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Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR −/− mice fed high-fat/high-cholesterol diet ± Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13 , Cd68 and Col1a1 . The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR −/− mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a fourfold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.

Hydroxysteroid 17β‐dehydrogenase 13 (HSD17B13) loss‐of‐function gene variants are associated with a decreased risk of metabolic dysfunction‐associated steatotic liver disease (MASLD). Our RNA‐seq analysis of steatotic liver from obese mice ± fenretinide treatment identified major beneficial effects of fenretinide on expression of hepatic genes including Hsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver‐specific knockdown. Hsd17b13 expression, which is unique to hepatocytes and associated with the lipid droplet, was elevated in multiple models of MASLD and normalised with the prevention of obesity and steatotic liver. Direct, liver‐specific, shRNA‐mediated knockdown of Hsd17b13 (shHsd17b13) in high‐fat diet (HFD)‐obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia. shHsd17b13 decreased elevated serum alanine aminotransferase (ALT), serum fibroblast growth factor 21 (FGF21) levels, and markers of liver fibrosis, for example, expression of Timp2. shHsd17b13 knockdown in HFD‐obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes, for example, Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) with shHsd17b13 expression and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) for example, phosphatidylcholine (PC) 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism, for example, Cept1, was also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion, Hsd17b13 knockdown in HFD‐obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and the development of liver fibrosis. What is the central question of this study? Hydroxysteroid 17β‐dehydrogenase 13 (HSD17B13) loss‐of‐function gene variants are associated with a decreased risk of metabolic dysfunction‐associated steatotic liver disease (MASLD) and metabolic dysfunction‐associated steatohepatitis (MASH): what is the relationship between Hsd17b13 expression and MASLD and can HSD17B13 be validated as a therapeutic target by liver‐specific knockdown? What is the main finding and its importance? Liver‐specific shRNA knockdown of Hsd17b13 in obese mice markedly improved hepatic steatosis and markers of liver health, for example, serum alanine aminotransferase and fibroblast growth factor 21 levels. Hsd17b13 influenced the expression of lipid/phospholipid metabolism genes and phosphatidylcholines PC 34:3 and PC 42:10. Our study suggests a mechanism of Hsd17b13's biological function and a strong rationale behind targeting HSD17B13 for MASLD/MASH.

Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) loss-of-function gene variants are associated with decreased risk of 'metabolic dysfunction-associated steatotic liver disease' (MASLD). Our RNA-seq analysis of steatotic liver from obese mice -/+ Fenretinide treatment identified major beneficial effects of Fenretinide on hepatic gene expression including Hsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver-specific knockdown. Hsd17b13 expression, which is unique to hepatocytes and associated with the lipid-droplet, was elevated in multiple models of MASLD and normalised with prevention of obesity and steatotic liver. Direct, liver-specific, shRNA-mediated knockdown of Hsd17b13 (shHsd17b13) in high-fat diet (HFD)-obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia. shHsd17b13 decreased elevated serum ALT, serum FGF21 levels and markers of liver fibrosis e.g. Timp2. shHsd17b13 knockdown in HFD-obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes e.g. Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) with shHsd17b13 and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) e.g. PC 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism e.g. Cept1, were also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion, Hsd17b13 knockdown in HFD-obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and development of liver fibrosis.Competing Interest StatementThe authors have declared no competing interest.

Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR-/- mice fed high-fat/high-cholesterol diet +/- Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR-/- mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a 4-fold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.

There are continued advances in the internet and communication fields regarding the deployment of 5G-based applications. It is expected that by 2030, 6G applications will emerge as a continued evolution of the mobile network. Blockchain technology is one of the leading supporting technologies predicted to provide a secure and unique network to 6G-enabled devices, transactions, and applications. It is anticipated that the 6G mobile networks will be virtualized, have cloud-based systems, and aim to be the foundation for the Internet of Everything. However, along with the development of communication technologies, threats from malicious parties have become more sophisticated, making security a significant concern for the 6G era in the future. Despite enormous efforts by researchers to improve security and authentication protocols, systems still face novel intrusion and attacks. Recently, multifactor authentication techniques (MFA) have been deployed as potential solutions to attacks in blockchains. The 6G applications and the cellular network have specific vulnerabilities that need to be addressed using blockchain-based MFA technologies. The current paper is a systematic review that discusses the three technologies under consideration; then, several studies are reviewed that discuss MFA techniques in general and use blockchains as potential solutions to future security and authentication issues that may arise for 6G applications.

Peste des petits ruminants (PPR) is an extremely transmissible viral disease caused by the PPR virus that impacts domestic small ruminants, namely sheep and goats. This study aimed to employ a methodical approach to evaluate the regional occurrence of PPR in small ruminants in Pakistan and the contributing factors that influence its prevalence. A thorough search was performed in various databases to identify published research articles between January 2004 and August 2023 on PPR in small ruminants in Pakistan. Articles were chosen based on specific inclusion and exclusion criteria. A total of 25 articles were selected from 1275 studies gathered from different databases. The overall pooled prevalence in Pakistan was calculated to be 51% (95% CI: 42–60), with heterogeneity I2 = 100%, τ2 = 0.0495, and p = 0. The data were summarized based on the division into five regions: Punjab, Baluchistan, KPK, Sindh, and GB and AJK. Among these, the pooled prevalence of PPR in Sindh was 61% (95% CI: 46–75), I2 = 100%, τ2 = 0.0485, and p = 0, while in KPK, it was 44% (95% CI: 26–63), I2 = 99%, τ2 = 0.0506, and p < 0.01. However, the prevalence of PPR in Baluchistan and Punjab was almost the same. Raising awareness, proper surveillance, and application of appropriate quarantine measures interprovincially and across borders must be maintained to contain the disease.

Enteric fever is a common infectious disease, especially in countries with poor sanitation and in the tropics. It is caused mainly by Salmonella typhi and accounts for nearly 27 million cases worldwide and 200,000 deaths annually. Enteric fever involves the reticuloendothelial system such as bone marrow, spleen, and liver. As it mostly involves the Peyer's patches of the terminal ileum, enteric perforation occurs commonly. However, gallbladder perforation can also occur, though not very often. Ultrasound as well as computerized tomography (CT) abdomen and pelvis lack specificity for detecting gallbladder perforations in enteric fever. Diagnosis is usually confirmed intraoperatively when the gallbladder is visualized and perforation is seen. Gallbladder perforation is usually seen in acute cholecystitis when the gallbladder becomes necrotic and gangrenous. In acalculous cholecystitis, perforation is rare. Enteric fever is one of the rarest causes of acalculous cholecystitis, leading to perforation. Here, we present the case of a 20-year-old man who presented with fever for 10 days along with loose stools, vomiting, and acute abdomen. Labs showed leukopenia, positive Typhidot test but X-ray erect abdomen and ultrasound abdomen and pelvis were nonspecific. Only after resuscitation and exploration of the abdomen was it found that the gallbladder had multiple perforations. The patient was improved after eight days of postoperative intravenous antibiotics. This is a unique and rare presentation of such a common infectious disease.