Biology subjects

Rong, Y.

Publications and source records attributed to Rong, Y..

31 records · Page 2Linked to original sources

bioRxiv2021

TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells

TMEM120A, a member of the Transmembrane protein 120 (TMEM120) family, has pivotal function in adipocyte differentiation and metabolism, and may also contribute to sensing mechanical pain by functioning as an ion channel named TACAN. Here we report that expression of TMEM120A is not sufficient in mediating poking- or stretch-induced currents in cells, and have solved cryo-EM structures of human TMEM120A (HsTMEM120A) in complex with an endogenous metabolic cofactor (coenzyme A, CoASH) and in the apo form. HsTMEM120A forms a symmetrical homodimer with each monomer containing an amino-terminal coiled-coil motif followed by a transmembrane domain with six membrane-spanning helices. Within the transmembrane domain, a CoASH molecule is hosted in a deep cavity and forms specific interactions with nearby amino acid residues. Mutation of a central tryptophan residue involved in binding CoASH dramatically reduced the binding affinity of HsTMEM120A with CoASH. HsTMEM120A exhibits distinct conformations at the states with or without CoASH bound. Our results suggest that TMEM120A may have alternative functional roles potentially involved in CoASH transport, sensing or metabolism.

biophysics↗

bioRxiv2021

Multi-domain touchscreen-based cognitive assessment of C57BL/6J female mice shows whole body exposure to 56Fe particle space radiation in maturity improves discrimination learning yet impairs stimulus-response habit learning

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Preclinical studies with mature, "astronaut-aged" rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As other preclinical work suggests the female rodent brain may be relatively resistant to charged particle-induced injury, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to whole-body 56Fe irradiation (3 x 6.7cGy 56Fe over 5 days, 600MeV/n) would improve performance vs.Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function (e.g. location discrimination reversal [LDR] and extinction, respectively). In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal rule-based learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASAs risk assessments from being based on a single cognitive domain.

animal behavior and cognition↗

bioRxiv2021

Brain image-derived phenotypes yield insights into causal risk of psychiatric disorders using a Mendelian randomization study

Brain imaging-derived phenotypes (IDPs) serve as underlying functional intermediates in psychiatric disorders, both of which are highly polygenic and heritable. Observational studies have elucidated the correlation between IDPs and psychiatric disorders, yet no systematic screening of IDPs to confer the causal liability in such disorders. We conducted a bidirectional two-sample Mendelian randomization framework to explore the causality of 1,901 IDPs on 10 psychiatric disorders and established the BrainMR database (http://brainmr.online/idp2psy/Index.php). We identified 17 causalities in forward MR analyses and 14 causalities in reverse MR analyses, which all rigorously examined them through various sensitivity analyses. The top significant relationship in forward was a unit lower volume of right central lateral of the thalamic nuclei, which was causally associated with an increased anorexia nervosa risk with an estimated OR of 0.52 (95% CI 0.41-0.64, P = 3.32 x 10-9). In reverse, the top significant IDP to be affected was the area of superior segment of the circular sulcus of the insula in the right hemisphere, which was increased by the reason of SCZ risk with an estimated association effect size of 0.068 (95% CI 0.046-0.090, P = 1.12 x 10-6). Overall, our study provides unique insights into causal pathways of psychiatric disorders at the imaging levels.

neuroscience↗

bioRxiv2021

Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

Polycomb group (PcG) proteins are crucial chromatin regulators during development. H2Aub and H3K27me3 are catalyzed by Polycomb-repressive Complex 1 and 2 (PRC1/2) respectively, and largely overlap in the genome due to mutual recruitment of the two complexes. However, whether PRC1/H2Aub and PRC2/H3K27me3 can function independently remains obscure. Here we uncovered a genome-wide decoupling of H2Aub and H3K27me3 in preimplantation mouse embryos, at both canonical PcG targets and broad distal domains. H2Aub represses future bivalent genes without H3K27me3 but does not contribute to maintenance of H3K27me3-dependent non-canonical imprinting. Our study thus revealed their distinct and independent functions in early mammalian development.

molecular biology↗

bioRxiv2020

Phenome-wide investigation of the causal associations between childhood BMI and adult outcomes: A two-sample Mendelian randomization study

BackgroundCompelling observational studies have reported that childhood obesity is associated with the risk of many complex diseases in adulthood. However, results from observational studies are unable to fully account for confounding factors. The causal effects of childhood obesity have not been systematically characterized. We aimed to assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR). Methods and findingsOver 5,000 datasets for adult outcomes were obtained from various resources. After data filtering, 269 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. The number of independent outcomes was 148, setting the significant threshold as P < 3.38 x 10-4. Inverse-variance weighted method, MR-Egger, weighted median method, and weighted mode method were used to estimate the causal effects. We identified potential causal effects of childhood obesity on 60 adult traits (27 disease-related traits, 27 lifestyle factors, and 6 other traits). Higher childhood BMI was associated with a reduced overall health rating ({beta} = -0.10, 95% CI: -0.13 to -0.07, P = 6.26 x 10-11). Findings on diseases included some novel effects, such as the adverse effects of higher childhood BMI on cholelithiasis (OR = 1.26, 95% CI: 1.18 to 1.35, P = 3.29 x 10-5). For dietary habits, we found that higher childhood BMI was positively associated adult diet portion size ({beta} = 0.26, 95% CI: 0.18 to 0.34, P = 7.34 x 10-11). Different from the conventional impression, our results showed that higher childhood BMI was positively associated with low calorie density food intake. With 76 adult BMI single-nucleotide polymorphisms (SNPs) as instruments, we confirmed that adulthood BMI was positively associated with heel bone mineral density. However, the association no longer present after excluding the SNPs existing in or in linkage disequilibrium (LD) with childhood BMI. Network MR analyses suggested that past tobacco smoking and portion size mediated 6.39% and 10.90% of the associations between childhood BMI and type 2 diabetes, respectively. The main study limitation is that it is difficult to tease out the independent effects of childhood BMI due to the strong correlation between childhood and adulthood BMI. ConclusionsIn summary, we provided a phenome-wide view of the effects of childhood BMI on adult traits. Our results highlight the need to intervene in childhood to reduce obesity from a young age and its later-life effects. Author summaryWhy was this study done? O_LIChildhood obesity is a worldwide public health problem. The prevalence has increased at an alarming rate. C_LIO_LIObservational epidemiological studies have reported that childhood obesity is associated with the risk of many complex diseases in adulthood, such as coronary artery disease (CAD) and diabetes. However, observational studies are limited in explaining causality because of possible bias from unmeasured confounding factors. C_LI What did the researchers do and find? O_LIA Mendelian randomization (MR) approach was used to provide a phenome-wide view of the causal associations between childhood BMI and adult outcomes. Potential causal effects of childhood obesity on 60 adult traits were identified. C_LIO_LIHigher childhood BMI was associated with reduced overall health rating, and caused increased risk of some diseases, such as cholelithiasis, hypothyroidism, CAD, and type 2 diabetes (T2D). In contrast, childhood BMI was positively associated with adult heel bone mineral density and low calorie density food intake. C_LIO_LIPortion size and smoking behavior might mediate the association between childhood BMI and T2D risk. C_LI What do these findings mean? O_LIOur results highlight the importance to address rising childhood obesity prevalence rate and early interventions on obesity might help to promote health equity in later life. C_LI

genetics↗

bioRxiv2020

3D chromatin organization changes modulate adipogenesis and osteogenesis

Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated RNA-seq, histone modification ChIP-seq and ATAC-seq data for integrative analysis before and after differentiation. We quantitatively identified differential contact loops and unique loops. After integrating with multi-omics data, we demonstrate that strengthened loops after differentiation are associated with gene expression activation. Specially, unique loops are linked with cell fate determination. We also proposed loop-mediated regulatory networks and identified IRS2 and RUNX2 as being activated by cell-specific loops to facilitate adipocytes and osteoblasts commitment, respectively. These results are expected to help better understand the long-range regulation in controlling hMSC differentiation, and provide novel targets for studying adipocytes and osteoblasts determination.

genetics↗

bioRxiv2020

Molecular Graph Enhanced Transformer for Retrosynthesis Prediction

With massive possible synthetic routes in chemistry, retrosynthesis prediction is still a challenge for researchers. Recently, retrosynthesis prediction is formulated as a Machine Translation (MT) task. Namely, since each molecule can be represented as a Simplified Molecular-Input Line-Entry System (SMILES) string, the process of retrosynthesis is analogized to a process of language translation from the product to reactants. However, the MT models that applied on SMILES data usually ignore the information of natural atomic connections and the topology of molecules. To make more chemically plausible constrains on the atom representation learning for better performance, in this paper, we propose a Graph Enhanced Transformer (GET) framework, which adopts both the sequential and graphical information of molecules. Four different GET designs are proposed, which fuse the SMILES representations with atom embeddings learned from our improved Graph Neural Network (GNN). Empirical results show that our model significantly outperforms the vanilla Transformer model in test accuracy.

bioinformatics↗

bioRxiv2019

In Vitro Platform Establishes Antigen-Specific CD8+ T Cell Cytotoxicity to Encapsulated Cells via Indirect Antigen Recognition

Cell replacement therapy has the potential to cure diseases caused by the absence or malfunction of specialized cells. A substantial impediment to the success of any non-autologous cellular transplant is the need for systemic immunosuppressive drugs to prevent host-mediated rejection of the foreign cells. Cellular encapsulation, i.e., the entrapment of cells within stable polymeric hydrogels, has been clinically explored to prevent host immune recognition and attack, but the efficacy of these encapsulated grafts is poor. While several studies have explored improvements in innate immune acceptance of these encapsulated cells, little attention has been paid to the roles of adaptive immune responses, specifically graft-targeting T cell activation, in graft destabilization. Herein, we established an efficient, single-antigen in vitro platform capable of delineating direct and indirect host T cell recognition to microencapsulated cellular grafts and evaluating their consequential impacts. Using alginate as the model hydrogel, encapsulated membrane-bound ovalbumin (mOVA) stimulator cells were incubated with antigen-specific OTI lymphocytes and subsequent OVA-specific CD8+ T cell activation and effector function were quantified. We established that alginate microencapsulation abrogates direct T cell activation by interrupting donor-host interaction; however, indirect T cell activation mediated by host antigen presenting cells (APCs) primed with shed donor antigens still occurs. These activated T cells imparted cytotoxicity on the encapsulated cells, likely via diffusion of cytotoxic solutes. Overall, this platform delivers unique mechanistic insight into the impacts of hydrogel encapsulation on host adaptive immune responses, as well as a tool for the efficient immune screening on new encapsulation methods and/or synergistic immunomodulatory agents.

bioengineering↗

bioRxiv2019

An allele-specific functional SNP associated with two autoimmune diseases modulates IRF5 expression by long-range chromatin loop formation

Both Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies (GWASs) have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through combining fine-mapping and functional epigenomic analyses, we prioritized a potential independent functional SNP (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element. Functional analysis integrating expression quantitative trait locus (eQTL) and high-throughput chromatin interaction (Hi-C) demonstrated that IRF5 is the distal target gene (~118kb) of rs13239597, which is a key regulator of pathogenic autoantibody dysregulation increased risk of both SLE and SSc. We experimentally validated the long-range chromatin interactions between rs13239597 and IRF5 using chromosome conformation capture (3C) assay. We further demonstrated that rs13239597-A acted as an allele-specific enhancer regulating IRF5 expression, independently of TNPO3 by using dual-luciferase reporter assays and CRISPR-Cas9. Particularly, the transcription factor EVI1 could preferentially bind to rs13239597-A allele and increase the enhancer activity to regulate IRF5 expression. Taken together, our results uncovered the mechanistic insight connecting between a noncoding functional variant with a distal immunologically pathogenic gene IRF5, which might obligate in understanding the complex genetic architectures of SLE and SSc pathogenesis.

genetics↗

bioRxiv2018

Humanized Monoclonal Antibody Rescues Rhesus macaques from Aerosolized Ricin Toxin Exposure

Ricin toxin (RT) ranks at the top of the list of potential bioweapons of concern to civilian and military personnel alike due to its high potential for morbidity and mortality after inhalation. In non-human primates, aerosolized ricin triggers a severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and severe necrotizing bronchiolitis and alveolitis. There are currently no approved countermeasures for ricin intoxication. In this report, we demonstrate the therapeutic potential of huPB10, a toxin-neutralizing humanized monoclonal antibody (MAb) against an immunodominant epitope on ricins enzymatic A chain (RTA). Five rhesus macaques that received intravenous huPB10 (10 mg/kg) four hours after lethal dose ricin aerosol exposure all survived the toxin challenge, as compared to control animals, which succumbed to ricin intoxication within 30 h. Antibody treatment at 12 h after ricin exposure resulted in the survival of only one of five monkeys, indicating that, in the majority of animals, ricin intoxication and local tissue damage had progressed beyond the point where huPB10 intervention was beneficial. Change in pro-inflammatory cytokine/chemokines levels in bronchial alveolar lavage fluids before and after toxin challenge successfully clustered monkeys based on survival, as well as treatment group. IL-6 was the most apparent marker of ricin intoxication. This study represents the first demonstration in nonhuman primates that the lethal effects of inhalational ricin exposure can be negated by a drug candidate and opens up a path forward for product development.

immunology↗

bioRxiv2018

Modeling circRNAs expression pattern with integrated sequence and epigenetic features identifies H3K79me2 as regulators for circRNAs expression

Circular RNAs (circRNAs) are an abundant class of noncoding RNAs with widespread, cell/tissue specific pattern. Because of their involvement in the pathogenesis of multiple disease, they are receiving increasing attention. Previous work suggested that epigenetic features might be related to circRNA expression. However, current algorithms for circRNAs prediction neglect these features, leading to constant results across different cells.\n\nHere we built a machine learning framework named CIRCScan, to predict expression status and expression levels of circRNAs in various cell lines based on sequence and epigenetic features. Both expression status and expression levels can be accurately predicted by different groups of features. For expression status, the top features were similar in different cells. However, the top features for predicting expression levels were different in different cells. Noteworthy, the importance of H3K79me2 ranked high in predicting both circRNAs expression status and levels across different cells, indicating its important role in regulating circRNAs expression. Further validation experiment in K562 confirmed that knock down of H3K79me2 did result in reduction of circRNA production.\n\nOur study offers new insights into the regulation of circRNAs by incorporating epigenetic features in prediction models in different cellular contexts.

bioinformatics↗

bioRxiv2018

Fine Specificity Epitope Analysis by HX-MS Identifies Contact Points on Ricin Toxin Recognized by Protective Monoclonal Antibodies

Ricin is a fast-acting protein toxin classified by the Centers for Disease Control and Prevention as a biothreat agent. In this report we describe five new mouse monoclonal antibodies (mAbs) directed against an immunodominant region, so-called epitope cluster II, on the surface of ricins ribosome-inactivating enzymatic subunit, RTA. The five mAbs were tested alongside four previously described cluster II-specific mAbs for their capacity to passively protect mice against 10 x LD50 ricin challenge by injection. Only three of the mAbs (LE4, PH12 and TB12) afforded protection over the seven-day study period. Neither binding affinity nor in vitro toxin-neutralizing activity could fully account for LE4, PH12 and TB12s potent in vivo activity relative to the other six mAbs. However, epitope mapping studies by hydrogen exchange-mass spectrometry (HX-MS) revealed that LE4, PH12 and TB12 shared common contact points (i.e., \"strong\" protection by HX-MS) on RTA that encompassed residues 154-164 and 62-69, which correspond to RTA -helices D-E and {beta}-strands d-e, respectively, located on the back side of RTA relative to the active site. The other six mAbs recognized overlapping epitopes on RTA but none shared the same HX-MS profile as LE4, PH12 and TB12. A high-density competition ELISA with a panel of ricin-specific single domain camelid antibodies (VHHs) indicated that even though LE4, PH12 and TB12 make contact with similar secondary motifs, they ultimately approach RTA different from angles. These results underscore how subtle differences in epitope specificity have significant impacts on the antibody functionality in vivo and have important implications in the design of immune-based countermeasures against ricin.

immunology↗

bioRxiv2018

TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death

Inhalation of ricin toxin is associated with the onset of acute respiratory distress syndrome (ARDS), characterized by hemorrhage, inflammatory exudates, and tissue edema, as well as the near complete destruction of the lung epithelium. Here we report that the Calu-3 human airway epithelial cell line is relatively impervious to the effects of ricin, with little evidence of cell death even upon exposure to microgram amounts of toxin. However, the addition of exogenous soluble TNF-Related Apoptosis Inducing Ligand (TRAIL; CD253) dramatically sensitized Calu-3 cells to ricin-induced apoptosis. Calu-3 cell killing in response to ricin and TRAIL was reduced upon the addition of caspase-8 and caspase-3/7 inhibitors, but not caspase 9 inhibitors, consistent with involvement of extrinsic apoptotic pathways in cell death. We employed nCounter Technology to define the transcriptional response of Calu-3 cells to ricin, TRAIL, and the combination of ricin plus TRAIL. An array of genes associated with inflammation-and cell death were significantly up regulated upon treatment with ricin toxin, and further amplified upon addition of TRAIL. Of particular note was IL-6, whose expression in Calu-3 cells increased 300-fold upon ricin treatment and more than 750-fold upon ricin and TRAIL treatment. IL-6 secretion by Calu-3 cells was confirmed by cytometric bead array. Based on these finding, we speculate that the severe airway epithelial cell damage observed in animal models following ricin exposure is a result of a positive feedback loop driven by pro-inflammatory cytokines like TRAIL and IL-6.

immunology↗