Brincidofovir (BCV) and tecovirimat are the only two chemical drugs that have been approved to treat smallpox and can be requested for monkeypox (Mpox) treatment through a single-patient Emergency Investigational New Drug (EIND) application. Disappointedly, the efficacy of tecovirimat manifested in recent clinical trials is far from being satisfactory, while the clinical efficacy of BCV is still inconclusive. Given that monkeypox virus (MPXV), variola and other emerging orthopoxviruses are posing serious threats to global health, it is urgent to develop better therapeutics. In this study, we tested the antiviral effects of three novel prodrugs, which were designed based on previously reported parent drugs, either (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMPC, cidofovir) or (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA). We found that one of the (S)-HPMPA-based prodrugs, ODE-(S)-HPMPA formate, exhibited significantly better anti-orthopoxvirus activity than BCV both in vitro and in vivo, which also inhibited human adenovirus type 2 and type 21 more efficiently than BCV. Most strikingly, the EC50 and EC90 of ODE-(S)-HPMPA formate against MPXV were more than 40-fold lower than those of BCV. In contrast, we observed that the anti-herpes simplex virus type 1 (HSV-1) activities of the (S)-HPMPA-based prodrugs were less effective than those of the cidofovir-based prodrugs (BCV and BCV formate), especially in vivo. Moreover, we showed for the first time that cytidine and adenine analog combined therapies could provide mice with complete protection against lethal challenges of both vaccinia and HSV-1. Collectively, we propose that both the ODE-(S)-HPMPA formate and the BCV/ODE-(S)-HPMPA formate combination are worth further investigations for their potential clinical applications.
In this study, we synthesized two novel coordination molecular complexes, Ni(HL)2(H2O)2 (1) and Cu(HL)2(H2O)2 (2), using 5-(4-methylphenyl)-1H-pyrazole-3-carboxylic acid (H2L) as the primary ligand. Structural extension using 4,4 '-bipyridine linker resulted in two new complexes: [Ni(HL)2(4,4 '-bipy)]n (3) and [Cu3(L)2(4,4 '-bipy)]n (4). The four crystalline materials were studied by single-crystal and powder X-ray diffraction methods. Hirshfeld surface analysis showed that hydrogen bonds dominate in the supramolecular packing. Remarkably, complexes 3 and 4 exhibited emergent electrochemiluminescence (ECL) in DMSO solutions, with complex 4 achieving highintensity emission albeit with signal attenuation, while complex 3 demonstrated baseline stability.
Introduction:The study aimed to evaluate whether the association of sedentary behavior on suicide risk differs by sex and the modifying roles of social support and universal health coverage (UHC) index.Methods:We analyzed data from the Global School-based Student Health Survey across 53 countries (2013-2022). We examined the associations between sedentary time and suicide behaviors by binary logistic regression models and explored the modifying roles of social support by restricted cubic spline analysis. Stratified analyses were conducted based on overall social support and UHC groups.Results:A total of 190,329 adolescents (53.6% of girls) aged 12-17 years were included. The prevalence of suicidal ideation, plans, and attempts increased with daily sedentary time, with a more pronounced increase observed among girls. In boys, sedentary time of >8 h was associated with a 44% increase in higher risk suicide behavior (odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.36-1.53), while in girls, the increase was 88% (OR: 1.88, 95% CI: 1.79-1.97). In addition, compared to those with high support, both boys and girls with low social support showed a more pronounced increase in the risk of suicide behaviors as sedentary time increased. However, stratified analysis by UHC showed no significant differences between sedentary time and suicidal behavior among different social support groups.Conclusions:This study underscores the significant association between sedentary time and suicide behaviors among adolescents, particularly in girls. Furthermore, bolstering social support systems emerges as a promising approach to alleviate the negative associations of sedentary behavior.
The BCL-2 inhibitor venetoclax has shown promise in acute lymphoblastic leukemia (ALL), but its role in first-line therapy for newly diagnosed (ND) Philadelphia chromosome-negative (Ph⁻) ALL is undefined. In this prospective phase 2 study, 167 adolescents and adults (aged 14-60 years) with ND Ph⁻ ALL received venetoclax combined with pediatric-inspired chemotherapy. The primary endpoint was the rate of measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC) after induction. The complete remission rate was 91.0%, and 73.0% of responders achieved MFC-MRD negativity, meeting the primary endpoint. After a median follow-up of 19.3 months, median overall and disease-free survival were not reached; estimated 2-year survival rates were 78.5% and 76.7%, respectively. Propensity score-matched analysis confirmed superior survival compared with historical chemotherapy-only controls. Grade ≥ 3 adverse events were primarily hematologic toxicities and infections, with an incidence comparable to that of the historical cohort. These results demonstrate that adding venetoclax to pediatric-inspired chemotherapy significantly improves MRD response and survival outcomes in ND Ph⁻ ALL, with a manageable safety profile. This trial was registered with ClinicalTrials.gov under the identifier NCT05660473.
Numerous studies have established that the construction of nanosheet structures and the introduction of other elements represent two efficient approaches for strengthen the photocatalytic efficiency of g-C3N4 (graphitic carbon nitride). In this research, iodine-modified g-C3N4 nanosheets were effectively fabricated through a simple one-pot synthesis method. The optimal material (1.0I-DCN) exhibited highest photocatalytic efficiency, degrading diuron (k = 0.0134 min-1) and RhB (k = 0.0629 min-1) with rate constants 5.83 and 11.87 times than pristine g-C3N4. Two key factors contribute to the remarkable photocatalytic enhancement: (1) the twodimensional nanosheet architecture, which significantly enhances interfacial reaction sites, and (2) the optimized band structure and enhanced light absorption capacity. A series of characterization experiments confirmed that 1.0I-DCN possesses a superior ability to generate & sdot;O2-and e-with strong redox potential. Moreover, 1.0I-DCN demonstrated outstanding photocatalytic degradation efficiency for four phenylurea herbicides. The intermediates detected by HPLC-MS/MS were used to propose the degradation pathways of diuron, and the toxicity has been reduced. Additionally, 1.0I-DCN maintained excellent photocatalytic degradation performance even after four cycles. This study offers a sustainable and low-cost promising strategy for addressing environmental contamination in the future.
