Energy Dysregulation Research Articles

Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.

The vices and virtues of medical models of obesity.

Despite numerous public health organizations supporting the pathologization of obesity and considering recent obesity rates a health crisis, many researchers in the humanities, social sciences, and even in the health sciences remain unconvinced. In this paper, we address a set of arguments coming from these academic fields that criticize medical models of obesity for their supposedly flawed diagnostic categories that shift focus onto individuals and support moralizing judgements. Clarifying some key claims in these models and explicating the view of obesity in terms of energy dysregulation, we aim to tease apart misunderstandings and argue that not only do these models not say what they are often accused of saying, but their apparent vices may actually be virtues in helping to combat stigma. Building on the social psychology of stigma and disease labeling, we then suggest that current medical models are largely supportive of many moral and political aims promoted by critics of these models.

Resting-State EEG Alterations of Practice-Related Spectral Activity and Connectivity Patterns in Depression.

Depression presents with altered energy regulation and neural plasticity. Previous electroencephalography (EEG) studies showed that practice in learning tasks increases power in beta range (13-30 Hz) in healthy subjects but not in those with impaired plasticity. Here, we ascertain whether depression presents with alterations of spectral activity and connectivity before and after a learning task. We used publicly available resting-state EEG recordings (64 electrodes) from 122 subjects. Based on Beck Depression Inventory (BDI) scores, they were assigned to either a high BDI (hBDI, BDI > 13, N = 46) or a control (CTL, BDI < 7, N = 75) group. We analyzed spectral activity, theta-beta, and theta-gamma phase-amplitude coupling (PAC) of EEG recorded at rest before and after a learning task. At baseline, compared to CTL, hBDI exhibited greater power in beta over fronto-parietal regions and in gamma over the right parieto-occipital area. At post task, power increased in all frequency ranges only in CTL. Theta-beta and theta-gamma PAC were greater in hBDI at baseline but not after the task. The lack of substantial post-task growth of beta power in depressed subjects likely represents power saturation due to greater baseline values. We speculate that inhibitory/excitatory imbalance, altered plasticity mechanisms, and energy dysregulation present in depression may contribute to this phenomenon.

Metabolic and Biochemical Effects of Pyrroloquinoline Quinone (PQQ) on Inflammation and Mitochondrial Dysfunction: Potential Health Benefits in Obesity and Future Perspectives.

Obesity is defined as a complex, systemic disease characterized by excessive and dysfunctional adipose tissue, leading to adverse health effects. This condition is marked by low-grade inflammation, oxidative stress, and metabolic abnormalities, including mitochondrial dysfunction. These factors promote energy dysregulation and impact body composition not only by increasing body fat but also by promoting skeletal muscle mass atrophy. The decline in muscle mass is associated with an increased risk of all-cause mortality in individuals with this disease. The European Food Safety Authority approved pyrroloquinoline quinone (PQQ), a natural compound, as a dietary supplement in 2018. This narrative review aims to provide a comprehensive overview of the potential role of PQQ, based on its anti-inflammatory and antioxidant properties, in addressing dysfunctional adipose tissue metabolism and related disorders.

Mood Disorder Questionnaire Positivity in Systemic Lupus Erythematosus and Other Chronic Diseases including Screen Bipolar Disorders or Rhythm and Energy Dysregulation Syndromes (DYMERS).

This study explores the issue of paper-and-pencil screening tests for bipolar disorder, often leading to false positives. It discusses hypotheses that connect MDQ positivity with sleep disorders, a decline in health-related quality of life, and the impact of the COVID-19 pandemic on mood disorders. The study proposes that MDQ identifies a "Dysregulation of Mood, Energy, and Social Rhythms Syndrome" (DYMERS), indicating a stress-related condition. It aims to investigate the association between MDQ positivity and systemic lupus erythematosus (SLE) in comparison to other chronic disorders. This case-control study, conducted from April 2019 to February 2020, investigated MDQ positivity in patients with SLE. Ethical approvals were obtained, and statistical analysis was used for data assessment. This is a case-controlled study where MDQ positivity was significantly higher in systemic lupus erythematosus cases than controls. The analysis compared gender, age, and the presence of depressive episodes between MDQ-positive and MDQ-negative cases, revealing some differences but no significant variations. Interestingly, no association with high prednisone or biologics use was observed. The frequency of MDQ positivity in systemic lupus erythematosus was compared to other chronic pathologies, revealing varying associations with each condition. This study reveals a high rate of (MDQ) positivity in systemic lupus erythematosus (SLE), associated with the risk of bipolar disorder in SLE. Notable discrepancies in MDQ positivity risk factors between SLE and bipolar disorder are observed. The study emphasizes the ability of MDQ to identify a distinct syndrome characterized by rhythm dysregulation, posing a risk for bipolar disorder and other disorders.

Hyperactivity and Risk for Dysregulation of Mood, Energy, and Social Rhythms Syndrome (DYMERS): Standardization of a Simple One-Item Screener versus the Mood Disorder Questionnaire (MDQ).

Background: This study aims to verify the accuracy of item 10 on the energy level of the Short-Form Health Survey (SF-12) in an item screening according to Mood Disorder Questionnaire (MDQ) results, providing a measure of hyper-energy. Methods: Regression techniques were employed in a dataset comprising 4093 records of respondents to test both linear and nonlinear relationships between predictor and outcome variables (energy level and symptoms considered in the MDQ). We examined the relationship of energy level with cases identified using MDQ with a cut-off of 7. Results: Levels of energy, as rated on item 10 of the SF-12, were related to the MDQ score with sensitivity = 0.72 and specificity = 0.70. In linear regression, the associations were stronger with MDQ items on excessive energy or activity, showing a medium effect size and an explained variance of 10% or higher. A greater association was observed for items on excessive energy and activity, as expected, as well as for items concerning self-confidence, sociability, and talkativeness. Conclusions: This result may have implications for the research on risk factors and the pathogenesis of the dysregulation of mood, energy, and social rhythms syndrome (DYMERS), a syndrome that is hypothesized to occur in stressful conditions like those shown under the COVID-19 pandemic.

Vagus Nerve Suppression in Ischemic Stroke by Carotid Artery Occlusion: Implications for Metabolic Regulation, Cognitive Function, and Gut Microbiome in a Gerbil Model.

The vagus nerve regulates metabolic homeostasis and mediates gut-brain communication. We hypothesized that vagus nerve dysfunction, induced by truncated vagotomy (VGX) or carotid artery occlusion (AO), would disrupt gut-brain communication and exacerbate metabolic dysregulation, neuroinflammation, and cognitive impairment. This study aimed to test the hypothesis in gerbils fed a high-fat diet. The gerbils were divided into four groups: AO with VGX (AO_VGX), AO without VGX (AO_NVGX), no AO with VGX (NAO_VGX), and no AO without VGX (NAO_NVGX). After 5 weeks on a high-fat diet, the neuronal cell death, neurological severity, hippocampal lipids and inflammation, energy/glucose metabolism, intestinal morphology, and fecal microbiome composition were assessed. AO and VGX increased the neuronal cell death and neurological severity scores associated with increased hippocampal lipid profiles and lipid peroxidation, as well as changes in the inflammatory cytokine expression and brain-derived neurotrophic factor (BDNF) levels. AO and VGX also increased the body weight, visceral fat mass, and insulin resistance and decreased the skeletal muscle mass. The intestinal morphology and microbiome composition were altered, with an increase in the abundance of Bifidobacterium and a decrease in Akkermansia and Ruminococcus. Microbial metagenome functions were also impacted, including glutamatergic synaptic activity, glycogen synthesis, and amino acid biosynthesis. Interestingly, the effects of VGX were not significantly additive with AO, suggesting that AO inhibited the vagus nerve activity, partly offsetting the effects of VGX. In conclusion, AO and VGX exacerbated the dysregulation of energy, glucose, and lipid metabolism, neuroinflammation, and memory deficits, potentially through the modulation of the gut-brain axis. Targeting the gut-brain axis by inhibiting vagus nerve suppression represents a potential therapeutic strategy for ischemic stroke.

The Gut Microbial Regulation of Epigenetic Modification from a Metabolic Perspective.

Obesity is a global health challenge that has received increasing attention in contemporary research. The gut microbiota has been implicated in the development of obesity, primarily through its involvement in regulating various host metabolic processes. Recent research suggests that epigenetic modifications may serve as crucial pathways through which the gut microbiota and its metabolites contribute to the pathogenesis of obesity and other metabolic disorders. Hence, understanding the interplay between gut microbiota and epigenetic mechanisms is crucial for elucidating the impact of obesity on the host. This review primarily focuses on the understanding of the relationship between the gut microbiota and its metabolites with epigenetic mechanisms in several obesity-related pathogenic mechanisms, including energy dysregulation, metabolic inflammation, and maternal inheritance. These findings could serve as novel therapeutic targets for probiotics, prebiotics, and fecal microbiota transplantation tools in treating metabolic disruptions. It may also aid in developing therapeutic strategies that modulate the gut microbiota, thereby regulating the metabolic characteristics of obesity.

Well-Being As a Component Of Subjective Health Assessment In Students

Introduction. The effectiveness of professional education in students largely depends on subjective health assessments such as well-being, which affects psychological resistance in stressful situations and unusual conditions; prevention of maladjustment, neurotic disorders, and abnormal stress responses, and adaptability. Identification of aspects indicating decline in well-being (sleep-wake disorders, weakness of volition; autonomic dysfunction, and emotional dysregulation; signs of addiction; physical fatigue and mental exhaustion; psychological fatigue and lack of energy; fears and anxiety) is aimed at being the basis for a new program on mental health promotion and mental disorder prevention. Purpose. The goal was to determine the main aspects of well-being as a component of subjective health assessment in students. Methods and materials. A total of 712 adult students from Moscow universities participated in the study on a voluntary basis. In order to identify sleep-wake disorders, autonomic dysfunction and emotional dysregulation, signs of addiction, psychological fatigue and lack of energy, anxiety, and fears, the participants were provided with two questionnaires: “Mood is health,” elaborated by G. S. Odinokov, and “Symptomatic questionnaire of well-being,” developed by A. Volkov and N. E. Vodopyanova. Then, the data were processed using the Pearson correlation coefficient and the Chaddock–Snedecor scale. Results. It was revealed that the level of well-being as a component of subjective health assessment in students was above-average. There was an average level of sleep-wake disorders, emotional dysregulation, psychological fatigue and lack of energy, anxiety and fears, as well as a below-average level of weakness of volition, autonomic dysfunction and signs of addiction. A strong correlation between the total and final results of well-being aspects and sleep-wake disorders, weakness of volition, autonomic dysfunction and emotional dysregulation, signs of addiction, psychological fatigue and lack of energy, fears and anxiety indicates that the lower these components, the higher the well-being.

Dysregulation of mood, energy, and social rhythms syndrome (DYMERS): A working hypothesis.

A syndrome centered on the dysregulation of behavioral rhythms (DBR) is discussed. Recent pandemic brought to observe: (1) Having a DBR affecting sleep patterns, eating habits, and social interactions, before the lockdown period, was a determinant for depressive episodes during the lockdown; (2) In tighter lockdowns, DBR triggered depressive episodes in bipolar patients; (3) DBR in healthcare workers under pressure was a determinant of burnout; (4) DBR influenced the course of chronic diseases by altering immune responses. In addition, it was found that scoring positive on the Mood Disorder Questionnaire (MDQ) was closely associated with the dysregulation of sleep rhythms. MDQ is a screening tool for bipolar disorder (BD), criticized for detecting too many false positives. Studies showed that positivity to the MDQ implied a severe impairment of quality of life even in people without psychiatric diagnoses. According to this evidence, three different hyperactivation levels could be proposed (from normality to pathology): firstly, an adaptive increase in energy (e.g. athletes performing well); secondly, a DBR determined from the continuous stimulation of stress hormones, with possible positive scores on the MDQ without a diagnosis of bipolar disorder, like in burnout syndromes and, thirdly, hyperactivity during manic episodes. The Dysregulation of Mood, Energy, and Social Rhythms Syndrome (DYMERS), the second level of the scale, is proposed as a working hypothesis. DYMERS is also seen as a vulnerable condition that may evolve in other disorders (including BD) according to the individual susceptibility (including genetic predisposition) and the specific nature/level of the stressor.

Projection of Bipolarity to Mitochondria: GABA Shunt is related with Self pathology and Medical Comorbidity in Bipolar Disorder

The nature of the relationship with the self-object is the source of mental energy. At this point, the self is a spatiotemporal formation. The self has been found to be associated with the GAD enzyme activity responsible for GABA production at the molecular level. GABA is a metabolite of Krebs. Bipolar disorder is a biphasic state of energy dysregulation as a circadian rithms. Phasic nature of mitochondria to produce ATP may be crucial to the switching of affective states in bipolar disorder. The GABA shunt is an alternative energy production pathway that is activated in response to stress. The GABA shunt plays an important role in preventing the accumulation of reactive oxygen intermediates and cell death. On the other hand, GABA shunt impairs phosphorylation processes. Mitochondrial dysfunction is reflected in glucose, lipid and protein metabolism. A bipolar spectrum is possible at this point, including physical illnesses. A classification of mood disorders based on entropy levels is framed by medical comorbidity.

Does the Response to a Stressful Condition in Older Adults with Life Rhythm Dysregulations Provide Evidence of the Existence of the "Dysregulation of Mood, Energy, and Social Rhythms Syndrome"?

The COVID-19 lockdown periods have given rise to the "Dysregulation of Mood, Energy, and Social Rhythms Syndrome" (DYMERS). This syndrome is characterized by a poor regulation of biological, social, and behavioral rhythms, including sleep, nutrition, and social contacts. The purpose of this cohort study was to examine whether older adults with pre-existing DYMERS had a more negative perception of their health-related quality of life (H-QoL) during the COVID-19 pandemic lockdown, regardless of the presence of concurrent mood disorders. The entire study population (N = 93; age > 65 year) was categorized based on whether they exhibited dysregulated rhythms at the outset of the study. A comparison was made between DYMERS-positive individuals and DYMERS-negative individuals, and we assessed their H-QoL at the conclusion of the study. We also compared the H-QoL of individuals in the cohort who did not have a positive depression score to understand the impact of the rhythm dysregulation alone. The frequency of individuals with a critical health-related quality of life score (SF12 < 25) was higher in the cohort with pre-existing DYMERS during lockdown (33.33% vs. 6.17%). This difference remained significant even when only individuals without depressive symptomatology were considered (27.27% vs. 2.60%). The results of this study indicate that DYMERS can exert a substantial influence on health-related quality of life (H-QoL), even when mood disturbances are not present. Additional research is required to investigate the relationship between DYMERS and other psychiatric conditions as well as its nature as a standalone disorder.

Metabolomic response of striped marsh frog (Limnodynastes peronii) tadpoles exposed to the fire retardant Phos-Chek LC95W

Climate change and other factors have contributed to an increased frequency and intensity of global wildfires in recent years. Ammonium-based fire retardants are widely used to suppress or delay the spread of fire and have generally been regarded as presenting a low risk of acute toxicity to fauna. However, studies have raised concerns about their potential to cause indirect or sub-lethal effects, and toxicity information regarding the potential for such impacts in aquatic species is limited. To address these knowledge gaps, we used an untargeted metabolomics approach to evaluate the sub-lethal physiological and metabolic responses of striped marsh frog (Limnodynastes peronii) tadpoles exposed to a concentration gradient of the ammonium polyphosphate (APP)-based fire retardant Phos-Chek LC95W (PC). Acute exposure (96 h) to PC significantly altered the relative abundance of 14 metabolites in whole tadpoles. The overall metabolic response pattern was consistent with effects reported for ammonia toxicity and also suggestive of energy dysregulation and osmotic stress associated with alterations to physicochemical water quality parameters in the PC treatments. Results suggest that run-off or accidental application of this formulation into waterways can have significant sub-lethal consequences on the biochemical profiles (i.e., the metabolome) of aquatic organisms and may be a concern for frog species that breed and develop in small, often ephemeral, waterbodies. Our study highlights the benefits of integrating untargeted metabolomics with other ecological and toxicological endpoints to provide a more holistic characterisation of the sub-lethal impacts associated with bushfire-fighting chemicals and with environmental contaminants more broadly.

The impact of MDQ positivity on quality of life impairment: Does it support the hypothesis of "Dysregulation of Mood, Energy, and Social Rhythms Syndrome" (DYMERS)?

DSM-5 separates bipolar (BD) from depressive disorders, but some experts consider BD as part of a spectrum of mood disorders. The interpretation of numerous false positives of BD screened by the Mood Disorders Questionnaire (MDQ) is part of this debate. Recent study results suggest that the worsening of health-related quality of life (H-Qol) associated with MDQ positivity does not depend solely on mood disorders. This study aims to clarify whether the impairment may be due to other concomitant disorders, unrelated to mood disorders, leading to a worsening of H-Qol. Additionally, the study aims to explore if MDQ positivity itself observe clinical significance. The study involved pairs of cases (MDQ+) and controls (MDQ-) matched for sex, age, and absence of DSM-IV psychiatric comorbidity. The impact of MDQ positivity on the quality of life in a sample of MDQ+ comorbid with MDD was measured and compared to impact of MDD in other chronic disorders. The H-Qol was significantly worse in MDQ+ than in controls (both groups without any psychiatric co-morbidity). The worsening was similar to severe chronic disorders The burden of worsening quality of life due to MDD was mild in another sample of MDQ positives with comorbid MDD. The study hypothesizes that MDQ positivity may be related to hyperactivation and dysregulation of rhythms typical of stress disorders. In fact, MDQ+ was found strongly related to sleep disturbances. Future studies could verify if a "Dysregulation of Mood, Energy, and Social Rhythms Syndrome" (DYMERS), causes worsening the H-Qol in MDQ+.

Irisin, adropin, and preptin as biomarkers of energy dysregulation in depressive disorder

Objective Lack of energy, fatigue, debility are often seen in depression and hardly respond to treatment. Finding some biomarkers for these symptoms may be important for diagnosis and treatment. We aimed to investigate the possible relationship between depression and energy-related molecules irisin, adropin and preptin. Methods There were 117 patients with depression and 59 healthy volunteers included in the study. Sociodemographic characteristics and clinical features of groups were evaluated, and depressed patients were divided into subtypes, then irisin, adropin, preptin levels were compared between depressive patients and healthy controls and between subtypes. Depression severity, quality of life, functionality and the relations with irisin, adropin and preptin levels and associations between depression subtypes were evaluated. Results Irisin, adropin, and preptin levels were lower in depression, positively correlated with quality of life, and negatively correlated with depression severity and functional impairment. Depression subtypes showed no difference in irisin, adropin and preptin levels. Conclusions We found decreased serum irisin, adropin and preptin levels in depression. Our results may support investigation of irisin, adropin and preptin as biomarkers for depression but it might be more meaningful to evaluate these biomarkers in a long-term follow-up.

Does Screening for Bipolar Disorders Identify a "Dysregulation of Mood, Energy, and Social Rhythms Syndrome" (DYMERS)? A Heuristic Working Hypothesis.

The aim of this paper is to verify if people with a positive score on the Mood Disorder Questionnaire (MDQ) without comorbidity of mood disorders showed a worse level of Health-related Quality of life (HRQol) compared to a control-matched sample of MDQ negatives, identifying a specific syndrome. This is a case-control study based on a database from a community survey. Cases: MDQ-positive without mood disorders; Controls: MDQ negatives matched by sex, age, and psychiatric diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria. Tools: MDQ, the Advanced Neuropsychiatric Tools and Assessment Schedule (ANTAS) semi-structured interview for psychiatric diagnosis, and the Health Survey Short Form (SF-12) for measuring HRQol. People scoring positive on the MDQ without a diagnosis of mood disorders showed significantly lower scores on the SF-12 compared to people of the same age and of the same sex with an equal diagnosis of psychiatric disorders not related to mood disorders (35.21 ± 6.30 vs. 41.48 ± 3.39, p < 0.0001). In the debate whether a positive score on the MDQ selects an area of "malaise" due to the presence of disorders differing from Bipolar Disorders, or if a positive score on the MDQ may be considered a "subthreshold" form of bipolar disorder in people who may later develop bipolar disorder, a third hypothesis can be advanced, i.e., that a positive score on the MDQ identifies a specific "Dysregulation of Mood, Energy, and Social Rhythms Syndrome" (DYMERS), characterized by a considerable amount of suffering and not attributable to other disorders, and which might represent a trigger for the previously mentioned disorders with which a positive score on the MDQ is associated, probably including, in severe conditions, bipolar disorder.

Creatine energy substrate increases bone density in the Pahenu2 classical PKU mouse in the context of phenylalanine restriction

Pathophysiology of osteopenia in phenylalanine hydroxylase (PAH) deficient phenylketonuria (PKU) is poorly characterized. The Pahenu2 mouse is universally osteopenic where dietary phenylalanine (Phe) management with amino acid defined chow does not improve bone density. We previously demonstrated Pahenu2 osteopenia owes to a skeletal stem cell (SSC) developmental deficit mediated by energy dysregulation and oxidative stress. This investigation demonstrates complexity of Pahenu2 SSC energy dysregulation. Creatine use by bone tissue is recognized. In vitro Pahenu2 SSCs in osteoblast differentiation respond to creatine with increased in situ alkaline phosphatase activity and increased intracellular ATP content. Animal studies applied a 60-day creatine regimen to Pahenu2 and control cohorts. Control cohorts include unaffected littermates (wt/wt), Pahenu2 receiving no intervention, and dietary Phe restricted Pahenu2. Experimental cohorts (Phe unrestricted Pahenu2, Phe restricted Pahenu2) were provided 1% creatine ad libitum in water. After 60 days, microcomputed tomography assessed bone metrics. Equivalent osteopenia occurs in Phe-restricted and untreated Pahenu2 control cohorts. In Phe unrestricted Pahenu2, creatine was without effect as bone density remained equivalent to Pahenu2 control cohorts. Alternatively, Phe-restricted Pahenu2 receiving creatine present increased bone density. We hypothesize small molecule dysregulation in untreated Pahenu2 disallows creatine utilization; therefore, osteopenia persisted. Dietary Phe restriction enables creatine utilization to enhance SSC osteoblast differentiation and improve in vivo bone density. PKU intervention singularly focused on Phe reduction enables residual disease including osteopenia and neurologic elements. Intervention concurrently addressing Phe homeostasis and energy dysregulation will improve disease elements refractory to standard of care Phe reduction mono-therapy.

Transcriptomics unveils immune metabolic disruption and a novel biomarker of mortality in patients with HBV-related acute-on-chronic liver failure

HBV-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome associated with high short-term mortality. This study aims to reveal the molecular basis and identify novel HBV-ACLF biomarkers. Seventy patients with HBV-ACLF and different short-term (28 days) outcomes underwent transcriptome sequencing using peripheral blood mononuclear cells. Candidate biomarkers were confirmed in two external cohorts using ELISA. Cellular composition analysis with peripheral blood mononuclear cell transcriptomics showed that the proportions of monocytes, T cells and natural killer cells were significantly correlated with 28-day mortality. Significant metabolic dysregulation of carbohydrate, energy and amino acid metabolism was observed in ACLF non-survivors. V-set and immunoglobulin domain-containing 4 (VSIG4) was the most robust predictor of patient survival (adjusted p= 1.74×10-16; variable importance in the projection= 1.21; AUROC= 0.89) and was significantly correlated with pathways involved in the progression of ACLF, including inflammation, oxidative phosphorylation, tricarboxylic acid cycle and T-cell activation/differentiation. Plasma VSIG4 analysis externally validated its diagnostic value in ACLF (compared with chronic liver disease and healthy groups, AUROC= 0.983). The prognostic performance for 28-/90-day mortality (AUROCs= 0.769/0.767) was comparable to that of three commonly used scores (COSSH-ACLFs, 0.867/0.884; CLIF-C ACLFs, 0.840/0.835; MELD-Na, 0.710/0.737). Plasma VSIG4 level, as an independent predictor, could be used to improve the prognostic performance of clinical scores. Risk stratification based on VSIG4 expression levels (>122μg/ml) identified patients with ACLF at a high risk of death. The generality of VSIG4 in other etiologies was validated. This study reveals that immune-metabolism disorder underlies poor ACLF outcomes. VSIG4 may be helpful as a diagnostic and prognostic biomarker in clinical practice. Acute-on-chronic liver failure (ACLF) is a lethal clinical syndrome associated with high mortality. We found significant immune cell alterations and metabolic dysregulation that were linked to high mortality in patients with HBV-ACLF based on transcriptomics using peripheral blood mononuclear cells. We identified VSIG4 (V-set and immunoglobulin domain-containing 4) as a diagnostic and prognostic biomarker in ACLF, which could specifically identify patients with ACLF at a high risk of death.

Identification of global transcriptional variations in human PBMCs two months post heat injury helps categorization heat tolerant or heat intolerant phenotypes.

Thermal intolerance may limit activity in hostile environments. Following heat illness two physiologically distinct phenotypes evolve: Heat Tolerant (HT) and Heat Intolerant (HI). The recognition that heat illness alters gene expression justified revisiting the established physiological concept of HI. We used a DNA microarray to examine the global transcriptional response in Peripheral Blood Mononuclear Cells (PMBCs) from HI and HT phenotypes, categorized 2-mo post heat injury using a functional physiological Heat Tolerance Test (HTT, 40°C)-Recovery (R, 24°C) protocol. The impact of recurrent heat stress was studied in vitro using PBMCs from controls (participants with no history of heat injury), HI and HT (categorized by functional HTT) with a customized NanoString array. There were significant differences under basal conditions between the HI and HT. HI were more immunological alerted. Almost no shared genes were found between end-HTT and recovery phases, suggesting vast cellular plasticity. In HI, mitochondrial function was dysregulated, canonical pathways associated with exercise endurance-NRF2 and insulin were downregulated, while AMPK and PPAR were upregulated. HT exhibited reciprocal responses, suggesting that energy dysregulation found in HI interfered with performance in the heat. The endoplasmic-reticulum stress response was also suppressed in HI. In vitro HTT (43°C) abolished differences between HI and HT PBMCs including the HSPs genes, while controls showed profound HSPs upregulation.

Cirrhosis and Sarcopenia.

Sarcopenia is a progressive muscle wasting syndrome involving loss in skeletal muscle mass, strength, and function. It is closely associated with cirrhosis and its complications with up to more than half of cirrhotic patients demonstrating imaging findings of sarcopenia. The pathogenesis of this syndrome remains complex, including multiple factors involved in skeletal muscle homeostasis, systemic inflammation, and energy dysregulation. Many modalities exist in assessing and measuring sarcopenia. The use of cross-sectional imaging, such as computed tomography and magnetic resonance imaging, with accurate and clinically proven assessment software should be considered the gold standard. Sarcopenia has become the focus of ongoing extensive research with initial findings highlighting increased mortality and complication rates in patient with cirrhosis and hepatocellular carcinoma. Additional studies have demonstrated reversal and improved survival in sarcopenic patients who have undergone transjugular intrahepatic portosystemic shunt placement. Thus, accounting for sarcopenia can help risk stratify patients prior to interventional procedures to allow for better outcomes and improved survival.