Elife. 2024 Jan 10;13:e84613. doi: 10.7554/eLife.84613. Online ahead of print.

ABSTRACT

Mendelian diseases tend to manifest clinically in certain tissues, yet their affected cell types typically remain elusive. Single-cell expression studies showed that overexpression of disease-associated genes may point to the affected cell types. Here, we developed a method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT). We applied PrEDiCT to single-cell expression data of six human tissues, to infer the cell types affected in Mendelian diseases. Overall, we inferred the likely affected cell types for 328 diseases. We corroborated our findings by literature text-mining, expert validation, and recapitulation in mouse corresponding tissues. Based on these findings, we explored characteristics of disease-affected cell types, showed that diseases manifesting in multiple tissues tend to affect similar cell types, and highlighted cases where gene functions could be used to refine inference. Together, these findings expand the molecular understanding of disease mechanisms and cellular vulnerability.

PMID:38197427 | DOI:10.7554/eLife.84613

Mol Ecol. 2024 Jan 10:e17260. doi: 10.1111/mec.17260. Online ahead of print.

ABSTRACT

Biological systems occurring in ecologically heterogeneous and spatially discontinuous habitats provide an ideal opportunity to investigate the relative roles of neutral and selective factors in driving lineage diversification. The grey mangroves (Avicennia marina) of Arabia occur at the northern edge of the species' range and are subject to variable, often extreme, environmental conditions, as well as historic large fluctuations in habitat availability and connectivity resulting from Quaternary glacial cycles. Here, we analyse fully sequenced genomes sampled from 19 locations across the Red Sea, the Arabian Sea and the Persian/Arabian Gulf (PAG) to reconstruct the evolutionary history of the species in the region and to identify adaptive mechanisms of lineage diversification. Population structure and phylogenetic analyses revealed marked genetic structure correlating with geographic distance and highly supported clades among and within the seas surrounding the Arabian Peninsula. Demographic modelling showed times of divergence consistent with recent periods of geographic isolation and low marine connectivity during glaciations, suggesting the presence of (cryptic) glacial refugia in the Red Sea and the PAG. Significant migration was detected within the Red Sea and the PAG, and across the Strait of Hormuz to the Arabian Sea, suggesting gene flow upon secondary contact among populations. Genetic-environment association analyses revealed high levels of adaptive divergence and detected signs of multi-loci local adaptation driven by temperature extremes and hypersalinity. These results support a process of rapid diversification resulting from the combined effects of historical factors and ecological selection and reveal mangrove peripheral environments as relevant drivers of lineage diversity.

PMID:38197286 | DOI:10.1111/mec.17260

Anal Methods. 2024 Jan 10. doi: 10.1039/d3ay01842c. Online ahead of print.

ABSTRACT

Glycated hemoglobin (HbA1c) has been an important biomarker for long-term diagnosis and monitoring of diabetes mellitus. The development of a rapid, reliable, and less sophisticated device to measure HbA1c is imperative to facilitate efficient early-care diabetes management. To date, no existing aptamer-based biosensor (aptasensor) for detecting HbA1c has been developed using a quartz crystal microbalance (QCM). In this study, the aptamer specific to HbA1c as a novel biosensing receptor was covalently functionalized onto a QCM substrate via mixed self-assembled monolayers (SAMs). A portable QCM equipped with a liquid-flow module was used to investigate the biospecificity, sensitivity, and interaction dynamics of the aptamer functionalized surfaces. The real-time kinetic analysis of HbA1c binding to the surface-functionalized aptamers revealed "on" and "off" binding rates of 4.19 × 104 M-1 s-1 and 2.43 × 10-3 s-1, respectively. These kinetic parameters imply that the QCM-based aptasensor specifically recognizes HbA1c with an equilibrium dissociation constant as low as 57.99 nM. The linear detection of HbA1c spanned from 13 to 108 nM, with a limit of detection (LOD) of 26.29 nM. Moreover, the spiked plasma sample analysis offered compelling evidence that this aptasensor is a promising technique for developing a point-of-care device for diabetes mellitus.

PMID:38197200 | DOI:10.1039/d3ay01842c

Tree Physiol. 2024 Jan 9:tpae003. doi: 10.1093/treephys/tpae003. Online ahead of print.

ABSTRACT

Needle blights are serious fungal diseases affecting European natural and planted pine forests. Brown-spot needle blight disease (BSNB), caused by the fungus Lecanosticta acicola, causes canopy defoliation and severe productivity losses with consequences depending on host susceptibility. To gain new insights into BSNB plant-pathogen interactions, constitutive and pathogen-induced traits were assessed in two host species with differential disease susceptibility. Six-months-old Pinus radiata (susceptible) and Pinus pinea (more resistant) seedlings were needle inoculated with L. acicola under controlled conditions. Eighty days after inoculation, healthy-looking needles from symptomatic plants were assessed for physiological parameters and sampled for biochemical analysis. Disease progression, plant growth, leaf gas-exchanges and biochemical parameters were complemented with hormonal and untargeted primary metabolism analysis and integrated for a holistic analysis. Constitutive differences between pine species were observed. Pinus pinea presented higher stomatal conductance and transpiration rate and higher amino and organic acids, abscisic acid as well as putrescine content than P. radiata. Symptoms from BSNB disease were observed in 54.54% of P. radiata and 45.45% of P. pinea seedlings, being more pronounced and generalized in P. radiata. For both species, plant height, sub-stomatal CO2 concentration and water-use efficiency were impacted by infection. In P. radiata, total soluble sugars, starch and total flavonoids content increased after infection. No differences in hormone content after infection were observed. However, secondary metabolism was induced in P. pinea visible through total phenolics, flavonoids and putrescine accumulation. Overall, the observed results suggest that P. pinea constitutive and induced traits may function as two layers of a defence strategy which contributed for an increased BSNB resistance in comparison with P. radiata. This is the first integrative study linking plant physiological and molecular traits in Pinus-Lecanosticta acicola pathosystem, contributing to a better understanding of the underlying resistance mechanisms to BSNB disease in pines.

PMID:38195942 | DOI:10.1093/treephys/tpae003

Nat Cancer. 2024 Jan 9. doi: 10.1038/s43018-023-00695-9. Online ahead of print.

ABSTRACT

The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.

PMID:38195932 | DOI:10.1038/s43018-023-00695-9

Commun Biol. 2024 Jan 9;7(1):73. doi: 10.1038/s42003-023-05707-z.

NO ABSTRACT

PMID:38195918 | DOI:10.1038/s42003-023-05707-z

Bioinformatics. 2024 Jan 9:btae007. doi: 10.1093/bioinformatics/btae007. Online ahead of print.

ABSTRACT

MOTIVATION: Boolean networks can serve as straightforward models for understanding processes such as gene regulation, and employing logical rules. These rules can either be derived from existing literature or by data-driven approaches. However, in the context of large networks, the exhaustive search for intervention targets becomes challenging due to the exponential expansion of a Boolean network's state space and the multitude of potential target candidates, along with their various combinations. Instead, we can employ the logical rules and resultant interaction graph as a means to identify targets of specific interest within larger-scale models. This approach not only facilitates the screening process but also serves as a preliminary filtering step, enabling the focused investigation of candidates that hold promise for more profound dynamic analysis. However, applying this method requires a working knowledge of R, thus restricting the range of potential users. We, therefore, aim to provide an application that makes this method accessible to a broader scientific community.

RESULTS: Here, we introduce GatekeepR, a graphical, web-based R Shiny application that enables scientists to screen Boolean network models for possible intervention targets whose perturbation is likely to have a large impact on the system's dynamics. This application does not require a local installation or knowledge of R and provides the suggested targets along with additional network information and visualizations in an intuitive, easy-to-use manner. The supplementary material describes the underlying method for identifying these nodes along with an example application in a network modelling pancreatic cancer.

AVAILABILITY AND IMPLEMENTATION: https://www.github.com/sysbio-bioinf/GatekeepR https://abel.informatik.uni-ulm.de/shiny/GatekeepR/.

PMID:38195862 | DOI:10.1093/bioinformatics/btae007

Nat Genet. 2024 Jan 9. doi: 10.1038/s41588-023-01620-7. Online ahead of print.

ABSTRACT

Functional studies of long noncoding RNAs (lncRNAs) have been hindered by the lack of methods to assess their evolution. Here we present lncRNA Homology Explorer (lncHOME), a computational pipeline that identifies a unique class of long noncoding RNAs (lncRNAs) with conserved genomic locations and patterns of RNA-binding protein (RBP) binding sites (coPARSE-lncRNAs). Remarkably, several hundred human coPARSE-lncRNAs can be evolutionarily traced to zebrafish. Using CRISPR-Cas12a knockout and rescue assays, we found that knocking out many human coPARSE-lncRNAs led to cell proliferation defects, which were subsequently rescued by predicted zebrafish homologs. Knocking down coPARSE-lncRNAs in zebrafish embryos caused severe developmental delays that were rescued by human homologs. Furthermore, we verified that human, mouse and zebrafish coPARSE-lncRNA homologs tend to bind similar RBPs with their conserved functions relying on specific RBP-binding sites. Overall, our study demonstrates a comprehensive approach for studying the functional conservation of lncRNAs and implicates numerous lncRNAs in regulating vertebrate physiology.

PMID:38195860 | DOI:10.1038/s41588-023-01620-7

Bioinformatics. 2024 Jan 9:btae005. doi: 10.1093/bioinformatics/btae005. Online ahead of print.

ABSTRACT

SUMMARY: Today, hundreds of post-translational modification (PTM) sites are routinely identified at once, but the comparison of new experimental datasets to already existing ones is hampered by the current inability to search most PTM databases at the protein residue level. We present FLAMS, a Python3-based command line and web-tool that enables researchers to compare their PTM sites to the contents of the CPLM, the largest dedicated protein lysine modification database, and dbPTM, the most comprehensive general PTM database, at the residue level. FLAMS can be integrated into PTM analysis pipelines, allowing researchers to quickly assess the novelty and conservation of PTM sites across species in newly generated datasets, aiding in the functional assessment of sites and the prioritization of sites for further experimental characterization.

AVAILABILITY AND IMPLEMENTATION: FLAMS is implemented in Python3, and freely available under an MIT license. It can be found as a command line tool at https://github.com/hannelorelongin/FLAMS, pip and conda; and as a web service at https://www.biw.kuleuven.be/m2s/cmpg/research/CSB/tools/flams/.

SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online.

PMID:38195744 | DOI:10.1093/bioinformatics/btae005

Mol Oncol. 2024 Jan 9. doi: 10.1002/1878-0261.13586. Online ahead of print.

ABSTRACT

Extracellular vesicles (EVs) and EV proteins are promising biomarkers for cancer liquid biopsy. Herein, we designed a case-control study involving 100 controls and 100 patients with esophageal, stomach, colorectal, liver, or lung cancer to identify common and type-specific biomarkers of plasma-derived EV surface proteins for the five cancers. EV surface proteins were profiled using a sequencing-based proximity barcoding assay. In this study, five differentially expressed proteins (DEPs) and eight differentially expressed protein combinations (DEPCs) showed promising performance (area under curve, AUC > 0.900) in pan-cancer identification [e.g., TENM2 (AUC = 0.982), CD36 (AUC = 0.974), and CD36-ITGA1 (AUC = 0.971)]. Our classification model could properly discriminate between cancer patients and controls using DEPs (AUC = 0.981) or DEPCs (AUC = 0.965). When distinguishing one cancer from the other four, the accuracy of the classification model using DEPCs (85-92%) was higher than that using DEPs (78-84%). We validated the performance in an additional 14 cancer patients and 14 controls, and achieved an AUC value of 0.786 for DEPs and 0.622 for DEPCs, highlighting the necessity to recruit a larger cohort for further validation. When clustering EVs into subpopulations, we detected cluster-specific proteins highly expressed in immune-related tissues. In the context of colorectal cancer, we identified heterogeneous EV clusters enriched in cancer patients, correlating with tumor initiation and progression. These findings provide epidemiological and molecular evidence for the clinical application of EV proteins in cancer prediction, while also illuminating their functional roles in cancer physiopathology.

PMID:38194998 | DOI:10.1002/1878-0261.13586

Curr Biol. 2024 Jan 8;34(1):R23-R25. doi: 10.1016/j.cub.2023.11.052.

ABSTRACT

Stress disrupts sleep, but the neural mechanisms underlying this relationship remain unclear. Novel findings in mice reveal a hypothalamic circuit that fragments sleep and promotes arousal after stress.

PMID:38194923 | DOI:10.1016/j.cub.2023.11.052

J Autoimmun. 2024 Jan 8;143:103165. doi: 10.1016/j.jaut.2023.103165. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE).

METHODS: Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers.

RESULTS: Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE).

CONCLUSION: In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.

PMID:38194790 | DOI:10.1016/j.jaut.2023.103165

Ann Hematol. 2024 Jan 9. doi: 10.1007/s00277-023-05587-7. Online ahead of print.

ABSTRACT

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

PMID:38194088 | DOI:10.1007/s00277-023-05587-7

Plant Reprod. 2024 Jan 9. doi: 10.1007/s00497-023-00494-3. Online ahead of print.

ABSTRACT

Contrasting morphologies in Disocactus are the result of differential development of the vegetative and floral tissue where intercalary growth is involved, resulting in a complex structure, the floral axis. Species from the Cactaceae bear adaptations related with their growth in environments under hydric stress. These adaptations have translated into the reduction and modification of various structures such as leaves, stems, lateral branches, roots and the structuring of flowers in a so-called flower-shoot. While cacti flowers and fruits have a consistent structure with showy hermaphrodite or unisexual flowers that produce a fruit called cactidium, the developmental dynamics of vegetative and reproductive tissues comprising the reproductive unit have only been inferred through the analysis of pre-anthetic buds. Here we present a comparative analysis of two developmental series covering the early stages of flower formation and organ differentiation in Disocactus speciosus and Disocactus eichlamii, which have contrasting floral morphologies. We observe that within the areole, a shoot apical meristem commences to grow upward, producing lateral leaves with a spiral arrangement, rapidly transitioning to a floral meristem. The floral meristem produces tepal primordia and a staminal ring meristem from which numerous or few stamens develop in a centrifugal manner in D. speciosus and D. eichlamii, respectively. Also, the inferior ovary derives from the floral meristem flattening and an upward growth of the surrounding tissue of the underlying stem, producing the pericarpel. This structure is novel to cacti and lacks a clear anatomical delimitation with the carpel wall. Here, we present a first study that documents the early processes taking place during initial meristem determination related to pericarpel development and early floral organ formation in cacti until the establishment of mature floral organs.

PMID:38193922 | DOI:10.1007/s00497-023-00494-3

Plant Biotechnol J. 2024 Jan 9. doi: 10.1111/pbi.14276. Online ahead of print.

ABSTRACT

Root architecture and function are critical for plants to secure water and nutrient supply from the soil, but environmental stresses alter root development. The phytohormone jasmonic acid (JA) regulates plant growth and responses to wounding and other stresses, but its role in root development for adaptation to environmental challenges had not been well investigated. We discovered a novel JA Upregulated Protein 1 gene (JAUP1) that has recently evolved in rice and is specific to modern rice accessions. JAUP1 regulates a self-perpetuating feed-forward loop to activate the expression of genes involved in JA biosynthesis and signalling that confers tolerance to abiotic stresses and regulates auxin-dependent root development. Ectopic expression of JAUP1 alleviates abscisic acid- and salt-mediated suppression of lateral root (LR) growth. JAUP1 is primarily expressed in the root cap and epidermal cells (EPCs) that protect the meristematic stem cells and emerging LRs. Wound-activated JA/JAUP1 signalling promotes crosstalk between the root cap of LR and parental root EPCs, as well as induces cell wall remodelling in EPCs overlaying the emerging LR, thereby facilitating LR emergence even under ABA-suppressive conditions. Elevated expression of JAUP1 in transgenic rice or natural rice accessions enhances abiotic stress tolerance and reduces grain yield loss under a limited water supply. We reveal a hitherto unappreciated role for wound-induced JA in LR development under abiotic stress and suggest that JAUP1 can be used in biotechnology and as a molecular marker for breeding rice adapted to extreme environmental challenges and for the conservation of water resources.

PMID:38193234 | DOI:10.1111/pbi.14276

Innov Clin Neurosci. 2023 Dec 1;20(10-12):12-17. eCollection 2023 Oct-Dec.

ABSTRACT

Point-of-care genetic testing for single nucleotide polymorphisms (SNPs) to improve psychiatric treatment in outpatient settings remains a challenge. The presence or absence of certain genomic alleles determines the activity of the encoded enzymes, which ultimately defines the individual's drug metabolism rate. Classification of poor metabolizers (PMs) and rapid/ultrarapid metabolizers (RMs/UMs) would facilitate personalization and precision of treatment. However, current pharmacogenomic (PGx) testing of multiple genes is comprehensive and requires quantitative analyses for interpretations. We recommend qualitative, fast-track, point-of-care screenings, which are one- or-two gene-based analyses, as a quick initial screening tool to potentially eliminate the need for an expensive quantitative send-out test, which is a costly and lengthy process. We speculate that these tests will be relevant in two major scenarios: 1) clinical psychiatry for treating disease states such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), where trial and error is still the mainstay of drug selection and symptom management, a process that is associated with significant delay in optimizing individualized treatment and dose, and thus response; and 2) pain management, where quickly determining an effective level of analgesia while avoiding a toxic level can cause a drastic improvement in mental health.

PMID:38193100 | PMC:PMC10773601

Biophys Rev. 2023 Dec 15;15(6):1987-2003. doi: 10.1007/s12551-023-01172-4. eCollection 2023 Dec.

ABSTRACT

Protein self-association is a widespread phenomenon that results in the formation of multimeric protein structures with critical roles in cellular processes. Protein self-association can lead to finite protein complexes or open-ended, and potentially, infinite structures. This review explores the concept of protein agglomeration, a process that results from the infinite self-assembly of folded proteins. We highlight its differences from other better-described processes with similar macroscopic features, such as aggregation and liquid-liquid phase separation. We review the sequence, structural, and biophysical factors influencing protein agglomeration. Lastly, we briefly discuss the implications of agglomeration in evolution, disease, and aging. Overall, this review highlights the need to study protein agglomeration for a better understanding of cellular processes.

PMID:38192350 | PMC:PMC10771401 | DOI:10.1007/s12551-023-01172-4

Nat Methods. 2024 Jan 8. doi: 10.1038/s41592-023-02139-9. Online ahead of print.

ABSTRACT

Single-cell omics technologies have revolutionized the study of gene regulation in complex tissues. A major computational challenge in analyzing these datasets is to project the large-scale and high-dimensional data into low-dimensional space while retaining the relative relationships between cells. This low dimension embedding is necessary to decompose cellular heterogeneity and reconstruct cell-type-specific gene regulatory programs. Traditional dimensionality reduction techniques, however, face challenges in computational efficiency and in comprehensively addressing cellular diversity across varied molecular modalities. Here we introduce a nonlinear dimensionality reduction algorithm, embodied in the Python package SnapATAC2, which not only achieves a more precise capture of single-cell omics data heterogeneities but also ensures efficient runtime and memory usage, scaling linearly with the number of cells. Our algorithm demonstrates exceptional performance, scalability and versatility across diverse single-cell omics datasets, including single-cell assay for transposase-accessible chromatin using sequencing, single-cell RNA sequencing, single-cell Hi-C and single-cell multi-omics datasets, underscoring its utility in advancing single-cell analysis.

PMID:38191932 | DOI:10.1038/s41592-023-02139-9

Nat Cell Biol. 2024 Jan 8. doi: 10.1038/s41556-023-01323-5. Online ahead of print.

NO ABSTRACT

PMID:38191670 | DOI:10.1038/s41556-023-01323-5

Nat Commun. 2024 Jan 8;15(1):320. doi: 10.1038/s41467-023-44535-x.

NO ABSTRACT

PMID:38191605 | DOI:10.1038/s41467-023-44535-x