolysis regulation. ESD partially recovered the protein profiling changes in OA model. The effects of ESD were also assessed by measurement of behavioral activity and pathologic changes in the joints. ESD showed protective effects in suppressing inflammation, releasing joint pain, and attenuating cartilage degradation. Our study presented that ESD as a potential candidate to alleviate OA damage by reducing inflammation and modulating of immune system.

pharmacology and toxicology↗

bioRxiv2020

Comparison of manual and machine learning image processing approaches to determine fungiform papillae on the tongue

Human taste perception is associated with the papillae on the tongue as they contain a large proportion of chemoreceptors for basic tastes and other chemosensation. Especially the density of fungiform papillae (FP) is considered as an index for responsiveness to oral chemosensory stimuli. The standard procedure for FP counting involves visual identification and manual counting of specific parts of the tongue by trained operators. This is a tedious task and automated image analysis methods are desirable. In this paper a machine learning image processing method based on a convolutional neural network is presented. This automated method was compared with three standard manual FP counting procedures using tongue pictures from 132 subjects. Automated FP counts, within the selected areas and the whole tongue, significantly correlated with the manual counting methods (all {rho}s [≥] 0.76). When comparing the images for gender and PROP status, the density of FP predicted from automated analysis was in good agreement with data from the manual counting methods, especially in the case of gender. Moreover, the present results reinforce the idea that caution should be applied in considering the relationship between FP density and PROP responsiveness since this relationship can be an oversimplification of the complexity of phenomena arising at the central and peripherical levels. Indeed, no significant correlations were found between FP and PROP bitterness ratings using the automated method for selected areas or the whole tongue. Besides providing estimates of the number of FP, the machine learning approach used a tongue coordinate system that normalizes the size and shape of an individual tongue and generated a heat map of the FP position and normalized area they cover. The present study demonstrated that the machine learning approach could provide similar estimates of FP on the tongue as compared to manual counting methods and provide estimates of more difficult-to-measure parameters, such as the papillaes areas and shape.

physiology↗

bioRxiv2020

Identification of potent and safe antiviral therapeutic candidates against SARS-CoV-2

COVID-19 pandemic has infected millions of people with mortality exceeding 300,000. There is an urgent need to find therapeutic agents that can help clear the virus to prevent the severe disease and death. Identifying effective and safer drugs can provide with more options to treat the COVID-19 infections either alone or in combination. Here we performed a high throughput screen of approximately 1700 US FDA approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 24 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, and merfloquine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating wide therapeutic window compared to hydroxychloroquine which had safety index of 22 in similar experiments. Mechanistically, five of the effective compounds were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA approved compounds can provide much needed therapeutic options that we urgently need in the midst of the pandemic.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗

bioRxiv2020

The role of CLV signalling in the negative regulation of mycorrhizal colonisation and nitrogen response of tomato

Plants form mutualistic nutrient acquiring symbioses with microbes, including arbuscular mycorrhizal fungi. The formation of these symbioses is costly and plants employ a negative feedback loop termed autoregulation of mycorrhizae (AOM) to limit arbuscular mycorrhizae (AM) formation. We provide evidence for the role of one leucine-rich-repeat receptor like kinase (FAB), a hydroxyproline O-arabinosyltransferase enzyme (FIN) and additional evidence for one receptor like protein (SlCLV2) in the negative regulation of AM formation in tomato. Reciprocal grafting experiments suggest that the FAB gene acts locally in the root, while the SlCLV2 gene may act in both the root and the shoot. External nutrients including phosphate and nitrate can also strongly suppress AM formation. We found that FAB and FIN are required for nitrate suppression of AM but are not required for the powerful suppression of AM colonisation by phosphate. This parallels some of the roles of legume homologs in the autoregulation of the more recently evolved symbioses with nitrogen-fixing bacteria leading to nodulation. This deep homology in the symbiotic role of these genes suggests that in addition to the early signalling events that lead to the establishment of AM and nodulation, the autoregulation pathway might also be considered part of the common symbiotic toolkit that enabled plants to form beneficial symbioses. HighlightWe describe the role of CLV signalling elements in the negative regulation of arbuscular mycorrhizal symbioses of tomato, including influencing nitrate but not phosphate suppression of mycorrhizal colonisation.

plant biology↗

bioRxiv2020

Population Pharmacokinetics of an Anti-PD-1 Antibody Camrelizumab in Patients with Multiple tumor types and model informed dosing strategy

Objective Camrelizumab, a programmed cell death 1 (PD-1) inhibitor, has been approved for the treatment of relapsed or refractory classical Hodgkin lymphoma. The aim of this study was to perform a population pharmacokinetics (PK) analysis of camrelizumab to quantify the impact of patient characteristics on PK and to investigate the appropriateness of flat dose in the dosing regimen.Methods A total of 3298 camrelizumab concentrations from 133 patients from four studies were analyzed using nonlinear mixed effects modeling. Covariate model building was conducted using stepwise forward addition and backward elimination. Monte Carlo simulation was conducted to compare exposures of 200 mg and 3 mg/kg every 2-week regimens.Results The PK of camrelizumab were adequately described by a two-compartment model with parallel linear and nonlinear clearances. Baseline albumin had significant effects on linear clearance, and weight had effects on inter-compartmental clearance. Moreover, 200 mg and 3 mg/kg regimens provide similar exposure distributions with no advantage to either dosing approach.Conclusion Population PK analysis provided an integrated evaluation of the impact of albumin and weight on the PK of camrelizumab. It also provided evidence that neither the flat-dose nor the weight-based dose regimen was advantageous over the other for most patients with tumors.Competing Interest StatementThis study was sponsored by Jiangsu Hengrui Medicine Co. Ltd. Guang-li Ma, Da Xu and Yu-ya Wang are employees of Jiangsu Hengrui Medicine Co. Ltd.AbbreviationsAICAkaike’s information criterion;AUCarea under the concentration-time curve;AUCsssteady-state area under the concentration-time curve;BSVBetween-subject variability;Ccamrelizumab concentration;C1concentration of central compartment;Caverage,sssteady-state average concentration;CLclearance;CLlinearclearance of linear elimination;Cmax,sssteady-state peak concentration;CLnonlinearclearance of nonlinear elimination;Cmin,sssteady-state trough concentration;CWRESconditional weighted residuals;DVobserved concentration;IPREDindividual predicted concentrations;k0infusion rate;k23elimination rate from central compartment to peripheral compartment;k32elimination rate from peripheral compartment to central compartment;klinearlinear elimination rate;knonlinearnonlinear elimination rate;KmMichaelis–Menten constant;mAbmonoclonal antibody;NONMEMnonlinear mixed effect modeling;PD-1programmed cell death 1 receptor;PKpharmacokinetics;PREDpopulation predicted concentration;Qinter-compartmental clearance;Q2Wevery 2 weeks;Vmmaximum elimination rate;VPCvisual predictive check;V1distribution volume of central compartment;V2distribution volume of peripheral compartment;WBCwhite blood cell.View Full Text

cancer biology↗

bioRxiv2020

Trantrace: a reliable, traceable, and collaborative solution to streamline the translation of emerging biomedical resources

BackgroundPrecision medicine is gaining popularity in routine health care, which heavily relies on the interpretation of emerging biomedical databases and professional guidelines. Translation of those biomedical materials, that is crucial to deliver research discovery to health interventions in non-native English-speaking countries, remains a large amount of work for biomedical practitioners. ResultsWe presented an application called Trantrace to facilitate the routine of large-scale long-running translation. Especially for the case that many people joined multiple translation projects, it has a rigorous task division and cooperation process: assignment, translation, review, release, and iteration. Trantrace empowers users to build own projects with different permissions, version control all the translation operation without specific skills, and further improve the translation efficiency through real-time task management tools. ConclusionsBy providing a working platform for collaborative translation and enabling long-time version correction, the Trantrace contributes towards the creation of a multilingual biomedical knowledge commons, which would be a valuable aid for personalized therapies. The source code is freely accessible at https://github.com/sgi-drylab/trantrace.

bioinformatics↗

bioRxiv2020

Production of diverse beauveriolide analogs in closely related fungi: a rare case of fungal chemodiversity

Fungal chemodiversity is well known in part due to the production of diverse analogous compounds by a single biosynthetic gene cluster (BGCs). Usually, similar metabolites are produced by closely related fungal species. Here we report a rare case of the production of the cyclodepsipeptide beauveriolides (BVDs) in three insect pathogenic fungi. We found that the more closely-related fungi Beauveria bassiana and B. brongniartii produce structurally distinct analogs of BVDs whereas the rather divergently evolved species B. brongniartii and Cordyceps militaris produce structural analogs in a similar pattern. It was verified that a conserved BGC containing four genes is responsible for BVD biosynthesis in three fungi including a polyketide synthase (PKS) for the production of 3-hydroxy fatty acids (FAs) with chain length variations. In contrast to BVD production patterns, phylogenetic analysis of the BGC enzymes or enzyme domains largely resulted in the congruence relationship with fungal speciation. Feeding assays demonstrated that a FA with a chain length of eight carbon atoms was preferentially utilized whereas a FA with a chain longer than 10 carbon atoms could not be used as a substrate for BVD biosynthesis. We also found that addition of D-type amino acids could not enable B. bassiana to produce those analogs biosynthesized by other two fungi. Insect survival assays suggested that the contribution of BVD to fungal virulence might be associated with the susceptibility of insect species. The results of this study enrich the knowledge of fungal secondary metabolic diversity. IMPORTANCEFungal chemotaxonomy is an approach to classify fungi based on fungal production of natural compounds especially the secondary metabolites. We found an atypical example that could question chemical classification of fungi in this study: the more closely-related entomopathogenic species Beauveria bassiana and B. brongniartii produce structurally different analogs of the cyclodepsipeptide beauveriolides whereas the rather divergent species B. brongniartii and Cordyceps militaris biosynthesize similar analogs under the same growth condition. The conserved BGC containing four genes is present in each species and responsible for beauveriolide production. In contrast to the compound formation profiles, the phylogenies of biosynthetic enzymes or enzymatic domains show associations with fungal speciation relationship. Dependent on insect species, production of beauveriolides may contribute to fungal virulence against insect. The findings in this study augment the diversity of fungal secondary metabolisms.

microbiology↗

bioRxiv2020

A new long-read dog assembly uncovers thousands of exons and functional elements missing in the previous reference

Here we present a new high-quality canine reference genome with gap number reduced 41-fold, from 23,836 to 585. Analysis of existing and novel data, RNA-seq, miRNA-seq and ATAC-seq, revealed a large proportion of these harboured previously hidden elements, including genes, promoters and miRNAs. Short-read dark regions were detected, and genomic regions completed, including the DLA, TCR and 366 cancer genes. 10x sequencing of 27 dogs uncovered a total of 22.1 million SNPs, Indels and larger structural variants (SVs). 1.4% overlap with protein coding genes and could provide a source of normal or aberrant phenotypic modifications.

genomics↗

bioRxiv2020

Single-cell transcriptional atlas of the Chinese horseshoe bat (Rhinolophus sinicus) provides insight into the cellular mechanisms which enable bats to be viral reservoirs

Bats are a major "viral reservoir" in nature and there is a great interest in not only the cell biology of their innate and adaptive immune systems, but also in the expression patterns of receptors used for cellular entry by viruses with potential cross-species transmission. To address this and other questions, we created a single-cell transcriptomic atlas of the Chinese horseshoe bat (Rhinolophus sinicus) which comprises 82,924 cells from 19 organs and tissues. This atlas provides a molecular characterization of numerous cell types from a variety of anatomical sites, and we used it to identify clusters of transcription features that define cell types across all of the surveyed organs. Analysis of viral entry receptor genes for known zoonotic viruses showed cell distribution patterns similar to that of humans, with higher expression levels in bat intestine epithelial cells. In terms of the immune system, CD8+ T cells are in high proportion with tissue-resident memory T cells, and long-lived effector memory nature killer (NK) T-like cells (KLRG1, GZMA and ITGA4 genes) are broadly distributed across the organs. Isolated lung primary bat pulmonary fibroblast (BPF) cells were used to evaluate innate immunity, and they showed a weak response to interferon {beta} and tumor necrosis factor- compared to their human counterparts, consistent with our transcriptional analysis. This compendium of transcriptome data provides a molecular foundation for understanding the cell identities, functions and cellular receptor characteristics for viral reservoirs and zoonotic transmission.

cell biology↗

bioRxiv2020

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of COVID-19 Spike psedotype virus

BackgroundThe novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating. The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial. PurposeThe objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection. MethodsIn our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2h cells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2h cells. ResultsResults showed that HCQ is slightly more toxic to ACE2h cells than CQ. Both CQ and HCQ could bind to ACE2 with KD =(7.31{+/-}0.62)e-7 M and (4.82{+/-}0.87)e-7 M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2h cells. ConclusionsCQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection.

biochemistry↗

bioRxiv2020

A novel biparatopic antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provides a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain (NTD) of the viral S glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain (RBD) of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic virus infection in a standard assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.

immunology↗

bioRxiv2020

Thiamine pyrophosphokinase deficiency induces Alzheimer's pathology

BackgroundThiamine diphosphate (TDP) reduction plays an important role in cerebral glucose hypometabolism, the neurodegenerative indicator, in Alzheimers disease (AD). The mechanism underlying TDP reduction remains elusive. Thus, it is critical to define the mechanism and its effect on neurodegeneration, the pathological basis of the disease occurrence and progression. MethodsThe mRNA levels of all known genes associated with thiamine metabolism, including thiamine pyrophosphokinase (TPK), Solute Carrier Family 19 Member 2 (SLC19A2), SLC19A3, and SLC25A19, in brain samples of patients with AD and other neurodegenerative disorders in multiple independent datasets were analyzed. TPK protein levels were further examined in the brain tissues of AD patients and control subjects. A mouse model with conditional knockout (cKO) of TPK gene in the excitatory neurons of adult brain was established. ResultsThe brain TPK mRNA level was markedly lower in AD patients, but not in other neurodegenerative disorders. The brain TPK protein level was also significantly decreased in AD patients. TPK gene knockout in the mice caused cerebral glucose hypometabolism, {beta}-amyloid deposition, Tau hyperphosphorylation, neuroinflammation, and neuronal loss and brain atrophy. Cross-species correlation analysis revealed the similar changes of gene profiling between the cKO mice and AD patients. ConclusionsThe deficiency of brain TPK, a key enzyme for TDP synthesis, is specific to AD. The cKO mice show AD-associated phenotypes and could serve as a new mouse model for AD studies. Our study provides a novel insight into the critical role of TPK in AD pathogenesis and its potential for the disease treatment.

neuroscience↗

bioRxiv2020

Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung

Senescent cells are recognized drivers of aging-related decline in organ function, but deciphering the biology of senescence in vivo has been hindered by the paucity of tools to track and isolate senescent cells in tissues1-4. Deleting senescent cells from transgenic murine models have demonstrated therapeutic benefits in numerous age-related diseases5-11, but the identity, behavior, and function of the senescent cells deleted in vivo remain elusive. We engineered an ultra-sensitive reporter of p16INK4a, a biomarker of senescence12, to isolate and track p16INK4a+ cells in vivo. Surprisingly, p16INK4a+ mesenchymal cells appear in the basement membrane adjacent to epithelial progenitors in the lung shortly after birth, and these cells demonstrate senescent characteristics in vivo and ex vivo. Transcriptomic analysis of p16INK4a+ mesenchymal cells from non-aged lungs demonstrates a transition to a secretory phenotype upon airway epithelial injury. Heterotypic 3D organoid assays show that injured p16INK4a+ mesenchymal cells enhance epithelial progenitor proliferation, and we identified EREG as a novel airway progenitor mitogen produced by the secretory p16INK4a+ mesenchymal cells. Mesenchymal-specific deletion of the p16INK4a gene abrogates features of senescence in vivo, but also attenuates normal epithelial repair. Thus, p16INK4a+ mesenchymal cells can act as sentinels for the airway epithelial stem cell niche, poised to transition to a senescence-associated secretory phenotype to support barrier repair. Our data identify possible cellular targets in vivo for a rapidly growing list of senolytic therapies, but also raises important questions about the hidden cost of targeting senescent cells present in normal organs.

cell biology↗