Biology subjects

Wu, Y.

Publications and source records attributed to Wu, Y..

At least 1,009 records · Page 56Linked to original sources

bioRxiv2019

Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid

SOX2 has been viewed as a critical oncoprotein in osteosarcoma. Emerging evidence show that inducing the degradation of transcription factors such as SOX2 is a promising strategy to make them druggable. Here, we show that neogambogic acid (NGA), an active ingredients in garcinia, significantly inhibited the proliferation of osteosarcoma cells with ubiquitin proteasome-mediated degradation of SOX2 in vitro and in vivo. We further identified USP9x as a bona fide deubiquitinase for SOX2 and NGA directly interacts with USP9x in cells. Moreover, knockdown of USP9x inhibited the proliferation and colony formation of osteosarcoma cells, which could be rescued by overexpression of SOX2. Consistent with this, knockdown of USP9x inhibited the proliferation of osteosarcoma cells in a xenograft mouse model. Collectively, we identify USP9x as the first deubiquitinating enzyme for controlling the stability of SOX2 and USP9x is a direct target for NGA. We propose that targeting the USP9x/SOX2 axis represents a novel strategy for the therapeutic of osteosarcoma and other SOX2 related cancers.

cancer biology↗

bioRxiv2019

An actin nucleation complex catalyzes filament formation at sites of exocytosis

Due to the local enrichment of factors that influence its formation, dynamics, and organization, the actin cytoskeleton displays different shapes and functions within the same cell. In yeast cells post-Golgi vesicles ride on long actin cables to the bud tip. The scaffold proteins Boi1 and Boi2 participate in tethering and docking these vesicles to the plasma membrane. Here we show that Boi1/2 also recruit nucleation and elongation factors to form actin filaments at sites of exocytosis. Disrupting the physical connection between Boi1/2 and the nucleation factor Bud6 impairs filament formation in the bud, reduces the directed movement of the vesicles to the tip, and shortens their tethering time at the cortex. Artificially transplanting Boi1 from the bud tip to the peroxisomal membrane partially redirects the actin cytoskeleton and the vesicular flow towards the peroxisome, and creates an alternative, rudimentary vesicle-docking zone. We conclude that Boi1/2 is sufficient to induce the formation of a cortical actin structure that receives and aligns incoming vesicles before fusing with the membrane.

cell biology↗

bioRxiv2019

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

BackgroundCombining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP.\n\nMethodsA multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used represent three different phenotypes: responders, partial-responders, and non-responders.\n\nResultsThe multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8+ T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8+ T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders.\n\nConclusionsOverall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.

pharmacology and toxicology↗

bioRxiv2019

Recombinase system-dependent copackaging strategy for highly efficient neurocircuit tracing

Mapping the detailed cell-type-specific input networks and neuronal projectomes are essential to understand brain function in normal and pathological states. However, several properties of current tracing systems, including labeling sensitivity, trans-synaptic efficiencies, reproducibility among different individuals and different Cre-driver animals, still remained unsatisfactory. Here, we developed MAP-ENVIVIDERS, a recombinase system-dependent vector mixing-based strategy for highly efficient neurocircuit tracing. MAP-ENVIVIDERS enhanced tracing efficiency of input networks across the whole brain, with over 10-fold improvement in diverse previously poor-labeled input brain regions and particularly, up to 70-fold enhancement in brainstem compared with the current standard rabies-virus-mediated systems. MAP-ENVIVIDERS was over 10-fold more sensitive for cell-type-specific labeling than previous strategies, enabling us to capture individual cell-type-specific neurons with extremely complex axonal branches and presynaptic axonal boutons, both about one order of magnitude than previously reported and considered. MAP-ENVIVIDERS provides powerful tools for deconstructing novel input/output circuitry towards functional studies and disorders-related mechanisms.

neuroscience↗

bioRxiv2019

Enhancing single-cell cellular state inference by incorporating molecular network features

In biological systems, genes function in conjunction rather than in isolation. However, traditional single-cell RNA-seq (scRNA-seq) analyses heavily rely on the transcriptional similarity of individual genes, ignoring the inherent gene-gene interactions. Here, we present SCORE, a network-based method, which incorporates the validated molecular network features to infer cellular states. Using real scRNA-seq datasets, SCORE outperforms existing methods in accuracy, robustness, scalability, data integration and removal of batch effect. When applying SCORE to a newly generated human ileal scRNA-seq dataset, we identified several novel stem/progenitor clusters, including a Cripto-1+ cluster. Moreover, two distinct groups of goblet cells were identified and only one of them tended to secrete mucus. Besides, we found that the recently identified BEST4+OTOP2+ microfold cells also highly expressed CFTR, which is different from their colonic counterparts. In summary, SCORE enhances cellular state inference by simulating the dynamic changes of molecular networks, providing more biological insights beyond statistical interpretations.

bioinformatics↗

bioRxiv2019

Modular Thermal Control of Protein Dimerization

Protein-protein interactions and protein localization are essential mechanisms of cellular signal transduction. The ability to externally control such interactions using chemical and optogenetic methods has facilitated biological research and provided components for the engineering of cell-based therapies and materials. However, chemical and optical methods are limited in their ability to provide spatiotemporal specificity in light-scattering tissues. To overcome these limitations, we present \"thermomers,\" modular protein dimerization domains controlled with temperature - a form of energy that can be delivered to cells both globally and locally in a wide variety of in vitro and in vivo contexts. Thermomers are based on a sharply thermolabile coiled-coil protein, which we engineered to heterodimerize at a tunable transition temperature within the biocompatible range of 37-42 {degrees}C. When fused to other proteins, thermomers can reversibly control their association, as demonstrated via membrane localization in mammalian cells. This technology enables remote control of intracellular protein-protein interactions with a form of energy that can be delivered with spatiotemporal precision in a wide range of biological, therapeutic and living material scenarios.

synthetic biology↗

bioRxiv2019

Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a mechanically activated (MA) ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modelled variants results in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after four years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.

genomics↗

bioRxiv2019

Development of equations for converting random-zero to automated oscillometric blood pressure values

ObjectiveThis study aimed to collect data to compare blood pressure values between random-zero sphygmomanometers and automated oscillometric devices and generate equations to convert blood pressure values from one device to the other.\n\nMethodsOmron HEM-907, a widely used automated oscillometric device in many epidemiologic surveys and cohort studies, was compared here with random-zero sphygmomanometers. Two hundred and one participants aged 40-79 years (37% men) were enrolled and randomly assigned to one of two groups with blood pressure measurement first taken by automated oscillometric devices or by random-zero sphygmomanometers. The study design enabled comparisons of blood pressure values between random-zero sphygmomanometers and two modes of this automated oscillometric device - automated and manual, and assessment of effects of measurement order on blood pressure values.\n\nResultsAmong all participants, mean blood pressure levels were lowest when measured with random-zero sphygmomanometers compared with both modes of automated oscillometric devices. Several variables, including age and gender, were found to contribute to the blood pressure differences between random-zero sphygmomanometers and automated oscillometric devices. Equations were developed using multiple linear regression after taking those variables into account to convert blood pressure values by random-zero sphygmomanometers to automated oscillometric devices.\n\nConclusionEquations developed in this study could be used to compare blood pressure values between epidemiologic and clinical studies or identify shift of blood pressure distribution over time using different devices for blood pressure measurements.

epidemiology↗

bioRxiv2019

Estimation of the force of infection and infectious period of skin sores in remote Australian communities using interval-censored data

Prevalence of impetigo (skin sores) remains high in remote Australian Aboriginal communities, Fiji, and other areas of socio-economic disadvantage. Skin sore infections, driven primarily in these settings by Group A Streptococcus (GAS) contribute substantially to the disease burden in these areas. Despite this, estimates for the force of infection, infectious period and basic reproductive ratio -- all necessary for the construction of dynamic transmission models -- have not been obtained. By utilising three datasets each containing longitudinal infection information on individuals, we estimate each of these epidemiologically important parameters. With an eye to future study design, we also quantify the optimal sampling intervals for obtaining information about these parameters. We verify the estimation method through a simulation estimation study, and test each dataset to ensure suitability to the estimation method. We find that the force of infection differs by population prevalence, and the infectious period is estimated to be between 12 and 20 days. We also find that optimal sampling interval depends on setting, with an optimal sampling interval between 9 and 11 days in a high prevalence setting, and 21 and 27 days for a lower prevalence setting. These estimates unlock future model-based investigations on the transmission dynamics of GAS and skin sores.

epidemiology↗

bioRxiv2019

Interpretable Multimodality Embedding of Cerebral Cortex Using Attention Graph Network for Identifying Bipolar Disorder

Bipolar Disorder (BP) is a mental disorder that affects 1 [~] 2% of the population. Early diagnosis and targeted treatment can benefit from associated biological markers. The existing methods typically utilize biomarkers from anatomical MRI or functional BOLD imaging, but lack the ability of revealing the relationship between integrated modalities and disease. In this paper, we developed an Edge-weighted Graph Attention Network (EGAT) with Dense Hierarchical Pooling (DHP), to better understand the underlying roots of the disorder from the view of structure-function integration. For the input, the underlying graphs are constructed from functional connectivity matrices and the nodal features consist of both the anatomical features and the statistics of the connectivity. We investigated the potential benefits of using EGAT to classify BP vs. Healthy Control (HC). Compared with traditional machine learning classifiers, our proposed EGAT embedding increased improved 10 [~] 20% in the accuracy and F1-score, compared with alternative classifiers. More specifically, by examining the attention map and gradient sensitivity of nodal features, we indicated that associated with the abnormality of anatomical geometric properties, multiple interactive patterns among Default Mode, Fronto-parietal and Cingulo-opercular networks contribute to identifying BP.

neuroscience↗

bioRxiv2019

Metagenomic Next-generation Sequencing of Cerebrospinal Fluid for the Diagnosis of Central Nervous System Infections: A Multicentre Prospective Study

BackgroundInfectious encephalitis and meningitis are often treated empirically without identification of the causative pathogen. Metagenomic next-generation sequencing (mNGS) is a high throughput technology that enables the detection of pathogens independent of prior clinical or laboratory information.\n\nMethodsThe present study was a multicentre prospective evaluation of mNGS of cerebrospinal fluid (CSF) for the diagnosis of suspected central nervous system infections.\n\nResultsA total of 276 patients were enrolled in this study between Jan 1, 2017 and Jan 1, 2018. Identification of an etiologic pathogen in CSF by mNGS was achieved in 101 patients (36.6%). mNGS detected 11 bacterial species, 7 viral species, 2 fungal species, and 2 parasitic species. The five leading positive detections were varicella-zoster virus (17), Mycobacterium tuberculosis (14), herpes simplex virus 1 (12), Epstein-Barr virus (12), and Cryptococcus neoformans (7). False positives occurred in 12 (4.3%) patients with bacterial infections known to be widespread in hospital environments. False negatives occurred in 16 (5.8%) patients and included bacterial, viral and fungal aetiologies.\n\nConclusionsmNGS of CSF is a powerful diagnostic method to identify the pathogen for many central nervous system infections.

genomics↗

bioRxiv2019

Screening and functional analysis of differentially expressed genes in an animal model of EBV-associated lymphomas

Epstein-Barr virus (EBV) is an important human oncogenic virus. This paper is to explore how EBV induce malignant transformation of human lymphocytes and the related mechanism of lymphomagenesis. We have constructed hu-PBL/SCID chimeric mice and established a model of EBV-associated human-derived lymphomas. By using Agilent human whole genome microarray and a series of bioinformatic analyses, a total of 202 differentially expressed genes were screened from the EBV-induced lymphomas in hu-PBL/SCID mice, including 44 up-regulated and 158 down-regulated genes. Calculation of the rank score (RS) values of these genes in the HIPPIE protein interaction networks showed that topoisomerase II alpha (TOP2A), ubiquitin like with PHD and ring finger domains 1 (UHRF1), histone cluster 2 H2B family member E (HIST2H2BE), phosphoglycerate dehydrogenase (PHGDH), vinculin (VCL), insulin-like growth factor 1 receptor (IGF1R), Fos proto-oncogene (FOS), snail family transcriptional repressor 1 (SNAI1), PDZ binding kinase (PBK), and ring finger protein 144B (RNF144B) were the top 10 key node genes of EBV-induced lymphoma. In which, PBK, an up-regulated genes with the highest number of GO annotations, was verified by cellular function experiments and clinical lymphoma samples.\n\nAuthor summaryEB virus is closely associated with human lymphoma and nasopharyngeal carcinoma. Since the susceptible hosts of EBV limit to human and cottontop tammarins, there are no appropriate animal models so far to study the EBV-associated oncogenesis. In our previous experiments, the EBV-associated lymphomas were induced in hu-PBL/SCID chimera (a new humanized mouse model). However, the cellular and molecular mechanisms of malignant transformation of normal human cells and tumor formation induced by EBV remain unclear. In this study, we examined and compared the gene expression profiles of EBV-induced lymphomas and normal human lymphocytes of the same origin in SCID mice. By constructing the gene-function relationship network, we preliminarily found that TOP2A, UHRF1, HIST2H2BE, PHGDH, VCL, IGF1R, FOS, SNAI1, PBK, and RNF144B may be the key genes in EBV-induced lymphomas. These findings suggest that the induction of lymphoma by EBV is a complex process that involves multiple genes and pathways.

cancer biology↗

bioRxiv2019

Accelerating iterative deconvolution and multiview fusion by orders of magnitude

We describe theoretical and practical advances in algorithm and software design, resulting in ten to several thousand-fold faster deconvolution and multiview fusion than previous methods. First, we adapt methods from medical imaging, showing that an unmatched back projector accelerates Richardson-Lucy deconvolution by at least 10-fold, in most cases requiring only a single iteration. Second, we show that improvements in 3D image-based registration with GPU processing result in speedups of 10-100-fold over CPU processing. Third, we show that deep learning can provide further accelerations, particularly for deconvolution with a spatially varying point spread function. We illustrate the power of our methods from the subcellular to millimeter spatial scale, on diverse samples including single cells, nematode and zebrafish embryos, and cleared mouse tissue. Finally, we show that our methods facilitate the use of new microscopes that improve spatial resolution, including dual-view cleared tissue light-sheet microscopy and reflective lattice light-sheet microscopy.

bioengineering↗

bioRxiv2019

Infection-driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis

Transglutaminase 2 (TG2) is a ubiquitous enzyme with transamidating activity. We report here that the expression and activity of TG2 are enhanced in cells infected with the obligate intracellular bacteria Chlamydia trachomatis. Genetic or pharmacological inhibition of TG2 activity impair bacterial development. We show that TG2 increases glucose import by up-regulating the transcription of the glucose transporter genes GLUT-1 and GLUT-3. Furthermore, TG2 activation drives one specific glucose-dependent pathway in the host, i.e. hexosamine biosynthesis. Mechanistically, we identify the glucosamine:fructose-6-phosphate amidotransferase (GFPT) among the substrates of TG2. GFPT modification by TG2 increases its enzymatic activity, resulting in higher levels of UDP-N-acetylglucosamine biosynthesis. As a consequence, TG2 activation results in increased protein O-GlcNAcylation. The correlation between TG2 transamidating activity and O-GlcNAcylation is disrupted in infected cells because host hexosamine biosynthesis is being exploited by the bacteria, in particular to assist their division. In conclusion, our work establishes TG2 as a key player in controlling glucose-derived metabolic pathways in mammalian cells, themselves hijacked by C. trachomatis to sustain their own metabolic needs.

microbiology↗

bioRxiv2019

Intron-targeted mutagenesis reveals roles for Dscam1 RNA pairing-mediated splicing bias in neuronal wiring

Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam1) can potentially generate 38,016 different isoforms through stochastic, yet highly biased, alternative splicing. Genetic studies demonstrated that stochastic expression of multiple Dscam1 isoforms provides each neuron with a unique identity for self/non-self-discrimination. However, due to technical obstacles, the functional significance of the highly specific bias in isoform expression remains entirely unknown. Here, we provide conclusive evidence that Dscam1 splicing bias is required for precise mushroom body (MB) axonal wiring in flies in a variable exon-specific manner. We showed that targeted deletion of the intronic docking site perturbed base pairing-mediated regulation of inclusion of variable exons. Unexpectedly, we generated mutant flies with normal overall Dscam1 protein levels and an identical number but global changes in exon 4 and exon 9 isoform bias (Dscam{Delta}4D-/- and Dscam{Delta}9D-/-), respectively. Dscam{Delta}9D-/- mutant exhibited remarkable mushroom body defects, which were correlated with the extent of the disrupted isoform bias. By contrast, the Dscam{Delta}4D-/- animals exhibited a much less severe defective phenotype than Dscam{Delta}9D-/- animals, suggestive of a variable domain-specific requirement for isoform bias. Importantly, mosaic analysis revealed that changes in isoform bias caused axonal defects but did not influence the self-avoidance of axonal branches. We concluded that, in contrast to the Dscam1 isoform number that provides the molecular basis for neurite self-avoidance, isoform bias may play a non-repulsive role in mushroom body axonal wiring.

molecular biology↗

bioRxiv2019

Phenological matching drives wheat pest range shift under climate change

Shifting geographical ranges of crop pests and pathogens in response to climate change pose a threat to food security (1, 2). The orange wheat blossom midge (Sitodiplosis mosellana Gehin) is responsible for significant yield losses in China (3), the worlds largest wheat producer. Here we report that rising temperatures in the North China Plain have resulted in a mean northward range shift of 3.3{degrees} (58.8 km per decade) from the 1950s to 2010s, which accelerated to 91.3 km per decade after 1985 when the highly toxic pesticide hexachlorocyclohexane (HCH) was banned (4). Phenological matching between wheat midge adult emergence and wheat heading in this new expanded range has resulted in greater damage to wheat production. Around $286.5 million worth of insecticides were applied to around 19 million hectares in an attempt to minimize wheat midge damage to crops between 1985 and 2016. Despite use of these pesticides, wheat midge caused losses of greater than 0.95 million metric tons of grain during this period. Our results demonstrate the potential for indirect negative impacts of climate change on crop production and food security, and constitute the first large scale example of plant pest range shift due to global warming.

ecology↗

bioRxiv2019

N-Glycome regulation limits the transdifferentiation of endothelial cells into hematopoietic stem cells

Hematopoietic stem and progenitor cells (HSPCs) that establish and maintain the blood system in adult vertebrates arise from the transdifferentiation of hemogenic endothelial cells (hemECs) during embryogenesis. This endothelial-to-hematopoietic transition (EHT) is tightly regulated, but the mechanisms are poorly understood. Here, we show that microRNA (miR)-223-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. Single cell RNA-sequencing revealed that miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid/myeloid lineages by suppressing the expression of mannosyltransferase alg2 and sialyltransferase st3gal2, two enzymes involved in N-linked protein glycosylation. High-throughput glycomics of ECs lacking miR-223 showed a decrease of high mannose versus sialylated complex/hybrid sugars on N-glycoproteins involved in EHT such as the metalloprotease Adam10. Endothelial-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied the aberrant HSPC production of miR-223 mutants. Thus, the N-glycome plays a previously unappreciated role as an intrinsic regulator of EHT, with specific mannose and sialic acid modifications serving as key endothelial determinants of their hematopoietic fate. One Sentence SummaryThe N-glycan "sugar code" governs the hematopoietic fate of endothelial cells and regulates blood stem cell production in vivo.

developmental biology↗

bioRxiv2019

iRhom2 serves as a facilitator in obesity by enhancing adipose inflammation and insulin resistance

Chronic inflammation of adipose tissues contributes to obesity-triggered insulin resistance. Unfortunately, the potential molecular mechanisms regarding obesity associated systemic inflammation and metabolic disorder remain complicated. Here we display that inactive rhomboid-like protein 2 (iRhom2) is increased in mice fat with adipose inflammation. After 16 weeks on a high fat diet (HFD), obesity, chronic inflammation in adipose tissues and insulin resistance are markedly mitigated in iRhom2-knockout (iRhom2 KO) mice, but exaggerated in iRhom2-overactivated mice. The adverse impressions of iRhom2 on adipose inflammation and associated pathologies are determined in db/db mice. Also, we further exhibit that in response to HFD, iRhom2 KO mice and mice with deletion only in myeloid cells showed less severe adipose inflammation and insulin resistance than the control groups. Conversely, transplantation of bone marrow cells from normal mice to iRhom2 KO mice unleashed the severity of systemic inflammation and metabolic dysfunction after HFD ingestion. In conclusion, we identify iRhom2 as a key regulator that promotes obesity-associated metabolic disorder. Loss of iRhom2 from macrophages in adipose tissues inhibited the inflammation and insulin resistance. iRhom2 might be a therapeutic target for obesity-induced metabolic dysfunction.\n\nSignificanceIncreased inactive rhomboid-like protein 2 signaling has recently been shown to trigger inflammation-associated activation of innate immune responses. Herein we investigate that this signal also plays a crucial role in obesity-triggered adipose tissue inflammation infiltration and metabolic disorder, beyond the well-known assignment in innate immune supervision. Also, we have reported the iRhom2 as a key promoter in regulating metabolic function, which enhances obesity-stimulated inflammation and systemic insulin resistance by up regulation of macrophages pro-inflammatory activation. Our current study indicates that targeting the iRhom2 signaling in adipose tissues could possibly be an efficient strategy to mitigating obesity-associated systemic inflammation and metabolic dysfunction.

pathology↗