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• How do stocks respond to environmental, social, and governance (ESG) regulatory interventions? • How do ESG reputations influence the magnitude of such responses? • How establishing a mandate for "reasonable assurance" on ESG affected returns • ESG scores positively shielded firm-level investor reactions • Governance component most influential How do stocks respond to environmental, social, and governance (ESG) regulatory interventions, and in what way do ESG reputations influence the magnitude of such responses? Through an event study approach, we investigate how establishing a mandate for "reasonable assurance" on ESG metrics affected market and firm-level returns in India. Findings reveal persistent negative post-event cumulative abnormal market returns declining to –1.20 % during the [+1,+5] window. The imposition of the reasonable assurance mandate depressed the market. However, consistent with a reservoir of goodwill hypothesis, ESG scores positively shielded firm-level investor reactions, with the governance component of ESG being the most influential. [ABSTRACT FROM AUTHOR]

• Investigate whether the energy market signals a common trend toward volatility among green, brown, and sustainable energy indices. • Commonality among green energy indices is highest over others exhibiting similar characteristics. • The brown energy market possesses the least commonality, with heterogeneity among the brown energy indices. • The Paris Agreement lowered commonality in volatility across green and brown energy markets, thereby reducing risk exposure. Based on research conducted by Chordia et al. in 2000, we analyzed the volatility of energy indices to determine whether there is a commonality among them. Our dataset included green, sustainable, and brown energy indices, and we discovered that there is indeed a commonality in energy markets, with brown energy exhibiting the least commonality. Furthermore, we found that the commonality in volatility among energy markets has decreased since the Paris Agreement was signed. These results indicate that the Paris Agreement and other global policy initiatives are crucial for energy markets. [ABSTRACT FROM AUTHOR]

• Impact of macroeconomic tail risk on individual stock idiosyncratic volatility. • Macroeconomic tail risk positively impacts stock idiosyncratic volatility. • Divergences of opinions among investors intensifies effects. • Effect only present in assets with positive macroeconomic tail risk beta. We explore whether macroeconomic tail risk (MTR) is contagious at the individual stock level. We find that macroeconomic tail risk exacerbates stock idiosyncratic volatility. An increase in macroeconomic tail risk by one standard deviation is associated with an average increase in idiosyncratic volatility by 5.10%. Further, divergence of opinion intensifies the macro to stock idiosyncratic risk contagion. Results show that the positive impact of macroeconomic tail risk on idiosyncratic volatility is only observed in assets with positive MTR beta, indicating that risk-averse hedging trading behavior of investors during macroeconomic downturns is the potential reason for the macro-individual risk contagion. [ABSTRACT FROM AUTHOR]

• Investigate how tokenization impacts financial investments in transport and travel/tourism. • Utilizes quantile vector autoregressive (VAR) approach to analyze return connectedness. • Findings reveal varying connectedness between sectors at different quantiles, influenced by macroeconomic and pandemic factors. • Indicates a nonlinear and asymmetric relationship, with heightened connectedness during COVID-19. The advent of tokenization has transformed the financial landscape of the transportation and tourism industries, creating novel investment opportunities in travel and tourism tokens. This study investigates the interplay between transport and travel/tourism tokens using a quantile vector autoregressive (VAR) approach. Our findings indicate that the return connectedness varies across different quantiles. We also find that the connectedness varies over time and is influenced by macroeconomic and pandemic-related factors. Our results have important implications for token investors, issuers, regulators, and policymakers. [ABSTRACT FROM AUTHOR]

• Investigate whether markets in happier countries are less affected by tragic events. • 71 global stock market indices; an event study. • Immediate impact of the Israel–Hamas conflict on stock market returns. • Stock indices from happier nations are more resilient to geopolitical events. Do happier people care more, or less, about other people's problems? Indirectly to this question we investigate whether markets in happier countries are less affected by tragic events. Using a sample of 71 global stock market indices, we employ an event study method to analyze the immediate impact of the Israel–Hamas conflict on stock market returns. We find that stock indices from happier nations are more resilient to this geopolitical event. While the overall cumulative effect of the war remained largely negative, the Europe, Middle East, and Africa markets demonstrated heightened vulnerability to the conflict. [ABSTRACT FROM AUTHOR]

Autoimmunity can develop from an often undetermined interplay of genetic and environmental factors. Rare forms of autoimmune conditions may also result from single gene mutations as for autoimmune polyendocrinopathy-candidiasis–ectodermal dystrophy, an autosomal recessive disease associated with mutated forms of the autoimmune regulator gene. It was proposed that genetic variability in the autoimmune regulator locus, in particular heterozygous loss-of-function mutations, might favor the development of organ-specific autoimmunity by affecting the presentation of self-antigens in the thymus. Indeed, heterozygous mutations of the autoimmune regulator gene were reported in patients with organ-specific autoimmunity. Also, in primary immunodeficiencies, a breakdown in central/peripheral tolerance frequently produces association with autoimmunity. The causative link may involve a common genetic background and several gene defects have been identified as putative culprits. We report a unique patient, a 14 year old male from Lazio region, affected by common variable immunodeficiency associated with autoimmune manifestations (alopecia, onychodystrophy) and heterozygote for the S250C variant located in the SAND domain of the autoimmune regulator gene protein. To our knowledge this is the first report of the S250C variant in a patient bearing this unusual combination of autoimmunity and immunodeficiency. To obtain insights into the possible molecular effects of the S250C variant, we have carried out an in silico analysis of the SAND domain structure of the autoimmune regulator protein. In particular, homology modeling has allowed us to observe that the cysteine introduced by the S250C variant is surrounded by cationic residues, and by means of molecular dynamics simulations together with pK a calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pK a and thus conferring high chemical reactivity to the mutated residue. We propose that the enhanced reactivity of cysteine-250, which is likely to impair the protein function but probably insufficient to produce alone a phenotype as a heterozygous S250C variant due to compensation mechanisms, might become manifest when combined with other genetic/environmental factors. These results can provide the rationale for the patient's unusual phenotype, shedding new light into the pathogenesis of the clinical association of autoimmunity and immunodeficiency. [ABSTRACT FROM AUTHOR]

Abstract: Turner syndrome is a condition caused by numeric and structural abnormalities of the X chromosome, and is characterized by a series of clinical features, the most common being short stature and gonadal dysgenesis. An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in Turner patients. We present a unique case of mosaic Turner syndrome with a complex rearrangement consisting of a partial deletion of chromosome 2q and duplication of chromosome 10p {[46],XX,der(2)t(2;10)(2pter→2q37::10p13→10pter)[127]/45,X,der(2)t(2;10)(2pter→2q37::10p13→10pter)[23]}. The patient is affected by partial empty sella, in association with a group of multiorgan autoimmunity-related manifestations including Hashimoto''s thyroiditis, celiac disease, insulin-dependent diabetes mellitus (Type 1 diabetes, T1D), possible autoimmune inner ear disease with sensorineural deficit, preclinical Addison disease and alopecia universalis. The patient was previously described at the age of 2.4years and now re-evaluated at the age of 14years after she developed autoimmune conditions. AIRE gene screening revealed heterozygous c.834 C>G polymorphism (p.Ser278Arg) and IVS9+6G>A variation, thus likely excluding autoimmune polyendocrine syndrome Type 1 (APECED). Heterozygous R620W polymorphism of the protein tyrosine phosphatase non receptor type 22 (PTPN22) gene was detected in patient''s DNA. SNP-array analysis revealed that autoimmunity-related genes could be affected by the partial monosomy 2q and trisomy 10p. These data suggest that early genetic analysis in TS patients with complex associations of multiorgan autoimmune manifestations would permit a precise diagnostic classification and also be an indicator for undiscovered pathogenetic mechanisms. [Copyright &y& Elsevier]

Abstract: Nephropathic cystinosis (NC) is an autosomal recessive disorder characterized by the accumulation of the amino acid cystine in lysosomes, due to defective transport of cystine across the lysosomal membrane. Patients suffer from severe renal Fanconi syndrome from the first months of life and progress to end-stage renal failure during their second decade. Treatment with cysteamine delays the progression of chronic renal failure and improves most NC-related symptoms. Two less severe forms of cystinosis, a juvenile and an ocular form, have also been described. NC is caused by mutations in the CTNS gene that encodes for the cystinosin protein, a transmembrane lysosomal transporter. Cystinosin is a proton symporter, co-transporting cystine and protons in the same direction. Over 50 mutations have been described, including a common 57 kb deletion. Various metabolic and structural alterations have been described in cystinotic cells. These include decreased ATP and glutathione synthesis, increased apoptotic activity and mitochondrial damage. Although much progress has been made in the molecular and clinical fields, the mechanisms linking the accumulation of cystine in lysosomes and proximal tubular cell dysfunction are still poorly understood. [Copyright &y& Elsevier]

Abstract: Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is an autosomal recessive disease due to mutations of the autoimmune regulator (AIRE) gene. Typical manifestations include candidiasis, Addison''s disease, and hypoparathyroidism. Type 1 diabetes, alopecia, vitiligo, ectodermal dystrophy, celiac disease and other intestinal dysfunctions, chronic atrophic gastritis, chronic active hepatitis, autoimmune thyroid disorders, pernicious anemia and premature ovarian failure are other rare associated diseases although other conditions have been associated with APECED. Case presentation: What follows is the clinical, endocrinological and molecular data of a female APECED patient coming from Lithuania. The patient was affected by chronic mucocutaneous candidiasis, hypoparathyroidism and pre-clinical Addison''s disease. Using direct sequencing of all the 14 exons of the AIRE gene in the patient''s DNA, we identified in exon 6 the known mutation c.769 C>T (p.Arg257X) in compound heterozygosity with the newly discovered mutation c.1214delC (p.Pro405fs) in exon 10. The novel mutation results in a frameshift that is predicted to alter the sequence of the protein starting from amino acid 405 as well as to cause its premature truncation, therefore a non-functional Aire protein. Conclusions: A novel mutation has been described in a patient with APECED with classical clinical components, found in compound heterozygosity with the c.769 C>T variation. Expanded epidemiological investigations based on AIRE gene sequencing are necessary to verify the relevancy of the novel mutation to APECED etiopathogenesis in the Lithuanian population and to prove its diagnostic efficacy in association with clinical and immunological findings. [Copyright &y& Elsevier]

• The KLB rs17618244 variant increases the risk of ballooning and lobular inflammation in children with NAFLD. • KLB plasma levels are lower in carriers of the rs17618244 minor A allele. • KLB plasma levels are associated with lobular inflammation, ballooning and fibrosis. • KLB mutant induces intracellular lipid accumulation in HepG2 and Huh7. • KLB mutant causes upregulation of lipotoxic and proinflammatory genes. Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes. [ABSTRACT FROM AUTHOR]

Abstract: The cysteine/cystine (Cys/CySS) couple represents one of the major cell thiol/disulfide systems and is involved in the regulation of several metabolic pathways and the cell redox state. Nephropathic cystinosis (NC) is an autosomal recessive disease characterized by renal cellular dysfunction due to mutations in the CTNS gene, which encodes cystinosin, a CySS lysosomal transporter. To analyze the mechanisms involved in cell damage in NC, we have investigated the effects of CTNS gene overexpression or inhibition on cell thiol/disulfide systems and vice versa. Overexpression of the CTNS gene had no remarkable effect on intracellular Cys/CySS and GSH/GSSG redox state. Silencing the CTNS gene increased cell CySS and Cys and decreased cell GSH and GSSG and increased mildly the redox state of the Cys/CySS-couple. Extracellular CySS and Cys deprivation for 48 h caused an oxidation of the Cys/CySS (73 mV) and GSH/GSSG (100 mV) redox couples and increased CTNS mRNA levels by 1.9±0.2-fold (p <0.001). Conversely, a reduced cell environment associated with a GSH/GSSG reduction from −250.1±3.10 to −330.6±4.70 mV (p <0.001) and a Cys/CySS reduction from −167.0±11.30 to −240.0±8.17 mV (p <0.005) was associated with a 40% decrease in CTNS mRNA levels (p <0.05). By regression analysis, CTNS gene expression was correlated with intracellular Cys level and with Cys/CySS redox state. [Copyright &y& Elsevier]