Integr Zool. 2024 Dec 13. doi: 10.1111/1749-4877.12934. Online ahead of print.

ABSTRACT

The acoustic ecology of a previously unexamined dolphin population in the Mediterranean was assessed by investigating how sound emissions and acoustic features are influenced by concurrent conditions. Whistles and click-trains emission rates were compared among different environmental, social and behavioural conditions. Structural variability of 3928 good/high-quality vocalizations was analysed in relation to contexts through a two-stage approach. First, two multivariate MANOVA-models were fitted considering the entire set of acoustic parameters extracted from whistles and click trains, to investigate the effect of concomitant factors on the overall acoustic structure of each vocalization. Subsequently, GLMM models were applied to each acoustic feature individually to explore its response to different contextual factors. Emission rates increased significantly with calves and in larger groups, with also a positive effect of socialization on whistles and of muddy/sandy seabed and depth on impulsive sounds. The multivariate approach showed that all contextual factors influenced sounds' structure, with whistles being strongly affected by behaviour and calves' presence. The GLMM models highlighted that each acoustic parameter varied differently in response to specific factors, with (1) increasing trends in whistles' duration and inflection points during interaction with fishery and decreasing ones during socializing, and (2) decreasing inter-click-intervals and increasing click-repetition-rates in larger groups and during interactions with fishery. These results provide new findings on the acoustic plasticity of bottlenose dolphins and a more comprehensive view of the magnitude of the social, environmental and behavioural influence, highlighting how the complexity of the species' acoustic repertoire has yet to be unravelled at the local level.

PMID:39672673 | DOI:10.1111/1749-4877.12934

Gastroenterology. 2024 Nov 29:S0016-5085(24)05751-2. doi: 10.1053/j.gastro.2024.11.012. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although SSRIs are first line pharmacological treatments for these disorders, they may impart adverse effects including anxiety, anhedonia, dysmotility and, in children exposed in utero, an increased risk of cognitive, mood and gastrointestinal disorders. SSRIs act systemically to block SERT and enhance serotonergic signaling in the brain, intestinal epithelium and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development.

METHODS: We utilized transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial SERT or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development.

RESULTS: SERT ablation targeted to the intestinal epithelium promoted anxiolytic and anti-depressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms.

CONCLUSION: These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation and suggest a new link in humans between in utero SSRI exposure and DGBI development.

PMID:39672518 | DOI:10.1053/j.gastro.2024.11.012

Cell. 2024 Dec 12;187(25):7045-7063. doi: 10.1016/j.cell.2024.11.015.

ABSTRACT

Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.

PMID:39672099 | DOI:10.1016/j.cell.2024.11.015

Ecotoxicol Environ Saf. 2024 Dec 12;289:117531. doi: 10.1016/j.ecoenv.2024.117531. Online ahead of print.

ABSTRACT

Global warming-induced permafrost thawing raises concerns about the release of dormant microbes, including potentially harmful plant pathogens. However, the potential pathogenic risks associated with the thawing of permafrost remain poorly understood. Here, we conducted a 90-day soil incubation experiment at 4 °C to mimic extended permafrost thawing in Alaskan tundra soils stratified into active (A), transitional (T), and permanently frozen (P) layers. Following incubation, we examined the changes in bacterial abundance and community composition and tested the reactivation and pathogenicity of dormant plant pathogenic bacteria. Bacterial abundance, measured by colony-forming units and 16S rRNA gene copies, distinctly increased in the T and P layers after thawing. These layers also exhibited substantial shifts in bacterial community structure, with Fe-cycling taxa becoming more abundant and permafrost-dominant taxa decreasing in abundance. Notably, we isolated 52 strains with proteolytic activity, and our pathogenicity tests confirmed that Pseudomonas spp. isolates caused potato soft rot symptoms. Some Pseudomonas pathogens were undetectable in the amplicon sequencing data before thawing and emerged only in the thawed T and P layers. Our findings illustrate that permafrost acts as a reservoir of potential plant pathogens, and their resurgence upon thawing poses a potential risk to Arctic ecosystems.

PMID:39672037 | DOI:10.1016/j.ecoenv.2024.117531

Sci Adv. 2024 Dec 13;10(50):eadq0987. doi: 10.1126/sciadv.adq0987. Epub 2024 Dec 13.

ABSTRACT

The spatiotemporal configuration of genes with distal regulatory elements is believed to be crucial for transcriptional control, but full mechanistic understanding is lacking. We combine simultaneous live tracking of pairs of genomic loci and nascent transcripts with molecular dynamics simulations to assess the Sox2 gene and its enhancer. We find that both loci exhibit more constrained mobility than control sequences due to stalled cohesin at CCCTC-binding factor sites. Strikingly, enhancer mobility becomes constrained on transcriptional firing, homogenizing its dynamics with the gene promoter, suggestive of their cotranscriptional sharing of a nuclear microenvironment. Furthermore, we find transcription and loop extrusion to be antagonistic processes constraining regulatory loci. These findings indicate that modulating chromatin mobility can be an additional, underestimated means for effective gene regulation.

PMID:39671497 | DOI:10.1126/sciadv.adq0987

PLoS Genet. 2024 Dec 13;20(12):e1011332. doi: 10.1371/journal.pgen.1011332. Online ahead of print.

ABSTRACT

Genome-wide association studies (GWAS) traditionally analyze single traits, e.g., disease diagnoses or biomarkers. Nowadays, large-scale cohorts such as UK Biobank (UKB) collect imaging data with sample sizes large enough to perform genetic association testing. Typical approaches to GWAS on high-dimensional modalities extract predefined features from the data, e.g., volumes of regions of interest. This limits the scope of such studies to predefined traits and can ignore novel patterns present in the data. TransferGWAS employs deep neural networks (DNNs) to extract low-dimensional representations of imaging data for GWAS, eliminating the need for predefined biomarkers. Here, we apply transferGWAS on brain MRI data from UKB. We encoded 36, 311 T1-weighted brain magnetic resonance imaging (MRI) scans using DNN models trained on MRI scans from the Alzheimer's Disease Neuroimaging Initiative, and on natural images from the ImageNet dataset, and performed a multivariate GWAS on the resulting features. We identified 289 independent loci, associated among others with bone density, brain, or cardiovascular traits, and 11 regions having no previously reported associations. We fitted polygenic scores (PGS) of the deep features, which improved predictions of bone mineral density and several other traits in a multi-PGS setting, and computed genetic correlations with selected phenotypes, which pointed to novel links between diffusion MRI traits and type 2 diabetes. Overall, our findings provided evidence that features learned with DNN models can uncover additional heritable variability in the human brain beyond the predefined measures, and link them to a range of non-brain phenotypes.

PMID:39671448 | DOI:10.1371/journal.pgen.1011332

PLoS Genet. 2024 Dec 13;20(12):e1011513. doi: 10.1371/journal.pgen.1011513. Online ahead of print.

ABSTRACT

Enhancers play a critical role in regulating precise gene expression patterns essential for development and cellular identity; however, how gene-enhancer specificity is encoded within the genome is not clearly defined. To investigate how this specificity arises within topologically associated domains (TAD), we performed allele-specific genome editing of sequences surrounding the Lefty1 and Lefty2 paralogs in mouse embryonic stem cells. The Lefty genes arose from a tandem duplication event and these genes interact with each other in chromosome conformation capture assays which place these genes within the same TAD. Despite their physical proximity, we demonstrate that these genes are primarily regulated by separate enhancer elements. Through CRISPR-Cas9 mediated deletions to remove the intervening chromatin between the Lefty genes, we reveal a distance-dependent dosage effect of the Lefty2 enhancer on Lefty1 expression. These findings indicate a role for chromatin distance in insulating gene expression domains in the Lefty locus in the absence of architectural insulation.

PMID:39671433 | DOI:10.1371/journal.pgen.1011513

PLoS One. 2024 Dec 13;19(12):e0315534. doi: 10.1371/journal.pone.0315534. eCollection 2024.

ABSTRACT

INTRODUCTION: Hepatocellular carcinoma is one of the leading causes of cancer-related mortality worldwide. The actin-binding protein Girdin is overexpressed in various tumors, promoting tumorigenesis and progression. However, the exact mechanisms by which Girdin regulates liver cancer remain poorly understood.

METHODS: This study comprehensively analyzed the expression level of Girdin in liver cancer and adjacent tissue, along with the correlation between Girdin expression and the clinical characteristics and prognosis of liver cancer. The analysis integrated data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Subsequently, Girdin expression was knocked down to elucidate its role in the progression of liver cancer. Transcriptome sequencing was employed to investigate the mechanistic underpinnings of Girdin's regulatory impact on liver cancer. Additionally, the Comparative Toxicogenomics Database (CTD) was utilized to identify potential drugs or molecules for liver cancer treatment.

RESULTS: The findings revealed elevated Girdin expression in liver cancer tissues, and heightened Girdin expression correlating with adverse clinical features and prognosis. Silencing of Girdin markedly impeded the proliferation and migration of hepatocellular carcinoma cells. Moreover, transcriptome sequencing demonstrated that silencing Girdin led to differential expression of 176 genes and inhibition of the PI3K/Akt signaling pathway, as well as its upstream pathways-Cytokine-cytokine receptor interaction and Chemokine signaling pathway. Ultimately, we propose that Imatinib Mesylate, Orantinib, Resveratrol, Sorafenib, and Curcumin may interact with Girdin, potentially contributing to the treatment of liver cancer.

CONCLUSION: This study reveals the association between Girdin and hepatocellular carcinoma, providing novel clues for future research and treatment of hepatocellular carcinoma.

PMID:39671369 | DOI:10.1371/journal.pone.0315534

Cell Rep. 2024 Dec 12;43(12):115077. doi: 10.1016/j.celrep.2024.115077. Online ahead of print.

ABSTRACT

Stem cells integrate multiple environmental signals to activate appropriate fate programs. To ensure coherent responses, alternative fates must be concomitantly inactivated. However, mechanisms that coordinate fates in a signal-specific manner are not fully understood. Here, we investigate the role of a network of basic-helix-loop-helix (bHLH) transcription factors in neural stem cells, which integrate leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling to synergistically induce glial fibrillary acidic protein (GFAP), a key astrocyte-fate determinant. Using quantitative RNA-fluorescence in situ hybridization (FISH) and ectopic expression, we find that multiple bHLHs that promote alternative fates also repress GFAP but are all suppressed by BMP and, to a lesser extent, LIF. Mathematical modeling shows that synergy arises from this coordinated derepression of GFAP combined with its activation by LIF signaling. Finally, we determine how coordinated and tunable derepression results from extensive cross-regulation among bHLHs. Activation-derepression synergy could be broadly utilized to couple signaling and fate, particularly across the numerous developmental systems regulated by bHLH factors.

PMID:39671287 | DOI:10.1016/j.celrep.2024.115077

ACS Sens. 2024 Dec 13. doi: 10.1021/acssensors.4c02420. Online ahead of print.

ABSTRACT

The high rate of cancer worldwide and the heavy costs imposed on governments and humanity have always motivated researchers to develop point-of-care (POC) biosensors for easy diagnosis and monitoring of cancer treatment. Herein, we report on a label-free impedimetric biosensor based on Ti3C2Tx MXene and imprinted ortho-phenylenediamine (o-PD) for the detection of carcinoembryonic antigen (CEA), a biomarker for various cancers surveillance, especially colorectal cancer (CRC). Accordingly, MXene was drop-casted on the surface of a disposable silver electrode to increase the sensitivity and create high-energy nanoareas on the surface, which are usable for protein immobilization and detection. A self-assembled monolayer (SAM) was exploited for oriented CEA immobilization on the MXene-modified electrode. The monomer-protein interaction and successful protein removal were confirmed by molecular docking and atomic force microscopy (AFM) investigations to evaluate the quality of the fabricated molecularly imprinted polymer (MIP). Also, the role of MXene in increasing the electrical field inside the nanoareas was simulated using COMSOL Multiphysics software. A suitable limit of detection (9.41 ng/mL), an appropriate linear range of detection (10 to 100 ng/mL) in human serum, and a short detection time (10 min) resulted from the use of SAM/MIP next to MXene. This biosensor presented outstanding repeatability (97.60%) and reproducibility (98.61%). Moreover, acceptable accuracy (between 93.04 and 116.04%) in clinical serum samples was obtained compared with immunoassay results, indicating the high potential of our biosensor for real sample analysis. This biomimetic and disposable sensor provides a cost-effective method for facile and POC monitoring of cancer patients during treatment.

PMID:39671262 | DOI:10.1021/acssensors.4c02420

Int J Syst Evol Microbiol. 2024 Dec;74(12). doi: 10.1099/ijsem.0.006603.

ABSTRACT

A novel Gram-stain-positive, black-pigmented bacterium, designated as WL48A T, was isolated from the surface of badland sedimentary rock in the Red Desert of Wyoming and characterized using a polyphasic taxonomic approach. Good growth occurred at 28-32 °C, pH 7-9, and NaCl less than 1% (w/v). Colonies, growing well on International Streptomyces Project media (ISP) 3 and ISP 7, were black and adhering to the agar. Phylogenetic analyses based on 16S rRNA gene and draft genome sequences showed that strain WL48AT belongs to the family Geodermatophilaceae, forming a distinct sub-branch with Geodermatophilus bullaregiensis DSM 46841T. The organism showed 16S rRNA gene sequence similarity of 98.8% with G. bullaregiensis DSM 46841T. Digital DNA-DNA hybridization value between the genome sequences of strain WL48A T and G. bullaregiensis DSM 46841T was 51.8%, below the threshold of 70% for prokaryotic species delineation. The chemotaxonomic investigation revealed the presence of galactose, glucose, mannose, xylose and ribose as well as meso-DAP in the peptidoglycan layer. The polar lipid profiles contained phosphatidylcholine (PC), phosphatidylinositol (PI), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE) phosphoglycolipid, phospholipids and an unidentified lipid. The menaquinone profile consisted of MK-9(H4) (98.2%) and MK-9(H2) (10.8%). The major fatty acid profile (>15%) comprised iso-C15 : 0 and iso-C16 : 0. Based on phenotypic, genetic and genomic data, strain WL48AT (=DSM 116197T = NCIMB 15483T=NCCB 100957T =ATCC TSD-376T) merits to be considered as a novel species for which the name Geodermatophilus maliterrae sp. nov. is proposed.

PMID:39671238 | DOI:10.1099/ijsem.0.006603

Elife. 2024 Dec 13;13:RP96691. doi: 10.7554/eLife.96691.

ABSTRACT

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, neurokinin B (NKB), and dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases Slc17a6 (Vglut2) mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current that contributes to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of canonical transient receptor potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When Trpc5 channels in Kiss1ARH neurons were deleted using CRISPR/SaCas9, the slow excitatory postsynaptic potential was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of Kiss1ARH neurons, suggesting that E2 modifies ionic conductances in these neurons, enabling the transition from high-frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.

PMID:39671233 | DOI:10.7554/eLife.96691

Pac Symp Biocomput. 2025;30:360-376.

ABSTRACT

Patients experiencing adverse drug events (ADE) from polypharmaceutical regimens present a huge challenge to modern healthcare. While computational efforts may reduce the incidence of these ADEs, current strategies are typically non-generalizable for standard healthcare systems. To address this, we carried out a retrospective study aimed at developing a statistical approach to detect and quantify potential ADEs. The data foundation comprised of almost 2 million patients from two health regions in Denmark and their drug and laboratory data during the years 2011 to 2016. We developed a series of multistate Cox models to compute hazard ratios for changes in laboratory test results before and after drug exposure. By linking the results to data from a drug-drug interaction database, we found that the models showed potential for applications for medical safety agencies and improved efficiency for drug approval pipelines.

PMID:39670382

Heliyon. 2024 Jul 2;10(13):e33594. doi: 10.1016/j.heliyon.2024.e33594. eCollection 2024 Jul 15.

ABSTRACT

Measles, a highly contagious airborne disease, remains endemic in many developing countries with low vaccination coverage. In this paper, we present a deterministic mathematical compartmental model to analyze the dynamics of measles. We establish global stability conditions for both disease-free and endemic equilibria using the Lyapunov functional stability method. By using arbitrary parameters, we find that the proposed model exhibits forward bifurcation. To simulate the solution of the model for the forward problem, we perform numerical integration using MATLAB software. Moreover, we calibrate the model with real data from Ethiopia and estimate the parameters along with a 95 percent confidence interval (CI) by formulating an inverse problem. It is noteworthy that our model fits well with the actual data from Ethiopia. The estimated basic reproduction number ( R 0 ) is determined to be R 0 = 1.3973 , demonstrating the endemic status of the disease. Additionally, our local sensitivity analysis indicates that reducing the transmission rate and increasing vaccination coverage can effectively minimize R 0 .

PMID:39670224 | PMC:PMC11637132 | DOI:10.1016/j.heliyon.2024.e33594

Neurobiol Pain. 2024 Nov 25;16:100173. doi: 10.1016/j.ynpai.2024.100173. eCollection 2024 Jul-Dec.

ABSTRACT

OBJECTIVE: This study aimed to evaluate pain metrics and gut microbiota differences from human subjects with complex regional pain syndrome (CRPS) compared to cohabitants (HHC) and non-cohabitating (biobank) controls. In addition, we aimed evaluate longitudinal changes of gut microbiota using a mouse model of acute and chronic CRPS.

METHODS: In an observational, cross-sectional study, 25 patients with CRPS and 24 household controls (HHC) were recruited, completed pain questionnaires, and submitted stool samples. 23 biobank stool samples were matched to the CRPS group. Additionally, longitudinal stool samples were collected from a mouse model of acute and chronic CRPS. 16S rRNA gene sequencing analysis was performed on all samples.

RESULTS: A diagnosis of CRPS is associated with higher pain, increased pain interference, and decreased physical and social function when compared to HHC. Interestingly, 46% of HHC reported significant daily pain. In the households where HHC were also suffering from pain, there was decreased bacterial richness and diversity when compared to households wherein only the participant with CRPS suffered from pain. Furthermore, when comparing households where the HHC had significant pain, CRPS was clinically more severe. In the mouse model of CRPS, we observed decreased bacterial richness and diversity when compared to non-cohabitating littermate controls.

CONCLUSIONS: Both humans living in chronic pain households and mice shared distinct taxa over the time course of disease and pain chronicity. These findings suggest that microbiota changes seen in CRPS as well as in a mouse model of CRPS may reflect pain chronicity and may indicate that pain alone can contribute to microbiota dysbiosis. The trial was registered at ClinicalTrials.gov (NCT03612193).

PMID:39670171 | PMC:PMC11636187 | DOI:10.1016/j.ynpai.2024.100173

Plant Direct. 2024 Aug 21;8(8):e70000. doi: 10.1002/pld3.70000. eCollection 2024 Aug.

ABSTRACT

RNA methylation plays a central regulatory role in plant biology and is a relatively new target for plant improvement efforts. In nearly all cases, perturbation of the RNA methylation machinery results in deleterious phenotypes. However, a recent landmark paper reported that transcriptome-wide use of the human RNA demethylase FTO substantially increased the yield of rice and potatoes. Here, we have performed the first independent replication of those results and demonstrated broader transferability of the trait, finding increased flower and fruit count in the model species Arabidopsis thaliana. We also performed RNA-seq of our FTO-transgenic plants, which we analyzed in conjunction with previously published datasets to detect several previously unrecognized patterns in the functional and structural classification of the upregulated and downregulated genes. From these, we present mechanistic hypotheses to explain these surprising results with the goal of spurring more widespread interest in this promising new approach to plant engineering.

PMID:39669404 | PMC:PMC11636547 | DOI:10.1002/pld3.70000

Chem Sci. 2024 Dec 3. doi: 10.1039/d4sc06246a. Online ahead of print.

ABSTRACT

CH-π interactions between carbohydrates and aromatic amino acids play an essential role in biological systems that span all domains of life. Quantifying the strength and importance of these CH-π interactions is challenging because these interactions involve several atoms and can exist in many distinct orientations. To identify an orientational landscape of CH-π interactions, we constructed a dataset of close contacts formed between β-d-galactose residues and the aromatic amino acids, tryptophan, tyrosine, and phenylalanine, across crystallographic structures deposited in the Protein Data Bank. We carried out quantum mechanical calculations to quantify their interaction strengths. The data indicate that tryptophan-containing CH-π interactions have more favorable interaction energies than those formed by tyrosine or phenylalanine. The energetic differences between these amino acids are caused by the aromatic ring system electronics and size. We use individual distance and angle features to train random forest models to successfully predict the first-principles computed energetics of CH-π interactions. Using insights from our models, we define a tradeoff in CH-π interaction strength arising from the proximity of galactose carbons 1 and 2 versus carbons 4 and 6 to the aromatic amino acid. Our work demonstrates that a feature of CH-π stacking interactions is that numerous orientations allow for highly favorable interaction strengths.

PMID:39669175 | PMC:PMC11632809 | DOI:10.1039/d4sc06246a

Anim Biosci. 2024 Dec 13. doi: 10.5713/ab.24.0631. Online ahead of print.

ABSTRACT

OBJECTIVE: Mammalian sperm acquire fertilizing ability in the female reproductive tract and develop hyperactivated motility, which is indispensable for male fertility. Hyperactivated motility is initiated by Ca2+ influx via the sperm-specific ion channel, CatSper. CATSPER1, a CatSper pore subunit, possesses a long N-terminal intracellular domain and its degradation correlates with unsuccessful sperm migration in the female tract. However, the cellular function and molecular significance of the CATSPER1 N-terminal domain are not well understood. Here, we identify the interactome of the CATSPER1 N-terminal domain and propose a function for the intracellular domain in mammalian sperm.

METHODS: To identify CATSPER1 N-terminus interactome, we produced recombinant CATSPER1-N-terminus in bacterial system. The purified protein was incubated with testicular lysates and eluted together with testicular interacting proteins. The elutes were subjected to proteomic analysis and CATSPER1-N-terminus interactome was profiled. Identified proteins were further analyzed by functional annotation.

RESULTS: We purified the partial CATSPER1 N-terminal domain and identified 57 testicular proteins as domain interactomes using mass spectrometry analysis. Functional annotation analysis revealed that 106 gene ontologies were significantly enriched, 16 of which were related to redox processes. We found that antioxidant enzymes, such as PARK7 and PRDX2, 4, and 6, were included in the enriched redox-related gene ontologies.

CONCLUSION: These results suggest that the CATSPER1 N-terminus could function in defending against oxidative stress to support the successful migration of mammalian sperm to fertilizing sites in the female reproductive tract.

PMID:39668395 | DOI:10.5713/ab.24.0631

Mol Syst Biol. 2024 Dec 12. doi: 10.1038/s44320-024-00081-2. Online ahead of print.

ABSTRACT

Elucidation of protein-protein interactions (PPIs) represents one of the most important methods in biomedical research. Recently, PPIs have started to be exploited for drug discovery purposes and have thus attracted much attention from both the academic and pharmaceutical sectors. We previously developed a sensitive method, Split Intein-Mediated Protein Ligation (SIMPL), for detecting binary PPIs via irreversible splicing of the interacting proteins being investigated. Here, we incorporated tripart nanoluciferase (tNLuc) into the system, providing a luminescence signal which, in conjunction with homogenous liquid phase operation, improves the quantifiability and operability of the assay. Using a reference PPI set, we demonstrated an improvement in both sensitivity and specificity over the original SIMPL assay. Moreover, we designed the new SIMPL-tNLuc ('SIMPL2') platform with an inherent modularity allowing for flexible measurement of molecular modulators of target PPIs, including inhibitors, molecular glues and PROTACs. Our results demonstrate that SIMPL2 is a sensitive, cost- and labor-effective tool suitable for high-throughput screening (HTS) in both PPI mapping and drug discovery applications.

PMID:39668253 | DOI:10.1038/s44320-024-00081-2

Nat Plants. 2024 Dec 12. doi: 10.1038/s41477-024-01854-1. Online ahead of print.

ABSTRACT

In animals and plants, organ shape is primarily determined during primordium development by carefully coordinated growth and cell division1-3. Rare examples of post-primordial change in morphology (reshaping) exist that offer tractable systems for the study of mechanisms required for organ shape determination and diversification. One such example is morphogenesis in Capsella fruits whose heart-shaped appearance emerges by reshaping of the ovate spheroid gynoecium upon fertilization4. Here we use whole-organ live-cell imaging and single-cell RNA sequencing (scRNA-seq) analysis to show that Capsella fruit shape determination is based on dynamic changes in cell growth and cell division coupled with local maintenance of meristematic identity. At the molecular level, we reveal an auxin-induced mechanism that is required for morphological alteration and ultimately determined by a single cis-regulatory element. This element resides in the promoter of the Capsella rubella SHOOTMERISTEMLESS5 (CrSTM) gene. The CrSTM meristem identity factor positively regulates its own expression through binding to this element, thereby providing a feed-forward loop at the position and time of protrusion emergence to form the heart. Independent evolution of the STM-binding element in STM promoters across Brassicaceae species correlates with those undergoing a gynoecium-to-fruit shape change. Accordingly, genetic and phenotypic studies show that the STM-binding element is required to facilitate the shape transition and suggest a conserved molecular mechanism for organ morphogenesis.

PMID:39668212 | DOI:10.1038/s41477-024-01854-1