Methods Mol Biol. 2024;2800:217-229. doi: 10.1007/978-1-0716-3834-7_15.

ABSTRACT

High-throughput microscopy has enabled screening of cell phenotypes at unprecedented scale. Systematic identification of cell phenotype changes (such as cell morphology and protein localization changes) is a major analysis goal. Because cell phenotypes are high-dimensional, unbiased approaches to detect and visualize the changes in phenotypes are still needed. Here, we suggest that changes in cellular phenotype can be visualized in reduced dimensionality representations of the image feature space. We describe a freely available analysis pipeline to visualize changes in protein localization in feature spaces obtained from deep learning. As an example, we use the pipeline to identify changes in subcellular localization after the yeast GFP collection was treated with hydroxyurea.

PMID:38709487 | DOI:10.1007/978-1-0716-3834-7_15

Sports Med. 2024 May 6. doi: 10.1007/s40279-024-02026-z. Online ahead of print.

ABSTRACT

BACKGROUND: Preterm birth and low birthweight (LBW) might be associated with reduced physical fitness, although evidence remains inconclusive.

OBJECTIVE: To examine the influence of preterm birth and LBW on physical fitness, as well as to assess whether variables such as gestational age, birthweight, or age at assessment moderate these effects.

METHODS: PubMed, Scopus, and PsycINFO were systematically searched from inception to 7 December 2023 for case-control and cohort studies analyzing the association between preterm birth or LBW (or gestational age or birthweight as continuous variables) with at least one physical fitness-related outcome (i.e., cardiorespiratory fitness (CRF), muscle strength, flexibility, speed, agility). Random-effects meta-analysis and meta-regression models were used to estimate the pooled effect size, as well as to examine potential associations between the magnitude of the effect and gestational age, birthweight, or age at assessment.

RESULTS: Fifty-two studies (n = 920,603 participants, average age ranging from 4.7 to 34.4 years) were included. Preterm birth was associated with reduced CRF (standardized mean difference (SMD) = -0.38, 95% confidence interval (CI) = -0.51 to -0.25) and muscle strength (SMD = -0.44, 95% CI = -0.79 to -0.08). LBW was associated with reduced CRF (SMD = -0.40, 95% CI = -0.64 to -0.17), muscle strength (SMD = -0.18, 95% CI = -0.24 to -0.13), flexibility (SMD = -0.11, 95% CI = -0.22 to -0.01), and agility (SMD = -0.99, 95% CI = -1.91 to -0.07). Meta-regression analyses showed that a lower gestational age or birthweight were associated with larger reductions in physical fitness, whereas no consistent association was found for the age at assessment.

CONCLUSION: Both preterm birth and LBW seem associated with reduced physical fitness regardless of age, with larger reductions overall observed in individuals with lower gestational age or birthweight. These findings might support the implementation of preventive strategies (e.g., fitness monitoring and physical exercise interventions) in these populations through the life course. PROSPERO registration: CRD42021231845.

PMID:38709451 | DOI:10.1007/s40279-024-02026-z

Microbiol Spectr. 2024 May 6:e0034624. doi: 10.1128/spectrum.00346-24. Online ahead of print.

ABSTRACT

Across the Burkholderia genus O-linked protein glycosylation is highly conserved. While the inhibition of glycosylation has been shown to be detrimental for virulence in Burkholderia cepacia complex species, such as Burkholderia cenocepacia, little is known about how specific glycosylation sites impact protein functionality. Within this study, we sought to improve our understanding of the breadth, dynamics, and requirement for glycosylation across the B. cenocepacia O-glycoproteome. Assessing the B. cenocepacia glycoproteome across different culture media using complementary glycoproteomic approaches, we increase the known glycoproteome to 141 glycoproteins. Leveraging this repertoire of glycoproteins, we quantitively assessed the glycoproteome of B. cenocepacia using Data-Independent Acquisition (DIA) revealing the B. cenocepacia glycoproteome is largely stable across conditions with most glycoproteins constitutively expressed. Examination of how the absence of glycosylation impacts the glycoproteome reveals that the protein abundance of only five glycoproteins (BCAL1086, BCAL2974, BCAL0525, BCAM0505, and BCAL0127) are altered by the loss of glycosylation. Assessing ΔfliF (ΔBCAL0525), ΔmotB (ΔBCAL0127), and ΔBCAM0505 strains, we demonstrate the loss of FliF, and to a lesser extent MotB, mirror the proteomic effects observed in the absence of glycosylation in ΔpglL. While both MotB and FliF are essential for motility, we find loss of glycosylation sites in MotB or FliF does not impact motility supporting these sites are dispensable for function. Combined this work broadens our understanding of the B. cenocepacia glycoproteome supporting that the loss of glycoproteins in the absence of glycosylation is not an indicator of the requirement for glycosylation for protein function.

IMPORTANCE: Burkholderia cenocepacia is an opportunistic pathogen of concern within the Cystic Fibrosis community. Despite a greater appreciation of the unique physiology of B. cenocepacia gained over the last 20 years a complete understanding of the proteome and especially the O-glycoproteome, is lacking. In this study, we utilize systems biology approaches to expand the known B. cenocepacia glycoproteome as well as track the dynamics of glycoproteins across growth phases, culturing media and in response to the loss of glycosylation. We show that the glycoproteome of B. cenocepacia is largely stable across conditions and that the loss of glycosylation only impacts five glycoproteins including the motility associated proteins FliF and MotB. Examination of MotB and FliF shows, while these proteins are essential for motility, glycosylation is dispensable. Combined this work supports that B. cenocepacia glycosylation can be dispensable for protein function and may influence protein properties beyond stability.

PMID:38709084 | DOI:10.1128/spectrum.00346-24

Heliyon. 2024 Apr 25;10(9):e30329. doi: 10.1016/j.heliyon.2024.e30329. eCollection 2024 May 15.

ABSTRACT

Both high glucose intake with a high-fat meal and inhibition of dipeptidyl peptidase-4 (DPP4) have been associated with plasma lipid-lowering effects, but mechanistic understanding linking glucose and fat absorption is lacking. We here hypothesized that glucose ameliorates intestinal fatty acid uptake via a pathway involving DPP4. A concentration of 50 mM glucose reduced mean DPP4 activity in differentiated Caco-2 enterocytes by 42.5 % and fatty acid uptake by 66.0 % via nutrient sensing by the sweet taste receptor subunit TAS1R3 and glucose transporter GLUT-2. No effect of the DPP4 substrates GLP-1 and GIP or of the cellular energy status on the reduced uptake of fatty acids was seen, but a direct interaction between DPP4 and fatty acid transporters is suggested. Conclusively we identified DPP4 as a regulator of fatty acid absorption in Caco-2 enterocytes that mediates the inhibition of intestinal fatty acid uptake by glucose via an interplay of GLUT-2 and TAS1R3.

PMID:38707340 | PMC:PMC11066672 | DOI:10.1016/j.heliyon.2024.e30329

Natl Sci Rev. 2024 Jan 30;11(6):nwae037. doi: 10.1093/nsr/nwae037. eCollection 2024 Jun.

ABSTRACT

Spiking neural networks (SNNs) have superior energy efficiency due to their spiking signal transmission, which mimics biological nervous systems, but they are difficult to train effectively. Although surrogate gradient-based methods offer a workable solution, trained SNNs frequently fall into local minima because they are still primarily based on gradient dynamics. Inspired by the chaotic dynamics in animal brain learning, we propose a chaotic spiking backpropagation (CSBP) method that introduces a loss function to generate brain-like chaotic dynamics and further takes advantage of the ergodic and pseudo-random nature to make SNN learning effective and robust. From a computational viewpoint, we found that CSBP significantly outperforms current state-of-the-art methods on both neuromorphic data sets (e.g. DVS-CIFAR10 and DVS-Gesture) and large-scale static data sets (e.g. CIFAR100 and ImageNet) in terms of accuracy and robustness. From a theoretical viewpoint, we show that the learning process of CSBP is initially chaotic, then subject to various bifurcations and eventually converges to gradient dynamics, consistently with the observation of animal brain activity. Our work provides a superior core tool for direct SNN training and offers new insights into understanding the learning process of a biological brain.

PMID:38707198 | PMC:PMC11067972 | DOI:10.1093/nsr/nwae037

Function (Oxf). 2024 Mar 28;5(3):zqae012. doi: 10.1093/function/zqae012. eCollection 2024.

ABSTRACT

Acute kidney injury (AKI) is a heterogeneous syndrome, comprising diverse etiologies of kidney insults that result in high mortality and morbidity if not well managed. Although great efforts have been made to investigate underlying pathogenic mechanisms of AKI, there are limited therapeutic strategies available. Extracellular vesicles (EV) are membrane-bound vesicles secreted by various cell types, which can serve as cell-free therapy through transfer of bioactive molecules. In this review, we first overview the AKI syndrome and EV biology, with a particular focus on the technical aspects and therapeutic application of cell culture-derived EVs. Second, we illustrate how multi-omic approaches to EV miRNA, protein, and genomic cargo analysis can yield new insights into their mechanisms of action and address unresolved questions in the field. We then summarize major experimental evidence regarding the therapeutic potential of EVs in AKI, which we subdivide into stem cell and non-stem cell-derived EVs. Finally, we highlight the challenges and opportunities related to the clinical translation of animal studies into human patients.

PMID:38706963 | PMC:PMC11065115 | DOI:10.1093/function/zqae012

iScience. 2024 Apr 10;27(5):109708. doi: 10.1016/j.isci.2024.109708. eCollection 2024 May 17.

ABSTRACT

During aging, skin homeostasis is essential for maintaining appearance, as well as biological defense of the human body. In this study, we identified thrombospondin-1 (THBS1) and fibromodulin (FMOD) as positive and negative regulators, respectively, of the TGF-β1-SMAD4 axis in human skin aging, based on in vitro and in vivo omics analyses and mathematical modeling. Using transcriptomic and epigenetic analyses of senescent dermal fibroblasts, TGF-β1 was identified as the key upstream regulator. Bifurcation analysis revealed a binary high-/low-TGF-β1 switch, with THBS1 as the main controller. Computational simulation of the TGF-β1 signaling pathway indicated that THBS1 expression was sensitively regulated, whereas FMOD was regulated robustly. Results of sensitivity analysis and validation showed that inhibition of SMAD4 complex formation was a promising method to control THBS1 production and senescence. Therefore, this study demonstrated the potential of combining data-driven target discovery with mathematical approaches to determine the mechanisms underlying skin aging.

PMID:38706856 | PMC:PMC11066433 | DOI:10.1016/j.isci.2024.109708

iScience. 2024 Apr 16;27(5):109748. doi: 10.1016/j.isci.2024.109748. eCollection 2024 May 17.

ABSTRACT

We previously reported that loss of function of TYW1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation. However, whether TYW1 loss affects neural differentiation is unknown. In this study, we first demonstrated that TYW1 loss blocked the formation of OHyW in tRNAphe and therefore affected the translation efficiency of UUU codon. Using the brain organoid model, we showed impaired neuron differentiation when TYW1 was depleted. Interestingly, retrotransposons were differentially regulated in TYW1-/- hESCs (human embryonic stem cells). In particular, one kind of human-specific endogenous retrovirus-K (HERVK/HML2), whose reactivation impaired human neurodevelopment, was significantly up-regulated in TYW1-/- hESCs. Consistently, a UUU codon-enriched protein, SMARCAD1, which was a key factor in controlling endogenous retroviruses, was reduced. Taken together, TYW1 loss leads to up-regulation of HERVK in hESCs by down-regulated SMARCAD1, thus impairing neuron differentiation.

PMID:38706838 | PMC:PMC11066470 | DOI:10.1016/j.isci.2024.109748

Front Public Health. 2024 Apr 19;12:1340673. doi: 10.3389/fpubh.2024.1340673. eCollection 2024.

ABSTRACT

BACKGROUND: Tuberculosis (TB) is a major public health emergency in many countries, including Kazakhstan. Despite the decline in the incidence rate and having one of the highest treatment effectiveness in the world, the incidence rate of TB remains high in Kazakhstan. Social and environmental factors along with host genetics contribute to pulmonary tuberculosis (PTB) incidence. Due to the high incidence rate of TB in Kazakhstan, our research aimed to study the epidemiology and genetics of PTB in Kazakhstan.

MATERIALS AND METHODS: 1,555 participants were recruited to the case-control study. The epidemiology data was taken during an interview. Polymorphisms of selected genes were determined by real-time PCR using pre-designed TaqMan probes.

RESULTS: Epidemiological risk factors like diabetes (χ2 = 57.71, p < 0.001), unemployment (χ2 = 81.1, p < 0.001), and underweight-ranged BMI (<18.49, χ2 = 206.39, p < 0.001) were significantly associated with PTB. VDR FokI (rs2228570) and VDR BsmI (rs1544410) polymorphisms were associated with an increased risk of PTB. A/A genotype of the TLR8 gene (rs3764880) showed a significant association with an increased risk of PTB in Asians and Asian males. The G allele of the rs2278589 polymorphism of the MARCO gene increases PTB susceptibility in Asians and Asian females. VDR BsmI (rs1544410) polymorphism was significantly associated with PTB in Asian females. A significant association between VDR ApaI polymorphism and PTB susceptibility in the Caucasian population of Kazakhstan was found.

CONCLUSION: This is the first study that evaluated the epidemiology and genetics of PTB in Kazakhstan on a relatively large cohort. Social and environmental risk factors play a crucial role in TB incidence in Kazakhstan. Underweight BMI (<18.49 kg/m2), diabetes, and unemployment showed a statistically significant association with PTB in our study group. FokI (rs2228570) and BsmI (rs1544410) polymorphisms of the VDR gene can be used as possible biomarkers of PTB in Asian males. rs2278589 polymorphism of the MARCO gene may act as a potential biomarker of PTB in Kazakhs. BsmI polymorphism of the VDR gene and rs2278589 polymorphism of the MARCO gene can be used as possible biomarkers of PTB risk in Asian females as well as VDR ApaI polymorphism in Caucasians.

PMID:38706548 | PMC:PMC11066200 | DOI:10.3389/fpubh.2024.1340673

Brief Bioinform. 2024 Mar 27;25(3):bbae208. doi: 10.1093/bib/bbae208.

ABSTRACT

Antiviral peptides (AVPs) have shown potential in inhibiting viral attachment, preventing viral fusion with host cells and disrupting viral replication due to their unique action mechanisms. They have now become a broad-spectrum, promising antiviral therapy. However, identifying effective AVPs is traditionally slow and costly. This study proposed a new two-stage computational framework for AVP identification. The first stage identifies AVPs from a wide range of peptides, and the second stage recognizes AVPs targeting specific families or viruses. This method integrates contrastive learning and multi-feature fusion strategy, focusing on sequence information and peptide characteristics, significantly enhancing predictive ability and interpretability. The evaluation results of the model show excellent performance, with accuracy of 0.9240 and Matthews correlation coefficient (MCC) score of 0.8482 on the non-AVP independent dataset, and accuracy of 0.9934 and MCC score of 0.9869 on the non-AMP independent dataset. Furthermore, our model can predict antiviral activities of AVPs against six key viral families (Coronaviridae, Retroviridae, Herpesviridae, Paramyxoviridae, Orthomyxoviridae, Flaviviridae) and eight viruses (FIV, HCV, HIV, HPIV3, HSV1, INFVA, RSV, SARS-CoV). Finally, to facilitate user accessibility, we built a user-friendly web interface deployed at https://awi.cuhk.edu.cn/∼dbAMP/AVP/.

PMID:38706321 | DOI:10.1093/bib/bbae208

Brief Bioinform. 2024 Mar 27;25(3):bbae206. doi: 10.1093/bib/bbae206.

ABSTRACT

The advent of rapid whole-genome sequencing has created new opportunities for computational prediction of antimicrobial resistance (AMR) phenotypes from genomic data. Both rule-based and machine learning (ML) approaches have been explored for this task, but systematic benchmarking is still needed. Here, we evaluated four state-of-the-art ML methods (Kover, PhenotypeSeeker, Seq2Geno2Pheno and Aytan-Aktug), an ML baseline and the rule-based ResFinder by training and testing each of them across 78 species-antibiotic datasets, using a rigorous benchmarking workflow that integrates three evaluation approaches, each paired with three distinct sample splitting methods. Our analysis revealed considerable variation in the performance across techniques and datasets. Whereas ML methods generally excelled for closely related strains, ResFinder excelled for handling divergent genomes. Overall, Kover most frequently ranked top among the ML approaches, followed by PhenotypeSeeker and Seq2Geno2Pheno. AMR phenotypes for antibiotic classes such as macrolides and sulfonamides were predicted with the highest accuracies. The quality of predictions varied substantially across species-antibiotic combinations, particularly for beta-lactams; across species, resistance phenotyping of the beta-lactams compound, aztreonam, amoxicillin/clavulanic acid, cefoxitin, ceftazidime and piperacillin/tazobactam, alongside tetracyclines demonstrated more variable performance than the other benchmarked antibiotics. By organism, Campylobacter jejuni and Enterococcus faecium phenotypes were more robustly predicted than those of Escherichia coli, Staphylococcus aureus, Salmonella enterica, Neisseria gonorrhoeae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Streptococcus pneumoniae and Mycobacterium tuberculosis. In addition, our study provides software recommendations for each species-antibiotic combination. It furthermore highlights the need for optimization for robust clinical applications, particularly for strains that diverge substantially from those used for training.

PMID:38706320 | DOI:10.1093/bib/bbae206

Brief Bioinform. 2024 Mar 27;25(3):bbae202. doi: 10.1093/bib/bbae202.

ABSTRACT

Inference of cell-cell communication (CCC) provides valuable information in understanding the mechanisms of many important life processes. With the rise of spatial transcriptomics in recent years, many methods have emerged to predict CCCs using spatial information of cells. However, most existing methods only describe CCCs based on ligand-receptor interactions, but lack the exploration of their upstream/downstream pathways. In this paper, we proposed a new method to infer CCCs, called Intercellular Gene Association Network (IGAN). Specifically, it is for the first time that we can estimate the gene associations/network between two specific single spatially adjacent cells. By using the IGAN method, we can not only infer CCCs in an accurate manner, but also explore the upstream/downstream pathways of ligands/receptors from the network perspective, which are actually exhibited as a new panoramic cell-interaction-pathway graph, and thus provide extensive information for the regulatory mechanisms behind CCCs. In addition, IGAN can measure the CCC activity at single cell/spot resolution, and help to discover the CCC spatial heterogeneity. Interestingly, we found that CCC patterns from IGAN are highly consistent with the spatial microenvironment patterns for each cell type, which further indicated the accuracy of our method. Analyses on several public datasets validated the advantages of IGAN.

PMID:38706319 | DOI:10.1093/bib/bbae202

Brief Funct Genomics. 2024 May 5:elae018. doi: 10.1093/bfgp/elae018. Online ahead of print.

ABSTRACT

Non-coding RNA encodes micropeptides from small open reading frames located within the RNA. Interestingly, these micropeptides are involved in a variety of functions within the body. They are emerging as the resolving piece of the puzzle for complex biomolecular signaling pathways within the body. Recent studies highlight the pivotal role of small peptides in regulating important biological processes like DNA repair, gene expression, muscle regeneration, immune responses, etc. On the contrary, altered expression of micropeptides also plays a pivotal role in the progression of various diseases like cardiovascular diseases, neurological disorders and several types of cancer, including colorectal cancer, hepatocellular cancer, lung cancer, etc. This review delves into the dual impact of micropeptides on health and pathology, exploring their pivotal role in preserving normal physiological homeostasis and probing their involvement in the triggering and progression of diseases.

PMID:38706311 | DOI:10.1093/bfgp/elae018

NPJ Microgravity. 2024 May 4;10(1):51. doi: 10.1038/s41526-024-00397-1.

ABSTRACT

Human Wharton's jelly stem cells (hWJSCs) are multipotent stem cells that are extensively employed in biotechnology applications. However, the impact of simulated lunar microgravity (sμG) on the growth, differentiation, and viability of this cell population is incompletely characterized. We aimed to determine whether acute (72 h) exposure to sμG elicited changes in growth and lineage differentiation in hWJSCs and if putative changes were maintained once exposure to terrestrial gravity (1.0 G) was restored. hWJSCs were cultured under standard 1.0 G conditions prior to being passaged and cultured under sμG (0.16 G) using a random positioning machine. Relative to control, hWJSCs cultured under sμG exhibited marked reductions in growth but not viability. Cell population expression of characteristic stemness markers (CD 73, 90, 105) was significantly reduced under sμG conditions. hWJSCs had 308 significantly upregulated and 328 significantly downregulated genes when compared to 1.0 G culture conditions. Key markers of cell replication, including MKI67, were inhibited. Significant upregulation of osteocyte-chondrocyte lineage markers, including SERPINI1, MSX2, TFPI2, BMP6, COMP, TMEM119, LUM, HGF, CHI3L1 and SPP1, and downregulation of cell fate regulators, including DNMT1 and EZH2, were detected in sμG-exposed hWJSCs. When returned to 1.0 G for 3 days, sμG-exposed hWJSCs had accelerated growth, and expression of stemness markers increased, approaching normal (i.e. 95%) levels. Our data support earlier findings that acute sμG significantly reduces the cell division potential of hWJSCs and suggest that acute sμG-exposure induces reversible changes in cell growth accompanied by osteocyte-chondrocyte changes in lineage differentiation.

PMID:38704360 | DOI:10.1038/s41526-024-00397-1

Environ Res. 2024 May 2:119017. doi: 10.1016/j.envres.2024.119017. Online ahead of print.

ABSTRACT

In the last years, lipid physiology has become an important research target for systems biology applied to the field of ecotoxicology. Lipids are not only essential components of biological membranes, but also participate in extra and intracellular signaling processes and as signal transducers and amplifiers of regulatory cascades. Particularly in sauropsids, lipids are the main source of energy for reproduction, growth, and embryonic development. In nature, organisms are exposed to different stressors, such as parasites, diseases and environmental contaminants, which interact with lipid signaling and metabolic pathways, disrupting lipid homeostasis. The system biology approach applied to ecotoxicological studies is crucial to evaluate metabolic regulation under environmental stress produced by xenobiotics. In this review, we cover information of molecular mechanisms that contribute to lipid metabolism homeostasis in sauropsids, specifically in crocodilian species. We focus on the role of lipid metabolism as a powerful source of energy and its importance during oocyte maturation, which has been increasingly recognized in many species, but information is still scarce in crocodiles. Finally, we highlight priorities for future research on the influence of environmental stressors on lipid metabolism, their potential effect on the reproductive system and thus on the offspring, and their implications on crocodilians conservation.

PMID:38704009 | DOI:10.1016/j.envres.2024.119017

Mol Syst Biol. 2024 May 3. doi: 10.1038/s44320-024-00037-6. Online ahead of print.

ABSTRACT

The physical interactome of a protein can be altered upon perturbation, modulating cell physiology and contributing to disease. Identifying interactome differences of normal and disease states of proteins could help understand disease mechanisms, but current methods do not pinpoint structure-specific PPIs and interaction interfaces proteome-wide. We used limited proteolysis-mass spectrometry (LiP-MS) to screen for structure-specific PPIs by probing for protease susceptibility changes of proteins in cellular extracts upon treatment with specific structural states of a protein. We first demonstrated that LiP-MS detects well-characterized PPIs, including antibody-target protein interactions and interactions with membrane proteins, and that it pinpoints interfaces, including epitopes. We then applied the approach to study conformation-specific interactors of the Parkinson's disease hallmark protein alpha-synuclein (aSyn). We identified known interactors of aSyn monomer and amyloid fibrils and provide a resource of novel putative conformation-specific aSyn interactors for validation in further studies. We also used our approach on GDP- and GTP-bound forms of two Rab GTPases, showing detection of differential candidate interactors of conformationally similar proteins. This approach is applicable to screen for structure-specific interactomes of any protein, including posttranslationally modified and unmodified, or metabolite-bound and unbound protein states.

PMID:38702390 | DOI:10.1038/s44320-024-00037-6

Life Sci Alliance. 2024 May 3;7(7):e202402603. doi: 10.26508/lsa.202402603. Print 2024 Jul.

ABSTRACT

Excess abdominal fat is a sexually dimorphic risk factor for cardio-metabolic disease and is approximated by the waist-to-hip ratio adjusted for body mass index (WHRadjBMI). Whereas this trait is highly heritable, few causal genes are known. We aimed to identify novel drivers of WHRadjBMI using systems genetics. We used two independent cohorts of adipose tissue gene expression and constructed sex- and depot-specific Bayesian networks to model gene-gene interactions from 8,492 genes. Using key driver analysis, we identified genes that, in silico and putatively in vitro, regulate many others. 51-119 key drivers in each network were replicated in both cohorts. In other cell types, 23 of these genes are found in crucial adipocyte pathways: Wnt signaling or mitochondrial function. We overexpressed or down-regulated seven key driver genes in human subcutaneous pre-adipocytes. Key driver genes ANAPC2 and RSPO1 inhibited adipogenesis, whereas PSME3 increased adipogenesis. RSPO1 increased Wnt signaling activity. In differentiated adipocytes, MIGA1 and UBR1 down-regulation led to mitochondrial dysfunction. These five genes regulate adipocyte function, and we hypothesize that they regulate fat distribution.

PMID:38702075 | DOI:10.26508/lsa.202402603

Stem Cell Reports. 2024 Apr 26:S2213-6711(24)00110-3. doi: 10.1016/j.stemcr.2024.04.004. Online ahead of print.

ABSTRACT

Embryo size, specification, and homeostasis are regulated by a complex gene regulatory and signaling network. Here we used gene expression signatures of Wnt-activated mouse embryonic stem cell (mESC) clones to reverse engineer an mESC regulatory network. We identify NKX1-2 as a novel master regulator of preimplantation embryo development. We find that Nkx1-2 inhibition reduces nascent RNA synthesis, downregulates genes controlling ribosome biogenesis, RNA translation, and transport, and induces severe alteration of nucleolus structure, resulting in the exclusion of RNA polymerase I from nucleoli. In turn, NKX1-2 loss of function leads to chromosome missegregation in the 2- to 4-cell embryo stages, severe decrease in blastomere numbers, alterations of tight junctions (TJs), and impairment of microlumen coarsening. Overall, these changes impair the blastocoel expansion-collapse cycle and embryo cavitation, leading to altered lineage specification and developmental arrest.

PMID:38701778 | DOI:10.1016/j.stemcr.2024.04.004

Stem Cell Reports. 2024 Apr 22:S2213-6711(24)00108-5. doi: 10.1016/j.stemcr.2024.04.002. Online ahead of print.

ABSTRACT

Embryonic stem cells (ESCs) are defined as stem cells with self-renewing and differentiation capabilities. These unique properties are tightly regulated and controlled by complex genetic and molecular mechanisms, whose understanding is essential for both basic and translational research. A large number of studies have mostly focused on understanding the molecular mechanisms governing pluripotency and differentiation of ESCs, while the regulation of proliferation has received comparably less attention. Here, we investigate the role of ZZZ3 (zinc finger ZZ-type containing 3) in human ESCs homeostasis. We found that knockdown of ZZZ3 negatively impacts ribosome biogenesis, translation, and mTOR signaling, leading to a significant reduction in cell proliferation. This process occurs without affecting pluripotency, suggesting that ZZZ3-depleted ESCs enter a "dormant-like" state and that proliferation and pluripotency can be uncoupled also in human ESCs.

PMID:38701777 | DOI:10.1016/j.stemcr.2024.04.002

Mol Cell. 2024 May 2;84(9):1802-1810.e4. doi: 10.1016/j.molcel.2024.03.028.

ABSTRACT

Polyphosphate (polyP) is a chain of inorganic phosphate that is present in all domains of life and affects diverse cellular phenomena, ranging from blood clotting to cancer. A study by Azevedo et al. described a protein modification whereby polyP is attached to lysine residues within polyacidic serine and lysine (PASK) motifs via what the authors claimed to be covalent phosphoramidate bonding. This was based largely on the remarkable ability of the modification to survive extreme denaturing conditions. Our study demonstrates that lysine polyphosphorylation is non-covalent, based on its sensitivity to ionic strength and lysine protonation and absence of phosphoramidate bond formation, as analyzed via 31P NMR. Ionic interaction with lysine residues alone is sufficient for polyP modification, and we present a new list of non-PASK lysine repeat proteins that undergo polyP modification. This work clarifies the biochemistry of polyP-lysine modification, with important implications for both studying and modulating this phenomenon. This Matters Arising paper is in response to Azevedo et al. (2015), published in Molecular Cell. See also the Matters Arising Response by Azevedo et al. (2024), published in this issue.

PMID:38701741 | DOI:10.1016/j.molcel.2024.03.028