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Papillary thyroid cancer (PTC) is the 8th most common cancer among women overall. Licorice contains over 300 active compounds, many of them with anti-cancer properties. Glycyrrhetinic acid (GA) is a major component of licorice. The aim of this study was to investigate the potential anti-proliferative effects of licorice and GA on PTC cell cultures. Licorice extract (LE) was produced from the root and tested on BCPAP and K1 cell lines, as well as GA and aldosterone. We used the MTT test to investigate the anti-proliferative activity, the wound healing test for the migratory activity, and finally, we analyzed cell cycle distribution, apoptosis, and oxidative stress after LE, GA, or aldosterone incubation. Both LE and GA reduced cell viability at 48 h and cell migration at 24 h in both PTC cultures. Aldosterone reduced cell migration only in K1 cells. LE and GA induced cell cycle arrest in the G0/G1 phase in the BCPAP cell line, while LE and aldosterone induced it in the K1 culture. GA but not LE increased the apoptosis rate in both cell lines, whereas LE but not GA increased oxidative stress in both cultures. This study presents the first evidence of the in vitro anti-proliferative and anti-migratory activity of LE and GA on PTC. [ABSTRACT FROM AUTHOR]

Nowadays, emissions from internal combustion engines are a relevant topic of investigation, taking into account the continuous reduction of emission limits imposed by environmental regulatory agencies around the world, obviously as the result of earnest studies that have pointed out the impact on the human health of high levels of contaminants released into the environment. Over recent years, the use of biofuels has contributed to attenuating this environmental issue; however, new problems have been raised, such as NOx emissions tend to increase as the biofuel percentage in the fuel used in engines increases. In this research, the emissions of a compression ignition internal combustion engine modeled as a variable volume reactor with homogeneous combustion were numerically investigated. To analyze the combustion process, a detailed kinetics model tailored specifically for this purpose was used. The kinetics model comprised 30,975 chemical reactions involving 691 chemical species. Mixtures of fuel surrogates were then created to represent the fuel used in the Brazilian fuel marketplace, involving (i) fossil diesel—"diesel A", (ii) soybean diesel—"biodiesel", and (iii) hydrotreated vegetable oil— "HVO". Surrogate species were then selected for each of the aforementioned fuels, and blends of those surrogates were then proposed as mixture M1 (diesel A:biodiesel:HVO—90:10:0), mixture M2 (diesel A:biodiesel:HVO—85:15:0), and mixture M3 (diesel A:biodiesel:HVO—80:15:5). The species allowed in the kinetics model included all the fuel surrogates used in this research as well as the target emission species of this study: total hydrocarbons, non-methane hydrocarbons, carbon monoxide, methane, nitrogen oxides, carbon dioxide, soot, and soot precursors. When compared to experimental trends of emissions available in the literature, it was observed that, for all the proposed fuel surrogates blends, the numerical approach performed in this research was able to capture qualitative trends for engine power and the target emissions in the whole ranges of engine speeds and engine loads, despite the CO and NOx emissions at specific engine speeds and loads. [ABSTRACT FROM AUTHOR]

Resistance training (RT) can ameliorate outcomes related to sarcopenia by promoting beneficial changes in muscular strength, skeletal muscle mass (SMM), and muscle quality. This study compared the effects of 12 weeks of RT performed 2 and 3 sessions a week on body composition, muscular strength, muscle quality, and metabolic biomarkers in sarcopenic older women. Thirty-four sarcopenic older women (>60 years) were randomly assigned to perform a whole-body RT program, either 2 (G2X, n = 18) or 3 (G3X, n = 16) sessions a week during 12 weeks (8 exercises, single set of 10-15 repetitions). Body composition, muscular strength, muscle quality, and metabolic biomarkers were assessed before and after the intervention. Both groups increased (p < 0.05) 1 repetition maximum total muscular strength (G2X = +20.4% and G3X = +21.0%), SMM (G2X = +4.0% and G3X = +7.0%), and improved muscle quality (G2X = +16.7% and G3X = +13.6%), with no differences between groups (p > 0.05). No change overtime was found for IGF-1 and testosterone (p > 0.05). Our results suggest that 12 weeks of RT performed at a lower weekly frequency is as effective as a higher frequency in improving muscular strength, SMM, and muscle quality in sarcopenic older women. [ABSTRACT FROM AUTHOR]

This article discusses a case of Wieacker-Wolff syndrome (WRWS), an ultra-rare X-linked disorder characterized by congenital multiplex arthrogryposis (CMA), in a female patient. WRWS is caused by pathogenic variants in the ZC4H2 gene, which is involved in nervous system development. The syndrome is associated with a wide range of symptoms, including neurological, endocrinological, and cardiac involvement. This case report highlights the multisystemic nature of the syndrome and suggests that heart assessment should be included in the follow-up of female patients. [Extracted from the article]

Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of licorice, glycyrrhetinic acid (GA), which acts by blocking the 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor (MR) as an agonist. The management of licorice-induced PHA depends on several individual factors, such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism. The clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with MR blockers and potassium supplements. Through this case series of licorice-induced PHA, we aim to increase awareness about exogenous PHA, and the possible risk associated with excess intake of licorice. An accurate history is mandatory in patients with hypertension and hypokalemia to avoid unnecessary testing. GA is a component of several products, such as candies, breath fresheners, beverages, tobacco, cosmetics, and laxatives. In recent years, the mechanisms of action of licorice and its active compounds have been better elucidated, suggesting its benefits in several clinical settings. Nevertheless, licorice should still be consumed with caution, considering that licorice-induced PHA is still an underestimated condition, and its intake should be avoided in patients with increased risk of licorice toxicity due to concomitant comorbidities or interfering drugs. [ABSTRACT FROM AUTHOR]

We study the causal effect of mood on the productivity of call-center workers. Mood is measured through an online "mood questionnaire" which the workers are encouraged to fill out daily. We find that better mood actually decreases worker productivity for workers whose compensation is largely fixed. The negative effect of mood is attenuated for workers whose compensation is based on performance (high-powered incentives). This finding holds both at a correlational level and in two IV settings, where mood is instrumented for by weather or, alternatively, by whether the local professional sports team played/won the day before. We rule out a number of threats to the exclusion restrictions, and discuss the mechanisms that could generate our findings (JEL J24, J28, M52, C26). [ABSTRACT FROM AUTHOR]

This article provides a comprehensive overview of the assessment and treatment of reflux-like symptoms in the community. It emphasizes the limitations of using proton pump inhibitors (PPIs) as a first-line treatment and advocates for a holistic approach that considers various factors contributing to symptoms. The article offers practical strategies for patients to identify triggers and provides tailored lifestyle advice. The goal is to empower patients to manage their symptoms through a combination of treatments and self-care practices. The article also highlights the potential for collaboration between primary care and community pharmacies to support patients. Further research in this area is needed. [Extracted from the article]

The β-cell plays a crucial role in the pathogenesis of type 1 diabetes, in part through the posttranslational modification of self-proteins by biochemical processes such as deamidation. These neoantigens are potential triggers for breaking immune tolerance. We report the detection by LC-MS/MS of 16 novel Gln and 27 novel Asn deamidations in 14 disease-related proteins within inflammatory cytokine–stressed human islets of Langerhans. T-cell clones responsive against one Gln- and three Asn-deamidated peptides could be isolated from peripheral blood of individuals with type 1 diabetes. Ex vivo HLA class II tetramer staining detected higher T-cell frequencies in individuals with the disease compared with control individuals. Furthermore, there was a positive correlation between the frequencies of T cells specific for deamidated peptides, insulin antibody levels at diagnosis, and duration of disease. These results highlight that stressed human islets are prone to enzymatic and biochemical deamidation and suggest that both Gln- and Asn-deamidated peptides can promote the activation and expansion of autoreactive CD4+ T cells. These findings add to the growing evidence that posttranslational modifications undermine tolerance and may open the road for the development of new diagnostic and therapeutic applications for individuals living with type 1 diabetes. Article Highlights: Posttranslationally modified neoantigens are formed in β-cells under conditions of inflammation, but studies to date have focused on a limited number of antigens. We sought to identify disease-relevant β-cell neoantigens through unbiased proteomic analysis and confirmation by antigen-specific T-cell assays. We detected novel Gln and Asn deamidations within 14 type 1 diabetes–related proteins in cytokine-stressed human islets and verified disease-associated T-cell recognition for three corresponding epitopes. These results demonstrate that both enzymatic and biochemical deamidation in cytokine-exposed islets undermine self-tolerance and lay a foundation for new diagnostic and therapeutic approaches for individuals living with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. Methods: We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. Results: Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis. Conclusions: Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids. -ATVUCqmTNz-ui1hDGfVzb Video Abstract [ABSTRACT FROM AUTHOR]

Background: Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. Methods: We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. Results: Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis. Conclusions: Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids. -ATVUCqmTNz-ui1hDGfVzb Video Abstract [ABSTRACT FROM AUTHOR]

This document is a letter to the editor of the journal Neurological Sciences. It discusses the diagnosis of a rare form of congenital myopathy in an 8-year-old girl. The case highlights the importance of clinical phenotype and next-generation sequencing in diagnosing rare muscular diseases. The girl presented with symptoms such as congenital hypotonia, respiratory issues, cardiac involvement, and delayed motor and cognitive development. Through genetic testing, a homozygous deletion in the TRIP4 gene was identified, leading to a diagnosis of TRIP4 myopathy. The letter emphasizes the need for further research and genetic screening in cases of congenital myopathy and muscular dystrophy. [Extracted from the article]

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue. [ABSTRACT FROM AUTHOR]

In this article we present the results obtained applying the multiple scale expansion up to the order ε6 to a dispersive multilinear class of equations on a square lattice depending on 13 parameters. We show that the integrability conditions given by the multiple scale expansion give rise to 4 nonlinear equations, 3 of which seem to be new, depending at most on 2 parameters. [ABSTRACT FROM AUTHOR]

Background. To assess the associations between anxiety and depressive symptoms and post- COVID-19 condition (PCC) by exploring the direction of these associations and their relevance in the definition of PCC. Methods. Nationwide survey among French adults, recruited between March and April, 2022, using a quota method to capture a representative sample of the general population with regard to sex, age, socioeconomic status, size of the place of residence, and region. We included all participants who met the World Health Organization (WHO) definition of PCC in addition to a random sample of participants infected with SARS-COV-2 for at least 3 months but without PCC. Self-reported anxiety and depressive symptoms, chronic anxiety and depression (for more than 3 years), and anxiety and depression were measured using the GAD-2 and PHQ-2 questionnaires, respectively. Results. In a sample of 1,095 participants with PCC and 1,021 participants infected with SARSCOV- 2 without PCC, 21% had self-reported anxiety and 18% self-reported depression, whereas 33% and 20% had current measured symptoms of anxiety and depression, respectively. The high prevalence of these symptoms cannot only be explained by the characterization of PCC, as only 13.4% of anxiety symptoms and 7.6% of depressive symptoms met the WHO criteria for PCC. Only one participant met the WHO criteria based on self-reported anxiety or depressive symptoms alone, as these were always combined with other symptoms in patients with PCC. Chronic symptoms were associated with PCC (aOR 1.27; 95% CI: 1.00-1.61). In addition, measured anxiety was associated with PCC (aOR = 1.29; 95% CI: 1.02-1.62). Conclusions. Pre-COVID-19 chronic anxiety and depression may play a role in the development of PCC or share vulnerability factors with it. Our results challenge the inclusion of anxiety and depression in the definition of PCC. [ABSTRACT FROM AUTHOR]

We describe the development and validation of an HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple-negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30 mg/Kg daily) in six-week-old severe combined immunodeficiency disease (SCID) mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 h (6.47 and 9.01 μM, respectively) and 24 h (0.13 and 0.16 μM, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 h (15.06 and 8.72 μM, respectively) and 24 h (0.17 and 0.17 μM, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-life after acute and chronic treatment ranged between 4.4–7.1 h (plasma) and 4.5–5.0 h (tumour) for ZST316, and 4.2–5.3 h (plasma) and 3.6–4.9 h (tumour) for L-257. The results of our study demonstrate the (a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, (b) rapid conversion of ZST316 into L-257, (c) good intra-tumour penetration of both compounds, and (d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. Compared to a previous method developed by our group to investigate ZST316 in plasma, the main advantages of the new method include a wider range of linearity which reduces the need for dilutions and the combined assessment of ZST316 and L-257 in plasma and tumour tissue which limits the required amount of matrix. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC. [ABSTRACT FROM AUTHOR]

Mercury is one of the most dangerous contaminants on the planet. In recent years, evidence of mercury contamination in the Amazon has significantly increased, notably due to gold-mining activities. Although mercury contamination in fish has consistently been documented, little is known about the risk associated with fish consumption by populations in urban areas of the Amazon. We sampled 1010 fish sold in public markets in six state capitals and 11 additional cities. Mercury levels were determined for each specimen, and the evaluation of the health risks associated with consuming mercury-contaminated fish was conducted according to the methodology proposed by the World Health Organization (WHO). Our study reveals that more than one-fifth (21.3%) of the fish sold in urban centers had mercury levels above the safe limits (≥0.5 µg/g) established by the Brazilian Health Surveillance Agency (ANVISA). The prevalence of Hg contamination ≥0.5 µg/g was approximately 14 times higher in carnivorous than in noncarnivorous fish. The analysis of the risk attributable to fish consumption reveals that daily mercury intake exceeded the reference dose recommended by the U.S. EPA in all population groups analyzed, reaching up to 7 and 31 times in women of childbearing age and children from 2 to 4 years old, respectively. However, these risks are diverse depending on the type of fish consumed and must be considered to formulate appropriate nutritional guidelines for safe fish consumption by the local community. [ABSTRACT FROM AUTHOR]

This document is a response to a letter from Tapia-Castillo et al regarding a previous commentary. The authors discuss the expression of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in liver and visceral adipose tissue in extremely obese subjects. They found that there was an overexpression of 11βHSD1 in the liver, but peripheral cortisol levels remained normal due to hepatic metabolism. The authors also discuss the inflammatory effect of high amounts of aldosterone in mononuclear leukocytes (MNLs) and the role of NAD and NADP in regulating 11βHSD1 function. They conclude that the regulation of cortisol and cortisone levels is complex and involves various factors. [Extracted from the article]

Aims/hypothesis: TNF-α plays a role in pancreatic beta cell loss in type 1 diabetes mellitus. In clinical interventions, TNF-α inhibition preserves C-peptide levels in early type 1 diabetes. In this study we evaluated the crosstalk of TNF-α, as compared with type I IFNs, with the type 1 diabetes candidate gene PTPN2 (encoding protein tyrosine phosphatase non-receptor type 2 [PTPN2]) in human beta cells. Methods: EndoC-βH1 cells, dispersed human pancreatic islets or induced pluripotent stem cell (iPSC)-derived islet-like cells were transfected with siRNAs targeting various genes (siCTRL, siPTPN2, siJNK1, siJNK3 or siBIM). Cells were treated for 48 h with IFN-α (2000 U/ml) or TNF-α (1000 U/ml). Cell death was evaluated using Hoechst 33342 and propidium iodide staining. mRNA levels were assessed by quantitative reverse transcription PCR (qRT-PCR) and protein expression by immunoblot. Results: PTPN2 silencing sensitised beta cells to cytotoxicity induced by IFN-α and/or TNF-α by 20–50%, depending on the human cell model utilised; there was no potentiation between the cytokines. We silenced c-Jun N-terminal kinase (JNK)1 or Bcl-2-like protein 2 (BIM), and this abolished the proapoptotic effects of IFN-α, TNF-α or the combination of both after PTPN2 inhibition. We further observed that PTPN2 silencing increased TNF-α-induced JNK1 and BIM phosphorylation and that JNK3 is necessary for beta cell resistance to IFN-α cytotoxicity. Conclusions/interpretation: We show that the type 1 diabetes candidate gene PTPN2 is a key regulator of the deleterious effects of TNF-α in human beta cells. It is conceivable that people with type 1 diabetes carrying risk-associated PTPN2 polymorphisms may particularly benefit from therapies inhibiting TNF-α. [ABSTRACT FROM AUTHOR]

Response to fertilisation with biochar is greatest in field crops on acidic tropical soils, but limited information is available for vegetable crops. As a case-study using vegetable production in Timor-Leste, we assessed if biochar alleviates nutritional constraints to vegetables in low-nutrient soils. Field trials on vegetable crops were conducted with fertiliser combinations of rice husk biochar, phosphate and local fertiliser at three sites. A pot soil incubation trial of biochar was undertaken with soil from the acid site, where rice husk biochar had a larger effect on productivity than the other fertilisers in chili pepper, tomato and soybean with an average yield increase with biochar of 230% over control. Combining phosphate with biochar augmented the yield over biochar alone in chili pepper, tomato and soybean. At neutral and alkaline sites, fertilisation with biochar lifted mean yield over the control. Soil constraints alleviated by fertiliser were primarily from P and Zn deficiencies. Marked increases in vegetable yields, among the highest globally, were achieved with fertilisation with biochar individually and in combination with phosphate in low nutrient soil in Timor-Leste. Clearly, rice husk biochar is a promising avenue to fertilise the soil with P and Zn and increase crop productivity in Timor-Leste. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. Methods: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. Results: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10−9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. Conclusions/interpretation: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. Data availability: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal (https://t2d.hugeamp.org/downloads.html) and through the GWAS catalog (https://www.ebi.ac.uk/gwas/, accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog (https://www.pgscatalog.org, publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445). [ABSTRACT FROM AUTHOR]

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Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults. [ABSTRACT FROM AUTHOR]

Improvements in sodium intercalation in sodium cathodes have been debated in recent years. In the present work, we delineate the significant effect of the carbon nanotubes (CNTs) and their weight percent in the intercalation capacity of the binder-free manganese vanadium oxide (MVO)-CNTs composite electrodes. The performance modification of the electrode is discussed taking into account the cathode electrolyte interphase (CEI) layer under optimal performance. We observe an intermittent distribution of the chemical phases on the CEI, formed on these electrodes after several cycles. The bulk and superficial structure of pristine and Na + cycled electrodes were identified via micro-Raman scattering and Scanning X-ray Photoelectron Microscopy. We show that the inhomogeneous CEI layer distribution strongly depends on the CNTs weight percentage ratio in an electrode nano-composite. The capacity fading of MVO-CNTs appears to be associated with the dissolution of the Mn 2 O 3 phase, leading to electrode deterioration. This effect is particularly observed in electrodes with low weight percentage of the CNTs in which the tubular topology of the CNTs are distorted due to the MVO decoration. These results can deepen the understanding of the CNTs role on the intercalation mechanism and capacity of the electrode, where there are variations in the mass ratio of CNTs and the active material. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-βH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown. Methods: We enrolled 82 individuals, male or female, non-diabetic or diabetic, from different origins, in different supervised training protocols for 8–12 weeks (including training at home during the COVID-19 pandemic). EndoC-βH1 cells were treated with 'exercised' serum or with the exerkine clusterin to ascertain cytoprotection from ER stress. Results: The exercise interventions were effective and improved V ̇ O 2 peak values in both younger and older, non-obese and obese, non-diabetic and diabetic participants. Serum obtained after training conferred significant beta cell protection (28% to 35% protection after 4 and 8 weeks of training, respectively) from severe ER stress-induced apoptosis. Cytoprotection was not affected by the type of exercise training or participant age, sex, BMI or ancestry, and persisted for up to 2 months after the end of the training programme. Serum from exercised participants with type 1 or type 2 diabetes was similarly protective. Clusterin reproduced the beneficial effects of exercised sera. Conclusions/interpretation: These data uncover the unexpected potential to preserve beta cell health by exercise training, opening a new avenue to prevent or slow diabetes progression through humoral muscle–beta cell crosstalk. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and increased cardiovascular risk. Recent studies suggest a possible role of aldosterone as a pro-inflammatory hormone in the pathogenesis of the disease. Cortisol is also an important mediator of stress reaction, but its role is controversial in endometriosis. The aim of this study was to evaluate aldosterone and cortisol levels and blood pressure values in women with endometriosis. We measured blood pressure, plasma aldosterone, renin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) in 20 women with untreated minimal or mild pelvic endometriosis compared with 20 healthy controls matched for age and body mass index. Aldosterone values were similar in the two groups, while renin was significantly lower and the aldosterone to renin ratio was significantly higher in patients with endometriosis than in controls. Systolic blood pressure was in the normal range, but significantly higher in patients with endometriosis. Morning plasma cortisol was normal, but significantly lower in patients with endometriosis compared with controls, while DHEAS to cortisol ratio was similar in the two groups. These preliminary results are evidence of increased biological aldosterone activity and dysregulation of the hypothalamic-pituitary-adrenal axis in early stages of endometriosis. These alterations could play a role in disease development, suggesting new therapeutic targets for aldosterone receptor blockers. [ABSTRACT FROM AUTHOR]

A recent discovery effort resulted in identification of novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documentation of their recognition by CD8+ T cells from peripheral blood and human islets. In the current study, we applied a systematic discovery process to identify novel CD4+ T cell epitopes derived from these candidate antigens. We predicted 145 potential epitopes spanning unique splice junctions and within conventional secretory granule antigens and measured their in vitro binding to DRB1*04:01. We generated HLA class II tetramers for the 35 peptides with detectable binding and used these to assess immunogenicity and isolate T cell clones. Tetramers corresponding to peptides with verified immunogenicity were then used to label T cells specific for these putative epitopes in peripheral blood. T cells that recognize distinct epitopes derived from a cyclin I splice variant, neuroendocrine convertase 2, and urocortin-3 were detected at frequencies that were similar to those of an immunodominant proinsulin epitope. Cells specific for these novel epitopes predominantly exhibited a Th1-like surface phenotype. Among the three epitopes, responses to the cyclin I peptide exhibited a distinct memory profile. Responses to neuroendocrine convertase 2 were detected among pancreatic infiltrating T cells. These results further establish the contribution of unconventional antigens to the loss of tolerance in autoimmune diabetes. [ABSTRACT FROM AUTHOR]

In acute ischemic stroke (AIS), there are no data on whether oxidative stress biomarkers have effects above and beyond known risk factors and measurements of stroke volume. This study was conducted in 122 mild-moderate AIS patients and 40 controls and assessed the modified ranking scale (mRS) at baseline, and 3 and 6 months later. We measured lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products, paraoxonase 1 (PON1) activities and PON1 Q192R genotypes, high density lipoprotein cholesterol (HDL), sulfhydryl (-SH) groups), and diffusion-weighted imaging (DWI) stroke volume and fluid-attenuated inversion recovery (FLAIR) signal intensity. We found that (a) AIS is characterized by lower chloromethyl acetate CMPAase PON1 activity, HDL and -SH groups and increased LOOH and neurotoxicity (a composite of LOOH, inflammatory markers and glycated hemoglobin); (b) oxidative and antioxidant biomarkers strongly and independently predict mRS scores 3 and 6 months later, DWI stroke volume and FLAIR signal intensity; and (c) the PON1 Q192R variant has multiple effects on stroke outcomes that are mediated by its effects on antioxidant defenses and lipid peroxidation. Lipid peroxidation and lowered -SH and PON1-HDL activity are drug targets to prevent AIS and consequent neurodegenerative processes and increased oxidative reperfusion mediators due to ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Successful water management is critical to achieving high performance in proton exchange membrane fuel cells (PEMFCs). The relatively high sensitivity of terahertz radiation to liquid water is promising as a complementary alternative for flooding detection in PEMFCs. Using a novel, commercially available terahertz source and camera, this paper investigates the feasibility of a compact and low‐cost terahertz imaging system for visualizing water build‐up inside an operating PEMFC, supported by simultaneous high‐resolution optical imaging. Several phenomena of water accumulation and transport, such as membrane hydration, main droplet appearance, water pool formation, growth, and eventual flush out by gases are imaged by terahertz imaging. These results agree with optical imaging and cell voltage readings. The proposed setup is also able to distinguish the effect of different air flow rates. [ABSTRACT FROM AUTHOR]

Background and Purpose: Endoplasmic reticulum (ER) stress triggers an adaptive response in tumours which fosters cell survival and resilience to stress. Activation of the ER stress response, through its PERK branch, promotes phosphorylation of the α‐subunit of the translation initiation factor eIF2, thereby repressing general protein translation and augmenting the translation of ATF4 with the downstream CHOP transcription factor and the protein disulfide oxidase, ERO1‐alpha Experimental Approach: Here, we show that ISRIB, a small molecule that inhibits the action of phosphorylated eIF2alpha, activating protein translation, synergistically interacts with the genetic deficiency of protein disulfide oxidase ERO1‐alpha, enfeebling breast tumour growth and spread. Key Results: ISRIB represses the CHOP signal, but does not inhibit ERO1. Mechanistically, ISRIB increases the ER protein load with a marked perturbing effect on ERO1‐deficient triple‐negative breast cancer cells, which display impaired proteostasis and have adapted to a low client protein load in hypoxia, and ERO1 deficiency impairs VEGF‐dependent angiogenesis. ERO1‐deficient triple‐negative breast cancer xenografts have an augmented ER stress response and its PERK branch. ISRIB acts synergistically with ERO1 deficiency, inhibiting the growth of triple‐negative breast cancer xenografts by impairing proliferation and angiogenesis. Conclusion and Implications: These results demonstrate that ISRIB together with ERO1 deficiency synergistically shatter the PERK‐dependent adaptive ER stress response, by restarting protein synthesis in the setting of impaired proteostasis, finally promoting tumour cytotoxicity. Our findings suggest two surprising features in breast tumours: ERO1 is not regulated via CHOP under hypoxic conditions, and ISRIB offers a therapeutic option to efficiently inhibit tumour progression in conditions of impaired proteostasis. [ABSTRACT FROM AUTHOR]

Introduction: Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation. Methods: Using high-throughput RNA sequencing data from human islets and EndoC-βH1 cells exposed to IFNα or IFNg/IL1β, we evaluated the role of ADAR1 in human pancreatic β cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing. Results: We show that both IFNα and IFNγ/IL1β stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-βH1 cells as well as in primary human islets. Discussion: We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the β cell transcriptome under inflammatory conditions. [ABSTRACT FROM AUTHOR]

We show that Steklov eigenfunctions in a bounded Lipschitz domain have wavelength dense nodal sets near the boundary, in contrast to what can happen deep inside the domain. Conversely, in a 2D Lipschitz domain |$\Omega $|⁠ , we prove that any nodal domain of a Steklov eigenfunction contains a half-ball centered at |$\partial \Omega $| of radius |$c_{\Omega }/{\lambda }$|⁠. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) have recently been implicated in impaired β-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-βH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human β cells. We identified ~5000 β-cell-expressed circRNAs, of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed the enrichment of cytokine signaling pathways, indicative of circRNA transcription from inflammatory genes in response to cytokines. Multiple binding sites for β-cell-enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as 'sponges' or 'decoys'. We also present evidence for circRNA sequence conservation in multiple species, the presence of cytokine-induced regulatory elements, and putative protein-coding potential for the DE circRNAs. This study highlights the complex regulatory potential of circRNAs, which may play a crucial role during immune-mediated β-cell destruction in type 1 diabetes. [ABSTRACT FROM AUTHOR]

We study workers who are employed by a large US retailer, work in many store locations, and are paid based on performance. By means of a border-discontinuity analysis, we document that workers become more productive and are terminated less often after a minimum wage increase. These effects are stronger among workers whose pay is more often supported by the minimum wage. However, when workers are monitored less intensely, the minimum wage depresses productivity. We interpret these findings through an efficiency wage model. After a minimum wage increase, profits decrease, and a calibration exercise suggests that worker welfare increases. [ABSTRACT FROM AUTHOR]

Background: The degree of immunosuppression required for adequate graft‐versus‐host disease (GVHD) prevention, while keeping an adequate graft‐versus‐leukemia effect, in children with acute leukemia has not been established. We report the results of a retrospective comparison of cyclosporine levels and relapse rate in children and adolescents with acute lymphoblastic leukemia (ALL). Methods: Patients <21 y/o with ALL in remission who underwent TBI‐based hematopoietic cell transplantation from related or unrelated donors between 2008 and 2021 were included. Cyclosporine levels were measured twice a week and we calculated the area under the curve (AUC) from D0 to D + 7, D + 14, and D + 21. Results: We included 76 patients. There was a trend towards a lower incidence of relapse in patients with a mean AUC < 200 ng/ml at D + 21 (HR = 0.41; p =.08). The 5‐year relapse rate was 26.9% for patients with a mean AUC < 200 ng/ml at D + 21 and 43.9% for patients with a mean AUC≥200 ng/ml at D + 21. Relapse protection was restricted to relapses happening after D + 120 (HR = 0.21; p =.04). Conclusions: Our results show evidence that pediatric patients with ALL might benefit from lower cyclosporine levels between D0 and D + 21 without a detectable increase in GVHD. Large prospective studies comparing different cyclosporine levels are awaited. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases and alternative donors, including haploidentical, play a significant role in HCT. Despite the increasing use of haplo-HCT with PTCy, some questions remain open. The objective of the present study was to investigate risk factors for adverse outcomes after haplo-HCT with PTCy. This is a retrospective study conducted at two Brazilian centers. A total of 103 patients with hematologic malignancies who underwent first allogeneic, haploidentical HCT with PTCy were included. Risk factors for death were age at transplant (HR = 1.03 for each year; p = 0.002) and high/very high disease risk index (DRI; HR = 2.77; p = 0.0007) and mother as the donor compared with other donors (HR = 3.53; p = 0.005). In multivariate analysis, PFS was significantly poorer for older patients (HR = 1.02; p = 0.006), high/very high DRI (HR = 2.39; p = 0.003), and mother as the donor compared with other donors (HR = 3.18; p = 0.006). Relapse rate was higher for high/very high DRI (HR = 4.01; p = 0.002) and mother as the donor compared with other donors (HR = 2.52; p = 0.05). NRM was higher for older patients (HR = 1.03 for each year; p = 0.03). Tacrolimus was a protective factor for grades II–IV aGVHD (HR = 0.46; p = 0.04) compared with cyclosporine. Peripheral blood (PBSC) was a risk factor for cGVHD (HR = 3.48; p = 0.006), while tacrolimus was protective (HR = 0.30; p = 0.009). Mother as the donor compared with other donors was also a risk factor for poorer OS, PFS, and relapse, suggesting that this combination should be avoided. Tacrolimus was protective for both grades II–IV aGVHD and cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse. Prospective studies comparing tacrolimus with cyclosporine are awaited. [ABSTRACT FROM AUTHOR]

Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D. [ABSTRACT FROM AUTHOR]

Background: Preterm extremely low birth weight infants (ELBWi) are known to be at greater risk of developing neuropsychiatric diseases. Identifying early predictors of outcome is essential to refer patients for early intervention. Few studies have investigated neurodevelopmental outcomes in Italian ELBWi. This study aims to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year single-center cohort of Italian ELBWi and to identify early risk factors for adverse neurodevelopmental outcomes. Methods: All infants born with birth weight < 1000 g and admitted to the Neonatal Intensive Care Unit of the "Fondazione IRCCS Policlinico San Matteo" hospital in Pavia, Italy, from Jan 1, 2005 to Dec 31, 2015 were eligible for inclusion. At 24 months, Griffiths' Mental Developmental Scales Extended Revised (GMDS-ER) were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). Univariate and multivariate multinomial logistic regression models were performed to analyze the correlation between neonatal variables and neurodevelopmental outcome. Results: 176 ELBWi were enrolled (mean gestational age 26.52 weeks sd2.23; mean birthweight 777.45 g sd142.89). 67% showed a normal outcome at 24 months, 17% minor sequelae and 16% major sequelae (4.6% cerebral palsy on overall sample). The most frequent major sequela was cognitive impairment (8.52%). In the entire sample the median score on the Hearing-Speech subscale was lower than the median scores recorded on the other subscales and showed a significantly weaker correlation to each of the other subscales of the GMDS-ER. Severely abnormal cUS findings (RRR 10.22 p 0.043) and bronchopulmonary dysplasia (RRR 4.36 p 0.008) were independent risk factors for major sequelae and bronchopulmonary dysplasia for minor sequelae (RRR 3.00 p 0.018) on multivariate multinomial logistic regression. Conclusions: This study showed an improvement in ELBWI survival rate without neurodevelopmental impairment at 24 months compared to previously reported international cohorts. Cognitive impairment was the most frequent major sequela. Median scores on GMDS-ER showed a peculiar developmental profile characterized by a selective deficit in the language domain. Severely abnormal cUS findings and bronchopulmonary dysplasia were confirmed as independent risk factors for major sequelae. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) has been considered a relentlessly worsening disease, due to the progressive deterioration of the pancreatic beta cell functional mass. Recent evidence indicates, however, that remission of T2D may occur in variable proportions of patients after specific treatments that are associated with recovery of beta cell function. Here we review the available information on the recovery of beta cells in (a) non-diabetic individuals previously exposed to metabolic stress; (b) T2D patients following low-calorie diets, pharmacological therapies or bariatric surgery; (c) human islets isolated from non-diabetic organ donors that recover from "lipo-glucotoxic" conditions; and (d) human islets isolated from T2D organ donors and exposed to specific treatments. The improvement of insulin secretion reported by these studies and the associated molecular traits unveil the possibility to promote T2D remission by directly targeting pancreatic beta cells. [ABSTRACT FROM AUTHOR]