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Aim. The aim of this study was to evaluate the self-help behaviour of individuals with eating disorders in an Internet-based self-help programme developed in the Asia-Pacific region and to determine their compliance with the programme. Background. Eating disorders represent a growing health problem affecting both Western and Asian countries. Without timely and adequate treatment, individuals with eating disorders are at risk of premature death. Self-help approaches for treating eating disorders offer therapeutic promise. Design. An open trial design was used. Method. This study, conducted from August 2006-July 2011, included 280 participants recruited from outpatient eating disorder clinics and treatment units and through a university student newspaper and Internet websites. This open trial evaluated an Internet-based self-help programme, which included components on healthy eating, family education, health assessment, motivation enhancement, self-help strategies, and psychological health promotion. The progress of participants was followed up via monthly e-mails. A tracking system was implemented to determine their compliance with the programme. Findings. A small majority of the participants (56·9%) were already undergoing treatment for their eating disorders. About 63% ( n = 176) demonstrated self-help behaviour, as manifested by their completion of health assessment questionnaires, involvement in motivation enhancement exercises, or the use of self-help strategies such as monitoring, normalizing eating behaviour, and stress management. Improvements were observed in their eating disorder psychopathology, motivational stage of change and psychological health from baseline to the 1-month follow up. Conclusion. Internet-based self-help programmes for eating disorders are helpful adjuncts to professional treatment. [ABSTRACT FROM AUTHOR]

Nucleoporins, essential proteins building the nuclear pore, are pivotal for ensuring nucleocytoplasmic transport. While traditionally confined to the nuclear envelope, emerging evidence indicates their presence in various cytoplasmic structures, suggesting potential non-transport-related roles. This review consolidates findings on cytoplasmic nucleoporin assemblies across different states, including normal physiological conditions, stress, and pathology, exploring their structural organization, formation dynamics, and functional implications. We summarize the current knowledge and the latest concepts on the regulation of nucleoporin homeostasis, aiming to enhance our understanding of their unexpected roles in physiological and pathological processes. [ABSTRACT FROM AUTHOR]

Threats to coastal wetlands, including sea-level rise and subsidence, led the National Wildlife Refuge (NWR) System to protect over 500,000 hectares of coastal wetlands during the twentieth century, with approximately 20% occurring in the South Atlantic geography. This effort has involved systematic long-term monitoring of changes in marsh elevation using surface elevation tables and marker horizons at 20 sites across 19 NWRs in the southeastern coastal USA. From 2012 to 2021, the rates of change in surface elevation (−9.3 to 7.1 mm/year), accretion (−0.3 to 17.5 mm/year), and net vertical elevation change (−14.3 to 3.1 mm/year) were highly variable among monitoring sites and varied with coastal wetland type (oligohaline marsh, salt marsh, pocosin, or forested wetland), land surface elevation, and estuarine salinity and geomorphology (i.e., tidally influenced or embayed). Of 20 sites included in our study, only six were gaining elevation at a rate that was equal to or greater than the long-term rates of sea-level rise and therefore considered resilient. Only Waccamaw and Currituck NWRs, both located in oligohaline marshes, were gaining elevation at a rate that exceeded sea-level rise by 1 mm/year. These results support the mounting evidence that many coastal wetlands, particularly in the South Atlantic geography of the USA, will undergo ecological transformations in the next several decades. The NWR System and other coastal management entities will need to use strategic decision-making frameworks to identify management actions that can mitigate the loss of coastal wetlands to support the conservation of coastal wetland–dependent and obligate species. [ABSTRACT FROM AUTHOR]

A social worker member of the gender identity team of a Psychiatry Department is responsible for the social assessment of the transsexual who applies for sex reassignment surgery. This paper synthesizes the dynamics and processes in conducting the social assessment for eight male-to-female transsexuals from 1986 to April 1988. Role theory was used as the underlying theoretical framework for the assessment. Social criteria for the eligibility of the surgery are delineated. Three cases demonstrate how the social worker used these criteria for the assessment, the difficulties in the process and ways of resolving them. [ABSTRACT FROM AUTHOR]

Background: Carboxylesterase 1(CES1) is expressed mainly in the liver and adipose tissue and is highly hypothesized to play an essential role in metabolism. Our study aimed to investigate the association between CES1 and metabolic syndrome (MetS) and metabolic dysfunction associated steatotic liver disease (MASLD) in children with obesity in China. Methods: This study included 72 children with obesity aged 6-13years (including 25(35%) diagnosed as MetS and 36(50%) diagnosed as MASLD). All subjects were measured in anthropometry, serum level of biochemical parameters related to obesity, circumstance levels of insulin-like growth factor1, adipokines (adiponectin, leptin and growth differentiation factor 15) and CES1. Results: Higher serum CES1 level were found in the MetS group (P = 0.004) and the MASLD group (P < 0.001) of children with obesity. Serum CES1 levels were positively correlated with alanine aminotransferase, aspartate aminotransferase, triglyceride, cholesterol, low-density lipoprotein cholesterol, GDF15, Leptin and negatively correlated with high-density lipoprotein cholesterol, adiponectin and IGF1. We also found a multivariable logistic regression analysis of MASLD and MetS predicted by CES1 significantly (MASLD P < 0.01, MetS P < 0.05). The combination of CES1, sex, age and BMI Z-score showed a sensitivity and specificity of 92.7% for the identification of MASLD and 78.6% for the identification of MetS. The cutoff for CES1 of MASLD is 56.30 ng/mL and of MetS is 97.79 ng/mL. Conclusions: CES1 is associated with an increasing risk of MetS and MASLD and can be established as a biomarker for metabolic syndrome and MASLD of children with obesity. [ABSTRACT FROM AUTHOR]

Positive-strand RNA viruses encompass a variety of established and emerging eukaryotic pathogens. Their genome replication is confined to specialized cytoplasmic membrane compartments known as replication organelles (ROs). These ROs derive from host membranes, transformed into distinct structures such as invaginated spherules or intricate membrane networks including single- and/or double-membrane vesicles. ROs play a vital role in orchestrating viral RNA synthesis and evading detection by innate immune sensors of the host. In recent years, groundbreaking cryo–electron microscopy studies conducted with several prototypic viruses have significantly advanced our understanding of RO structure and function. Notably, these studies unveiled the presence of crown-shaped multimeric viral protein complexes that seem to actively participate in viral RNA synthesis and regulate the release of newly synthesized RNA into the cytosol for translation and packaging. These findings have shed light on novel viral functions and fascinating macromolecular complexes that delineate promising new avenues for future research. [ABSTRACT FROM AUTHOR]

The US Federal Reserve has been using quantitative easing as an unconventional monetary policy tool for providing liquidity and credit-market facilities to banks, and undertaking large-scale asset purchases in periods of crisis. This study carefully examines whether the US stock market has been responsive to the use of quantitative easing over time. A major contribution of this study to the extant literature is the introduction of the novel rolling windows nonparametric causality-in-quantiles approach to studying the reaction of the stock market to quantitative easing. This approach provides a means of investigating the time-varying causality between the variables across quantiles. The standard nonparametric causality-in-quantiles test results show that stock market performance is significantly predicted by quantitative easing, except at very low and very high levels of stock returns (volatility). The rolling windows nonparametric causality-in-quantiles test results indicate that the causal effect of quantitative easing on stock market volatility and returns becomes pronounced during periods of crisis. The reactions are most significant in periods corresponding to the Asian financial crisis, the global financial crisis and the COVID-19 pandemic outbreak. Overall, the causal effect of quantitative easing on both stock market returns and volatility changes through time; the effect on stock market returns is also greater than on stock market volatility. [ABSTRACT FROM AUTHOR]

Background: Lucilia cuprina (Wiedemann, 1830) (Diptera: Calliphoridae) is the main causative agent of flystrike of sheep in Australia and New Zealand. Female flies lay eggs in an open wound or natural orifice, and the developing larvae eat the host's tissues, a condition called myiasis. To improve our understanding of host-seeking behavior, we quantified gene expression in male and female antennae based on their behavior. Methods: A spatial olfactometer was used to evaluate the olfactory response of L. cuprina mated males and gravid females to fresh or rotting beef. Antennal RNA-Seq analysis was used to identify sensory receptors differentially expressed between groups. Results: Lucilia cuprina females were more attracted to rotten compared to fresh beef (> fivefold increase). However, males and some females did not respond to either type of beef. RNA-Seq analysis was performed on antennae dissected from attracted females, non-attracted females and males. Transcripts encoding sensory receptors from 11 gene families were identified above a threshold (≥ 5 transcript per million) including 49 ATP-binding cassette transporters (ABCs), two ammonium transporters (AMTs), 37 odorant receptors (ORs), 16 ionotropic receptors (IRs), 5 gustatory receptors (GRs), 22 odorant-binding proteins (OBPs), 9 CD36-sensory neuron membrane proteins (CD36/SNMPs), 4 chemosensory proteins (CSPs), 4 myeloid lipid-recognition (ML) and Niemann-Pick C2 disease proteins (ML/NPC2), 2 pickpocket receptors (PPKs) and 3 transient receptor potential channels (TRPs). Differential expression analyses identified sex-biased sensory receptors. Conclusions: We identified sensory receptors that were differentially expressed between the antennae of both sexes and hence may be associated with host detection by female flies. The most promising for future investigations were as follows: an odorant receptor (LcupOR46) which is female-biased in L. cuprina and Cochliomyia hominivorax Coquerel, 1858; an ABC transporter (ABC G23.1) that was the sole sensory receptor upregulated in the antennae of females attracted to rotting beef compared to non-attracted females; a female-biased ammonia transporter (AMT_Rh50), which was previously associated with ammonium detection in Drosophila melanogaster Meigen, 1830. This is the first report suggesting a possible role for ABC transporters in L. cuprina olfaction and potentially in other insects. [ABSTRACT FROM AUTHOR]

Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam3CSK4 inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam3CSK4 blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam3CSK4 treatment protected animals from infection and mortality. Overall, Pam3CSK4 is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections. Author summary: Rift Valley fever virus (RVFV) is an emerging mosquito-borne pathogen, which has shown the potential to spread geographically, and which can cause severe disease in humans. One of the most serious complications of RVFV infection is invasion into the brain. There are no approved treatments for RVFV infection, or any other bunyavirus that infects the brain. We found that the classically antiviral interferon pathway was not protective in neurons. This led us to screen for new antivirals, and we identified Pam3CSK4, which inhibited RVFV and related bunyaviruses, but not vesicular stomatitis virus. We found that the antiviral activity of Pam3CSK4 was separate from its previously characterized activity as a TLR2 agonist. Instead, Pam3CSK4 blocked RVFV entry at the step of viral membrane fusion. Importantly, we found that Pam3CSK4 prevented RVFV infection in the mouse brain. This work reveals that Pam3CSK4 prevents encephalitic bunyavirus infection in neurons, a vulnerable cell type, and future research should evaluate the therapeutic potential of Pam3CSK4. [ABSTRACT FROM AUTHOR]

Purpose: The SCOFF questionnaire was designed as a simple, memorable screening tool to raise suspicion that a person might have an eating disorder. It is over 20 years since the creation of the SCOFF, during which time it has been widely used. Considering this, we wish to review the use of the SCOFF in peer-reviewed scientific journals, and to assess whether it is being used appropriately in the manner in which it was originally devised and tested. Methods: The Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) guidelines were followed, and all search strategies and methods were determined before the onset of the study. PubMed and Wiley Online Library were searched using the terms SCOFF and eating. Two reviewers were involved in the reviewing process. Criteria for appropriate use of the SCOFF were formalised with the tool's original authors. Results: 180 articles were included in the final review. 48 articles had used the SCOFF appropriately, 117 articles inappropriately and 15 articles had been mixed in the appropriateness of their use. Conclusion: This systematic review highlights the inappropriate use of the SCOFF in diverse languages and settings. When used correctly the SCOFF has made a significant contribution to the understanding of eating disorders and its simplicity has been applauded and led to widespread use. However in over two-thirds of studies, the use of the SCOFF was inappropriate and the paper highlights how and in what way it was misused, Guidelines for the appropriate use of the SCOFF are stated. Future validation and avenues of research are suggested. Level of evidence: Level I. [ABSTRACT FROM AUTHOR]

Influenza and SARS-CoV-2 are two major respiratory pathogens that cocirculate in humans and cause serious illness with the potential to exacerbate disease in the event of co-infection. To develop a bivalent vaccine, capable of protecting against both infections, we inserted the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein into hemagglutinin (HA) molecule or into the open reading frame of the truncated nonstructural protein 1 (NS1) of live attenuated influenza vaccine (LAIV) virus and assessed phenotypic characteristics of the rescued LAIV-RBD viruses, as well as their immunogenicity in mouse and Syrian hamster animal models. A panel of 9 recombinant LAIV-RBD viruses was rescued using the A/Leningrad/17 backbone. Notably, only two variants with RBD insertions into the HA molecule could express sufficient quantities of RBD protein in infected MDCK cells. Intranasal immunization of mice induced high levels of anti-influenza antibody responses in all chimeric LAIV-RBD viruses, which was comparable to the LAIV virus vector. The RBD-specific antibody responses were most pronounced in the variant expressing RBD194 fragment as a chimeric HA protein. This candidate was further tested in Syrian hamsters and was shown to be immunogenic and capable of protecting animals against both infections. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a well-known virus that causes liver diseases such as liver cirrhosis and hepatocellular carcinoma. For several decades, numerous studies have been conducted to unravel the life cycle and molecular mechanisms of this virus with the aim of developing strategies to combat diseases caused by its infection. In this review, we summarize HCV assembly to budding, focusing on one of the structural proteins, the core, a viral capsid that binds both the viral genome and host membrane, along with the core-interacting host partners. The HCV core matures in the endoplasmic reticulum (ER), localizes at the lipid droplet (LD), and shuttles between the LD and ER to form viral particles. This process is controlled by many host factors known to binds core proteins, such as diacylglycerol acyltransferase-1 (DGAT-1), Rab18, μ subunit of the clathrin adaptor protein complex 2 (AP2M1), nuclear pore complex protein 98 (Nup98), Cortactin, group IVA phospholipase A2 (PLA2G4A) etc. Virion budding is thought to involve contributions from endosomal sorting complexes required for transport (ESCRT), similar to other envelope viruses. We delved into potential perspectives to enhance our understanding of the HCV mechanism by drawing insights from existing studies. [ABSTRACT FROM AUTHOR]

Viral infections trigger the expression of interferons (IFNs) and interferon stimulated genes (ISGs), which are crucial to modulate an antiviral response. The human guanylate binding protein 1 (GBP1) is an ISG and exhibits antiviral activity against several viruses. In a previous study, GBP1 was described to impair replication of the hepatitis C virus (HCV). However, the impact of GBP1 on the HCV life cycle is still enigmatic. To monitor the expression and subcellular distribution of GBP1 and HCV we performed qPCR, Western blot, CLSM and STED microscopy, virus titration and reporter gene assays. In contrast to previous reports, we observed that HCV induces the expression of GBP1. Further, to induce GBP1 expression, the cells were stimulated with IFNγ. GBP1 modulation was achieved either by overexpression of GBP1-Wt or by siRNA-mediated knockdown. Silencing of GBP1 impaired the release of viral particles and resulted in intracellular HCV core accumulation, while overexpression of GBP1 favored viral replication and release. CLSM and STED analyses revealed a vesicular distribution of GBP1 in the perinuclear region. Here, it colocalizes with HCV core around lipid droplets, where it acts as assembly platform and thereby favors HCV morphogenesis and release. Collectively, our results identify an unprecedented function of GBP1 as a pro-viral factor. As such, it is essential for viral assembly and release acting through tethering factors involved in HCV morphogenesis onto the surface of lipid droplets. Author summary: Morphogenesis and release of the hepatitis C virus (HCV) are still not fully understood. Here we describe a novel so far unprecedented pro-viral function of the interferon stimulated gene (ISG) human guanylate binding protein 1 (GBP1). In contrast to the supposed antiviral effect, we observe that GBP1 favors morphogenesis and release of HCV by acting as an assembly platform on the surface of lipid droplets. This extends our knowledge about the functions of GBP1 and the life cycle of HCV and should be considered for curative approaches targeting innate immunity. [ABSTRACT FROM AUTHOR]

The health consequences associated with using electronic cigarettes (ECs) are of great public interest because of their potential role in smoking cessation. In 110 participants, including 41 nonusers, 34 people who exclusively use ECs (EC group), and 35 people who smoke tobacco cigarettes (TCs) including 12 dual users (collectively called the TC-D group), the heart rate (HR), blood pressure (BP), and heart rate variability (HRV) were compared at baseline. People in the EC or the TC-D groups were also compared after using a 4th generation EC with or without nicotine, a TC with or without nicotine (TC-D group only), and a straw-control. Baseline HR, BP, and HRV parameters were not different among the EC, the TC-D, and nonuser groups. In people who exclusively use ECs, acute nicotine-EC use increased HR and BP, and produced changes in HRV patterns suggestive of increased cardiac sympathetic influence. In people in the TC-D group, BP increased similarly after acutely smoking a nicotine-TC or a nicotine-EC. However, the increase in HR was significantly greater after smoking a TC compared with the nicotine-EC despite similar acute increases in plasma nicotine. Overall, all exposures containing nicotine significantly increased HR and BP in both cohorts when compared with non-nicotine exposures. Since acute EC use 1) produces an abnormal HRV pattern associated with increased cardiac sympathetic tone in people who chronically use ECs, and 2) similar hemodynamic increases compared with acute TC smoking in people who chronically smoke TCs including dual users, the role of ECs as part of a harm reduction strategy is questioned. [ABSTRACT FROM AUTHOR]

Background: Progressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study. Methods: HepG2-Na+/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148's impact on HBV in vivo was investigated using an established rcccDNA mouse model. Results: ZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRα) expression by binding to the RXRα promoter sequence. RXRα binding site mutation or RXRα overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model. Conclusions: ZNF148 inhibited HBV replication by downregulating RXRα transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies. [ABSTRACT FROM AUTHOR]

The intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma‐derived HBV (genotype B and C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT‐PCR (RNA, covalently closed circular DNA [cccDNA], extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon‐stimulated genes [ISG]) to interferon‐α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well‐differentiated ICOs using spinoculation, with time and donor‐dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor‐dependent drug responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon‐α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor‐dependent variation in viral dynamics and cellular responses. These features can be utilized for the development of personalized drug testing platform for antivirals. [ABSTRACT FROM AUTHOR]

Ran‐binding protein 2 (RANBP2)/Nup358 is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g., SUMOylation, regulation of nucleocytoplasmic transport) and subcellular localizations (e.g., at the nuclear envelope, kinetochores, annulate lamellae), it is involved in many cellular processes. RANBP2 dysregulation or mutation leads to the development of human pathologies, such as acute necrotizing encephalopathy 1, cancer, neurodegenerative diseases, and it is also involved in viral infections. The chromosomal region containing the RANBP2 gene is highly dynamic, with high structural variation and recombination events that led to the appearance of a gene family called RANBP2 and GCC2 Protein Domains (RGPD), with multiple gene loss/duplication events during ape evolution. Although RGPD homoplasy and maintenance during evolution suggest they might confer an advantage to their hosts, their functions are still unknown and understudied. In this review, we discuss the appearance and importance of RANBP2 in metazoans and its function‐related pathologies, caused by an alteration of its expression levels (through promotor activity, post‐transcriptional, or post‐translational modifications), its localization, or genetic mutations. [ABSTRACT FROM AUTHOR]

Background and aims: The future development of hepatocellular carcinoma (HCC) in patients after sustained virologic response (SVR) is an important issue. The purposes of this study were to investigate pathological alterations in organelle of the liver of SVR patients and to characterize organelle abnormalities that may be related to carcinogenesis after SVR. Methods: The ultrastructure of liver biopsy specimens from patients with chronic hepatitis C (CHC) and SVR were compared to cell and mouse models and assessed semi‐quantitatively using transmission electron microscopy. Results: Hepatocytes in patients with CHC showed abnormalities in the nucleus, mitochondria, endoplasmic reticulum, lipid droplet, and pericellular fibrosis, comparable to those seen in hepatitis C virus (HCV)‐infected mice and cells. DAA treatment significantly reduced organelle abnormalities such as the nucleus, mitochondria, and lipid droplet in the hepatocytes of patients and mice after SVR, and cured cells, but it did not change dilated/degranulated endoplasmic reticulum and pericellular fibrosis in patients and mice after SVR. Further, samples from patients with a post‐SVR period of >1 year had significantly larger numbers of abnormalities in the mitochondria and endoplasmic reticulum than those of <1 year. A possible cause of organelle abnormalities in patients after SVR could be oxidative stress of the endoplasmic reticulum and mitochondria associated with abnormalities of the vascular system due to fibrosis. Interestingly, abnormal endoplasmic reticulum was associated with patients with HCC for >1 year after SVR. Conclusions: These results indicate that patients with SVR exhibit a persistent disease state and require long‐term follow‐up to detect early signs of carcinogenesis. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral, and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma derived HBV (genotype B & C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT‐PCR (RNA, cccDNA, extracellular DNA), and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon‐stimulated genes [ISG]) to interferon‐α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well‐differentiated ICOs using spinoculation, with time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg, and HBsAg. Donor dependent drug‐responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon‐α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor dependent variation in viral dynamics and cellular responses. These features can be utilized for development of personalized drug testing platform for antivirals. [ABSTRACT FROM AUTHOR]

Liver-generated plasma Apolipoprotein E (ApoE)-containing lipoproteins (LPs) (ApoE-LPs) play central roles in lipid transport and metabolism. Perturbations of ApoE can result in several metabolic disorders and ApoE genotypes have been associated with multiple diseases. ApoE is synthesized at the endoplasmic reticulum and transported to the Golgi apparatus for LP assembly; however, the ApoE-LPs transport pathway from there to the plasma membrane is largely unknown. Here, we established an integrative imaging approach based on a fully functional fluorescently tagged ApoE. We found that newly synthesized ApoE-LPs accumulate in CD63-positive endosomes of hepatocytes. In addition, we observed the co-egress of ApoE-LPs and CD63-positive intraluminal vesicles (ILVs), which are precursors of extracellular vesicles (EVs), along the late endosomal trafficking route in a microtubule-dependent manner. A fraction of ApoE-LPs associated with CD63-positive EVs appears to be co-transmitted from cell to cell. Given the important role of ApoE in viral infections, we employed as well-studied model the hepatitis C virus (HCV) and found that the viral replicase component nonstructural protein 5A (NS5A) is enriched in ApoE-containing ILVs. Interaction between NS5A and ApoE is required for the efficient release of ILVs containing HCV RNA. These vesicles are transported along the endosomal ApoE egress pathway. Taken together, our data argue for endosomal egress and transmission of hepatic ApoE-LPs, a pathway that is hijacked by HCV. Given the more general role of EV-mediated cell-to-cell communication, these insights provide new starting points for research into the pathophysiology of ApoE-related metabolic and infection-related disorders. Author summary: The post-Golgi egress pathway of hepatocyte-derived ApoE-containing lipoproteins (ApoE-LPs) is largely unknown. By using integrative imaging analyses, we show that ApoE-LPs are enriched in CD63-positive endosomes suggesting that these endosomes might be a central hub for the storage of ApoE-LPs from which they are released into the circulation. In addition, we provide evidence for the co-egress of ApoE-LPs with extracellular vesicles (EVs) along the late endosomal route and their transfer from cell to cell. This pathway is hijacked by the hepatitis C virus that induces the production of ApoE-associated EVs containing viral RNA. Given the important role of ApoE in multiple metabolic, degenerative, and infectious diseases, and the role of EVs in cell-to-cell communication, these results provide important information how perturbations of ApoE might contribute to various pathophysiologies. [ABSTRACT FROM AUTHOR]

The liver is an immune organ that plays a vital role in the detection, capture, and clearance of pathogens and foreign antigens that invade the human body. During acute and chronic infections, the liver transforms from a tolerant to an active immune state. The defence mechanism of the liver mainly depends on a complicated network of intrahepatic and translocated immune cells and non-immune cells. Therefore, a comprehensive liver cell atlas in both healthy and diseased states is needed for new therapeutic target development and disease intervention improvement. With the development of high-throughput single-cell technology, we can now decipher heterogeneity, differentiation, and intercellular communication at the single-cell level in sophisticated organs and complicated diseases. In this concise review, we aimed to summarise the advancement of emerging high-throughput single-cell technologies and re-define our understanding of liver function towards infections, including hepatitis B virus, hepatitis C virus, Plasmodium, schistosomiasis, endotoxemia, and corona virus disease 2019 (COVID-19). We also unravel previously unknown pathogenic pathways and disease mechanisms for the development of new therapeutic targets. As high-throughput single-cell technologies mature, their integration into spatial transcriptomics, multiomics, and clinical data analysis will aid in patient stratification and in developing effective treatment plans for patients with or without liver injury due to infectious diseases. [ABSTRACT FROM AUTHOR]

Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens. Herein, we systematically review electrophilic warheads employed during the development of reversible covalent drugs. We hope the structural insights of electrophilic warheads would provide helpful information to medicinal chemists and aid in designing covalent drugs with better on-target selectivity and improved safety. [ABSTRACT FROM AUTHOR]

Interferon regulatory factors (IRFs) are key elements of antiviral innate responses that regulate the transcription of interferons (IFNs) and IFN-stimulated genes (ISGs). While the sensitivity of humancoronaviruses to IFN shasbeencharacterized, antiviral roles of IRFs during human coronavirus infection are not fully understood. Type I or II IFN treatment protected MRC5 cells from human coronavirus 229E infection, but not OC43. Cells infected with 229E or OC43 upregulated ISGs, indicating that antiviral transcription is not suppressed. Antiviral IRFs, IRF1, IRF3 and IRF7, were activated in cells infected with 229E, OC43 or severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). RNAi knockdown and overexpression of IRFs demonstrated that IRF1 and IRF3 have antiviral properties against OC43, while IRF3 and IRF7 are effective in restricting 229E infection. IRF3activation effectively promotes transcriptionof antiviral genes duringOC43or229Einfection. Our study suggests that IRFsmay be effective antiviral regulators against human coronavirus infection. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed. Methods: Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. Results: Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. Conclusion: Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. 3KsUMj7wB7yx5QgLH83TLM Video Abstract [ABSTRACT FROM AUTHOR]

The development of a safe and effective vaccine is essential to protect populations against coronavirus disease 2019 (COVID‐19). There are several vaccine candidates under investigation with different mechanisms of action. In the present study, we have evaluated the safety and immunogenicity of a recombinant receptor‐binding domain (RBD)‐based protein subunit vaccine (Noora vaccine) against COVID‐19 in adults. This Phase 1 trial is a randomized, double‐blind, placebo‐controlled study to evaluate the safety and immunogenicity of the recombinant RBD‐based protein subunit vaccine (Noora vaccine) against COVID‐19 in healthy adults volunteers. Eligible participants were included in this study after evaluating their health status and considering the exclusion criteria. They were then randomized into three groups and received three doses of vaccine (80 µg, 120 µg, and placebo) on Days 0, 21, and 35. Primary outcomes including solicited, unsolicited, and medically attended adverse events were recorded during this study. Secondary outcomes including the humoral and cellular immunity (including anti‐RBD IgG antibody and neutralizing antibody) were measured on Days 0, 21, 28, 35, 42, and 49 by using the ELISA kit and the Virus Neutralization Test (VNT) was performed on day 49. Totally 70 cases were included in this Phase 1 trial and 60 of them completed the study. Safety assessments showed no severe adverse events. Local pain at the vaccine injection site occurred in 80% of the vaccinated volunteers. Induration and redness at the injection site were the other adverse reactions of this vaccine. There was no significant difference between the studied groups regarding adverse reactions. Anti‐RBD IgG antibody and neutralizing antibody assessment showed significant seroconversion in comparison to the placebo group (80%, and 100% respectively, p < 0.001). The cellular immunity panel also showed mild to moderate induction of TH1 responses and the VNT showed 78% of seroprotection. The results of this Phase 1 trial showed acceptable safety without serious adverse events and significant seroconversions in the humoral and cellular immunity panel. The dose of 80 µg is an appropriate dose for injection in the next phases of the trial. [ABSTRACT FROM AUTHOR]

Hepatocytes, the major parenchymal cells in the liver, are responsible for a variety of cellular functions including carbohydrate, lipid and protein metabolism, detoxification and immune cell activation to maintain liver homeotasis. Recent studies show hepatocytes play a pivotal role in liver inflammation. After receiving liver insults and inflammatory signals, hepatocytes may undergo organelle damage, and further respond by releasing mediators and expressing molecules that can act in the microenvironment as well as initiate a robust inflammatory response. In this review, we summarize how the hepatic organelle damage link to liver inflammation and introduce numerous hepatocyte-derived pro-inflammatory factors in response to chronic liver injury. [ABSTRACT FROM AUTHOR]

This study aims to shed light on the effects of financial development and accumulation of capital on the productivity of labor in the sub-Sahara African region within the period of 1990–2018. In this work, we used the (dynamic) common correlated effects estimator-mean group and additional techniques such as cross-section autoregressive distributed lag to calibrate the sample into the African subregion to ensure robustness. The findings reveal that financial progress in the region over time leads to an increase in productivity of labor and also the accumulation of capital. Furthermore, financial markets have a progressive impact on the productivity of labor within sub-Saharan African regions. We extend the very limited literature on the nexus between financial development and labor productivity by incorporating capital accumulation into our model which has not been previously studied. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. Previous studies on the prevalence of cSVD are mostly based on single geographically defined cohorts in high-income countries. Studies investigating the prevalence of cSVD in low- and middle-income countries (LMICs) are expanding but have not been systematically assessed. Aim: This study aims to systematically review the prevalence of cSVD in LMICs. Results: Articles were searched from the Ovid MEDLINE and EMBASE databases from 1 January 2000 to 31 March 2022, without language restrictions. Title/abstract screening, full-text review, and data extraction were performed by two to seven independent reviewers. The prevalence of cSVD and study sample size were extracted by pre-defined world regions and health status. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). A meta-analysis of proportion was performed to assess the prevalence of different magnetic resonance imaging markers of cSVD, and a meta-regression was performed to investigate associations between cSVD prevalence and type of study, age, and male: female ratio. Of 2743 studies identified, 42 studies spanning 12 global regions were included in the systematic review. Most of the identified studies were from China (n = 23). The median prevalence of moderate-to-severe white matter hyperintensities (WMHs) was 20.5%, 40.5%, and 58.4% in the community, stroke, and dementia groups, respectively. The median prevalence of lacunes was 0.8% and 33.5% in the community and stroke groups. The median prevalence of cerebral microbleeds (CMBs) was 10.7% and 22.4% in the community and stroke groups. The median prevalence of moderate-to-severe perivascular spaces was 25.0% in the community. Meta-regression analyses showed that the weighted median age (51.4 ± 0.0 years old; range: 36.3–80.2) was a significant predictor of the prevalence of moderate-to-severe WMH and lacunes, while the type of study was a significant predictor of the prevalence of CMB. The heterogeneity of studies was high (>95%). Male participants were overrepresented. Conclusions: This systematic review and meta-analysis provide data on cSVD prevalence in LMICs and demonstrated the high prevalence of the condition. cSVD research in LMICs is being published at an increasing rate, especially between 2010 and 2022. More data are particularly needed from Sub-Saharan Africa and Central Europe, Eastern Europe, and Central Asia. [ABSTRACT FROM AUTHOR]

Introduction: Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still posing detrimental effects on people. An association between contracting COVID-19 and the ABO blood group type has been determined. However, factors that determine the severity of COVID-19 are not yet fully understood. Thus, the current study aimed to investigate whether the ABO blood group type has a role in the severity of complications due to COVID-19. Materials and methods: Eighty-Six ICU-admitted COVID-19 patients and 80 matched-healthy controls were recruited in the study from Baish general hospital, Saudi Arabia. ABO blood grouping, complete blood count (CBC), CBC-derived inflammatory markers, coagulation profile, D-Dimer and anti-T antigen were reported. Results: Our data showed that patients with blood groups O and B are more protective against severe complications from COVID-19, as compared to patients with blood groups A and AB. This could be partially attributed to the presence of anti-T in blood group A individuals, compared to non-blood group A. Conclusion: The current study reports an association between the ABO blood group and the susceptibility to severe complications from COVID-19, with a possible role of anti-T in driving the mechanism of the thrombotic tendency, as it was also correlated with an elevation in D-dimer levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: Radio frequency electric field (RFEF) is a novel technology for the microbial disinfection of liquids such as water and fruit juices. Here we investigated the development of microbial tolerance against RFEF to assess the long‐term suitability of this technology. We applied a constant electric field, outlet temperature and treatment time of 14 kV cm−1, 40 °C and 1.275 ms, respectively, to Escherichia coli inoculated in saline water to observe whether the descendants of the surviving bacteria could develop tolerance against RFEF. Escherichia coli that survived the RFEF treatment were recultivated and treated under similar processing conditions for 15 generations. RESULTS: The results showed that although inactivation levels due to RFEF treatments fluctuated during consecutive generations, no significant difference between inactivation at cycles 1 and 15 was observed. Furthermore, inactivation levels during consecutive generations hovered around an average value of 2.18 log10 CFU mL−1. For short‐term effect, which compared untreated cells to treated ones at cycle 1, proteomics showed mixed trends of up‐ and down‐regulated differentially expressed proteins (DEPs). However, in the long term, which compared treated cells at cycles 1 and 15, DEPs involved in stress response, cell wall structure and antioxidant activities were all up‐regulated. CONCLUSION: The results indicate that although cell wall is the main target for the effect of electric field, they suggest that, in the long term, oxidative stress may also be induced. © 2022 Society of Chemical Industry (SCI). [ABSTRACT FROM AUTHOR]

The ideal dialogue established by James Joyce with Oscar Wilde is not immediately obvious, but one feels bewildered when its hidden 'borrowings' are revealed, starting from "Telemachus", the very first episode of Ulysses. How can one not feel puzzled when discovering that the famous "cracked mirror of a servant girl" referred to by Stephen Dedalus as "a symbol of Irish art" is not Joyce's, but Wilde's conception? Joyce drew on Wilde not only to talk about the fate of Irish art, as in the article he dedicated to him in Trieste's Piccolo della Sera on 24 March 1909, but also to allude in his writings to the theme of homosexuality. As a matter of fact, Joyce's entire work overflows with debts, references, allusions and quotations, more or less explicit, to Wilde's texts. One need only mention Stephen Dedalus's habit of speaking in aphorisms and epigrams, in apologies and parables. Their very common condition of exiles/artists would be enough to read their works and biographies in the light of some parallelism. If, in "Telemachus", Joyce has Buck Mulligan proclaim that "We have grown out of Wilde and paradoxes", in this contribution I will try to show how far this is from reality. Wilde inhabits not only Ulysses, but also - and especially - Finnegans Wake, where Joyce thematises the topic of the 'fall' and traces the ultimate 'portrait' of a long series. [ABSTRACT FROM AUTHOR]

Background: Zedoary turmeric oil extracted from the roots of curcuma (Curcuma aeruginosa Roxb.) is used for the treatment of myocarditis in China. EMCV infection causes abortion in pregnant sows and myocarditis in piglets. Our previous studies demonstrated that curcumol significantly increased the expression of IFN-β in EMCV infected HEK-293T cells. The present results showed that curcumol inhibits EMCV replication by interfering the host cell cholesterol homeostasis and reducing ROs production through activation of the JAK/STAT signaling pathway. Method: This study was designed to explore whether curcumol can inhibit the replication of encephalomyocarditis viruses (EMCV) in cell culture. The expression level of JAK1, IRF9, STAT2, P-STAT2, CH25H, PI4KA and OSBP in EMCV-infected HEK-293T cells treated with curcumol, ribavirin or hydroxypropyl-β-CD (HPCD) were determined by Western blotting (WB). The cholesterol level in EMCV infected HEK-293T cells treated with curcumol and HPCD were detected using Amplex™ Red Cholesterol Assay Kit. The antiviral effects of curcumol and HPCD on EMCV were also quantitatively detected by real-time fluorescence quantitative PCR (q-PCR). The amount and morphology of ROs were observed by transmission electron microscopy (TEM). Results: The results demonstrated that curcumol significantly (P < 0.05) increased the expression of JAK1, IRF9, P-STAT2 and CH25H proteins, while that of STAT2, PI4KA and OSBP were remained unchanged. Compared with virus group (0.134 μg.μg-1 proteins), the total cholesterol level was significantly (P < 0.05) reduced by curcumol (0.108 μg.μg-1 proteins) and HPCD (0.089 μg.μg-1 proteins). Compared with virus group (88237 copies), curcumol (41802 copies) and HPCD (53 copies) significantly (P < 0.05) reduced EMCV load. Curcumol significantly reduced the production of ROs in EMCV-infected HEK-293T cells and activated CH25H through the JAK/STAT signaling pathway. Conclusion: Curcumol inhibited EMCV replication by affecting the cholesterol homeostasis and the production of ROs in HEK-293T cell. [ABSTRACT FROM AUTHOR]

Ribbed mussels, Geukensia demissa, are marsh fauna that are used in coastal management and restoration due to the ecosystem services they provide. Ribbed mussel restoration efforts may be improved with a greater understanding of the environmental drivers of ribbed mussel distribution at multiple spatial scales to predict areas where restoration could be successful. This study sought to estimate the effects of within-marsh (4 m) and landscape (500 m) factors on ribbed mussel distribution. Ribbed mussel densities were surveyed at 11 sites along the coast of Georgia, USA, and overlaid with spatial data for within-marsh factors (elevation, distance to marsh features, slope) as well as landscape factors (percent cover by subtidal creek, forest, and development within a 500-m radius). The distribution model was then validated using three previously unsurveyed marshes and explained 55% of the variance in ribbed mussel abundance. Ribbed mussel abundances and occupancy were most sensitive to changes in within-marsh factors (elevation and distance to subtidal creeks, bodies of water inundated during the full tidal cycle) but were also sensitive to landscape features (percent landcover of forests and development). The highest ribbed mussel densities were found in mid-elevation areas (~ 0.7 m NAVD88), far from subtidal creeks, and in marshes surrounded with forest and development. These results contrast with distributions in the northeastern USA, where ribbed mussels are distributed along subtidal creek banks. This work suggests that restoration may be most effective when focused on appropriate elevations and at locations away from the marsh-creek ecotone. [ABSTRACT FROM AUTHOR]

The rapid development of effective vaccines to combat the SARS-CoV-2 virus has been an effective counter measure to decrease hospitalization and the mortality rate in many countries. However, with the risk of mutated strains decreasing the efficacy of the vaccine, there has been an increasing demand for antivirals to treat COVID-19. While antivirals, such as remdesivir, have had some success treating COVID-19 patients in hospital settings, there is a need for orally bioavailable, cost-effective antivirals that can be administered in outpatient settings to minimize COVID-19-related hospitalizations and death. Nirmatrelvir (PF-07321332) is an orally bioavailable Mpro (also called 3CLpro) inhibitor developed by Pfizer. It is administered in combination with ritonavir, a potent CYP3A4 inhibitor that decreases the metabolism of nirmatrelvir. This review seeks to outline the history of the rational design, the target selectivity, synthesis, drug resistance, and future perspectives of nirmatrelvir. [ABSTRACT FROM AUTHOR]

The mosquito protein AEG12 encompasses a large (~ 3800 Å3) hydrophobic cavity which binds and delivers unsaturated fatty acids into biological membranes, allowing it to lyse cells and neutralize a wide range of enveloped viruses. Herein, the lytic and antiviral activities are modified with non‐naturally occurring lipid ligands. We generated novel AEG12 complexes in which the endogenous fatty acid ligands were replaced with hydrophobic viral inhibitors. The resulting compounds modulated cytotoxicity and infectivity against SARS‐CoV‐2, potentially reflecting additional mechanisms of action beyond membrane destabilization. These studies provide valuable insight into the design of novel broad‐spectrum antiviral therapeutics centred on the AEG12 protein scaffold as a delivery vehicle for hydrophobic therapeutic compounds. [ABSTRACT FROM AUTHOR]

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody–drug conjugates. [ABSTRACT FROM AUTHOR]