Elimination of Hepatitis C Virus from Hepatocytes by a Selective Activation of Therapeutic Molecules

To eliminate hepatitis C virus (HCV) from infected hepatocytes, we generated two therapeutic molecules specifically activated in cells infected with HCV. A dominant active mutant of interferon (IFN) regulatory factor 7 (IRF7) and a negative regulator of HCV replication, VAP-C (Vesicle-associated membrane protein-associated protein subtype C), were fused with the C-terminal region of IPS-1 (IFNβ promoter stimulator-1), which includes an HCV protease cleavage site that was modified to be localized on the ER membrane, and designated cIRF7 and cVAP-C, respectively. In cells expressing the HCV protease, cIRF7 was cleaved and the processed fragment was migrated into the nucleus, where it activated various IFN promoters, including promoters of IFNα6, IFNβ, and IFN stimulated response element. Activation of the IFN promoters and suppression of viral RNA replication were observed in the HCV replicon cells and in cells infected with the JFH1 strain of HCV (HCVcc) by expression of cIRF7. Suppression of viral RNA replication was observed even in the IFN-resistant replicon cells by the expression of cIRF7. Expression of the cVAP-C also resulted in suppression of HCV replication in both the replicon and HCVcc infected cells. These results suggest that delivery of the therapeutic molecules into the liver of hepatitis C patients, followed by selective activation of the molecules in HCV-infected hepatocytes, is a feasible method for eliminating HCV

Women Anesthesiologists in Sub-Saharan Africa in the Pre-COVID Era: A Multinational Demographic Study.

BACKGROUND: Gender imbalance and poor representation of women complicate the anesthesiology workforce crisis in sub-Saharan Africa (SSA). This study was performed to obtain a better understanding of gender disparity among medical graduates and anesthesiologists in SSA. METHODS: Using a quantitative, participatory, insider research study, led by female anesthesiologists as the national coordinators in SSA, we collected data from academic or national health authorities and agencies. National coordinators were nominees of anesthesiology societies that responded to our email invitations. Data gathered from 13 countries included information on medical graduates, anesthesiologists graduating between 1998 and 2021, and number of anesthesiologists licensed to practice in 2018. We compared data between Francophone and Anglophone countries, and between countries in East Africa and West Africa/Central Africa. We calculated anesthesiology workforce densities and compared representation of women among graduating anesthesiologists and medical graduates.Data analysis was performed using linear regression. We used F-tests on regression slopes to assess the trends in representation of women over the years and the differences between the slopes. A value of P < .050 was considered statistically significant. RESULTS: Over a 20-year period, the representation of female medical graduates in SSA increased from 29% (1998) to 41% (2017), whereas representation of female anesthesiologists was inconsistent, with an average of 25%, and lagged behind. Growth and gender disparity patterns were different between West Africa/Central Africa and East Africa. Representation of female anesthesiologists was higher in East Africa (39.4%) than West Africa/Central Africa (19.7%); and the representation of female medical graduates in East Africa (42.5%) was also higher that West Africa/Central Africa (33.1%). CONCLUSIONS: On average, in SSA, female medical graduates (36.9%), female anesthesiologists (24.9%), and female anesthesiology residents projected to graduate between 2018 and 2022 (25.2%) were underrepresented when compared to their male counterparts. Women were underrepresented in SSA, despite evidence that their representation in medicine and anesthesiology in East African countries was rising

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders