Signal integration and adaptive sensory diversity tuning in Escherichia coli chemotaxis.

In uncertain environments, phenotypic diversity can be advantageous for survival. However, as the environmental uncertainty decreases, the relative advantage of having diverse phenotypes decreases. Here, we show how populations of E. coli integrate multiple chemical signals to adjust sensory diversity in response to changes in the prevalence of each ligand in the environment. Measuring kinase activity in single cells, we quantified the sensitivity distribution to various chemoattractants in different mixtures of background stimuli. We found that when ligands bind uncompetitively, the population tunes sensory diversity to each signal independently, decreasing diversity when the signal's ambient concentration increases. However, among competitive ligands, the population can only decrease sensory diversity one ligand at a time. Mathematical modeling suggests that sensory diversity tuning benefits E. coli populations by modulating how many cells are committed to tracking each signal proportionally as their prevalence changes.

DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer.

Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

Tracking Chlamydia - Host interactions and antichlamydial activity in Caenorhabditis elegans.

The fading efficacy of antibiotics is a growing global health concern due to its life-threatening consequences and increased healthcare costs. Non-genetic mechanisms of antimicrobial resistance, such as those employed by Chlamydia pneumoniae and Chlamydia trachomatis, complicate treatment as these bacteria can enter a non-replicative, persistent state under stress, evading antibiotics and linking to inflammatory conditions. Understanding chlamydial persistence at the molecular level is challenging, and new models for studying Chlamydia-host interactions in vivo are urgently needed. Caenorhabditis elegans offers an alternative given its immune system and numerous orthologues of human genes. This study established C. elegans as an in vivo model for chlamydial infection. Both Chlamydia species reduced the worm's lifespan, their DNA being detectable at three- and six-days post-infection. Azithromycin at its MIC (25 nM) failed to prevent the infection-induced lifespan reduction, indicating a persister phenotype. In contrast, the methanolic extract of Schisandra chinensis berries showed anti-chlamydial activity both in vitro (in THP-1 macrophages) and in vivo, significantly extending the lifespan of infected C. elegans and reducing the bacterial load. Moreover, S. chinensis increased the transcriptional activity of SKN-1 in the worms, but was unable to impact the bacterial load or lifespan in a sek-1 defective C. elegans strain. In summary, this study validated C. elegans as a chlamydial infection model and showcased S. chinensis berries' in vivo anti-chlamydial potential, possibly through SEK/SKN-1 signaling modulation.

Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony.

In aging, physiologic networks decline in function at rates that differ between individuals, producing a wide distribution of lifespan. Though 70% of human lifespan variance remains unexplained by heritable factors, little is known about the intrinsic sources of physiologic heterogeneity in aging. To understand how complex physiologic networks generate lifespan variation, new methods are needed. Here, we present Asynch-seq, an approach that uses gene-expression heterogeneity within isogenic populations to study the processes generating lifespan variation. By collecting thousands of single-individual transcriptomes, we capture the Caenorhabditis elegans "pan-transcriptome"-a highly resolved atlas of non-genetic variation. We use our atlas to guide a large-scale perturbation screen that identifies the decoupling of total mRNA content between germline and soma as the largest source of physiologic heterogeneity in aging, driven by pleiotropic genes whose knockdown dramatically reduces lifespan variance. Our work demonstrates how systematic mapping of physiologic heterogeneity can be applied to reduce inter-individual disparities in aging.

Timing-specific parental effects of ocean warming in a coral reef fish.

Population and species persistence in a rapidly warming world will be determined by an organism's ability to acclimate to warmer conditions, especially across generations. There is potential for transgenerational acclimation but the importance of ontogenetic timing in the transmission of environmentally induced parental effects remains mostly unknown. We aimed to disentangle the effects of two critical ontogenetic stages (juvenile development and reproduction) to the new-generation acclimation potential, by exposing the spiny chromis damselfish Acanthochromis polyacanthus to simulated ocean warming across two generations. By using hepatic transcriptomics, we discovered that the post-hatching developmental environment of the offspring themselves had little effect on their acclimation potential at 2.5 months of life. Instead, the developmental experience of parents increased regulatory RNA production and protein synthesis, which could improve the offspring's response to warming. Conversely, parental reproduction and offspring embryogenesis in warmer water elicited stress response mechanisms in the offspring, with suppression of translation and mitochondrial respiration. Mismatches between parental developmental and reproductive temperatures deeply affected offspring gene expression profiles, and detrimental effects were evident when warming occurred both during parents' development and reproduction. This study reveals that the previous generation's developmental temperature contributes substantially to thermal acclimation potential during early life; however, exposure at reproduction as well as prolonged heat stress will likely have adverse effects on the species' persistence.

Comparison of different animal models for estimating genetic parameters for early growth traits and reproductive traits in Tianmu Sainuo sheep.

As the economic level of individuals rises, so too does the demand for mutton. Enhancing the breeds of mutton sheep not only boosts production efficiency and economic benefits but also fosters the sustainable growth of the mutton sheep breeding industry. Thus, this study examines the early growth and reproductive traits of Tianmu Sainuo sheep, analyzing the genetic interactions among these traits to furnish a theoretical foundation for refining breeding strategies and expediting the genetic advancement of this breed. The investigation compiled 29,966 data entries, involving 111 sires for birth weight (BWT) and 113 for other metrics. The data encompassed 10,415 BWT records from 1,633 dams, 12,753 weaning weight (WWT) records from 1,570 dams, 12,793 average daily gain (ADG) records from 1,597 dams, and 13,594 litter size (LS) records from 1,499 dams. Utilizing the GLM procedure in SAS 9.2 software, the study analyzed the non-genetic influences on lamb BWT, WWT, ADG, and LS. Concurrently, DMU software estimated the variance components across various animal models for each trait. Employing the Akaike Information Criterion (AIC) and likelihood ratio test (LRT), six models were tested, incorporating or excluding maternal inheritance and environmental impacts, to identify the optimal model for deriving genetic parameters. The findings reveal that birth year (BY), birth quarter (BQ), birth type (BT), age of mother (AM), and birth sex (BS) exerted significant impacts on BWT, WWT, and ADG (p < 0.01). Additionally, BQ and AM significantly influenced LS (p < 0.01). The most accurate genetic evaluation model determined the heritability of BWT, WWT, ADG, and LS to be 0.0695, 0.0849, 0.0777, and 0.1252, respectively.

Transfer of membrane(s) matter(s)-non-genetic inheritance of (metabolic) phenotypes?

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are anchored at the outer phospholipid layer of eukaryotic plasma membranes exclusively by a glycolipid. GPI-APs are not only released into extracellular compartments by lipolytic cleavage. In addition, certain GPI-APs with the glycosylphosphatidylinositol anchor including their fatty acids remaining coupled to the carboxy-terminus of their protein components are also detectable in body fluids, in response to certain stimuli, such as oxidative stress, radicals or high-fat diet. As a consequence, the fatty acid moieties of GPI-APs must be shielded from access of the aqueous environment by incorporation into membranes of extracellular vesicles or into micelle-like complexes together with (lyso)phospholipids and cholesterol. The GPI-APs released from somatic cells and tissues are transferred via those complexes or EVs to somatic as well as pluripotent stem cells with metabolic consequences, such as upregulation of glycogen and lipid synthesis. From these and additional findings, the following hypotheses are developed: i) Transfer of GPI-APs via EVs or micelle-like complexes leads to the induction of new phenotypes in the daughter cells or zygotes, which are presumably not restricted to metabolism. ii) The membrane topographies transferred by the concerted action of GPI-APs and interacting components are replicated by self-organization and self-templation and remain accessible to structural changes by environmental factors. iii) Transfer from mother cells and gametes to their daughter cells and zygotes, respectively, is not restricted to DNA and genes, but also encompasses non-genetic matter, such as GPI-APs and specific membrane constituents. iv) The intergenerational transfer of membrane matter between mammalian organisms is understood as an epigenetic mechanism for phenotypic plasticity, which does not rely on modifications of DNA and histones, but is regarded as molecular mechanism for the inheritance of acquired traits, such as complex metabolic diseases. v) The missing interest in research of non-genetic matter of inheritance, which may be interpreted in the sense of Darwin's "Gemmules" or Galton's "Stirps", should be addressed in future investigations of the philosophy of science and sociology of media.

Matching maternal and paternal experiences underpin molecular thermal acclimation.

The environment experienced by one generation has the potential to affect the subsequent one through non-genetic inheritance of parental effects. Since both mothers and fathers can influence their offspring, questions arise regarding how the maternal, paternal and offspring experiences integrate into the resulting phenotype. We aimed to disentangle the maternal and paternal contributions to transgenerational thermal acclimation in a reef fish, Acanthochromis polyacanthus, by exposing two generations to elevated temperature (+1.5°C) in a fully factorial design and analysing the F2 hepatic gene expression. Paternal and maternal effects showed not only common but also parent-specific components, with the father having the largest influence in shaping the offspring's transcriptomic profile. Fathers contributed to transcriptional transgenerational response to warming through transfer of epigenetically controlled stress-response mechanisms while mothers influenced increased gene expression associated with lipid metabolism regulation. However, the key to acclimation potential was matching thermal experiences of the parents. When both parents were exposed to the same condition, offspring showed increased expression of genes related to structural RNA production and transcriptional regulation, whereas environmental mismatch in parents resulted in maladaptive parental condition transfer, revealed by translation suppression and endoplasmic reticulum stress. Interestingly, the offspring's own environmental experience had the smallest influence on their hepatic transcription profiles. Taken together, our results show the complex nature of the interplay among paternal, maternal and offspring cue integration, and reveal that acclimation potential to ocean warming might depend not only on maternal and paternal contributions but importantly on congruent parental thermal experiences.

Paternal starvation affects metabolic gene expression during zebrafish offspring development and lifelong fitness.

Dietary restriction in the form of fasting is a putative key to a healthier and longer life, but these benefits may come at a trade-off with reproductive fitness and may affect the following generation(s). The potential inter- and transgenerational effects of long-term fasting and starvation are particularly poorly understood in vertebrates when they originate from the paternal line. We utilised the externally fertilising zebrafish amenable to a split-egg clutch design to explore the male-specific effects of fasting/starvation on fertility and fitness of offspring independently of maternal contribution. Eighteen days of fasting resulted in reduced fertility in exposed males. While average offspring survival was not affected, we detected increased larval growth rate in F1 offspring from starved males and more malformed embryos at 24 h post-fertilisation in F2 offspring produced by F1 offspring from starved males. Comparing the transcriptomes of F1 embryos sired by starved and fed fathers revealed robust and reproducible increased expression of muscle composition genes but lower expression of lipid metabolism and lysosome genes in embryos from starved fathers. A large proportion of these genes showed enrichment in the yolk syncytial layer suggesting gene regulatory responses associated with metabolism of nutrients through paternal effects on extra-embryonic tissues which are loaded with maternal factors. We compared the embryo transcriptomes to published adult transcriptome datasets and found comparable repressive effects of starvation on metabolism-associated genes. These similarities suggest a physiologically relevant, directed and potentially adaptive response transmitted by the father, independently from the offspring's nutritional state, which was defined by the mother.

Understanding the Genetic and Non-Genetic Interconnections in the Aetiology of Syndromic Congenital Heart Disease: An Updated Review: Part 2.

PURPOSE OF REVIEW: Approximately 30% of syndromic cases diagnosed with CHD, which lure us to further investigate the molecular and clinical challenges behind syndromic CHD (sCHD). The aetiology of sCHD in a majority of cases remains enigmatic due to involvement of multiple factors, namely genetic, epigenetic and environmental modifiable risk factors for the development of the disease. Here, we aim to update the role of genetic contributors including chromosomal abnormalities, copy number variations (CNVs) and single gene mutations in cardiac specific genes, maternal lifestyle conditions, environmental exposures and epigenetic modifiers in causing CHD in different genetic syndromes. RECENT FINDINGS: The exact aetiology of sCHD is still unknown. With the advancement of next-generation technologies including WGS, WES, transcriptome, proteome and methylome study, numerous novel genes and pathways have been identified. Moreover, our recent knowledge regarding epigenetic and environmental regulation during cardiogenesis is still evolving and may solve some of the mystery behind complex sCHD. Here, we focus to understand how the complex combination of genetic, environmental and epigenetic factors interact to interfere with developmental pathways, culminating into cardiac and extracardiac defects in sCHD.

Alteration of chromosome structure impacts gene expressions implicated in pancreatic ductal adenocarcinoma cells.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a five-year survival rate of approximately 10%. Genetic mutations are pivotal drivers in PDAC pathogenesis, but recent investigations also revealed the involvement of non-genetic alterations in the disease development. In this study, we undertook a multi-omics approach, encompassing ATAC-seq, RNA-seq, ChIP-seq, and Hi-C methodologies, to dissect gene expression alterations arising from changes in chromosome accessibility and chromatin three-dimensional interactions in PDAC. RESULTS: Our findings indicate that chromosomal structural alterations can lead to abnormal expressions on key genes during PDAC development. Notably, overexpression of oncogenes FGFR2, FOXA2, CYP2R1, and CPOX can be attributed to the augmentation of promoter accessibility, coupled with long-range interactions with distal elements. Additionally, our findings indicate that chromosomal structural alterations caused by genomic instability can lead to abnormal expressions in PDACs. As an example, by analyzing chromosomal changes, we identified a putative oncogenic gene, LPAR1, which shows upregulated expression in both PDAC cell lines and clinical samples. The overexpression is correlated with alterations in LPAR1-associated 3D genome structure and chromatin state. We further demonstrated that high LPAR1 activity is required for enhanced PDAC cell migration in vitro. CONCLUSIONS: Collectively, our findings reveal that the chromosomal conformational alterations, in addition to the well-known genetic mutations, are critical for PDAC tumorigenesis.

Intravital photoacoustic brain stimulation with high-precision.

Significance: Neural regulation at high precision vitally contributes to propelling fundamental understanding in the field of neuroscience and providing innovative clinical treatment options. Recently, photoacoustic brain stimulation has emerged as a cutting-edge method for precise neuromodulation and shows great potential for clinical application. Aim: The goal of this perspective is to outline the advancements in photoacoustic brain stimulation in recent years. And, we also provide an outlook delineating several prospective paths through which this burgeoning approach may be substantively refined for augmented capability and wider implementations. Approach: First, the mechanisms of photoacoustic generation as well as the potential mechanisms of photoacoustic brain stimulation are provided and discussed. Then, the state-of-the-art achievements corresponding to this technology are reviewed. Finally, future directions for photoacoustic technology in neuromodulation are provided. Results: Intensive research endeavors have prompted substantial advancements in photoacoustic brain stimulation, illuminating the unique advantages of this modality for noninvasive and high-precision neuromodulation via a nongenetic way. It is envisaged that further technology optimization and randomized prospective clinical trials will enable a wide acceptance of photoacoustic brain stimulation in clinical practice. Conclusions: The innovative practice of photoacoustic technology serves as a multifaceted neuromodulation approach, possessing noninvasive, high-accuracy, and nongenetic characteristics. It has a great potential that could considerably enhance not only the fundamental underpinnings of neuroscience research but also its practical implementations in a clinical setting.

Genetic analysis of first lactation and lifetime performance traits in composite Vrindavani cattle: important considerations for higher milk production.

The present study was aimed to evaluate the influence of non-genetic factors on several first lactation and lifetime performance traits and elucidate their genetic parameters in an organized Vrindavani cattle population. Data on eight first-lactation and thirteen lifetime traits were collected on 2400 cows with pedigree records that were reared during 33-year period (1989-2021). The first-lactation traits included age at first calving (AFC), total milk yield (FTMY), standard milk yield (FSMY305), peak yield (FPY), lactation length (FLL), dry period (FDP), service period (FSP) and calving interval (FCI). Whereas, the lifetime traits mainly included total lifetime milk yield (TLMY), total standard milk yield (TSMY), number of lactations completed (NL), total lactation length (TLL), herd life (HL), productive life (PL), average milk yield per day of herd life (TLMY/HL), average milk yield per day of productive life (TLMY/PL), average milk yield per day of productive life (TLMY/TLL). Other lifetime production traits included average service period (ASP), average dry period (ADP), average calving interval (ACI) and unproductive days (UD). The heritability estimates of first-lactation traits ranged between 0.026 and 0.228 and were found to be low for AFC (0.180 ± 0.042), FCI (0.191 ± 0.125), FSMY305 (0.145 ± 0.061), FTMY (0.165 ± 0.048), FDP (0.052 ± 0.049) and FSP (0.026 ± 0.033); however, FLL (0.229 ± 0.044) and FPY (0.202 ± 0.046) showed moderate heritability. Positive phenotypic correlation (p < 0.001) was revealed among FTMY, TLMY, TLL, HL and PL. The AFC produced a significant effect (p < 0.05) on several traits i,e, TLL, TLMY/HL, FSMY305, FPY, TLMY, HL and TLMY/PL. Lower AFC was associated with higher TLMY, TLL and TLMY/HL; while FSMY305, FPY, HL and TLMY/PL were higher in heifers that calved late in their life. The results revealed that AFC may be optimized with first lactation and lifetime traits for this population.

Dual-Fluorescence Chromosome-Located Labeling System for Accurate In Vivo Single-Cell Gene Expression Analysis in Pseudomonas syringae.

Epigenetic regulation as a means for bacterial adaptation is receiving increasing interest in the last decade. Significant efforts have been directed towards understanding the mechanisms giving raise to phenotypic heterogeneity within bacterial populations and its adaptive relevance. Phenotypic heterogeneity mostly refers to phenotypic variation not linked to genetic differences nor to environmental stimuli. Recent findings on the relevance of phenotypic heterogeneity on some bacterial complex traits are causing a shift from traditional assays where bacterial phenotypes are defined by averaging population-level data, to single-cell analysis that focus on bacterial individual behavior within the population. Fluorescent labeling is a key asset for single-cell gene expression analysis using flow cytometry, fluorescence microscopy, and/or microfluidics.We previously described the generation of chromosome-located transcriptional gene fusions to fluorescent reporter genes using the model bacterial plant pathogen Pseudomonas syringae. These fusions allow researchers to follow variation in expression of the gene(s) of interest, without affecting gene function. In this report, we improve the analytic power of the method by combining such transcriptional fusions with constitutively expressed compatible fluorescent reporter genes integrated in a second, neutral locus of the bacterial chromosome. Constitutively expressed fluorescent reporters allow for the detection of all bacteria comprising a heterogeneous population, regardless of the level of expression of the concurrently monitored gene of interest, thus avoiding the traditional use of stains often incompatible with samples from complex contexts such as the leaf.

A metabolomic perspective on the mechanisms by which environmental pollutants and lifestyle lead to male infertility.

The incidence of male infertility (MI) is rising annually. According to epidemiological studies, environmental pollution (e.g., organic, inorganic, and air pollutants), occupational exposure (e.g., high temperature, organic solvents, and pesticides), and poor lifestyle (e.g., diet, sleep, smoking, alcohol consumption, and exercise) are important non-genetic causative factors of MI. Due to multiple and complex causative factors, the dose-effect relationship, and the uncertainty of pathogenicity, the pathogenesis of MI is far from fully clarified. Recent data show that the pathogenesis of MI can be monitored by the metabolites in serum, seminal plasma, urine, testicular tissue, sperm, and other biological samples. It is considered that these metabolites are closely related to MI phenotypes and can directly reflect the individual pathological and physiological conditions. Therefore, qualitative and quantitative analysis of the metabolome, the related metabolic pathways, and the identification of biomarkers will help to explore the MI-related metabolic problems and provide valuable insights into its pathogenic mechanisms. Here, we summarized new findings in MI metabolomics biomarkers research and their abnormal metabolic pathways triggered by the presented non-genetic risk factors, providing a metabolic landscape of semen and seminal plasma in general MI patients. Then, we compared the similarities and differences in semen and seminal plasma biomarkers between MI patients exposed to environmental and poor lifestyle factors and MI patients in general, and summarized some common biomarkers. We provide a better understanding of the biological underpinnings of MI pathogenesis, which might offer novel diagnostic, prognostic, and precise treatment approaches to MI.

Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non-Genetic Neuromodulation.

Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment of neurological diseases. However, developing a non-invasive and well-controllable system to deliver accurate and effective neural stimulation is challenging. Micro/nanorobots have shown great potential in various biomedical applications because of their precise controllability. Here, a magnetically-manipulated optoelectronic hybrid microrobot (MOHR) is presented for optically targeted non-genetic neuromodulation. By integrating the magnetic component into the metal-insulator-semiconductor junction design, the MOHR has excellent magnetic controllability and optoelectronic properties. The MOHR displays a variety of magnetic manipulation modes that enables precise and efficient navigation in different biofluids. Furthermore, the MOHR could achieve precision neuromodulation at the single-cell level because of its accurate targeting ability. This neuromodulation is achieved by the MOHR's photoelectric response to visible light irradiation, which enhances the excitability of the targeted cells. Finally, it is shown that the well-controllable MOHRs effectively restore neuronal activity in neurons damaged by ß-amyloid, a pathogenic agent of Alzheimer's disease. By coupling precise controllability with efficient optoelectronic properties, the hybrid microrobot system is a promising strategy for targeted on-demand optical neuromodulation.

Non-genetic mechanisms of drug resistance in acute leukemias.

Acute leukemia is characterized by clonal heterogeneity that contributes to poor drug responses in patients. Despite treatment advances, the occurrence of relapse remains a major barrier to achieving cures as current therapeutic approaches are inadequate to effectively prevent or overcome resistance. Given that only a few genetic mutations are associated with relapse in acute leukemia patients, there is a growing focus on 'non-genetic' mechanisms that affect the hallmarks of cancer to allow leukemic cells to survive post therapy. In this review, we provide an overview of the therapeutic landscape in acute leukemias. Importantly, we discuss non-genetic mechanisms exploited by leukemic cells to promote their survival after treatment. Last, we present current strategies to prevent or overcome drug resistance in this disease.

Prostate Cancer in the Caribbean.

Prostate cancer (PC) is one of the principal causes of cancer death worldwide. The mortality rate for PC in the Caribbean is higher than in many developed countries, and there is a difference in the incidence among the various Caribbean nations. Besides surveillance and screening, these factors increase concerns about genetic and other risk factors causing PC incidence. PC research is limited in scope and regularity in the Caribbean, creating a literature gap. This literature review aims to examine the PC situation in the Caribbean to highlight where further studies are needed. This review includes all available studies on PC in the specified Caribbean population from 1958 to 2023 utilising the keywords "Prostate Cancer and Caribbean" on PubMed, Scopus, and ScienceDirect databases. The information is then structured by Caribbean countries and by seven themes. These themes are PC incidence and mortality, demographics, clinicopathology, genetics, non-genetic risks, diagnosis and treatment, and PC control. The findings demonstrated that countries with low resources are burdened by more severe illnesses with worse PC outcomes. Furthermore, territories with national cancer registries seemed to have enhanced methods for PC management. In conclusion, this review is significant because it provides initial support for researchers, administrators, and planners for PC healthcare. Additionally, it gives an opportunity for further epidemiological analyses that can supply more significant insights into the PC situation in the Caribbean. Further research should focus on prevention strategies and the standardisation of treatment procedures to enhance surveillance and improve patient outcomes.

CRIPTO-based micro-heterogeneity of mouse muscle satellite cells enables adaptive response to regenerative microenvironment.

Skeletal muscle repair relies on heterogeneous populations of satellite cells (SCs). The mechanisms that regulate SC homeostasis and state transition during activation are currently unknown. Here, we investigated the emerging role of non-genetic micro-heterogeneity, i.e., intrinsic cell-to-cell variability of a population, in this process. We demonstrate that micro-heterogeneity of the membrane protein CRIPTO in mouse-activated SCs (ASCs) identifies metastable cell states that allow a rapid response of the population to environmental changes. Mechanistically, CRIPTO micro-heterogeneity is generated and maintained through a process of intracellular trafficking coupled with active shedding of CRIPTO from the plasma membrane. Irreversible perturbation of CRIPTO micro-heterogeneity affects the balance of proliferation, self-renewal, and myogenic commitment in ASCs, resulting in increased self-renewal in vivo. Our findings demonstrate that CRIPTO micro-heterogeneity regulates the adaptative response of ASCs to microenvironmental changes, providing insights into the role of intrinsic heterogeneity in preserving stem cell population diversity during tissue repair.