Biology subjects

He, Z.

Publications and source records attributed to He, Z..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

Spinal cord injury: a systematic review and meta-analysis of microRNA alterations

Spinal cord injury (SCI) often results in life-long disability, lost wages, reduced quality of life, and high economic burden. A bottle neck in the performance of clinical trials exists, in part, due to a lack of diagnostic and prognostic markers of injury severity and neurologic recovery. In addition, while many interventions show promise in preclinical animal models, there are currently no neurorestorative treatments for SCI patients. The development of objective biological markers (biomarkers) and molecular targets for novel treatments for SCI represent two urgent unmet clinical needs. MicroRNAs (miRNAs) represent promising molecules as objective and informative molecules of injury severity and recovery and as potential therapeutic targets. miRNAs are small, stable, regulatory RNA molecules that are evolutionarily conserved across species. miRNAs represent powerful predictors of pathology, particularly with respect to neurologic disorders. Here, we present a systematic review and meta-analysis investigating the conserved inter- and intra-species miRNA changes that occur post-SCI and provide a comprehensive resource for the SCI community. Our analysis identifies a robust set of miRNAs that are involved in the pathophysiologic processes activated in response to SCI.

neuroscience↗

bioRxiv2023

A gel-coated air-liquid-interface culture system with tunable substrate stiffness matching healthy and diseased lung tissues

Since its invention in the late 1980s, the air-liquid-interface (ALI) culture system has been the standard in vitro model for studying human airway biology and pulmonary diseases. However, in a conventional ALI system, cells are cultured on a porous plastic membrane that is much stiffer than human airway tissues. Here, we develop a gel-ALI culture system by simply coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We determine the optimum gel thickness that does not impair the transport of nutrients and biomolecules essential to cell growth. We show that the gel-ALI system allows human bronchial epithelial cells (HBECs) to proliferate and differentiate into a pseudostratified epithelium. Further, we discover that HBECs migrate significantly faster on hydrogel substrates with stiffness matching that of fibrotic lung tissues, highlighting the importance of mechanical cues to human airway remodeling. The developed gel-ALI system provides a facile approach to studying the effects of mechanical cues on human airway biology and in modeling pulmonary diseases. New and NoteworthyIn a conventional air-liquid-interface (ALI) system, cells are cultured on a plastic membrane that is much stiffer than human airway tissues. We develop a gel-ALI system by coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We discover that human bronchial epithelial cells migrate significantly faster on hydrogel substrates with pathological stiffness, highlighting the importance of mechanical cues to human airway remodeling.

bioengineering↗

bioRxiv2023

Species -Shared and -Unique Gyral Peaks on Human and Macaque Brains

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, we defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. In this study, we identified shared and unique gyral peaks in human and macaque, and investigated the similarities and differences in the spatial distribution, anatomical morphology, and functional connectivity of them.

neuroscience↗

bioRxiv2023

Contribution of the delta-class glutathione S-transferase to agrochemical adaptation in Apis mellifera

The European honey bee, Apis mellifera, serves as the principle managed pollinator species globally. In recent decades, honey bee populations have been facing serious health threats from combined biotic and abiotic stressors, including diseases, limited nutrition, and agrochemical exposure. Understanding the molecular mechanisms underlying xenobiotic adaptation of A. mellifera is critical, considering its extensive exposure to phytochemicals and agrochemicals present in flowers, propolis, hives, and the environment. In this study, we conducted a comprehensive structural and functional characterization of AmGSTD1, a delta class glutathione S-transferase (GST) enzyme, to unravel its roles in agrochemical detoxification and antioxidative stress responses. Significantly, we determined the 3D structure of a honey bee GST using protein crystallography for the first time, providing new insights into its molecular structure. Our investigations revealed that AmGSTD1 efficiently metabolizes model substrates, including 1-chloro-2,4-dinitrobenzene (CDNB), p-nitrophenyl acetate (PNA), phenylethyl isothiocyanate (PEITC), propyl isothiocyanate (PITC), and the oxidation byproduct 4-hydroxynonenal (4-HNE). Moreover, we discovered that AmGSTD1 exhibits binding affinity with the fluorophore 8-Anilinonaphthalene-1-sulfonic acid (ANS), which can be inhibited with various herbicides, fungicides, insecticides, and their metabolites. These findings highlight the potential contribution of AmGSTD1 in safeguarding honey bee health against various agrochemicals and their metabolites, while also mitigating oxidative stress resulting from exposure to these substances.

pharmacology and toxicology↗

bioRxiv2023

Temporal transcriptomic dynamics in developing macaque neocortex

Despite intense research on mice, the transcriptional regulation of neocortical neurogenesis remains limited in humans and non-human primates. Cortical development in rhesus macaque is known to recapitulate multiple facets of cortical development in humans, including the complex composition of neural stem cells and the thicker supragranular layer. To characterize temporal shifts in transcriptomic programming responsible for differentiation from stem cells to neurons, we sampled parietal lobes of rhesus macaque at E40, E50, E70, E80, and E90, spanning the full period of prenatal neurogenesis. Single-cell RNA sequencing produced a transcriptomic atlas of the developing rhesus macaque neocortex parietal lobe. Identification of distinct cell types and neural stem cells emerging in different developmental stages revealed a terminally bifurcating trajectory from stem cells to neurons. Notably, deep-layer neurons appear in the early stages of neurogenesis, while upper-layer neurons appear later. While these different lineages show overlap in their differentiation program, cell fates are determined post-mitotically. Pseudotime trajectories from vRGs to oRGs revealed differences in dynamic gene expression profiles and identified divergence in their activation of BMP, FGF, and WNT signaling pathways. These results provide a comprehensive picture of the temporal patterns of gene expression leading to different fates of radial glial progenitors during neocortex layer formation.

developmental biology↗

bioRxiv2023

Estimating temporally variable selection intensity from ancient DNA data II

Recent technological innovations, such as next generation sequencing and DNA hybridisation enrichment, have made it possible to recover DNA information from historical and archaeological biological materials, which has motivated the development of various statistical approaches for inferring selection from allele frequency time series data. Recently, He et al. (2023a,b) introduced methods that can utilise ancient DNA (aDNA) data in the form of genotype likelihoods, therefore enabling the modelling of sample uncertainty arising from DNA molecule damage and fragmentation. However, their performance suffers from the underlying dependency on the allele age. Here we introduce a novel particle marginal Metropolis-Hastings within Gibbs framework for Bayesian inference of time-varying selection from aDNA data in the form of genotype like-lihoods. To circumvent the performance issue encountered in He et al. (2023a,b), we devise a novel numerical scheme for backward-in-time simulation of the Wright-Fisher diffusion and mix forward- and backward-in-time simulations in the particle filter for likelihood computation. Our framework also enables us to reconstruct the underlying population allele frequency trajectories, integrate temporal information in genotype likelihood calculations and test hypotheses on the drivers of past selection events. We conduct extensive evaluations through simulations and show its utility with an application to aDNA data from pigmentation loci in ancient horses.

genetics↗

bioRxiv2023

A trade-off between proliferation and defense in the fungal pathogen Cryptococcus at alkaline pH is controlled by the transcription factor GAT201

Cryptococcus is a fungal pathogen whose virulence relies on proliferation in and dissemination to host sites, and on synthesis of a defensive yet metabolically costly polysaccharide capsule. Regulatory pathways required for Cryptococcus virulence include a GATA-like transcription factor, Gat201, that regulates Cryptococcal virulence in both capsule-dependent and capsule-independent ways. Here we show that Gat201 is part of a negative regulatory pathway that limits fungal survival at alkaline pH. RNA-seq analysis found strong induction of GAT201 expression within minutes of transfer to RPMI media at alkaline pH. Microscopy, growth curves, and colony forming unit assays show that in RPMI at alkaline pH wild-type Cryptococcus neoformans yeast cells produce capsule but do not bud or maintain viability, while gat201{Delta} cells make buds and maintain viability, yet fail to produce capsule. GAT201 is required for transcriptional upregulation of a specific set of genes, the majority of which are direct Gat201 targets. Evolutionary analysis shows that Gat201 is in a subfamily of GATA-like transcription factors that is conserved within pathogenic fungi but absent in model yeasts. This work identifies the Gat201 pathway as controlling a trade-off between proliferation and production of defensive capsule. The assays established here will allow characterisation of the mechanisms of action of the Gat201 pathway. Together, our findings urge improved understanding of the regulation of proliferation as a driver of fungal pathogenesis. Author SummaryMicro-organisms face trade-offs in adapting to their environments. For example, pathogens adapting to host niches must balance investing in proliferation - reproduction and growth - against investing in defense against the host immune system. Cryptococcus neoformans is an encapsulated fungal pathogen that can infect human airways and, in immunocompromised people, can move to the brain to cause life-threatening meningitis. It is well appreciated that fungal persistence in these sites depends on production of a sugar capsule that surrounds the cell, hiding it from host detection. However, in both the lung and brain, fungal proliferation through budding is also a major driver of pathogenesis: both cryptococcal pneumonia and meningitis are characterised by high yeast burden. This presents a trade-off between production of a metabolically costly capsule and cellular proliferation. The regulators of Cryptococcus proliferation are poorly understood, as they are distinct from other model yeasts at the level of cell cycle and morphogenesis. In this work, we study this trade off growing Cryptococcus under conditions that approximate the alkaline surface of human airways, and that restrict fungal growth. We identify a GATA-like transcription factor, Gat201, and its target, Gat204, that positively regulate capsule production and negatively regulate proliferation. The GAT201 pathway is conserved within pathogenic fungi but lost in other model yeasts. Together our findings reveal how a fungal pathogen regulates the balance between defense and proliferation and highlight the need for improved understanding of proliferation in non-model systems.

microbiology↗

bioRxiv2023

Seasonal Variation in Bacterial Community Structures of Mangrove Sediments

Climate change globally and sea level rise affect the mangrove ecosystem. The high diversity and temporal heterogeneity of the mangrove ecosystem will lead to a high diversity of sediment bacterial community structure and function. However, seasonal variations and potential assembly mechanisms of sediment bacterial communities in mangrove ecosystems remain to be discovered. We collected rhizosphere sediments and bulk sediments from Kandelia obovata and Aegiceras corniculatum at three locations covering Dongzhai Harbour in spring, summer, autumn, and winter, and sequenced 16S rRNAs. The results indicated that the alpha and beta diversity of bacterial communities in mangrove sediments differed significantly between seasons, and the bacterial communities in rhizosphere sediments had smaller seasonal changes and were more stable than those in bulk sediment bacterial communities. The seasonal changes in carbon, nitrogen content, and pH were the main influencing factors. The stochastic process dominated the assembly of bacterial communities in mangrove sediments. The assembly of bacterial communities varies between seasons. We found that the proportion of dispersal limitation was significantly negatively correlated with the carbon and nitrogen content in the sediment. Compared with bulk components, the dispersal limitation of bacterial communities in rhizosphere sediments accounted for a lower proportion of community construction, which might be caused by higher carbon and nitrogen content conditions in rhizosphere sediments. We found that beta diversity based on Bray-Curtis distance was significantly positively correlated with dispersal limitation, which explained why the beta diversity of bacterial communities in rhizosphere sediments was significantly lower than that of bulk components. This study increases the understanding of the responses of mangrove bacterial communities to seasonal change and may be beneficial for the protection of mangrove ecosystems in the face of climate change.

ecology↗

bioRxiv2023

The Secondary Somatosensory Cortex Gates Mechanical and Thermal Sensitivity

The cerebral cortex is vital for the perception and processing of sensory stimuli. In the somatosensory axis, information is received by two distinct regions, the primary (S1) and secondary (S2) somatosensory cortices. Top-down circuits stemming from S1 can modulate mechanical and cooling but not heat stimuli such that circuit inhibition causes blunted mechanical and cooling perception. Using optogenetics and chemogenetics, we find that in contrast to S1, an inhibition of S2 output increases mechanical and heat, but not cooling sensitivity. Combining 2-photon anatomical reconstruction with chemogenetic inhibition of specific S2 circuits, we discover that S2 projections to the secondary motor cortex (M2) govern mechanical and thermal sensitivity without affecting motor or cognitive function. This suggests that while S2, like S1, encodes specific sensory information, that S2 operates through quite distinct neural substrates to modulate responsiveness to particular somatosensory stimuli and that somatosensory cortical encoding occurs in a largely parallel fashion.

neuroscience↗

bioRxiv2023

Discovery of new deaminase functions by structure-based protein clustering

The elucidation of protein function and its exploitation in bioengineering have greatly contributed to the development of the life sciences. Existing protein mining efforts generally rely on amino acid sequences rather than protein structures due to technical difficulties in structural elucidation. We describe here for the use of AlphaFold2 to predict and subsequently cluster an entire protein family based on predicted structure similarities. We selected the deaminase family of proteins to analyze and through this approach identified many previously unknown deaminase properties. We applied these new deaminases to the development of new cytosine base editors with distinct features. Although we found many new double-stranded DNA deaminases from the DddA-like protein clade, we were surprised to find that most of the proteins in this family were not actually double-stranded DNA cytidine deaminases. From this protein clade, we engineered the smallest single-strand specific cytidine deaminase, which facilitates the first efficient cytosine base editor to be packaged into a single AAV vector. Importantly, we also profiled a deaminase from this clade that edits robustly in soybean plants, which previously suffered from poor editing by cytosine base editors. These newly discovered deaminases based on AI-assisted structural predictions greatly expand the utility of base editors for therapeutic and agricultural applications.

molecular biology↗

bioRxiv2023

Skin permeable polymer for noninvasive transdermal insulin delivery

Subcutaneous injection of insulin is the current standard medication for many diabetic patients. Convenient and painless noninvasive transdermal insulin delivery has long been pursued but yet succeeded due to no such technologies for large biomacromolecules. We find a tertiary amine oxide-based polyzwitterion, OPDMA, that can efficiently penetrate both the stratum corneum (SC) and viable epidermis into circulation. So its conjugate with insulin, OPDMA-I, applied on the skin can exhibit hypoglycemic effects as efficiently as subcutaneously injected insulin in type-1 diabetic mice and minipigs. The unique pH-dependent cationic-to-zwitterionic transition of OPDMA in the characteristic acidic-to-neutral pH gradient from the skin surface to deep SC enables fast transdermal delivery of OPDMA and its conjugate. On the skin, OPDMA binds to carboxylic acids in the acidic sebum layer, enriching OPDMA-I on the SC. As pH increases in deeper SC layers, binding between OPDMA-I and the skin weakens gradually, allowing for diffusion through inter-corneocyte gaps and penetration into viable epidermis and finally entering the systemic circulation via dermal lymphatic vessels. This process does not alter SC microstructures or cause any physiological changes in the skin. This study represents a groundbreaking example of noninvasive transdermal protein delivery.

bioengineering↗

bioRxiv2023

Transcriptomic Analysis Of The Ocular Posterior Segment Completes A Cell Atlas Of The Human Eye

Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here we used high-throughput single nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in the extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases - for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From [~]151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the new data complete a "Version 1" cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.

cell biology↗

bioRxiv2023

Dynamics of the epigenetic landscape during development and in response to drought stress in sorghum

Sorghum bicolor is a C4 plant with the characteristics of high stress tolerance, which may be conferred partly by the underlying epigenetic mechanism unique to sorghum. In this study, we revealed some epigenomic features in sorghum that have never been reported before. The long H3K27me3 regions clustered in four areas, which we defined as H3K27me3 islands, were identified in sorghum. H3K36me3 plays some role in inhibiting the deposition of both H3K27me3 and H2A.Z, which may serve as partial motivation for the removal of H3K27me3 and H2A.Z in leaf and root. All the 7 histone marks are involved in the regulation of tissue-specific genes, especially the specific expression of C4 genes in leaf and peroxidase (POD) encoding genes in root, which are involved in the photosynthesis in leaf and lignin synthesis in root, respectively. These marks except H3K36me3 and H3K27me3 also engage in the regulation of stress genes in response to PEG treatment. However, we found that differential enrichment of histone marks on many tissue-specific genes was observed only between leaf and root but hardly in response to PEG treatment, although expression of these genes changed after PEG treatment.

plant biology↗

bioRxiv2023

An allocentric human odometer for perceiving distances on the ground plane

We reliably judge locations of static objects when we walk despite the retinal images of these objects moving with every step we take. Here, we showed our brains solve this optical illusion by adopting an allocentric spatial reference frame. We measured perceived target location after the observer walked a short distance from the home base. Supporting the allocentric coding scheme, we found the intrinsic bias1, 2, which acts as a spatial reference frame for perceiving location of a dimly lit target in the dark, remained grounded at the home base rather than traveled along with the observer. The path-integration mechanism responsible for this can utilize both active and passive (vestibular) translational motion signals, but only along the horizontal direction. This anisotropic path-integration finding in human visual space perception is reminiscent of the anisotropic spatial memory finding in desert ants3, pointing to natures wondrous and logically simple design for terrestrial creatures.

neuroscience↗

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

Fast and accurate DNASeq Variant Calling workflow composed of LUSH toolkit

BackgroundWhole genome sequencing (WGS) is becoming increasingly prevalent for molecular diagnosis, staging and prognosis because of its declining costs and the ability to detect nearly all genes associated with a patients disease. The currently widely accepted variant calling pipeline, GATK, is limited in terms of its computational speed and efficiency, which cannot meet the growing analysis needs. MethodsIn this study, we propose a fast and accurate DNASeq variant calling workflow that is purely composed of tools from LUSH toolkit. The LUSH pipeline is highly optimized for the WGS pipeline based on SOAPnuke, BWA and GATK which can be deployed on any general-purpose CPU-based computing system. We validated the accuracy, speed and scalability of the LUSH pipeline on several standard WGS datasets. ResultsOur test results show that the LUSH pipeline and the GATK pipeline are highly consistent in terms of accuracy, achieving over 99% precision and recall on NA12878. For speed, the LUSH pipeline completes 30x WGS data in 1.6 hours, which is about 17x faster than the GATK pipeline. From BAM to VCF, LUSH_HC even takes only 12 minutes, about 76x faster than GATK. Moreover, the LUSH pipeline shows favorable scalability in terms of thread and sequencing depth. ConclusionThe LUSH pipeline provides far superior computational speed to GATK while maintaining a high level of accuracy comparable to that of GATK, which greatly facilitates bedside analysis of acute patients, large-scale cohort data analysis, and variant calling in crop breeding programs.

bioinformatics↗

bioRxiv2023

Active maintenance of CD8+ T cell naivety through regulation of global genome architecture

The differentiation of naive CD8+ cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naive, effector and memory virus-specific CD8+ T cells. We observed that the architecture of the naive CD8+ T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naive chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naive CD8+ T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naive chromatin state. One Sentence SummaryCD8+ T cell naivety is actively maintained by transcription factors that enforce a distinct, naive chromatin architecture. HighlightsO_LICD8+ T cell differentiation states are underscored by distinct chromatin looping architectures. C_LIO_LIChromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes. C_LIO_LIEffector and memory CTLs have similar genome architectures, explaining rapid memory recall. C_LIO_LICTL differentiation is restrained by BACH2 and SATB1, which enforce a naive loop architecture. C_LI

immunology↗

bioRxiv2023

Uni-Fold MuSSe: De Novo Protein Complex Prediction with Protein Language Models

AO_SCPLOWBSTRACTC_SCPLOWAccurately solving the structures of protein complexes is crucial for understanding and further modifying biological activities. Recent success of AlphaFold and its variants shows that deep learning models are capable of accurately predicting protein complex structures, yet with the painstaking effort of homology search and pairing. To bypass this need, we present Uni-Fold MuSSe (Multimer with Single Sequence inputs), which predicts protein complex structures from their primary sequences with the aid of pre-trained protein language models. Specifically, we built protein complex prediction models based on the protein sequence representations of ESM-2, a large protein language model with 3 billion parameters. In order to adapt the language model to inter-protein evolutionary patterns, we slightly modified and further pre-trained the language model on groups of protein sequences with known interactions. Our results highlight the potential of protein language models for complex prediction and suggest room for improvements.

bioinformatics↗