Nat Immunol. 2025 Jan 8. doi: 10.1038/s41590-024-02041-2. Online ahead of print.

ABSTRACT

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new 'regulatory' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

PMID:39779870 | DOI:10.1038/s41590-024-02041-2

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08383-z. Online ahead of print.

ABSTRACT

Plants lack specialized and mobile immune cells. Consequently, any cell type that encounters pathogens must mount immune responses and communicate with surrounding cells for successful defence. However, the diversity, spatial organization and function of cellular immune states in pathogen-infected plants are poorly understood1. Here we infect Arabidopsis thaliana leaves with bacterial pathogens that trigger or supress immune responses and integrate time-resolved single-cell transcriptomic, epigenomic and spatial transcriptomic data to identify cell states. We describe cell-state-specific gene-regulatory logic that involves transcription factors, putative cis-regulatory elements and target genes associated with disease and immunity. We show that a rare cell population emerges at the nexus of immune-active hotspots, which we designate as primary immune responder (PRIMER) cells. PRIMER cells have non-canonical immune signatures, exemplified by the expression and genome accessibility of a previously uncharacterized transcription factor, GT-3A, which contributes to plant immunity against bacterial pathogens. PRIMER cells are surrounded by another cell state (bystander) that activates genes for long-distance cell-to-cell immune signalling. Together, our findings suggest that interactions between these cell states propagate immune responses across the leaf. Our molecularly defined single-cell spatiotemporal atlas provides functional and regulatory insights into immune cell states in plants.

PMID:39779856 | DOI:10.1038/s41586-024-08383-z

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08391-z. Online ahead of print.

ABSTRACT

Transcriptional regulation, which involves a complex interplay between regulatory sequences and proteins, directs all biological processes. Computational models of transcription lack generalizability to accurately extrapolate to unseen cell types and conditions. Here we introduce GET (general expression transformer), an interpretable foundation model designed to uncover regulatory grammars across 213 human fetal and adult cell types1,2. Relying exclusively on chromatin accessibility data and sequence information, GET achieves experimental-level accuracy in predicting gene expression even in previously unseen cell types3. GET also shows remarkable adaptability across new sequencing platforms and assays, enabling regulatory inference across a broad range of cell types and conditions, and uncovers universal and cell-type-specific transcription factor interaction networks. We evaluated its performance in prediction of regulatory activity, inference of regulatory elements and regulators, and identification of physical interactions between transcription factors and found that it outperforms current models4 in predicting lentivirus-based massively parallel reporter assay readout5,6. In fetal erythroblasts7, we identified distal (greater than 1 Mbp) regulatory regions that were missed by previous models, and, in B cells, we identified a lymphocyte-specific transcription factor-transcription factor interaction that explains the functional significance of a leukaemia risk predisposing germline mutation8-10. In sum, we provide a generalizable and accurate model for transcription together with catalogues of gene regulation and transcription factor interactions, all with cell type specificity.

PMID:39779852 | DOI:10.1038/s41586-024-08391-z

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08371-3. Online ahead of print.

ABSTRACT

Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression1-3. We previously demonstrated that serotonylation4-10 and dopaminylation9,11-13 of Gln5 of histone H3 (H3Q5ser and H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), and alter both local and global chromatin states. Here we found that TG2 additionally functions as an eraser and exchanger of H3 monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays diurnally rhythmic expression in brain and contributes to circadian gene expression and behaviour. We found that H3Q5his, in contrast to H3Q5ser, inhibits the binding of WDR5, a core member of histone H3 Lys4 (H3K4) methyltransferase complexes, thereby antagonizing methyltransferase activities on H3K4. Taken together, these data elucidate a mechanism through which a single chromatin regulatory enzyme has the ability to sense chemical microenvironments to affect the epigenetic states of cells, the dynamics of which have critical roles in the regulation of neural rhythmicity.

PMID:39779849 | DOI:10.1038/s41586-024-08371-3

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08349-1. Online ahead of print.

ABSTRACT

Sequencing-based genetic tests have uncovered a vast array of BRCA2 sequence variants1. Owing to limited clinical, familial and epidemiological data, thousands of variants are considered to be variants of uncertain significance2-4 (VUS). Here we have utilized CRISPR-Cas9-based saturation genome editing in a humanized mouse embryonic stem cell line to determine the functional effect of VUS. We have categorized nearly all possible single nucleotide variants (SNVs) in the region that encodes the carboxylate-terminal DNA-binding domain of BRCA2. We have generated function scores for 6,551 SNVs, covering 96.4% of possible SNVs in exons 15-26 spanning BRCA2 residues 2479-3216. These variants include 1,282 SNVs that are categorized as missense VUS in the clinical variant database ClinVar, with 77.2% of these classified as benign and 20.4% classified as pathogenic using our functional score. Our assay provides evidence that 3,384 of the SNVs in the region are benign and 776 are pathogenic. Our classification aligns closely with pathogenicity data from ClinVar, orthogonal functional assays and computational meta predictors. We have integrated our embryonic stem cell-based BRCA2-saturation genome editing dataset with other available evidence and utilized the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for clinical classification of all possible SNVs. This classification is available as a sequence-function map and serves as a valuable resource for interpreting unidentified variants in the population and for physicians and genetic counsellors to assess BRCA2 VUS in patients.

PMID:39779848 | DOI:10.1038/s41586-024-08349-1

Sci Rep. 2025 Jan 8;15(1):1369. doi: 10.1038/s41598-025-85249-y.

ABSTRACT

Inflammatory bowel disease (IBD) is a multisystem condition that could affect the cutaneous systems, namely cutaneous extraintestinal manifestations (EIMs). It has been suggested that IBD is associated with erythema nodosum (EN), malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, the potential causal relationship between IBD and the mentioned above cutaneous EIMs is still unclear. This study aims to determine the effect of IBD on EN, MM and NMSC within a Mendelian randomization (MR) design. Summary-level data for IBD, EN, MM, NMSC were obtained from large-scale genome-wide association studies. We utilized five different methods, including the inverse variance weighted model (IVW), MR Egger, Weighted median, Simple mode, Weighted mode in the MR analysis, then the Cochran's Q test, the MR-Egger pleiotropy test, the MR-PRESSO global pleiotropy test and leave-one-out sensitivity test were used to evaluate the heterogeneity and pleiotropy of identified IVs. To further ensure the validity of our findings, we evaluated the strength of the instrumental variables using the F-statistic and estimated the statistical power of our study. Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. MR analysis suggested that genetically determined IBD had a detrimental causal effect on NMSC (IVW: odds ratio [OR] = 1.002037, 95% confidence interval [CI] = 1.0001150-1.003962, P = 0.03776677), but not on EN (IVW: [OR] = 1.0937191, 95% [CI] = 0.9685831-1.235022, P = 0.1484349) and MM (IVW: [OR] = 0.9998064, 95% [CI] = 0.9994885-1.000124, P = 0.2326482). Besides, a positive causal effect of IBD on NMSC was verified in an independent validation dataset (IVW: [OR] = 1.002651, 95% [CI] = 1.0006524-1.004654, P = 0.009307506). The present study corroborated the causal relationship between IBD and NMSC. In contrast, our results showed no evidence of a causal association of IBD on EN and MM. These findings provide new insights into increasing attention to patients with IBD to prevent concurrent NMSC.

PMID:39779820 | DOI:10.1038/s41598-025-85249-y

Sci Rep. 2025 Jan 8;15(1):1324. doi: 10.1038/s41598-024-83401-8.

ABSTRACT

This study aimed to address the limitations of conventional methods for measuring skeletal muscle mass for sarcopenia diagnosis by introducing an artificial intelligence (AI) system for direct computed tomography (CT) analysis. The primary focus was on enhancing simplicity, reproducibility, and convenience, and assessing the accuracy and speed of AI compared with conventional methods. A cohort of 3096 cases undergoing CT imaging up to the third lumbar (L3) level between 2011 and 2021 were included. Random division into preprocessing and sarcopenia cohorts was performed, with further random splits into training and validation cohorts for BMI_AI and Body_AI creation. Sarcopenia_AI utilizes the Skeletal Muscle Index (SMI), which is calculated as (total skeletal muscle area at L3)/(height)2. The SMI was conventionally measured twice, with the first as the AI label reference and the second for comparison. Agreement and diagnostic change rates were calculated. Three groups were randomly assigned and 10 images before and after L3 were collected for each case. AI models for body region detection (Deeplabv3) and sarcopenia diagnosis (EfficientNetV2-XL) were trained on a supercomputer, and their abilities and speed per image were evaluated. The conventional method showed a low agreement rate (κ coefficient) of 0.478 for the test cohort and 0.236 for the validation cohort, with diagnostic changes in 43% of cases. Conversely, the AI consistently produced identical results after two measurements. The AI demonstrated robust body region detection ability (intersection over Union (IoU) = 0.93), accurately detecting only the body region in all images. The AI for sarcopenia diagnosis exhibited high accuracy, with a sensitivity of 82.3%, specificity of 98.1%, and a positive predictive value of 89.5%. In conclusion, the reproducibility of the conventional method for sarcopenia diagnosis was low. The developed sarcopenia diagnostic AI, with its high positive predictive value and convenient diagnostic capabilities, is a promising alternative for addressing the shortcomings of conventional approaches.

PMID:39779762 | DOI:10.1038/s41598-024-83401-8

NPJ Biofilms Microbiomes. 2025 Jan 8;11(1):6. doi: 10.1038/s41522-024-00639-w.

ABSTRACT

This study aims to evaluate differences in gut microbiota structures between infertile women undergoing frozen embryo transfer (FET) with gestational diabetes mellitus (GDM) and healthy controls (HCs), and to identify potential markers. We comprehensively enrolled 193 infertile women undergoing FET (discovery cohort: 38 HCs and 31 GDM; validation cohort: 85 HCs and 39 GDM). Gut microbial profiles of the discovery cohort were investigated during the pre-pregnancy (Pre), first trimester (T1), and second trimester (T2). The microbial community in the HCs group remained relatively stable throughout the pregnancy, while the microbial structure alteration occurred in the GDM group during T2. A model based on ten bacteria and ten metabolites simultaneously was used to predict the risk of GDM developing in the pre-pregnancy state with the ROC value of 0.712. Algorithms on the basis of marker species and biochemical parameters can be used as effective tools for GDM risk evaluation before pregnancy.

PMID:39779730 | DOI:10.1038/s41522-024-00639-w

Nat Commun. 2025 Jan 8;16(1):498. doi: 10.1038/s41467-024-55660-6.

ABSTRACT

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

PMID:39779672 | DOI:10.1038/s41467-024-55660-6

Med Oncol. 2025 Jan 8;42(2):41. doi: 10.1007/s12032-024-02560-w.

ABSTRACT

CRC has the third-highest cancer incidence and death. Many human cancers, including colorectal cancer, are connected to abnormal signaling pathway gene expression. Many human malignancies include Hippo and Rap1 signaling. This research examined curcumin's therapeutic effects on colorectal cancer cell lines' Hippo and Rap1 signaling pathway genes. The role of the above signaling pathways is considered in colorectal cancer development. No research has examined curcumin's influence on key genes in these pathways; thus, this work is meant to uncover its more precise mechanism. First, the gene expression omnibus database is queried to discover GSE8671, a dataset that contains differentially expressed genes associated in CRC formation. DAVID was used to discover the corporation of these genes and signaling pathways (Hippo and Rap1), and the cancer genome atlas (TCGA) database was utilized to select genes and assess their expression and biomarker potential. MTT, apoptosis, and quantitative PCR were used to assess whether curcumin is therapeutic for colorectal cancer cell lines. An in-silico analysis identified the dysregulation of several critical genes AXIN2, MYC, TEAD4, MET, LPAR1, and ADCY9 in colorectal cancer, highlighting their involvement in the Hippo and Rap1 signaling pathways. Experimental assessments, including MTT assays, apoptosis assays, and quantitative PCR (qPCR) analysis, demonstrated that the targeted modulation of these genes effectively inhibits cancer cell proliferation. Specifically, treatment with curcumin resulted in a significant reduction in cell viability in HT-29 and HCT-116 colorectal cancer cell lines, thereby facilitating apoptotic cell death. Furthermore, curcumin administration was associated with the upregulation of LPAR1 and ADCY9 gene expression, while concurrently downregulating AXIN2, MYC, TEAD4, and MET in both cell lines. This study reveals compelling evidence of curcumin's potent anticancer properties, highlighting its transformative influence on the Hippo and Rap1 signaling pathways within colorectal cancer cells. These findings not only underscore curcumin's potential as a therapeutic agent but also pave the way for innovative strategies in the fight against colorectal cancer.

PMID:39779534 | DOI:10.1007/s12032-024-02560-w

Nucleic Acids Res. 2025 Jan 7;53(1):gkae1235. doi: 10.1093/nar/gkae1235.

ABSTRACT

Dinucleases of the DEDD superfamily, such as oligoribonuclease, Rexo2 and nanoRNase C, catalyze the essential final step of RNA degradation, the conversion of di- to mononucleotides. The active sites of these enzymes are optimized for substrates that are two nucleotides long, and do not discriminate between RNA and DNA. Here, we identified a novel DEDD subfamily, members of which function as dedicated deoxydinucleases (diDNases) that specifically hydrolyze single-stranded DNA dinucleotides in a sequence-independent manner. Crystal structures of enzyme-substrate complexes reveal that specificity for DNA stems from a combination of conserved structural elements that exclude diribonucleotides as substrates. Consistently, diDNases fail to complement the loss of enzymes that act on diribonucleotides, indicating that these two groups of enzymes support distinct cellular functions. The genes encoding diDNases are found predominantly in genomic islands of Actinomycetes and Clostridia, which, together with their association with phage-defense systems, suggest potential roles in bacterial immunity.

PMID:39778863 | DOI:10.1093/nar/gkae1235

Planta Med. 2025 Jan 8. doi: 10.1055/a-2512-8928. Online ahead of print.

ABSTRACT

In recent years, the incidence of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has shown a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese Medicine (TCM), with its multi-component and multi-target characteristics, offers a promising approach for the treatment of neurodegenerative diseases. However, it is difficult to comprehensively elucidate the complex mechanisms underlying TCM formulations. As an emerging systems biology approach, network pharmacology has provided a crucial tool for uncovering the multi-target mechanisms of TCM through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases with TCM, analyzes the current status of relevant databases and technological methods, discusses the limitations in the research, and proposes future directions to promote the modernization of TCM and the development of precision medicine. Keywords: Neurodegenerative diseases, Traditional Chinese Medicine, Network pharmacology, Therapeutic targets.

PMID:39778593 | DOI:10.1055/a-2512-8928

Cell Syst. 2024 Dec 31:101163. doi: 10.1016/j.cels.2024.12.004. Online ahead of print.

ABSTRACT

Deep learning is a promising strategy for modeling cis-regulatory elements. However, models trained on genomic sequences often fail to explain why the same transcription factor can activate or repress transcription in different contexts. To address this limitation, we developed an active learning approach to train models that distinguish between enhancers and silencers composed of binding sites for the photoreceptor transcription factor cone-rod homeobox (CRX). After training the model on nearly all bound CRX sites from the genome, we coupled synthetic biology with uncertainty sampling to generate additional rounds of informative training data. This allowed us to iteratively train models on data from multiple rounds of massively parallel reporter assays. The ability of the resulting models to discriminate between CRX sites with identical sequence but opposite functions establishes active learning as an effective strategy to train models of regulatory DNA. A record of this paper's transparent peer review process is included in the supplemental information.

PMID:39778579 | DOI:10.1016/j.cels.2024.12.004

PLoS Pathog. 2025 Jan 8;21(1):e1012823. doi: 10.1371/journal.ppat.1012823. Online ahead of print.

ABSTRACT

Malaria parasites must respond quickly to environmental changes, including during their transmission between mammalian and mosquito hosts. Therefore, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. While the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, changes in the spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known. Therefore, we have conducted the first quantitative, comparative transcriptomics and DIA-MS proteomics of Plasmodium parasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes of P. yoelii, we found that ~200 transcripts are released for translation soon after fertilization, including those encoding essential functions. Moreover, we identified that many transcripts remain repressed beyond this point. TurboID-based proximity proteomics of the DOZI/CITH/ALBA regulatory complex revealed substantial spatial and/or compositional changes across this transmission event, which are consistent with recent, paradigm-shifting models of translational control. Together, these data provide a model for the essential translational control mechanisms that promote Plasmodium's efficient transmission from mammalian host to mosquito vector.

PMID:39777415 | DOI:10.1371/journal.ppat.1012823

Synth Syst Biotechnol. 2024 Jul 30;9(4):861-870. doi: 10.1016/j.synbio.2024.07.006. eCollection 2024 Dec.

ABSTRACT

Saccharomyces cerevisiae, a widely utilized model organism, has seen continuous updates to its genome-scale metabolic model (GEM) to enhance the prediction performance for metabolic engineering and systems biology. This study presents an auxotrophy-based curation of the yeast GEM, enabling facile upgrades to yeast GEMs in future endeavors. We illustrated that the curation bolstered the predictive capability of the yeast GEM particularly in predicting auxotrophs without compromising accuracy in other simulations, and thus could be an effective manner for GEM refinement. Last, we leveraged the curated yeast GEM to systematically predict auxotrophs, thereby furnishing a valuable reference for the design of nutrient-dependent cell factories and synthetic yeast consortia.

PMID:39777162 | PMC:PMC11704421 | DOI:10.1016/j.synbio.2024.07.006

Patterns (N Y). 2024 Dec 6;5(12):101115. doi: 10.1016/j.patter.2024.101115. eCollection 2024 Dec 13.

ABSTRACT

Guidelines in statistical modeling for genomics hold that simpler models have advantages over more complex ones. Potential advantages include cost, interpretability, and improved generalization across datasets or biological contexts. We directly tested the assumption that small gene signatures generalize better by examining the generalization of mutation status prediction models across datasets (from cell lines to human tumors and vice versa) and biological contexts (holding out entire cancer types from pan-cancer data). We compared model selection between solely cross-validation performance and combining cross-validation performance with regularization strength. We did not observe that more regularized signatures generalized better. This result held across both generalization problems and for both linear models (LASSO logistic regression) and non-linear ones (neural networks). When the goal of an analysis is to produce generalizable predictive models, we recommend choosing the ones that perform best on held-out data or in cross-validation instead of those that are smaller or more regularized.

PMID:39776849 | PMC:PMC11701843 | DOI:10.1016/j.patter.2024.101115

Theranostics. 2025 Jan 1;15(3):1094-1109. doi: 10.7150/thno.96488. eCollection 2025.

ABSTRACT

Rationale: The mannose receptor (CD206, expressed by the gene Mrc1) is a surface marker overexpressed by anti-inflammatory and pro-tumoral macrophages. As such, CD206+ macrophages play key roles in the immune response to different pathophysiological conditions and represent a promising diagnostic and therapeutic target. However, methods to specifically target these cells remain challenging. In this study, we describe a multi-mannose approach to develop CD206-targeting fluorescent and MRI agents that specifically and sensitively detect and monitor CD206+ macrophage immune response in different disease conditions. Methods: We designed and synthesized fluorescent agents MR1-cy5 and MR2-cy5, and MRI agents Mann2-DTPA-Gd and MannGdFish. Cellular assays using pro-inflammatory and anti-inflammatory macrophages differentiated from RAW 264.7 cells were performed, and signals were detected by fluorescence microscopy and inductively coupled plasma mass spectrometry (ICP-MS) to validate specificity in vitro. In vivo specificity and efficacy of the agents were evaluated by MRI in a subcutaneous wound healing model and experimental glioma with Mrc1 +/+ without and with D-mannose treatment, Mrc1 +/-, and Mrc1 -/- mice, and in stroke. One-way ANOVA and two-way ANOVA tests were used for data analysis. P < 0.05 was considered statistically different. Results: Both in vitro fluorescence imaging with MR2-cy5, ICP-MS with Mann2-DTPA-Gd, and in vivo MRI in Mrc1 -/- mice confirmed the specificity of our approach. Mann2-DTPA-Gd MRI can track the changes of CD206+ macrophages at different stages of wound healing, correlating well with flow cytometry data using another anti-inflammatory macrophage marker (arginase-1). The specificity and efficacy of Mann2-DPTA-Gd were further validated in experimental glioma, in which Mann2-DTPA-Gd imaging detected CD206+ tumor-associated macrophages (TAMs), demonstrated significantly decreased signals in Mrc1 +/- mice and Mrc1 -/- mice, and tracked treatment changes in D-mannose-treated Mrc1 +/+ mice. Furthermore, Mann2-DTPA-Gd can report microglia/macrophages and correlate with histology in stroke. The more Gd-stable agent MannGdFish demonstrated similar efficacy as Mann2-DTPA-Gd in vivo with favorable biodistribution and pharmacokinetics. Conclusion: We have developed a fluorescent agent (MR2-cy5) and MRI agents (Mann2-DTPA-Gd and MannGdFish) with two mannose moieties that are highly specific to CD206 and can track CD206+ macrophages in disease models of wound healing, tumor, and neurological disease. Importantly, MannGdFish, with its high specificity, stability, favorable biodistribution, and pharmacokinetics, is a promising translational candidate to noninvasively monitor CD206+ macrophages in repair/regeneration and tumors in patients. In addition, with the specific binding motif to CD206, other imaging modalities and therapeutic agents could also be introduced for theranostic applications.

PMID:39776805 | PMC:PMC11700851 | DOI:10.7150/thno.96488

JBMR Plus. 2024 Dec 10;9(2):ziae159. doi: 10.1093/jbmrpl/ziae159. eCollection 2025 Feb.

ABSTRACT

Human genetic studies have nominated cadherin-like and PC-esterase domain-containing 1 (CPED1) as a candidate target gene mediating bone mineral density (BMD) and fracture risk heritability. Recent efforts to define the role of CPED1 in bone in mouse and human models have revealed complex alternative splicing and inconsistent results arising from gene targeting, making its function in bone difficult to interpret. To better understand the role of CPED1 in adult bone mass and morphology, we conducted a comprehensive genetic and phenotypic analysis of cped1 in zebrafish, an emerging model for bone and mineral research. We analyzed two different cped1 mutant lines and performed deep phenotyping to characterize more than 200 measures of adult vertebral, craniofacial, and lean tissue morphology. We also examined alternative splicing of zebrafish cped1 and gene expression in various cell/tissue types. Our studies fail to support an essential role of cped1 in adult zebrafish bone. Specifically, homozygous mutants for both cped1 mutant alleles, which are expected to result in loss-of-function and impact all cped1 isoforms, exhibited no significant differences in the measures examined when compared to their respective wildtype controls, suggesting that cped1 does not significantly contribute to these traits. We identified sequence differences in critical residues of the catalytic triad between the zebrafish and mouse orthologs of CPED1, suggesting that differences in key residues, as well as distinct alternative splicing, could underlie different functions of CPED1 orthologs in the two species. Our studies fail to support a requirement of cped1 in zebrafish bone and lean tissue, adding to evidence that variants at 7q31.31 can act independently of CPED1 to influence BMD and fracture risk.

PMID:39776615 | PMC:PMC11701521 | DOI:10.1093/jbmrpl/ziae159

Gut Microbiome (Camb). 2024 May 31;5:e7. doi: 10.1017/gmb.2024.5. eCollection 2024.

ABSTRACT

Breastfeeding represents a strong selective factor for shaping the infant gut microbiota. Besides providing nutritional requirements for the infant, human milk is a key source of oligosaccharides, human milk oligosaccharides (HMOs), and diverse microbes in early life. This study aimed to evaluate the influence of human milk microbiota and oligosaccharides on the composition of infant faecal microbiota at one, three, and nine months postpartum. We profiled milk microbiota, HMOs, and infant faecal microbiota from 23 mother-infant pairs at these time points. The predominant genera in milk samples were Streptococcus, Staphylococcus, and an unclassified Enterobacteriaceae genus-level taxon (Enterobacteriaceae uncl.), whereas the infant faecal microbiota was predominated by Bifidobacterium, Bacteroides, and Enterobacteriaceae uncl. Mother-infant dyads frequently shared bacterial amplicon sequence variants (ASVs) belonging to the genera Bifidobacterium, Streptococcus, Enterobacteriaceae uncl., Veillonella, Bacteroides, and Haemophilus. The individual HMO concentrations in the milk showed either no change or decreased over the lactation period, except for 3-fucosyllactose (3-FL), which increased. Neither maternal secretor status nor HMO concentrations were significantly associated with microbiota composition at the different ages or the bacterial ASVs of maternal milk and infant faeces. This study suggests an age-dependent role of milk microbes in shaping the gut microbiota, while variations in HMO concentrations show limited influence.

PMID:39776540 | PMC:PMC11706684 | DOI:10.1017/gmb.2024.5

Lab Chip. 2025 Jan 8. doi: 10.1039/d4lc00779d. Online ahead of print.

ABSTRACT

Point-of-care testing (POCT) holds significant importance in the field of infectious disease prevention and control, as well as personalized precision medicine. The emerging microfluidics, capable of minimal reagent consumption, integration, and a high degree of automation, play a pivotal role in POCT. Centrifugal microfluidics, also termed lab-on-a-disc (LOAD), is a significant subfield of microfluidics that integrates crucial analytical steps onto a single chip, thereby optimizing the process and enabling high-throughput, automated analysis. By utilizing rotational mechanics to precisely control fluid dynamics without external pressure sources, centrifugal microfluidics facilitates swift operations ideal for urgent medical and field settings. This review provides a comprehensive overview of the latest advancements in centrifugal microfluidics for POCT, covering both theoretical principles and practical applications. We begin by introducing the fundamental operational principles, fluidic control mechanisms, and signal output detection methods. Subsequently, we delve into the typical applications of centrifugal microfluidic platforms in immunoassays, nucleic acid testing, antimicrobial susceptibility testing, and other tests. We also discuss the strengths and potential limitations of centrifugal microfluidic platforms, underscoring their transformative impact on traditional conventional procedures and their significant role in diagnostic practices.

PMID:39776118 | DOI:10.1039/d4lc00779d