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关键词： Fowl adenovirus   whole genome   coinfection   pathogenicity   differential transcriptomics  

摘要： Fowl adenoviruses (FAdVs) are widely distributed in poultry populations around the world, and many diseases are associated with FAdV infection in chickens. This study documented the first characterization of coinfection with fowl adenovirus serotypes 1 and 4 (FAdV-1 and -4) associated with hydropericardium hepatitis syndrome (HHS) in Chinese layer flocks, revealing a novel viral cooperation mechanism. Two novel strains (CH/SX/201805-1 and -4) were identified and isolated, with whole-genome sequencing showing CH/SX/201805-1 clustering with FAdV-1 (99.7% identity to FAdV-A-61/11z), whereas CH/SX/201805-4 displayed characteristic ORF19/27/29 deletions mirroring emergent Chinese FAdV-4 variants. Experimental coinfection in SPF chickens resulted in 87.5% mortality, which was 16.7% greater than that resulting from infection alone, with exacerbated pathology. In vitro coinfection experiments demonstrated concurrent viral replication within same LMH cells, a previously unreported phenomenon, where FAdV-1 increased FAdV-4 replication efficiency 21-fold (p < 0.001). Transcriptomic profiling revealed heat shock protein A2 (HSPA2) as the most differentially expressed gene, which was upregulated 2.8-fold during coinfection compared with infection with FAdV-4 alone. Functional validation through HSPA2 knockdown reduced FAdV-4 replication, establishing that FAdV-1 potentiates FAdV-4 through HSPA2-mediated host modulation. These findings provide the first evidence of HSPA2-dependent interserotype synergy in FAdV and can be used to develop a cellular model for FAdV coinfection studies. These insights redefine the understanding of FAdV pathogenesis and create new avenues for targeted intervention strategies against emerging FAdV coinfections.

关键词： Antimicrobial peptide   hepcidin   anguillid herpesvirus 1   antiviral activity   envelope protein ORF51  

摘要： Frequent outbreaks of eel "mucus sloughing and hemorrhagic septicemia disease" caused by Anguillid herpesvirus 1 (AngHV) are a major epidemic in both wild and farmed eels. This virus has garnered global attention due to heavy losses on eel farms and the lack of protective vaccines or effective drugs, highlighting the urgent need for potent antiviral agents. In this study, we revealed a hepcidin homolog LJ-hep2 from Japanese seabass (Lateolabrax japonicus) can bind to AngHV and impede viral entry into cells. LJ-hep2 could directly destroy the viral envelope and showed a higher anti-AngHV activity than AA-hep (a hepcidin homolog cloned from Anguilla anguilla). It was found that the destruction of viral structure by LJ-hep2 was related to the binding of the peptide to AngHV envelope protein ORF51, and the two amino acid residues at the N-terminus of the peptide (lysine and phenylalanine) might play a key role. Comparative antiviral experiments with mutated LJ-hep2 (LJ-hep2A4A5) and multi-species hepcidin further confirmed this finding and demonstrated that these two amino acids were indispensable in the inhibition of AngHV infection by LJ-hep2. In an established eel immersion infection model, LJ-hep2 treatment reduced viral accumulation in tissues, inhibited horizontal transmission, alleviated skin lesions, and improved eel survival. Taken together, this study suggests that LJ-hep2 could inhibit AngHV infection in vitro and in vivo, and identify ORF51 as a potential target for the development of anti-AngHV drugs.

关键词： Endothelin-1   carotid-femoral pulse wave velocity   aortic stiffness   chronic kidney disease  

摘要： Increased aortic stiffness (AS) is a recognized predictor of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), and endothelin-1 (ET-1), a potent vasoconstrictor, has been associated with vascular dysfunction and atherosclerosis. This study examined the relationship between serum ET-1 levels and AS in patients with non-dialysis CKD. A total of 232 adults with CKD stages 3-5 were enrolled. Fasting blood samples were obtained to measure serum ET-1 concentrations using an enzyme immunoassay, and AS was assessed by carotid-femoral pulse wave velocity (cfPWV) measured using cuff-based volumetric displacement, with cfPWV >10 m/s defining AS. Among the participants, 75 patients (32.3%) were classified as having AS. Compared with those without AS, patients with AS were older and had higher prevalences of diabetes mellitus and hypertension, as well as significantly higher serum ET-1 levels, blood pressure, fasting glucose, HbA1c, and urine protein-to-creatinine ratio. Serum ET-1 levels were positively correlated with cfPWV and remained independently associated with cfPWV in multivariable linear regression analysis. Furthermore, multivariable logistic regression identified serum ET-1, age, diastolic blood pressure, and diabetes mellitus as independent factors associated with AS, with consistent results observed in bootstrap analyses. These findings demonstrate an independent association between serum ET-1 levels and increased cfPWV and AS in patients with non-dialysis CKD.

关键词： IVX-121   respiratory syncytial virus   RSV   vaccine   virus-like particle  

摘要： Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in all age groups, with substantial burden in older adults. Here, we report the safety and immunogenicity of IVX-121, an investigational virus-like particle vaccine against RSV. This Phase 1/1b trial (EudraCT number: 2020-003633-38) randomized 90 healthy young (18-45 y of age;Phase 1) and 130 older adults (60-75 y of age;Phase 1b) to receive a single intramuscular injection of IVX-121 at low (25 & micro;g), medium (75 & micro;g), or high (250 & micro;g) dose, with/without the adjuvant aluminum hydroxide (Al[OH]3), or placebo. Outcomes were assessed through Day 180. Older adult participants who had received IVX-121 or placebo could continue into an extension study in which safety was assessed for an additional 6 months before receiving IVX-121 (75 & micro;g, unadjuvanted, open-label) on Day 365;safety and immunogenicity were assessed up to Day 546. Adverse reactions were generally mild, and there were no vaccine-related serious adverse events. All IVX-121 dose levels and formulations boosted preexisting RSV neutralizing antibody (nAb) responses. Although not statistically powered to compare treatment groups, there was no clear dose response and the adjuvant Al(OH)3 did not appear to improve immunogenicity. For both age groups, IVX-121 induced nAbs against RSV A and B, which remained above baseline levels for at least 6 months. A second dose of IVX-121 in older adults elicited a modest increase in nAbs against RSV A but not RSV B. Overall, IVX-121 had a favorable safety profile and induced immune responses against RSV in young and older adults.

关键词： Monkeypox virus   Mpox   Cambodia   lineage C.1   Bayesian phylodynamics  

摘要： Mpox is an infectious disease caused by the Monkeypox virus, which is divided into two main genetic clades: Clade I and Clade II. A large-scale outbreak linked to Clade IIb emerged in 2022 and rapidly spread to more than 100 countries worldwide. Here, we describe the first and only documented Mpox outbreak in Cambodia (2023-2024), the public health outbreak response efforts and analysis, and integrating epidemiological and genomic *** investigate the outbreak, samples from suspect cases were confirmed using qPCR before virus whole genome sequences were obtained for phylogenomic *** investigation revealed transmission primarily through intimate contact within socially connected networks, exclusively among men who have sex with men. None of the confirmed cases reported recent international travel or zoonotic exposure. Phylogenomic analysis showed that all Cambodian Mpox genomes belonged to lineage C.1, nested within Clade IIb. Bayesian analysis of publicly available C.1 genomes indicated that the most closely related sequence was from Thailand. Monophyletic clustering of Cambodian sequences, alongside a high proportion of APOBEC3 mutations, indicates localized human-to-human transmission after ***, these results illustrate the risk of regional lineages like C.1 introducing Mpox into previously unaffected countries, where socially connected human networks can sustain outbreaks despite control efforts.

关键词： Multidrug resistance   ABCB1   ABCB1 inhibitors   aminocoumarin-derived coumarin   triazolo[1,5-a]pyrimidine  

摘要： ABCB1-mediated drug efflux is a key determinant of multidrug resistance (MDR) in cancer. To overcome this mechanism, a series of thiol-substituted aminocoumarin-derived, coumarin-containing triazolo[1,5-a]pyrimidine derivatives (5a-5s) was synthesised, and compound 5r (NYH-707) was identified as the most potent ABCB1 inhibitor. NYH-707 markedly restored paclitaxel sensitivity in SW620/Ad300 MDR cells, reducing the IC50 from 4.55 +/- 0.73 & micro;M to 0.011 +/- 0.002 & micro;M (reversal factor = 413.6). Molecular docking predicted strong binding (-9.7 kcal/mol) through hydrogen bonding with LYS-826 and SER-880 and pi-pi stacking with PHE-994. CETSA confirmed direct ABCB1 engagement, while drug-accumulation assays demonstrated inhibition of ABCB1-mediated efflux. In vivo, co-administration of NYH-707 and paclitaxel significantly suppressed SW620/Ad300 xenograft growth without detectable systemic toxicity. These findings indicate that NYH-707 acts as a potent and selective ABCB1 modulator capable of reversing MDR likely by modulating ABCB1 conformational dynamics, thereby enhancing chemotherapeutic efficacy in resistant tumours.

关键词： Hypertension   circadian blood pressure   dipper hypertension   non-dipper hypertension   endothelin-1   endothelin-2   endothelial dysfunction  

摘要： Objective: The aim of this study was to evaluate serum endothelin-1 (ET-1) and endothelin-2 (ET-2) levels in patients with dipper and non-dipper hypertension compared to normotensive controls and to investigate the potential diagnostic value of these biomarkers in distinguishing circadian blood pressure phenotypes. Methods: This prospective case-control study included 163 participants classified into three groups based on 24-hour ambulatory blood pressure monitoring (ABPM): normotensive controls (n = 60), dipper hypertensive (n = 61), and non-dipper hypertensive (n = 42) patients. Dipper status was defined as a 10% nocturnal reduction in both systolic and diastolic blood pressure. Individuals with diabetes, established cardiovascular disease, or secondary hypertension were excluded. Serum endothelin-1 (ET-1) ET-1 and endothelin-2 (ET-2) ET-2 levels were analyzed using double-antibody sandwich ELISA kits. Results: ET-1 levels were significantly lower in dipper hypertensive patients (p < 0.001) compared to other groups. Conversely, ET-2 levels did not significantly differ between hypertensive phenotypes. ET-1 proved to be a strong diagnostic marker for distinguishing non-dipper hypertension (AUC = 0.830, sensitivity 83.3%, specificity 75.4%). While advanced age independently predicted the non-dipper pattern (OR = 1.101, p = 0.002), BMI and D-dimer were associated with the dipper phenotype. Conclusion: This study identifies serum endothelin-1 is a strong, independent marker of the non-dipper hypertensive phenotype, which is associated with increased cardiovascular risk. The preservation of low endothelin-1 levels in dipper hypertension patients reflects intact endothelial and circadian regulation, whereas the absence of this response in non-dipper patients indicates impaired vascular adaptation. The inverse association of endothelin-2 with non-dipper status further suggests a protective buffering role that may be attenuated by increasing metabolic burden.

关键词： Myotonic dystrophy type 1 (DM1)   organ system involvement   clinical burden   economic burden   HCRU   healthcare cost   healthcare resource utilization  

摘要： Objectives: Myotonic dystrophy type 1 (DM1) is a multi-systemic disease affecting skeletal and smooth muscle, the eye, brain, and heart. No disease-modifying therapies are available. Prior studies on clinical care and economic burden combined DM1 and DM type 2. This study describes the US DM1 population aged >= 12 years, assessed organ system involvement over time, estimated healthcare resource utilization (HCRU), associated costs, and identified predictors of high-cost status. Methods: Linked open claims and EHR data (Clarivate) from 1 January 2015 to 25 August 2023 were analyzed. Eligible individuals had a DM1 diagnosis (index), >= 6 months pre-index data, and were aged >= 12 years;congenital DM was excluded. Organ system involvement rates up to 7 years post-index were estimated using the Kaplan-Meier method. Annual HCRU rates and costs to payers (2023 USD) were summarized by setting, type of care and specialty and compared by organ involvement. Predictors of high-cost status were evaluated using multivariable logistic regression. Results: The cohort included 1,343 people with DM1. Over 7 years, most experienced neurological, gastrointestinal, cardiac, pulmonary, and/or musculoskeletal system involvement. Annually post-index, approximately 24% of patients had emergency room visits, and 15% had inpatient visits. Common specialty visits included rehabilitation (13%), cardiology (13%), and neurology (11%). Frequent device use included noninvasive positive-pressure ventilation (12%), assistive devices (7%), and oxygen therapy (4%). Mean annual total cost of care was $20,687 (SD = $122,082), primarily driven by inpatient and outpatient hospital visits. Cardiac and pulmonary complications were significant predictors of high-cost status. Conclusion: DM1 imposes significant clinical and economic burden, marked by extensive organ involvement and variable healthcare costs. As any patient may progress to costly cardiac or pulmonary complications, early proactive management i

关键词： Parkinson's disease   N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives   monoamine oxidase B   neuroprotective agents   selective inhibitors  

摘要： Monoamine oxidase B (MAO-B) inhibitors may be an effective therapeutic approach for Parkinson's disease. This study designed and synthesised a series of N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives and evaluated their inhibitory activity against human MAO-B (hMAO-B). Most compounds exhibited inhibitory activity and selectivity, with compounds 29 and 34 demonstrating the strongest inhibitory potency (IC50 = 0.066 +/- 0.03 mu M and 0.070 +/- 0.002 mu M, respectively) and selectivity indices (SI > 151 and 134), which were superior to the positive control rasagiline. Enzyme kinetic studies confirmed that these representative active compounds exhibited mixed reversible inhibition of hMAO-B. Molecular docking and kinetic analyses indicated that compound 29 binds stably to the hMAO-B active site. Concurrently, they exhibited low neurotoxicity and protective effects against 6-OHDA-induced damage in SH-SY5Y neuroblastoma cells. Therefore, we propose these active compounds as potential drug candidates for further investigation.