Biology subjects

Wang, C.

Publications and source records attributed to Wang, C..

At least 1,099 records · Page 61Linked to original sources

bioRxiv2018

PARylation modulates stress granule assembly, phase separation, and neurotoxicity of ALS-related RNA-binding proteins

Mutations in RNA-binding proteins localized in ribonucleoprotein (RNP) granules, such as hnRNP A1 and TDP-43, promote aberrant protein aggregations, which are pathological hallmarks in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Protein posttranslational modifications (PTMs) are known to regulate RNP granules. In this study, we investigate the function of PARylation, an important PTM involved in DNA damage repair and cell death, in RNP-related neurodegeneration. We reveal that PARylation levels are a major regulator of the dynamic assembly-disassembly of RNP granules, and the disease-related RNPs such as hnRNP A1 and TDP-43 can both be PARylated and bind to PARylated proteins. We further identify the PARylation site of hnRNP A1 at K298, which controls the cytoplasmic translocation of hnRNP A1 in response to stress, as well as the PAR-binding motif (PBM) of hnRNP A1, which is required for the delivery and association of hnRNP A1 to stress granules. Moreover, we show that PAR not only dramatically enhances the liquid-liquid phase separation of hnRNP A1, but also promotes the co-phase separation of hnRNP A1 and TDP-43 in vitro and their interaction in vivo. Finally, we establish that both genetic and pharmacological inhibition of PARP mitigates hnRNP A1 and TDP-43-mediated neurotoxicity in cell and Drosophila models of ALS. Together, our findings indicate a novel and crucial role of PARylation in regulating the assembly and the dynamics of RNP granules, and dysregulation of PARylation may contribute to ALS disease pathogenesis.

neuroscience↗

bioRxiv2018

Large-scale whole-genome sequencing of three diverse Asian populations in Singapore

Asian populations are currently underrepresented in human genetics research. Here we present whole-genome sequencing data of 4,810 Singaporeans from three diverse ethnic groups: 2,780 Chinese, 903 Malays, and 1,127 Indians. Despite a medium depth of 13.7x, we achieved essentially perfect (>99.8%) sensitivity and accuracy for detecting common variants and good sensitivity (>89%) for detecting extremely rare variants with <0.1% allele frequency. We found 89.2 million single-nucleotide polymorphisms (SNPs) and 9.1 million small insertions and deletions (INDELs), more than half of which have not been cataloged in dbSNP. In particular, we found 126 common deleterious mutations (MAF>0.01) that were absent in the existing public databases, highlighting the importance of local population reference for genetic diagnosis. We describe fine-scale genetic structure of Singapore populations and their relationship to worldwide populations from the 1000 Genomes Project. In addition to revealing noticeable amounts of admixture among three Singapore populations and a Malay-related novel ancestry component that has not been captured by the 1000 Genomes Project, our analysis also identified some fine-scale features of genetic structure consistent with two waves of prehistoric migration from south China to Southeast Asia. Finally, we demonstrate that our data can substantially improve genotype imputation not only for Singapore populations, but also for populations across Asia and Oceania. These results highlight the genetic diversity in Singapore and the potential impacts of our data as a resource to empower human genetics discovery in a broad geographic region.

genetics↗

bioRxiv2018

Molecular and topological reorganizations in mitochondrial architecture interplay during Bax-mediated steps of apoptosis

During apoptosis, Bcl-2 proteins such as Bax and Bak mediate the release of pro-apoptotic proteins from the mitochondria by clustering on the outer mitochondrial membrane and thereby permeabilizing it. However, it remains unclear how outer membrane openings form. Here, we combined different correlative microscopy and electron cryo-tomography approaches to visualize the effects of Bax activity on mitochondria in human cells. Our data show that Bax clusters localize near outer membrane ruptures of highly variable size. Bax clusters contain structural elements suggesting a higher-order organization of their components. Furthermore, unfolding of inner membrane cristae is coupled to changes in the supramolecular assembly of ATP synthases, particularly pronounced at membrane segments exposed to the cytosol by ruptures. Based on our results, we propose a comprehensive model in which molecular reorganizations of the inner membrane and sequestration of outer membrane components into Bax clusters interplay in the formation of outer membrane ruptures.

cell biology↗

bioRxiv2018

Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain

Microglia are resident immune cells that play critical roles in maintaining normal physiology of the central nervous system. Remarkably, microglia have intrinsic capacity to replenish after being acutely ablated. However, the underlying mechanisms that drive such microglial restoration remain elusive. Here, we removed microglia via CSF1R inhibitor PLX5622 and characterized repopulation both spatially and temporally. We also investigated the cellular origin of repopulated microglia and report that microglia are replenished via self-renewal, with little contribution from non-microglial lineage progenitors, including nestin+ progenitors and the circulating myeloid population. Interestingly, spatial analyses with multi-color labeling reveal that newborn microglia recolonize the parenchyma by forming distinctive clusters that maintain stable territorial boundaries over time, indicating proximal expansion nature of adult microgliogenesis and stability of microglia tiling. Temporal transcriptome profiling from newborn microglia at different repopulation stages revealed that the adult newborn microglia gradually regain steady-state maturity from an immature state that is reminiscent of neonatal stage and follow a series of maturation programs that include NF-{kappa}B activation, interferon immune activation and apoptosis, etc. Importantly, we show that the restoration of microglial homeostatic density requires NF-{kappa}B signaling as well as apoptotic egress of excessive cells. In summary, our study reports key events that take place from microgliogenesis to homeostasis re-establishment.

neuroscience↗

bioRxiv2018

G-quadruplex dynamics contribute to epigenetic regulation of mitochondrial function

Single-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). Predicted G4-forming sequences in the mitochondrial genome are enriched on the heavy-strand and have been associated with formation of deletion breakpoints that cause mitochondrial disorders. However, the functional roles of G4 structures in regulating mitochondrial respiration in non-cancerous cells remain unclear. Here, we demonstrate that RHPS4, previously thought to be a nuclear G4-ligand, localizes primarily to mitochondria in live cells by mechanisms involving mitochondrial membrane potential. We find that RHPS4 exposure causes an acute inhibition of mitochondrial transcript elongation, leading to respiratory complex depletion. At higher ligand doses, RHPS4 causes mitochondrial DNA (mtDNA) replication pausing and genome depletion. Using these different levels of RHPS4 exposure, we describe discrete nuclear gene expression responses associated with mitochondrial transcription inhibition or with mtDNA depletion. Importantly, a mtDNA variant with increased anti-parallel G4-forming characteristic shows a stronger respiratory defect in response to RHPS4, supporting the conclusion that mitochondrial sensitivity to RHPS4 is G4-structure mediated. Thus, we demonstrate a direct role for G4 perturbation in mitochondrial genome replication, transcription processivity, and respiratory function in normal cells and describe the first molecule that differentially recognizes G4 structures in mtDNA.

molecular biology↗

bioRxiv2018

Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure

We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-the-art algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, ...), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores.

neuroscience↗

bioRxiv2018

Variation and diversification of the microbiome of Schlechtendalia chinensis on two alternate host plants

Schlechtendalia chinensis, a gall-inducing aphid, has two host plants in its life cycle. Its wintering host is a moss (typically Plagiomnium maximoviczii) and its main host is Rhus chinensis (Sumac), on which it forms galls during the summer.. This study investigated bacteria associated with S. chinensis living on the two different host plants by sequencing 16S rRNAs. A total of 183 Operational Taxonomic Units (OTUs) from 50 genera were identified from aphids living on moss, whereas 182 OTUs from 49 genera were found from aphids living in Sumac galls. The most abundant bacterial genus among identified OTUs from aphids feeding on both hosts was Buchnera. Despite similar numbers of OTUs, the composition of bacterial taxa showed significant differences between aphids living on moss and those living on R. chinensis. Specifically, there were 12 OTUs from 5 genera (family) unique to aphids living on moss, and 11 OTUs from 4 genera (family) unique to aphids feeding in galls on R. Chinensis. Principal Coordinate Analysis (PCoA) also revealed that bacteria from moss-residing aphids clustered differently from aphids collected from galls. Our results provid a foundation for future analyses on the roles of symbiotic bacteria in plant - aphid interactions in general, and how gall-specific symbionts differ in this respect.

microbiology↗

bioRxiv2018

Genome-wide characterization, evolutionary analysis of WRKY genes in Cucurbitaceae species and assessment of its roles in resisting to powdery mildew disease

The WRKY proteins constitute a large family of transcription factors that have been known to play a wide range of regulatory roles in multiple biological processes. Over the past few years, many reports have focused on analysis of evolution and biological function of WRKY genes at the whole genome level in different plant species. However, little information is known about WRKY genes in melon (Cucumis melo L.). In the present study, a total of 56 putative WRKY genes were identified in melon, which were randomly distributed on their respective chromosomes. A multiple sequence alignment and phylogenetic analysis using melon, cucumber and watermelon predicted WRKY domains indicated that melon WRKY proteins could be classified into three main groups (I-III). Our analysis indicated that no recent duplication events of WRKY genes were detected in melon, and strong purifying selection was observed among the 85 orthologous pairs of Cucurbitaceae species. Expression profiles of CmWRKY derived from RNA-seq data and quantitative RT-PCR (qRT-PCR) analyses showed distinct expression patterns in various tissues, and the expression of 16 CmWRKY were altered following powdery mildew infection in melon. Besides, we also found that a total of 24 WRKY genes were co-expressed with 11 VQ family genes in melon. Our comparative genomic analysis provides a foundation for future functional dissection and understanding the evolution of WRKY genes in cucurbitaceae species, and will promote powdery mildew resistance study in melon.

plant biology↗

bioRxiv2018

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Cranial growth and development affects the closely related traits of head circumference (HC) and intracranial volume (ICV). Here we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood.

genetics↗

bioRxiv2018

Identification of key genes related to dexamethasone-resistance in acute lymphoblastic leukemia

Drug resistance is the main cause of poor chemotherapy response in acute leukemia. Despite the extensive use of dexamethasone(DEX) in the treatment of acute lymphoblastic leukemia for many years, the mechanisms of dexamethasone - resistance has not been fully understood. We choose GSE94302 from GEO database aiming to identify key genes that contribute to the DEX resistance in acute lymphoblastic leukemia. Differentially expressed gene(DEGs) are selected by using GEO2R tools. A total of 837 DEGs were picked out, including 472 up-regulated and 365 down-regulated DEGs. All the DEGs were underwent gene ontology(GO) analysis and Kyoto Encyclopedia of Gene and Genome(KEGG) pathway analysis. In addition, the DEGs-encoded protein-protein interaction (PPI) was screened by using Cytoscape and Search Tool for the Retrieval of Interacting Genes(STRING). Total 20 genes were found as key genes related to DEX resistance with high degree of connectivity, including CDK1, PCNA, CCNB1, MYC, KPNA2, AURKA, NDC80, HSPA4, KIF11, UBE2C, PIK3CG, CD44, CD19, STAT1, DDX41, LYN, BCR, CD48, JAK1 and ITGB1. They could be used as biomarkers to identify the DEX-resistant acute lymphoblastic leukemia.

bioinformatics↗

bioRxiv2018

Antimicrobial Activity of Tetrabromobisphenol A (TBBPA) against Staphylococcus aureus Skin Infections

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant with selective antimicrobial activity against Gram-positive bacteria. We show that TBBPA exerts bactericidal effects by damaging the cell wall and membrane of Staphylococcus aureus (SA) without inducing antimicrobial resistance. In vivo skin infection assays indicate that a low dose of TBBPA could contribute to wound closure and attenuate SA infection and inflammatory infiltration. TBBPA has potential for use as an antimicrobial agent against Gram-positive pathogens.

microbiology↗

bioRxiv2018

Extracellular Degradation into Adenosine and the Activities of Adenosine Kinase and AMPK Mediate Extracellular NAD+-produced increases in the Adenylate Pool of BV2 Microglia under Basal Conditions

Cumulating evidence has indicated NAD+ deficiency as a common central pathological factor of multiple diseases and aging. NAD+ supplement is highly protective in various disease and aging models, while two key questions remain unanswered: 1) Does extracellular NAD+ also produce its effects through its degradation product adenosine? 2) Does extracellular NAD+ produce the protective effects by affecting cells under pathological insults only, or by affecting both normal cell and cells under pathological insults? Since extracellular NAD+ can be degraded into adenosine, and endogenous adenosine levels are in the nanomolar range under physiological conditions, extracellular NAD+ may produce its effects through its degradation into adenosine. In this study we used BV2 microglia as a cellular model to test our hypothesis that NAD+ treatment can increase the intracellular adenylate pool under basal conditions through its extracellular degradation into adenosine. Our study has shown that extracellular NAD+ increases the adenylate pool of BV2 microglia under basal conditions through its degradation into adenosine that enters the cells through equilibrative nucleoside transporters. The intracellular adenosine is converted to AMP by adenosine kinase, which increases intracellular ATP by both activating AMPK and increasing ADP that drives mitochondrial FoF1-ATP synthase. Collectively, our study has suggested that extracellular NAD+ can enhance defensive capacity of normal cells through a novel pathway, which includes extracellular NAD+ degradation into adenosine and the activities of adenosine kinase and AMPK. Our findings have also suggested that NAD+ administration in various disease and aging models may significantly affect the microglia under basal conditions.

cell biology↗

bioRxiv2018

UDP-glucose:anthocyanidin 3-O-glucoside-2”-O-glucosyltransferase catalyzes further glycosylation of anthocyanins in purple Ipomoea batatas

Glycosylation contributes to the diversity and stability of anthocyanins in plants. The process is catalyzed by various glucosyltransferases using different anthocyanidin aglycones and glycosyl donors. An anthocyanidin 3-O-glucoside-2\"-O-glucosyltransferase (3GGT) from purple sweetpotato (cv. Ayamurasaki) served for the catalytic conversion of anthocyanidin 3-O-glucoside into anthocyanidin 3-O-sophoroside, which is functionally different from the 3GGT ortholog of Arabidopsis. The phylogenetic analysis indicates regioselectivity of 3GGT using UDP-xylose or UDP-glucose as the glycosyl is divergent between Convolvulaceae and Arabidopsis. Homology-based protein modeling and site-directed mutagenesis of Ib3GGT and At3GGT suggested that the Thr-138 of Ib3GGT is a key amino acid residue for UDP-glucose recognition and plays a major role in sugar donor selectivity. The wild type and ugt79b1 mutants of Arabidopsis plants overexpressing Ib3GGT produced the new component cyanidin 3-O-sophoroside. Moreover, Ib3GGT expression was associated with anthocyanin accumulation in different tissues during Ayamurasaki plant development and was regulated by the transcription factor IbMYB1. The localization assay of Ib3GGT showed that further glycosylation occurs in the cytosol and not endoplasmic reticulum. The present study revealed the function of Ib3GGT in further glycosylation of anthocyanins and its Thr-138 is the key amino acid residue for UDP-glucose recognition.

plant biology↗

bioRxiv2018

Temporal changes in gut microbiota and signaling molecules of the gut-brain axis in mice fed meat protein diets

The purpose of this study was to characterize the dynamical changes of gut microbiota and explore the influence on bidirectional communications between the gut and the brain during a relatively long-term intake of different protein diets. The C57BL/6J mice were fed casein, soy protein and four kinds of processed meat proteins at a normal dose of 20% for 8 months. Protein diets dramatically affected the microbial composition and function and also the signaling molecule levels of the gut-brain axis in a dynamic manner, which consequently affected growth performance. Alistipes, Clostridiales vadinBB60, Anaerotruncus, Blautia and Oscillibacter had a relatively fast response to the diet, while Bacteroidales S24-7, Ruminiclostridium, Ruminococcaceae UCG-014, Coriobacteriaceae UCG-002 and Bilophila responded slowly. Rikenellaceae RC9 gut, Faecalibaculum and Lachnospiraceae showed a continuous change with feeding time. Bacteroidales S24-7 abundance increased from 4 months to 8 months, whereas those of Rikenellaceae RC9 gut, Akkermansia, Alistipes and Anaerotruncus remarkably decreased. Five and fifteen biological functions of microbiota were affected at 4 months and 8 months, respectively, and sixteen functions were observed to change over feeding time. Moreover, 28 and 48 specific operational taxonomy units were associated with the regulation of serotonin, peptide YY, leptin and insulin levels at two time points. Ruminococcaceae was positively associated with Lachnospiraceae and negatively associated with Bacteroidales S24-7. These results give an important insight into the effect of gut microbiota on the bidirectional communications between the gut and the brain under a certain type of diet.\n\nImportanceMany gastrointestinal and neuropsychiatric disorders may have a common pathophysiologic mechanism, involving bidirectional brain-gut axis signaling through humoral and neural pathways. The gut microbiota plays an important role in the communications between the gut and the brain. Recent evidence suggests that a growing number of subjects suffer from the above disorders. The significance of this study lies in the finding that long-term intake of different proteins at a normal dose induces dynamic alterations of specific microbiota in mice, which consequently affect bidirectional communications between the gut and the brain and results in different growth performance through dynamically regulating signaling molecule levels. Furthermore, this study indicates that intake of the same diet for a long time, irrespective of the diet source, may have an adverse effect on host health by altering gut microbiota.

microbiology↗

bioRxiv2018

Isolation and characterization of antagonistic bacteria with the potential for biocontrol of soil-borne wheat diseases

Bacillus amyloliquefaciens subsp. plantarum XH-9 is a plant-beneficial rhizobacterium that shows good antagonistic potential against phytopathogens by releasing diffusible and volatile antibiotics, and secreting hydrolytic enzymes. Furthermore, the XH-9 strain possesses important plant growth-promoting characteristics, including nitrogen fixation (7.92 {+/-} 1.05 mg/g), phosphate solubilization (58.67 {+/-} 4.20 g/L), potassium solubilization (10.07 {+/-} 1.26 g/mL), and the presence of siderophores (4.92 {+/-} 0.46 g/mL), indole-3-acetic acid (IAA) (7.76 {+/-} 0.51 g/mL) and 1-aminocyclopropane-1-carboxylic acid deaminase (ACC-deaminase) (4.67 {+/-} 1.21 nmol/[mg*h]). Moreover, the XH-9 strain showed good capacities for wheat, corn, and chili root colonization, which are critical prerequisites for controlling soil-borne diseases as a bio-control agent. Real-time quantitative polymerase chain reaction experiments showed that the amount of Fusarium oxysporum DNA associated with the XH-9 strain after treatment significantly decreased compared with control group. Accordingly, wheat plants inoculated with the XH-9 strain showed significant increases in the plant shoot heights (14.20%), root lengths (32.25%), dry biomass levels (11.93%), and fresh biomass levels (16.28%) relative to the un-inoculated plants. The results obtained in this study suggest that the XH-9 strain has potential as plant-growth promoter and biocontrol agent when applied in local arable land to prevent damage caused by F. oxysporum and other phytopathogens.\n\nImportancePlant diseases, particularly soilborne pathogens, play a significant role in the destruction of agricultural resources. Although these diseases can be controlled to some extent with crop and fungicides, while these measures increase the cost of production, promote resistance, and lead to environmental contamination, so they are being phased out. Plant growth-promoting rhizobacteria are an alternative to chemical pesticides that can play a key role in crop production by means of siderophore and indole-3-acetic acid production, antagonism to soilborne root pathogens, phosphate and potassium solubilization, and nitrogen fixation. These rhizobacteria can also promote a beneficial change in the microorganism community by significantly reducing its pathogenic fungi component. Their use is fully in accord with the principles of sustainability.

microbiology↗

bioRxiv2018

Super-resolution tracking of mitochondrial dynamics with a third-row transition metal complex dye

Combining luminescent transition metal complex (LTMC) with super-resolution microscopy is an excellent strategy for the long-term visualization of the dynamics of subcellular structures in living cells. However, it remains unclear whether iridium(III) complexes are applicable for a particular type of super-resolution technique, structured illumination microscopy (SIM), to image subcellular structures.\n\nAs described herein, we developed an iridium(III) dye, to track mitochondrial dynamics in living cells under SIM. The dye demonstrated excellent specificity and photostability and satisfactory cell permeability. While using SIM to image mitochondria, we achieved an approximately 80-nm resolution that allowed the clear observation of the structure of mitochondrial cristae. We used the dye to monitor and quantify mitochondrial dynamics relative to lysosomes, including fusion involved in mitophagy, and newly discovered mitochondria-lysosome contact (MLC) under different conditions. MLC remained intact and fusion vanished when five receptors, p62, NDP52, OPTN, NBR1, and TAX1BP1, were knocked out, suggesting that these two processes are independence.

biophysics↗

bioRxiv2018

Ankyrin-G Regulates Forebrain Connectivity and Network Synchronization via Interaction with GABARAP

GABAergic circuits are critical for the synchronization and higher order function of brain networks, and defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons where it interacts directly with the GABAO_SCPCAPAC_SCPCAP receptor associated protein (GABARAP) to stabilize cell surface GABAO_SCPCAPAC_SCPCAP receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

neuroscience↗

bioRxiv2018

H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development

Histone H3K4 mono-methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. To address MLL3/4 enzymatic activity in enhancer regulation, we have generated two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domains. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and prevents adipogenesis and adipose tissue development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases. Notably, deletion of the enzymatic SET domain of MLL3/4 in lineage-specific precursor cells mimics H3.3K4M expression and prevents adipose tissue development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and function. Together, our findings indicate that H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development.

molecular biology↗