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Hussein Franks posted an update 6 months, 2 weeks ago
The formation of neutrophil extracellular trap (NET) is a critical host defense when neutrophils migrate to infection sites. Pyroptosis is a newly identified programmed cell death, which is tightly regulated by inflammasome activation. However, the mechanism of pyroptotic signaling participating in NET production remains to be elucidated. In this study, the zebrafish larvae otic vesicle microinjection model was used to infect larvae with hemolysin-overexpressing Edwardsiella piscicida (EthA+), and a rapid migration of neutrophils to infection sites was observed. Intriguingly, EthA+ infection effectively induced significant neutrophil membrane rupture in vivo, which was dependent on caspase-B (caspy2) and gasdermin Eb (GSDMEb) but not caspase-A or gasdermin Ea. Specifically, the EthA+E. piscicida infection induced pyroptosis along with NETosis in vitro, and depletion of either caspy2 or GSDMEb impaired NET formation in vivo. Consequently, inhibition of the caspy2-GSDMEb axis-gated NETosis impaired bacterial clearance in vivo. Altogether, these data provide evidence that teleost fish innate immune cells, including neutrophils, express features of pyroptosis that are critical for NETosis in teleost innate immunity.African swine fever virus (ASFV) is a devastating infectious disease in pigs, severely threatening the global pig industry. To efficiently infect animals, ASFV must evade or inhibit fundamental elements of the innate immune system, namely the type I IFN response. In this study, we identified that ASFV MGF-505-7R protein exerts a negative regulatory effect on STING-dependent antiviral responses. MGF-505-7R interacted with STING and inhibited the cGAS-STING signaling pathway at STING level. MGF-505-7R overexpression either degraded STING or STING expression was reduced in ASFV-infected cells via autophagy, whereas STING expression was elevated in MGF-505-7R-deficient ASFV-infected cells. We further found that MGF-505-7R promoted the expression of the autophagy-related protein ULK1 to degrade STING, whereas ULK1 was elevated in MGF-505-7R-deficient ASFV-infected cells. Moreover, MGF-505-7R-deficient ASFV induced more IFN-β production than wild-type ASFV and was attenuated in replication compared with wild-type ASFV. The replicative ability of MGF-505-7R-deficient ASFV was also attenuated compared with wild-type. Importantly, MGF-505-7R-deficient ASFV was fully attenuated in pigs. Our results showed for the first time, to our knowledge, a relationship involving the cGAS-STING pathway and ASFV MGF-505-7R, contributing to uncover the molecular mechanisms of ASFV virulence and to the rational development of ASFV vaccines.The popularity of botanical and other purported medicinal natural products (NPs) continues to grow, especially among patients with chronic illnesses and patients managed on complex prescription drug regimens. With few exceptions, the risk of a given NP to precipitate a clinically significant pharmacokinetic NP-drug interaction (NPDI) remains understudied or unknown. Application of static or dynamic mathematical models to predict and/or simulate NPDIs can provide critical information about the potential clinical significance of these complex interactions. However, methods used to conduct such predictions or simulations are highly variable. Additionally, published reports using mathematical models to interrogate NPDIs are not always sufficiently detailed to ensure reproducibility. Consequently, guidelines are needed to inform the conduct and reporting of these modeling efforts. This recommended approach from the Center of Excellence for Natural Product Drug Interaction Research describes a systematic method for using mathematical models to interpret the interaction risk of NPs as precipitants of potential clinically significant pharmacokinetic NPDIs. A framework for developing and applying pharmacokinetic NPDI models is presented with the aim of promoting accuracy, reproducibility, and generalizability in the literature. SIGNIFICANCE STATEMENT Many natural products (NPs) contain phytoconstituents that can increase or decrease systemic or tissue exposure to, and potentially the efficacy of, a pharmaceutical drug; however, no regulatory agency guidelines exist to assist in predicting the risk of these complex interactions. This recommended approach from a multi-institutional consortium designated by National Institutes of Health as the Center of Excellence for Natural Product Drug Interaction Research provides a framework for modeling pharmacokinetic NP-drug interactions.
Cysteine-altering
variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear.
Cysteine-altering
variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls.
Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering
variants. Selleck Milademetan After adjustment for various covariates,
variant carriers had increased risk of stroke (OR 2.33, p=0.0004) and vascular dementia (OR 5.00, p=0.0ar dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.
Alemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified.
We retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity.
The regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.
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