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Mohamed M Adel El-Sokkary,1 Lizaveta Gotina,2,3 Mohammad M Al-Sanea,4 Ae Nim Pae,2,3 Rehab Mohammed Elbargisy1,5 1Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 2Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; 3Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Daejeon, Korea; 4Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia; 5Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi ArabiaCorrespondence: Mohamed M Adel El-SokkaryDepartment of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, EgyptEmail m_elsokkary2022@yahoo.comAe Nim PaeConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Hwarangno 14-Gil 5, Seongbuk-gu, Seoul 02792, Republic of KoreaEmail anpae@kist.re.krBackground: Identification and characterization of developed antiviral drug resistance mutations are key to the success of antiviral therapies against hepatitis C virus (HCV), which remains a worldwide highly prevalent pathogenic disease. Although most studies focus on HCV genotypes 1, 2 or 3, the investigation of drug resistance in HCV genotype 4, predominant in North Africa, is especially significant in Egypt.Methods: We performed mutational and genotypic analysis of the untranslated region (UTR) and nonstructural protein 5B (NS5B) drug resistance-associated regions of HCV for patients in the surrounding villages of Mansoura city, who were not responding to different antiviral treatments (sofosbuvir (SOF), ribavirin, and interferon). Furthermore, molecular modelling approaches (homology modelling and docking studies) were used to investigate the significance of the identified NS5B mutations for SOF and ribavirin binding in the HCV genotype 4a NS5B active site.Results: Genotypic analysis confirmed all samples to have genotype 4 with sub-genotype 4a predominant. Partial sequencing of the UTR and NS5B resistance-associated regions identified D258E, T282S and A307G mutations in all isolates of NS5B. The UTR mutation site at position 243 was associated with interferon resistance, whereas the NS5B T282S mutation was considered as significant for SOF and ribavirin resistance. Docking studies in the HCV genotype 4a homology model predict SOF and ribavirin to accommodate a nucleotide-like binding mode, in which the T282 residue does interfere with the binding as it would in HCV genotypes 1 and 2. Mutation energy calculations predict T282S to moderately destabilize the binding of SOF and ribavirin by 0.57 and 0.47 kcal/mol, respectively.Conclusion: The performed study identified and characterized several antiviral drug resistance mutations of HCV genotype 4a and proposed a mechanism by which the T282S mutation may contribute to SOF and ribavirin resistance.Keywords: hepatitis C virus, drug resistance, T282S mutation, direct-acting antivirals, molecular docking

BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (

Dissecting Familiarity I did not know about the clergy sexual abuse at Covenant Fellowship Church (CFC) until we, the contributors to this roundtable, started exploring this scandal in October 2022. [...]

Abstract: Coastal mountain rivers export disproportionately high quantities of terrestrial organic carbon (OC) directly to the ocean, feeding microbial communities and altering coastal ecology. To better predict and mitigate the effects of wildfires on aquatic ecosystems and resources, we must evaluate the relationships between fire, hydrology, and carbon export, particularly in the fire‐prone western United States. This study examined the spatiotemporal export of particulate and dissolved OC (POC and DOC, respectively) and particulate and dissolved black carbon (PBC and DBC, respectively) from five coastal mountain watersheds following the 2020 CZU Lightning Complex Fires (California, USA). Despite high variability in watershed burn extent (20–98%), annual POC, DOC, PBC, and DBC concentrations remained relatively stable among the different watersheds. Instead, they correlated significantly with watershed discharge. Our findings indicate that hydrology, rather than burn extent, is a primary driver of post‐fire carbon export in coastal mountain watersheds.

Abstract Objectives Renal cell carcinoma (RCC) is shown to have a tendency for late recurrence, occurring 5 or more years after curative surgery. Imaging diagnosis is required for follow‐up, and there is no definitive answer as to how long this should continue. Some patients discontinue follow‐up visits at their own discretion. How best to predict late recurrence and loss to follow‐up (LF) remains unclear. Patients and methods This study targeted patients diagnosed with non‐metastatic RCC who underwent either radical or partial nephrectomy at Chiba University Hospital between 1988 and 2021. Follow‐up for patients with RCC is typically lifelong. We used random survival forests (RSFs), a machine learning‐based survival analysis method, to predict late recurrence and LF. For verification of prediction accuracy, we applied the time‐dependent area under the receiver operating characteristic curve (t‐AUC). To analyse the risks of late recurrence and LF, SurvSHAP(t) and partial dependence plots were used. Results We analysed 1051 cases in this study. Median follow‐up was 58.5 (range: 0–376) months. The predictive accuracy of recurrence using RSF was t‐AUC 0.806, 0.761, 0.674 and 0.566 at 60, 120, 180 and 240 months postoperatively, respectively. The recurrence risk impact showed a time‐dependent increase up to approximately 50 months postoperatively. Beyond 50 months, there were no distinct risk factors characteristic of late recurrence. The predictive accuracy of LF using RSF was t‐AUC 0.542, 0.699, 0.685, 0.628 and 0.674 at 60, 120, 180, 240 and 300 months postoperatively, respectively. The risk of LF increased with advancing age beyond 70 years. Conclusion It is difficult to identify factors that predict late recurrence. For long‐term follow‐up observation, it is essential to pay particular attention to patients with RCC aged 70 years and above. Establishing frameworks to facilitate collaboration with local hospitals near patients' residences and providing care within the community is necessary.

Abstract We investigated the clinical and radiologic predictors of unruptured symptomatic intracranial artery dissection (IAD) outcomes. Unruptured symptomatic IAD patients who underwent vessel wall magnetic resonance imaging (VW-MRI) and time-of-flight magnetic resonance angiography (TOF-MRA) within 1 month after symptom onset, followed for over 12 months were included. Baseline features predicting the clinical outcome of recurrent symptoms and radiologic outcomes of aneurysmal dilatation and occlusion were analyzed using logistic regression analysis. The Kaplan–Meier method calculated the median time to morphological stability. Patients with aneurysmal dilatation were categorized into progressive and non-progressive enlargement subgroups. Seventy-three IADs from 65 patients were included. All patients showed benign clinical course (mRS 0–1). No baseline features were predictive of recurrent symptoms. Aneurysmal dilatation was associated with increased outer diameter in baseline VW-MRI (OR, 23.15; 95% CI, 3.78–141.75, P

While the theoretical models of morphological processing in Roman alphabets indicate prelexical activation, a model established in Korean suggests postlexical activation. To extend the model of Korean morphological processing, this study examined within-scriptal (Hangul-Hangul prime-target pairs) and cross-scriptal (Hanja-Hangul prime-target pairs) priming effects on the recognition of Sino-Korean compound words in Hangul as a function of adult readers' Hanja proficiency using priming lexical decision tasks. Experiment 1 (n = 54) examined the constituent morphemic effects of Hangul and Hanja primes, while Experiment 2 (n = 67) investigated morphemic decomposition in Hangul and Hanja primes. Participants with skilled Hanja proficiency showed robust constituent morphemic effects with both Hangul and Hanja primes in isolation, while less-skilled participants did not show the effects with Hangul and Hanja primes (Experiment 1). The skilled group showed efficient morphological decomposition in both within- and cross-script conditions. However, the less-skilled group did not show morphological effects in the cross-script condition but the same effect in the within-script condition (Experiment 2). The skilled group showed ortho-phonological inhibitory effects on Hangul recognition resulting from competitions among activated neighbors, but the less-skilled counterpart did not show the effect. Based on the findings of this study, two differing pathway models of morphological processing in Hangul are proposed for readers with different Hanja proficiency. Morphological processing in Sino-Korean compound words seems to be prelexical for skilled readers, whereas it is postlexical for less-skilled readers.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

Abstract Resilient individuals are less likely to develop psychiatric disorders despite extreme psychological distress. This study investigated the multimodal structural neural correlates of dispositional resilience among healthy individuals. Participants included 92 healthy individuals. The Korean version of the Connor-Davidson Resilience Scale and other psychological measures were used. Gray matter volumes (GMVs), cortical thickness, local gyrification index (LGI), and white matter (WM) microstructures were analyzed using voxel-based morphometry, FreeSurfer, and tract-based spatial statistics, respectively. Higher resilient individuals showed significantly higher GMVs in the inferior frontal gyrus (IFG), increased LGI in the insula, and lower fractional anisotropy values in the superior longitudinal fasciculus II (SLF II). These resilience’s neural correlates were associated with good quality of life in physical functioning or general health and low levels of depression. Therefore, the GMVs in the IFG, LGI in the insula, and WM microstructures in the SLF II can be associated with resilience that contributes to emotional regulation, empathy, and social cognition.

Abstract Background Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology. Methods Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex. Results We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model. Conclusions Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer’s disease.

Purpose This study investigated the clinical and ultrasonographic (US) findings of suture granulomas and recurrent tumors, and aimed to identify specific characteristics of suture granulomas through an experimental study. Methods This retrospective study included 20 pathologically confirmed suture granulomas and 40 recurrent tumors between January 2010 and December 2020. The clinical findings included suture material, surgery, and initial TNM stage. The US findings included shape, size, margin, echogenicity, heterogeneity, vascularity, and internal echogenic foci. The distribution, paired appearance, and "knot-and-ear" appearance of internal echogenic foci were assessed. An experiment using pork meat investigated the US configuration of suture knots. Results Eighteen patients with 20 suture granulomas (15 women; mean age, 52±13 years) and 37 patients with 40 recurrent tumors (24 women; 54±18 years) were included. Patients with suture granulomas exhibited earlier initial T and N stages than those with recurrent tumors. The knot-and-ear appearance, defined as an echogenic dot accompanied by two adjacent echogenic dots or lines based on experimental findings, was observed in 50% of suture granulomas, but not in recurrent tumors (P

Abstract Coastal mountain rivers export disproportionately high quantities of terrestrial organic carbon (OC) directly to the ocean, feeding microbial communities and altering coastal ecology. To better predict and mitigate the effects of wildfires on aquatic ecosystems and resources, we must evaluate the relationships between fire, hydrology, and carbon export, particularly in the fire‐prone western United States. This study examined the spatiotemporal export of particulate and dissolved OC (POC and DOC, respectively) and particulate and dissolved black carbon (PBC and DBC, respectively) from five coastal mountain watersheds following the 2020 CZU Lightning Complex Fires (California, USA). Despite high variability in watershed burn extent (20–98%), annual POC, DOC, PBC, and DBC concentrations remained relatively stable among the different watersheds. Instead, they correlated significantly with watershed discharge. Our findings indicate that hydrology, rather than burn extent, is a primary driver of post‐fire carbon export in coastal mountain watersheds.

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

As a method of business communication, emails play an essential role in establishing relationships and support systems among colleagues, partners, and sponsors to achieve business goals. Research has suggested that nonnative speakers of English and novice writers face challenges when composing professional email requests for business purposes. Previous studies have underscored the importance of phrase frames (p-frames), which are recurring multi-word sequences with a variable slot, to fulfill rhetorical functions in academic discourse. However, little research has explored how p-frames are used for written communications in business workplace contexts. This study investigated five-word p-frames used for rhetorical moves in business email requests. Using 1,148 authentic request emails extracted from the Avocado Research Email Collection corpus, we analyzed the distribution and linguistic characteristics of p-frames across five rhetorical moves. Results showed that p-frames were unevenly distributed across the rhetorical moves in business request emails. Two moves, making the inquiry and closing, showed the highest degree of formulaicity. P-frames were used in a variety of messages to soften demands and express politeness. This study has pedagogical implications for teaching English for business purposes to both L2 learners and novice writers.

Ionic liquids are being used to increase the stability and efficiency of perovskite solar cells (PSCs). Ionic liquids not only help to enlarge grain size of perovskite due to their high thermal stability and low volatility, but also passivate defects on the perovskite surface, increasing the stability and efficiency. 1-ethyl-3-methylimidazolium tetracyanoborate ionic liquid is one of the excellent ionic liquids, which greatly increased the growth of perovskite crystal particles and enhanced the stability of PSCs. From calculation by Gaussian 09 program, electron density of N in the B(CN)4− ion is about 6.3. So, B(CN)4− can form chelate bonds or hydrogen bonds with Pb2+ or I−. The power conversion efficiency (PCE) of the three-layer structured PSCs fabricated using this ionic liquid was 13.8 % for the maximum, and it was maintained above 80 % of the initial efficiency under full-spectrum sunlight at 60–65 °C in air with relative humidity ranging from 40 to 50 % after 240 h.