Organ Level Research Articles

The path forward for protein footprinting, covalent labeling, and mass spectrometry-based protein conformational analyses.

Mass spectrometry-based approaches to assess protein conformation have become widely utilized due to their sensitivity, low sample requirements, and broad applicability to proteins regardless of size and environment. Their wide applicability and sensitivity also make these techniques suitable for the analysis of complex mixtures of proteins, and thus, they have been applied at the cell and even the simple organism levels. These works are impressive, but they predominately employ "bottom-up" workflows and require proteolytic digestion prior to analysis. Once digested, it is not possible to distinguish the proteoform from which any single peptide is derived and therefore, one cannot associate distal-in primary structure-concurrent post-translational modifications (PTMs) or covalent labels, as they would be found on separate peptides. Thus, analyses via bottom-up proteomics report the average PTM status and higher-order structure (HOS) of all existing proteoforms. Second, these works predominately employ promiscuous reagents to probe protein HOS. While this does lead to improved conformational resolution, the formation of many products can divide the signal associated with low-copy number proteins below signal-to-noise thresholds and complicate the bioinformatic analysis of these already challenging systems. In this perspective, I further detail these limitations and discuss the positives and negatives of top-down proteomics as an alternative.

From whole bodies to single cells: A guide to transcriptomic approaches for ecology and evolutionary biology

AbstractRNA sequencing (RNAseq) methodology has experienced a burst of technological developments in the last decade, which has opened up opportunities for studying the mechanisms of adaptation to environmental factors at both the organismal and cellular level. Selecting the most suitable experimental approach for specific research questions and model systems can, however, be a challenge and researchers in ecology and evolution are commonly faced with the choice of whether to study gene expression variation in whole bodies, specific tissues, and/or single cells. A wide range of sometimes polarised opinions exists over which approach is best. Here, we highlight the advantages and disadvantages of each of these approaches to provide a guide to help researchers make informed decisions and maximise the power of their study. Using illustrative examples of various ecological and evolutionary research questions, we guide the readers through the different RNAseq approaches and help them identify the most suitable design for their own projects.

Embryo Microinjection for Transgenesis in Drosophila.

Transgenesis in Drosophila is an essential approach to studying gene function at the organism level. Embryo microinjection is a crucial step for the construction of transgenic flies. Microinjection requires some types of equipment, including a microinjector, a micromanipulator, an inverted microscope, and a stereo microscope.Plasmids isolated with a plasmid miniprep kit are qualified for microinjection. Embryos at the pre-blastoderm or syncytial blastoderm stage, where nuclei share a common cytoplasm, are subjected to microinjection. A cell strainer eases the process of dechorionating embryos. The optimal time for dechorionation and desiccation of embryos needs to be determined experimentally. To increase the efficiency of embryo microinjection, needles prepared by a puller need to be beveled by a needle grinder. In the process of grinding needles, we utilize a foot air pump with a pressure gauge to avoid the capillary effect of the needle tip. We routinely inject 120-140 embryos for each plasmid and obtain at least one transgenic line for around 85% of plasmids. This article takes the phiC31 integrase-mediated transgenesis in Drosophila as an example andpresents a detailed protocol for embryo microinjection for transgenesis in Drosophila.

The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes

Mitochondria perform an array of functions, many of which involve interactions with gene products encoded by the nucleus. These mitochondrial functions, particularly those involving energy production, can be expected to differ between sexes and across ages. Here, we measured mitochondrial effects on sex- and age-specific gene expression in parental and reciprocal F1 hybrids between allopatric populations of Tigriopus californicus with over 20% mitochondrial DNA divergence. Because the species lacks sex chromosomes, sex-biased mitochondrial effects are not confounded by the effects of sex chromosomes. Results revealed pervasive sex differences in mitochondrial effects, including effects on energetics and aging involving nuclear interactions throughout the genome. Using single-individual RNA sequencing, sex differences were found to explain more than 80% of the variance in gene expression. Males had higher expression of mitochondrial genes and mitochondrially targeted proteins (MTPs) involved in oxidative phosphorylation (OXPHOS), while females had elevated expression of non-OXPHOS MTPs, indicating strongly sex-dimorphic energy metabolism at the whole organism level. Comparison of reciprocal F1 hybrids allowed insights into the nature of mito-nuclear interactions, showing both mitochondrial effects on nuclear expression, and nuclear effects on mitochondrial expression. While based on a small set of crosses, sex-specific increases in mitochondrial expression with age were associated with longer life. Network analyses identified nuclear components of strong mito-nuclear interactions and found them to be sexually dimorphic. These results highlight the profound impact of mitochondria and mito-nuclear interactions on sex- and age-specific gene expression.

YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes.

Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease - affecting >1:500 individuals. Advanced forms of HCM clinically present with hypercontractility, hypertrophy and fibrosis. Several single-point mutations in b-myosin heavy chain (MYH7) have been associated with HCM and increased contractility at the organ level. Different MYH7 mutations have resulted in increased, decreased, or unchanged force production at the molecular level. Yet, how these molecular kinetics link to cell and tissue pathogenesis remains unclear. The Hippo Pathway, specifically its effector molecule YAP, has been demonstrated to be reactivated in pathological hypertrophic growth. We hypothesized that changes in force production (intrinsically or extrinsically) directly alter the homeostatic mechano-signaling of the Hippo pathway through changes in stresses on the nucleus. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we asked whether homeostatic mechanical signaling through the canonical growth regulator, YAP, is altered 1) by changes in the biomechanics of HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We use genetically edited hiPSC-CM with point mutations in MYH7 associated with HCM, and their matched controls, combined with micropatterned traction force microscopy substrates to confirm the hypercontractile phenotype in MYH7 mutants. We next modulate contractility in healthy and disease hiPSC-CMs by treatment with positive and negative inotropic drugs and demonstrate a correlative relationship between contractility and YAP activity. We further demonstrate the activation of YAP in both HCM mutants and healthy hiPSC-CMs treated with contractility modulators is through enhanced nuclear deformation. We conclude that the overactivation of YAP, possibly initiated and driven by hypercontractility, correlates with excessive CCN2 secretion (connective tissue growth factor), enhancing cardiac fibroblast/myofibroblast transition and production of known hypertrophic signaling molecule TGFβ. Our study suggests YAP being an indirect player in the initiation of hypertrophic growth and fibrosis in HCM. Our results provide new insights into HCM progression and bring forth a testbed for therapeutic options in treating HCM.

Navigating centriolar satellites: the role of PCM1 in cellular and organismal processes.

Centriolar satellites are ubiquitous membrane-less organelles that play critical roles in numerous cellular and organismal processes. They were initially discovered through electron microscopy as cytoplasmic granules surrounding centrosomes in vertebrate cells. These structures remained enigmatic until the identification of pericentriolar material 1 protein (PCM1) as their molecular marker, which has enabled their in-depth characterization. Recently, centriolar satellites have come into the spotlight due to their links to developmental and neurodegenerative disorders. This review presents a comprehensive summary of the major advances in centriolar satellite biology, with a focus on studies that investigated their biology associated with the essential scaffolding protein PCM1. We begin by exploring the molecular, cellular, and biochemical properties of centriolar satellites, laying the groundwork for a deeper understanding of their functions and mechanisms at both cellular and organismal levels. We then examine the implications of their dysregulation in various diseases, particularly highlighting their emerging roles in neurodegenerative and developmental disorders, as revealed by organismal models of PCM1. We conclude by discussing the current state of knowledge and posing questions about the adaptable nature of these organelles, thereby setting the stage for future research.

Scientific and methodological grounds for iterative prediction of risk and harm to human health under chemical environmental exposures: From protein targets to systemic metabolic disorders

Increasing the predictive potential of early diagnostics and correction of negative outcomes is becoming especially relevant for preventing and reducing personalized and population health risks, including those caused by environmental exposures. The purpose of the study was to develop scientific and methodological grounds for iterative numerical prediction of risk and harm to human health under chemical environmental exposures. The study design was based on the consistent implementation of an algorithm for system analysis of the development of negative effects under a chemical environmental exposure, from protein targets to systemic metabolic disorders. The in-depth examination covered more than 1 million people living under real long-term combined inhalation exposure at doses up to 5–10 RfC. About 350 digital multifactor models, including about 5.5 thousand parameters, were evaluated. Structural bioinformation matrices were constructed to identify the sequence of response events at the molecular-cellular level. These events are initiated by the transformation of the protein-peptide profile of human blood plasma, which determine the metabolome. The study clarifies the elements of involvement of 20 target proteins in the pathogenesis of metabolic disorders associated with hypertension, dyslipidemia, obesity, hepatosis, and cognitive dysfunction associated with chemical combined exposure. The criteria for the safe content of 10 contaminants were substantiated, taking into account their combinations in human biological media. Predictive assessments of pathogenetic pathways were confirmed by the facts of their implementation at the cellular-tissue, organ and body level as metabolic disorders and existing diseases of the cardiovascular, nervous systems, lipoprotein metabolism, etc., proven to be associated with effects produced by airborne pollutants, including combined ones. The study expands the existing methodological approaches to assessing combined effects of chemicals taking into account parameterized cause-effect relations of biomarkers of exposure and effects and quantitative assessment of additional cases of risk occurrence. Assessment of the developed digital models revealed that combined chemical exposures were predominantly synergic and emergent (up to 70 % cases). We developed conceptual grounds and architecture of iterative risk prediction and the development of risk-associated diseases, including real harm to health upon elevated expression of protein targets. Thus, the digitized version of the forecast (digital platform), as a multi-level cascade model, is a tool for scientific analysis of a hygienic situation with the parameterization of expected negative outcomes. It determines methods for their correction and prevention, which increases the reliability of hygienic assessments and the validity of management decisions.

Научно-методические основы итерационного прогноза риска и вреда здоровью человека при воздействии химических факторов среды обитания: От белковых мишеней до системных метаболических нарушений

Increasing the predictive potential of early diagnostics and correction of negative outcomes is becoming especially relevant for preventing and reducing personalized and population health risks, including those caused by environmental exposures. The purpose of the study was to develop scientific and methodological grounds for iterative numerical prediction of risk and harm to human health under chemical environmental exposures. The study design was based on the consistent implementation of an algorithm for system analysis of the development of negative effects under a chemical environmental exposure, from protein targets to systemic metabolic disorders. The in-depth examination covered more than 1 million people living under real long-term combined inhalation exposure at doses up to 5–10 RfC. About 350 digital multifactor models, including about 5.5 thousand parameters, were evaluated. Structural bioinformation matrices were constructed to identify the sequence of response events at the molecular-cellular level. These events are initiated by the transformation of the protein-peptide profile of human blood plasma, which determine the metabolome. The study clarifies the elements of involvement of 20 target proteins in the pathogenesis of metabolic disorders associated with hypertension, dyslipidemia, obesity, hepatosis, and cognitive dysfunction associated with chemical combined exposure. The criteria for the safe content of 10 contaminants were substantiated, taking into account their combinations in human biological media. Predictive assessments of pathogenetic pathways were confirmed by the facts of their implementation at the cellular-tissue, organ and body level as metabolic disorders and existing diseases of the cardiovascular, nervous systems, lipoprotein metabolism, etc., proven to be associated with effects produced by airborne pollutants, including combined ones. The study expands the existing methodological approaches to assessing combined effects of chemicals taking into account parameterized cause-effect relations of biomarkers of exposure and effects and quantitative assessment of additional cases of risk occurrence. Assessment of the developed digital models revealed that combined chemical exposures were predominantly synergic and emergent (up to 70 % cases). We developed conceptual grounds and architecture of iterative risk prediction and the development of risk-associated diseases, including real harm to health upon elevated expression of protein targets. Thus, the digitized version of the forecast (digital platform), as a multi-level cascade model, is a tool for scientific analysis of a hygienic situation with the parameterization of expected negative outcomes. It determines methods for their correction and prevention, which increases the reliability of hygienic assessments and the validity of management decisions.

Mineral Content, Antioxidant Properties <i>in vitro</i>, Reduction of Inflammation, and Liver Steatosis <i>in vivo</i> by Ngaoundal Propolis in Wistar Rats Fed an Atherogenic Diet

Several studies have reported the benefits of Propolis in the treatment of various disorders such as parasitic infections, bacterial infections, wounds, and burns. The overall aim of this study was to evaluate the preventive effects and anti-inflammatory activities of the hydroethanolic extract (EthP) and the fraction powder ≤ 125 µm of Propolis (PP) on atherogenic diet-induced non-alcoholic fatty liver disease. Dry Propolis was finely ground, a first part was macerated in a mixture (30:70 v/v water and ethanol) and a second part was fractionated by sieving with a sieve mesh (≤125 µm). The powder fraction≤ 125µm (PP) and Propolis hydroethanolic extract (EthP) obtained were used to characterize the mineral composition <i>in vitro</i> and <i>in vivo</i> antioxidant and anti-inflammatory properties. 20 male Wistar rats were divided into 5 groups EthP and PP were administered orally to the rats at the same dose (250 mg/kg bw) and fed simultaneously with an atherogenic diet for 45 days. At the end of the experiment, the lipid profile, transaminase aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in serum, and antioxidants were measured at the organ level (aorta, liver, kidney, and heart). The activities of all parameters were significant (p < 0.05). The results of this study show that Propolis had a significantly (<i>p<0.0001</i>) lower <i>in vitro</i> mineral composition in Iron by 32.56%; in Zinc by 83.21%; in Calcium by 10.82% and in Manganese by 21.40% at the PP level compared to EthP. Antioxidant capacity (DPPH, TAC, and FRAP), which increased with Propolis concentration. High polyphenol content (EthP>PP). Treatment with EthP<sub>250</sub> and PP<sub>250</sub> significantly (<i>p<0.05</i>) reduced serum ALT by 34.27% and 47.36%, creatinine by 67.36% and 37.5%, TG by 63.91% and by 20.18%, IL-17 expression by 50.25% and 100% respectively. HDL-c levels were significantly increased by 47.7% (<i>p<0.001</i>) in serum compared with TN. NO levels increased significantly (<i>p<0.001</i>) by 1.38% and 1.63% in the aorta respectively. MDA levels were significantly reduced by 55.12% (<i>p<0.0001</i>) and 76.09% (<i>p<0.05</i>) in the liver respectively. This study demonstrated the efficacy of Propolis in the management of non-alcoholic hepatic steatosis and its anti-inflammatory capacity.

OXYGEN HOMEOSTASIS FROM SEA LEVEL TO HIGH ALTITUDES

In the beginning there was no oxygen (O2) on planet Earth, today the atmosphere hosts 21%, after considerable oscillations of it through millions of years. Over time, living organisms evolved by mounting mechanisms to detect and respond to fluctuations in O2 concentration in their internal environment. Oxygen sensors in the carotid body, and the HIF system in all cells, play a crucial role in maintaining O2 homeostasis at the organism and cellular level. Therefore, in normoxia, HIFs are rapidly synthesized and destroyed, but in hypoxia, their degradation is inhibited. HIFs, regulate protein expression to compensate for hypoxia, increasing O2 delivery to tissues, and reducing O2 consumption. Millions of people live at high altitudes, such as in the Andean and Tibetan plateaus. Newborns in these regions weigh less than those in the lowlands, but this difference in Tibetans is smaller than in the Andeans. There is a greater increase in utero­placental blood flow in Andean and Tibetan women compared to pregnancies in Europeans, at the same altitude. These increases are due to synthesis in NO and PGI2, generated by HIFs. The Andean populations display Chronic Mountain Sickness (CMS), characterized by increase in hemoglobin concentration, diminution of PO2 and pulmonary hypertension. In contrast, the Tibetans do not have these conditions due to polymorphisms of two genes, the EPAS-1 that encodes for HIF-2a, expressing polymorphisms with loss-of-function and the EGLN-1 gene that encodes for prolyl hydroxylase-2, with gain-of-function polymorphisms, thus reducing HIFs tasks, decreasing hemoglobin concentration and pulmonary arterial hypertension.

A multiscale sensorimotor model of experience-dependent behavior in a minimal organism

To survive in ever-changing environments, living organisms need to continuously combine the ongoing external inputs they receive, representing present conditions, with their dynamical internal state, which includes influences of past experiences. It is still unclear in general, however 1) how this happens at the molecular and cellular levels and 2) how the corresponding molecular and cellular processes are integrated with the behavioral responses of the organism. Here, we address these issues by modeling mathematically a particular behavioral paradigm in a minimal model organism, namely chemotaxis in the nematode C. elegans. Specifically, we use a long-standing collection of elegant experiments on salt chemotaxis in this animal, in which the migration direction varies depending on its previous experience. Our model integrates the molecular, cellular, and organismal levels to reproduce the experimentally observed experience-dependent behavior. The model proposes specific molecular mechanisms for the encoding of current conditions and past experiences in key neurons associated with this response, predicting the behavior of various mutants associated with those molecular circuits.

Organ transformation by environmental disruption of protein integrity and epigenetic memory in Drosophila.

Despite significant progress in understanding epigenetic reprogramming of cells, the mechanistic basis of "organ reprogramming" by (epi-)gene-environment interactions remained largely obscure. Here, we use the ether-induced haltere-to-wing transformations in Drosophila as a model for epigenetic "reprogramming" at the whole organism level. Our findings support a mechanistic chain of events explaining why and how brief embryonic exposure to ether leads to haltere-to-wing transformations manifested at the larval stage and on. We show that ether interferes with protein integrity in the egg, leading to altered deployment of Hsp90 and widespread repression of Trithorax-mediated establishment of active H3K4me3 chromatin marks throughout the genome. Despite this global reduction, Ubx targets and wing development genes preferentially retain higher levels of H3K4me3 that predisposes these genes for later up-regulation in the larval haltere disc, hence the wing-like outcome. Consistent with compromised protein integrity during the exposure, the penetrance of bithorax transformations increases by genetic or chemical reduction of Hsp90 function. Moreover, joint reduction in Hsp90 and trx gene dosage can cause bithorax transformations even without exposure to ether, supporting an underlying epistasis between Hsp90 and trx loss-of-functions. These findings implicate environmental disruption of protein integrity at the onset of histone methylation with altered epigenetic regulation of developmental patterning genes. The emerging picture provides a unique example wherein the alleviation of the Hsp90 "capacitor function" by the environment drives a morphogenetic shift towards an ancestral-like body plan. The morphogenetic impact of chaperone response during a major setup of epigenetic patterns may be a general scheme for organ reprogramming by environmental cues.

Optimal design of light microclimate and planting strategy for Chinese solar greenhouses using 3D light environment simulations

Light has a significant impact on crop production. The objective of this study was to explore the optimal lighting structure parameters and the corresponding planting strategy of Chinese solar greenhouses (CSG). Taking CSG-grown melons as the experimental subject, we have developed a detailed 3D model capable of calculating the light interception at a single organ level, e.g., for individual leaves. The quantitative research was carried out after verifying the proposed model using field data. The results indicated that the reasonable ridge height for the most common 9 m span CSG was 4.9 m, and the horizontal projection on rear roof was 1.6 m in Shenyang area. In comparison with the experimental greenhouse, the optimized greenhouse improved crop light interception by 0.5 % and increased the average air temperature by 9.3 % during winter. The suitable planting strategy was E-W row orientation, with a ridge spacing of 1.2 m, a row spacing of 0.4 m, and a plant spacing of 0.38 m. Compared with the N–S row orientation, the crop light interception increased by 7.1 % and 10.8 % in the two growing seasons, respectively. The model described herein can serve as a foundation for the production of CSG.

CytoSIP: an annotated structural atlas for interactions involving cytokines or cytokine receptors

Therapeutic agents targeting cytokine-cytokine receptor (CK-CKR) interactions lead to the disruption in cellular signaling and are effective in treating many diseases including tumors. However, a lack of universal and quick access to annotated structural surface regions on CK/CKR has limited the progress of a structure-driven approach in developing targeted macromolecular drugs and precision medicine therapeutics. Herein we develop CytoSIP (Single nucleotide polymorphisms (SNPs), Interface, and Phenotype), a rich internet application based on a database of atomic interactions around hotspots in experimentally determined CK/CKR structural complexes. CytoSIP contains: (1) SNPs on CK/CKR; (2) interactions involving CK/CKR domains, including CK/CKR interfaces, oligomeric interfaces, epitopes, or other drug targeting surfaces; and (3) diseases and phenotypes associated with CK/CKR or SNPs. The database framework introduces a unique tri-level SIP data model to bridge genetic variants (atomic level) to disease phenotypes (organism level) using protein structure (complexes) as an underlying framework (molecule level). Customized screening tools are implemented to retrieve relevant CK/CKR subset, which reduces the time and resources needed to interrogate large datasets involving CK/CKR surface hotspots and associated pathologies. CytoSIP portal is publicly accessible at https://CytoSIP.biocloud.top, facilitating the panoramic investigation of the context-dependent crosstalk between CK/CKR and the development of targeted therapeutic agents.

The Loss of an Orphan Nuclear Receptor NR2E3 Augments Wnt/β-catenin Signaling via Epigenetic Dysregulation that Enhances Sp1-β catenin-p300 Interactions in Hepatocellular Carcinoma.

The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player that modulates chromatin accessibility to activate p53 during liver injury. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) development remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/β-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation accompanied by enhanced activation of Wnt/β-catenin signaling pathway and inactivation of p53 signaling. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/β-catenin pathway with increased chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, β-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 activates Wnt/β-catenin signaling at cellular and organism levels and this dysregulation is associated with aggressive HCC development and poor clinical outcomes. In summary, NR2E3 is a novel tumor suppressor with a significant prognostic value, maintaining epigenetic homeostasis to suppress the Wnt/β-catenin signaling pathway that promotes HCC development.

Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum venetum flowers via enhancing immune response, reducing oxidative stress, and regulating gut microbiota in mice

IntroductionEmerging proof suggests that Apocynum venetum flowers polysaccharide (AVFP) has immunomodulatory effects in vitro. However, the action mechanism of AVFA is still unclear in vivo. The purpose of this study is to probe into the potential mechanism of AVFA in immunosuppressed mice by investigating organ index, cytokine levels, anti-oxidative stress capacity, transcriptomics, and gut microbiota.MethodsImmunocompromised mice induced by cyclophosphamide (CTX) were divided into six groups. The enzyme-labeled method, hematoxylin and eosin, transcriptomics, and high-throughput sequencing were used to detect the regulatory effects of AVFP on immunocompromised mice and the function of AVFP on the concentration of short-chain fatty acids (SCFAs) by high-performance liquid chromatography (HPLC) analysis. The Spearman correlation analysis was used to analyze the correlation between the intestinal microbiota and biochemical indexes.ResultsThe experimental results illustrated that AVFP has protective effects against CTX-induced immunosuppression in mice by prominently increasing the organ index and levels of anti-inflammatory factors in serum in addition to enhancing the antioxidant capacity of the liver. Meanwhile, it could also signally decrease the level of pro-inflammatory cytokines in serum, the activity of transaminase in serum, and the content of free radicals in the liver, and alleviate the spleen tissue damage induced by CTX. Transcriptomics results discovered that AVFP could play a role in immune regulation by participating in the NF-κB signaling pathway and regulating the immune-related genes Bcl3, Hp, Lbp, Cebpd, Gstp2, and Lcn2. Gut microbiota results illustrated that AVFP could increase the abundance of beneficial bacteria, reduce the abundance of harmful bacteria, and regulate the metabolic function of intestinal microorganisms while dramatically improving the content of SCFAs, modulating immune responses, and improving the host metabolism. The Spearman analysis further evaluated the association between intestinal microbiota and immune-related indicators.ConclusionThese findings demonstrated that AVFP could enhance the immune effects of the immunosuppressed mice and improve the body’s ability to resist oxidative stress.

Accurately deciphering spatial domains for spatially resolved transcriptomics with stCluster.

Spatial transcriptomics provides valuable insights into gene expression within the native tissue context, effectively merging molecular data with spatial information to uncover intricate cellular relationships and tissue organizations. In this context, deciphering cellular spatial domains becomes essential for revealing complex cellular dynamics and tissue structures. However, current methods encounter challenges in seamlessly integrating gene expression data with spatial information, resulting in less informative representations of spots and suboptimal accuracy in spatial domain identification. We introduce stCluster, a novel method that integrates graph contrastive learning with multi-task learning to refine informative representations for spatial transcriptomic data, consequently improving spatial domain identification. stCluster first leverages graph contrastive learning technology to obtain discriminative representations capable of recognizing spatially coherent patterns. Through jointly optimizing multiple tasks, stCluster further fine-tunes the representations to be able to capture complex relationships between gene expression and spatial organization. Benchmarked against six state-of-the-art methods, the experimental results reveal its proficiency in accurately identifying complex spatial domains across various datasets and platforms, spanning tissue, organ, and embryo levels. Moreover, stCluster can effectively denoise the spatial gene expression patterns and enhance the spatial trajectory inference. The source code of stCluster is freely available at https://github.com/hannshu/stCluster.

Diabetes and Cancer: A Twisted Bond.

This paper presents an overview of the interconnection between various factors related to both cancer and type 2 diabetes mellitus (T2DM). Hyperglycemia, hyperinsulinemia, chronic inflammation, and obesity are involved in the development and progression of both diseases but, strong evidence for a direct causal relationship between diabetes and cancer, is lacking. Several studies described a relationship between hyperglycemia and cancer at the cellular, tissular and organismic levels but at the same time recent Mendelian randomization studies proved a significant causal relationship only between hyperglycemia and breast cancer. On the other hand, the association between both hyperinsulinemia and obesity and several cancer types appears to be robust as demonstrated by Mendelian randomized studies. Metabolic alterations, including the Warburg effect and excessive glucose consumption by tumors, are discussed, highlighting the potential impact of dietary restrictions, such as fasting and low-carb diets, on tumor growth and inflammation. Recent data indicates that circulating branched-chain amino acids levels, may represent novel biomarkers that may contribute to both better diabetes control and early pancreatic cancer detection. Understanding the underlying mechanisms and shared risk factors between cancer and T2DM can provide valuable insights for cancer prevention, early detection, and management strategies.

Near-infrared lipid droplets polarity fluorescent probe for early diagnosis of nonalcoholic fatty liver disease

Nowadays, it has been proven that lipid droplets (LDs) not only maintain the fundamental cellular functions, but also play an essential role in the pathogenesis of numerous diseases. Non-alcoholic fatty liver disease (NAFLD) is among these diseases. In this work, we designed two polarity sensitive fluorescent probes TST and TSO with D-π-A-D structure by introducing different electron acceptor groups according to the low polarity of LDs. The experimental discovered that probe TST exhibited the characteristics of near-infrared emission, high selectivity towards polarity, large Stokes shift, rapid targeting ability of LDs, and robust wash-free biological imaging capability. Confocal images illustrated that probe TST has been successfully applied in monitoring LDs polarity during ferroptosis, as well as visualizing changes in LDs polarity at both tissue and organ levels in fatty liver conditions. With these exceptional properties, probe TST was anticipated to make further contributions to the field of LDs research.

Warming and shifts in litter quality drive multiple responses in freshwater detritivore communities

Aquatic detritivores are highly sensitive to changes in temperature and leaf litter quality caused by increases in atmospheric CO2. While impacts on detritivores are evident at the organismal and population level, the mechanisms shaping ecological communities remain unclear. Here, we conducted field and laboratory experiments to examine the interactive effects of changes in leaf litter quality, due to increasing atmospheric CO2, and warming, on detritivore survival (at both organismal and community levels) and detritus consumption rates. Detritivore community consisted of the collector-gathering Polypedilum (Chironomidae), the scraper and facultative filtering-collector Atalophlebiinae (Leptophlebiidae), and Calamoceratidae (Trichoptera), a typical shredder. Our findings reveal intricate responses across taxonomic levels. At the organismal level, poor-quality leaf litter decreased survivorship of Polypedilum and Atalophlebiinae. We observed taxon-specific responses to warming, with varying effects on growth and consumption rates. Notably, species interactions (competition, facilitation) might have mediated detritivore responses to climate stressors, influencing community dynamics. While poor-quality leaf litter and warming independently affected detritivore larvae abundance of Atalophebiinae and Calamoceratidae, their combined effects altered detritus consumption and emergence of adults of Atalophlebiinae. Furthermore, warming influenced species abundances differently, likely exacerbating intraspecific competition in some taxa while accelerating development in others. Our study underscores the importance of considering complex ecological interactions in predicting the impact of climate change on freshwater ecosystem functioning. Understanding these emergent properties contributes to a better understanding of how detritivore communities may respond to future environmental conditions, providing valuable insights for ecosystem management and conservation efforts.