Biology subjects

Yang, Y.

Publications and source records attributed to Yang, Y..

At least 883 records · Page 49Linked to original sources

bioRxiv2022

Evaluation of Renal Markers in Systemic Autoimmune Diseases

Renal involvement is a common occurrence in subjects with systemic autoimmune diseases. The renal manifestation and its severity depend on the underlying condition and may reversely complicate the clinical course of autoimmune diseases. Renal function markers have been widely used in the assessment of normal functioning of kidneys including glomerular filtration rate and concentrating and diluting capacity of the kidney. An increase or decrease in the values of these markers may indicate kidney dysfunction. In this study, a number of critical renal markers were examined in seropositive autoimmune diseases including systemic lupus erythematosus (SLE), connective tissue disorder (CTD), and rheumatoid arthritis (RA). The data from three cohorts of subjects enrolled in renal markers and autoimmune antibody testing between January 2015 to August 2019 were retrospectively studied. The prevalence of renal markers that were out of the reference range and their average levels in female and male subgroups across SLE, CTD, and RA cohorts were compared and analyzed. The levels of renal markers are significantly affected by the presence of autoantibodies, in particular eGFR, cystatin C, and albumin. Autoantibodies were also more frequent in subjects with severe renal function damage. Close follow-up of both renal markers and autoantibodies may potentially assist in the early diagnosis of kidney diseases and improve the survival and life expectancy of autoimmune patients.

immunology↗

bioRxiv2022

Deep-learning based bioactive therapeutic peptides generation and screening

Many bioactive peptides demonstrated therapeutic effects over-complicated diseases, such as antiviral, antibacterial, anticancer, etc. Similar to the generating de novo chemical compounds, with the accumulated bioactive peptides as a training set, it is possible to generate abundant potential bioactive peptides with deep learning. Such techniques would be significant for drug development since peptides are much easier and cheaper to synthesize than compounds. However, there are very few deep learning-based peptide generating models. Here, we have created an LSTM model (named LSTM_Pep) to generate de novo peptides and finetune learning to generate de novo peptides with certain potential therapeutic effects. Remarkably, the Antimicrobial Peptide Database has fully utilized in this work to generate various kinds of potential active de novo peptide. We proposed a pipeline for screening those generated peptides for a given target, and use Main protease of SARS-COV-2 as concept-of-proof example. Moreover, we have developed a deep learning-based protein-peptide prediction model (named DeepPep) for fast screening the generated peptides for the given targets. Together with the generating model, we have demonstrated iteratively finetune training, generating and screening peptides for higher predicted binding affinity peptides can be achieved. Our work sheds light on to the development of deep learning-based methods and pipelines to effectively generating and getting bioactive peptides with a specific therapeutic effect, and showcases how artificial intelligence can help discover de novo bioactive peptides that can bind to a particular target.

bioinformatics↗

bioRxiv2022

The GxcM-Fbp17/RacC-WASP signaling cascade regulates polarized cortex assembly in migrating cells

The actin-rich cortex plays a fundamental role in many cellular processes. Its architecture and molecular composition vary across cell types and physiological states. The full complement of actin assembly factors driving cortex formation and how their activities are spatiotemporally regulated remain to be fully elucidated. Using Dictyostelium as a model for polarized and rapidly migrating cells, we show that GxcM, a RhoGEF localized specifically in the rear of migrating cells, functions together with F-BAR protein Fbp17, a small GTPase RacC, and the actin nucleation-promoting factor WASP to coordinately promote Arp2/3 complex-mediated cortical actin assembly. Over-activation of this signaling cascade leads to excessive actin polymerization in the rear cortex, whereas its disruption causes defects in cortical integrity and function. Therefore, different from its well-defined role in the formation of the front protrusions, the Arp2/3 complex-based actin carries out a previously unappreciated function in building the rear cortical subcompartment in rapidly migrating cells.

cell biology↗

bioRxiv2022

Clustered Cases of Human Adenovirus types 4, 7 and 14 Infections during the 2018 - 2019 Season revealed by US Department of Defense Respiratory Pathogen Surveillance and Whole Genome Sequencing

Human adenoviruses (HAdV) are genetically diverse and can infect a number of tissues with severities varied from mild to fatal. HAdV types 3, 4, 7, 11, 14, 21 and 55 were associated with acute respiratory illnesses (ARI) outbreaks in the US and in other countries. The risk of outbreaks can be effectively controlled by HAdV vaccination or mitigated by screening and preventive measures. During the influenza season 2018 - 2019, the DoD Global Respiratory Pathogen Surveillance Program (DoDGRS) received 24,300 specimens. HAdV samples that produced positive cytopathic effects in viral cultivation were subjected to next-generation sequencing for genome sequence assembly, genome typing, whole genome phylogeny, and sequence comparative analyses. Variety of HAdV types were identified in this study, including HAdV types 1 - 7, 14, 55 and 56. HAdV types 4, 7 and 14 were found in clustered cases in Colorado, Florida, New York, and South Carolina. Comparative sequence analyses of these isolates revealed the emergence of novel genetic mutations despite the stability of adenovirus genomes. Genomic surveillance of HAdV related to possible outbreaks, shed light on prevalence, genetic divergence, and viral evolution of human adenoviruses. Continued surveillance will inform risk assessment and countermeasures.

genomics↗

bioRxiv2022

Systematic mining and genetic characterization of regulatory factors for wheat spike development

The spike architecture of wheat plays a crucial role in determining grain number, making it a key trait to optimize in wheat breeding programs. In this study, through a multi-omic approach, we analyzed the transcriptome and epigenome profiles of the shoot apex at eight developmental stages, revealing coordinated changes in chromatin accessibility and H3K27me3 abundance during the flowering transition. We constructed a core transcriptional regulatory network (TRN) that drives wheat spike formation, and experimentally validated a multi-layer regulatory module involving TaSPL15, TaAGLG1, and TaFUL2. By integrating the TRN with genome-wide association analysis (GWAS), we identified 227 transcription factors (TFs), including 42 with known functions and 185 with unknown functions. Further investigation of 61 novel TFs using multiple homozygous mutant lines uncovered 36 TFs with altered spike architecture or flowering time, such as TaMYC2-A1, TaMYB30-A1, and TaWRKY37-A1. Of particular interest, TaMYB30-A1, downstream and repressed by WFZP, was found to regulate fertile spikelet number. Notably, during the domestication and breeding process in China, the excellent haplotype of TaMYB30-A1 containing a C allele at the WFZP binding site was enriched, leading to improved agronomic traits. Our study presents novel and high-confidence regulators and offers an effective strategy for understanding the genetic basis of wheat spike development, with practical impact for wheat breeding applications.

plant biology↗

bioRxiv2022

Patient Clustering and Classification for Vital Organ Failure Using ICD Code with Graph Attention

ObjectiveHeart failure, respiratory failure and kidney failure are three severe organ failures (OF) that have high mortalities and are most prevalent in intensive care units. The objective of this work is to offer insights on OF clustering from the aspects of graph neural network and diagnosis history. MethodsThis paper proposes a neural network-based pipeline to cluster three types of organ failure patients by incorporating embedding pre-train using an ontology graph of International Classification of Diseases (ICD) codes. We employ an autoencoder-based deep clustering architecture jointly trained with a K-means loss, and a non-linear dimension reduction is performed to obtain patient clusters on the MIMIC-III dataset. ResultsThe clustering pipeline shows superior performance on a public-domain image dataset. For MIMIC-III, the model gives two distinct clusters that are related to the severity of the diseases. The learnt ICD embeddings present strong power in identifying the OF type in supervised learning. ConclusionOur proposed pipeline gives stable clusters, however, they do not correspond to the type of OF which indicates these OF share significant hidden characteristics in diagnosis. These clusters can be used to signal possible complications and severity of illness. SignificanceWe are the first to apply an unsupervised approach to offer insights from a biomedical engineering perspective on these three types of organ failure, and publish the pre-trained embeddings for future transfer learning.

bioengineering↗

bioRxiv2022

Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-{beta} (A{beta})], causes dominantly inherited Alzheimers disease. Here we report the high-resolution cryo-EM structures of A{beta} filaments from the frontal cortex of a previously described case (A{beta}PParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II A{beta}42. When compared to the structures of wild-type A{beta}42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant A{beta} molecules and promote filament formation. A minority of A{beta}42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of A{beta} filaments with the Arctic mutation from mouse knock-in line AppNL-G-F. Most filaments are made of two identical mutant protofilaments that extend from D1-G37 (murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The murine Arctic fold differs from the human Arctic folds, but shares some substructure.

neuroscience↗

bioRxiv2022

(Z, Z, Z)-3,6,9-nonadecadiene, a potential inhibitor of sex pheromone of Ectropis grisescens Warren (Lepidoptera: Geometridae): electroantennogram test, wind tunnel, and in silico study

Application of sex pheromone is the most environmental-friendly technique to control pests. Moreover, it has been discovered that pheromone analogs can disturb or inhibit mating communication in some species of moths. Ectropis grisescens Warren (Lepidoptera: Geometridae), is the most severe tea defoliator in China. Thus, in our study, an analog of the pest sex pheromone component, (Z, Z, Z)-3,6,9-nonadecadiene (Z3Z6Z9-19:Hy), was selected to determine its potential activity in controlling the pest. Electroantennogram (EAG), Y-tube olfactometer, and wind tunnel experiments separately showed potential inhibition of Z3Z6Z9-19:Hy. The response elicited by Z3Z6Z9-19:Hy displayed a dose-dependent way in EAG test. Furthermore, in Y-tube olfactometer, percentage of positive response of E. grisescens males was significantly (P<0.01) reduced by Z3Z6Z9-19:Hy up to 70%. In wind tunnel, all types of behavioral response were significantly (P<0.01) inhibited by Z3Z6Z9-19:Hy, percentage of contacting source was utterly inhibited at the lowest dose tested. Based on these results, the combination of the analog and SNMP1 protein was also studied. Our study revealed the potential of Z3Z6Z9-19:Hy as a sex pheromone inhibitor, which would provide new perspectives in monitoring and mating disruption of E. grisescens in pest-control strategies.

ecology↗

bioRxiv2022

The splicing switch of SLK controls tumor progression partially via different associations with occludin

RNA splicing control is a pivotal aspect of gene regulation and is closely associated with cancer development. From a pan-cancer transcriptome investigation in the splicing layer, we discovered a critical cancer-associated alternative splicing (AS) event at exon 13 of SLK which produces two isoforms, SLK-L and SLK-S. The splicing is dramatically shifted towards SLK-L across multiple prevalent cancer types. We demonstrated that SLK-L plays an essential role in cancer development, especially in metastasis both in cells and in mice, whereas splicing toward SLK-S inhibits cancer development. RNA-seq revealed the two SLK isoforms play different roles in pathways related to cell migration. Furthermore, different SLK isoforms demonstrate varying binding affinities to certain cell junction markers, in part indicating the AS of SLK contributes to cancer cell migration. In addition, the splicing factor Rbfox2 was identified to specifically inhibit the inclusion of exon 13 by binding intron 12 of SLK. Collectively, our study innovatively uncovers the biological consequences and underlying mechanisms for one of the most mis-spliced genes in cancer, highlighting its potential significance in cancer diagnosis and treatment.

cancer biology↗

bioRxiv2022

TRPV1-mediated sonogenetic neuromodulation of motor cortex in freely moving mice

BackgroundNoninvasive and cell-type-specific neuromodulation tools are critically needed for probing intact brain function. Sonogenetics for noninvasive activation of neurons engineered to express thermosensitive transient receptor potential vanilloid 1 (TRPV1) by transcranial focused ultrasound (FUS) was recently developed to address this need. However, using TRPV1-mediated sonogenetics to evoke behavior by targeting the cortex is challenged by its proximity to the skull due to high skull absorption of ultrasound and increased risks of thermal-induced tissue damage. ObjectiveThis study evaluated the feasibility and safety of TRPV1-mediated sonogenetics in targeting the motor cortex to modulate the locomotor behavior of freely moving mice. MethodsAdeno-associated virus was delivered to the mouse motor cortex via intracranial injection to express TRPV1 in excitatory neurons. A wearable FUS device was installed on the mouse head after a month to control neuronal activity by activating virally expressed TRPV1 through FUS sonication at different acoustic pressures. Immunohistochemistry staining of ex vivo brain slices was performed to verify neuron activation and evaluate safety. ResultsTRPV1-mediated sonogenetic stimulation at 0.7 MPa successfully evoked rotational behavior in the direction contralateral to the stimulation site, activated cortical neurons as indicated by the upregulation of c-Fos, and did not induce significant changes in inflammatory or apoptotic markers (GFAP, lba1, and Caspase-3). Sonogenetic stimulation of TRPV1 mice at a higher acoustic pressure, 1.1 MPa, induced significant changes in motor behavior and upregulation of c-Fos compared with FUS sonication of naive mice at 1.1 MPa. However, signs of damage at the meninges were observed at 1.1 MPa. ConclusionsTRPV1-mediated sonogenetics can achieve effective and safe neuromodulation at the cortex with carefully selected FUS parameters. These findings expand the application of this technique to include superficial brain targets.

bioengineering↗

bioRxiv2022

A new polymodal gating model of the proton-activated chloride channel

The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we interrogated PAC channel gating using its unique bidirectional modulator C77304 as a pharmacological probe. C77304 activated the PAC channel by acting on its proton gating, while simultaneously inhibiting channel activity at higher doses, through interaction with two modulatory sites with different affinities and state-dependence. Excitingly, we revealed that PAC undergoes intrinsic proton gating-independent voltage activation, which was defined by an ion-flux gating mechanism. Scanning-mutagenesis and molecular dynamics simulation confirmed that E181, E257, and E261 in human PAC form the primary proton sensors, as alanine mutations eliminated the channels proton gating while sparing the voltage-dependent gating. This proton sensing mechanism was basically conserved among orthologous PAC channels. Collectively, our data unveils the polymodal gating and proton sensing mechanisms in the PAC channel which may inspire potential drug development.

neuroscience↗

bioRxiv2022

A contamination focused approach for optimizing thesingle-cell RNA-seq experiment

Achieving high data quality in single-cell RNA-seq (scRNA-seq) experiments has always been a significant challenge stemming from minute signal that can be detected in individual cells. Droplet-based scRNA-seq additionally suffers from ambient contamination, comprising nucleic acid materials released by dead cells into the loading buffer and co-encapsulated with real cells, which further washes out real biological signals. Here, we developed quantitative, ambient contamination-based metrics and an associated software package that can both evaluate current datasets and guide new experimental optimizations. We performed a series of experimental optimizations using the inDrops platform to address the mechanical and microfluidic cell encapsulation aspect of an scRNA-seq experiment, with a focus on minimizing ambient contamination. We report improvements that can be achieved via cell fixation, microfluidic loading, microfluidic dilution, and nuclei versus cell preparation; many of these parameters are inaccessible on commercial platforms. We provide insights into previously obscured factors that can affect scRNA-seq data quality and suggest mitigation strategies that can guide future experiments.

genomics↗

bioRxiv2022

Over two orders of magnitude difference in rate of single chromosome loss among sundew (Drosera L., Droseraceae) lineages

Chromosome number change is a driver of speciation in eukaryotic organisms. Carnivorous sundews, the plant genus Drosera L., exhibit single chromosome number variation among and within species, especially in the Australian Drosera subg. Ergaleium D.C., potentially linked to the presence of holocentromeres. We reviewed literature, verified chromosome counts, and using an rbcL chronogram, tested alternate models where the gain, loss, and doubling rates (+1, -1, x2) were the same or different between D. subg. Ergaleium and the other subgenera. Ancestral chromosome number estimations were performed, and the distributions of self-compatibility and genome size were visualized across the genus. The best model for chromosome evolution had equal rates of polyploidy (0.014 per million years; Myr) but higher rates of single chromosome number gain (0.19 and 0.027 per Myr) and loss (0.23 and 0.00059 per Myr) in D. subg. Ergaleium compared to the other subgenera. We found no evidence for differences in single chromosome evolution to be due to differences in diploidization after polyploidy or to holocentromeres as had been proposed. This study highlights the complexity of factors influencing rates of chromosome number evolution.

evolutionary biology↗

bioRxiv2022

Uncovering transcriptional regulatory network during regeneration for boosting wheat transformation

Genetic transformation is important for gene functional study and crop breeding. Though it is available in many plant species, the transformation efficiency in wheat is generally low, which greatly restricts the genetic manipulation in wheat. Here, we use multi-omic analysis strategy to uncover core transcriptional regulatory network (TRN) driving wheat shoot regeneration and identify key factors that boost the transformation efficiency. RNA-seq, ATAC-seq and CUT&Tag were used to profile the transcriptome and chromatin dynamic during regeneration process from immature embryo of wheat variety Fielder. Sequential expression of gene clusters that mediating cell fate transition during regeneration is induced by auxin signaling, in coordination with changes of chromatin accessibility, H3K27me3 and H3K4me3 status. The TRN driving wheat shoot regeneration was built-up and 446 key transcriptional factors (TFs) occupied the core of network were identified, including functionally tested regeneration factors in other species. We further compared the regeneration process between wheat and Arabidopsis and found that DNA binding with one finger (DOF) TFs show distinct patterns in two species. Furthermore, we found that TaDOF5.6 (TraesCS6A02G274000) and TaDOF3.4 (TraesCS2B02G592600) can significantly improve the transformation efficiency of different wheat varieties. Thus, our data uncovers the molecular regulatory insights for wheat shoot regeneration process and provides potential novel targets for improving transformation efficiency in wheat.

developmental biology↗

bioRxiv2022

Targeting the pathological network: feasibility of network-based optimization of transcranial magnetic stimulation coil placement for treatment of psychiatric disorders

It has been recognized that the efficacy of TMS-based modulation may depend on the network profile of the stimulated regions throughout the brain. However, what profile of this stimulation network optimally benefits treatment outcomes is yet to be addressed. The answer to the question is crucial for informing network-based optimization of stimulation parameters, such as coil placement, in TMS treatments. In this study, we aimed to investigate the feasibility of taking a disease-specific network as the target of stimulation network for guiding individualized coil placement in TMS treatments. We present here a novel network-based model for TMS targeting of the pathological network. First, combining E-field modeling and resting-state functional connectivity, stimulation networks were modeled from locations and orientations of the TMS coil. Second, the spatial anti-correlation between the stimulation network and the pathological network of a given disease was hypothesized to predict the treatment outcome. The proposed model was validated to predict treatment efficacy from the position and orientation of TMS coils in two depression cohorts and one auditory verbal hallucinations cohort. We further demonstrate the utility of the proposed model in guiding individualized TMS treatment for psychiatric disorders. In this proof-of-concept study, we demonstrated the feasibility of the novel network-based targeting strategy that uses the whole-brain, system-level abnormity of a specific psychiatric disease as a target. Results based on empirical data suggest that the strategy may potentially be utilized to identify individualized coil parameters for maximal therapeutic effects. HighlightsO_LIProposed a model of targeting pathological brain networks for pre-treatment TMS coil placement planning in the treatment of psychiatric disorders; C_LIO_LIValidated the network targeting model in three cohorts of patients with depression or auditory verbal hallucinations, via prediction of individual TMS treatment efficacy from the parameters of coil placement; C_LIO_LIDemonstrated the utility of the network targeting model in guiding individualized TMS coil placement. C_LI

neuroscience↗

bioRxiv2022

The C-terminal domain of RNase H and the C-terminus amino acid residue regulate virus release and autoprocessing of a defective HIV-1 possessing M50I and V151I changes in integrase

Previously, we reported that an HIV-1 variant containing Met-to-Ile change at codon 50 and Val-to-Ile mutation at codon 151 of integrase (IN), HIV(IN:M50I/V151I), was an impaired virus. Despite the mutations being in IN, the virus release was significantly suppressed (p < 0.0001) and the initiation of autoprocessing was inhibited; the mechanism of the defect remains unknown. In the current study, we attempted to identify the critical domains or amino acid (aa) residue(s) that promote defects in HIV(IN:M50I/V151I), using a series of variants, including truncated or aa-substituted RNase H (RH) or IN. The results demonstrated that virus release and the initiation of autoprocessing were regulated by the C-terminal domains (CTDs) of RH and IN. Further studies illustrated that Asp at codon 109 of RH CTD and Asp at the C terminus of IN induces the defect. This result indicated that the CTD of RH and IN in GagPol and particular aa positions in RH and IN regulated the virus release and the initiation of autoprocessing, and these sites could be potential targets for the developing new therapies.

microbiology↗

bioRxiv2022

Evolutionary blocks to anthocyanin accumulation and the loss of an anthocyanin carrier protein in betalain-pigmented Caryophyllales

{square} The order Caryophyllales exhibits complex pigment evolution, with mutual exclusion of anthocyanin and betalain pigments. Given recent evidence for multiple shifts to betalain pigmentation, we re-evaluated potential mechanisms underpinning the exclusion of anthocyanins from betalain-pigmented lineages. {square}We examined the evolution of the flavonoid pathway using transcriptomic and genomic datasets covering 309 species in 31 families. Orthologs and paralogs of known flavonoid synthesis genes were identified by sequence similarity, with gene duplication and gene loss inferred by phylogenetic and syntenic analysis. Relative transcript abundances were assessed to reveal broad-scale gene expression changes between betalain- and anthocyanin-pigmented lineages. {square}Most flavonoid genes are retained and transcribed in betalain-pigmented lineages, and many also show evidence of extensive gene duplication within betalain-pigmented lineages. However, expression of several flavonoid genes is reduced in betalain-pigmented lineages, especially the late-stage genes dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS). Notably flavonoid 3',5'-hydroxylase (F3'5'H) homologs have been repeatedly lost in belatain-pigmented lineages, and Anthocyanin9 (AN9) homologs are undetectable in any betalain-pigmented lineages. {square}Down-regulation of ANS and DFR homolog expression (limiting synthesis) and reiterative loss of AN9 homologs (limiting transport), coincident with multiple shifts to betalain pigmentation, are likely crucial the loss of anthocyanins in betalain-pigmented Caryophyllales.

evolutionary biology↗

bioRxiv2022

Understanding Vascular Endothelial Cell Behavior Using a Mechanical Strain Gradient Generated by an Electromagnetic Stretching Device

Cardiovascular diseases cause an estimated 17.9 million deaths globally each year (World Health Organization). Endothelial cells that line the vasculature and the endocardium are subjected to cyclic mechanical stretch. Deviation from physiological stretch can alter the endothelial function, having the risk of atherosclerosis and myocardial infarction. To understand the mechanical stretch effects, cell culture platforms that provide mechanical stretch have been developed. However, most of them have fixed strain and frequency, sometime not in the pathophysiological range. We thus developed a novel, electromagnetically driven, uniaxial stretching device, where cells were grown on a flexible polydimethylsiloxane (PDMS) membrane mounted onto a 3-D printed track. The strain of the membrane was readily controlled by tailoring the track design and the frequency was determined by electromagnetic actuation. Furthermore, the mechanical strain gradient was generated on a PDMS membrane with a tapered thickness. This strain gradient, ranging from 1.5% to 40%, covered both physiological and pathological vascular stretch ranges. When human vascular endothelial cells were subjected to the cyclic stretch, the cells exhibited strain-dependent cell and nuclear orientation and elongation perpendicular to the stretching direction, compared to the random cell and nuclear orientation under the static condition. However, the overstretching led to deviation from the aforementioned orientation and elongation, and impaired the tight junctions, leading to a leaky endothelium. This novel, versatile, cost-effective, pathophysiologically relevant stretching device provides a useful platform for advancement of vascular disease research and treatment.

bioengineering↗