Biology subjects

Han, Z.

Publications and source records attributed to Han, Z..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Competition and Compromise between Exogenous Probiotics and Native Microbiota

Probiotic interventions are effective strategies to modulate the gut microbiome, but how exogenous probiotics compete with native gut microbiota remains elusive. Here, we use a mouse model and a well-documented probiotic Bifidobacterium animalis subsp. lactis V9 (BV9) to mechanistically investigate its competitive strategies. We perform metagenomic and whole genome sequencing of stool samples and isolated BV9, longitudinally collected from 24 mice orally administered with BV9 and different diets. Results show that a high-fiber diet most effectively supports the colonization of BV9, where BV9 selectively competes with Parabacteroides distasonis (P. distasonis), rather than extensively with other gut bacteria. By comparing the genomic structures of BV9 and P. distasonis isolated during the washout period, we infer their co-evolution mechanisms, highlighting their competition and compromise in utilizing inulin-derived glucose. Finally, our in vitro co-culture experiments validate such competitive dynamics. This study fills a critical gap in our understanding of niche competition in colonization.

microbiology↗

bioRxiv2024

Predatory aggression evolved through adaptations to noradrenergic circuits

Behaviors are adaptive traits evolving through natural selection. Crucially, the genetic, molecular, and neural modifications that shape behavioral innovations are poorly understood. Here, we identify specialized adaptations linked to the evolution of aggression in the predatory nematode Pristionchus pacificus. Using machine learning, we identified robust behavioral states associated with aggressive episodes. These depend on modifications to the invertebrate noradrenergic pathway, with octopamine promoting predatory bouts, and tyramine antagonistically suppressing predation. Strikingly, aggression coincides with rewiring of key circuits across nematode evolution. We find additional octopaminergic neurons with morphological adaptations, including neurites extending to teeth-like structures, and expanded receptor expression throughout head sensory neurons gating prey detection. Thus, evolutionary adaptations in noradrenergic circuits facilitated the emergence of aggressive behavioral states associated with complex predatory traits.

animal behavior and cognition↗

bioRxiv2024

The state-of-the-art machine learning model for Plasma Protein Binding Prediction: computational modeling with OCHEM and experimental validation

Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Prediction of PPB is an alternative to experimental approaches that are known to be time-consuming and costly. Although there are various models and web servers for PPB prediction already available, they suffer from low prediction accuracy and poor interpretability, in particular for molecules with high values, and are most often not properly validated in prospective studies. Here, we carried out strict data curation, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model was further validated in a prospective study to predict 63 poly-fluorinated and another 25 highly diverse compounds, and its performance for both these sets was superior to that of other previously reported models. To identify structural features related to PPB, we analyzed a model based on Morgan2 fingerprints and identified that features such as aromatic rings, halogen atoms, heterocyclic rings can discriminate high- and low-PPB molecules. In conclusion, we have established a PPB prediction model that showed state-of-the-art performance in prospective screening, which we have made publicly available in the OCHEM platform (https://ochem.eu/article/29). Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/603170v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@660730org.highwire.dtl.DTLVardef@61f81corg.highwire.dtl.DTLVardef@1e80d07org.highwire.dtl.DTLVardef@1af719a_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Identifying Alzheimer's disease-related pathways based on whole-genome sequencing data

Alzheimers disease (AD) is a highly inheritable neurodegenerative disorder for which pathway-specific genetic profiling provides insights into its key biological mechanisms and potential treatment targets. Traditional disease-pathway analyses for AD have certain limitations, such as environmental interference and arbitrary sample division. We present a comprehensive framework that starts with genome data, avoiding these drawbacks and offering intrinsic pathway-specific genetic profiling for AD. Whole genome sequencing data from 173 individuals were used to quantify transcriptomes in 14 brain regions, estimate individual-level pathway variant scores, and analyze AD risk for each patient. These results were combined to identify AD-related pathways and quantify their interactions. The predicted expression levels were consistent with previous findings, and the estimated AD risk showed a significant correlation with Braak/Thal scores. A total of 3,798 pathways were identified as potentially associated with AD, with about 19.7% previously reported. Key pathways, including NF-{kappa}B signaling and GSK3{beta} activation, were linked to AD pathogenesis. The interactions among pathways highlighted shared gene functions in AD. In summary, we provided an effective framework for disease-pathway analysis, revealing the interdependence or compensatory effects of pathways in AD.

bioinformatics↗

bioRxiv2024

Mapping the impact of age and APOE risk factors for late onset Alzheimer disease on long range brain connections through multiscale bundle analysis

Alzheimers disease currently has no cure and is usually detected too late for interventions to be effective. In this study we have focused on cognitively normal subjects to study the impact of risk factors on their long-range brain connections. To detect vulnerable connections, we devised a multiscale, hierarchical method for spatial clustering of the whole brain tractogram and examined the impact of age and APOE allelic variation on cognitive abilities and bundle properties including texture e.g., mean fractional anisotropy, variability, and geometric properties including streamline length, volume, and shape, as well as asymmetry. We found that the third level subdivision in the bundle hierarchy provided the most sensitive ability to detect age and genotype differences associated with risk factors. Our results indicate that frontal bundles were a major age predictor, while the occipital cortex and cerebellar connections were important risk predictors that were heavily genotype dependent, and showed accelerated decline in fractional anisotropy, shape similarity, and increased asymmetry. Cognitive metrics related to olfactory memory were mapped to bundles, providing possible early markers of neurodegeneration. In addition, physiological metrics such as diastolic blood pressure were associated with changes in white matter tracts. Our novel method for a data driven analysis of sensitive changes in tractography may differentiate populations at risk for AD and isolate specific vulnerable networks.

neuroscience↗

bioRxiv2024

Collective phases and long-term dynamics in a fish school model with burst-and-coast swimming

Intermittent and asynchronous burst-and-coast swimming is widely adopted by various species of fish as an energy-efficient locomotion mode. This swimming mode significantly influences the way in which fish integrate information and make decisions in a social context. Here, we introduce a simplified fish school model in which individuals have an asynchronous burst-and-coast swimming mode and selectively interact only with one or two neighbors that exert the largest influence on their behavior and over a limited spatial range. The interactions consist for a fish to be attracted and aligned with these neighbors. We show that, by adjusting the interactions between individuals above a sufficiently high level, depending on the relative strength of attraction and alignment, the model is able to produce a cohesive fish school that replicates the main collective phases observed in nature: schooling, milling and swarming when each individual interacts with only one neighbor, and schooling and swarming when each individual interacts with two neighbors. Moreover, the model shows that these patterns can be maintained over long simulations. However, with the exception of swarming, these patterns do not persist indefinitely in time and fish lose cohesion and progressively disperse. We further identify the mechanisms leading to the dispersion.

animal behavior and cognition↗

bioRxiv2024

Genetic regulation of lncRNA expression in the whole human brain

Long non-coding RNAs (lncRNAs) play a key role in the human brain, and genetic variants regulate their expression. Herein, the expression quantitative trait loci (eQTL) of lncRNAs encompassing ten brain regions from 134 individuals was analyzed, and novel variants influencing lncRNA expression (eSNPs) and the respective affected lncRNAs (elncRNAs) were identified. The eSNPs are proximate to their corresponding elncRNAs, enriched in the non-coding genome, and have a high minor allele frequency. The elncRNAs exhibit a high-level and complex pattern of expression. The genetic regulation is more tissue-specific for lncRNAs than for protein-coding genes, with notable differences between cerebrum and cerebellum. However, it shows relatively similar patterns across the cortex regions. Furthermore, we observed a significant enrichment of eSNPs among variants associated with neurological disorders, especially insomnia, and identified insomnia-related lncRNAs involved in immune response functions. Moreover, the present study offers an improved tool for lncRNA quantification, a novel approach for lncRNA function analysis, and a database of lncRNA expression regulation in the human brain. These findings and resources will advance the research on non-coding gene expression regulation in neuroscience.

bioinformatics↗

bioRxiv2024

The cornerstone of early diagnosis and immunotherapy of prostate cancer:screening characteristic genes

BackgroundProstate cancer (PCA) has become a common malignant tumor globally, posing a substantial risk to the health of middle-aged and elderly men. However, there is still a lack of effective strategies for early detection and treatment of prostate cancer. The introduction of gene therapy in recent years has shown promise as a potential approach for cancer diagnosis and treatment. Methodology & Theoretical OrientationThe training set data GSE45016, GSE46602, and GSE69223 from the Gene Expression Omnibus (GEO) dataset, along with validation training set data GSE17951, were utilized. Differentially expressed genes (DEGs) between normal individuals and tumor patients were identified by combining the training set data. Subsequent analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were conducted on the DEGs. WGCNA analysis was then performed on the gene expression matrix to identify module genes highly correlated with PCA, followed by the application of the LASSO algorithm to obtain PCA candidate genes. The candidate genes were validated using the area under the receiver operating characteristic (ROC) curve (AUC) to determine key feature genes. Finally, the relationship between key characteristic genes and immune cells was explored. FindingsA total of 54 DEGs were identified, with 26 down-regulated genes and 28 up-regulated genes. The GO function analysis revealed enrichment in processes such as establishment of protein localization to membrane and protein targeting to membrane. KEGG analysis showed enrichment in pathways like eutrophil degranulation, neutrophil activation involved in immune response, and regulation of cell morphogenesis. GSEA analysis highlighted enrichment in pathways like CTRL_VS_ACT_IL4 AND ANTI_IL12_12H_CD4_TCELL_DN. Through WGCNA and LASSO regression analysis, key characteristic genes MARCKSL1, TMTC4, and TTLL12 were identified, with AUC values greater than 0.8 in both the training and validation sets, and were found to be closely associated with immune cell infiltration. Conclusion & SignificanceMARCKSL1, TMTC4, and TTLL12 emerge as crucial genes in the process of PCA, showing significant relevance to immune cell infiltration.this study offers valuable clinical insights into the diagnosis and treatment of prostate cancer through the identification of specific genes associated with the disease.

genomics↗

bioRxiv2024

A Drosophila model to screen Alport syndrome COL4A5 variants for their functional pathogenicity

Alport syndrome is a hereditary chronic kidney disease, attributed to rare pathogenic variants in either of three collagen genes (COL4A3/4/5) with most localized in COL4A5. Trimeric type IV Collagen 345 is essential for the glomerular basement membrane that forms the kidney filtration barrier. A means to functionally assess the many candidate variants and determine pathogenicity is urgently needed. We used Drosophila, an established model for kidney disease, and identify Col4a1 as the functional homolog of human COL4A5 in the fly nephrocyte (equivalent of human podocyte). Fly nephrocytes deficient for Col4a1 showed an irregular and thickened basement membrane and significantly reduced nephrocyte filtration function. This phenotype was restored by expressing human reference (wildtype) COL4A5, but not by COL4A5 carrying any of three established pathogenic patient-derived variants. We then screened seven additional patient COL4A5 variants; their ClinVar classification was either likely pathogenic or of uncertain significance. The findings support pathogenicity for four of these variants; the three others were found benign. Thus, demonstrating the effectiveness of this Drosophila in vivo kidney platform in providing the urgently needed variant-level functional validation. SUMMARY STATEMENTDrosophila, an established model of kidney disease, was used to develop an in vivo functional screen to determine causation for COL4A5 genetic variants linked to Alport syndrome, a progressive nephropathy.

genetics↗

bioRxiv2024

HIV-1 Nef acts in synergy with APOL1-G1 to induce nephrocyte cell death in a new Drosophila model of HIV-related kidney diseases

BackgroundPeople carrying two APOL1 risk alleles (RA) G1 or G2 are at greater risk of developing HIV-associated nephropathy (HIVAN). Studies in transgenic mice showed that the expression of HIV-1 genes in podocytes, and nef in particular, led to HIVAN. However, it remains unclear whether APOL1-RA and HIV-1 Nef interact to induce podocyte cell death. MethodWe generated transgenic (Tg) flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. ResultsWe found that HIV-1 Nef acts in synergy with APOL1-G1 resulting in nephrocyte structural and functional defects. Specifically, HIV-1 Nef itself can induce endoplasmic reticulum (ER) stress without affecting autophagy. Furthermore, Nef exacerbates the organelle acidification defects and autophagy reduction induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating ER stress, triggering nephrocyte dysfunction and ultimately cell death. ConclusionsUsing a new Drosophila model of HIV-1-related kidney diseases, we identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high relevance between Drosophila nephrocytes and human podocytes, this finding suggests ER stress as a new therapeutic target for HIV-1 and APOL1-associated nephropathies. HIGHLIGHTSO_LIA new transgenic Drosophila model to study the pathogenesis of HIV-1-related kidney diseases with nephrocyte-specific expression of HIV-1 nef and an APOL1-G1 risk allele derived from a patient with HIVAN. C_LIO_LIAPOL1-G1 caused organelle acidification defects, reduced formation of autophagolysosomes, and reduced autophagy and protein aggregation, which culminated in ER stress. C_LIO_LIHIV-1 Nef induced ER stress through an autophagy-independent pathway. Furthermore, Nef and APOL1-G1 acted synergistically to heighten ER stress, which resulted in nephrocyte dysfunction and cell death. C_LI SIGNIFICANCE STATEMENTAPOL1 risk alleles are strongly linked to HIV-associated nephropathy (HIVAN) in people of African descent, but how HIV-1 and APOL1 interact and which pathways they might converge upon is unclear. A new Drosophila model to study HIV-1 Nef and APOL1-G1 (a risk allele) showed that Nef can induce ER stress in nephrocytes by itself, as well as exacerbate the organelle acidification defects and reduced autophagy induced by APOL1-G1, which further stimulates ER stress to a level that could cause nephrocyte cell death. Thus, we identified ER stress as the converging point for the synergy between APOL1-G1 and HIV-1 Nef in kidney cells, providing a potential therapeutic target for HIV-1 and APOL1-associated nephropathies.

molecular biology↗

bioRxiv2024

Novel Polymycoviruses Are Encapsidated in Filamentous Virions

Polymycoviridae is a new viral family that was established nearly five years ago, but their viral morphologies (naked or encapsidated) remain controversy since only one member namely, Colletotrichum camelliae filamentous virus 1 (CcFV1), was identified as being encapsidated in filamentous virions. Here, three novel dsRNA viruses belonging to the family Polymycoviridae were identified in three phytopathogenic fungal strains and tentatively named Pseudopestalotiopsis camelliae-sinensis polymycovirus 1 (PscPmV1), and Phyllosticta capitalensis polymycovirus 1 (PhcPmV1) and -2 (PhcPmV2), respectively. PscPmV1 and PhcPmVs have five or six genomic dsRNAs, ranging from 1055 to 2405 bp, encoding five or seven putative open reading frames (ORFs), of which ORF1 encodes an RNA-dependent RNA polymerase, ORF5 encodes a P-A-S-rich protein behaving as coat protein (CP); and dsRNAs 4 and 6 encode putative proteins with unknown functions and share no detectable identities with known viral sequences. Upon examination under transmission electron microscopy after purification from fungal mycelia, PscPmV1 and PhcPmVs were found to be encapsidated in filamentous particles, as was a known polymycovirus, Botryosphaeria dothidea RNA virus 1 (BdRV1), which was previously assumed to likely have no conventional virions. The morphology of PscPmV1 was further supported by the observation that its particles could be decorated by polyclonal antibodies against its CP and bound by immuno-gold particles conjugated to the specific CP antibody. Together with CcFV1 and BdRV1, PcsPmV1 PhcPmVs provide strong evidence to support the notion that polymycoviruses are encapsidated in filamentous virions constituted by P-A-S-rich CPs. Moreover, their biological effects on their fungal hosts were assessed. Significance statementPolymycoviridae, a recently established viral family, has raised questions about encapsidation. Here, we identify and characterize three novel polymycoviral dsRNA viruses in phytopathogenic fungal strains, tentatively named Pseudopestalotiopsis camelliae-sinensis polymycovirus 1, and Phyllosticta capitalensis polymycovirus 1 and -2, respectively. These polymycoviruses possess five or six genomic dsRNAs, ranging from 1055 to 2405 bp, with two encoding putative proteins of unknown functions and sharing no detectable identities with known viral sequences. Their morphologies indicate filamentous virions constituted by P-A-S-rich coat proteins, observed using immunosorbent electron microscopy combined with immune-gold labeling techniques. Additionally, Botryosphaeria dothidea RNA virus 1, previously assumed to lack conventional virions, is also shown to be encapsidated in filamentous particles. This study provides new evidence supporting the encapsidation of polymycoviruses into elongated and flexuous virions, significantly contributing to our understanding of the evolutionary particle architecture within the virosphere and expanding our knowledge of viral diversity and evolution.

microbiology↗

bioRxiv2024

JAK-STAT pathway activation compromises nephrocyte function in a Drosophila high-fat diet model of chronic kidney disease

Chronic kidney disease is a major health issue and is gaining prevalence. Using a Drosophila model for chronic kidney disease, we show that a high-fat diet (HFD) disrupts the slit diaphragm filtration structure in nephrocytes, the fly functional equivalent of mammalian podocytes. The structural disruption resulted in reduced filtration function in the affected nephrocytes. We demonstrate that HFD activates the JAK-STAT pathway in nephrocytes, which has previously been linked to diabetic kidney disease. JAK-STAT activation was initiated by increased expression and release of the adipokine, Upd2, from the fat body. This leptin-like hormone is a known ligand of JAK-STAT. Both genetic and pharmacological inhibition of JAK-STAT restored nephrocyte HFD-associated dysfunction. Altogether, our study reveals the importance of the JAK-STAT signaling pathway in the adipose tissue-nephrocyte axis and its contribution to HFD-associated nephropathy. These findings open new avenues for intervention in treating diabetic nephropathy and chronic kidney disease. HIGHLIGHTSO_LIHigh-fat diet (HFD) disrupt nephrocyte slit diaphragm structure and filtration C_LIO_LIHFD releases fat body adipokine, Upd2, which activates JAK-STAT in nephrocytes C_LIO_LIGenetic/pharmacological inhibition of JAK-STAT reverses HFD nephrocyte dysfunction C_LIO_LIJAK-STAT signaling mediates adipose-nephrocyte axis in HFD-associated nephropathy C_LI IMPACT STATEMENTUsing a Drosophila model for chronic kidney disease, Zhao et al. show that a high-fat diet induces excretion of a leptin-like JAK-STAT ligand from the fat body. Thus, driving the adipose-nephrocyte (podocyte equivalent) axis through activated JAK-STAT signaling. These findings link obesity to kidney disease, implicating new avenues for therapeutics.

molecular biology↗

bioRxiv2024

Screening and assessment of functional variants by regulatory features from epigenomic data in livestock species

BackgroundUnderstanding the functional impact of genetic variants is essential for advancing animal genomics and improving livestock breeding. Variants that disrupt transcription factor (TF) motifs provide a means to assess functional potential, but the lack of TF ChIP-seq data for farm animals presents a challenge. ResultsTo address this, we curated nearly 900 epigenomic datasets from 10 farm animal species and annotated eight regulatory regions to assess how variants affect TF motifs. Over 127 million candidate functional variants were classified into five functional confidence categories across the species. Variants with high confidence were enriched in eQTLs and trait-associated SNPs, showing greater potential to affect gene expression and phenotypes. Incorporating these functional variants into genomic prediction models improved the accuracy of Estimated Breeding Values (EBVs). Active variants also revealed trait-related tissues, and single-cell RNA sequencing (scRNA-seq) identified the cell types most associated with production traits. To facilitate research, we developed the Integrated Functional Mutation (IFmut) platform, enabling users to explore variant functions easily. Our study provides a flexible platform and resource for studying genomic variation in farm animals, setting a new standard for research and breeding strategies. ConclusionThe results indicated that evaluating functional potential by annotating and categorizing variants that interfere with transcription factor motifs can help elucidate changes in gene expression and phenotype. By focusing on high-confidence variants enriched in eQTL and trait-associated SNPs, it improves the accuracy of genomic predictions in research and breeding strategies.

genomics↗

bioRxiv2024

Chromosome segment scanning for gain- or loss-of-function screening (CHASING) and its application in metabolic engineering

Constructing a library of thousands of single-gene knockout or interference strains is a powerful tool to understand the relation between genotype and phenotype, but it is labor and cost intensive. Powered by the computer-aided gene annotation and functional grouping of non-essential genes, we showed that targeting a single gene directly to a specific observed phenotype could be quickly achieved for a specific microorganism via constructing a library of strains containing single chromosome-segment-deletion per strain. As a proof-of-concept, a genome-scale library consisting of 70 chromosome-segment-deletion strains for B. subtilis was constructed by CRISPR-based methods and strains with six loss-of- and gain-of-function phenotypes were screened out. To facilitate the rapid genotyping, we developed a web tool to visualize the potential targets of each chromosome segment associated with a particular function, successfully identifying the genes for valuable representative phenotypes. To apply the library to metabolic engineering, the hosts with improved production capacity of acetoin and lycopene were screened in the presence of pathway genes. This work demonstrated the significance of our strategy of chromosome segment scanning for gain- or loss-of-function screening (CHASING) on functional genomics investigation, robust chassis engineering, and chemical overproduction. O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/578163v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@19b4938org.highwire.dtl.DTLVardef@1e41d2eorg.highwire.dtl.DTLVardef@137d4b3org.highwire.dtl.DTLVardef@6d4bfc_HPS_FORMAT_FIGEXP M_FIG TOC C_FIG

bioengineering↗

bioRxiv2024

Polydopamine Nanoparticles as Mimicking RPE Melanin for the Protection of Retinal Cells Against Blue Light-Induced Phototoxicity

Exposure of the eyes to blue light can induce the overproduction of reactive oxygen species (ROS) in the retina and retinal pigment epithelium (RPE) cells, potentially leading to pathological damage of age-related macular degeneration (AMD). While the melanin in RPE cells absorbs blue light and prevents ROS accumulation, the loss and dysfunction of RPE melanin due to age-related changes may contribute to photooxidation toxicity. Herein, we present a novel approach utilizing a polydopamine-replenishing strategy via a single-dose intravitreal (IVT) injection to protect retinal cells against blue light-induced phototoxicity. To investigate the effects of overexposure to blue light on retinal cells, we created a blue light exposure Nrf2-deficient mouse model, which are susceptible to light-induced retinal lesions. After blue light irradiation, we observed retina degeneration and an overproduction of ROS. The Polydopamine-replenishing strategy demonstrated effectiveness in maintaining retinal structural integrity and preventing retina degeneration by reducing ROS production in retinal cells against the phototoxicity of blue light exposure. Our findings highlight the potential of polydopamine as a simple and effective replenishment for providing photoprotection against high-energy blue light exposure. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/575719v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1e60e66org.highwire.dtl.DTLVardef@bb7071org.highwire.dtl.DTLVardef@1d31a7aorg.highwire.dtl.DTLVardef@6f51f5_HPS_FORMAT_FIGEXP M_FIG C_FIG The graphic illustration of PDA-mediated photoprotection strategies to mimic natural melanin in RPE cells against blue light-induced phototoxicity in an Nrf2-deficient mouse model via a single-dose intravitreal (IVT) administration.

pharmacology and toxicology↗

bioRxiv2024

De novo multi-mechanism antimicrobial peptide design via multimodal deep learning

Artificial intelligence (AI)-driven discovery of antimicrobial peptides (AMPs) is yet to fully utilise their three-dimensional (3D) structural characteristics, microbial specie-specific antimicrobial activities and mechanisms. Here, we constructed a QLAPD database comprising the sequence, structures and antimicrobial properties of 12,914 AMPs. QLAPD underlies a multimodal, multitask, multilabel, and conditionally controlled AMP discovery (M3-CAD) pipeline, which is proposed for the de novo design of multi-mechanism AMPs to combat multidrug-resistant organisms (MDROs). This pipeline integrates the generation, regression, and classification modules, using a innovative 3D voxel coloring method to capture the nuanced physicochemical context of amino acids, significantly enhancing structural characterizations. QL-AMP-1, discovered by M3-CAD, which possesses four antimicrobial mechanisms, exhibited low toxicity and significant activity against MDROs. The skin wound infection model demonstrates its considerable antimicrobial effects and negligible toxicity. Altogether, integrating 3D features, specie-specific antimicrobial activities and mechanisms enhanced AI-driven AMP discovery, making the M3-CAD pipeline a viable tool for de novo AMP design.

bioengineering↗

bioRxiv2023

Cardiac neurons expressing a glucagon-like receptor mediate cardiac arrhythmia induced by high-fat diet in Drosophila

Cardiac arrhythmia leads to increased risks for stroke, heart failure, and cardiac arrest. Arrhythmic pathology is often rooted in the cardiac conduction system, but the mechanism is complex and not fully understood. For example, how metabolic diseases, like obesity and diabetes, increase the risk for cardiac arrhythmia. Glucagon regulates glucose production, mobilizes lipids from the fat body, and affects cardiac rate and rhythm, attributes of a likely key player. Drosophila is an established model to study metabolic diseases and cardiac arrhythmias. Since glucagon signaling is highly conserved, we used high-fat diet (HFD)-fed flies to study its effect on heart function. HFD led to increased heartbeat and an irregular rhythm. The HFD-fed flies showed increased levels of adipokinetic hormone (Akh), the functional equivalent to human glucagon. Both genetic reduction of Akh and eliminating the Akh producing cells (APC) rescued HFD-induced arrhythmia, whereas heart rhythm was normal in Akh receptor mutants (AkhRnull). Furthermore, we discovered a pair of cardiac neurons that express high levels of Akh receptor. These are located near the posterior heart, make synaptic connections at the heart muscle, and regulate heart rhythm. Altogether, this Akh signaling pathway provides new understanding of the regulatory mechanisms between metabolic disease and cardiac arrhythmia. HIGHLIGHTSO_LIHigh-fat diet activates Akh (glucagon-like)-producing neurons near the esophagus in Drosophila C_LIO_LIReducing Akh prevents high-fat diet-induced cardiac arrhythmia in flies C_LIO_LIDiscovery of two neurons located at the posterior end of the heart that express the Akh receptor (AkhR) and innervate the heart C_LIO_LIEliminating one of the two AkhR-expressing cardiac neurons (ACN) results in cardiac arrhythmia, whereas the absence of functional AkhR prevents high-fat diet-induced cardiac arrhythmia in flies C_LI

molecular biology↗

bioRxiv2023

UDP-glucosyltransferase 71C4 regulates seed development by redistributing phenylpropanoid metabolism in cotton

Seeds are important for plant reproduction, and hence it is important to identify genes regulating seed development. Here, we focused on a member of the glycosyltransferase (GT) family, UDP-glucosyltransferase 71C4 (UGT71C4), which influences the seed width, seed length, and yield traits (lint percentage and seed index) by regulating the lignin and flavonoid pathways of phenylpropane metabolism, affects the oil and protein contents of mature seeds, and controls the seed size by regulating cell proliferation. Overexpression of UGT71C4 leads to seed enlargement by activating expression of peroxiredoxins and the flavonoid metabolism pathway; induces accumulation of ROS, which promotes cell proliferation; and significantly improves yield traits, with the seed index increasing from 10.66 to 11.91 and protein increasing by 5.34%, but oil content decreasing 8.98%. Conversely, knockout of UGT71C4 causes seeds to become smaller; the lignin metabolism pathway to be activated, especially enzymes relating to lignin synthesis leading to increased ectopic deposition of lignin in the ovule and constrained ovule growth and development; and significant improvement of yield traits, with lint percentage increasing from 39.62% to 41.94%, seed index decreasing from 10.66 to 8.60, protein content decreasing 4.28%, and no significant change in oil content. Our research provides new insights into seed size regulation through UDP-glucosyltransferase, providing potential methods for improving plant yield.

plant biology↗