A PROTEIN COMPLEX OF LIVER ORIGIN ACTIVATES A PRO-INFLAMMATORY PROGRAM THAT DRIVES HEPATIC AND INTESTINAL INJURY IN ALCOHOL-ASSOCIATED LIVER DISEASE.

BACKGROUND AND AIMS: There is limited information on how the liver-to-gut axis contributes to alcohol-associated liver disease (AALD). We previously identified that high-mobility group box-1 (HMGB1) undergoes oxidation in hepatocytes and demonstrated elevated serum levels of oxidized HMGB1 ([O] HMGB1) in alcoholic patients. Since interleukin-1 beta (IL1B) increases in AALD, we hypothesized hepatocyte-derived [O] HMGB1 could interact with IL1B to activate a pro-inflammatory program that, besides being detrimental to the liver, drives intestinal barrier dysfunction. RESULTS: Alcohol-fed RageΔMye mice exhibited decreased NFκB signaling, a pro-inflammatory signature, and reduced total intestinal permeability, resulting in protection from AALD. Additionally, [O] HMGB1 bound and signaled through the receptor for advanced-glycation end-products (RAGE) in myeloid cells, driving hepatic inflammation, intestinal permeability, and increased portal blood lipopolysaccharide in AALD. We identified that [O] HMGB1 formed a complex with IL1B, which was found in the livers of patients with acute alcoholic hepatitis and mice with AALD. This complex originated from the liver, as it was absent in the intestine when hepatocytes did not produce [O] HMGB1. Mechanistically, the complex bound RAGE in Kupffer cells and macrophages induces a pro-inflammatory program. Moreover, it bound RAGE in intestinal macrophages and epithelial cells, leading to intestinal inflammation, altered intestinal epithelial cell tight junction protein expression, increased intestinal permeability, and elevated portal blood lipopolysaccharide, enhancing AALD pathogenesis. CONCLUSION: We identified a protein complex of liver origin that amplifies the pro-inflammatory feedback loop in AALD; therefore, targeting this complex could have significant therapeutic potential.

Socioeconomic inequality and urban-rural disparity of antenatal care visits in Bangladesh: A trend and decomposition analysis.

BACKGROUND: Socioeconomic inequality in antenatal care visits is a great concern in developing countries including Bangladesh; however, there is a scarcity of investigation to assess the factors of inequality and these changes over time. In this study, we investigated the trend of socioeconomic inequalities (2004-2017) in 1+ANC and 4+ANC visits, and extracted determinants contributions to the observed inequalities and urban-rural disparities in Bangladesh over the period from 2011 to 2017. METHODS: The data from the Bangladesh Demographic and Health Surveys (BDHS) conducted in 2004, 2007, 2011 and 2017 were analyzed in this study. The analysis began with exploratory and bivariate analysis, followed by the application of logistic regression models. To measure the inequalities, the Erreygers concentration index was used, and regression-based decomposition analyses were utilized to unravel the determinant's contribution to the observed inequalities. The Blinder-Oaxaca type decomposition is also used to decompose the urban-rural disparity into the factors. RESULTS: Our analysis results showed that the prevalence of 1+ANC and 4+ANC visits has increased across all the determinants, although the rate of 4+ANC visits remains notably low. The magnitudes of socioeconomic inequality in 4+ANC visits represented an irregular pattern at both the national and urban levels, whereas it increased gradually in rural Bangladesh. However, inequalities in 1+ANC visits declined substantially after 2011 across the national, rural and urban areas of Bangladesh. Decomposition analyses have suggested that wealth status, women's education, place of residence (only for 4+ANC visits), caesarean delivery, husband education, and watching television (TV) are the main determinants to attribute and changes in the level of inequality and urban-rural disparity between the years 2011 and 2017. CONCLUSIONS: According to the findings of our study, it is imperative for authorities to ensure antenatal care visits are more accessible for rural and underprivileged women. Additionally, should focus on delivering high-quality education, ensuring the completion of education, reducing income disparity as well as launching a program to enhance awareness about health facilities, and the impact of caesarean delivery.

Ablation of secreted phosphoprotein-1 in hepatocytes increases fatty acid oxidation and ameliorates alcohol-associated liver disease.

BACKGROUND: Previously, we demonstrated that Spp1-/- mice exhibit a greater susceptibility to alcohol-induced liver injury than wild-type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte-derived SPP1 in either mitigating or exacerbating alcohol-associated liver disease (AALD) has yet to be elucidated. We hypothesized that hepatocyte-derived SPP1 plays a role in AALD by modulating the regulation of steatosis. METHODS: We analyzed hepatic SPP1 expression using four publicly available datasets from patients with alcoholic hepatitis (AH). Additionally, we examined SPP1 expression in the livers of WT mice subjected to either a control or ethanol Lieber-DeCarli (LDC) diet for 6 weeks. We compared the relationship between SPP1 expression and significantly dysregulated genes in AH with controls using correlation and enrichment analyses. To investigate the specific impact of hepatocyte-derived SPP1, we generated hepatocyte-specific Spp1 knock-out (Spp1ΔHep) mice and subjected them to either a control or ethanol Lieber-DeCarli diet for 6 weeks. RESULTS: Alcohol induced hepatic SPP1 expression in both humans and mice. Our analysis, focusing on genes correlated with SPP1, revealed an enrichment of fatty acid oxidation (FAO) in three datasets, and peroxisome proliferator-activated receptor signaling in one dataset. Notably, FAO genes correlating with SPP1 were downregulated in patients with AH. Ethanol-fed WT mice exhibited higher serum-free fatty acids (FFAs), adipose tissue lipolysis, and hepatic fatty acid (FA) transporters. In contrast, ethanol-fed Spp1ΔHep mice displayed lower liver triglycerides, FFAs, and serum alanine transaminase and greater FAO gene expression than WT mice, indicating a protective effect against AALD. Primary hepatocytes from Spp1∆Hep mice exhibited heightened expression of genes encoding proteins involved in FAO. CONCLUSIONS: Alcohol induces the expression of SPP1 in hepatocytes, leading to impaired FAO and contributing to the development of AALD.

Dynamics of dissociative electron attachment to aliphatic thiols.

Dissociative electron attachment (DEA) shows functional group-dependent site selectivity in H- ion channels. In this context, thiol functional groups have yet to be studied in great detail, although they carry importance in radiation damage studies where low-energy secondary electrons are known to induce damage through the DEA process. In this context, we report detailed measurements of absolute cross-sections and momentum images of various anion fragments formed in the DEA process in simple aliphatic thiols. We also compare the observed dynamics with that reported earlier in hydrogen sulphide, the precursor molecule for this functional group, and with that in aliphatic alcohols. Our findings show substantial resemblance in the underlying dynamics in these compounds and point to a possible generalisation of these features in the DEA to thiols. In addition, we identify various pathways that contribute to the S- and SH- channels.

Redox-sensitive high-mobility group box-1 isoforms contribute to liver fibrosis progression and resolution in mice.

BACKGROUND & AIMS: High-mobility group box-1 (HMGB1) significantly increases and undergoes post-translational modifications (PTMs) in response to liver injury. Since oxidative stress plays a major role in liver fibrosis and induces PTMs in proteins, we hypothesized that redox-sensitive HMGB1 isoforms contribute to liver fibrosis progression and resolution. METHODS: We used ESI-LC-MS (electrospray ionization-liquid chromatography-mass spectrometry) to study PTMs of HMGB1 during fibrosis progression and resolution. Conditional knockout mice were used for functional analyses. RESULTS: We identified that disulfide ([O]) and sulfonated ([SO3]) HMGB1 increase during carbon tetrachloride-induced liver fibrosis progression, however, while [O] HMGB1 declines, [SO3] HMGB1 drops but remains, during fibrosis resolution. Conditional knockout of Hmgb1 revealed that production of [O] and [SO3] HMGB1 occurs mostly in hepatocytes. Co-injection of [O] HMGB1 worsens carbon tetrachloride-induced liver fibrosis more than co-injection of [H] HMGB1. Conversely, ablation of [O] Hmgb1 in hepatocytes reduces liver fibrosis. Moreover, ablation of the receptor for advanced-glycation end-products (Rage) reveals that the profibrogenic effect of [O] HMGB1 is mediated by RAGE signaling in hepatic stellate cells (HSCs). Notably, injection of [SO3] HMGB1 accelerates fibrosis resolution due to RAGE-dependent stimulation of HSC apoptosis. Importantly, gene signatures activated by redox-sensitive HMGB1 isoforms in mice, classify patients with fibrosis according to fibrosis and inflammation scores. CONCLUSION: Dynamic changes in hepatocyte-derived [O] and [SO3] HMGB1 signal through RAGE-dependent mechanisms on HSCs to drive their profibrogenic phenotype and fate, contributing to progression and resolution of liver fibrosis. IMPACT AND IMPLICATIONS: Since oxidative stress plays a major role in liver fibrosis and induces post-translational modifications of proteins, we hypothesized that redox-sensitive HMGB1 isoforms contribute to liver fibrosis progression and resolution. This study is significant because a rise in [H] HMGB1 could flag 'patient at risk', the presence of [O] HMGB1 could suggest 'disease in progress or active scarring', while the appearance of [SO3] HMGB1 could point at 'resolution under way'. The latter could be used as a readout for response to pharmacological intervention with anti-fibrotic agents.

Overexpression of HMGB1 in hepatocytes accelerates PTEN inactivation-induced liver cancer.

BACKGROUND: Liver cancer is increasing due to the rise in metabolic dysfunction-associated steatohepatitis (MASH). High-mobility group box-1 (HMGB1) is involved in the pathogenesis of chronic liver disease, but its role in MASH-associated liver cancer is unknown. We hypothesized that an increase in hepatocyte-derived HMGB1 in a mouse model of inactivation of PTEN that causes MASH could promote MASH-induced tumorigenesis. METHODS: We analyzed publicly available transcriptomics datasets, and to explore the effect of overexpressing HMGB1 in cancer progression, we injected 1.5-month-old Pten∆Hep mice with adeno-associated virus serotype-8 (AAV8) vectors to overexpress HMGB1-EGFP or EGFP, and sacrificed them at 3, 9 and 11 months of age. RESULTS: We found that HMGB1 mRNA increases in human MASH and MASH-induced hepatocellular carcinoma (MASH-HCC) compared to healthy livers. Male and female Pten∆Hep mice overexpressing HMGB1 showed accelerated liver tumor development at 9 and 11 months, respectively, with increased tumor size and volume, compared to control Pten∆Hep mice. Moreover, Pten∆Hep mice overexpressing HMGB1, had increased incidence of mixed HCC-intrahepatic cholangiocarcinoma (iCCA). All iCCAs were positive for nuclear YAP and SOX9. Male Pten∆Hep mice overexpressing HMGB1 showed increased cell proliferation and F4/80+ cells at 3 and 9 months. CONCLUSION: Overexpression of HMGB1 in hepatocytes accelerates liver tumorigenesis in Pten∆Hep mice, enhancing cell proliferation and F4/80+ cells to drive MASH-induced liver cancer.

Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown. METHODS: We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH. RESULTS: This study demonstrated that MFs with high expression of SPP1 are enriched in patients and mice with nonalcoholic fatty liver disease (NAFLD), and show metabolic but not pro-inflammatory properties. Conditional knockin of Spp1 in myeloid cells (Spp1KI Mye) or in hepatic macrophages (Spp1KI LvMF) conferred protection, whereas conditional knockout of Spp1 in myeloid cells (Spp1ΔMye) worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1KI Mye mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1KI Mye also protected through sex-specific extrahepatic mechanisms. CONCLUSION: MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN-OSM-ARG2 crosstalk between MFs and hepatocytes may be beneficial for patients with NASH.

Abundance of ACVR1B transcript is elevated during septic conditions: Perspectives obtained from a hands-on reductionist investigation.

Sepsis is a complex heterogeneous condition, and the current lack of effective risk and outcome predictors hinders the improvement of its management. Using a reductionist approach leveraging publicly available transcriptomic data, we describe a knowledge gap for the role of ACVR1B (activin A receptor type 1B) in sepsis. ACVR1B, a member of the transforming growth factor-beta (TGF-beta) superfamily, was selected based on the following: 1) induction upon in vitro exposure of neutrophils from healthy subjects with the serum of septic patients (GSE49755), and 2) absence or minimal overlap between ACVR1B, sepsis, inflammation, or neutrophil in published literature. Moreover, ACVR1B expression is upregulated in septic melioidosis, a widespread cause of fatal sepsis in the tropics. Key biological concepts extracted from a series of PubMed queries established indirect links between ACVR1B and "cancer", "TGF-beta superfamily", "cell proliferation", "inhibitors of activin", and "apoptosis". We confirmed our observations by measuring ACVR1B transcript abundance in buffy coat samples obtained from healthy individuals (n=3) exposed to septic plasma (n = 26 melioidosis sepsis cases)ex vivo. Based on our re-investigation of publicly available transcriptomic data and newly generated ex vivo data, we provide perspective on the role of ACVR1B during sepsis. Additional experiments for addressing this knowledge gap are discussed.

Deficiency of neutrophil high-mobility group box-1 in liver transplant recipients exacerbates early allograft injury in mice.

BACKGROUND AND AIMS: Early allograft dysfunction (EAD) is a severe event leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients protects from post-LT EAD. APPROACH AND RESULTS: We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells increased reactive oxygen species (ROS) and inflammation in liver grafts and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). On LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver and enhanced production of ROS and pro-inflammatory cytokines when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody attenuated graft injury in recipients with myeloid cell Hmgb1 ablation. CONCLUSIONS: Neutrophil HMGB1 derived from recipients is central to regulate their activation, limits the production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury.

Matrisome gene-based subclassification of patients with liver fibrosis identifies clinical and molecular heterogeneities.

BACKGROUND AIMS: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis. APPROACH RESULTS: We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG Low and LFMG High , with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4 + activated HSC increased in LFMG High patients and were primarily responsible for the LFMG signature expression and dysregulation. CONCLUSIONS: The microfibrillar-associated protein 4 + -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments.

Anxiety and Stress Related to COVID-19 Among the Community Dwelling Older Adults Residing in the Largest Refugee Camp of the World.

The current cross-sectional study was conducted among 864 older adults aged ≥ 60 years residing in Rohingya refugee camp through face-to-face interviews during November-December 2021. COVID-19-related anxiety was measured using the five-point Coronavirus Anxiety Scale (CAS) and perceived stress using the 10-point Perceived Stress Scale (PSS). The linear regression model identified the factors associated with COVID-19-related anxiety and perceived stress. The prevalence of COVID-19-related anxiety and perceived stress was 68% and 93%, respectively. The average COVID-19-related anxiety score expected to be significantly higher among those who were physically inactive, concerned about COVID-19, had a close friend/family member diagnosed with COVID-19, and had some difficulty in getting food and routine medical care during the COVID-19 pandemic. Meanwhile, the average perceived stress score was expected to be significantly higher among those without partners, who were feeling overwhelmed by COVID-19, and who experienced COVID-19-related anxiety during the pandemic. The findings suggest providing immediate psychosocial support to older Rohingya adults.

Hepatocellular carcinomas, exhibiting intratumor fibrosis, express cancer-specific extracellular matrix remodeling and WNT/TGFB signatures, associated with poor outcome.

BACKGROUND AND AIMS: HCC, the third leading cause of cancer-related death, arises in the context of liver fibrosis. Although HCC is generally poorly fibrogenic, some tumors harbor focal intratumor extracellular matrix (ECM) deposits called "fibrous nests." To date, the molecular composition and clinical relevance of these ECM deposits have not been fully defined. APPROACH AND RESULTS: We performed quantitative matrisome analysis by tandem mass tags mass spectrometry in 20 human cancer specific matrisome (HCCs) with high or low-grade intratumor fibrosis and matched nontumor tissues, as well as in 12 livers from mice treated with vehicle, carbon tetrachloride, or diethylnitrosamine. We found 94 ECM proteins differentially abundant between high and low-grade fibrous nests, including interstitial and basement membrane components, such as several collagens, glycoproteins, proteoglycans, enzymes involved in ECM stabilization and degradation, and growth factors. Pathway analysis revealed a metabolic switch in high-grade fibrosis, with enhanced glycolysis and decreased oxidative phosphorylation. Integrating the quantitative proteomics with transcriptomics from HCCs and nontumor livers (n = 2,285 samples), we identified a subgroup of fibrous nest HCCs, characterized by cancer-specific ECM remodeling, expression of the WNT/TGFB (S1) subclass signature, and poor patient outcome. Fibrous nest HCCs abundantly expressed an 11-fibrous-nest - protein signature, associated with poor patient outcome, by multivariate Cox analysis, and validated by multiplex immunohistochemistry. CONCLUSIONS: Matrisome analysis highlighted cancer-specific ECM deposits, typical of the WNT/TGFB HCC subclass, associated with poor patient outcomes. Hence, histologic reporting of intratumor fibrosis in HCC is of clinical relevance.

Virtual voltage vector based predictive current control of speed sensorless induction motor drives.

Nowadays, predictive current control (PCC) strategy has been recognized as a promising option for the control of electric drives for their control flexibility, fast dynamic response and weighting factorless structure of objective function. However, such kinds of conventional control strategies make drives to suffer from the ingress of significant harmonics in stator current, increasing further the steady state flux ripple followed by a noticeable torque ripple. To ameliorate these aforementioned shortcomings of conventional scheme, the present work employs the concept of virtual voltage vector (V3) in PCC strategy. The mathematical steps of the proposed V3PCC make the scheme more frontward in delay compensation, and also less parameter sensitive than the conventional one. As a baseline for the performance analysis, the present V3PCC is compared with a weighting factorless V3 based predictive flux control (PFC) scheme in induction motor (IM) drive. A speed adaptive flux observer is considered for the speed estimation purpose in both the control schemes. The performance of both the sensorless schemes for IM drive are analysed in MATLAB/Simulink, and also experimentally verified in a 2.2 kW IM drive test bench.

COVID-19 related anxiety and its associated factors: a cross-sectional study on older adults in Bangladesh.

BACKGROUND: The COVID-19 pandemic has resulted in serious mental health conditions, particularly among older adults. This research explored the prevalence of COVID-19-related anxiety and its associated factors among older adults residing in Bangladesh. METHODS: This cross-sectional study was conducted among 1,045 older Bangladeshi adults aged ≥ 60 years through telephone interviews in September 2021. A semi-structured interview schedule was used to collect data on participants' characteristics and COVID-19-related anxiety. The anxiety level was measured using the Bengali version of the five-point Coronavirus Anxiety Scale (CAS). A linear regression model explored the factors associated with COVID-19-related anxiety. RESULTS: Overall, the prevalence of COVID-19-related anxiety was 23.2%. The regression analysis revealed that the average COVID-19-related anxiety score was significantly higher among females (ß: 0.43, 95% CI: 0.05 to 0.81), and among those who faced difficulty getting medicine (ß: 0.57, 95% CI: 0.16 to 0.97), felt isolated (ß: 0.60, 95% CI: 0.24 to 0.95), and felt requiring additional care during the pandemic (ß: 0.53, 95% CI: 0.16 to 0.91). Alternatively, the average COVID-19-related anxiety score was significantly lower among those who were widowed (ß: -0.46, 95% CI: -0.87 to -0.04) and living distant from the health centre (ß: -0.48, 95% CI: -0.79 to -0.17). CONCLUSION: The findings of the present study suggest providing immediate psychosocial support package to the older adults, particularly females and those who are vulnerable to receive health and social care support during the COVID-19 pandemic in Bangladesh.

Association of overweight and obesity with hypertension, diabetes and comorbidity among adults in Bangladesh: evidence from nationwide Demographic and Health Survey 2017-2018 data.

OBJECTIVES: The study aimed to determine the association of overweight and obesity with hypertension, diabetes and comorbidity among the adults of Bangladesh. STUDY DESIGN: This study used cross-sectional data from the nationally representative Bangladesh Demographic and Health Survey conducted in 2017-2018. The main outcome variables were hypertension, diabetes and comorbidity. Comorbidity was defined as the coexistence of hypertension and diabetes. Overweight and obesity, as measured by body mass index, were the main explanatory variables. The strength of the association was determined using the adjusted multiple logistic regression models. SETTING: Rural and urban areas in Bangladesh. PARTICIPANTS: The study included a total of 11 881 adults (5241 men and 6640 women) aged 18 years or older. RESULTS: The prevalence of hypertension, diabetes and comorbidity among the sample population were 28.5%, 9.9% and 4.5%, respectively. Among the respondents, 20.1% were overweight and 4.1% were obese. The risk of hypertension was 2.47 times more likely in the overweight group (adjusted OR (AOR) 2.47; 95% CI 2.22 to 2.75) and 2.65 times more likely in the obese group (AOR 2.65; 95% CI 2.16 to 3.26) compared with the normal or underweight group. Adults who were overweight and obese had 59% (AOR 1.59; 95% CI 1.37 to 1.84) and 88% (AOR 1.88; 95% CI 1.46 to 2.42) higher odds of having diabetes, respectively, than normal or underweight adults. Moreover, the risk of comorbidity was 2.21 times higher in overweight adults (AOR 2.21; 95% CI 1.81 to 2.71) and 2.86 times higher in obese adults (AOR 2.86; 95% CI 2.09 to 3.91) compared with normal or underweight adults. CONCLUSIONS: Using large-scale nationally representative data, we found that overweight and obesity were significantly associated with hypertension, diabetes and comorbidity. So, nationally representative data can be used for programme planning to prevent and treat these chronic conditions.

Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function.

BACKGROUND & AIMS: The gut-liver axis plays a key role in the pathogenesis of alcohol-associated liver disease (ALD). We demonstrated that Opn-/- develop worse ALD than wild-type (WT) mice; however, the role of intestinal osteopontin (OPN) in ALD remains unknown. We hypothesized that overexpression of OPN in intestinal epithelial cells (IECs) could ameliorate ALD by preserving the gut microbiome and the intestinal barrier function. METHODS: OpnKI IEC, OpnΔIEC, and WT mice were fed control or ethanol Lieber-DeCarli diet for 6 weeks. RESULTS: OpnKI IEC but not OpnΔIEC mice showed improved intestinal barrier function and protection from ALD. There were less pathogenic and more beneficial bacteria in ethanol-fed OpnKI IEC than in WT mice. Fecal microbiome transplant (FMT) from OpnKI IEC to WT mice protected from ALD. FMT from ethanol-fed WT to OpnKI IEC mice failed to induce ALD. Antimicrobial peptides, Il33, pSTAT3, aryl hydrocarbon receptor (Ahr), and tight-junction protein expression were higher in IECs from jejunum of ethanol-fed OpnKI IEC than of WT mice. Ethanol-fed OpnKI IEC showed more tryptophan metabolites and short-chain fatty acids in portal serum than WT mice. FMT from OpnKI IEC to WT mice enhanced IECs Ahr and tight-junction protein expression. Oral administration of milk OPN replicated the protective effect of OpnKI IEC mice in ALD. CONCLUSION: Overexpression of OPN in IECs or administration of milk OPN maintain the intestinal microbiome by intestinal antimicrobial peptides. The increase in tryptophan metabolites and short-chain fatty acids signaling through the Ahr in IECs, preserve the intestinal barrier function and protect from ALD.

Molecular surveillance for operationally relevant genetic polymorphisms in Plasmodium falciparum in Southern Chad, 2016-2017.

BACKGROUND: Resistance to anti-malarials is a serious threat to the efforts to control and eliminate malaria. Surveillance based on simple field protocols with centralized testing to detect molecular markers associated with anti-malarial drug resistance can be used to identify locations where further investigations are needed. METHODS: Dried blood spots were collected from 398 patients (age range 5-59 years, 99% male) with Plasmodium falciparum infections detected using rapid diagnostic tests over two rounds of sample collection conducted in 2016 and 2017 in Komé, South-West Chad. Specimens were genotyped using amplicon sequencing or qPCR for validated markers of anti-malarial resistance including partner drugs used in artemisinin-based combination therapy (ACT). RESULTS: No mutations in the pfk13 gene known to be associated with artemisinin resistance were found but a high proportion of parasites carried other mutations, specifically K189T (190/349, 54.4%, 95%CI 49.0-59.8%). Of 331 specimens successfully genotyped for pfmdr1 and pfcrt, 52% (95%CI 46.4-57.5%) carried the NFD-K haplotype, known to be associated with reduced susceptibility to lumefantrine. Only 20 of 336 (6.0%, 95%CI 3.7-9.0%) had parasites with the pfmdr1-N86Y polymorphism associated with increased treatment failures with amodiaquine. Nearly all parasites carried at least one mutation in pfdhfr and/or pfdhps genes but 'sextuple' mutations in pfdhfr-pfdhps including pfdhps -A581G were rare (8/336 overall, 2.4%, 95%CI 1.2-4.6%). Only one specimen containing parasites with pfmdr1 gene amplification was detected. CONCLUSIONS: These results provide information on the likely high efficacy of artemisinin-based combinations commonly used in Chad, but suggest decreasing levels of sensitivity to lumefantrine and high levels of resistance to sulfadoxine-pyrimethamine used for seasonal malaria chemoprevention and intermittent preventive therapy in pregnancy. A majority of parasites had mutations in the pfk13 gene, none of which are known to be associated with artemisinin resistance. A therapeutic efficacy study needs to be conducted to confirm the efficacy of artemether-lumefantrine.

Ablation of high-mobility group box-1 in the liver reduces hepatocellular carcinoma but causes hyperbilirubinemia in Hippo signaling-deficient mice.

Silencing the Hippo kinases mammalian sterile 20-like 1 and 2 (MST1/2) activates the transcriptional coactivator yes-associated protein (YAP) in human hepatocellular carcinoma (HCC). Hepatocyte-derived high-mobility group box-1 (HMGB1) regulates YAP expression; however, its contribution to HCC in the context of deregulated Hippo signaling is unknown. Here, we hypothesized that HMGB1 is required for hepatocarcinogenesis by activating YAP in Hippo signaling-deficient (Mst1/2ΔHep ) mice. Mst1/2ΔHep mice developed HCC within 3.5 months of age and had increased hepatic expression of HMGB1 and elevated YAP activity compared to controls. To understand the contribution of HMGB1, we generated Mst1/2&Hmgb1ΔHep mice. They exhibited decreased YAP activity, cell proliferation, inflammation, fibrosis, atypical ductal cell expansion, and HCC burden at 3.5 months compared to Mst1/2∆Hep mice. However, Mst1/2&Hmgb1ΔHep mice were smaller, developed hyperbilirubinemia, had more liver injury with intrahepatic biliary defects, and had reduced hemoglobin compared to Mst1/2ΔHep mice. Conclusion: Hepatic HMGB1 promotes hepatocarcinogenesis by regulation of YAP activity; nevertheless, it maintains intrahepatic bile duct physiology under Hippo signaling deficiency.

Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis.

Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte-derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome-based OPN correlation network was associated with HCC incidence along 10 years of follow-up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (OpnHep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (OpnΔHep ) expressed a similar phenotype. The acute response to DEN was reduced in OpnΔHep , which also showed more cancer stem/progenitor cells (CSCs, CD44+ AFP+ ) at 5 months. CSCs from OpnHep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from OpnHep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn-/- compared with wild-type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44-/- OpnHep Tg mice. Conclusions: Hepatocyte-derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro-tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation.

The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.