Biology subjects

Peng, X.

Publications and source records attributed to Peng, X..

At least 163 records · Page 9Linked to original sources

bioRxiv2020

Cdc42 is required for lymphatic branching, maturation and valve formation during embryonic development

Cdc42, a Ras-related GTPase that regulates the actin cytoskeleton, was recently shown to play an indispensable role in vasculogenesis and endothelial cell (EC) survival. Here, we determined whether Cdc42 also contributes to lymphatic development by generated two different Cdc42 knockout mice lines by crossing Cdc42/flox mice with either vascular endothelial cadherin-Cre (Cdh5-Cre) mice or Prox1-CreERT2 mice. Our results demonstrated that depleting ECs of Cdc42 expression resulted in embryonic lethality with severe edema. Whole-mount immunofluorescence staining of both knockout embryos showed that the deletion of Cdc42 in ECs impaired lymphatic vessel branching and that the lymphatic lumen size significantly increased. Moreover, we found that the inactivation of Cdc42 compromised mesenteric collecting lymphatic vessel maturation and prevented valve formation. We go on to show that Cdc42 can be activated by vascular endothelial growth factor c (VEGFc) in cultured human dermal lymphatic ECs (HDLECs), and that knocking down Cdc42 expression in these cells using siRNA decreased VEGFc-induced focal adhesion kinase (FAK) phosphorylation. These findings, when taken together with the fact that inactivating FAK plus one allele of Cdc42 in ECs was sufficient to recapitulate the phenotypes of the Cdc42 EC knockout embryos, suggests that Cdc42 and FAK interact genetically during lymphatic development. In addition, Cdc42 and FAK regulated signal transduction is essential for blood and lymphatic vessel separation. Taken together, our data highlights the important role played by Cdc42 in the development of the lymphatic system.

developmental biology↗

bioRxiv2020

Src/FAK complex phosphorylates cardiac myosin binding protein c (cMyBP-C) in vitro and in vivo

Cardiac myosin binding protein C (cMyBP-C) is a phosphorylation-dependent force regulator and plays an important role in controlling myosin and actin dynamic interaction. Point-mutations of cMyBP-C that interfere with cMyBP-C threonine/serine phosphorylation resulted in hypertrophic cardiomyopathy and cardiac failure. However, it remains largely unknown how cMyBP-C tyrosine phosphorylation is regulated during cardiac hypertrophy and heart failure. Integrins are receptors of extracellular matrix and are the sensors of cardiac mechanical stretch. Focal adhesion kinase (FAK) plays an essential role in integrin-initiated signal transduction and regulates multiple cellular functions in various types of cells including cardiomyocytes. To identify the regulatory mechanism of cMyBP-C tyrosine phosphorylation during cardiac hypertrophy, we examined the effect of FAK on phosphorylation of cMyBP-C. Immunoprecipitation analysis showed that FAK and cMyBP-C are associated within the intact mouse heart. Results from our mutagenesis experiments demonstrated that the FAK kinase domain was required for FAK to associate with cMyBP-C. Our data also documented that the FAK Y397 site is required for FAK and cMyBP-C association. Importantly, overexpression dominant active Src Y527F with FAK significantly enhanced cMyBP-C phosphorylation. Interestingly, overexpression of cMyBP-C inhibited FAK phosphorylation. Taken together, cMyBP-C is one of effectors of Src/FAK complex in cardiomyocyte.

molecular biology↗

bioRxiv2020

A mediation analysis of schizophrenia variants: Risk alleles may affect a gene's expression differently from how the expression affects risk

Variants identified by genome-wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory. Across many datasets analyses show that variants often affect multiple genes. Lacking data on many tissue types, developmental time points and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a by-stander and puts into question the direction of expression effect of on the risk, since the many variant - regulated genes may have opposing effects, imperfectly balancing each other. We used two brain gene expression datasets (CommonMind and BrainSeq) for mediation analysis of schizophrenia-associated variants. We confirm that eQTL target genes often mediate risk but the direction in which expression affects risk is often different from that in which the risk allele changes expression. Of 38 mediator genes significant in both datasets 33 showed consistent mediation direction (Chi2 test P=6*10-6). One might expect that the expression would correlate with the risk allele in the same direction it correlates with disease. For 15 of these 33 (45%), however, the expression change associated with the risk allele was protective, suggesting the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease while those that are, might have different than expected directions.

genetics↗

bioRxiv2019

Millet-based supplement restored microbiota diversity of acute undernourished pigs

The strong connection between undernutrition and gut microbiota (GM) has enabled microbiota-targeting to become an evolving strategy, which witnessed urgent need for fortified formula of supplementary food in undernutrition therapy. Using undernourished pigs as models, we investigated how corn- and millet-based nutritional supplement acted differently in modulating microbiota. Undernourished pigs at age of 9 weeks were fed with pure maize diet (Maize), corn-based (CSB+) and millet-based (MSB+) supplementary food for 3 weeks. Compared with Maize group, both CSB+ and MSB+ improved serum total protein and globulin level, but no physiological improvement was observed by short-term food intervention. MSB+ shown superior influence on GM immaturity which were more normally-grown like at both structural and functional level. Higher level of Bacteriodetes, Firmicutes and lower level of Preteobacteria were detected in MSB+ fed piglets in contrast with CSB+. Lachnospira.spp was significantly raised after nutritional intervention, indicating high correlation with the undernutrition-associated phenotype. Thus, especially from the GM aspect, millet could be one promising source to help undernourished children reconstruct balanced microbiota in short therapeutic term.

microbiology↗

bioRxiv2019

Reconstructing lost BOLD signal in individual participants using deep machine learning

The blood oxygen level-dependent (BOLD) signal in functional neuroimaging suffers from magnetic susceptibility artifacts and interference from metal implants. The resulting signal loss hampers functional neuroimaging studies and can lead to misinterpretation of findings. Here, we reconstructed compromised BOLD signal using deep machine learning. We trained a deep learning model to learn principles governing BOLD activity in one dataset and reconstructed artificially-compromised regions in another dataset, frame by frame. Strikingly, BOLD time series extracted from reconstructed frames were correlated with the original time series, even though the frames did not independently carry information about BOLD fluctuations through time. Moreover, reconstructed functional connectivity (FC) maps exhibited good correspondence with the original FC maps, indicating that the deep learning model recovered functional relationships among brain regions. We replicated this result in patients whose scans suffered signal loss due to intracortical electrodes. Critically, the reconstructions captured individual-specific information rather than group information learned during training. Deep machine learning thus presents a unique opportunity to reconstruct compromised BOLD signal while capturing features of an individuals own functional brain organization.

neuroscience↗

bioRxiv2019

In Vivo Study of Key Transcription Factors in Muscle Satellite Cells by CRISPR/Cas9/AAV9-sgRNA Mediated Genome Editing

Skeletal muscle satellite cells (SCs) are adult muscle stem cells responsible for injury induced muscle regeneration. Despite advances in the knowledge of molecular mechanisms regulating SC lineage progression, our understanding of key transcription factors (TFs) and their regulatory functions in SCs in particularly the quiescent and early activation stages remains incomplete due to the lack of efficient method to screen and investigate the stage-specific key TFs. In this study, we succeeded in defining a distinct list of key TFs in early stages of SC fate transition using the paradigm of super enhancers (SEs). Particularly, leveraging the Cre-dependent Cas9 knockin mice and AAV9 mediated sgRNAs delivery, we generated a facile muscle specific genome editing system which allows gene depletion in SCs in vivo. Using MyoD locus as a proof of concept, we demonstrated that this CRISPR/Cas9/AAV9-sgRNA system can efficiently introduce mutagenesis at target locus and recapture the phenotypes reported in knockout mice. Further application of the system on key TFs, Myc, Bcl6 and Pknox2, revealed their distinct functions in the early stage of SC activation and damage induced muscle regeneration. Altogether our findings have proven the CRISPR/Cas9/AAV9-sgRNA system as a robust way for in vivo genome editing and elucidation of key factors governing SC activities.

genetics↗

bioRxiv2019

Differential protein metabolism and regeneration in hypertrophic diaphragm and atrophic gastrocnemius muscles in hibernating Daurian ground squirrels

Whether differences in regulation of protein metabolism and regeneration are involved in the different phenotypic adaptation mechanisms of muscle hypertrophy and atrophy in hibernators? Two fast-type muscles (diaphragm and gastrocnemius) in summer active and hibernating Daurian ground squirrels were selected to detect changes in cross-sectional area (CSA), fiber type distribution, and protein expression indicative of protein synthesis metabolism (protein expression of P-Akt, P-mTORC1, P-S6K1, and P-4E-BP1), protein degradation metabolism (MuRF1, atrogin-1, calpain-1, calpain-2, calpastatin, desmin, troponin T, Beclin1, and LC3-II), and muscle regeneration (MyoD, myogenin, and myostatin). Results showed the CSA of the diaphragm muscle increased significantly by 26.1%, whereas the CSA of the gastrocnemius muscle decreased significantly by 20.4% in the hibernation group compared with the summer active group. Both muscles displayed a significant fast-to-slow fiber-type transition in hibernation. Our study further indicated that increased protein synthesis, decreased protein degradation, and increased muscle regeneration potential contributed to diaphragm muscle hypertrophy, whereas decreased protein synthesis, increased protein degradation, and decreased muscle regeneration potential contributed to gastrocnemius muscle atrophy. In conclusion, the differences in muscle regeneration and regulatory pattern of protein metabolism may contribute to the different adaptive changes observed in the diaphragm and gastrocnemius muscles of ground squirrels.

physiology↗

bioRxiv2019

Systematic profiling of full-length immunoglobulin and T-cell receptor repertoire diversity in rhesus macaque through long read transcriptome sequencing

The diversity of immunoglobulin (Ig) and T-cell receptor (TCR) repertoires is a focal point of immunological studies. Rhesus macaques are key for modeling human immune responses, placing critical importance on the accurate annotation and quantification of their Ig and TCR repertoires. However, due to incomplete reference resources, the coverage and accuracy of the traditional targeted amplification strategies for profiling rhesus Ig and TCR repertoires are largely unknown. Here, using long read sequencing, we sequenced four Indian-origin rhesus macaque tissues and obtained high quality, full-length sequences for over 6,000 unique Ig and TCR transcripts, without the need for sequence assembly. We constructed the first complete reference set for the constant regions of all known isotypes and chain types of rhesus Ig and TCR repertoires. We show that sequence diversity exists across the entire variable regions of rhesus Ig and TCR transcripts. Consequently, existing strategies using targeted amplification of rearranged variable regions comprised of V(D)J gene segments miss a significant fraction (27% to 53% and 42% to 49%) of rhesus Ig/TCR diversity. To overcome these limitations, we designed new rhesus-specific assays that remove the need for primers conventionally targeting variable regions and allow single cell-level Ig and TCR repertoire analysis. Our improved approach will enable future studies to fully capture rhesus Ig and TCR repertoire diversity and is applicable for improving annotations in any model organism.

immunology↗

bioRxiv2019

ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling

ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome. However, its role in neural development and pathology remains unclear. Using mESC (mouse embryonic stem cell) directional neural differentiation as a model, we show that ADNP is required for ESC neural induction and neuronal differentiation by maintaining Wnt signaling. Mechanistically, ADNP functions to maintain the proper protein levels of {beta}-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and hyperphosphorylation of {beta}-Catenin by GSK3{beta} and subsequent degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. We further show that ADNP plays key role in cerebellar neuron formation. Finally, adnp gene disruption in zebrafish embryos recapitulates key features of the mouse phenotype, including the reduced Wnt signaling, defective embryonic cerebral neuron formation and the massive neuron death. Thus, our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.

developmental biology↗

bioRxiv2019

Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment

In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) impedes their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and measured their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and their spatial ordering impact diffusive transport. P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited [~]40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to particles functionalized with gold standard poly(ethylene) glycol or iRGD peptide ligand. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC=\"FIGDIR/small/659524v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@18bc04forg.highwire.dtl.DTLVardef@1feb597org.highwire.dtl.DTLVardef@14403e5org.highwire.dtl.DTLVardef@5bbf6c_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2019

A combinatorial biomolecular strategy to identify peptides for improved transport across the sputum of cystic fibrosis patients and the underlying epithelia

Drugs and drug delivery systems have to traverse multiple biological barriers to achieve therapeutic efficacy. In diseases of mucosal-associated tissues such as cystic fibrosis (CF), successful delivery of gene and drug therapies remains a significant challenge due to an abnormally concentrated viscoelastic mucus, which prevents ~99% of all drugs and particles from penetrating the mucus barrier and the underlying epithelia for effective therapy, resulting in decreased survival. We used combinatorial peptide-presenting phage libraries and next-generation sequencing to identify hydrophilic, close to net-neutral charged peptides that penetrate the mucus barrier ex vivo in sputum from CF patients with ~600-fold better penetration than a positively charged control. After mucus penetration, nanoparticles conjugated with our selected peptides successfully translocated into lung epithelial cells derived from CF patients and demonstrated up to three-fold improved cell uptake compared to non-modified carboxylated- and gold standard PEGylated-nanoparticles. The selected peptides act as surface chemistries with synergistic functions to significantly improve the ability of drug delivery systems to overcome the human mucosal barriers and provide efficient cellular internalization. Our screening strategy provides a biologically-based discovery assay that directly addresses transport through mucus and cell barriers and has the potential to advance drug and gene delivery to multiple mucosal barriers.

bioengineering↗

bioRxiv2019

Protein structure determination using Riemannian approach

The protein nuclear magnetic resonance (NMR) structure determination is one of the most extensively studied problems due to its increasing importance in biological function analysis. We adopt a novel method, based on one of the matrix completion (MC) techniques-the Riemannian approach, to solve the protein structure determination problem. We formulate the protein structure in terms of low-rank matrix which can be solved by an optimization problem in the Riemannian spectrahedron manifold whose objective function has been delimited with the derived boundary condition. Two efficient algorithms in Riemannian approach-the trust-region (Tr) algorithm and the conjugate gradient (Cg) algorithm are used to reconstruct protein structures. We first use the two algorithms in a toy model and show that the Tr algorithm is more robust. Afterwards, we rebuild the protein structure from the NOE distance information deposited in NMR Restraints Grid (http://restraintsgrid.bmrb.wisc.edu/NRG/MRGridServlet). A dataset with both X-ray crystallographic structure and NMR structure deposited in Protein Data Bank (PDB) is used to statistically evaluate the performance of our method. By comparing both our rebuilt structures and NMR counterparts with the \"standard\" X-ray structures, we conclude that our rebuilt structures have similar (sometimes even smaller) RMSDs relative to \"standard\" X-ray structures in contrast with the reference NMR structures. Besides, we also validate our method by comparing the Z-scores between our rebuilt structures with reference structures using Protein Structure Validation Software suit. All the validation scores indicate that the Riemannian approach in MC techniques is valid in reconstructing the protein structures from NOE distance information. The software based on Riemannian approach is freely available at https://github.com/xubiaopeng/Protein_Recon_MCRiemman.\n\nAuthor summaryMatrix Completion is a technique widely used in many aspects, such as the global positioning in sensor networks, collaborative filtering in recommendation system for many companies and face recognition, etc. In biology, distance geometry used to be a popular method for reconstructing protein structures related to NMR experiment. However, due to the low quality of the reconstructed results, those methods were replaced by other dynamic methods such as ARIA, CYANA and UNIO. Recently, a new MC technique named Riemannian approach is introduced and proved mathematically, which promotes us to apply it in protein structure determination from NMR measurements. In this paper, by combining the Riemannian approach and some post-processing procedures together, we reconstruct the protein structures from the incomplete distance information measured by NMR. By evaluating our results and comparing with the corresponding PDB NMR deposits, we show that the current Riemannian approach method is valid and at least comparable with (if not better than) the state-of-art methods in NMR structure determination.

bioinformatics↗

bioRxiv2019

Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models

Human papillomavirus (HPV) infections are commonly thought to be strictly sexually transmitted. However, studies have demonstrated the presence of HPV in cancers of many non-sexual internal organs, raising the question as to how the viruses gain access to these sites. A possible connection between blood transfusion and HPV-associated disease has not received much attention. We show, in two animal models, that blood infected with papillomavirus yields infections at permissive sites. Furthermore, we demonstrate that blood from actively infected mice can transmit the infection to naive animals. Finally, we report papillomavirus infections in the stomach tissues of animals infected via the blood. Stomach tissues are not known to be permissive for papillomavirus infection, although the literature suggests that HPVs may be associated with a subset of gastric cancers. These results indicate that the human blood supply, which is not screened for papillomaviruses, could be a potential source of HPV infection and subsequent cancers. SUMMARYHuman papillomaviruses cause 5% of human cancers. Currently, blood banks do not screen for these viruses. We demonstrate that blood transfused from papillomavirus-infected animals produces infections in recipients. Public health implications are significant if the same is true for humans. DefinitionsLocal papillomavirus infection: An infection initiated by the direct application of virus or viral DNA to the site of infection Intravenous (IV) papillomavirus infection: An infection resulting from blood-borne delivery of virus or viral DNA to the site of infection.

microbiology↗

bioRxiv2019

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↗

bioRxiv2018

IgG is differentially and selectively transferred across the placenta in HIV-infected women

SUMMARY\n\nThe transplacental transfer of maternal IgG to the developing fetus is critical for infant protection against infectious pathogens in the first year of life. However, factors that modulate the transplacental transfer efficiency of maternal IgG that could be harnessed for maternal vaccine design remain largely undefined. HIV-infected women have impaired placental IgG transfer, yet the mechanism underlying this impaired transfer is unknown, presenting an opportunity to explore factors that contribute to the efficiency of placental IgG transfer. We measured the transplacental transfer efficiency of maternal HIV and other pathogen-specific IgG in historical U.S. (n=120) and Malawian (n=47) cohorts of HIV-infected mothers and their HIV- exposed uninfected and HIV-infected infants. We then examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, and IgG Fc region subclass and glycan signatures and their association with transplacental transfer efficiency of maternal antigen-specific IgG. We established 3 distinct phenotypes of placental IgG transfer efficiency in HIV-infected women, including: 1) efficient transfer of the majority of antigen-specific IgG populations; 2) generally poor IgG transfer phenotype that was strongly associated with maternal CD4+ T cell counts, hypergammaglobulinemia, and frequently yielded non-protective levels of vaccine-specific IgG; and 3) variable transfer of IgG across distinct antigen specificities. Interestingly, maternal IgG characteristics, such as binding to placentally expressed Fc receptors Fc{gamma}RIIa and Fc{gamma}RIIIa, IgG subclass frequency, and Fc region glycan profiles were associated with placental IgG transfer efficiency. These maternal IgG transplacental transfer determinants were distinct among different antigen-specific IgG populations. Our findings suggest that in HIV-infected women, both maternal disease progression and Fc region characteristics modulate the selective placental transfer of distinct IgG subpopulations, with implications for both the health of HIV-exposed uninfected infants and maternal vaccine design.\n\nHighlightsO_LILow peripheral blood CD4 + T cell count and hypergammaglobulinemia are associated with inefficient transplacental IgG transfer in HIV-infected women\nC_LIO_LIAntigen-specific IgG binding strength to placentally-expressed Fc receptors, but not placental Fc receptor expression levels, mediates selective placental IgG transfer\nC_LIO_LIAntigen-specific IgG Fc region glycan profiles also contribute to the selective placental IgG transfer of maternal IgG populations in HIV-infected women\nC_LI

microbiology↗

bioRxiv2018

Establishment and Characterization of a Multi-Purpose Large Animal Exposure Chamber for Investigating Health Effects

Air pollution poses a significant threat to the environment and human health. Most in-vivo health studies conducted regarding air pollutants, including particulate matter (PM) and gas phase pollutants, have been either through traditional medical intranasal treatment or using a tiny chamber, which limit animal activities. In this study, we designed and tested a large, whole-body, multiple animal exposure chamber with uniform dispersion and exposure stability for animal studies. The chamber simultaneously controls particle size distribution and PM mass concentration. Two different methods were used to generate aerosol suspension through either soluble material (Alternaria extract), liquid particle suspension (Nanosilica solution) or dry powder (silica powder). We demonstrate that the chamber system provides well controlled and characterized whole animal exposures, where dosage is by inhalation of particulate matter.

bioengineering↗

bioRxiv2018

Vitamin A supplement after neonatal Streptococcus pneumoniae pneumonia alters CD4+T cell subset and inhibits allergic asthma in mice model

BackgroundPreviously, we showed that neonatal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) promoted adulthood ovalbumin (OVA) induced allergic asthma. Many studies have demonstrated that vitamin A deficiency induced the development of allergic asthma. Whether neonatal S. pneumoniae pneumonia promoted allergic asthma development was associated with vitamin A concentrations remains unclear.\n\nMethodsFemale BALB/c neonates were infected with S. pneumoniae strain D39 and subsequently treated with vitamin A. Vitamin A concentrations in lung, serum and liver were monitored on 2, 5, 7, 14, 21, 28 days post infection. Four weeks after infection, mice were sensitized and challenged with OVA to induce allergic airway disease (AAD) in early adulthood. Twenty-four hours after the final challenge, lung histo-pathology, cytokine concentrations in bronchoalveolar lavage fluid (BALF), airway hyperresponsiveness (AHR) and lung CD4+T cells were measured.\n\nResultsWe demonstrated that neonatal S. pneumoniae pneumonia induce lung vitamin A deficiency up to early adulthood. Moreover, neonatal S. pneumoniae pneumonia aggravated airway inflammatory cells accumulation and increased AHR during AAD, decreased Foxp3+Treg and Th1 productions remarkably, while Th2 cell expression was increased significantly. Further study indicated that vitamin A supplement after neonatal S. pneumoniae pneumonia can promote Foxp3+Treg and Th1 productions, decrease Th2 cell expressions, alleviate AHR and inflammatory cells infiltration during AAD.\n\nConclusionsUsing a mouse model, we demonstrate that Vitamin A supplement after neonatal Streptococcus pneumoniae pneumonia alters the CD4+T cell subset and inhibits the development of early adulthood allergic asthma.

immunology↗

bioRxiv2018

COMPASS Family Histone Methyltransferase ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signalling

Cell fate specification in neural progenitor cells (NPCs) is orchestrated via extrinsic and intrinsic molecular programs, and histone methylation in these decisions has been ascribed to a crucial function regulating gene expression. Here, we show that the COMPASS family histone methyltransferase co-factor ASH2L is required in NPCs proliferation and upper layer cortical projection neurons production and position. Deletion of Ash2l impairs trimethylation of H3K4 and transcriptional machinery specifically for subsets of Wnt-{beta}-catenin signalling, disrupting their transcription and consequently inhibiting the proliferation ability of NPCs in late stages of neurogenesis. Consistently, Ash2l conditional mutants exhibit thinning neocortex with reduced upper layer neurons and altered neuronal position. Moreover, overexpressing {beta}-catenin after Ash2l elimination or knockdown can rescue the proliferation deficiency of NPCs both in vivo and in vitro. These results demonstrate an essential and highly specific role for Ash2l in controlling NPCs proliferation and late-born neurons lamination in corticogenesis via transcriptionally regulating Wnt-{beta}-catenin signalling, and provide clues to how the COMPASS family epigenetic factors coordinate cell fate determination during cortex development.

neuroscience↗