Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 325 records · Page 18Linked to original sources

bioRxiv2024

Versatile Stain Transfer in Histopathology Using a Unified Diffusion Framework

Histological staining is vital in clinical pathology for visualizing tissue structures. However, these techniques are laborious and time-consuming. Digital virtual staining offers a promising solution, but existing methods typically rely on Generative Adversarial Networks (GANs), which may suffer from artifacts and mode collapse. Motivated by the success of diffusion models, we present DUST, a novel Diffusion-based Unified framework for versatile Stain Transfer in histopathology. To enhance domain awareness and task-specific performance, we propose a dual encoding strategy that integrates the stain types of both the source and target domains. Additionally, we introduce a dynamic dual-output head to address the unstable intensity issue encountered with conventional DDPM implementations. Validated on a curated fourstain kidney histopathological dataset (H&E, MT, PAS, and PASM), DUST demonstrates superior versatile stain transfer capabilities. Our research highlights the potential of diffusion models to advance virtual staining, paving the way for more efficient digital pathology analyses.

pathology↗

bioRxiv2024

scTrace+: enhance the cell fate inference by integrating the lineage-tracing and multi-faceted transcriptomic similarity information

Deciphering the cell state dynamics is crucial for understanding biological processes. Single-cell lineage tracing technologies provide an effective way to track the single-cell lineages by heritable DNA barcodes, but the high missing rates of lineage barcodes and the intra-clonal heterogeneity bring great challenges for dissecting the mechanisms of cell fate decision. Here, we systematically evaluate the feature of single-cell lineage tracing data, and then develop an algorithm scTrace+ to enhance the cell dynamic traces by incorporating multi-faceted transcriptomic similarities into lineage relationships via a Kernelized Probabilistic Matrix Factorization model. We assess its feasibility and performance by conducting ablation and benchmarking experiments on multiple real datasets, and show scTrace+ can accurately predict the fates of cells. Further, scTrace+ effectively identifies some important driver genes implicated in cellular fate decision of diverse biological processes, such as the cell differentiation or the tumor drug responses.

bioinformatics↗

bioRxiv2024

Common AAV gene therapy vectors show indiscriminate transduction of living human brain cell types

The development of cell-type-specific gene therapy vectors for treating neurological diseases holds great promise, but has relied on animal models with limited translational utility. We have adapted an ex vivo organotypic model to evaluate adeno-associated virus (AAV) transduction properties in living slices of human brain tissue. Using fluorescent reporter expression and single-nucleus RNA sequencing, we found that common AAV vectors show broad transduction of normal cell types, with protein expression most apparent in astrocytes; this work introduces a pipeline for identifying and optimizing AAV gene therapy vectors in human brain samples.

bioengineering↗

bioRxiv2024

Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in tumor growth and immune modulating functions. Previous research indicated that a VIP antagonist (VIPhyb) enhances T-cell activation and induces T-cell-dependent anti-leukemic activity in mice. We created a combinatorial library of VIPhyb C-terminal sequence variations to develop a more potent VIP-receptor (VIP-R) antagonist, hypothesizing that specific amino acid substitutions would improve receptor binding and plasma stability. In silico screening analyses identified sequences with improved docking scores predicting increased binding affinity to human VIP receptors VPAC1 and VPAC2. Fifteen peptides were synthesized and tested for their ability to potentiate activation of purified mouse and human T cells and enhance T cell-dependent anti-leukemia responses in murine models of acute myeloid leukemia. Treating C57Bl/6 mice engrafted with a C1498 myeloid leukemia cell line with daily subcutaneous injections of VIP-R antagonist peptides induced T cell activation resulting in specific anti-leukemia responses. Strikingly, the predicted binding affinity of the VIP-R antagonists to VIP receptors correlated positively with their ability to augment mouse T-cell proliferation and anti-leukemia activity. ANT308 and ANT195 emerged as top candidates due to their high predicted VIP-R binding, low EC50 for in vitro T cell activation, and potent anti-leukemia activities. ANT308 decreased CREB phosphorylation, a downstream signaling pathway of the VIP receptor, and stimulated granzyme B and perforin expression in CD8+ T cells from AML patients. Combining in silico modeling, in vitro T cell activation properties, and in vivo anti-leukemia activity has identified promising VIP-R antagonist candidates for further development as novel immunotherapies for AML, especially for patients with relapsed disease.

immunology↗

bioRxiv2024

Interpretable PROTAC degradation prediction with structure-informed deep ternary attention framework

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional ligands that form ternary complexes with Protein Of Interests (POIs) and E3 ligases, exploiting the ubiquitin-proteasome system to degrade disease-associated proteins, promising to drug the undruggable. While PROTAC research primarily relies on costly and time-consuming wet experimental approaches, deep learning offers a promising avenue to accelerate development and reduce expenses. However, existing deep learning methods for PROTAC degradation prediction often overlook the significance of hierarchical molecular representation and protein structural information, hindering effective data modeling. Moreover, their black-box nature limits the interpretability of computational outcomes, failing to provide intuitive insights into substructure interactions within the PROTAC system. This study introduces PROTAC-STAN, a structure-informed deep ternary attention network (STAN) framework for interpretable PROTAC degradation prediction. PROTAC-STAN represents PROTAC molecules across atom, molecule, and property hierarchies and incorporates structure information for POIs and E3 ligases using a protein language model infused with structural data. Furthermore, it simulates interactions among three entities at the atom and amino acid levels via a novel ternary attention network tailored for the PROTAC system, providing unprecedented insights into the degradation mechanism. By integrating hierarchical PROTAC molecule representation, structural embedding of POI and E3 ligase, and ternary attention network modeling interactions, our approach substantially improves prediction accuracy by 10.95% while enabling significant model interpretability via atomic and residue level visualization of molecule and complex. Experiments on the refined public PROTAC dataset demonstrate that PROTAC-STAN outperforms state-of-the-art baselines in overall performance. The excellent performance of PROTAC-STAN is anticipated to establish it as a foundational tool in future research on PROTAC-related drugs, thereby accelerating the development of this field.

bioinformatics↗

bioRxiv2024

Image-based DNA Sequencing Encoding for Detecting Low-Mosaicism Somatic Mobile Element Insertions

Active LINE-1 (L1), Alu, and SVA mobile elements in the human genome are capable of retrotransposition, resulting in novel mobile element insertions (MEIs) in both germline and somatic tissues. Detecting MEIs through DNA sequencing relies on supporting reads overlapping MEI junctions; however, artifacts from DNA amplification, sequencing, and alignment errors produce numerous false positives. Systematic detection of somatic MEIs, particularly those with low mosaicism, remains a significant challenge. Previous methods had required a high number of supporting reads which limits the detection sensitivity, or human inspections that are susceptible to biases. Here, we developed RetroNet, an algorithm that encodes MEI-supporting sequencing reads into images, and employs a deep neural network to identify somatic MEIs with as few as two reads. Trained on extensive and diverse datasets and benchmarked across various conditions, RetroNet surpasses previous methods and eliminates the need for extensive manual examinations. The RetroNet analysis on the Illumina sequencing of 161x or 195x of a cancer cell line achieved an average precision of 0.885 and recall of 0.579 for detecting somatic L1 insertions that are present in as few as 1.79% of the cells. Additionally, we demonstrated that RetroNet is effective for analyzing highly degraded DNA, such as circulating tumor DNA. RetroNet is applicable to the rapidly generated short-read sequencing data and has the potential to provide further insights into the functional and pathological implications of somatic retrotranspositions.

genomics↗

bioRxiv2024

YY1 Enhances the Stability of HIF-1α Protein by Interacting with NUSAP1 in Macrophages within the Prostate Cancer Microenvironment

Immune checkpoint therapy for prostate cancer (PCa) has failed in clinical trials; however, the precise underlying mechanisms involved remain elusive. PCa, a classic "immune-cold" tumor, is characterized by an immunosuppressive tumor microenvironment. Within this milieu, macrophages, the predominant immune cell population, have a propensity to infiltrate the hypoxic zones of tumors. In a previous study, we showed that Yin Yang 1 (YY1) is highly expressed in macrophages in PCa tissues. Here, through multiplexed imaging mass cytometry (IMC) of a PCa tissue microarray, we further demonstrate that YY1+ macrophages aggregate in hypoxic areas of tumors and that hypoxia promotes the phase separation of YY1 in the nucleus by increasing YY1 tyrosine phosphorylation in macrophages. Furthermore, YY1 binds to NUSAP1 and promotes the SUMOylation of HIF-1, which promotes phase separation and stabilization of the HIF-1 protein. We also demonstrated that either treatment with a small molecule inhibitor (tenapanor) to decrease the YY1-NUSAP1-HIF-1 interaction or myeloid-specific YY1 gene knockout impairs subcutaneous PCa tumor formation. Furthermore, we present a first-generation tetrahedral DNA nanostructure (TDN) based on the proteolysis targeting chimera (PROTAC) technique, named YY1-DcTAC, which targets and degrades YY1 in tumor-associated macrophages. In a PCa mouse model, YY1-DcTAC exhibited prolonged drug efficacy, robust macrophage-specific responsiveness, potent antitumor effects, and increased CD8+ T cell tumor infiltration. In summary, our findings underscore the pivotal role of YY1 within the hypoxia/HIF-1 pathway in tumor-associated macrophages and affirm the therapeutic potential of targeting YY1 for treating PCa.

cancer biology↗

bioRxiv2024

RBPMS and RBPMS2 Cooperate to Safeguard Cardiac Splicing

BackgroundMutations in cardiac splicing factors (SFs) cause cardiomyopathy and congenital heart disease, underscoring the critical role of SFs in cardiac development and disease. Cardiac SFs are implicated to cooperatively regulate the splicing of essential cardiac genes, but the functional importance of their collaboration remains unclear. RNA Binding Protein with Multiple Splicing (RBPMS) and RBPMS2 are SFs involved in heart development and exhibit similar splicing regulatory activities in vitro, but it is unknown whether they cooperate to regulate splicing in vivo. MethodsRbpms and Rbpms2 single or double cardiomyocyte (CM)-specific knockout (KO) mice were generated and analyzed for cardiac phenotypes. RNA sequencing was performed to assess gene expression and splicing changes in single and double KOs. In silico analyses were used to dissect the mechanisms underlying distinct and overlapping roles of RBPMS and RBPMS2 in heart development. ResultsMice lacking both RBPMS and RBPMS2 in CMs died before embryonic day 13.5 and developed sarcomere disarray, whereas Rbpms or Rbpms2 single CM-specific KO mice had normal sarcomere assembly and survived to adulthood. Defective sarcomere assembly is likely owing to the widespread mis-splicing of genes essential for cardiac contraction in double KO mice, underscoring the overlapping role of RBPMS and RBPMS2 in splicing regulation. Mechanistically, we found RBPMS and RBPMS collectively promote cardiac splicing program while repressing non-cardiac splicing programs. Moreover, RNA splicing maps suggested that the binding location of RBPMS and RBPMS2 on pre-mRNA dictates whether they function as splicing activators or repressors. Lastly, the requirement for RBPMS and/or RBPMS2 for splicing regulation arises from intrinsic features of the target exons. ConclusionsOur results demonstrate that RBPMS and RBPMS2 work in concert to safeguard the splicing of genes essential for cardiac contraction, highlighting the importance of SF collaboration in maintaining cardiac splicing signature, which should be taken into consideration when devising future therapeutic approaches through modulating the activity of SFs. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIMutations in cardiac splicing factors (SFs) cause cardiomyopathy and congenital heart disease, and the splicing of cardiac genes is regulated by multiple SFs. However, the functional importance of the collaboration among specific cardiac SFs is unknown. C_LIO_LIRBPMS has emerged as a cardiac SF for sarcomere genes but is not required for sarcomere assembly. C_LIO_LIRBPMS2 can substitute RBPMS in in vitro splicing assays, yet its role in mammalian cardiomyocytes (CMs) remains unclear. C_LI What New Information Does This Article Contribute?O_LIRBPMS and RBPMS2 have both distinct and overlapping roles in CMs. C_LIO_LIRBPMS and RBPMS2 collectively contribute to the maintenance of cardiac splicing program, which is essential for sarcomere assembly and embryonic survival. C_LIO_LIRNA splicing map of RBPMS and RBPMS2 reveals that they can function either as splicing activators or repressors, depending on their binding locations on pre-mRNA. C_LI This study provides compelling evidence of cooperation between cardiac splicing factors during heart development, which, to our knowledge, has not been demonstrated in vivo. Rbpms and Rbpms2 CM-specific double KO mice die in utero and exhibit sarcomere disarray, whereas single KO mice survive to adulthood with normal sarcomere structure but manifest distinct cardiac phenotypes, suggesting RBPMS and RBPMS2 possess both distinct and overlapping functions in CMs. Although mis-splicing in cardiac genes can be seen in all three KOs, the splicing signature of double KO hearts drastically shifts towards non-cardiac tissues, including more prominent mis-splicing in genes related to cardiac contractile function. Our study further reveals that the splicing regulation of RBPMS and RBPMS2 has the characteristics of "positional effects", i.e., the binding location on pre-mRNA dictates whether they function as splicing activators or repressors; and the intrinsic features of the target exon determine the requirement for one or two RBPMS proteins for splicing regulation. Our study sheds light on the functional importance of cardiac SF cooperation in maintaining cardiac splicing signature during heart development.

developmental biology↗

bioRxiv2024

Systems metabolic engineering of Corynebacterium glutamicum for efficient L-tryptophan production

Corynebacterium glutamicum is a versatile industrial microorganism for producing various amino acids. However, there have been no reports of well-defined C. glutamicum strains capable of hyperproducing L-tryptophan. This study presents a comprehensive metabolic engineering approach to establish robust C. glutamicum strains for L-tryptophan biosynthesis, including: (1) identification of potential targets by enzyme-constrained genome-scale modeling; (2) enhancement of the L-tryptophan biosynthetic pathway; (3) reconfiguration of central metabolic pathways; (4) identification of metabolic bottlenecks through comparative metabolome analysis; (5) engineering of the transport system, shikimate pathway, and precursor supply; and (6) repression of competing pathways and iterative optimization of key targets. The resulting C. glutamicum strain achieved a remarkable L-tryptophan titer of 50.5 g/L in 48h with a yield of 0.17 g/g glucose in fed-batch fermentation. This study highlights the efficacy of integrating computational modeling with systems metabolic engineering for significantly enhancing the production capabilities of industrial microorganisms.

synthetic biology↗

bioRxiv2024

Isotonic medium treatment limits burn wound microbial colonization and improves tissue repair

Burn injuries undergo a complex healing process in which progressive spreading of epithelial damage can lead to secondary complications such as wound infection, which is a major driver of mortality among burn patients. We recently reported that burning larval zebrafish triggers dysregulated keratinocyte dynamics compared to mechanical injury. Here, we investigate keratinocyte behavior following burn injury and the subsequent potential for microbial colonization of burn wounds over time. Real-time imaging, coupled with tracking of photoconverted cells, revealed that early keratinocyte motility contributes to the spread of epithelial damage beyond the initial site of burn injury and that increased epithelial damage was associated with wound colonization by the fungal pathogen Candida albicans. Modulating osmotic balance by treating larval zebrafish with isotonic medium limited the spread of epithelial damage and reduced microbial colonization of burn wounds. Using cultured human skin, we found that topical treatment with isotonic solution (saline) similarly prevented the spread of epithelial damage over time. These findings indicate that keratinocyte behavior contribute to burn wound progression in larval zebrafish and link keratinocyte dynamics to microbial colonization of burn wounded tissue.

cell biology↗

bioRxiv2024

Genome-wide investigation of outer membrane protein families under mosaic evolution in Escherichia coli

Several genes in Gram-negative bacteria encoding outer membrane proteins (OMPs) have been reported to show patterns of mosaic evolution featured by mixture of negative selection and local recombination. Here, we proposed a strategy, and applied it to screen OMPs under mosaic evolution in Escherichia coli in the genome level. In total, 21 OMP families, including 16 new ones, were detected with the typical patterns of mosaic evolution. An abosolute majority of the protein families are conserved in E. coli for the composition, genomic loci and the overall structures. Highly Variable Regions (HVRs) can be recognized, which are frequently located extracellularly within the protruding loops. There are only limited number of major HVR sequence types, within which positively selected sites can be detected ocassionally. Based on the simulated results of multiple models, the OMPs under mosaic evolution are often with good antigenicity, with HVRs of various sequence types coinciding with the B-cell epitopes of the strongest immunogenicity. The study futher broadened our understanding of the characteristics of mosaic evolution and the functions of OMPs in Gram-negative bacteria, laying an important foundation for their potential translational applications. ImportanceIt is important to understand the evolutionary mechanisms of bacterial OMP-encoding genes, which would facilitate the development of anti-bacterial reagents. This study made the first genome-wide screening of bacterial OMPs under mosaic evolution, and increased the list of candidate OMP families by 3 folds in E. coli, far more than we expected. The study further confirmed the hypothesis about the evolutionary, micro-evolutionary and structural features of these OMPs, and facilitated the functional theory of mosaic evolution. Moreover, the findings of limited HVR sequence types and strong immunogenicity of HVRs paved important foundation for application of these OMPs and their HVRs in development of antibodies or other anti-bacterial treatment.

microbiology↗

bioRxiv2024

Rational Design of Enhanced Nme2Cas9 and Nme2SmuCas9 Nucleases and Base Editors

CRISPR-Cas genome editing tools enable precise, RNA-guided modification of genomes within living cells. The most clinically advanced genome editors are Cas9 nucleases, but many nuclease technologies provide only limited control over genome editing outcomes. Adenine base editors (ABEs) and cytosine base editors (CBEs) enable precise and efficient nucleotide conversions of A:T-to-G:C and C:G-to-T:A base pairs, respectively. Therapeutic use of base editors (BEs) provides an avenue to correct approximately 30% of human pathogenic variants. Nonetheless, factors such as protospacer adjacent motif (PAM) availability, accuracy, product purity, and delivery limit the full therapeutic potential of BEs. We previously developed Nme2Cas9 and its BE derivatives, including ABEs compatible with single adeno-associated virus (AAV) vector delivery, in part to enable editing near N4CC PAMs. Further engineering yielded domain-inlaid BEs with enhanced activity, as well as Nme2Cas9/SmuCas9 chimeras that target single-cytidine (N4C) PAMs. Here we further enhance Nme2Cas9 and Nme2SmuCas9 editing effectors for improved efficiency and vector compatibility through site-directed mutagenesis and deaminase linker optimization. Finally, we define the editing and specificity profiles of the resulting variants by using paired guide-target libraries.

molecular biology↗

bioRxiv2024

Quantitative light element (sodium and potassium) profiling in plant tissues using monochromatic X-ray fluorescence analysis

Accurately determining the elemental composition of plant tissues is essential for physiological studies on plant stress, including salinity tolerance. However, high-throughput routine analysis of light elements (range of sodium to calcium) in plant samples is challenging due to the need for complete sample dissolution and expensive inductively coupled plasma-mass-spectrometry (ICP-MS) analysis. Lower costs method (ion chromatography, ion selective electrodes) exists, but also require sample dissolution and lack sensitivity for very small samples (<10 mg). This study reports on a new method for the quantitative analysis of light elements in plant tissues using monochromatic X-ray fluorescence (XRF) instrumentation and innovative sample preparation and mounting. We used this approach to assess elemental uptake, distribution, and accumulation in Arabidopsis thaliana and Oryza sativa plants subjected to salt stress. The method can be used on samples as small as 1 mg making it suitable for small Arabidopsis thaliana plants. We systematically evaluated different sample preparations methods, repeatability, and measurement times to confirm the robustness of the technique. The results show that the monochromatic XRF method delivers rapid, non-destructive, and extraction-free analysis, strongly correlating with ICP-MS acquired data. As such, the monochromatic XRF method is a reliable and efficient alternative for studying salinity tolerance ideally suited for investigating elemental composition of early plant developmental stages, offering new possibilities for research into early stimuli sensing, perception and nutrient efficiency.

plant biology↗

bioRxiv2024

WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.

cancer biology↗

bioRxiv2024

NSD2 promotes cell durotaxis and drives the transition from PKD to tubulocystic renal cell carcinoma through integrin/FAK/AKT signaling

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase which has been reported to participate in diverse biological processes and human tumors. However, its role in RCC remains unclear. Here, we found that NSD2 is highly expressed in RCC, which is associated with poor survival in RCC patients. NSD2 facilitates the transition from Myc-induced polycystic kidney disease to tubulocystic renal cell carcinoma (TCRCC), which is a rare RCC subtype with distinctive clinicopathologic and genetic characterizations. The mice with kidney-specific overexpression of MYC and NSD2 (KMN) display severe cyst burden at only 6 weeks of age, and develop into TCRCC at 12 weeks of age. Mechanistically, NSD2 transcriptionally upregulates the expressions of integrins (Itga4 and Itga11), to further activate the FAK/AKT pathway. In addition, we found that NSD2 enhances the cell proliferation on the stiff matrix of PEGDA hydrogel. Moreover, inhibition of FAK signaling relieves the symptoms of KMN mice, and significantly rescues the enhanced cell proliferation caused by NSD2 overexpression in vitro. Together, our findings highlight an epigenetic mechanism by which NSD2 regulates TCRCC tumorigenesis through the integrin/FAK/AKT pathway. This study may also pave the way for the development of targeted, patient-tailored therapies for TCRCC patients with NSD2 amplification or high expression.

cancer biology↗

bioRxiv2024

Fucoidan-Copper Nanoparticles to Potentiate Synergistic Cancer Cell Cuproptosis and Immunotherapy

Cuproptosis, a newly characterized form of regulated cell death initiated by copper binding to lipoylated components of the tricarboxylic acid cycle, presents a promising target for cancer therapy. Here, we report the development of fucoidan-copper nanoparticles (Fu-Cu) that exploit this mechanism to selectively induce cytotoxicity in HuH-7 liver cancer cells. The Fu-Cu was synthesized using fucoidan, a sulfated polysaccharide with inherent anticancer properties, as a natural nanocarrier for copper ions. Characterization confirmed successful copper incorporation and the formation of stable nanoparticles. Fu-Cu treatment enhanced intracellular copper levels and oxidative stress, triggering cuproptosis mediated by mitochondrial carrier homolog 2. Knockout of ferredoxin 1 in HuH-7 cells mitigated the cytotoxic effects, underscoring its critical role in copper-induced cell death. In vivo studies using a subcutaneous tumor model in BALB/c nude mice demonstrated that Fu-Cu effectively inhibited tumor growth and stimulated antitumor immunity, evidenced by increased infiltration of T cells, natural killer cells, and macrophages within the tumor microenvironment. These findings highlight Fu-Cu as a novel therapeutic strategy for HCC, leveraging the mechanism of cuproptosis and immune activation to suppress tumor progression.

cancer biology↗

bioRxiv2024

Bio-medical Big Data Operating System (Bio-OS): An Integrated Data Mining Environment for Data Intensive Scientific Research

The advent of high throughput sequencing has ushered life science and clinical research into the era of big data, posing significant challenges for reproducibility due to the complexity of data integration and analysis. Although the FAIR principles advocate for the transparent and reliable sharing of scientific data, their implementation remains hampered by technical barriers. The Global Alliance for Genomics and Health (GA4GH) has made strides in standardizing data and tools, yet a comprehensive solution for reproducibility is lacking. In response, we present BioOS, an open source, cloud native Biomedical big data Operating System. This system encapsulates study components data, code, tools, and environments into workspaces, enhancing reproducibility and validation. BioOS employs JSON Schema for machine readability and includes a Hierarchy Hash Mechanism to ensure data integrity. Adhering to GA4GH protocols, BioOS simplifies complex technological implementations, making advanced research tools accessible. Demonstrated through representative workspaces, BioOS fosters seamless research replication, peer review, and editorial evaluation. Its cloud native infrastructure supports dynamic resource allocation, enabling efficient handling of large scale analyses. By integrating AI driven Large Language Models, BioOS enhances user interaction and operational flexibility. As an evolving open source platform, BioOS exemplifies a transformative approach to biomedical research, aligning with FAIR principles and advancing the AI for Science paradigm, thus promoting a more connected, efficient, and impactful research environment.

bioinformatics↗

bioRxiv2024

Phosphorylation-dependent tuning of mRNA deadenylation rates

mRNA decay is a major determinant of gene regulation that is controlled through shortening of mRNA poly(A) tails by the Ccr4-Not complex. The specificity of deadenylation can be mediated through RNA adaptors - RNA-binding proteins that tether substrate mRNAs to Ccr4-Not in a regulated and context-specific manner. Interaction with Ccr4-Not is mediated by intrinsically disordered regions (IDRs) within the RNA adaptors. Due to the difficulty in studying large IDR-containing complexes, the determinants of specificity and their regulation remain unclear. Here we use structural biology and biochemical reconstitution to show that dispersed segments within IDRs of RNA adaptors bind to several distinct binding sites on Ccr4-Not through multivalent interactions. We further demonstrate that binding can be modulated by phosphorylation, altering the consequent deadenylation rate in a continuously tunable manner. This mechanism is broadly applicable in evolutionarily divergent IDRs from multiple RNA adaptors including fission yeast Puf3, and human Pumilio/PUM1 and Tristetraprolin/TTP. Together, our work suggests that multivalent interactions and phosphorylation represent conserved strategies for regulating gene expression. Thus, in response to cellular cues, mRNA decay can be regulated by a graded mechanism, rather than a bistable on/off switch, rationalizing how post-transcriptional gene expression is fine-tuned.

molecular biology↗