Molecular Basis of Arthritogenic Alphavirus Receptor MXRA8 Binding to Chikungunya Virus Envelope Protein.

Arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), cause severe and debilitating rheumatic diseases worldwide, resulting in severe morbidity and economic costs. Recently, MXRA8 was reported as an entry receptor. Here, we present the crystal structures of the mouse MXRA8, human MXRA8 in complex with the CHIKV E protein, and the cryo-electron microscopy structure of human MXRA8 and CHIKV virus-like particle. MXRA8 has two Ig-like domains with unique structural topologies. This receptor binds in the "canyon" between two protomers of the E spike on the surface of the virion. The atomic details at the interface between the two binding entities reveal that both the two domains and the hinge region of MXRA8 are involved in interaction with CHIKV E1-E2 residues from two protomers. Notably, the stalk region of MXRA8 is critical for CHIKV virus entry. This finding provides important information regarding the development of therapeutic countermeasures against those arthritogenic alphaviruses.

Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.

The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUbn (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (MDA5CARDs). Cryoelectron microscopy structures of a polyUb13-bound MDA5CARDs tetramer and a polyUb11-bound MDA5CARDs-MAVSCARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging MDA5CARDs and MAVSCARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1ß-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

Replication is the key barrier during the dual-host adaptation of mosquito-borne flaviviruses.

Mosquito-borne flaviviruses (MBFs) adapt to a dual-host transmission circle between mosquitoes and vertebrates. Dual-host affiliated insect-specific flaviviruses (dISFs), discovered from mosquitoes, are phylogenetically similar to MBFs but do not infect vertebrates. Thus, dISF­MBF chimeras could be an ideal model to study the dual-host adaptation of MBFs. Using the pseudoinfectious reporter virus particle and reverse genetics systems, we found dISFs entered vertebrate cells as efficiently as the MBFs but failed to initiate replication. Exchange of the untranslational regions (UTRs) of Donggang virus (DONV), a dISF, with those from Zika virus (ZIKV) rescued DONV replication in vertebrate cells, and critical secondary RNA structures were further mapped. Essential UTR-binding host factors were screened for ZIKV replication in vertebrate cells, displaying different binding patterns. Therefore, our data demonstrate a post-entry cross-species transmission mechanism of MBFs, while UTR-host interaction is critical for dual-host adaptation.

Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.

Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.

Therapeutic stapled peptides: Efficacy and molecular targets.

Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced proteolytic stability, compared to the original peptides, and provides an effective solution to accelerate the rapid development of peptide drugs. Various reviews present peptide stapling chemistries, anchoring residues and one- or two-component cyclization, however, therapeutic stapled peptides have not been systematically summarized, especially focusing on various disease-related targets. This review highlights the latest advances in therapeutic peptide drug development facilitated by the application of stapling technology, including different stapling techniques, synthetic accessibility, applicability to biological targets, potential for solving biological problems, as well as the current status of development. Stapled peptides as therapeutic drug candidates have been classified and analysed mainly by receptor- and ligand-based stapled peptide design against various diseases, including cancer, infectious diseases, inflammation, and diabetes. This review is expected to provide a comprehensive reference for the rational design of stapled peptides for different diseases and targets to facilitate the development of therapeutic peptides with enhanced pharmacokinetic and biological properties.

Prediction of tumor regression grade in far-advanced gastric cancer after preoperative immuno-chemotherapy using dual-energy CT-derived extracellular volume fraction.

OBJECTIVES: This study examines the effectiveness of dual-energy CT (DECT) delayed-phase extracellular volume (ECV) fraction in predicting tumor regression grade (TRG) in far-advanced gastric cancer (FAGC) patients receiving preoperative immuno-chemotherapy. MATERIALS AND METHODS: A retrospective analysis was performed on far-advanced gastric adenocarcinoma patients treated with preoperative immuno-chemotherapy at our institution from August 2019 to March 2023. Patients were categorized based on their TRG into pathological complete response (pCR) and non-pCR groups. ECV was determined using the delayed-phase iodine maps. In addition, tumor iodine densities and standardized iodine ratios were meticulously analyzed using the triple-phase enhanced iodine maps. Univariate analysis with five-fold cross-validation and Spearman correlation determined DECT parameters and clinical indicators association with pCR. The predictive accuracy of these parameters for pCR was evaluated using a weighted logistic regression model with five-fold cross-validation. RESULTS: Of the 88 patients enrolled (mean age 60.8 ± 11.1 years, 63 males), 21 (23.9%) achieved pCR. Univariate analysis indicated ECV's significant role in differentiating between pCR and non-pCR groups (average p value = 0.021). In the logistic regression model, ECV independently predicted pCR with an average odds ratio of 0.911 (95% confidence interval, 0.798-0.994). The model, incorporating ECV, tumor area, and IDAV (the relative change rate of iodine density from venous phase to arterial phase), showed an average area under curves (AUCs) of 0.780 (0.770-0.791) and 0.766 (0.731-0.800) for the training and validation sets, respectively, in predicting pCR. CONCLUSION: DECT-derived ECV fraction is a valuable predictor of TRG in FAGC patients undergoing preoperative immuno-chemotherapy. CLINICAL RELEVANCE STATEMENT: This study demonstrates that DECT-derived extracellular volume fraction is a reliable predictor for pathological complete response in far-advanced gastric cancer patients receiving preoperative immuno-chemotherapy, offering a noninvasive tool for identifying potential treatment beneficiaries.

Association between Perceived Stress and Motoric Cognitive Risk Syndrome in an Elderly Population: Rugao Longevity and Aging Study.

INTRODUCTION: Previous studies have indicated a correlation between perceived stress and cognitive decline. However, it remains unknown whether high levels of perceived stress can result in motoric cognitive risk (MCR) syndrome. This study investigated the relationship between perceived stress and MCR in a community-based population. METHODS: The study cohort comprised 852 elderly individuals from the Rugao Longitudinal Aging Cohort. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10), while MCR was defined as the coexistence of subjective memory complaints (SMCs) and slow gait speed. RESULTS: The average age of the study participants is 79.84 ± 4.34 years. The mean score of PSS-10 among participants is 10.32 (range = 0-33; [SD] = 5.71), with a median score of 10.00 (6.00, 14.00). The prevalence of MCR is 9.3%. In the logistic regression analysis, for each 1-SD (5.71) increase in the global PSS-10 score, the risk of MCR increased by 40% (95% CI 1.09-1.80). Additionally, in the aspect of two components of MCR, with a 1-SD increase (5.71) in the global PSS-10 score, there was a 50% (95% CI 1.29-1.75) increase in the risk of SMCs and a 27% (95% CI 1.04-1.55) increase in the risk of slow gait speed. In terms of specific walking speed, there was a reverse correlation between the global PSS-10 score and walking speed (r = -0.14, p < 0.001). CONCLUSIONS: This study provided preliminary evidence that high levels of perceived stress were associated with the risk of MCR in a community-dwelling population.

Management of patient with Fusobacterim nucletum related pleural empyema: intrapleural antibiotic therapy can be considered for salvage therapy.

Pleural empyema can lead to significant morbidity and mortality despite chest drainage and antibiotic treatment, necessitating novel and minimally invasive interventions. Fusobacterium nucleatum is an obligate anaerobe found in the human oral and gut microbiota. Advances in sequencing and puncture techniques have made it common to detect anaerobic bacteria in empyema cases. In this report, we describe the case of a 65-year-old man with hypertension who presented with a left-sided encapsulated pleural effusion. Initial fluid analysis using metagenomic next-generation sequencing (mNGS) revealed the presence of Fusobacterium nucleatum and Aspergillus chevalieri. Unfortunately, the patient experienced worsening pleural effusion despite drainage and antimicrobial therapy. Ultimately, successful treatment was achieved through intrapleural metronidazole therapy in conjunction with systemic antibiotics. The present case showed that intrapleural antibiotic therapy is a promising measure for pleural empyema.

Balancing interlayer spacing, pore structures and conductivity endows hard carbon with high capacity for rechargeable aluminum batteries.

As a key configuration, hard carbon (HC) is widely regarded as a promising cathode for rechargeable aluminum batteries (RABs), because of its enlarged interlayer spacing and well-developed pore structures. However, the trade-off between the pore structure, interlayer spacing and conductivity easily leads to an unsatisfactory electrochemical performance in terms of capacity and cycling stability. Hence, N-doped hard carbon (P-M) is synthesized at a relatively low temperature (700 °C) and anion intercalation associated with the energy storage process is investigated. The results demonstrate that the introduction of a N-doping agent not only expands the layer spacing and creates rich pore structures, but also boosts the conductivity. Compared with HC without N-doping, the expanded interlayer spacing in P-M can increase ion storage ability, and the rich pore channels contribute to electron transfer. Besides, compared with HC annealed at a higher temperature (900 °C), the enhanced conductivity in P-M is conducive to accelerating ion diffusion. Benefiting from these structure merits, the optimized P-M cathode delivers a high capacity (323 mA h g-1 at 500 mA g-1) and a prolonged cycle lifespan over 1000 cycles at 1 A g-1 retaining 109 mA h g-1. This work can provide a guidance for developing other high-performance hard carbon cathodes.

Predicting Severity in Hypertriglyceridemia-Induced Acute Pancreatitis: The Role of Neutrophils, Calcium, and Apolipoproteins.

BACKGROUND Hypertriglyceridemia-induced acute pancreatitis (HTG-AP), representing 10% of all acute pancreatitis cases, is characterized by younger onset age and more severe progression, often leading to higher ICU admission rates. This condition poses a significant challenge due to its rapid progression and the potential for severe complications, including multiple organ failure. HTG-AP is distinct from other forms of pancreatitis, such as those caused by cholelithiasis or alcohol, in terms of clinical presentation and outcomes. It's essential to identify early markers that can predict the severity of HTG-AP to improve patient management and outcomes. MATERIAL AND METHODS This study divided 127 HTG-AP patients into mild acute pancreatitis (MAP, n=71) and moderate-to-severe acute pancreatitis (MSAP/SAP, n=56) groups. Blood biological indicators within the first 24 hours of admission were analyzed. Risk factors for HTG-AP progression were determined using binary logistic regression and ROC curves. RESULTS Elevated levels of HCT, NLR, TBI, DBI, AST, Cre, and AMS were noted in the MSAP/SAP group, with lower levels of LYM, Na⁺, Ca²âº, ApoA, and ApoB compared to the MAP group (p<0.05). NEUT%, Ca²âº, ApoA, and ApoB were significantly linked with HTG-AP severity. Their combined ROC analysis yielded an area of 0.81, with a sensitivity of 61.8% and specificity of 90%. CONCLUSIONS NEUT%, Ca²âº, ApoA, and ApoB are significant risk factors for progressing to MSAP/SAP in HTG-AP. Their combined assessment provides a reliable predictive measure for early intervention in patients at risk of severe progression.

Deep learning image reconstruction generates thinner slice iodine maps with improved image quality to increase diagnostic acceptance and lesion conspicuity: a prospective study on abdominal dual-energy CT.

BACKGROUND: To assess the improvement of image quality and diagnostic acceptance of thinner slice iodine maps enabled by deep learning image reconstruction (DLIR) in abdominal dual-energy CT (DECT). METHODS: This study prospectively included 104 participants with 136 lesions. Four series of iodine maps were generated based on portal-venous scans of contrast-enhanced abdominal DECT: 5-mm and 1.25-mm using adaptive statistical iterative reconstruction-V (Asir-V) with 50% blending (AV-50), and 1.25-mm using DLIR with medium (DLIR-M), and high strength (DLIR-H). The iodine concentrations (IC) and their standard deviations of nine anatomical sites were measured, and the corresponding coefficient of variations (CV) were calculated. Noise-power-spectrum (NPS) and edge-rise-slope (ERS) were measured. Five radiologists rated image quality in terms of image noise, contrast, sharpness, texture, and small structure visibility, and evaluated overall diagnostic acceptability of images and lesion conspicuity. RESULTS: The four reconstructions maintained the IC values unchanged in nine anatomical sites (all p > 0.999). Compared to 1.25-mm AV-50, 1.25-mm DLIR-M and DLIR-H significantly reduced CV values (all p < 0.001) and presented lower noise and noise peak (both p < 0.001). Compared to 5-mm AV-50, 1.25-mm images had higher ERS (all p < 0.001). The difference of the peak and average spatial frequency among the four reconstructions was relatively small but statistically significant (both p < 0.001). The 1.25-mm DLIR-M images were rated higher than the 5-mm and 1.25-mm AV-50 images for diagnostic acceptability and lesion conspicuity (all P < 0.001). CONCLUSIONS: DLIR may facilitate the thinner slice thickness iodine maps in abdominal DECT for improvement of image quality, diagnostic acceptability, and lesion conspicuity.

Comparison between oral dydrogesterone versus micronized vaginal progesterone gel in clinical outcome within the first HRT-FET cycle: a retrospective analysis.

OBJECTIVE: The purpose of this study is to compare the clinical efficacy of oral dydrogesterone and micronized vaginal progesterone (MVP) gel during the first HRT-FET cycle. METHODS: A retrospective cohort study based on a total of 344 women undergoing their first HRT-FET cycles without Gonadotropin-Releasing Hormone agonist (GnRH-a) pretreatment was conducted. All the cycles were allocated to two groups in the reproductive medical center at the University of Hong Kong-Shenzhen Hospital. One group (n = 193) received oral dydrogesterone 30 mg/d before embryo transfer, while the other group (n = 151) received MVP gel 180 mg/d. RESULTS: The demographics and baseline characteristics of two groups were comparable. We found no statistically significant difference in live birth rate (24.35% vs. 31.13%, P = 0.16), clinical pregnancy rate (34.72% vs. 36.42%, P = 0.74), embryo implantation rate (25.09% vs. 28.36%, P = 0.43), positive pregnancy rate (42.49% vs 38.41%, P = 0.45), miscarriage rate (9.33% vs 3.97%, P = 0.05), or ectopic pregnancy rate (0.52% vs. 0.66%, P = 0.86) between the oral dydrogesterone group and MVP gel group. In the multivariate logistic regression analysis for covariates, medication used for luteal support was not associated with live birth rate (OR = 0.73, 95% CI: 0.32-1.57, P = 0.45). And the different luteal support medication did not have a significant positive association with the live birth rate in the cycles with day 2 embryo transferred (OR = 1.39, 95% CI:0.66-2.39, P = 0.39) and blastocyst transferred (OR = 1.31 95% CI:0.64-2.69, P = 0.46). CONCLUSION: 30 mg/d oral dydrogesterone and 180 mg/d MVP gel revealed similar reproductive outcomes in HRT-FET cycles in the study.

Effectiveness of a Teach-Back Education Program on Perioperative Pain in Patients With Lung Cancer: An Intervention Study Using Behavior Change Wheel.

OBJECTIVE: To assess the effect of a teach-back educational intervention using Behavior Change Wheel (BCW) framework on perioperative pain among patients with lung cancer. METHODS: A prospective quasi-experimental study was conducted in 88 patients with lung cancer from a tertiary hospital in China. According to the order of admission, they were allocated to either control group or intervention group, with 44 patients in each group. Patients in the control group received routine nursing care, while patients in the intervention group were given a teach-back education program based on BCW framework. The visual analog scale (VAS) was adopted to evaluate patients' pain on the day of surgery (T0), 1 (T1), 2 (T2), and 3 (T3) days after surgery. We also recorded the use of patient-controlled analgesia (PCA), the length of hospital stay, and the degree of patients' satisfaction. RESULTS: Rest pain, pain when coughing, and pain during activity that patients in the intervention group experienced were significantly less severe than those in the control group on T0 and T1. The pain when coughing in the intervention group was also significantly milder on T2 and T3. In addition, the number of self-control time, use duration, and total dose of PCA were significantly lower in the intervention group. Moreover, patients' satisfaction of nursing service was significantly higher in the intervention group. CONCLUSION: A teach-back education program based on BCW framework was effective in pain management among the perioperative patients with lung cancer. This study demonstrates the application of teach-back method and the BCW in the development of patient education intervention to mitigate perioperative pain.

A noise robust sparse time-frequency representation method for measuring underwater gas leakage rate.

Passive acoustic monitors analyze sound signals emitted by seafloor gas bubbles to measure leakage rates. In scenarios with low-flux gas leaks, individual bubble sounds are typically non-overlapping. Measurement methods for these bubble streams aim to estimate the frequency peak of each bubble sound, which correlates with the bubble's size. However, the presence of ocean ambient noise poses challenges to accurately estimating these frequency peaks, thereby affecting the measurement of gas leakage rates in shallow sea environments using passive acoustic monitors. To address this issue, we propose a robust measurement method that includes a noise-robust sparse time-frequency representation algorithm and an adaptive thresholding approach for detecting bubble frequencies. We demonstrate the effectiveness of our proposed method using experimental data augmented with ocean ambient noise and ship-transit noise recorded from a bay area.

Thrombectomy in young adults with embolic stroke of undetermined source: Analysis of the Young ESUS study.

OBJECTIVES: Embolic Stroke of Undetermined Source (ESUS) is a distinct stroke entity that disproportionately affects young adults. We sought to describe characteristics, workup and outcomes of young adult ESUS patients who underwent thrombectomy, and compare outcomes to those reported in different age groups. MATERIALS AND METHODS: Young-ESUS is a multicenter longitudinal cohort study that enrolled consecutive patients aged 21-50 years at 41 stroke centers in 13 countries between 2017- 2019. Between-group comparisons were performed using Wilcoxon rank sum test for continuous variables or Fisher's exact test for binary variables. Distribution of functional outcomes after thrombectomy for our young adult cohort versus pediatric and older adult cohorts reported in the literature were described using the Kruskal-Wallis test. RESULTS: Of 535 patients enrolled in Young-ESUS, 65 (12.1%) were treated with endovascular thrombectomy. Patients who underwent thrombectomy were more likely to undergo in-depth cardiac testing than those who did not, but cardiac abnormalities were not detected more often in this group. Among thrombectomy patients, 35/63 (55.6%) had minimal to no functional disability at follow up. When adjusted for age, stroke severity and IV alteplase, the odds of achieving favorable outcome did not differ between treated versus untreated patients. CONCLUSIONS: Thrombectomy is not rare in young adults with ESUS. Despite extensive workup, cardiac abnormalities were not more prevalent in the thrombectomy group. More research to determine optimal workup, etiologic factors and favorable outcome of stroke across the lifespan is needed.

Wfs1 loss-of-function disrupts the composition of mouse pancreatic endocrine cells from birth and impairs Glut2 localization to cytomembrane in pancreatic ß cells.

Wfs1 is an endoplasmic reticulum (ER) membrane located protein highly expressed in pancreatic ß cells and brain. Wfs1 deficiency causes adult pancreatic ß cells dysfunction following ß cells apoptosis. Previous studies mainly focus on the Wfs1 function in adult mouse pancreatic ß cells. However, whether Wfs1 loss-of-function impairs mouse pancreatic ß cell from its early development is unknown. In our study, Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from early postnatal day 0 (P0) to 8 weeks old, with decreased percentage of ß cells and increased percentage of α and δ cells. Meanwhile, Wfs1 loss-of-function leads to reduced intracellular insulin content. Notably, Wfs1 deficiency impairs Glut2 localization and causes the accumulation of Glut2 in mouse pancreatic ß cell cytoplasm. In Wfs1-deficient mice, glucose homeostasis is disturbed from early 3 weeks old to 8 weeks old. This work reveals that Wfs1 is significantly required for the composition of pancreatic endocrine cells and is essential for Glut2 localization in mouse pancreatic ß cells.

ADAM17 is an essential attachment factor for classical swine fever virus.

Classical swine fever virus (CSFV) is an important pathogen in the swine industry. Virion attachment is mediated by envelope proteins Erns and E2, and E2 is indispensable. Using a pull-down assay with soluble E2 as the bait, we demonstrated that ADAM17, a disintegrin and metalloproteinase 17, is essential for CSFV entry. Loss of ADAM17 in a permissive cell line eliminated E2 binding and viral entry, but compensation with pig ADAM17 cDNA completely rescued these phenotypes. Similarly, ADAM17 silencing in primary porcine fibroblasts significantly impaired virus infection. In addition, human and mouse ADAM17, which is highly homologous to pig ADAM17, also mediated CSFV entry. The metalloproteinase domain of ADAM17 bound directly to E2 protein in a zinc-dependent manner. A surface exposed region within this domain was mapped and shown to be critical for CSFV entry. These findings clearly demonstrate that ADAM17 serves as an essential attachment factor for CSFV.

Comparison of the immunogenicity of nasal-spray rVSV vector, adenovirus vector, and inactivated COVID-19-based vaccines in rodent models.

Intranasal (i.n.) vaccines can induce mucosal and systemic immunity against respiratory pathogens. Previously, we demonstrated that the recombinant vesicular stomatitis virus (rVSV)-based COVID-19 vaccine rVSV-SARS-CoV-2, with poor immunogenicity via the intramuscular route (i.m.), is more suitable for i.n. administration in mice and nonhuman primates. Here, we found that the rVSV-SARS-CoV-2 Beta variant was more immunogenic than the wild-type strain and other variants of concern (VOCs) in golden Syrian hamsters. Furthermore, the immune responses elicited by rVSV-based vaccine candidates via the i.n. route were significantly higher than those of two licensed vaccines: the inactivated vaccine KCONVAC delivered via the i.m. route and the adenovirus-based Vaxzevria delivered i.n. or i.m. We next assessed the booster efficacy of rVSV following two i.m. doses of KCONVAC. Twenty-eight days after receiving two i.m. doses of KCONVAC, hamsters were boosted with a third dose of KCONVAC (i.m.), Vaxzevria (i.m. or i.n.), or rVSVs (i.n.). Consistent with other heterologous booster studies, Vaxzevria and rVSV elicited significantly higher humoral immunity than the homogenous KCONVAC. In summary, our results confirmed that two i.n. doses of rVSV-Beta elicited significantly higher humoral immune responses than commercial inactivated and adeno-based COVID vaccines in hamsters. As a heterologous booster dose, rVSV-Beta induced potent, persistent, and broad-spectrum humoral and mucosal neutralizing responses against all VOCs, highlighting its potential to be developed into a nasal-spray vaccine.

Long-term outcomes of moyamoya disease versus atherosclerosis-associated moyamoya vasculopathy using high-resolution MR vessel wall imaging.

OBJECTIVES: We aimed to compare the long-term outcomes and surgical benefits between moyamoya disease (MMD) and atherosclerosis-associated moyamoya vasculopathy (AS-MMV) using high-resolution MRI (HRMRI). METHODS: MMV patients were retrospectively included and divided into the MMD and AS-MMV groups according to vessel wall features on HRMRI. Kaplan-Meier survival and Cox regression were performed to compare the incidence of cerebrovascular events and prognosis of encephaloduroarteriosynangiosis (EDAS) treatment between MMD and AS-MMV. RESULTS: Of the 1173 patients (mean age: 42.4±11.0 years; male: 51.0%) included in the study, 881 were classified into the MMD group and 292 into the AS-MMV group. During the average follow-up of 46.0±24.7 months, the incidence of cerebrovascular events in the MMD group was higher compared with that in the AS-MMV group before (13.7% vs 7.2%; HR 1.86; 95% CI 1.17 to 2.96; p=0.008) and after propensity score matching (6.1% vs 7.3%; HR 2.24; 95% CI 1.34 to 3.76; p=0.002). Additionally, patients treated with EDAS had a lower incidence of events than those not treated with EDAS, regardless of whether they were in the MMD (HR 0.65; 95% CI 0.42 to 0.97; p=0.043) or AS-MMV group (HR 0.49; 95% CI 0.51 to 0.98; p=0.048). CONCLUSIONS: Patients with MMD had a higher risk of ischaemic stroke than those with AS-MMV, and patients with both MMD and AS-MMV could benefit from EDAS. Our findings suggest that HRMRI could be used to identify those who are at a higher risk of future cerebrovascular events.