Search

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]

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]

This research investigates antiviral potential of extracted honeybee products against COVID-19 main protease (Mpro) by computational methods. The crystal structure of COVID-19 Mpro was obtained from the protein data bank. Six synthetic drugs with antiviral properties were used as control samples in order to compare the results with those of natural ligands. The six honeybee components, namely 3,4,5-Tricaffeoylquinic acid, Kaempferol-3-O-glucoside, (E)-2′-Geranyl-3′,4′,7-Trihydroxyflavanone, 6-Cinnamylchrysin, (+)-Pinoresinol, and (24E)-3-Oxo-27,28-dihydroxycycloart-24-en-26-oic acid, have represented the lowest binding energies of −9.0, −8.5, −8.2, −7.8, −7.7, −7.3 and −6.7 Kcal/mol, respectively. These natural inhibitors were then picked for further investigations on their pharmacokinetic features. Also a 150 ns of Molecular dynamics simulations were carried out in order to evaluate their effects on protein structure and dynamics. The 3, 4, 5-Tricaffeoylquinic acid is hopefully proposed for COVID-19 Mpro inhibition if further in vitro, in vivo, and clinical trial studies will approve its effectiveness against COVID-19. [ABSTRACT FROM AUTHOR]

Behçet's disease (BD) is a chronic, multisystemic, inflammatory disease characterized by relapsing episodes of a wide spectrum of clinical findings. The role and mechanism of IFN-λs in BD remain unknown. The aim of this study was to investigate the relationship between IL29 and IL28B gene polymorphisms and BD or clinical manifestations. Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, single-nucleotide polymorphisms of IL28B rs8099917 (IL28 G/T), rs12979860 (IL28 C/T) and IL29 rs30461 (IL29 T/C) were studied in 94 patients with BD and 90 healthy controls. Our study did not show any relationship between Behçet Disease and genotype or allele frequencies of IL28B (rs8099917, rs12979860) and IL29 (rs30461) gene polymorphisms (p >.05). We found that the TT genotype of rs12979860 (IL28 C/T) polymorphism is higher in healthy controls and patients without central nervous system (CNS) involvement compared to patients with CNS involvement (p =.014 and p =.022). As a result, although the relationship was found between IL28 and IL29 gene polymorphisms with some clinical manifestations of BD, it was not directly related to the predisposition of the disease. The relationship between IL-28 and IL-29 which act as regulators in inflammatory processes, with Behçet disease, needs to be investigated in further studies. [ABSTRACT FROM AUTHOR]

Human innate cellular defence pathways have evolved to sense and eliminate pathogens, of which, viruses are considered one of the most dangerous. Their relatively simple structure makes the identification of viral invasion a difficult task for cells. In the course of evolution, viral nucleic acids have become one of the strongest and most reliable early identifiers of infection. When considering RNA virus recognition, RNA sensing is the central mechanism in human innate immunity, and effectiveness of this sensing is crucial for triggering an appropriate antiviral response. Although human cells are armed with a variety of highly specialized receptors designed to respond only to pathogenic viral RNA, RNA viruses have developed an array of mechanisms to avoid being recognized by human interferon-mediated cellular defence systems. The repertoire of viral evasion strategies is extremely wide, ranging from masking pathogenic RNA through end modification, to utilizing sophisticated techniques to deceive host cellular RNA degrading enzymes, and hijacking the most basic metabolic pathways in host cells. In this review, we aim to dissect human RNA sensing mechanisms crucial for antiviral immune defences, as well as the strategies adopted by RNA viruses to avoid detection and degradation by host cells. We believe that understanding the fate of viral RNA upon infection, and detailing the molecular mechanisms behind virus-host interactions, may be helpful for developing more effective antiviral strategies; which are urgently needed to prevent the far-reaching consequences of widespread, highly pathogenic viral infections. [ABSTRACT FROM AUTHOR]

Viruses are obligate intracellular parasites that exploit host cell machineries for replication. In this review, we focus on the current understanding of host cell nuclear proteins whose translocation from the nucleus to cytoplasm is induced and utilized by viruses to support viral replication and infection. Utilization of nuclear proteins for viral replication and infection involves disruption of nuclear import, enhancement of nuclear export, removal of nuclear localization signal (NLS) from nuclear proteins and alteration of nuclear pore complexes (NPCs) to cooperatively support viral replication. Understanding of nucleo-cytoplasmic transport system, and associated mechanisms, utilized by viruses will advance therapeutic development of strategies to produce optimal antiviral agents effective in control of viral diseases. [ABSTRACT FROM AUTHOR]

HCV envelope glycoproteins, E1 and E2, are multifunctional proteins. Until recently, E2 glycoprotein was thought to be the fusion protein and was the focus of investigations. However, the recently obtained partial structures of E2 and E1 rather support a role for E1 alone or in association with E2 in HCV fusion. Moreover, they suggest that HCV harbors a new fusion mechanism, distinct from that of other members of the Flaviviridae family. In this context, E1 aroused a renewed interest. Recent functional characterizations of E1 revealed a more important role than previously thought in entry and assembly. Thus, E1 is involved in the viral genome encapsidation step and influences the association of the virus with lipoprotein components. Moreover, E1 modulates HCV–receptor interaction and participates in a late entry step potentially fusion. In this review, we outline our current knowledge on E1 functions in HCV assembly and entry. [ABSTRACT FROM AUTHOR]

Excipients form a major component of pharmaceutical formulations and are classified as any ingredient other than the active ingredient which is included within the product formulation to improve drug product performance. Functional uses of excipients include improving solubility and stability, safety and efficacy, as bulking agents in lyophilized formulations, tonicity agents, and aiding in controlled or prolonged drug delivery. Parenteral formulations are sterile, pyrogen-free; free of particulate matter and by-pass the body's natural defense mechanisms. Excipients may demonstrate a synergistic effect when combined with an active ingredient but may also lead to unwanted reactions with the drugs and packaging components. Ideal excipients are required to be considered safe, inert and multifunctional. Contrary to the past, safety of excipients needs to be well established in order for their use in the pharmaceutical formulations. Therefore, careful consideration should be given while selecting an excipient. This review article provides an overview of the excipients used exclusively in small molecule and biological parenteral products including solutions, suspensions, and lyophilized formulations, information on the possible drug-excipient and drug-packaging interactions and the regulatory requirements for the use of pharmaceutical excipients. The readers will be able to have a comprehensive understanding of the excipients used in parenteral formulations. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) is a unique virus which interacts with cholesterol, iron and insulin metabolism. There is limited data on the effects of direct-acting antiviral agents (DAAs) on metabolic profiles. We aimed at evaluating the behavior of metabolic risk factors of chronically HCV-infected patients after sustained virologic response (SVR), comparing the outcomes with the new DAAs versus the old treatment regimen Peg-interferon ± ribavirin. Methods: A total of 178 patients who achieved SVR and completed one year of follow-up were prospectively included in this study: group 1 with 105 patients treated with DAAs and group 2 with 73 patients treated with old regimens. Outcomes included lipid, glucose and iron metabolism variation after SVR. Results: There was a significant increase in total cholesterol in both groups (group 1: p < .001, 95% CI: 0.41-0.78; group 2: p < .001, 95% CI: 0.24-0.69). Triglyceride levels significantly decreased (p = .015, 95% CI: −0.33-0.04) in group 1 and increased (p = .014, 95% CI: 0.07-0.59) in group 2. LDL levels increased in group 1 (p = .029, 95% CI: 0.05-0.88), but no significant variation was found in group 2. No significant variation in HDL, fast glucose and iron was seen in both groups. There was a significant increase of HOMA (p = .002, 95% CI: 0.17592-0.72317) only in group 2. Ferritin serum levels significantly decreased (p < .001, 95% CI:−138.3-74.4) in group 1 but no significant variation was found in group 2. Conclusion: Patients who have achieved SVR may have increased risk of cardiovascular outcomes due to development of hyperlipidemia and insulin resistance. [ABSTRACT FROM AUTHOR]

Nanomaterials (NMs) are used in an extremely diverse range of products and are increasingly entering the environment, driving a need to better understand their potential health effects in both humans and wildlife. A major challenge in nanoparticle (eco)toxicology is the ability to localise NMs post exposure, to enable more targeted biological effects analyses. A range of imaging techniques have been applied to do so, but they are limited, requiring either extensive processing of the material, staining or use of high intensity illumination that can lead to photo damage and/or have limited tissue penetration. Coherent anti-Stokes Raman scattering (CARS) microscopy is a label-free imaging technique, providing contrast based on the intrinsic molecular vibrations of a specimen, circumventing the need for chemical perturbation by exogenous labels. CARS uses near infra-red excitation wavelengths which allow microscopy at depths of several hundred microns in intact tissues and minimises photo-damage to live and delicate samples. Here we provide an overview of the CARS process and present a series of illustrative examples demonstrating its application for detecting NMs within biological tissues, ranging from isolated cells to whole organisms and including materials spanning metals to polymers. We highlight the advantages of this technique which include chemically selective live imaging and substantial depth penetration, but we also discuss its limitations when applied to nanotoxicology, which most notably include the lack of resolution for studies on single nanoparticles. [ABSTRACT FROM PUBLISHER]

The endoplasmic reticulum (ER) is a cellular membrane organelle that plays important roles in virus replication and maturation. Accumulating evidence indicates that virus infection often disturbs ER homeostasis and leads to ER stress, which is associated with a variety of prevalent diseases. To cope with the deleterious effects of virus-induced ER stress, cells activate critical signaling pathways including the unfolded protein response (UPR) and intrinsic mitochondrial apoptosis, which have complex effects on virus replication and pathogenesis. In this review, we present a comprehensive summary of recent research in this field, which revealed that about 36 viruses trigger ER stress and differentially activate ER stress-related signaling pathways. We also highlight the strategies evolved by viruses to modulate ER stress-related signaling networks including immune responses in order to ensure their survival and pathogenesis. Together, the knowledge gained from this field will shed light on unveiling the mechanisms of virus replication and pathogenesis and provide insight for future research as well as antiviral development. [ABSTRACT FROM AUTHOR]

CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining drug response and tolerability suggesting prospects for individualized drug therapies. Our review also discusses endogenous substrates of CES1 and assesses the potential of using metabolomic profiling of blood to identify proxies for the hepatic activity of CES1 that predict the rate of drug metabolism. Finally, the combination of genetics and metabolomics to obtain an accurate prediction of the individual response to CES1-dependent drugs is discussed. [ABSTRACT FROM AUTHOR]

One in four patients infected with hepatitis B virus (HBV) at birth or in early childhood will develop cirrhosis or hepatocellular carcinoma. Historically, guidelines have overlooked treatment in young people, as the immune tolerant disease phase is considered synonymous with chronic infection in the young. Current treatment aims to suppress HBV replication through long-term nucleos(t)ide therapy with little emphasis on virus eradication. To achieve HBsAg loss, it is accepted that effective immune control of virus is required, mimicking that seen in those who resolve acute HBV infection. We have recently challenged the accuracy of a generic immune tolerant state in young people, thus raising a potential role for earlier treatment. Here we report on our immunological analysis of HBV in young people and the role of a dedicated clinic; we make the case for earlier intervention to achieve effective immune control leading to better outcomes. [ABSTRACT FROM AUTHOR]

Worldwide, at least 170 million people are infected with hepatitis C virus (HCV), which is associated with hepatocellular carcinoma (HCC). With the recent success of Sofosbuvir (and other agents) antiviral therapy may be used as a future early-stage HCC treatment; however, in the short term, a cost-effective solution is needed to treat patients with viral-associated HCC. Here, we emphasize the potential of targeting gap junction intercellular communication (GJIC) as a therapeutic approach for HCC as HCV perturbs GJIC, which is linked to cellular transformation. We review the ROCK inhibitor Y-27632 and structurally related compounds that may inhibit the carcinogenic properties of HCV. [ABSTRACT FROM AUTHOR]

Chronic HBV infection is a major public health concern affecting over 240 million people worldwide. Although suppression of HBV replication is achieved in the majority of patients with currently available newer antivirals, discontinuation of therapy prior to hepatitis B surface antigen loss or seroconversion is associated with relapse of HBV in the majority of cases. Thus, new therapeutic modalities are needed to achieve eradication of the virus from chronically infected patients in the absence of therapy. The basis of HBV persistence includes viral and host factors. Here, we review novel strategies to achieve sustained cure or elimination of HBV. The novel approaches include targeting the viral and or host factors required for viral persistence, and novel immune-based therapies, including therapeutic vaccines. [ABSTRACT FROM AUTHOR]

1. Immunocompromised mice with humanized livers were developed in the mid-1990s to allow the study of human hepatotropic viruses, which normally replicate only in higher primates. The production of the uPA/SCID mouse was the vanguard of these models and remains the most widely worked upon model for an ever increasing range of applications. 2. Since toxicology is conducted in laboratory animal species with the implicit intent of predicting the outcome of accidental, or intentional, human exposure, the potential for using an in vivo model with a humanised metabolism opens up the possibility of better predicting the human response following exposure to drugs and industrial chemicals. Chimeric humanised mice provide the tool for bridging between the non-clinical laboratory safety and metabolism studies, carried out in rodent and non-rodent species, and the first in man clinical trials. 3. Chimeric mice carrying a human liver have now been validated against a wide range of different drugs and chemical classes, and have been shown to clearly differentiate metabolically from the recipient mouse, and to show metabolic pathways more similar to those expected from human liver. 4. This review critically appraises the available animal models carrying human livers and where future developments would improve the existing systems. [ABSTRACT FROM AUTHOR]

Self-reflection is critical for visitors to make sense of an exhibit collection in which they are the subject of investigation and may play an important role in any informal learning context. This study examines this construct by listening for self-reflective talk atMind, an exhibit collection focused on helping visitors explore aspects of themselves rather than external objects or phenomena. It addresses 3 questions: (a) What does self-reflective talk sound like in such a collection? (b) What categories of self-reflective talk are prevalent? (c) What types of exhibits engender what categories of self-reflective talk? Findings indicate that self-reflective talk comes in various forms. Self-monitoring talk, including self-assessments about how visitors are feeling and doing and what they know, is more prevalent than self-connecting talk, comments about visitors’ own lives, values, and their sense of self. Comparisons among different types of exhibits suggest that exhibits designed for multiple users prompt high frequencies of self-connecting talk and self-monitoring talk, whereas interactive exhibits and exhibits that pose a challenge elicit high frequencies of self-monitoring but not self-connecting talk. Additional work is needed to better understand self-reflection, its role in informal learning, and effective means of fostering self-reflection in science museums. [ABSTRACT FROM AUTHOR]

This research assessed the reported incidence, causes and reporting of medication errors in intensive care units (ICUs) and wards of Jordanian teaching hospitals. There are few studies about medication errors in Jordan. This survey was conducted in 2010 using a convenience sample of 212 nurses from four teaching hospitals. The response rate was 70.6% (212/300). The mean of the reported incidence of medication errors for the whole sample was 35%; 36.4% in ICUs and 33.8% in wards. An inaccurate rate of total parenteral nutrition (TPN) was the scenario most commonly classified as a drug error; for this nurses would notify the physician, and complete an incident report. Poor quality or damaged medication labels were the most commonly reported causes of errors. Nurses failed to report medication errors because they were afraid that they might be subjected to disciplinary actions. There were some significant differences between ICUs and wards in assessment of clinical scenarios, causes of medication errors as well as their reporting. Reporting of medication errors should be encouraged. Immediate interventions should be initiated by all healthcare professionals in all clinical settings, especially in wards. [ABSTRACT FROM AUTHOR]

This research assessed the reported incidence, causes and reporting of medication errors in intensive care units (ICUs) and wards of Jordanian teaching hospitals. There are few studies about medication errors in Jordan. This survey was conducted in 2010 using a convenience sample of 212 nurses from four teaching hospitals. The response rate was 70.6% (212/300). The mean of the reported incidence of medication errors for the whole sample was 35%; 36.4% in ICUs and 33.8% in wards. An inaccurate rate of total parenteral nutrition (TPN) was the scenario most commonly classified as a drug error; for this nurses would notify the physician, and complete an incident report. Poor quality or damaged medication labels were the most commonly reported causes of errors. Nurses failed to report medication errors because they were afraid that they might be subjected to disciplinary actions. There were some significant differences between ICUs and wards in assessment of clinical scenarios, causes of medication errors as well as their reporting. Reporting of medication errors should be encouraged. Immediate interventions should be initiated by all healthcare professionals in all clinical settings, especially in wards. [ABSTRACT FROM AUTHOR]

Eating disorders are a serious debilitating health problem, causing impairments in physical and psychosocial functioning and significantly affecting sufferers' quality of life. New technologies are being developed to meet the diverse treatment needs of people with eating disorders. This qualitative study examined participants' views of an Internet-based self-help programme developed in the Asia-Pacific region for people with eating disorders. The aim of the study was to explore how the self-help programme facilitated individuals' recovery and identify the factors that contribute to the success in the programme. A purposive sample of 12 people with anorexia nervosa (N = 4), bulimia nervosa (N = 2), binge eating disorder (N = 1) and eating disorder not otherwise specified (N = 5) participated in the study. The data were collected primarily by telephone interview. The programme was found to improve individuals' awareness of eating disorders, their motivation, eating disorder symptoms and health. Recovery was enhanced by individuals' determination and motivation to get better, the support available, their perseverance, sense of control, and personal confidence, and facilitating living environment. [ABSTRACT FROM AUTHOR]

Eating disorders are a serious debilitating health problem, causing impairments in physical and psychosocial functioning and significantly affecting sufferers' quality of life. New technologies are being developed to meet the diverse treatment needs of people with eating disorders. This qualitative study examined participants' views of an Internet-based self-help programme developed in the Asia-Pacific region for people with eating disorders. The aim of the study was to explore how the self-help programme facilitated individuals' recovery and identify the factors that contribute to the success in the programme. A purposive sample of 12 people with anorexia nervosa (N = 4), bulimia nervosa (N = 2), binge eating disorder (N = 1) and eating disorder not otherwise specified (N = 5) participated in the study. The data were collected primarily by telephone interview. The programme was found to improve individuals' awareness of eating disorders, their motivation, eating disorder symptoms and health. Recovery was enhanced by individuals' determination and motivation to get better, the support available, their perseverance, sense of control, and personal confidence, and facilitating living environment. [ABSTRACT FROM AUTHOR]

It is estimated that more than 170 million individuals worldwide are chronically infected with hepatitis C virus (HCV), with approximately 20% of the cases developing cirrhosis. Each year, between 1 and 4% of patients exhibiting cirrhosis develop hepatocellular carcinoma. Chronic HCV infection is also linked with the development of several metabolic disorders, including hepatic steatosis and insulin resistance. Research into HCV-related pathologies is hampered by a relative paucity of small animal models. As a result, little is known about the molecular mechanisms involved, and much of our current knowledge is drawn by inference from in vitro studies using overexpressed proteins. In this article, we will review the currently available animal models for the study of HCV pathogenesis, with an emphasis on murine models. Then, we will provide an overview of how these models have contributed to the deciphering of the molecular mechanisms underlying dysregulated lipid metabolism and hepatocellular carcinoma during HCV infection. [ABSTRACT FROM AUTHOR]