Biology subjects

Tang, C.

Publications and source records attributed to Tang, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Synthetic bacterial community colonizes wheat roots grown in soil and mimics the assembly pattern of a field community

The root microbiome is important for plant development. The impact of the root microbiome is the sum of multiple complex interactions among microorganisms, the plant and the environment. This complexity can be reduced by designing synthetic bacterial communities (SynComs) consisting of bacteria isolated from the roots, making it possible to study these interactions. However, the translational power from SynCom experiments to explain field observations is still very low, which demonstrates the need for development of SynComs that colonize plants comparable to what is observed in the field. Hence, we developed a SynCom consisting of 13 different strains from 13 genera with varying phenotypes originating from the roots of winter wheat (Triticum aestivum cv. Sheriff). The SynCom was inoculated into gamma-irradiated soil prior to sowing and community assembly was determined over 4 weeks using 16S rRNA amplicon sequencing. The SynCom supported growth of winter wheat over a 4-week period and developed in a comparable manner to a more diverse natural community (NatCom) obtained from a soil solution. Furthermore, the temporal dynamics of the majority of the SynCom strains mimicked the development in relative abundance of their respective genera in field grown winter wheat of similar cultivar. However, this could not be translated to a different cultivar (Herup). Our results demonstrate how SynComs inoculated into gamma-irradiated soil can provide a framework for bridging the gap between greenhouse and lab experiments and field observations. At the same time it highlights the plant-genotype specific impact on community assembly.

microbiology↗

bioRxiv2025

Illuminating the Virosphere's Dark Matter using Hierarchical Deep Learning

Systematic discovery of novel viruses is essential for pandemic preparedness, understanding tumor-associated viruses, developing viral delivery systems, and advancing biomedical applications. Yet, the majority of sequences in metagenomic datasets lack close relatives in existing references, representing a vast viral "dark matter" whose biology and evolution remain largely unknown. The central task is threefold: 1) to determine whether a genome is viral or non-viral, 2) to correctly assign viral genomes to known lineages when possible, and, critically, 3) to recognize when no existing lineage applies and thereby identify candidates for entirely novel viral groups. Existing approaches, which depend on sequence homology or narrow markers, struggle to capture this uncharted viral space. Here we present DeepVirus, a hierarchical transformer-based framework that models viral genomes as structured sequences of protein-coding genes. By combining protein-level embeddings from a foundation model with genome-aware representations, DeepVirus not only achieves accurate classification across deep taxonomic hierarchies, but also extends beyond conventional classification to detect and organize candidate novel viral lineages through open-set recognition. Applied to large-scale metagenomic resources, DeepVirus uncovered extensive viral diversity, including previously uncharacterized RNA-dependent RNA polymerases (RdRps), thereby expanding the known evolutionary space of RNA viruses. DeepVirus integrates deep learning with genome-aware open-set discovery to illuminate viral dark matter, providing a foundation for systematic viral taxonomy and advancing exploration of the global virosphere, with broad implications for safeguarding human health.

bioinformatics↗

bioRxiv2025

Dual inhibition of sEH and COX-2 Improved Cognition in Alzheimer's Disease via Enhanced Myogenic Response and Cerebral Artery Distensibility

Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimers disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the Novel Object Recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 M) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Vehicle-treated AD rats displayed impaired functional hyperemia, whereas PTUPB (1 M) significantly restored this response. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats indicated that PTUPB influences genes related to contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD, likely by enhancing myogenic response and increasing cerebral artery distensibility. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.

neuroscience↗

bioRxiv2025

Glycemia Shift Pancreatic Islets Rhythmicity via δ-α Cell in vivo, Impairment in Diabetes

Blood glucose homeostasis relies on the well-coordinated rhythmic activity of millions of islets throughout the pancreas. Islet rhythmicity is triggered by glucose elevation and mediated by paracrine interactions. However, the dynamics of islet population rhythmicity in healthy and diabetic pancreases in vivo remain poorly understood. Using simultaneous multi-islet Ca2+ imaging (20-100 islets per experiment) in both live mice and pancreatic tissue slices, we systematically studied how glycemia fluctuations and intra-islet paracrine signaling collectively shape the islet rhythmicity. In this study, we report that a transition from Hyperglycemia to Euglycemia induces a coordinated shift from slow to fast islet Ca2+ oscillations (HESF) in vivo. HESF is conserved in pancreatic tissue slices and isolated islets, however, not dispersed single cells in vitro, suggesting a mechanistic link with paracrine interactions. We found HESF arises from -cell activation, which is inhibited by {delta} cells upon glucose elevation. The autonomous islets mostly differ in phase and period at high glucose level. Diabetic mice with disrupted glycemic stability lost HESF both in vivo and in vitro. Interestingly, HESF is preserved in {beta}-cell knockout Gcgr transgenetic mice, both in vivo and in vitro, suggesting HESFs dependence on Glp1r. Indeed, HESF was restored in semaglutide-treated diabetic mice with stabilized glycemic stability. These findings offer a comprehensive understanding of how {delta} and cells influence islet rhythmicity and precisely maintain the stability of blood glucose.

physiology↗

bioRxiv2025

Intracellular auto-circularizing RNA using human tRNA splicing elements

Circular RNAs (circRNAs), a type of covalently closed RNA, have emerged as crucial regulatory factors in gene expression and development across various organisms. Understanding their formation and functional mechanisms holds potential for therapeutic applications, including novel RNA vaccines against diseases such as COVID-19. However, practical challenges still exist in the preparation of circRNAs. In this study, we explored the influence of human tRNA splicing elements on circRNAs formation and identified effective sequences for intracellular auto-circularization. We developed a generic auto-circularizing RNA (acRNA) framework template, optimized various key components of circRNAs formation, and proposed a more efficient and precise intracellular auto-circularization method. This study provides novel insights into the production mechanism of circRNA and establishes a simple and effective method for intracellular auto-circularization.

cell biology↗

bioRxiv2025

A Photo-regulatable Intein Based Trans-Splicing tool for Protein and Organelle Relocalization to Different Subcellular Compartments

The dynamics of protein subcellular localization are intricately regulated, requiring new tools for controlling protein translocation to uncover the biological significance of post-translational regulation of protein localization. Here, we developed a new method, Protein Rerouting via INtein-mediated Trans-Splicing (PRINTS), which enables precise control of protein translocation across diverse subcellular compartments. By reconstituting functional signaling peptides, PRINTS can efficiently relocalize fluorescent proteins to the 26S proteasome, nucleus, mitochondria, plasma membrane, endomembrane organelles, and liquid-liquid phase separation (LLPS) condensates. Furthermore, we incorporated the optically regulated dimerization domain CRY2clust into the PRINTS system, achieving light-mediated control of protein entry into the cell membrane and LLPS membraneless compartments. Strikingly, we observed that HNRNPA1 promiscuously recruit CRY2- or intein-containing proteins into LLPS condensate, whereas FXR1, another LLPS protein showed minimal non-specific activity. PRINTS also allow organelle relocalization, such as LLPS condensates or mitochondria to cell membrane in a light-controllable manner. Overall, PRINTS provides a versatile and robust platform for manipulating protein and organelle subcellular translocations, offering a powerful tool to investigate the regulatory coordination and crosstalk between membranous and membraneless compartments in response to physiological needs.

cell biology↗

bioRxiv2025

Real-time visualisation of the intracellular dynamics of Shigella virulence plasmid

Bacterial plasmids play critical roles in horizontal gene transfer, antibiotic resistance, virulence, and in shaping the interaction of bacteria with their environment, including those encountered in their hosts. They are integral to bacterial evolution as they act as vectors for rapid genetic change and adaptation. Shigella sonnei is a human-adapted pathogen that is a leading cause of bacillary dysentery and a significant threat to public health. In common to all species of Shigella, S. sonnei harbours an [~] 210 kb virulence plasmid, pINV, which is essential for its virulence. pINV encodes a Type III secretion system that mediates bacterial invasion of epithelial cells. Understanding the dynamics of replication and segregation of pINV is therefore necessary to define how Shigella retains the plasmid and thence virulence. In this study, we used three fluorescent tagging approaches to detect the presence of pINV in live S. sonnei to allow tracking of the plasmid during cell division. Conclusively, we found that tagging the plasmid with the parS-ParB partitioning system sequences from Caulobacter crescentus chromosome, allowed suitable visualization of the single copy pINV in S. sonnei. This comprehensively enabled us to monitor the location and segregation of the plasmid during bacterial growth.

molecular biology↗

bioRxiv2025

CD47 blockade enhances immunoradiotherapy response in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide, with limited treatment options for patients with locally advanced disease. CD47 immune checkpoint inhibitors have been used to block the CD47/SIRPa interaction that inhibits antigen-presenting cell phagocytosis, thereby enhancing antigen presentation to cytotoxic T-cells, and have shown promise in combination with anti-PD1 immunotherapy in tumors, including recurrent/metastatic HNSCC. We found that CD47 expression is associated with poor prognosis in HNSCC and explored the anti-tumor activity of CD47 blockade in combination with anti-PD1 and lymphatic-sparing radiotherapy in a locally advanced HNSCC model. Using the 4MOSC1 orthotopic, syngeneic murine model of HPV-negative HNSCC, treatment with an engineered CD47-blocking SIRP fusion protein (ALX301) similarly induced complete tumor regression in combination with anti-PD1, and a partial response as a standalone therapeutic. An anti-PD1 immune checkpoint inhibitor in a CD47-null tumor background led to complete tumor regression confirming a key role for CD47 in tumor immunity. Anti-CD47 treated mice demonstrated increased MHC-II expression on dendritic cells within the tumor and upregulation of CD86 co-stimulatory molecule on dendritic cells within the tumor, sentinel lymph nodes, and contralateral lymph nodes. Combination ALX301 and anti-PD1 treatment in an anti-PD1 resistant 4MOSC2 model demonstrated significant tumor regression, enhanced survivability, improved response with neoadjuvant radiotherapy, and greater retention of CD8+ T-cells within the tumor microenvironment. Notably, T-cell receptor sequencing revealed increased shared clonality between the tumor and sentinel lymph nodes of anti-CD47 treated mice. These data demonstrate that a combination of CD47 blockade and anti-PD1 therapy enhances tumor antigen presentation and immune cell infiltration, while further improving anti-tumor responses in combination with tumor-targeted radiotherapy. This study provides support for the rational design of combinatorial immunoradiotherapy, using anti-CD47 inhibitors and anti-PD1 therapy, in a clinical trial targeting locally advanced HPV-negative HNSCC.

cancer biology↗

bioRxiv2025

In Vivo Tensor-Valued Diffusion MRI Reveals Isotropic-Anisotropic Kurtosis Mismatch in a Rat MCAO Stroke Model

BackgroundTensor-valued diffusion MRI (dMRI) enables the separation of total kurtosis into isotropic and anisotropic components, offering improved specificity over conventional Diffusion Kurtosis Imaging (DKI). In this study, we introduce a novel framework for detecting anisotropic-isotropic kurtosis mismatch and evaluate its utility in characterizing stroke lesions. MethodsWe performed tensor-valued dMRI in a rat model of middle cerebral artery occlusion (MCAO). Metrics including anisotropic kurtosis (MKA) and isotropic kurtosis (MKI) were quantified to assess microstructural tissue heterogeneity. Histological validation was conducted using co-registered tissue sections. ResultsWe observed significant mismatches between mean diffusivity (MD), mean kurtosis (MK), as well as specifically in MKA and MKI in ischemic regions. Notably, MKA and MKI exhibited statistically significant alterations compared to contralateral regions. Moreover, these metrics strongly correlated with pathological findings. The mismatch highlighted microstructurally distinct subregions within the lesion. ConclusionsThis is the first study to propose an anisotropic-isotropic kurtosis mismatch framework in vivo. Tensor-valued dMRI may offer a more specific imaging biomarker for stroke, with potential for improving lesion subtyping and guiding therapeutic decisions.

biophysics↗

bioRxiv2025

DCX Enhances Glioblastoma Metabolism Through Synergistic Regulation of Glutamine Synthesis and Metabolism-Related Genes for Cellular Homeostasis

Gliomas are the most common primary intracranial tumors, comprising 81% of malignant brain tumors, and currently lack effective therapies. Recent advances in molecular biology have shown that cancer cells exploit microtubule-associated proteins (MAPs) under stress to activate various signaling pathways. This study investigates the role of Doublecortin (DCX) in glioma metabolism and its impact on tumor proliferation. In this study, CRISPR-engineered glioma models with DCX overexpression or knockdown were analyzed using integrated genomic, transcriptomic, and metabolomic approaches. Metabolic activity was assessed via RNA sequencing, Seahorse assays, and targeted mass spectrometry. Pharmacological inhibition of key pathways validated functional dependencies. We demonstrate that gliomas enriched with DCX exhibit elevated glycolytic activity while also relying on cellular respiration and oxidative phosphorylation (OXPHOS) for energy to support the abnormal proliferation of glioma cells. Upon integrative analysis of enriched genes and proteins, we observed genetic and metabolome-level signatures associated with differences in central carbon and energy metabolism in CRISPR-modified glioma cells expressing high DCX. Whole-genome transcriptome analysis revealed enriched metabolic entities promoting hydrolysis of glutamine and glutaminolysis in glioma cells and inhibition of selected differentially enriched genes with small molecule inhibitors abrogated metabolic enrichment and resulted in reduced energy levels and protein translation required for aberrant growth. Finally, we establish that DCX stimulates glutaminolysis to regulate homeostasis for energy supplements in glioma cells. Targeting DCX-mediated metabolic pathways may provide a novel therapeutic approach for glioblastoma, highlighting the potential for innovative treatments in this challenging disease.

cancer biology↗

bioRxiv2025

Scaling Large Language Models for Next-Generation Single-Cell Analysis

AO_SCPLOWBSTRACTC_SCPLOWSingle-cell RNA sequencing has transformed our understanding of cellular diversity, yet current single-cell foundation models (scFMs) remain limited in their scalability, flexibility across diverse tasks, and ability to natively integrate textual information. In this work, we build upon the Cell2Sentence (C2S) framework, which represents scRNA-seq profiles as textual "cell sentences," to train Large Language Models (LLMs) on a corpus comprising over one billion tokens of transcriptomic data, biological text, and metadata. Scaling the model to 27 billion parameters yields consistent improvements in predictive and generative capabilities and supports advanced downstream tasks that require synthesis of information across multi-cellular contexts. Targeted fine-tuning with modern reinforcement learning techniques produces strong performance in perturbation response prediction, natural language interpretation, and complex biological reasoning. This predictive strength enabled a dual-context virtual screen that nominated the kinase inhibitor silmitasertib (CX-4945) as a candidate for context-selective upregulation of antigen presentation. Experimental assessment in human cell models unseen during training supported this prediction, demonstrating that C2S-Scale can effectively guide the discovery of context-conditioned biology. C2S-Scale unifies transcriptomic and textual data at unprecedented scales, surpassing both specialized single-cell models and general-purpose LLMs to provide a platform for next-generation single-cell analysis and the development of "virtual cells."

bioinformatics↗

bioRxiv2025

deepTFBS: Improving within- and cross-species prediction of transcription factor binding using deep multi-task and transfer learning

The precise prediction of transcription factor binding sites (TFBSs) is crucial in understanding gene regulation. In this study, we present deepTFBS, a comprehensive deep learning (DL) framework that builds a robust DNA language model of TF binding grammar for accurately predicting TFBSs within and across plant species. Taking advantages of multi-task DL and transfer learning, deepTFBS is capable of leveraging the knowledge learned from large-scale TF binding profiles to enhance the prediction of TFBSs under small-sample training and cross-species prediction tasks. When tested using available information on 359 Arabidopsis TFs, deepTFBS outperformed previously described prediction strategies, including position weight matrix, deepSEA and DanQ, with a 244.49%, 49.15%, and 23.32% improvement of the area under the precision-recall curve (PRAUC), respectively. Further cross-species prediction of TFBS in wheat showed that deepTFBS yielded a significant PRAUC improvement of 30.6% over these three baseline models. deepTFBS can also utilize information from gene conservation and binding motifs, enabling efficient TFBS prediction in species where experimental data availability is limited. A case study, focusing on the WUSCHEL (WUS) transcription factor, illustrated the potential use of deepTFBS in cross-species applications, in our example between Arabidopsis and wheat. deepTFBS is publically available at https://github.com/cma2015/deepTFBS. One sentence summaryThe high-performing deep learning framework deepTFBS can flexibly perform within- and cross-species prediction of TF binding, transferring the transcription regulation from model to non-model species.

bioinformatics↗

bioRxiv2025

Bifunctional Phagocytic Synapse Enhancers for Cancer Immunotherapy

Immunotherapy profoundly impacted cancer treatments by harnessing the patients immune system. Phagocytosis, the process whereby immune cells engulf and destroy foreign particles or cells, plays a critical role in tumour cell clearance. Herein, we introduce a novel concept termed "ENPHASYS" - Enhancement of Phagocytic Synapses - designed to direct and amplify phagocytosis of cancer cells using heterobifunctional molecules named phagocytic synapse enhancers (PSEs). By engineering a de novo PD-L1 binder linked to a natural phagocytosis promoting peptide, tuftsin, the resulting PSE combines PD-L1 blockade with enhanced tumour cell phagocytosis; in addition, the PSEs induce macrophages to internalize a membrane or extracellular target. Intratumoural treatment of colorectal carcinoma- or glioblastoma-burdened immunocompetent animals resulted in beneficial overall survival, delayed tumour growth and a potent antitumor response driven by T-cell activation and TAM reprogramming, underpinning the translational relevance of ENPHASYS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/642658v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1673fd4org.highwire.dtl.DTLVardef@18fa319org.highwire.dtl.DTLVardef@11cf680org.highwire.dtl.DTLVardef@7b8784_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Excessive zinc reduces histone acetylation in mouse cardiomyocytes by downregulating acetyltransferases

Zinc plays a critical role in cellular functions, but its excess may lead to detrimental effects, including cardiac abnormalities. The impact of zinc overload on cardiomyocytes is investigated in this study. For the first time, we report the regulatory relationship between zinc and histone acetylation. Excessive zinc downregulates the transcription of Bmp4 in HL-1 cell line and primary cardiomyocytes. This downregulation is linked to reduced histone acetylation (H3K9ac), mediated by the suppression of histone acetyltransferases (HATs), rather than changes in histone deacetylases (HDACs). When zinc is introduced directly into the nucleus, Bmp4 expression is upregulated, suggesting that the reduction of histone acetylation by zinc is in an indirect way. This study underscores the importance of zinc homeostasis in maintaining cardiac health and provides insights into the molecular basis of zinc-induced cardiac dysfunction.

cell biology↗

bioRxiv2025

Endurance Exercise Ameliorates Aging-Related Bradyarrhythmia in Drosophila Resulting from miR-283 Knockdown in LNvs

MicroRNAs (miRNAs) are crucial in regulating cardiac aging and related diseases, yet few functional miRNAs have been identified. Prior studies showed miR-216a upregulation in heart failure patients, but its impact on aging hearts is unknown. Our study revealed systemic miR-283 overexpression or knockdown caused age-related bradycardia, mimicking human bradyarrhythmia. Importantly, we found that knockdown of miR-283 in ventral-lateral neurons (LNvs), rather than in the heart, led to the occurrence of bradyarrhythmia, which was mainly caused by the upregulation of miR-283 expression in the whole brain and heart. The gene of clockwork orange (cwo) may mediate miR-283s effect on heart rhythm. Additionally, to investigate the miRNA regulatory mechanism underlying exercise-induced delay in cardiac aging, we conducted a three-week endurance exercise program on miR-283 knockdown flies in LNvs. We found that exercise significantly downregulated the accumulation of miR-283 in the brain and myocardium caused by aging or miR-283 knockdown in LNvs, improved the structure of myocardial fibers, and effectively reduced bradyarrhythmia. Our findings provides a new perspective on distal neuromodulation and intervention in cardiac aging.

physiology↗

bioRxiv2025

Cystinosin is involved in Na+/H+ Exchanger 3 trafficking in the proximal tubular cells: new insights in the renal Fanconi syndrome in cystinosis

Cystinosis is a systemic lysosomal storage disease resulting from a defective CTNS gene, leading to the accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, the renal Fanconi syndrome (FS) is the first manifestation of cystinosis that presents early in life of the patients while other complications appear years later. Additionally, the cystine reduction therapy, cysteamine, does not prevent the FS. While the matter is still unresolved, it is apparent that specific function(s) of cystinosin in the proximal tubular cells (PTCs) beyond cystine transport explain the early tubular defects in cystinosis. Here, we report a novel interaction of cystinosin with the sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes in both yeast and mammalian cells. One isoform of Na+/H+ exchanger, NHE3, is a major absorptive sodium transporter at the apical membrane of the proximal tubules. Cystinosin was found to play a significant role in NHE3 subcellular localization, trafficking, and resulting sodium uptake in PTCs. Interestingly, introduction of CTNS successfully rescued these defects in CTNS-deficient PTCs, whereas CTNS-LKG, the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns-/- mice and cystinosis patient kidney. Interestingly, transplantation of wild-type hematopoietic stem and progenitor cells in Ctns-/- mice restored NHE3 expression at the brush border membrane. This study uncovers a new role of cystinosin in the trafficking of NHE3 in the PTCs that is evolutionary conserved, offering new insights in the pathogenesis of the renal FS in cystinosis and potential new therapeutic avenue for this pathology. SignificanceThis study reveals a new role of cystinosin in the trafficking of NHE3, the Na+/H+ exchanger in the proximal tubular cells (PTCs) in the kidney. NHE3 contributes to the majority of renal sodium absorption and is essential for maintaining the homeostasis of the PTCs. Thus, this study offers new molecular insights in the endosomal trafficking of NHE3 and provides a new mechanism that may explain the underlying pathogenesis and early onset of the renal Fanconi syndrome in cystinosis. Additionally, these findings provide potential new drug targets for this pathology and are also relevant to our ongoing stem cell gene therapy clinical trial for cystinosis, offering valuable information on the potential impact of hematopoietic stem cell transplantation on renal Fanconi syndrome.

molecular biology↗

bioRxiv2025

DMB labelling for detection and analysis of capsular polysaccharides

Bacterial capsules are major virulence factors enabling systemic infection by undermining innate and adaptive immunity. Capsular polysaccharides are also the antigen in some of the most successful antibacterial vaccines - including the pneumococcal, neisserial and Hib conjugate vaccines. However, it remains exceptionally challenging to study capsules, primarily due to their high chemical diversity and the limited methods available for their detection and analysis. We describe a robust biochemical method for detection and analysis of ABC transporter-dependent capsular polysaccharides, a major class of capsules that are associated with extraintestinal pathogenic Escherichia coli (ExPEC). The method involves release and fluorescent tagging of polysaccharides from the cell surface. Anion exchange chromatography of labelled samples reveals the presence, relative abundance, and length-distribution of these diverse polysaccharide antigens. The method provides a modern approach to detecting the capsule phenotype, bridging a critical gap left by the decline of serotyping assays. It will enhance our understanding of fundamental capsule biology and advance the development of capsule-targeting vaccines.

biochemistry↗

bioRxiv2024

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗