Activity

Profiling of tutuilamide A against mainly human serine proteases revealed high selectivity for HNE (IC50 0.73 nM) and pleiotropic activity against kallikrein 7 (KLK7, IC50 5.0 nM), without affecting other kallikreins, similarly to lyngbyastatin 7 (IC50 0.85 nM for HNE and 3.1 nM for KLK7). A comprehensive molecular docking study for elastases and KLK7 afforded deeper insight into the intricate differences between inhibitor interactions with HNE and PPE, accounting for the differential activities for both compounds. The synthesis and molecular studies serve as a proof-of-concept that the macrocyclic scaffold can be diversified to fine-tune the activity of serine protease inhibitors.Infection by enveloped viruses includes endocytosis and/or membrane fusion at the plasma membrane, where host cell proteases play an essential role. Selleck PT2977 Among them, elastase-mediated infection has been documented for several enveloped viruses. Porcine reproductive and respiratory syndrome virus (PRRSV), an economically critical factor in global swine industry, is previously reported to infect host cells via low pH-dependent clathrin-mediated endocytosis (CME) and undergo membrane fusion in recycling endosomes. In the current study, we identified that elastase was significantly elevated in the lung tissues of highly pathogenic PRRSV (HP-PRRSV)-infected pigs compared to the mock-infected ones. We subsequently demonstrated that elastase contributed to HP-PRRSV infection in both MARC-145 cells and porcine alveolar macrophages (PAMs). Mechanistically, HP-PRRSV entered host cells at the cell surface via elastase-mediated membrane fusion, independent of low pH and CME, and its glycoprotein 5 (GP5) was cleaved by the protease during this process. All these findings deepen our understanding of HP-PRRSV infection, and are beneficial for prevention and control of the disease.Like obligate intracellular parasites, viruses co-opt host cell resources to establish productive infections. Polyamines are key aliphatic molecules that perform important roles in cellular growth and proliferation. They are also needed for the successful multiplication of various viruses. Little is known about the effects of polyamines on Arteriviridae infections. Here, porcine reproductive and respiratory syndrome virus (PRRSV), an economically prominent porcine virus, was used to investigate virus-polyamine interactions. We found that PRRSV infection significantly downregulated the levels of cellular polyamines. Using an inhibitor or specific short interfering RNAs (siRNAs) of ornithine decarboxylase 1, a key anabolic enzyme involved in the classical de novo biosynthesis of polyamines, we found that polyamine depletion abrogated PRRSV proliferation, and this effect was recoverable by adding exogenous spermidine and spermine, but not putrescine to the cells, suggesting that the host inhibits polyamine biosynthesis to restrict PRRSV proliferation. Further analysis revealed that the expression level of spermidine-spermine acetyltransferase 1 (SAT1), a catabolic enzyme that reduces spermidine and spermine levels, was upregulated during PRRSV infection, but conversely, SAT1 had an inhibitory effect on PRRSV reproduction. Our data show that polyamines are important molecules during PRRSV-host interactions, and polyamines and their biosynthetic pathways are potential therapeutic targets against PRRSV infection.

The growing prevalence of tobacco use in low “to middle” income countries (LMICs) and the hurdles of conducting tobacco cessation in that context necessitates a focus on the scope of randomized controlled trials (RCTs) in LMICs to guide tobacco cessation in this environment. We conducted a scoping review to identify LMIC tobacco cessation RCTs.

Consistent with PRISMA-ScR guidelines and without language restrictions, we systematically searched peer-reviewed databases (MEDLINE, Embase, PsycINFO, articles published since inception, latest searches in March 2020) and gray literature (clinical trials registries, searches between September and December 2019). We searched for data on RCT type, outcome significance and intervention description. Inclusion research conducted in LMICs; tobacco cessation; RCT. Exclusion research conducted in high income countries; non-RCT; studies involving only those aged <18. Data was extracted from published reports. We generated narrative summaries of each LMIC’s tobacco cessation RCT research environment.

Of 8404 articles screened, we identified 92 studies. Tobacco cessation RCTs were recorded in 16 of 138 countries/territories in LMICs. Evidence was weak in quality and severely limited. Most RCTs were psychosocial, with limited behavioral and pharmacological variants.

Tobacco control within LMICs is essential to reduce the tobacco mortality burden. Researchers should be cognizant that tobacco cessation in LMICs is still not an environment where best practice has been established. We suggest that developing solutions specific for LMICs is key to effective tobacco control in LMICs.

Tobacco control within LMICs is essential to reduce the tobacco mortality burden. Researchers should be cognizant that tobacco cessation in LMICs is still not an environment where best practice has been established. We suggest that developing solutions specific for LMICs is key to effective tobacco control in LMICs.Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by reactivation of JC virus during a time of cell mediated immune suppression. One potential rare cause of PML is Idiopathic CD4 lymphocytopenia (ICL) in which there is an unexplained deficit of CD4 T cells. We present a case of cerebellar PML in the absence of known immunosuppression leading to the diagnosis of ICL.

This observational cross-sectional multicenter study aimed to evaluate the longitudinal impact of the coronavirus disease 2019 (COVID-19) pandemic on neurosurgical practice.

We included 29 participating neurosurgeons in centers from all geographical regions in the Kingdom of Saudi Arabia. The study period, which was between March 5, 2020 and May 20, 2020, was divided into three equal periods to determine the longitudinal effect of COVID-19 measures on neurosurgical practice over time.

During the 11-week study period, 474 neurosurgical interventions were performed. The median number of neurosurgical procedures per day was 5.5 (interquartile range [IQR] 3.5-8). The number of cases declined from 72 in the first week and plateaued at the 30’s range in subsequent weeks. The most and least number of performed procedures were oncology (129 [27.2 %]) and functional procedures (6 [1.3 %]), respectively. Emergency (Priority 1) cases were more frequent than non-urgent (Priority 4) cases (178 [37.6 %] vs. 74 [15.6 %], respectively).