Biology subjects

He, Q.

Publications and source records attributed to He, Q..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

Alternating Polarity as a Novel Strategy for Cultivating Electro-Methanogenic Microbial Communities Capable of Robust Biogas Production

Electro-methanogenic microbial communities can produce biogas with high efficiency. Extensive efforts have been made to cultivate these communities in engineered systems. Conventional cultivation strategies can select electrotrophic methanogens but not their electron-donating partners, resulting in communities that are sensitive to perturbations. Herein, we developed an alternating polarity strategy to simultaneously select both microbial populations. In two-chamber bioelectrochemical systems amended with activated carbon, the electrode potential was alternated between +0.8 V and -0.4 V vs. standard hydrogen electrode every three days. After eight alternating cycles, cultivated activated carbon was transferred into new bioreactors, and the enrichment procedure was repeated four times. Cumulative biogas production under alternating polarity increased from 45 L/L/kg-activated carbon after start-up to 125 L/L/kg after the 4th enrichment, significantly higher than that under intermittent cathode (-0.4 V/open circuit), continuous cathode (-0.4 V), and open circuit. The communities cultivated under alternating polarity were electroactive and structurally different from those cultivated under other conditions. One Methanobacterium population and two Geobacter populations were consistently abundant and active in the communities. Their 16S rRNA was upregulated by electrode potentials. Bayesian networks inferred close associations between these populations. The cultivation strategy can enhance biogas production, and the cultivated communities may serve as a model system for elucidating the mechanisms of extracellular electron uptake. SynopsisAn alternating polarity strategy was developed in this study to cultivate electro-methanogenic microbial communities. The cultivated communities can produce biogas more efficiently and help us understand the ecophysiology of the key microbial populations.

ecology↗

bioRxiv2023

Enhancing visual perceptual learning using transcranial electrical stimulation: transcranial alternating current stimulation outperforms both transcranial direct current and random noise stimulation

Diverse strategies can be employed to enhance visual skills, including visual perceptual learning (VPL) and transcranial electrical stimulation (tES). Combining VPL and tES is a popular method that holds promise for significant improvements in visual acuity within a short time frame. However, there is still a lack of comprehensive evaluation regarding the effects of combining different types of tES and VPL on enhancing visual function, especially with a larger sample size. In the present study, we recruited four groups of subjects (26 subjects each) to learn an orientation discrimination task with five daily training sessions. During training, subjects occipital region was stimulated by one type of tES (anodal transcranial direct current stimulation (tDCS), alternating current stimulation (tACS) at 10 Hz, high-frequency random noise stimulation (tRNS), and sham tACS) while performing the training task. We found that compared with the sham stimulation, both the high-frequency tRNS and the 10 Hz tACS facilitated VPL efficiently in terms of learning rate and performance improvement, while there was little modulatory effect in the anodal tDCS condition. Remarkably, the 10 Hz tACS condition exhibited superior modulatory effects to the tRNS condition, demonstrating the strongest modulation among the most commonly used tES types for further enhancing vision when combined with VPL. Our results suggest that alpha oscillations play a vital role in VPL. Our study provides a practical guide for vision rehabilitation.

neuroscience↗

bioRxiv2023

SAW: An efficient and accurate data analysis workflow for Stereo-seq spatial transcriptomics

The basic analysis steps of spatial transcriptomics involve obtaining gene expression information from both space and cells. This process requires a set of tools to be completed, and existing tools face performance issues when dealing with large data sets. These issues include computationally intensive spatial localization, RNA genome alignment, and excessive memory usage in large chip scenarios. These problems affect the applicability and efficiency of the process. To address these issues, a high-performance and accurate spatial transcriptomics data analysis workflow called Stereo-Seq Analysis Workflow (SAW) has been developed for the Stereo-Seq technology developed by BGI. This workflow includes mRNA spatial position reconstruction, genome alignment, gene expression matrix generation and clustering, and generate results files in a universal format for subsequent personalized analysis. The excutation time for the entire analysis process is [~]148 minutes on 1G reads 1*1 cm chip test data, 1.8 times faster than unoptimized workflow.

bioinformatics↗

bioRxiv2023

Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provide alternative therapeutic strategies.

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting about 1% of the world population. The first line treatment, lithium (Li), is effective in only a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from BD patients responsive (LR) or not (LNR) to lithium and combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics to report mechanistic insights into neuronal hyperactivity in BD, and Lis mode of action. We show a selective rescue of neuronal hyperactivity by Li in BD LR neurons through changes in Na+ currents. The whole transcriptome sequencing revealed altered gene expression in BD neurons in pathways related to glutamatergic transmission, and Li selectively altered those involved in cell signaling and ion transport/channel activity. We found the therapeutic effect of Li in BD LR patients was associated with Akt signaling and confirmed that an Akt activator mimics Li effect in BD LR neurons. Further, we showed that AMP-activated protein kinase (AMPK) reduces neural network activity and sodium currents in BD LNR patients. These findings suggest the potential for novel treatment strategies in BD, such as Akt activators in BD LR cases, and the use of AMPK activators for BD LNR patients.

neuroscience↗

bioRxiv2023

Molecular quantitative trait loci in reproductive tissues impact male fertility in a large mammal

Breeding bulls are well suited to investigate inherited variation in male fertility because they are genotyped and their reproductive success is monitored through semen analyses and thousands of artificial inseminations. However, functional data from relevant tissues are lacking, which prevents fine-mapping fertility-associated genomic regions. Here, we characterize gene expression and splicing variation in testis, epididymis, and vas deferens transcriptomes of 118 mature bulls and conduct association tests between 417k molecular phenotypes and 21M genome-wide variants to identify 41k regulatory loci. We show broad consensus in tissue-specific and tissue-enriched gene expression between the three bovine tissues and their human and murine counterparts. Expression- and splicing-mediating variants are more than three times as frequent in testis than epididymis and vas deferens, highlighting the transcriptional complexity of testis. Finally, we identify genes (WDR19, SPATA16, KCTD19, ZDHHC1) and molecular phenotypes that are associated with quantitative variation in male fertility through transcriptome-wide association and colocalization analyses.

genomics↗

bioRxiv2023

Tessellation Of Artificial Touch Via Microstimulation Of Human Somatosensory Cortex

When we interact with objects, we rely on signals from the hand that convey information about the object and our interaction with it. A basic feature of these interactions, the locations of contacts between the hand and object, is often only available via the sense of touch. Information about locations of contact between a brain-controlled bionic hand and an object can be signaled via intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes touch sensations that are localized to a specific patch of skin. To provide intuitive location information, tactile sensors on the robotic hand drive ICMS through electrodes that evoke sensations at skin locations matching sensor locations. This approach requires that ICMS-evoked sensations be focal, stable, and distributed over the hand. To systematically investigate the localization of ICMS-evoked sensations, we analyzed the projected fields (PFs) of ICMS-evoked sensations - their location and spatial extent - from reports obtained over multiple years from three participants implanted with microelectrode arrays in S1. First, we found that PFs vary widely in their size across electrodes, are highly stable within electrode, are distributed over large swaths of each participants hand, and increase in size as the amplitude or frequency of ICMS increases. Second, while PF locations match the locations of the receptive fields (RFs) of the neurons near the stimulating electrode, PFs tend to be subsumed by the corresponding RFs. Third, multi-channel stimulation gives rise to a PF that reflects the conjunction of the PFs of the component channels. By stimulating through electrodes with largely overlapping PFs, then, we can evoke a sensation that is experienced primarily at the intersection of the component PFs. To assess the functional consequence of this phenomenon, we implemented multi-channel ICMS-based feedback in a bionic hand and demonstrated that the resulting sensations are more localizable than are those evoked via single-channel ICMS.

neuroscience↗

bioRxiv2023

A conserved and druggable pocket in class B G protein coupled receptors for orally active small molecule agonists

Class B G protein-coupled receptors (GPCRs), including glucagon-like receptor 1 (GLP-1R) and parathyroid hormone receptor 1 (PTH1R), are peptide hormone receptors and important drug targets. Injectable peptide drugs targeting class B GPCRs have been developed for the treatment of many diseases, including type 2 diabetes, obesity, and osteoporosis, but orally available small molecule drugs are hotly pursued in the field, especially small molecule agonists of GLP-1R and PTH1R. Here we report the first high-resolution structure of the human PTH1R in complex with the stimulatory G protein (Gs) and a small molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the interface of PTH1R and Gs. The binding site of PCO371 is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. Residues that make up the PCO371 binding pocket are mostly conserved in class B GPCRs and a single mutation in PTH type 2 receptor (PTH2R) and two residue mutations in GLP-1R convert these receptors to respond to PCO371 activation. Functional assays reveal that PCO371 is a G-protein biased agonist that is defective in promoting PTH1R-mediated arrestin signaling. Together, these results uncover a distinct binding site for designing small molecule agonists for PTH1R and possible other members of class B GPCRs and define a receptor conformation that is only specific for G protein activation but not arrestin signaling. These insights should facilitate the design of distinct types of class B GPCR small molecule agonists for various therapeutic indications.

biochemistry↗

bioRxiv2023

Predicting Blomia tropicalis allergens using a multiomics approach

The domestic mite Blomia tropicalis is a major source of allergens in tropical and subtropical regions. Despite its great medical importance, the allergome of this mite is not sufficiently studied. Only 14 allergen groups have been identified in B. tropicalis so far, even though early radioimmunoelectrophoresis techniques (27 uncharacterized allergen complexes) and comparative data based on 40 allergen groups officially recognized by WHO/IUIS in domestic astigmatid mites, suggest that a large set of additional allergens may be present. Here, we use a multiomics approach to assess the allergome of B. tropicalis using genomic, transcriptomic sequence data, and a highly sensitive protein abundance quantification. Out of 14 known allergen groups, we confirmed 13 (one WHO/IUIS allergen, Blo t 19, was found to be a contaminant originated from a nematode) and identified 16 potentially novel allergens using sequence similarity. These data indicate that B. tropicalis shares 27 known/deduced allergen groups with pyroglyphid house dust mites (genus Dermatophagoides). Among them, five allergen-encoding genes were highly expressed at the transcript level: Blo t 1, Blo t 5, Blo t 21 (known), Blo t 15, and Blo t 18 (predicted). However, at the protein level, a different set of most abundant allergens was found: Blo t 2, 10, 11, 20 and 21 (mite bodies) or Blo t 3, 4, 6 and predicted Blo t 13, 14 and 36 (mite feces). We show the use of an integrated omics method to identify and predict an array of mite allergens and advanced, label-free proteomics to determine allergen protein abundance. Our research identifies a large set of novel putative allergens and shows that expression levels of allergen-encoding genes may not be strictly correlated with the actual allergenic protein abundance in the mite bodies.

molecular biology↗

bioRxiv2023

Long-term reliable neural decoding based on flexible implantable microelectronics and machine learning for seizure prediction application

Neural decoding is useful for understanding brain functions and developing neural interface applications. However, neural interfaces based on rigid electronics often suffer from recording instability due to the foreign body responses caused by their mechanical mismatch with soft tissues, limiting the longitudinal accuracy of neural decoding methods. Herein, it is reported that flexible electronics can be integrated with machine learning algorithms to achieve long-term reliable neural decoding. Wet-spun conductive polymer microfibers showed mechanical robustness and flexibility, low impedance, and chronic biocompatibility, enabling intracerebral neural recordings in epileptic mice at a high signal-to-noise ratio eight weeks after implantation. When the signals recorded by the flexible electrodes were used in machine learning analyses with diverse complex algorithms, they consistently showed higher prediction accuracy for epileptic seizures than stiff metal electrode signals, particularly in the case of using long-term recordings for testing or small-sample datasets for training. A real-time warning system based on the flexible neural electrodes was built that predicted seizures eight minutes in advance with a low false alarm rate. Our work bridges flexible electronics and artificial intelligence for neural decoding applications such as long-term treatment of chronic neurological disorders.

bioengineering↗

bioRxiv2023

Antigenic strain diversity explains different biogeographic patterns of invasion and maintenance of anti-malarial drug resistance

The establishment and spread of anti-malarial drug resistance vary drastically across different biogeographic regions. Though most infections occur in Sub-Saharan Africa, resistant strains often emerge in low-transmission regions. Existing models on resistance evolution lack consensus on the relationship between transmission intensity and drug resistance, possibly due to overlooking the feedback between antigenic diversity, host immunity, and selection for resistance. To address this, we developed a novel compartmental model that tracks sensitive and resistant parasite strains, as well as the host dynamics of generalized and antigen-specific immunity. Our results show a negative correlation between parasite prevalence and resistance frequency, regardless of resistance cost or efficacy. Validation using chloroquine-resistant marker data supports this trend. Post discontinuation of drugs, resistance remains high in low-diversity, low-transmission regions, while it steadily decreases in high-diversity, high-transmission regions. Our study underscores the critical role of malaria strain diversity in the biogeographic patterns of resistance evolution.

evolutionary biology↗

bioRxiv2023

StereoCell enables high accuracy single cell segmentation for spatial transcriptomic dataset

BackgroundOwing to recent advances in resolution and field-of-view, spatially resolved transcriptomics sequencing, such as Stereo-seq, has emerged as a cutting-edge technology for the interpretation of large tissues at the single-cell level. To generate accurate single-cell spatial gene expression profiles from high-resolution spatial omics data, a powerful computational tool is required. FindingsWe present CellBin, an image-facilitated one-stop pipeline for high-resolution and large field-of-view spatial transcriptomic data of Stereo-seq. CellBin provides a comprehensive and systematic platform for generating high-confidence single-cell spatial gene expression profiles, which specifically includes image stitching, image registration, tissue segmentation, nuclei segmentation and molecule labeling. CellBin is user-friendly and does not require a specific level of omics and image analysis expertise. ConclusionsDuring image stitching and molecule labeling, CellBin delivers better-performing algorithms to reduce stitching error and time, in addition to improving the signal-to-noise ratio of single-cell gene expression data, in comparison with existing methods. Additionally, CellBin has been shown to obtain highly accurate single-cell spatial data using mouse brain tissue, which facilitated clustering and annotation.

bioinformatics↗

bioRxiv2023

Motifs in SARS-CoV-2 evolution

We present a novel framework enhancing the prediction of whether novel lineage poses the threat of eventually dominating the viral population. The framework is based purely on genomic sequence data, without requiring prior established biological analysis. Its building blocks are sets of co-evolving sites in the alignment (motifs), identified via co-evolutionary signals. The collection of such motifs forms a relational structure over the polymorphic sites. Motifs are constructed using distances quantifying the co-evolutionary coupling of pairs and manifest as co-evolving clusters of sites. We present an approach to genomic surveillance based on this notion of relational structure. Our system will issue an alert regarding a lineage, based on its contribution to drastic changes in the relational structure. We then conduct a comprehensive retrospective analysis of the COVID-19 pandemic based on SARS-CoV-2 genomic sequence data in GISAID from October 2020 to September 2022, across 21 lineages and 27 countries with weekly resolution. We investigate the performance of this surveillance system in terms of its accuracy, timeliness and robustness. Lastly, we study how well each lineage is classified by such a system.

bioinformatics↗

bioRxiv2022

Category-induced global effects of feature-based attention in human visual system

Global effects of FBA are generally limited to stimuli sharing the same or similar features, as hypothesized in the "feature-similarity gain model". Visual perception, however, often reflects categories acquired via experience; whether the global-FBA effect can be induced by the categorized features remains unclear. Here human subjects were trained to classify motion-directions into two discrete categories and performed a classical motion-based attention task. We found a category-induced global-FBA effect in both the MT+ and frontoparietal areas, where attention to a motion-direction globally spread to unattended motion-directions within the same category, but not to those in a different category. Effective connectivity analysis showed that the category-induced global-FBA effect in MT+ was derived by feedback from the IFJ. Altogether, our results reveal for the first time a category-induced global-FBA effect and identify a source for this effect in human prefrontal cortex, implying that FBA is of greater ecological significance than previously thought.

neuroscience↗

bioRxiv2022

The nutrient-sensing GCN2 signaling pathway is essential for circadian clock function by regulating histone acetylation under amino acid starvation

Circadian clocks are evolved to adapt to the daily environment changes under different conditions. The ability to maintain circadian clock functions in response to various stress and perturbations is important for organismal fitness. Here, we show that the nutrient sensing GCN2 signaling pathway is required for robust circadian clock function under amino acid starvation in Neurospora. The deletion of GCN2 pathway components disrupts rhythmic transcription of clock gene frq by suppressing WC complex binding at the frq promoter due to its reduced histone H3 acetylation levels. Under amino acid starvation, the activation of GCN2 kinase and its downstream transcription factor CPC-1 establish a proper chromatin state at the frq promoter by recruiting the histone acetyltransferase GCN-5. The arrhythmic phenotype of the GCN2 kinase mutants under amino acid starvation can be rescued by inhibiting histone deacetylation. Finally, genome-wide transcriptional analysis indicates that the GCN2 signaling pathway maintains robust rhythmic expression of metabolic genes under amino acid starvation. Together, these results uncover an essential role of GCN2 signaling pathway in maintaining robust circadian clock function in response to amino acid starvation and the importance of histone acetylation at the frq locus in rhythmic gene expression.

genetics↗

bioRxiv2022

Novel inhibitors against COVID-19 main protease suppressed viral infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can cause severe disease with high mortality rates, especially among older and vulnerable populations. Despite the recent success of vaccines and approval of first-generation anti-viral inhibitor against SARS-CoV-2, an expanded arsenal of anti-viral compounds that limit viral replication and ameliorate disease severity is still urgently needed in light of the continued emergence of viral variants of concern (VOC). The main protease (Mpro) of SARS-CoV-2 is the major non-structural protein required for the processing of viral polypeptides encoded by the open reading frame 1 (ORF1) and ultimately replication. Structural conservation of Mpro among SARS-CoV-2 variants make this protein an attractive target for the anti-viral inhibition by small molecules. Here, we developed a structure-based in-silico screening of approximately 11 million compounds in ZINC15 database inhibiting Mpro, which prioritized 9 lead compounds for the subsequent in vitro validation in SARS-CoV-2 replication assays using both Vero and Calu-3 cells. We validated three of these compounds significantly inhibited SARS-CoV-2 replication in the micromolar range. In summary, our study identified novel small-molecules significantly suppressed infection and replication of SARS-CoV-2 in human cells.

pathology↗

bioRxiv2022

Structure of the human UBR5 E3 ubiquitin ligase

The human UBR5 (also known as EDD) is a single polypeptide chain HECT-type E3 ubiquitin ligase essential for embryonic development in mammals. Although widely expressed, UBR5 is markedly amplified and overexpressed in breast, ovarian, prostate, gastric and pancreatic cancers. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis, making UBR5 a potential target for therapeutics. Unexpectedly, we found that human UBR5 assembles a dimer and a tetramer in solution. We determined the dimer structure at 2.8 [A] and the tetramer structure at 3.5 [A] average resolution. UBR5 is a crescent shaped molecule with a seven-bladed {beta}-propeller and two small {beta}-barrel domains (SBB1/2) at the N-terminal region, a catalytic HECT domain at the C-terminus, and an extended helical scaffold and an N-degron-recognizing UBR box in the middle. The dimer is assembled as a stable head-to-tail dimer via extensive interactions in the middle helical scaffold region. The tetramer is assembled via SBB2-SBB2 interaction from two face-to-face dimers, forming a large cage with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an "intermolecular jaw" in the dimer. Using enzymatic and cellular assays, we showed that the jaw-lining residues are important for function, suggesting that the intermolar jaw functions to recruit ubiquitin loaded E2 to UBR5 for the transthiolation reaction. Further work is needed to understand how oligomerization regulates the UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development against the distinctive HECT E3 ligase and contributes to a growing appreciation of E3 ligase diversity.

biochemistry↗

bioRxiv2022

Novel Master Regulators of Microglial Phagocytosis and Repurposed FDA-approved Drug for Treatment of Alzheimer Disease

Microglia, the innate immune cells of the brain, are essential determinants of late-onset Alzheimers Disease (LOAD) neuropathology. Here, we developed an integrative computational systems biology approach to construct causal network models of genetic regulatory programs for microglia in Alzheimers Disease (AD). This model enabled us to identify novel key driver (KDs) genes for microglial functions that can be targeted for AD pharmacotherapy. We prioritized FCER1G, HCK, LAPTM5, ITGB2, SLC1A2, PAPLN, GSAP, NTRK2, and CIRBP as KDs of microglial phagocytosis promoting neuroprotection and/or neural repair. In vitro, shRNA knockdown of each KD significantly reduced microglial phagocytosis. We repurposed riluzole, an FDA-approved ALS drug that upregulates SLC1A2 activity, and discovered that it stimulated phagocytosis of A{beta}1-42 in human primary microglia and decreased hippocampal amyloid plaque burden/phosphorylated tau levels in the brain of aged 3xTg-AD mice. Taken together, these data emphasize the utlility of our integrative approach for repurposing drugs for AD therapy.

neuroscience↗

bioRxiv2022

PF-D-Trimer, a broadly protective SARS-CoV-2 subunit vaccine: immunogenicity and application

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and still has a considerable impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, the primary responsible for the host immune response upon infection. Here we show the preclinical studies of a broad protective SARS-CoV-2 subunit vaccine developed from our Trimer Domain platform using the Delta spike protein, from antigen design to purification, vaccine evaluation and manufacturability. The prefusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. The immunogenicity studies demonstrated that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous virus challenge. The neutralizing antibodies induced by this vaccine display a cross-reactive capacity against the ancestral WA1 and Delta variants as well as different Omicron, including BA.5.2. The Trimer Domain platform was proven to be a key technology in the rapid production of the PF-D-Trimer vaccine and may be crucial to accelerate the development of updated versions of SARS-CoV-2 vaccines.

immunology↗