Biology subjects

Yang, Y.

Publications and source records attributed to Yang, Y..

At least 1,081 records · Page 60Linked to original sources

bioRxiv2021

Structure-based Classification of Tauopathies

Ordered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimers disease (1,2), chronic traumatic encephalopathy (CTE) (3), Picks disease (4) and corticobasal degeneration (CBD) (5) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimers disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from aging-related tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimers disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.

neuroscience↗

bioRxiv2021

Plasmodiophora brassicae infection threshold - How many resting spores are required for infection of canola (Brassica napus)

Clubroot, caused by Plasmodiophora brassicae, is an important disease of canola and other brassica crops. Improved understanding of host and pathogen biology is frequently useful in guiding management strategies. In order to better understand infection thresholds, seven-day old seedlings of canola cultivar Westar were inoculated with serially diluted concentrations of P. brassicae resting spores. Controlled soil and plant inoculation assays were performed and the plants maintained in a greenhouse for 42 days and clubroot disease severity evaluated visually. Clubroot symptoms were observed in soils containing as low as one spore/mL soil and on plants inoculated with as few as [≤] 100 resting spores. These thresholds were lower than any previously reported. The results indicated the importance of highly sensitive detection methods for P. brassicae diagnosis and quantification methods for clubroot risk prediction in soils. Furthermore, these results highlighted the low probability of obtaining P. brassicae single spore isolates.

microbiology↗

bioRxiv2021

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies and provides long-term protection against SARS-CoV-2 in rhesus macaques

Coronavirus disease 2019 (COVID-19), which is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, continues to threaten global public health. Developing a vaccine that only requires single immunization but provides long-term protection for the prevention and control of COVID-19 is important. Here, we developed an adeno-associated virus (AAV)-based vaccine expressing a stable receptor-binding domain (SRBD) protein. The vaccine requires only a single shot but provides effective neutralizing antibodies (NAbs) over 598 days in rhesus macaques (Macaca mulatta). Importantly, our results showed that the NAbs were kept in high level and long lasting against authentic wild-type SARS-CoV-2, Beta, Delta and Omicron variants using plaque reduction neutralization test. Of note, although we detected pre-existing AAV2/9 antibodies before immunization, the vaccine still induced high and effective NAbs against COVID-19 in rhesus macaques. AAV-SRBD immune serum also efficiently inhibited the binding of ACE2 with RBD in the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1/P.2 (Gamma), B.1.617.2 (Delta), B.1.617.1/3(Kappa), and C.37 (Lambda) variants. Thus, these data suggest that the vaccine has great potential to prevent the spread of SARS-CoV-2.

immunology↗

bioRxiv2021

Systematic characterization of short intronic splicing-regulatory elements

Intronic splicing enhancers and silencers (ISEs and ISSs) are two groups of splicing-regulatory elements (SREs) that play critical roles in determining splice-site selection, particularly for alternatively spliced introns or exons. SREs are often short motifs; their mutation or dysregulation of their cognate proteins frequently causes aberrant splicing and results in disease. To date, however, knowledge about SRE sequences and how they regulate splicing remains limited. Here, using an SMN2 minigene, we generated a complete pentamer-sequence library that comprises all possible combinations of 5 nucleotides in intron 7, at a fixed site downstream of the 5' splice site. We systematically analyzed the effects of all 1023 mutant pentamers on exon 7 splicing, in comparison to the wild-type minigene, in HEK293 cells. Our data show that the majority of pentamers significantly affect exon 7 splicing: 584 of them are stimulatory and 230 are inhibitory. To identify actual SREs, we utilized a motif set enrichment analysis (MSEA), from which we identified groups of stimulatory and inhibitory SRE motifs. We experimentally validated several strong SREs in SMN1/2 and MAPT minigene settings. Our results provide a valuable resource for understanding how short RNA sequences regulate splicing. Many novel SREs can be explored further to elucidate their mechanism of action.

molecular biology↗

bioRxiv2021

The Global Protein-RNA Interaction map of Epithelial Splicing Regulatory Protein 1 defines a post-transcriptional program that is essential for epithelial cell function

The epithelial splicing regulatory proteins, ESRP1 and ESRP2 are essential for mammalian development through regulation of a global program of alternative splicing of genes involved in maintenance of epithelial cell function. To further inform our understanding of the molecular functions of ESRP1 we performed enhanced crosslinking immunoprecipitation coupled with high throughput sequencing (eCLIP) in epithelial cells of mouse epidermis. The genome-wide binding sites of ESRP1 were integrated with RNA-Seq analysis of alterations in splicing and total gene expression that result from epidermal ablation of Esrp1 and Esrp2. These studies demonstrated that ESRP1 functions in splicing regulation occur primarily through direct binding in a position-dependent manner to either promote exon inclusion or skipping. In addition, we also identified widespread binding of ESRP1 in 3 and 5 untranslated regions (UTRs) of genes involved in epithelial cell function suggesting that its post-transcriptional functions extend beyond splicing regulation.

molecular biology↗

bioRxiv2021

Mutational signatures of complex genomic rearrangements in human cancer

Complex genomic rearrangements (CGRs) are common in cancer and are known to form via two aberrant cellular structures--micronuclei and chromatin bridge. However, which mechanism is more relevant to CGR formation in cancer cells and whether there are other undiscovered mechanisms remain open questions. Here, we analyze 2,014 CGRs from 2,428 whole-genome sequenced tumors and deconvolute six CGR signatures based on the topology of CGRs. Through rigorous benchmarking, we show that our CGR signatures are highly accurate and biologically meaningful. Three signatures can be attributed to known biological processes--micronuclei- and chromatin-bridge-induced chromothripsis and extrachromosomal DNA. More than half of the CGRs belong to the remaining three newly discovered signatures. A unique signature (we named "hourglass chromothripsis") with highly localized breakpoints and small amount of DNA loss is abundant in prostate cancer. Through genetic association analysis, we find SPOP as a candidate gene causing hourglass chromothripsis and playing important role in maintaining genome integrity. Our study offers valuable insights into the formation of CGRs.

genomics↗

bioRxiv2021

Automated, high-accuracy, remote measurement of heart rate

Arrhythmia is a marked symptom of many cardiovascular diseases (CVDs). The accurate and timely detection of heart rate can greatly reduce the harm of arrhythmia to people. However, it is still a challenge to robustly and remotely measure heart rate in daily life due to the changing environmental conditions during measurement, such as the varying light intensity, the movement of people, and the uncertain distance between the sensor to people. In this study, we propose a method to accurately measure human heart rate within a distance of 4.5 meters under different light intensities by simply using a surveillance camera. After a 20-second color video of a persons hand is captured by the camera, a method based on the Fast Fourier Transform (FFT) algorithm is designed to extract the blood volume pulse wave to calculate the heart rate. According to the comparison between the real heart rate and results measured by electrocardiography (ECG), the proposed method achieves an accuracy of 95.8% when the measurement is performed within a distance of 4.5 meters and 90% when within 5.0 meters. Our experiments show that when the illuminance varies between 100-1000 lux (lighting level indoor), we still get the correct results. Our experiments also demonstrate that the proposed method accurately obtain heart rate even when the light intensity is below 32 lux (300-500 lux in a workplace environment). The methods strong adaptability to changing environmental conditions makes it applicable to many scenarios, such as homes of the elderly, classrooms, and other public spaces.

physiology↗

bioRxiv2021

Remote spatially variant debiased profiling of cell and tissue mechanical properties

The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a novel unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in tissue mechanical assessment for novel on line assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering.

bioengineering↗

bioRxiv2021

Neural correlates of semantic number: A cross-linguistic investigation

One aspect of natural language comprehension is understanding how many of what or whom a speaker is referring to. While previous work has documented the neural correlates of general number comprehension and quantity comparison, we investigate semantic number from a cross-linguistic perspective with the goal of identifying cortical regions involved in distinguishing plural from singular nouns. We use three fMRI datasets in which Chinese, French, and English native speakers listen to an audiobook of a childrens story in their native language. We select these three languages because they differ in their number semantics. While Chinese lacks nominal pluralization, French and English nouns are overtly marked for number. We find a number of known semantic processing regions in common, including dorsomedial prefrontal cortex and the pars orbitalis, in which cortical activation is greater for plural than singular nouns and posit a cross-linguistic role for number in semantic comprehension.

neuroscience↗

bioRxiv2021

Genetic, Genomic and Biophysical Case Study: Familial 46, XY Sex Reversal due to a Novel Inherited Mutation in Human Testis-Determining Factor SRY

ObjectiveTo describe the clinical, histopathological and molecular features of a novel inherited SRY allele (p.Met64Val; consensus box position 9) observed within an extensive pedigree: two 46, XY sisters with primary amenorrhea (16 and 14 years of age; probands P1 and P2), their normal father and brother, and an affected paternal XY grandaunt. Design, Setting, Participants and Outcome MeasurementsFollowing DNA sequencing to identify the SRY mutation, hormonal studies of the probands and histopathological examination of their gonads were performed. Functional consequences of p.Met64Val (and other mutations at this site) were also investigated. ResultsBreast development in P1 and P2 was Tanner II and IV, respectively. Mullerian structures and gonads resembling ovaries were found in each sister. Histopathology revealed gonadal dysgenesis, gonadablastoma and dysgerminoma. AMH/MIS, P450 SCC, and P450 aromatase were expressed in gonadoblastoma tissues. Genomic sequencing revealed no candidate mutations in other genes related to sexual differentiation. Variant p.Met64Val impaired Sox9 transcriptional activation associated with attenuated occupancy of the testis-specific enhancers Enh13 and TESCO. Biophysical studies indicated that the mutant HMG box retains specific DNA binding and DNA bending but with accelerated rate of protein-DNA dissociation. ConclusionThe partial biological activity of p.Met64Val SRY, maintained at the threshold of SRY function, rationalizes opposing paternal and proband phenotypes (the "the father-daughter paradox"). Steroidal biosynthesis by gonadoblastoma may delay genetic diagnosis and recognition of gonadal tumors. Quantitative assessment of inherited SRY alleles highlights the tenuous transcriptional threshold of developmental decision-making in the bipotential gonadal ridge.

developmental biology↗

bioRxiv2021

Decoding the silence: Neural bases of zero pronoun resolution in Chinese

Chinese is one of many languages that can drop subjects. We report an fMRI study of language comprehension processes in these "zero pronoun" cases. The fMRI data come from Chinese speakers who listened to an audiobook. We conducted both univariate GLM and multivariate pattern analysis (MVPA) on these data time-locked to each verb with a zero pronoun subject. We found increased left middle temporal gyrus activity for zero pronouns compared to overt subjects, suggesting additional effort searching for an antecedent during zero pronoun resolution. MVPA further revealed that the intended referent of a zero pronoun seems to be physically represented in the Precuneus and the Parahippocampal Gyrus shortly after its presentation. This highlights the role of memory and discourse-level processing in resolving referential expressions, including unspoken ones, in naturalistic language comprehension.

neuroscience↗

bioRxiv2021

WGDI: A user-friendly toolkit for evolutionary analyses of whole-genome duplications and ancestral karyotypes

Evidence of whole-genome duplications (WGDs) and subsequent karyotype changes has been detected in most major lineages of life on Earth. To clarify the complex resulting multiple-layered patterns of gene collinearity in genome analyses there is a need for convenient and accurate toolkits. To meet this need, we introduce here WGDI (Whole-Genome Duplication Integrated analysis), a Python-based command-line tool that facilitates comprehensive analysis of recursive polyploidizations and cross-species genome alignments. WGDI supports three main workflows (polyploid inference, hierarchical inference of genomic homology, and ancestral chromosomal karyotyping) that can improve detection of WGD and characterization of related events. It incorporates a more sensitive and accurate collinearity detection algorithm than previous softwares, and can accelerate WGD-related karyotype research. As a freely available toolkit at GitHub (https://github.com/SunPengChuan/wgdi), WGDI outperforms similar tools in terms of efficiency, flexibility and scalability. In an illustrative example of its application, WGDI convincingly clarified karyotype evolution in Aquilegia coerulea and Vitis vinifera following WGDs and rejected the hypothesis that Aquilegia contributed as a parental lineage to the allopolyploid origin of core dicots.

bioinformatics↗

bioRxiv2021

Machine-Perception Nanosensor Platform to Detect Cancer Biomarkers

Conventional molecular recognition elements, such as antibodies, present issues for the development of biomolecular assays for use in point-of-care devices, implantable/wearables, and under-resourced settings. Additionally, antibody development and use, especially for highly multiplexed applications, can be slow and costly. We developed a perception-based platform based on an optical nanosensor array that leverages machine learning algorithms to detect multiple protein biomarkers in biofluids. We demonstrated this platform in gynecologic cancers, which are often diagnosed at advanced stages, leading to low survival rates. We investigated the platform for detection in uterine lavage samples, which are enriched with cancer biomarkers compared to blood. We found that the method enables the simultaneous detection of multiple biomarkers in patient samples, with F1-scores of ~0.95 in uterine lavage samples from cancer patients. This work demonstrates the potential of perception-based systems for the development of multiplexed sensors of disease biomarkers without the need for specific molecular recognition elements.

bioengineering↗

bioRxiv2021

Spatial transcriptome sequencing revealed spatial trajectory in the Non-Small Cell Lung Carcinoma

Deepening understanding in the heterogeneity of tumors is critical for clinical treatment. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal lung cancer using the spatial transcriptomics (ST) technology. We identified gene expression gradients in stroma adjacent to tumor regions that allow for re-understanding of the tumor micro-environment. The establishment of these profiles was the first step towards an unbiased view of lung cancer and can serve as a dictionary for future studies. Tumor subclones were detected by ST technology in our research, while we contrast the EMT ability among in subclones which inferred the possible trajectory of tumor metastasis and invasion, which was confirmed by constructing the pseudo-time model of spatial transition within subclones. Together, these results uncovered lung cancer spatial heterogeneity, highlight potential tumor micro-environment differences and spatial evolution trajectory, and served as a resource for further investigation of tumor microenvironment.

cancer biology↗

bioRxiv2021

Multi-tissue integrative analysis of personal epigenomes

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of personal epigenomes, for [~]25 tissues and >10 assays in four donors (>1500 open-access functional genomic and proteomic datasets, in total). Each dataset is mapped to a matched, diploid personal genome, which has long-read phasing and structural variants. The mappings enable us to identify >1 million loci with allele-specific behavior. These loci exhibit coordinated epigenetic activity along haplotypes and less conservation than matched, non-allele-specific loci, in a fashion broadly paralleling tissue-specificity. Surprisingly, they can be accurately modelled just based on local nucleotide-sequence context. Combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci and enables models for transferring known eQTLs to difficult-to-profile tissues. Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

genomics↗

bioRxiv2021

Emergent vulnerability to intensive coastal anthropogenic disturbances in mangrove forests

Mangrove forests, as one of the most productive coastal ecosystems in tropical and subtropical areas, provide multiple valuable ecosystem services for human well-being. Mangrove coverage has been declining dramatically across much of developing regions due to extensive coastal anthropogenic disturbances such as reclamation, aquaculture, and seawall construction. As coastal human activities increase, there is urgent need to understand not only the direct loss, but also the vulnerability of mangroves to anthropogenic disturbances. In this study, we evaluated spatial pattern of mangrove vulnerability based on the conceptual framework of "Exposure-Sensitivity-Resilience" using geospatial datasets in mainland China. We find that within all 25,829 ha mangroves in five coastal provinces of mainland China in 2015, nearly 76% of mangroves was exposed or threatened by anthropogenic disturbances. Coastal reclamation and aquaculture were the key threats causing mangrove vulnerability. The overall distribution of high, medium and low vulnerability was following similar trend of aquaculture distribution, which suggests aquaculture was the greatest anthropogenic disturbance agent to mangroves. Hotspot regions for mangrove vulnerability are located at the developing provinces such as Guangxi and Hainan. This study provides the first spatially explicit evidence of the vulnerability of mangrove forests to intensive coastal anthropogenic disturbances at national scale, cloud serve as a benchmark for navigating coastal ecological redline management and coastal ecosystem restoration.

ecology↗

bioRxiv2021

A gene regulatory network for neural induction

During early vertebrate development, signals from a special region of the embryo, the organizer, can re-direct the fate of non-neural ectoderm cells to form a complete, patterned nervous system. This is called neural induction and has generally been imagined as a single signalling event, causing a switch of fate. Here we undertake a comprehensive analysis, in very fine time-course, of the events following exposure of ectoderm to the organizer. Using transcriptomics and epigenomics we generate a Gene Regulatory Network comprising 175 transcriptional regulators and 5,614 predicted interactions between them, with fine temporal dynamics from initial exposure to the signals to expression of mature neural plate markers. Using in situ hybridization, single-cell RNA-sequencing and reporter assays we show that neural induction by a grafted organizer closely resembles normal neural plate development. The study is accompanied by a comprehensive resource including information about conservation of the predicted enhancers in different vertebrate systems.

developmental biology↗

bioRxiv2021

Evaluation of different concentrations antibiotics on gut bacteria and growth of Ectropis obliquaProut (Lepidoptera: Geometridae)

The use of antibiotics to remove gut bacteria is a commonly used method to study gut function of insects. We assessed the impact of the artificial diet made from tea powder with different concentrations of antibiotics mixture (containing tetracycline, gentamicin, penicillin, and rifampicin) on Ectropis obliqua Prout (Lepidoptera: Geometridae) survival, growth, and reproduction. Antibiotic-induced bacterial clearance was monitored by Polymerase Chain Reaction (PCR) and by Colony-counting Methods. The results indicated that administration of the antibiotic mixture at a concentration of 200g/ml caused the increase of gut bacteria, while a concentration of 300g/ml was more effective in clearing gut bacteria but the concentration of 400g/ml caused a large number of larval deaths. The concentration of 300g/ml had no significant effect on the growth and development of E. obliqua, but had impact on fecundity. Therefore, we could use 300g/ml concentrations of the antibiotic mixture to obtain sterile E. obliqua to study the function of intestinal microbes.

animal behavior and cognition↗