Normal Regulation Research Articles

Optogenetics for sensors: On-demand fluorescent labeling of histone epigenetics

Post-translational modifications of histones to a large extent determine the functional state of chromatin loci. Dynamic visualization of histone modifications with genetically encoded fluorescent sensors makes it possible to monitor changes in the epigenetic state of a single living cell. At the same time, the sensors can potentially compete with endogenous factors recognizing these modifications. Thus, prolonged binding of the sensors to chromatin can affect normal epigenetic regulation. Here, we report an optogenetic sensor for live-cell visualization of histone H3 methylated at lysine-9 (H3K9me3) named MPP8-LAMS (MPP8-based light-activated modification sensor). MPP8-LAMS consists of several fusion protein parts (from N- to C-terminus): i) nuclear export signal (NES), ii) far-red fluorescent protein Katushka, iii) H3K9me3-binding reader domain of the human M phase phosphoprotein 8 (MPP8), iv) the light-responsive AsLOV2 domain, which exposes a nuclear localization signal (NLS) upon blue light stimulation. In the dark, due to the NES, MPP8-LAMS is localized in the cytosol. Under blue light illumination, MPP8-LAMS underwent an efficient translocation from cytosol to nucleus, enabling visualization of H3K9me3-enriched loci. Such an on-demand visualization minimizes potential impact on cell physiology as most of the time the sensor is separated from its target. In general, the present work extends the application of optogenetics to the area of advanced use of genetically encoded sensors.

Prognostic value of the prognostic nutritional index for patients with acute myocardial infarction undergoing percutaneous coronary intervention with variable glucose metabolism statuses: a retrospective cohort study

BackgroundThe prognostic nutritional index (PNI) and different glucose metabolisms have been separately reported to be correlated with long-term prognosis in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). However, PNI application in patients with an impaired glucose metabolism has not been well validated, especially in pre-diabetic patients. This study evaluated whether PNI influences a long-term risk of mortality along different glucose metabolism statuses.MethodsA total of 17,697 patients with AMI and a history of PCI were enrolled in this retrospective observational cohort study from January 2007 to December 2020. Three subgroups with different glucose metabolism statuses, including normal glucose regulation (NGR), pre-diabetes mellitus (pre-DM), and diabetes mellitus (DM), were divided into three groups according to the tertiles of PNI, respectively.ResultsAll-cause mortality occurred in 2613 (14.8%) patients within a median of 4.1 years of follow-up. Upon analyzing the Kaplan–Meier plots for the NGR, pre-DM, and DM groups, the incidence of all-cause or cardiovascular mortality in the low PNI (PNI-L, ≤ 42.7) subgroup was significantly higher than that in the median PNI (PNI-M, > 42.7 and ≤ 48.2) and high PNI (PNI-H, > 48.2) subgroups (all, P < 0.001). After adjusting for confounding factors, the hazard ratio (HR) for all-cause mortality in the PNI-L group significantly increased compared to that in the PNI-H subgroups of the NGR group (HR, 1.35; 95% CI 1.14–1.66; P < 0.001), pre-DM group (HR, 1.29; 95% CI 1.02–1.62; P < 0.001), and DM group (HR, 1.36; 95% CI 1.13–1.63; P < 0.001). Given that there was evidence of interactions between PNI and different glucose statuses (P for interaction < 0.001), patients were divided into nine subgroups, and we found that DM patients with PNI-L statuses had the highest risk of all-cause mortality compared to NGR patients with PNI-H statuses (HR, 1.69; 95% CI 1.42–2.01; P < 0.001).ConclusionLower PNI is a significant and independent risk factor for all-cause mortality in AMI patients undergoing PCI with different glucose metabolism statuses, and this risk further increases with DM compared to NGR or pre-DM statuses.

The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria, tyrosinemia type 1 and comorbid neurodevelopmental disorders

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro-psychiatric symptoms typically present in ADHD, possibly indicating an impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 μM), either low (35 μM) or high concentrations of tyrosine (275 or 835 μM) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered in neurometabolic disorders, such as PKU and TYRSN1, with implications for the treatment of cognitive symptoms resulting from comorbid neurodevelopmental disorders.

DCAF13 and RNF114 participate in the regulation of early porcine embryo development.

Ubiquitination plays a pivotal role in a multitude of cellular functions; however, the precise contributions of various ubiquitin ligases in governing early developmental processes remain largely unexplored. This study revealed that the E3 ubiquitin ligases DCAF13 and RNF114 are both necessary for the normal regulation of early porcine embryo development. Ubiquitylation is required for normal regulation of many biological functions by modulating several protein facets such as structure, stability, interaction, localization, and degradation. In this study, we explored the roles of two E3 ubiquitin ligases (E3s), the DDB1- and CUL4-associated factor 13 (DCAF13) and the Ring finger protein 114 (RNF114), in the regulation of porcine embryo development. Attenuation of DCAF13 mRNA decreased embryo development at the blastocyst stage, while the development of RNF114-attenuated embryos was not significantly different than that of control embryos. The average number of cells per blastocyst was decreased in DCAF13-attenuated embryos and increased in RNF114-attenuated embryos compared to controls. The relative mRNA abundance of the histone methyltransferase SUV39H1, which regulates histone H3 lysine 9 trimethylation (H3K9me3), was increased in both DCAF13- and RNF114-attenuated embryos, but nuclear immunofluorescence signal for H3K9me3 on day 3 embryos was not significantly altered between attenuated and control embryos. Nuclear immunofluorescence signal for H3K4m3 was decreased in DCAF13-attenuated embryos, but it was increased in RNF114-attenuated embryos compared to controls. Attenuation of DCAF13 and RNF114 mRNAs increased transcript levels for the DNA recombinase RAD51 and decreased expression of phosphorylated histone H2A.X (γH2AX), which suggests an impact on DNA damage repair. In addition, lower mRNA expression of the lysine demethylases 5B (KDM5B) and 5C (KDM5C), both involved in embryo genome activation and DNA repair, was detected in DCAF13-attenuated embryos. These findings indicated that both DCAF13 and RNF114 have important roles in the regulation of the early development of porcine embryos.

Somatic evolution of Cancer: A new synthesis

Cancers have been interpreted either as somatic evolution of cheater cells that escape replication regulation or alternatively as non-healing wounds. Both the interpretations have substantial support as well as glaring anomalies but the two have not been put together to make a coherent synthesis. We argue here that mechanisms and pathways to escape the normal regulation of cell proliferation do not need to evolve de novo. Mechanisms to override the normal regulation have already evolved for wound healing and tissue regeneration. Almost all of the hallmarks of cancer are also seen in the wound healing process. This suggests that cancer develops not by any de novo gain of function but by exaptation of pre-evolved wound healing functions. Somatic evolution that makes the wound healing triggers constitutive is not mutation limited but selection limited and the selective forces are dependent on the tissue microenvironment. Some mechanisms for such selection have been suggested. Many more need to be investigated. A series of mechanisms have evolved to minimize the risk of cancers which may fail in an altered lifestyle context. We support our synthesis with multiple lines of evidence and also make differential testable predictions. This evolutionary perspective challenges multiple prevalent ideas, suggests novel lines of research and also has translatable implications for cancer prevention.

Relationship between stress hyperglycemia and worsening heart failure in patients with significant secondary mitral regurgitation

Background and aimsSecondary mitral regurgitation (sMR), a major valvular disease, is prevalent in patients with coronary artery disease (CAD), and is associated with higher incidence of heart failure (HF) and mortality when present in combination with abnormal glucose metabolism. We aimed to evaluate the relationship between stress hyperglycemia ratio (SHR) and worsening HF in CAD patients with significant (grade ≥2) sMR. MethodsWe performed a multi-center observational study of 874 participants with significant sMR following percutaneous coronary intervention (PCI) in the Cardiorenal Improvement-II (CIN-II) cohort. Patients with glucose and glycated hemoglobin (HbA1c) data at admission were included in the analysis, and categorized according to the SHR, the ratio of mmol/L blood glucose to % HbA1c, as quartiles: Q1: <0.74; Q2: 0.74–0.91; Q3: 0.91–1.14; and Q4: ≥1.14. The primary clinical endpoint was worsening HF and the secondary endpoint was major adverse cardiac events (MACE). ResultsOf the 874 participants (64.1 ± 10.8 years, 80% male), 174 showed worsening HF and 226 developed MACE during a median follow-up of 3.7 years (interquartile range: 1.8–6.2 years). Compared to participants in the lowest quartile (Q1) of SHR, the highest quartile group (Q4) was at significantly higher risks of worsening HF (adjusted hazard ratio, 2.44; 95% confidence interval, 1.51–3.94; p< 0.001), while this was not associated with increased risk of MACE (p>0.05) after adjustment for potential covariates. For worsening HF, the results obtained for the normal glucose regulation subgroup may be more meaningful than those for the diabetes mellitus (DM) and pre-DM groups (p-interaction<0.001). For MACE, the acute myocardial infarction (AMI) (Q4 vs. Q1; HR: 0.65, 95%CI: 0.26–1.59) and non-AMI (Q4 vs. Q1; HR: 2.20, 95%CI: 1.36–3.54) subgroups differed significantly on MACE (p-interaction = 0.006). ConclusionsIncreasing SHR is associated with a higher risk of worsening of HF in patients with significant sMR, especially in those with normoglycemia.

RNA Editing-Dependent and -Independent Roles of Adenosine Deaminases Acting on RNA Proteins in Herpesvirus Infection-Hints on Another Layer of Complexity.

The Adenosine Deaminases Acting on RNA (ADAR) catalyze the posttranscriptional deamination of adenosine residues to inosine in double-stranded RNAs (dsRNAs, A-to-I editing), preventing the overactivation of dsRNA sensor molecules and interferons. RNA editing is the cornerstone of innate immunity that distinguishes between self and non-self (virus), and it is essential for normal regulation of cellular homeostasis. Although much is already known about the role of ADAR proteins in RNA virus infection, the role of ADAR proteins in herpesvirus infection remains largely unexplored. In this review, we provide several lines of evidence from studies of different herpesviruses for another level of complexity in regulating the already intricate biphasic life cycle of herpesviruses.

Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS)

Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.

Elucidating disease-associated mechanisms triggered by pollutants via the epigenetic landscape using large-scale ChIP-Seq data

BackgroundDespite well-documented effects on human health, the action modes of environmental pollutants are incompletely understood. Although transcriptome-based approaches are widely used to predict associations between chemicals and disorders, the molecular cues regulating pollutant-derived gene expression changes remain unclear. Therefore, we developed a data-mining approach, termed “DAR-ChIPEA,” to identify transcription factors (TFs) playing pivotal roles in the action modes of pollutants.MethodsLarge-scale public ChIP-Seq data (human, n = 15,155; mouse, n = 13,156) were used to predict TFs that are enriched in the pollutant-induced differentially accessible genomic regions (DARs) obtained from epigenome analyses (ATAC-Seq). The resultant pollutant–TF matrices were then cross-referenced to a repository of TF–disorder associations to account for pollutant modes of action. We subsequently evaluated the performance of the proposed method using a chemical perturbation data set to compare the outputs of the DAR-ChIPEA and our previously developed differentially expressed gene (DEG)-ChIPEA methods using pollutant-induced DEGs as input. We then adopted the proposed method to predict disease-associated mechanisms triggered by pollutants.ResultsThe proposed approach outperformed other methods using the area under the receiver operating characteristic curve score. The mean score of the proposed DAR-ChIPEA was significantly higher than that of our previously described DEG-ChIPEA (0.7287 vs. 0.7060; Q = 5.278 × 10–42; two-tailed Wilcoxon rank-sum test). The proposed approach further predicted TF-driven modes of action upon pollutant exposure, indicating that (1) TFs regulating Th1/2 cell homeostasis are integral in the pathophysiology of tributyltin-induced allergic disorders; (2) fine particulates (PM2.5) inhibit the binding of C/EBPs, Rela, and Spi1 to the genome, thereby perturbing normal blood cell differentiation and leading to immune dysfunction; and (3) lead induces fatty liver by disrupting the normal regulation of lipid metabolism by altering hepatic circadian rhythms.ConclusionsHighlighting genome-wide chromatin change upon pollutant exposure to elucidate the epigenetic landscape of pollutant responses outperformed our previously described method that focuses on gene-adjacent domains only. Our approach has the potential to reveal pivotal TFs that mediate deleterious effects of pollutants, thereby facilitating the development of strategies to mitigate damage from environmental pollution.

Optimized core design and shield analysis of a medium temperature heat pipe cooled reactor

Medium Temperature heat pipe cooled Reactor (MTR) is a new reactor concept proposed by Li et al. in (2022). Low enriched uranium zirconium hydride fuel and mercury heat pipe are introduced in MTR. The unique advantages of MTR have been verified (Li et al., 2022) and it is considered as a potential candidate for energy supply in decentralized markets. In this work, an optimized MTR core design is proposed with detailed neutronic analysis and evaluation on mercury heat pipe, reflector and control rod arrangement, further increasing the economic efficiency and mobility of MTR. Heat transfer limit of the improved heat pipe model is further increased, contributing to a great reduction on core volume. Reflector material and thickness are analyzed in detail for mass minimization. Core physics characteristics are analyzed for four control rod arrangement schemes. The control mechanism is further simplified with only 9 control rods involved in the normal regulation of the core. Core lifetime is far more than 10 years. High inherent safety of the core is ensured. Besides, preliminary design of the shielding system is also carried out. A shieling layer of 60 cm LiH and 20 cm Pb can reduce the total dose to less than 40 % of the design limits. The total mass of the optimized core is greatly reduced and its specific power is increased by 60 % compared with that of the previous design.

A Comparative Study on Carbon Emission Trade System Between China and US

It has been years since the Paris Agreement and most states are still struggling with their goals to reduce the carbon emission. Many ways and measures are taken but few show effectiveness. Because the industrial development and daily lives of the common people count on the activities that emit much carbon dioxide. Most governments are reluctant to restrict the carbon emission of local industry. Whats more, in the international level, the developed countries refused to take all reduction responsibilities based on their historical emission volume. While the developing ones are eager to pursue more progress in industry. To overcome such difficulty, the market-orientation carbon emission regulations are created to tackle with the challenges that the normal order-control regulations cannot deal with. In contrast to the carbon tax that is more direct and obvious, the carbon emission trade system is favored by both China and US. The system of carbon emission trade system is much younger and less experienced than it is in the US. The comparative study on the carbon emission trade system needs to be done to find more possible solutions to improve the current carbon emission trading system of China. In the paper, main research method is the comparative research and system analysis. In conclusion, the carbon emission trade system of China is relatively immature, lacking the legal support and clear regulations. The carbon emission trade system in China needs stronger laws to support, achieving more active flexible form of trading. The central and local governments should also provide the proper policies like open auction and third-party supervision.

Intra-articular triamcinolone acetonide injection results in increases in systemic insulin and glucose concentrations in horses without insulin dysregulation.

Corticosteroids are a commonly used, inexpensive intra-articular treatment for osteoarthritis which may increase the risk for laminitis in horses due, in part, to hyperinsulinaemia. Humans with metabolic syndrome experience increases in insulin and glucose concentrations post-injection, but responses in horses are unknown. To determine the effect of a single intra-articular (IA) dose of triamcinolone acetate (TA) on blood insulin and glucose concentrations. Before-after study. Ten horses with normal insulin regulation as assessed by an oral sugar test received 18 mg of TA into one middle carpal joint. Insulin and glucose concentrations were evaluated at baseline and 4, 6, 8, 24, 48, and 72 h following IA corticosteroid injection. Differences from baseline were evaluated using a repeated measures ANOVA with Dunnett's multiple comparison testing or a Friedman test with Dunn's correction (significant at p < 0.05). Mean ± SD blood insulin concentration post IA TA injection was increased at 6 h (15.8 ± 3.1 μIU/mL, p = 0.01), 24 h (23 ± 5.8 μIU/mL, p ≤ 0.001), and 48 h (29 ± 13 μIU/mL, p ≤ 0.01) compared to baseline (10 ± 12.3 μIU/mL), with the peak at 48 h. Median ± 95% CI blood glucose concentration post IA TA injection was increased at 6 h (112.7 ± 20.3 mg/dL, p = 0.006), 8 h (112.9 ± 21.4 mg/dL, p = 0.004), 24 h (122.6 ± 14.6, p ≤ 0.0001), and 48 h (123.5 ± 15.4 mg/dL, p ≤ 0.0001) compared to baseline (89.2 ± 6.6 mg/dL), with the peak at 48 h. Only horses with normal insulin regulation were evaluated. Blood insulin and glucose concentrations modestly increased for 48 h following IA TA.

Association Between Systemic Immune Inflammation Level and Poor Prognosis Across Different Glucose Metabolism Status in Coronary Artery Disease Patients.

Blood glucose levels significantly affect the clinical prognosis of patients with coronary artery disease (CAD), and systemic immune inflammation is a common risk factor for both CAD and diabetes. However, the relationship between immune inflammation levels and poor prognosis in patients with CAD with different glucose metabolic statuses remains unclear. Between January 2007 and December 2020, we recruited 84,645 patients with CAD. The systemic immune inflammation index (SII) was used to comprehensively reflect the immune and inflammatory levels of patients and was calculated using the following formula: neutrophils × platelets/lymphocytes. The patients were classified into nine groups according to their glucose metabolism status (diabetes mellitus [DM], pre-diabetes mellitus [pre-DM], and normal glucose regulation [NGR]). Cox regression models and competing risk Fine and Gray models were used to investigate the association between SII and clinical outcomes. During the follow-up period, 12,578 patients died, including 5857 cardiovascular-related and 1251 cancer-related deaths. The risk of all-cause and cause-specific mortality increased with increasing SII tertiles in CAD patients with NGR, pre-DM, and DM. When considering glucose metabolism status, the multivariate cox regression revealed that CAD patients with DM and SII-H levels had the highest risk of all-cause mortality (1.69 [1.56-1.83]), cardiovascular mortality (2.29 [2.02-2.59]), and cancer mortality (1.29 [1.01-1.66]). Moreover, incorporating the SII into traditional risk factor models significantly improved the C-index for predicting all-cause and cardiovascular mortality. Systemic immune inflammation levels on admission were correlated with a higher risk of all-cause and cause-specific mortality in patients with CAD, particularly in those with DM.

THE ROLE OF NEUROENDOCRINE ACTIVITY IN THE REGULATION OF THE IMMUNE REACTIVITY OF THE ORGANISM IN AN EXPERIMENTALLY CREATED EXTREME SITUATION

The activity of the body's immune reactivity changes because it disrupts the neuroendocrine interaction mechanism in the experimental extreme state created by cobalt acetate and in the subsequent period. Therefore, due to this effect, the mechanism of normal regulation between the neuroimmunoendocrine systems of the body is disturbed and deep pathologies of various nature occur. Research in the direction of such mutual regulation mechanism is important. It is also recommended to conduct an examination of the immune reactivity of people living in areas contaminated with heavy metals.

The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates

During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.

Evolution Game Analysis of Chemical Risk Supervision Based on Special Rectification and Normal Regulation Modes

Chemical safety is closely related to public health, safety, and environmental concerns. Strengthening chemical safety supervision is not only vital for ensuring safe production but also plays a crucial role in maintaining overall social safety. This paper aims to analyze the evolutionary game strategies between chemical enterprises and government regulators under different regulatory modes, namely, ‘special rectification’ and ‘normal regulation’. The results indicate that under the ‘special rectification’ pattern, the strategic choices of chemical enterprises regarding safety investment rely on the cost–benefit analysis of safety non-investment. Conversely, in the ‘normal regulation’ mode, the decision to invest in safety is based on the comparison between the cost of safety investment and the cost of not investing in safety. Increasing government sanctions encourages chemical enterprises to prioritize safety investment under both supervision modes. Notably, while punishment significantly impacts safety investment behavior under the ‘normal regulation’ mode, it exhibits negligible influence under the ‘special rectification’ pattern. These research findings provide valuable decision-making support for government agencies tasked with effectively supervising the safety production of chemical enterprises.

Protective Effects of Silymarin against Chronic Exposure to Manganese-Induced Hematological Alterations, Biochemical Perturbations and Genotoxicity in Rats

Manganese (Mn), a trace metal, is essential for maintaining the normal regulation of many biochemical and cellular processes

The role of circadian rhythm in breast cancer, lung cancer, and colorectal cancer

Circadian rhythm is a biological rhythm system with a self-regulating function and a 24-hour cycle that is synchronized with the alternation of day and night and is driven by circadian clock genes and clock-control genes. The circadian clock governs and controls processes like immune, metabolism, endocrine, cell division and proliferation, apoptosis, and sleep, allowing cells, tissues, and organs to carry out different living activities in an organized and coordinated way. The root cause of tumors is gene mutations that cause the body to lose its normal regulation of cell growth. According to studies, cancer and problems of biological rhythm are tightly linked. Related epidemiological studies are related to the occurrence and inhibition of tumors by circadian rhythms the molecular mechanism of action has become a hot issue. In this paper, combined with relevant research at home and abroad, we focus on the specific association between circadian rhythm and the high occurrence of breast cancer, lung cancer, and colorectal cancer in three populations, as well as the part circadian clocks play at the molecular level in tumor development and progression, and discuss the timing of cancer. Therapeutics is a novel therapeutic field that has the potential to increase efficacy and minimize negative effects. A sounder theoretical foundation for the identification, management, and prognosis of clinical cancers will be made possible by the clarification of the circadian clock in cancer.

The Signal Peptidase FoSpc2 Is Required for Normal Growth, Conidiation, Virulence, Stress Response, and Regulation of Light Sensitivity in Fusarium odoratissimum.

Signal peptidase (SPase) is responsible for cleavage of N-terminal signal peptides in most secretory precursor proteins and many membrane proteins during maturation. In this study, we identified four components of the SPase complex (FoSec11, FoSpc1, FoSpc2, and FoSpc3) in the banana wilt fungal pathogen Fusarium odoratissimum. We proved that interactions exist among the four SPase subunits by bimolecular fluorescence complementation (BiFC) and affinity purification and mass spectrometry (AP-MS) assays. Among the four SPase genes, FoSPC2 was successfully deleted. FoSPC2 deletion caused defects in vegetative growth, conidiation, and virulence. Loss of FoSPC2 also affected the secretion of some pathogenicity-related extracellular enzymes, suggesting that SPase without FoSpc2 may have a lower efficiency in managing the maturation of the extracellular enzymes in F. odoratissimum. In addition, we found that the ΔFoSPC2 mutant had increased sensitivity to light, and the colonies of the mutant grew faster under all-dark conditions than under all-light conditions. We further observed that deletion of FoSPC2 affected expression of the blue light photoreceptor gene FoWC2, leading to cytoplasmic accumulation of FoWc2 under all-light conditions. Since FoWc2 has signal peptides, FoSpc2 may regulate the expression and subcellular localization of FoWc2 indirectly. Contrary to its response to light, the ΔFoSPC2 mutant displayed a significant decreased sensitivity to osmotic stress, and culturing the mutant under osmotic stress conditions restored both the localization of FoWc2 and light sensitivity of the ΔFoSPC2, suggesting that a cross talk between osmotic stress and light response pathways in F. odoratissimum and FoSpc2 takes part in these processes. IMPORTANCE In this study, we identified four components of SPase in the banana wilt pathogen Fusarium odoratissimum and characterized the SPase FoSpc2. Loss of FoSPC2 affected the secretion of extracellular enzymes, suggesting that SPase without FoSpc2 may have a lower efficiency in managing the maturation of the extracellular enzymes in F. odoratissimum. In addition, this is the first time that we have found a relationship between the SPase and fungal light response. Deletion of FoSPC2 resulted in decreased sensitivity to the osmotic stresses but with increased sensitivity to light. Continuous light inhibited the growth rate of the ΔFoSPC2 mutant and affected the cellular localization of the blue light photoreceptor FoWc2 in this mutant, but culturing the mutant under osmotic stress both restored the localization of FoWc2 and eliminated the light sensitivity of the ΔFoSPC2 mutant, suggesting that loss of FoSPC2 may affect a cross talk between the osmotic stress and light response pathways in F. odoratissimum.

Greater anhedonia scores in healthy individuals are associated with less decline in 24-hour energy expenditure with fasting: Evidence for a link between behavioral traits and spendthrift phenotype

Obesity rates are increasing and affecting mental health. It is important to understand how behavioral traits such as anhedonia are associated with physiologic traits that may predict weight-change in clinical and non-clinical populations. We studied whether 24-hour energy expenditure (24hEE) changes with fasting and overfeeding are associated with anhedonia in a healthy cohort. We performed behavioral assessments (physical anhedonia scale (PAS) and inventory for depressive symptoms (IDS)) followed by measures of 24hEE and urinary catecholamines in a whole-room indirect calorimeter (respiratory chamber) during energy balance, and then randomly during fasting and 2 different overfeeding diets. Participants (n=98) were medically healthy, between 18 and 55 years of age, with normal glucose regulation and weight-stable 6 months before admission. Women were premenopausal and not pregnant. Higher PAS was significantly associated with lesser decrease in 24hEE with fasting and higher urinary catecholamine excretion rates – consistent with spendthrift metabolism. As IDS increased, the association between anhedonia and the change in 24hEE from energy balance to fasting decreased (B-values were lower for change in EE). Here, higher PAS scores may reflect the ability to respond with appropriate homeostatic reactions which balance energy needs. IDS scores blunting this response may explain how anhedonia and depression can lead to weight gain.