Biology subjects

Jin, Y.

Publications and source records attributed to Jin, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2020

Activation of MAP3K DLK and LZK in Purkinje Cells Causes Rapid and Slow Degeneration Depending on Signaling Strength

The conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Mkk7, strongly attenuates Purkinje cell degeneration induced by activation of LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

neuroscience↗

bioRxiv2020

The ER chaperones BiP and Grp94 regulate the formation of insulin-like growth factor 2 (IGF2) oligomers

While cytosolic Hsp70 and Hsp90 chaperones have been extensively studied, less is known about how the ER Hsp70 and Hsp90 paralogs (BiP and Grp94) recognize clients and influence their folding. Here, we examine how BiP and Grp94 influence the folding of insulin-like growth factor 2 (IGF2). Full-length proIGF2 is composed of an insulin-like hormone and an E-peptide that has sequence characteristics of an intrinsically disordered region. We find that the E-peptide region allows proIGF2 to form oligomers. BiP and Grp94 influence both the folding and the oligomerization of proIGF2. BiP and Grp94 exert a similar holdase function on proIGF2 folding by preferentially binding the proIGF2 unfolded state, rather than stabilizing specific folding intermediates and changing the proIGF2 folding process. In contrast, BiP and Grp94 exert counteracting effects on proIGF2 oligomerization. BiP suppresses proIGF2 oligomerization under both ADP and ATP conditions. Interestingly, Grp94 can enhance proIGF2 oligomerization when Grp94 adopts an open conformation (ADP conditions), but not when Grp94 is in the closed conformation (ATP conditions). We propose that BiP and Grp94 regulate the assembly of proIGF2 oligomers, and that regulated oligomerization may enable proIGF2 to be effectively packaged for export from the ER to the Golgi.

biochemistry↗

bioRxiv2020

RBM20 phosphorylation on serine/arginine domain is crucial to regulate pre-mRNA splicing and protein shuttling in the heart

Molecular and cellular mechanisms of mutations of splicing factors in heart function are not well understood. The splicing of precursor mRNA is dependent on an essential group of splicing factors containing serine-arginine (SR) domain(s) that are critical for protein-RNA and protein-protein interaction in the spliceosome assembly. Phosphorylation of SR domains plays a key role in splicing control and the distribution of splicing factors in the cell. RNA binding motif 20 (RBM20) is a splicing factor predominantly expressed in muscle tissues with the highest expression level in the heart. However, its phosphorylation status is completely unknown up-to-date. In this study, we identified sixteen amino acid residues that are phosphorylated by middle-down mass spectrometry. Four of them are located in the SR domain, and two out of the four residues, S638 and S640, play an essential role in splicing control and facilitate RBM20 shuttling from the nucleus to the cytoplasm. Re-localization of RBM20 promotes protein aggregation in the cytoplasm. We have also verified that SR-protein kinases (SRPKs), cdc2-like kinases (CLKs) and protein kinase B (PKB or AKT) phosphorylate S638 and S640. Mutations of S638A and S640G reduce RBM20 phosphorylation and disrupt the splicing. Taken together, we determine the phosphorylation status of RBM20 and provide the first evidence that phosphorylation on SR domain is crucial for pre-mRNA splicing and protein trafficking. Our findings reveal a new role of RBM20 via protein shuttling in cardiac function.

cell biology↗

bioRxiv2020

EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K/eNOS-dependent manner during inflammation

Coagulopathy is associated with both inflammation and infection, including infection with the novel SARS-CoV-2 (COVID-19). Endothelial cells (ECs) fine tune hemostasis via cAMP-mediated secretion of von Willebrand factor (vWF), which promote the process of clot formation. The exchange protein directly activated by cAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a key role in stabilizing ECs and suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized our EPAC1-null mouse model and revealed an increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1 in vitro mimicked the EPAC1-/- phenotype. EPAC1 regulated TNF-triggered vWF secretion from human umbilical vein endothelial cells (HUVECs) in a phosphoinositide 3-kinases (PI3K)/endothelial nitric oxide synthase (eNOS)-dependent manner. Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, both in vivo and in vitro. Our data delineate a novel regulatory role of EPAC1 in vWF secretion and shed light on potential development of new strategies to controlling thrombosis during inflammation. Key PointPI3K/eNOS pathway-mediated, inflammation-triggered vWF secretion is the target of the pharmacological manipulation of the cAMP-EPAC system.

cell biology↗

bioRxiv2020

Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17

After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal and distal axon degeneration were previously thought to be controlled by two distinct pathways, involving activation of the kinase DLK and loss of the axon survival factor NMNAT2, respectively. However, we found that mutual palmitoylation by the palmitoyl acyltransferase ZDHHC17 couples the DLK and NMNAT2 signals, which together form a "trust, but verify system". In healthy optic nerves, ZDHHC17-dependent palmitoylation ensures NMNAT-dependent distal axon integrity, while following ONC, ZDHHC17-dependent palmitoylation is critical for DLK-dependent somal degeneration. We found that ZDHHC17 also controls survival-versus-degeneration decisions in sensory neurons and identified motifs in NMNAT2 and DLK that govern their ZDHHC17-dependent regulation. These findings suggest that the control of somal and distal axon integrity should be considered as a single, holistic process, involving two palmitoylation-dependent pathways acting in concert.

neuroscience↗

bioRxiv2020

MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

ObjectiveAlthogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions. Methods4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs. Results2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26x10-4) and rs2620381 (miR-627, OR=0.77, P=2.55x10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0x10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0x10-5) and FDA approved drug target genes (P=0.014). Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26x10-4), rs2620381 (miR-627, P=2.55x10-3), rs4285314 (miR-3135b, P=1.10x10-13), rs28477407 (miR-4308, P=3.44x10-5), rs5997893 (miR-3928, P=5.9x10-3) and rs45596840 (miR-4482, P=6.6x10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

genetics↗

bioRxiv2020

Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency

Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Despite various genetic and epigenetic signatures are found to be related with active origins, it remains elusive how the selection of origins is determined. The classic Rosette model proposes that the origins clustered in a chromatin domain are preferentially and simultaneously fired, but direct imaging evidence has been lacking due to insufficient spatial resolution. Here, we applied dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We found that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase, in contrary to the Rosette model. Intriguingly, while both active and dormant origins are distributed homogeneously in the TAD during the G1 phase, active origins relocate to the TAD periphery before entering the S phase. We proved that such origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observed that the replication machinery protein PCNA forms immobile clusters around the TADs at the G1/S transition, which explains why origins at the TAD periphery are preferentially fired. Thus, we propose a "Chromatin Re-organization Induced Selective Initiation" (CRISI) model that the transcription-coupled chromatin structural re-organization determines the selection of replication origins, which transcends the scope of specific genetic and epigenetic signatures for origin efficiency. Our in situ super-resolution imaging unveiled coordination among DNA replication, transcription, and chromatin organization inside individual TADs, providing new insights into the biological functions of sub-domain chromatin structural dynamics.

genomics↗

bioRxiv2020

Drone phenotyping and machine learning enable discovery of loci regulating daily floral opening in lettuce

Flower opening and closure are traits of reproductive importance in all angiosperms because they determine the success of self- and cross-pollination. The temporal nature of this phenotype rendered it a difficult target for genetic studies. Cultivated and wild lettuce, Lactuca spp., have composite inflorescences comprised of multiple florets that open only once. Different accessions were observed to flower at different times of day. An F6 recombinant inbred line population (RIL) had been derived from accessions of L. serriola x L. sativa that originated from different environments and differed markedly for daily floral opening time. This population was used to map the genetic determinants of this trait; the floral opening time of 236 RILs was scored over a seven-hour period using time-course image series obtained by drone-based remote phenotyping on two occasions, one week apart. Floral pixels were identified from the images using a support vector machine (SVM) machine learning algorithm with an accuracy above 99%. A Bayesian inference method was developed to extract the peak floral opening time for individual genotypes from the time-stamped image data. Two independent QTLs, qDFO2.1 (Daily Floral Opening 2.1) and qDFO8.1, were discovered. Together, they explained more than 30% of the phenotypic variation in floral opening time. Candidate genes with non-synonymous polymorphisms in coding sequences were identified within the QTLs. This study demonstrates the power of combining remote imaging, machine learning, Bayesian statistics, and genome-wide marker data for studying the genetics of recalcitrant phenotypes such as floral opening time. One sentence summaryMachine learning and Bayesian analyses of drone-mediated remote phenotyping data revealed two genetic loci regulating differential daily flowering time in lettuce (Lactuca spp.).

genetics↗

bioRxiv2020

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

genomics↗

bioRxiv2020

Structure Basis for Inhibition of SARS-CoV-2 by the Feline Drug GC376

The pandemic of SARS-CoV-2 coronavirus disease-2019 (COVID-19) caused by SARS-COV-2 continues to ravage many countries in the world. Mpro is an indispensable protein for viral translation in SARS-CoV-2 and a potential target in high-specificity anti-SARS-CoV-2 drug screening. In this study, to explore potential drugs for treating COVID-19, we elucidated the structure of SARS-CoV-2 Mpro and explored the interaction between Mpro and GC376, an antiviral drug used to treat a range of coronaviruses in Feline via inhibiting Mpro. The availability and safety of GC376 were proved by biochemical and cell experiments in vitro. We determined the structure of an important protein, Mpro, in SARS-CoV-2, and revealed the interaction of GC376 with the viral substrate and inhibition of the catalytic site of SARS-CoV-2 Mpro.

biophysics↗

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↗

bioRxiv2019

Sensing Traction Force on Matrix Induces Cell-Cell Distant Mechanical Communications for Self-assembly

The long-range biomechanical force propagating across large scale may reserve the capability to trigger coordinative responses within cell population such as during angiogenesis, epithelial tubulogenesis, and cancer metastasis. How cells communicate in a distant manner within the group for self-assembly remains largely unknown. Here we found that airway smooth muscle cells (ASMCs) rapidly self-assembled into well-constructed network on 3D Matrigel containing type I collagen (COL), which relied on long-range biomechanical force across the matrix to direct cell-cell distant interactions. Similar results happened by HUVEC cells to mimic angiogenesis. Interestingly, single ASMCs initiated multiple extended protrusions precisely pointing to neighboring cells in distance, depending on traction force sensing. Separate ASMCs sensed each other to move directionally on both non-fibrous Matrigel and more efficiently when containing fibrous COL, but lost mutual sensing on fixed gel or coated glass due to no long-range force transmission. Beads tracking assay demonstrated distant transmission of traction force, and finite element method modeling confirmed the consistency between maximum strain distribution on matrix and cell directional movements in experiments. Furthermore, ASMCs recruited COL from the hydrogel to build fibrous network to mechanically stabilize cell network. Our results revealed for the first time that cells can sense traction force transmitted through the matrix to initiate cell-cell distant mechanical communications, resulting in cell directional migration and coordinative self-assembly with active matrix remodeling. As an interesting phenomenon, cells sound able to make phone call via long-range biomechanics, which implicates physiological importance such as for tissue pattern formation.

biophysics↗

bioRxiv2019

Cost implications of a nationwide survey of schistosomiasis and other intestinal helminthiases in Sudan

BackgroundIt is vital to share details of concrete experiences of conducting a nationwide survey, so that the global health community could adapt it to expand geographic mapping programs, eventually contributing to the development of control and elimination strategies with limited resources. A nationwide survey of schistosomiasis and nine other intestinal helminthiases was conducted from December 2016 to March 2017 in Sudan. ObjectivesWe aimed to describe details of the key activities and components required for the nationwide survey of schistosomiasis and other intestinal helminthiases and to analyze its costs. MethodsWe estimated financial and economic costs from the providers perspective. Cash expenditures incurred to implement the survey were defined as financial costs. We took into account all of the resources invested in the survey for economic costs, including the components that were not paid for, such as vehicles and survey equipment provided by the Ministry of Health, Sudan and the opportunity costs of primary school teachers time spent on the survey. We ran one-way sensitivity and probabilistic analyses using Monte-Carlo methods with 10,000 draws to examine the robustness of the primary analysis results. ResultsA total of USD 1,465,902 and USD 1,516,238 was incurred for the financial and economic costs, respectively. The key cost drivers of the nationwide survey were personnel and transportation, for both financial and economic costs. Personnel and transportation accounted for around 64% and 18% of financial costs, respectively. ConclusionsThe cost is expected to vary depending on the quantity and quality of existing laboratory facilities, equipment, and consumables, and the capability of laboratory technicians and sample collectors. Establishing central-level and independent supervision mechanisms to ensure the quality of the survey is equally important. We expect the global health community to draw on this study when developing nationwide surveys of schistosomiasis and other intestinal helminthiases. Author SummaryAlthough large-scale mapping of schistosomiasis and other intestinal helminthiases has been conducted in some countries, little is known about the details of nationwide surveys, such as the necessary scale of the workforce, logistics, and the cost of conducting a nationwide survey. A nationwide survey of schistosomiasis and nine other intestinal helminthiases was conducted from December 2016 to March 2017 in Sudan. A total of 105,167 students participated in the survey from 1,772 primary schools in 183 districts of all 18 states of Sudan. Herein, we present the activities that were necessary to prepare and conduct a nationwide neglected tropical disease survey, along with details on the types and amounts of personnel, survey equipment, and consumables that are required. In addition, through an analysis of the costs of the nationwide survey, we generated average costs at the district and sub-district level. The key cost drivers were personnel and transportation, both of which were recurrent costs. Establishing a steering committee to develop and reach consensus on a survey protocol, assessing the capacities of potential staff (particularly laboratory technicians), and training laboratory technicians and data collectors were key components required to prepare a nationwide survey. If a government finds a way to mobilize existing government officials with no additional payment using the health system already in place, the cost of a nationwide survey would be remarkably lower. We expect the global health community to draw on this study to develop nationwide surveys for schistosomiasis and other intestinal helminthiases.

microbiology↗

bioRxiv2019

Comparative transcriptomics reveals domestication-associated features of Atlantic salmon lipid metabolism

Domestication of Salmo salar has imposed strong selection for production traits since the 1970s. The domestication has also imposed a radical shift in diet. Whereas wild salmon eats invertebrates, crustaceans and fish, the dietary lipids in domestic feed has since 1990 gradually shifted from fish oil (FO) to vegetable oil (VO), causing a decrease intake of long-chain polyunsaturated fatty acids (LC-PUFA). We tested the hypothesis that this shift has induced domestication-specific features of lipid metabolism in a 96-day feeding trial of domesticated and wild salmon fed diets based on FO, VO or phospholipids (PL). We addressed this by sampling tissues central in fat uptake (pyloric caeca) and processing (liver) and quantifying RNA expression and fatty acid composition. Domesticated salmon grew faster than wild salmon, with higher gene expression in glucose and lipid metabolism pathways. The promoters of differentially expressed genes were enriched for transcription factors involved in circadian clock regulation. Domesticated salmon had lower expression of cry2 and nr1d1, genes involved in negative regulation of circadian rhythm, with possible implications for the diurnal cycle of feed ingestion and basal metabolic rate. Only wild salmon showed a significant impact on growth of VO versus PL or FO feed, whereas domesticated but not wild salmon upregulated key LC-PUFA synthesis genes fads2d5 and fads2d6a in response to VO diet. Domesticated salmon had higher LC-PUFA but lower 18:3n-3 and 18:2n-6 in liver when fed VO, suggesting that domesticated salmon can better compensate for dietary shortage of LC-PUFA compared to wild salmon.

molecular biology↗

bioRxiv2019

Neuronal transcriptome analyses reveal novel neuropeptide modulators of excitation and inhibition imbalance in C. elegans

Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which are previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.\n\nAUTHOR SUMMARYNeuropeptides are secreted small molecules that regulate a variety of neuronal functions and are also implicated in many diseases. However, it remains poorly understood how expression of neuropeptides is regulated, particularly in disease states. Using a genetic animal model that mimics epilepsy, we identified dozens of neuropeptides that are up-regulated when neuronal activities are altered. Some of these neuropeptides share similarity to insulin-like properties (ILPs). Strikingly, one of these ILPs is expressed in sensory neurons that normally respond to acute carbon dioxide exposure. We show that the mis-regulation of this ILP expression is activity-dependent. Moreover, these neuropeptides act in concert to modulate animal behaviors. The findings in this study provide further evidence that neuropeptides are key mediators of aberrant cholinergic signaling, and suggest complex neural network effects from sensory neurons onto motor function.

genetics↗

bioRxiv2019

Effect of Changing Heart Rate on the Ocular Pulse and Dynamic Biomechanical Behavior of the Optic Nerve Head

PurposeTo study the effect of changing heart rate on the ocular pulse and the dynamic biomechanical behaviour of the optic nerve head (ONH) using a comprehensive mathematical model.\n\nMethodsIn a finite element model of a healthy eye, a biphasic choroid consisted of a solid phase with connective tissues and a fluid phase with blood, and the lamina cribrosa (LC) was viscoelastic as characterized by a stress-relaxation test. We applied arterial pressures at 18 ocular entry sites (posterior ciliary arteries) and venous pressures at four exit sites (vortex veins). In the model, the heart rate was varied from 60 bpm to 120 bpm (increment: 20 bpm). We assessed the ocular pulse amplitude (OPA), pulse volume, ONH deformations and the dynamic modulus of the LC at different heart rates.\n\nResultsWith an increasing heart rate, the OPA decreased by 0.04 mmHg for every 10 bpm increase in heart rate. The ocular pulse volume decreased linearly by 0.13 {micro}L for every 10 bpm increase in heart rate. The storage modulus and the loss modulus of the LC increased by 0.014 MPa and 0.04 MPa, respectively, for every 10 bpm increase in heart rate.\n\nconclusionsIn our model, the OPA, pulse volume, and ONH deformations decreased with an increasing heart rate, while the LC became stiffer. The effects of blood pressure / heart rate changes on ONH stiffening may be of interest for glaucoma pathology.\n\nSupportSingapore Ministry of Education, Academic Research Fund, Tier 2 (R-397-000-280-112).\n\nCommercial relationshipNone

bioengineering↗

bioRxiv2019

Toxicants Associated with Spontaneous Abortion in the Comparative Toxicogenomics Database (CTD)

BackgroundUp to 70% of all pregnancies result in either implantation failure or spontaneous abortion (SA). Many events occur before women are aware of their pregnancy and we lack a comprehensive understanding of high-risk SA chemicals. In epidemiologic research, failure to account for a toxicants impact on SA can also bias toxicant-birth outcome associations. Our goal was to identify chemicals with a high number of interactions with SA genes, based on known toxicogenomic responses.\n\nMethodsWe used reference SA (MeSH: D000022) and chemical gene lists from the Comparative Toxicogenomics Database in three species (human, mouse, and rat). We prioritized chemicals (n=25) found in maternal blood/urine samples or in groundwater, tap water, or Superfund sites. For chemical-disease gene sets of sufficient size (n=13 chemicals, n=20 comparisons), chi-squared enrichment tests and proportional reporting ratios (PRR) were calculated. We then cross-validated enrichment results. Finally, among the SA genes, we assessed enrichment for gene ontology biological processes and for chemicals associated with SA in humans, we visualized specific gene-chemical interactions.\n\nResultsThe number of unique genes annotated to a chemical ranged from 2 (bromacil) to 5,607 (atrazine), and 121 genes were annotated to SA. In humans, all chemicals tested were highly enriched for SA gene overlap (all p<0.001; parathion PRR=7, cadmium PRR=6.5, lead PRR=3.9, arsenic PRR=3.5, atrazine PRR=2.8). In mice, highest enrichment (p<0.001) was observed for naphthalene (PRR=16.1), cadmium (PRR=12.8), arsenic (PRR=11.6), and carbon tetrachloride (PRR=7.7). In rats, we observed highest enrichment (p<0.001) for cadmium (PRR=8.7), carbon tetrachloride (PRR=8.3), and dieldrin (PRR=5.3). Our findings were robust to 1,000 permutations each of gene sets ranging in size from 100 to 10,000. SA genes were overrepresented in biological processes: inflammatory response (q=0.001), collagen metabolic process (q=1x10-13), cell death (q=0.02), and vascular development (q=0.005).\n\nConclusionWe observed chemical gene sets (parathion, cadmium, naphthalene, carbon tetrachloride, arsenic, lead, dieldrin, and atrazine) were highly enriched for SA genes. Exposures to chemicals linked to SA, thus linked to probability of live birth, may deplete fetuses susceptible to adverse birth outcomes. Our findings have critical public health implications for successful pregnancies as well as the interpretation of environmental pregnancy cohort analyses.

pharmacology and toxicology↗