Biology subjects

Huang, Z.

Publications and source records attributed to Huang, Z..

At least 181 records · Page 10Linked to original sources

bioRxiv2024

Differentiable simulation enables large-scale training of detailed biophysical models of neural dynamics

Biophysiscal neuron models provide insights into cellular mechanisms underlying neural computations. However, a central challenge has been the question of how to identify the parameters of detailed biophysical models such that they match physiological measurements at scale or such that they perform computational tasks. Here, we describe a framework for simulation of detailed biophysical models in neuroscience--JO_SCPLOWAXLEYC_SCPLOW--which addresses this challenge. By making use of automatic differentiation and GPU acceleration, JO_SCPLOWAXLEYC_SCPLOW opens up the possibility to efficiently optimize large-scale biophysical models with gradient descent. We show that JO_SCPLOWAXLEYC_SCPLOW can learn parameters of biophysical neuron models with several hundreds of parameters to match voltage or two photon calcium recordings, sometimes orders of magnitude more efficiently than previous methods. We then demonstrate that JO_SCPLOWAXLEYC_SCPLOW makes it possible to train biophysical neuron models to perform computational tasks. We train a recurrent neural network to perform working memory tasks, and a feedforward network of morphologically detailed neurons with 100,000 parameters to solve a computer vision task. Our analyses show that JO_SCPLOWAXLEYC_SCPLOW dramatically improves the ability to build large-scale data- or task-constrained biophysical models, creating unprecedented opportunities for investigating the mechanisms underlying neural computations across multiple scales.

neuroscience↗

bioRxiv2024

Enhancing Variant Calling in Whole Exome Sequencing (WES) Data Using Population-Matched Reference Genomes

Whole exon sequencing (WES) data are frequently used for cancer diagnosis and genome-wide association studies (GWAS), hinging upon high-coverage read mapping, informative variant calling, and high-quality reference genomes. The center position of the currently used genome assembly, GRCh38, is now challenged by two newly publicized telomere-to-telomere or T2T genomes, T2T-CHM13 and T2T-YAO, and it becomes urgent to have a comparative study to test population specificity using the three reference genomes based on real case WES data. We here report our analysis along this line for 19 tumor samples collected from Chinese patients. The primary comparison of the exon regions among the three references reveals that the sequences in up to [~]1% target regions in YAO are widely diversified from GRCh38 and may lead to off-target in sequence capture. However, YAO still outperforms GRCh38 genomes by obtaining 7.41% more mapped reads. Due to more reliable read-mapping and closer phylogenetic relationship with the samples than GRCh38, YAO reduces half of variant calls of clinical significance which are mostly benign while keeping sensitivity in identifying pathogenic variants. YAO also outperforms CHM13 in reducing calls of Chinese-specific variants. Our findings highlight the critical need for employing population-specific reference genomes in genomic analysis to ensure accurate variant analysis and the significant benefits of tailoring these approaches to the unique genetic backgrounds of each ethnic group.

genomics↗

bioRxiv2024

Exploiting functional regions in the viral RNA genome as druggable entities

RNA-targeting compounds or small interfering RNAs (siRNAs) offer a potent means for controlling viral infections. An essential prerequisite to their design depends on identifying conserved and functional viral RNA structures in cells. Techniques that probe RNA structures in situ have been developed recently including SHAPE-MaP, which has been helpful in analyzing the secondary structures of RNA. In this study, we report on the application of SHAPE-MaP to the Porcine Epidemic Diarrhoea Virus (PEDV) RNA genome to categorize different functional regions including potential quadruplex forming sequence and target sites of siRNA. Our results show that these structures can be exploited to inhibit viral proliferation and that SHAPE-MaP is an effective method to the identification of secondary structures in RNA genomes.

genomics↗

bioRxiv2024

Detection of genome structural variation in normal cells and tissues by single molecule sequencing

Rare genome structural-variants (SVs) in somatic cells and tissues are difficult to measure in bulk DNA because library preparation can create chimeric junctions that mimic authentic events. Based on our previous Single-Molecule Mutation sequencing (SMM-seq) assay, we developed a new method, SMM-SV-seq, which combines a chimera-suppressing library preparation with duplex confirmation of breakpoint-supporting molecules. Using libraries from mixtures of human and Drosophila DNA, we show a remaining artifact rate of 1.52 +/- 0.53 detectable cross-species chimeras per billion bases, providing an empirical background for correcting breakpoint frequencies. In a benchmark of evaluable homozygous germline deletions in the GM24385 cell line, SMM-SV-seq achieved 81.4% precision and 85.7% recall, exceeding the precision of established short-read callers while maintaining comparable recall. The assay detected dose-associated increases in SV-breakpoint frequencies in cells treated with bleomycin, a known clastogen. Biological relevance was demonstrated by a significantly greater irradiation-associated increase in translocation-like breakpoint frequencies in the BRCA1 185delAG-heterozygous mammary epithelial clone than in its isogenic wild-type control. These results establish SMM-SV-seq as a practical assay for calibrated, duplex-confirmed detection of rare somatic SV breakpoints directly in bulk DNA from non-clonal cell populations.

genomics↗

bioRxiv2024

Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

It is known that M1 macrophages are the dominant phenotype in progressive atherosclerosis (AS). Studies have shown that telomerase in macrophages can be activated during the atherosclerosis formation, but how to regulate the telomerase activity of M1 macrophages is the focus of treatment of AS. Herein, we report a dual-targeted microbubbles delivery system encapsulating the telomerase inhibitor BIBR1532 (Ab-MMB1532), designed for precise targeted therapy of AS. The Ab-MMB1532 exhibits excellent biocompatibility and remarkable targeting capability towards M1 macrophages with its targeting advantage notably accentuated under high shear forces. Furthermore, it significantly downregulates telomerase activity. Metabolomics analysis indicates that the decrease in telomerase activity upregulates the expression of aspartic acid, a key protein in the Caspase pathway of apotosis. In vivo, Ab-MMB1532 efficiently targeted and accumulated within AS lesions, leading to significantly delay of the AS progression by inhibiting telomerase activity and promoting apoptosis of M1 macrophages after 4-week treatment. In summary, Ab-MMB1532 provides a new approach for potentially safer and more effective treatment of AS in the future.

bioengineering↗

bioRxiv2024

PPR767 affects plant architecture and drought resistance by modulating complex I activity and ROS content in rice

The RNA-binding proteins (RBPs) encoded by nucleus are essential for the metabolism of RNAs in eukaryotes. The pentatricopeptide repeat (PPR) proteins, a large subset of RBPs, participate in organellar RNA processing for plant development and reproduction. Here, we identified an E-type PPR protein, PPR767, which functions in mitochondria. Knocking out PPR767 resulted in shorter plant height, thinner stems, shorter and narrower blades, and consequently affected yield traits, compared to those of the wild type. PPR767 primarily participated in the editing of 4 sites, nad1-674, nad3-155, nad3-172, and nad7-317. And PPR767 interplayed with MORF1 and MORF8, suggesting the editosome in rice is complicated. Meanwhile, the activity of mitochondrial complex I was decreased, and the structure of mitochondria was compromised in the mutants. Furthermore, mutation of PPR767 influenced rice drought tolerance and the expression levels of genes involved in the reactive oxygen species (ROS) accumulation. These findings suggest that PPR767 guarantees the complex I activity by properly regulating the RNA editing efficiency of mitochondrial genes and affects drought tolerance by modulating ROS content in rice, providing valuable insights into the mechanisms by which PPRs fulfil their functions.

molecular biology↗

bioRxiv2024

Deep learning linking mechanistic models to single-cell transcriptomics data reveals transcriptional bursting in response to DNA damage

Cells must adopt flexible regulatory strategies to make decisions regarding their fate, including differentiation, apoptosis, or survival in the face of various external stimuli. One key cellular strategy that enables these functions is stochastic gene expression programs. However, understanding how transcriptional bursting, and consequently, cell fate, responds to DNA damage on a genome-wide scale poses a challenge. In this study, we propose an interpretable and scalable inference framework, DeepTX, that leverages deep learning methods to connect mechanistic models and scRNA-seq data, thereby revealing genome-wide transcriptional burst kinetics. This framework enables rapid and accurate solutions to transcription models and the inference of transcriptional burst kinetics from scRNA-seq data. Applying this framework to several scRNA-seq datasets of DNA-damaging drug treatments, we observed that fluctuations in transcriptional bursting induced by different drugs was associated with distinct fate decisions: IdU treatment was associated with differentiation in mouse embryonic stem cells by increasing the burst size of gene expression, while low- and high-dose 5FU treatments in human colon cancer cells were associated with changes in burst frequency that corresponded to apoptosis- and survival-related fate, respectively. Together, these results show that DeepTX enables genome-wide inference of transcriptional bursting from single-cell transcriptomics data and can generate hypotheses about how bursting dynamics relate to cell fate decisions.

systems biology↗

bioRxiv2024

SMCHD1 maintains heterochromatin and genome compartments in human myoblasts

Mammalian genomes are subdivided into euchromatic A compartments that contain mostly active chromatin, and inactive, heterochromatic B compartments. However, it is unknown how A and B genome compartments are established and maintained. Here we studied SMCHD1, an SMC-like protein in human male myoblasts. SMCHD1 colocalizes with Lamin B1 and the heterochromatin mark H3K9me3. Loss of SMCHD1 leads to extensive heterochromatin depletion at the nuclear lamina and acquisition of active chromatin states along all chromosomes. In absence of SMCHD1, long range intra-chromosomal and inter-chromosomal contacts between B compartments are lost while many new TADs and loops are formed. Inactivation of SMCHD1 promotes numerous B to A compartment transitions accompanied by activation of silenced genes. SMCHD1 functions as an anchor for heterochromatin domains ensuring that these domains are inaccessible to epigenome modification enzymes that typically operate in active chromatin. Therefore, A compartments are formed by default when not prevented by SMCHD1.

genomics↗

bioRxiv2024

Ultra-resolution Deconvolution of Spatial Transcriptomics Unveils Spatiotemporal Cellular Dynamics in Complex Microenvironments

Immune cells infiltrate tissues in response to exogenous pathogens or spontaneous tumors, generating protective immunity to safeguard tissues. Despite advancements in spatial transcriptomics (ST), the precise spatial distribution and functional specialization of immune cells within tissue microenvironments remain elusive. Here, we introduce an ultra-precision ST deconvolution algorithm (UCASpatial) that enhances the mapping of cell subpopulations to spatial locations by leveraging the contribution of genes indicative of cell identity through entropy-based weighting. Using both in silico and real ST datasets, we demonstrate that UCASpatial improves the robustness and accuracy in identifying low-abundant cell subpopulations and distinguishing transcriptionally heterogeneous cell subpopulations. Applying UCASpatial to human colorectal cancer (CRC), we link genomic alterations in individual cancer clones to multi-cellular characteristics of the tumor immune microenvironment (TIME) and reveal the co-evolution of tumor cells and TIME at a clonal resolution. We show that the copy number gain on chromosome 20q (chr20q-gain) in tumor cells orchestrates a T cell-excluded TIME, indicative of resistance to immunotherapy in CRC, and is associated with tumor-intrinsic human endogenous retrovirus subfamily H (HERV-H) silencing and impaired type I interferon response. In murine wound healing models, we illuminate the spatiotemporal dynamics of individual cell subsets across various stages of the healing process. We discovered that the scarring-healing mice (C57BL/6) exhibited a replacement of Prg4+ chondrogenic progenitors to Igfbp5+ chondrocytes in the wound bed at the regeneration stage, a change not observed in the regenerative strain (MRL/MpJ). The Igfbp5+ chondrocyte, spatially coordinating with Cd36+ Gpnmb+ Il1b- macrophage and Fmod+ fibroblast, forms a pro-fibrotic community associated with regeneration failure. The cell-cell interactions within this three-cell cluster, mediated by the IL11-IL11RA axis, drive the pro-fibrotic community formation and limit regeneration in C57BL/6 mice. Our findings present UCASpatial as a versatile tool for deciphering fine-grained cellular landscapes in ST and exploring intercellular mechanisms in complex and dynamic microenvironments.

bioinformatics↗

bioRxiv2024

Multi-talker speech comprehension at different temporal scales in listeners with normal and impaired hearing

Comprehending speech requires deciphering a range of linguistic representations, from phonemes to narratives. Prior research suggests that in single-talker scenarios, the neural encoding of linguistic units follows a hierarchy of increasing temporal receptive windows. Shorter temporal units like phonemes and syllables are encoded by lower-level sensory brain regions, whereas longer units such as sentences and paragraphs are processed by higher-level perceptual and cognitive areas. However, the brains representation of these linguistic units under challenging listening conditions, such as a cocktail party situation, remains unclear. In this study, we recorded electroencephalogram (EEG) responses from both normal-hearing and hearing-impaired participants as they listened to individual and dual speakers narrating different parts of a story. The inclusion of hearing-impaired listeners allowed us to examine how hierarchically organized linguistic units in competing speech streams affect comprehension abilities. We leveraged a hierarchical language model to extract linguistic information at multiple levels--phoneme, syllable, word, phrase, and sentence--and aligned these model activations with the EEG data. Our findings showed distinct neural responses to dual-speaker speech between the two groups. Specifically, compared to normal-hearing listeners, hearing-impaired listeners exhibited poorer model fits at the acoustic, phoneme, and syllable levels as well as the sentence levels, but not at the word and phrase levels. These results suggest that hearing-impaired listeners experience disruptions at both shorter and longer temporal scales, while their processing at medium temporal scales remains unaffected.

neuroscience↗

bioRxiv2024

VASCilia (Vision Analysis StereoCilia): A Napari Plugin for Deep Learning-Based 3D Analysis of Cochlear Hair Cell Stereocilia Bundles

Cochlear hair cells are essential for hearing, and their stereocilia bundles are critical for mechanotransduction. However, analyzing the 3D morphology of these bundles can be challenging due to their complex organization and the presence of other cellular structures in the tissue. To address this, we developed VASCilia (Vision Analysis StereoCilia), a Napari plugin suite that automates the analysis of 3D confocal microscopy datasets of phalloidin-stained cochlear hair cell bundles. VASCilia includes five deep learning-based models that streamline the analysis process, including: (1) Z-Focus Tracker (ZFT) for selecting relevant slices in a 3D image stack; (2) PCPAlignNet (Planar Cell Polarity Alignment Network) for automated orientation of image stacks; (3) a segmentation model for identifying and delineating stereocilia bundles; (4) a tonotopic Position Prediction tool; and (5) a classification tool for identifying hair cell subtypes. In addition, VASCilia provides automated computational tools and measurement capabilities. Using VASCilia, we demonstrate its utility on challenging datasets, including neonatal wildtype and Eps8 KO 5-day old mice), revealing that total actin content does not necessarily scale with bundle height. We further showcase its power by quantifying complex bundle disorganization in Cdh23-/- cochleae via texture analysis, which revealed systematically more heterogeneous and less regular bundles than in controls. These novel biological findings demonstrate the power of VASCilia in facilitating detailed quantitative analysis of stereocilia. VASCilia also provides a user-friendly interface that allows researchers to easily navigate and use the tool, with the added capability to reload all their analyses for review or sharing purposes. We believe that VASCilia will be a valuable resource for researchers studying cochlear hair cell development and function, addressing a longstanding need in the hair cell research community for specialized deep learning-based tools capable of high-throughput image quantitation. We have released our code along with a manually annotated dataset that includes approximately 55 3D stacks featuring instance segmentation (https://github.com/ucsdmanorlab/Napari-VASCilia). This dataset comprises a total of 502 inner and 1,703 outer hair cell bundles annotated in 3D. As the first open-source dataset of its kind, we aim to establish a foundational resource for constructing a comprehensive atlas of cochlea hair cell images. Ultimately, this initiative will support the development of foundational models adaptable to various species, markers, and imaging scales to accelerate advances within the hearing research community.

bioinformatics↗

bioRxiv2024

A novel monomeric amyloid β-activated signaling pathway regulates brain development via inhibition of microglia

Amyloid {beta} (A{beta}) forms aggregates in the Alzheimers disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether A{beta} also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of A{beta} in vitro that plays essential roles in the regulation of microglial activity and the assembly of neocortex during development in vivo. We find that activation of this pathway depends on the function of amyloid precursor (APP) and the heterotrimeric G protein regulator Ric8a in microglia and inhibits microglial immune activation at transcriptional and post-transcriptional levels. Genetic disruption of this pathway during neocortical development results in microglial dysregulation and excessive matrix proteinase activation, leading to basement membrane degradation, neuronal ectopia, and laminar disruption. These results uncover a previously unknown function of A{beta} as a negative regulator of brain microglia and substantially elucidate the underlying molecular mechanisms. Considering the prominence of A{beta} and neuroinflammation in the pathology of Alzheimers disease, they also highlight a potentially overlooked role of A{beta} monomer depletion in the development of the disease.

neuroscience↗

bioRxiv2024

Nitazoxanide ameliorates OVA-induced airway inflammation in asthmatic mice via p38-MAPK/ NFκB and AMPK/STAT3 pathways

Nitazoxanide has an anti-inflammatory effect, we clarified the ameliorative effect of nitazoxanide on asthmatic airway inflammation by conducting in vitro and in vivo experiments. In vitro, we assessed the effect of nitazoxanide on cytokine production by lipopolysaccharide-stimulated RAW 264.7 cells, as well as the diastolic effect of nitazoxanide on isolated rat airways. Nitazoxanide was found to have a diastolic effect on isolated tracheal spasms caused by spasmogenic substances, and to inhibit IL-6 and IL-1{beta} production by RAW 264.7 cells. Meanwhile, nitazoxanide can inhibit the proliferation and migration of human bronchial smooth muscle cells (HBSMCs). In vivo, an ovalbumin (OVA)-induced asthma model was established in mice, and the airway resistance was measured by Whole Body Plethysmography (WBP) after inhalation of acetylcholine in mice, and the levels of IL-4, IL-6, IL-12, and IL-17 were detected in bronchoalveolar lavage fluid (BALF) of mice by ELISA and the inflammatory cells were counted. H&E staining was used to observe the changes in lung histopathology, and the expression of NFkB, MAPK, AMPK, and STAT3 in lung tissues was quantified using Western-blot. Nitazoxanide reduced inflammatory cell infiltration and goblet cell proliferation in the lungs of asthmatic mice. Moreover, the expression of IL-4, IL-5, and IL-6 in BALF was down-regulated in asthmatic mice. In addition, nitazoxanide could inhibit the expression of NFkB, MAPK, STAT 3 proteins and ascend the expression of AMPK in lung tissues. In conclusion, nitazoxanide could diastole airway smooth muscle and ameliorate OVA-induced airway inflammation in asthmatic mice via NFkB/MAPK and AMPK/STAT3 pathways.

pharmacology and toxicology↗

bioRxiv2024

Genomic and Genetic Insights into Mendel's Pea Genes

Pea, Pisum sativum, is an excellent model system through which Gregor Mendel established the foundational principles of inheritance. Surprisingly, till today, the molecular nature of the genetic differences underlying the seven pairs of contrasting traits that Mendel studied in detail remains partially understood. Here, we present a genomic and phenotypic variation map, coupled with haplotype-phenotype association analyses across a wide range of traits in a global Pisum diversity panel. We focus on a genomics-enabled genetic dissection of each of the seven traits Mendel studied, revealing many previously undescribed alleles for the four characterized genes, R, Le, I and A, and elucidating the gene identities and mutations for the remaining three uncharacterized traits. Notably, we identify: (1) a ca. 100kb deletion upstream of the Chlorophyll synthase (ChlG) gene, which generates aberrant transcripts and confers the yellow pod phenotype of gp mutants; (2) an in-frame premature stop codon mutation in a Dodeca-CLE41/44 signalling peptide which explains the parchmentless mutant phenotype corresponding to p; and (3) a 5bp in-frame deletion in a CIK-like receptor kinase gene corresponding to the fasciated stem phenotype fa, which Mendel described in terms of flower position, and we postulate the existence of a Modifier of fa (Mfa) locus that masks this meristem defect. Mendel noted the pleiotropy of the a mutation, including inhibition of axil ring anthocyanin pigmentation, a trait we found to be controlled by allelic variants of the gene D within an R2R3-MYB gene cluster. Furthermore, we characterize and validate natural variation of a quantitative genetic locus governing both pod width and seed weight, characters that Mendel deemed were not sufficiently demarcated for his analyses. This study establishes a cornerstone for fundamental research, education in biology and genetics, and pea breeding practices.

genetics↗

bioRxiv2024

Optogenetic inhibition of light-captured alcohol-taking striatal engrams facilitates extinction and suppresses reinstatement

BackgroundAlcohol use disorder (AUD) is a complex condition, and it remains unclear which specific neuronal substrates mediate alcohol-seeking and -taking behaviors. Engram cells and their related ensembles, which encode learning and memory, may play a role in this process. We aimed to assess the precise neural substrates underlying alcohol-seeking and -taking behaviors and determine how they may affect one another. MethodsUsing FLiCRE (Fast Light and Calcium-Regulated Expression; a newly developed technique which permits the trapping of acutely activated neuronal ensembles) and operant-self administration (OSA), we tagged striatal neurons activated during alcohol-taking behaviors. We used FLiCRE to express an inhibitory halorhodopsin in alcohol-taking neurons, permitting loss-of-function manipulations. ResultsWe found that the inhibition of OSA-tagged alcohol-taking neurons decreased both alcohol-seeking and -taking behaviors in future OSA trials. In addition, optogenetic inhibition of these OSA-tagged alcohol-taking neurons during extinction training facilitated the extinction of alcohol-seeking behaviors. Furthermore, inhibition of these OSA-tagged alcohol-taking neurons suppressed the reinstatement of alcohol-seeking behaviors, but, interestingly, it did not significantly suppress alcohol-taking behaviors during reinstatement. ConclusionsOur findings suggest that alcohol-taking neurons are crucial for future alcohol-seeking behaviors during extinction and reinstatement. These results may help in the development of new therapeutic approaches to enhance extinction and suppress relapse in individuals with AUD.

neuroscience↗

bioRxiv2024

Phagocytosis-driven neurodegeneration through opposing roles of an ABC transporter in neurons and phagocytes

Lipid homeostasis is critical to the survival of neurons. Lipid transporters from the ATP-binding cassette A (ABCA) subfamily are important regulators of lipid trafficking and are associated with multiple neurodegenerative diseases. How ABCA transporters regulate specific aspects of lipid homeostasis to impact neurodegeneration is an outstanding question. Here we report that the Drosophila ABCA protein Engulfment ABC Transporter in the ovary (Eato) contributes to phagocytosis-dependent neurodegeneration by playing two opposing roles in neurons and nearby phagocytes: In neurons, Eato prevents dendrites and axons from being attacked and engulfed by neighboring phagocytes; in phagocytes, however, Eato enhances the ability of these cells to detect neurons as engulfment targets. Thus, Eato deficiency in neurons alone results in severe phagocytosis-dependent dendrite and axon degeneration, whereas removing Eato from both neurons and phagocytes completely rescues the neurite degeneration. Surprisingly, Eato exerts its functions in both neurons and phagocytes by suppressing the effects of the eat-me signal phosphatidylserine (PS) exposed on the cell surface. Interestingly, multiple human and C. elegans ABCA homologs can compensate for the loss of Eato in phagocytes but not in neurons, suggesting both conserved and cell type-specific activities of these ABCA proteins. These results reveal how ABCA proteins participate in neurodegeneration by regulating PS homeostasis and imply possible mechanisms of neuron-phagocyte interactions in neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Comparative genomics of three non-hematophagous leeches (Whitmania spp.): focusing on antithrombotic genes

Leeches are well known for their blood-feeding habits and are widely used for medicinal purposes as they secrete various antithrombotic substances. However, some leeches such as Whitmania spp. exhibit non-hematophagous feeding habits and their significance for medicinal use is debated. In this study, we provide chromosome-level genomes of two non-hematophagous leeches Whitmania acranulata and Whitmania laevis, and combined with our previous results of Whitmania pigra, we systematically analyzed the similarities and differences on the genomes and especially their antithrombotic genes among the three non-hematophagous Whitmania leeches. For W. acranulata, W. laevis, and W. pigra, the genome size (181.72 Mb, 173.87 Mb, and 173.56), the percentage of repeat sites (29.55%, 28.28%, and 27.02%), and the number of protein-coding genes (27,068, 23,805, and 24,156) were close to each other, respectively. In contrast, both the total number of the antithrombotic genes (100, 63, and 79), and the detailed constitutes of different antithrombotic gene families were obviously different among the three leeches. There were also massive genetic variations among the members within each antithrombotic gene/protein family. RNA-Seq-based gene expression estimation showed that the expression profiles of the antithrombotic gene families were apparently different among the three leeches. This is the most comprehensive comparison of the genomes and antithrombic biomacromolecules for the Whitmania leeches to date. Our results will greatly facilitate the evolutionary research and application of leech derivatives for medical and pharmaceutical purposes of thrombosis.

genomics↗

bioRxiv2024

Nicotine Ameliorates α-synuclein Pre-formed Fibril-Induced Behavioral Deficits and Pathological Features in Mice

BackgroundEpidemiologic study suggests nicotine reduces risk of PD, could be potential treatment for Parkinsons disease. ObjectiveTo study the effect of nicotine on behavioral phenotypes and pathological characteristics of mice induced by human alpha-synuclein preformed fibers (-syn-PFF). MethodsMice were injected with 5 g of human -syn-PFF in the hippocampus while administering nicotine-containing drinking water (200g/mL). After 1 month, the motor ability, mood, spatial learning, and memory ability of the Parkinsons disease(PD)phenotype-like model were detected using open field, rotarod, Y maze, and O maze tests. The expression of pathological -syn, apoptotic proteins and the numbers of glial cells and neural stem cells in the hippocampus of mice were detected using western blotting and immunofluorescence. ResultsNicotine significantly reduced pathological -syn accumulation, -syn serine 129 phosphorylation and cell death caused by PFF injection in the hippocampus of mice, inhibited the increase of glial, microglia and apoptotic cells, decreased the expression levels of PI3K and Akt. ConclusionsNicotine may have inhibitory effects on human -syn-PFF-induced neuroinflammation and apoptosis. Thus, it reduces human -syn-PFF-induced behavioral deficits and pathological changes in mice.

animal behavior and cognition↗