Gastroenterology. 2024 Dec 17:S0016-5085(24)05788-3. doi: 10.1053/j.gastro.2024.11.024. Online ahead of print.

NO ABSTRACT

PMID:39701193 | DOI:10.1053/j.gastro.2024.11.024

Cell Syst. 2024 Dec 18;15(12):1105-1106. doi: 10.1016/j.cels.2024.11.015.

ABSTRACT

Turing patterns are a key theoretical foundation for understanding organ development and organization. While they have been found to occur in natural systems, implementing new biological systems that form Turing patterns has remained challenging. To address this, Tica et al.1 used synthetic genetic networks to engineer living cellular computers that successfully generate Turing patterns within growing bacterial populations.

PMID:39701030 | DOI:10.1016/j.cels.2024.11.015

EBioMedicine. 2024 Dec 18;111:105525. doi: 10.1016/j.ebiom.2024.105525. Online ahead of print.

NO ABSTRACT

PMID:39700897 | DOI:10.1016/j.ebiom.2024.105525

Inflamm Bowel Dis. 2024 Dec 19:izae269. doi: 10.1093/ibd/izae269. Online ahead of print.

ABSTRACT

The past 2 decades have witnessed extraordinary advances in our understanding of the genetic factors influencing inflammatory bowel disease (IBD), providing a foundation for the approaching era of genomic medicine. On behalf of the NIDDK IBD Genetics Consortium, we herein survey 11 grand challenges for the field as it embarks on the next 2 decades of research utilizing integrative genomic and systems biology approaches. These involve elucidation of the genetic architecture of IBD (how it compares across populations, the role of rare variants, and prospects of polygenic risk scores), in-depth cellular and molecular characterization (fine-mapping causal variants, cellular contributions to pathology, molecular pathways, interactions with environmental exposures, and advanced organoid models), and applications in personalized medicine (unmet medical needs, working toward molecular nosology, and precision therapeutics). We review recent advances in each of the 11 areas and pose challenges for the genetics and genomics communities of IBD researchers.

PMID:39700476 | DOI:10.1093/ibd/izae269

J Exp Bot. 2024 Dec 19:erae500. doi: 10.1093/jxb/erae500. Online ahead of print.

ABSTRACT

The plasma membrane aquaporin ZmPIP1;6 is expressed in maize stomatal complexes, with higher expression during the day than at night. To elucidate the role of ZmPIP1;6 in gas exchange and stomatal movement, it was expressed in maize (inbred line B104) under the control of p35S promoter (OE) or its native promoter fused with mYFP cDNA (mYFP-ZmPIP1;6). In stomatal complexes of the leaf mature zone, mYFP-ZmPIP1;6 showed higher expression in subsidiary cells than in guard cells, with light and dark treatments influencing its subcellular localization. Notably, ZmPIP1;6 internalization increased in dark conditions versus light. Stomatal opening was greater in ZmPIP1;6 OE than in wild type (WT), while closure exhibited greater sensitivity to elevated CO2 concentration or ABA treatment. Our finding revealed that reactive oxygen species (H2O2) was involved in ABA-induced stomatal closure, while ZmPIP1;6 was unable to facilitate H2O2 diffusion when expressed in yeast. Finally, ZmPIP1;6 OE and mYFP-ZmPIP1;6 transgenic plants exhibited higher abaxial stomatal density than WT. Overall, these results indicate that ZmPIP1;6 plays important roles in stomatal opening and CO2- and ABA-induced stomatal closure.

PMID:39700432 | DOI:10.1093/jxb/erae500

STAR Protoc. 2024 Dec 18;6(1):103514. doi: 10.1016/j.xpro.2024.103514. Online ahead of print.

ABSTRACT

Feature selection by expectation maximization test (Festem) enables the direct selection of cell type marker genes, facilitating downstream clustering of single-cell RNA sequencing (scRNA-seq) data. Here, we present a protocol for using Festem to identify marker genes in scRNA-seq data and perform subsequent analyses. We describe comprehensive steps for setting up the environment, marker gene selection, clustering, and marker gene assignment. This protocol yields both clustering results and identified marker genes, enhancing the interpretation of biological information in scRNA-seq data. For complete details on the use and execution of this protocol, please refer to Chen et al.1.

PMID:39700012 | DOI:10.1016/j.xpro.2024.103514

Elife. 2024 Dec 19;12:RP87517. doi: 10.7554/eLife.87517.

ABSTRACT

Targeted low-throughput studies have previously identified subcellular RNA localization as necessary for cellular functions including polarization, and translocation. Furthermore, these studies link localization to RNA isoform expression, especially 3' Untranslated Region (UTR) regulation. The recent introduction of genome-wide spatial transcriptomics techniques enables the potential to test if subcellular localization is regulated in situ pervasively. In order to do this, robust statistical measures of subcellular localization and alternative poly-adenylation (APA) at single-cell resolution are needed. Developing a new statistical framework called SPRAWL, we detect extensive cell-type specific subcellular RNA localization regulation in the mouse brain and to a lesser extent mouse liver. We integrated SPRAWL with a new approach to measure cell-type specific regulation of alternative 3' UTR processing and detected examples of significant correlations between 3' UTR length and subcellular localization. Included examples, Timp3, Slc32a1, Cxcl14, and Nxph1 have subcellular localization in the mouse brain highly correlated with regulated 3' UTR processing that includes the use of unannotated, but highly conserved, 3' ends. Together, SPRAWL provides a statistical framework to integrate multi-omic single-cell resolved measurements of gene-isoform pairs to prioritize an otherwise impossibly large list of candidate functional 3' UTRs for functional prediction and study. In these studies of data from mice, SPRAWL predicts that 3' UTR regulation of subcellular localization may be more pervasive than currently known.

PMID:39699003 | DOI:10.7554/eLife.87517

Alzheimers Dement. 2024 Dec 19. doi: 10.1002/alz.14401. Online ahead of print.

ABSTRACT

INTRODUCTION: While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC).

METHODS: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.

RESULTS: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death.

DISCUSSION: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+) microglia.

HIGHLIGHTS: Cross-tissue interaction between HCMV and the adaptive immune response in a subset of persons with AD. Presence of CD83(+) microglial associated with IgG4 and HCMV in the gut. CD83(+) microglia are also associated presence of HCMV and IgG4 in the cortex and vagal nerve. Replication of key association in an independent cohort of AD subjects. HCMV infection of cerebral organoids accelerates the production of AD neuropathological features.

PMID:39698934 | DOI:10.1002/alz.14401

Nucleic Acids Res. 2024 Dec 19:gkae1219. doi: 10.1093/nar/gkae1219. Online ahead of print.

ABSTRACT

Transcripts produced by RNA polymerase II (RNAPII) are fundamental for cellular responses to environmental changes. It is therefore no surprise that there exist multiple avenues for the regulation of this process. To explore the regulation mediated by RNAPII-interacting proteins, we used a small interfering RNA (siRNA)-based screen to systematically evaluate their influence on RNA synthesis. We identified several proteins that strongly affected RNAPII activity. We evaluated one of the top hits, SCAF1 (SR-related C-terminal domain-associated factor 1), using an auxin-inducible degradation system and sequencing approaches. In agreement with our screen results, acute depletion of SCAF1 decreased RNA synthesis, and showed an increase of Serine-2 phosphorylated-RNAPII (pS2-RNAPII). We found that the accumulation of pS2-RNAPII within the gene body occurred at GC-rich regions and was indicative of stalled RNAPII complexes. The accumulation of stalled RNAPII complexes was accompanied by reduced recruitment of initiating RNAPII, explaining the observed global decrease in transcriptional output. Furthermore, upon SCAF1 depletion, RNAPII complexes showed increased association with components of the proteasomal-degradation machinery. We concluded that in cells lacking SCAF1, RNAPII undergoes a rather interrupted passage, resulting in intervention by the proteasomal-degradation machinery to clear stalled RNAPII. While cells survive the compromised transcription caused by absence of SCAF1, further inhibition of proteasomal-degradation machinery is synthetically lethal.

PMID:39698826 | DOI:10.1093/nar/gkae1219

Genetics. 2024 Dec 19:iyae211. doi: 10.1093/genetics/iyae211. Online ahead of print.

ABSTRACT

For many problems in population genetics, it is useful to characterize the distribution of fitness effects (DFE) of de novo mutations among a certain class of sites. A DFE is typically estimated by fitting an observed site frequency spectrum (SFS) to an expected SFS given a hypothesized distribution of selection coefficients and demographic history. The development of tools to infer gene trees from haplotype alignments, along with ancient DNA resources, provides us with additional information about the frequency trajectories of segregating mutations. Here, we ask how useful this additional information is for learning about the DFE, using the joint distribution on allele frequency and age to summarize information about the trajectory. To this end, we introduce an accurate and efficient numerical method for computing the density on the age of a segregating variant found at a given sample frequency, given the strength of selection and an arbitrarily complex population size history. We then use this framework to show that the unconditional age distribution of negatively selected alleles is very closely approximated by re-weighting the neutral age distribution in terms of the negatively selected SFS, suggesting that allele ages provide little information about the DFE beyond that already contained in the present day frequency. To confirm this prediction, we extended the standard Poisson Random Field (PRF) method to incorporate the joint distribution of frequency and age in estimating selection coefficients, and test its performance using simulations. We find that when the full SFS is observed and the true allele ages are known, including ages in the estimation provides only small increases in the accuracy of estimated selection coefficients. However, if only sites with frequencies above a certain threshold are observed, then the true ages can provide substantial information about the selection coefficients, especially when the selection coefficient is large. When ages are estimated from haplotype data using state-of-the-art tools, uncertainty about the age abrogates most of the additional information in the fully observed SFS case, while the neutral prior assumed in these tools when estimating ages induces a downward bias in the case of the thresholded SFS.

PMID:39698825 | DOI:10.1093/genetics/iyae211

J Clin Exp Hepatol. 2025 Mar-Apr;15(2):102450. doi: 10.1016/j.jceh.2024.102450. Epub 2024 Nov 12.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma is the sixth most common malignancy reported globally. This highlights the need for reliable biomarkers that can be employed for diagnostic and prognostic applications. The present study aimed to classify and characterize the clinical potential of delta like non-canonical Notch ligand 1-type III iodothyronine deiodinase (DLK1-DIO3) and miR-379/656 cluster genes in hepatocellular carcinoma.

METHODS: We extensively studied the clinical potential of DLK1-DIO3 genes through a comprehensive systems biology approach and assessed the diagnostic and prognostic potential of the genes associated with the region. Additionally, we have predicted the gene targets of the miR-379/656 cluster associated with the locus and have identified the gene ontology, pathway, and disease associations.

RESULTS: We report this region as a potential biomarker for hepatocellular carcinoma. About thirty clustered miRNAs, a long-non-coding RNA, and two coding genes of the region were underexpressed in tumors. The receiver operating characteristic analysis identified 11 clustered miRNAs with diagnostic potential. Survival analyses identified maternally expressed gene 3 and the miR-379/656 cluster as prognostically significant. Further, the random forest model predicted that the miRNA cluster classifies patients according to Tumor, Node, Metastasis (TNM) staging. Furthermore, overrepresentation analysis identified several key pathways, molecular functions, and biological processes associated with the cluster gene targets.

CONCLUSION: Our study suggests that DLK1-DIO3 genes, miR-379/656 cluster, and its target gene network might be potential diagnostic and prognostic markers for hepatocellular carcinoma management and therapy.

PMID:39698049 | PMC:PMC11650283 | DOI:10.1016/j.jceh.2024.102450

Plant Physiol. 2024 Dec 19:kiae615. doi: 10.1093/plphys/kiae615. Online ahead of print.

ABSTRACT

Collections of insertional mutants have been instrumental for characterizing the functional relevance of genes in different model organisms, including Arabidopsis (Arabidopsis thaliana). However, mutations may often result in subtle phenotypes, rendering it difficult to pinpoint the function of a knocked-out gene. Here, we present a data-integrative modeling approach that enables predicting the effects of mutations on metabolic traits and plant growth. To test the approach, we gathered lipidomics data and physiological read-outs for a set of 64 Arabidopsis lines with mutations in lipid metabolism. Use of flux sums as a proxy for metabolite concentrations allowed us to integrate the relative abundance of lipids and facilitated accurate predictions of growth and biochemical phenotype in approximately 73% and 76% of the mutants, respectively, for which phenotypic data were available. Likewise, we showed that this approach can pinpoint alterations in metabolic pathways related to silent mutations. Therefore, our study paves the way for coupling model-driven characterization of mutant lines from different mutagenesis approaches with metabolomic technologies, as well as for validating knowledge structured in large-scale metabolic networks of plants and other species.

PMID:39696931 | DOI:10.1093/plphys/kiae615

Bioessays. 2024 Dec 18:e202400211. doi: 10.1002/bies.202400211. Online ahead of print.

ABSTRACT

Circadian rhythms are ∼24-h biological oscillations that enable organisms to anticipate daily environmental cycles, so that they may designate appropriate day/night functions that align with these changes. The molecular clock in animals and fungi consists of a transcription-translation feedback loop, the plant clock is comprised of multiple interlocking feedback-loops, and the cyanobacterial clock is driven by a phosphorylation cycle involving three main proteins. Despite the divergent core clock mechanisms across these systems, all circadian clocks are able to buffer period length against changes in the ambient growth environment, such as temperature and nutrients. This defining capability, termed compensation, is critical to proper timekeeping, yet the underlying mechanism(s) remain elusive. Here we examine the known players in, and the current models for, compensation across five circadian systems. While compensation models across these systems are not yet unified, common themes exist across them, including regulation via temperature-dependent changes in post-translational modifications.

PMID:39696884 | DOI:10.1002/bies.202400211

Chin Med. 2024 Dec 19;19(1):172. doi: 10.1186/s13020-024-01044-3.

ABSTRACT

BACKGROUND: Pulsatilla chinensis (PC) is a traditional Chinese medicine (TCM) known for its beneficial activities. It has been historically used to treat dysentery, vaginal trichomoniasis, bacterial infections, and malignant tumors. The therapeutic potential of PC in the management of hypercholesterolemia remains largely unexplored.

METHODS: A high-throughput screening based on high-throughput sequencing was conducted in HepG2 cells to construct gene expression profiles for several hundred TCMs. In vivo evaluation of the efficacy of PC was performed using rats with hypercholesterolemia. Transcriptome analysis was carried out on PC-treated rat livers and HepG2 cells to investigate the mechanism of action of PC in vitro. The findings were further validated using RT-qPCR and western blot techniques.

RESULTS: PC was identified as similar to Rhizoma Coptidis based on signature genes related to metabolism. Administration of PC via gavage in rats with hypercholesterolemia for 11 weeks resulted in substantially reduced serum total cholesterol and low-density lipoprotein (LDL) cholesterol and ameliorated fatty liver. Transcriptome analysis revealed that PC regulated various pathways associated with lipid metabolism. The LDL receptor (LDLR), a key player in cholesterol metabolism, was upregulated by PC both in vivo and in vitro. It was discovered that PC achieved this upregulation by activating extracellular regulated protein kinase (ERK) signaling in HepG2 cells. To uncover the major bioactive components responsible for the anti- hypercholesterolemia effect of PC, two major saponins, named Pulsatilla saponin D (PCD) and PC anemoside B4 (PCB4), were assessed. PCD, but not PCB4, was identified as the active ingredient responsible for the upregulation of LDLR by PC.

CONCLUSION: These findings demonstrated that PC acts as an antihypercholesterolemic agent by upregulating LDLR in an ERK-dependent manner and holds potential in the treatment of hypercholesterolemia.

PMID:39696673 | DOI:10.1186/s13020-024-01044-3

Biomark Res. 2024 Dec 19;12(1):159. doi: 10.1186/s40364-024-00705-7.

ABSTRACT

The leukocyte immunoglobulin-like receptor B (LILRB) proteins, characterized by their transmembrane nature and canonical immunoreceptor tyrosine-based inhibitory motifs (ITIM) signaling, play a pivotal role in maintaining immune homeostasis and are implicated in the pathogenesis of various disease states. This comprehensive review will focus on the intricate involvement of the LILRB family in hematologic malignancies. These receptors have emerged as valuable diagnostic and prognostic biomarkers in leukemia, lymphoma, and myeloma. Beyond their prognostic implications, LILRBs actively shape the immune microenvironment and directly influence the disease pathogenesis of hematologic malignancies. Furthermore, their identification as potential therapeutic targets offer a promising avenue for precision medicine strategies in the treatment of these disorders. Currently, multiple LILRB directed therapies are in the preclinical and clinical trial pipelines. This review underscores the multifaceted role of the LILRB family in hematologic malignancies, highlighting their significance from diagnostic and prognostic perspectives to their broader impact on disease pathophysiology and as valuable therapeutic targets.

PMID:39696628 | DOI:10.1186/s40364-024-00705-7

Genome Biol. 2024 Dec 19;25(1):317. doi: 10.1186/s13059-024-03453-x.

ABSTRACT

Longitudinal studies are crucial for understanding complex microbiome dynamics and their link to health. We introduce TEMPoral TEnsor Decomposition (TEMPTED), a time-informed dimensionality reduction method for high-dimensional longitudinal data that treats time as a continuous variable, effectively characterizing temporal information and handling varying temporal sampling. TEMPTED captures key microbial dynamics, facilitates beta-diversity analysis, and enhances reproducibility by transferring learned representations to new data. In simulations, it achieves 90% accuracy in phenotype classification, significantly outperforming existing methods. In real data, TEMPTED identifies vaginal microbial markers linked to term and preterm births, demonstrating robust performance across datasets and sequencing platforms.

PMID:39696594 | DOI:10.1186/s13059-024-03453-x

Genome Biol. 2024 Dec 18;25(1):310. doi: 10.1186/s13059-024-03449-7.

ABSTRACT

The inherent similarities between natural language and biological sequences have inspired the use of large language models in genomics, but current models struggle to incorporate chromatin interactions or predict in unseen cellular contexts. To address this, we propose EpiGePT, a transformer-based model designed for predicting context-specific human epigenomic signals. By incorporating transcription factor activities and 3D genome interactions, EpiGePT outperforms existing methods in epigenomic signal prediction tasks, especially in cell-type-specific long-range interaction predictions and genetic variant impacts, advancing our understanding of gene regulation. A free online prediction service is available at http://health.tsinghua.edu.cn/epigept .

PMID:39696471 | DOI:10.1186/s13059-024-03449-7

BMC Biol. 2024 Dec 18;22(1):292. doi: 10.1186/s12915-024-02087-6.

ABSTRACT

BACKGROUND: Many members of the oxysterol-binding protein-related protein (ORP) family have been characterized in detail over the past decades, but the lipid transport and other functions of ORP7 still remain elusive. What is known about ORP7 points toward an endoplasmic reticulum and plasma membrane-localized protein, which also interacts with GABA type A receptor-associated protein like 2 (GABARAPL2) and unlipidated Microtubule-associated proteins 1A/1B light chain 3B (LC3B), suggesting a further autophagosomal/lysosomal association. Functional roles of ORP7 have been suggested in cholesterol efflux, hypercholesterolemia, and macroautophagy. We performed a hypothesis-free multi-omics analysis of chemical ORP7 inhibition utilizing transcriptomics and lipidomics as well as proximity biotinylation interactomics to characterize ORP7 functions in a primary cell type, human umbilical vein endothelial cells (HUVECs). Moreover, assays on angiogenesis, cholesterol efflux, and lipid droplet quantification were conducted.

RESULTS: Pharmacological inhibition of ORP7 leads to an increase in gene expression related to lipid metabolism and inflammation, while genes associated with cell cycle and cell division were downregulated. Lipidomic analysis revealed increases in ceramides and lysophosphatidylcholines as well as saturated and monounsaturated triacylglycerols. Significant decreases were seen in all cholesteryl ester and in some unsaturated triacylglycerol species, compatible with the detected decrease of mean lipid droplet area. Along with the reduced lipid stores, ATP-binding cassette subfamily G member 1 (ABCG1)-mediated cholesterol efflux and angiogenesis decreased. Interactomics revealed an interaction of ORP7 with AKT1, a central metabolic regulator.

CONCLUSIONS: The transcriptomics results suggest an increase in prostanoid as well as oxysterol synthesis, which could be related to the observed upregulation of proinflammatory genes. We envision that the defective angiogenesis in HUVECs subjected to ORP7 inhibition could be the result of an unfavorable plasma membrane lipid composition and/or reduced potential for cell division. To conclude, the present study suggests multifaceted functions of ORP7 in lipid homeostasis, angiogenic tube formation, and gene expression of lipid metabolism, inflammation, and cell cycle in primary endothelial cells.

PMID:39695567 | DOI:10.1186/s12915-024-02087-6

Sci Rep. 2024 Dec 18;14(1):30541. doi: 10.1038/s41598-024-80498-9.

ABSTRACT

When infected with SARS-CoV-2, Syrian hamsters (Mesocricetus auratus) develop moderate disease severity presenting key features of human COVID-19. We here develop a biomathematical model of the disease course by translating known biological mechanisms of virus-host interactions and immune responses into ordinary differential equations. We explicitly describe the dynamics of virus population, affected alveolar epithelial cells, and involved relevant immune cells comprising for example CD4+ T cells, CD8+ T cells, macrophages, natural killer cells and B cells. We also describe the humoral response dynamics of neutralising antibodies and major regulatory cytokines including CCL8 and CXCL10. The model is developed and parametrized based on experimental data collected at days 2, 3, 5, and 14 post infection. Pulmonary cell composition and their transcriptional profiles were obtained by lung single-cell RNA (scRNA) sequencing analysis. Parametrization of the model resulted in a good agreement of model and data. The model can be used to predict, for example, the time course of the virus population, immune cell dynamics, antibody production and regeneration of alveolar cells for different therapy scenarios or after multiple-infection events. We aim to translate this model to the human situation in the future.

PMID:39695178 | DOI:10.1038/s41598-024-80498-9

Brain Res. 2024 Dec 16:149403. doi: 10.1016/j.brainres.2024.149403. Online ahead of print.

ABSTRACT

BACKGROUND: Epilepsy affects nearly 50 million people worldwide. Previous studies have indicated the neuroprotective effects of statin on several neuropathological conditions. However, it is very much unknown whether fluvastatin was able to alter the seizure types related to neuronal excitability and progression mediated by NMDA receptor activation, and the mechanisms involved in these actions are not completely understood so far. Our study evaluated the effects of fluvastatin on the NMDA-induced seizure, BKCa channels activity, NMDA receptor activation opens BKCa current, sodium channel current, NMDA receptor-mediated current, and hyperexcitable neuronal activity associated with activation of NMDA receptor.

METHODS: The effects of fluvastatin on seizure thresholds induced by NMDA were monitored in mice. The cell-attached and whole-cell patch-clamp recordings were applied to evaluate the ionic currents and action potentials of rCN or SHSY5Y neuroblastoma cells.

RESULTS: The results of our study have demonstrated that fluvastatin did increase the NMDA-induced seizure threshold and suppressed the frequency of action potentials induced by NMDA. Notably, our findings provide the evidence that fluvastatin exhibits inhibitory effects on NMDA receptor-mediated current, BKCa channels currents, NMDA receptor activation opens BKCa current, and sodium channel currents in rCN and SHSY5Y neuroblastoma cells.

CONCLUSION: Our findings suggested that fluvastatin may protect against seizure types related to neuronal excitability and NMDA receptor activation by inhibiting NMDA-mediated action potentials, NMDA receptor-mediated currents, BKCa channels, and sodium channels.

PMID:39694167 | DOI:10.1016/j.brainres.2024.149403