The early, delayed, and systemic effects of acute traumatic brain injury (TBI) are the result of inflammatory mediators which initiate systemic inflammatory response syndrome (SIRS), subsequent complement deficits and coagulopathy. Once SIRS is triggered by acute inflammation, it can detrimentally self-propagate. Systemic inflammation causes tissue damage leading to further inflammation and damage, leaving the body in a vicious cycle of hyperinflammation. Therefore, important inflammatory mediators like interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF) alpha, are targeted in compensatory anti-inflammatory response syndrome (CARS) in an attempt to control the development of SIRS. The hypothalamus-pituitary (HPA)-axis and sympathetic nervous system (SNS) efferent limbs in CARS provide negative feedback for the production of inflammatory mediators. However, in the case of acute TBI, the activation of CARS often leads to the complication of immunosuppression which may result in multi-organ dysfunction syndrome (MODS) and mortality. In light of this, the activation of the SIRS following acute TBI does not bode well. If left uncontrolled, multiple systems will be implicated making it difficult to remedy.

Canetti, Goldreich, Goldwasser, and Micali (STOC 2000) introduced the notion of resettable zeroknowledge proofs, where the protocol must be zero-knowledge even if a cheating verifier can reset the prover and have several interactions in which the prover uses the same random tape. Soon afterwards, Barak, Goldreich, Goldwasser, and Lindell (FOCS 2001) studied the closely related notion of resettable soundness, where the soundness condition of the protocol must hold even if the cheating prover can reset the verifier to have multiple interactions with the same verifier's random tape. The main problem left open by this work was whether it is possible to have a single protocol that is simultaneously resettable zero knowledge and resettably sound. We resolve this question by constructing such a protocol.At the heart of our construction is a new non-black-box simulation strategy, which we believe to be of independent interest. This new strategy allows for simulators which "marry" recursive rewinding techniques (common in the context of concurrent simulation) with non-black-box simulation. Previous non-black-box strategies led to exponential blowups in computational complexity in such circumstances, which our new strategy is able to avoid.

Inflammation in the periventricular white matter (PWM) of hypoxic neonatal brain causes myelination disturbances. In this connection, macrophage colony-stimulating factor (M-CSF) has been reported to regulate release of proinflammatory cytokines that may be linked to PWM damage. We sought to determine if M-CSF derived from amoeboid microglial cells (AMC) would promote proinflammatory cytokine production by astrocytes in the PWM following hypoxic exposure, and, if so, whether it is associated with axon degeneration and myelination disturbances. In 1-day hypoxic rats, expression of M-CSF was upregulated in AMC. This was coupled with increased expression of CSF-1 receptor, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in astrocytes, and TNF-receptor 1 and IL-receptor 1 on the axons. Neurofilament-200 immunopositive axons and myelin basic protein immunopositive processes appeared to undergo disruption in 14-days hypoxic rats. By electron microscopy, some axons showed degenerative changes affecting the microtubules and myelin sheath. Primary cultured microglial cells subjected to hypoxia showed enhanced release of M-CSF. Remarkably, primary cultured astrocytes treated with conditioned-medium derived from hypoxic microglia or M-CSF exhibited increased production of TNF-alpha and IL-1beta. Our results suggest that AMC-derived M-CSF promotes astrocytes to generate proinflammatory cytokines, which may be involved in axonal damage following a hypoxic insult.

Background Short-term recurrence of positive SARS-CoV-2 RNA PCR in discharged COVID-19 patients attracts the public’s concern. This study aimed to determine clinical and epidemiological results of such patients. Methods This retrospective study was conducted on 32 designated hospitals for COVID-19 patients discharged from January 14 th to March 10 th, 2020. After 28-day followed-up, re-positive patients confirmed by SARS-CoV-2 RNA RT-PCR were re-admitted to hospital for further treatments. All the close contacts of re-positive patients were asked 14-day self-segregating. Data of epidemiology, symptoms, laboratory tests and treatments were analyzed in re-positive patients and their close contacts were investigated. Results Of 1,282 discharged patients, 189 (14.74%) were tested re-positive of SARS-CoV-2 RNA during 28-day follow-up. The median time from discharge to re-positivity was 8 days (IQR 5-13). Patients in re-positive group were younger (34yr vs 45yr, p&0.001) with higher proportion of moderate symptoms (95.77% vs 84.35%, p&0.001) in the first hospitalization than negative group. During the second hospitalization, all re-positive patients showed normal in peripheral white blood cell and lymphocyte, and no new symptoms of COVID-19; 78.31% further improved on chest CT scan compared with the first discharge, yet 25.93% accepted antiviral therapy. The median time of re-positive to negative was 8 days (IQR 4-15). None of close contacts developed COVID-19. Conclusions Our data suggested that the short term recurrence of positive SARS-CoV-2 RNA in discharged patients is not a relapse of COVID-19, and the risk of onward transmission is very low. This provides important information for managing COVID-19 patients.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has led to several million confirmed cases and hundreds of thousands of deaths worldwide. To support the ongoing research and development of COVID-19 therapeutics, this report provides an overview of protein targets and corresponding potential drug candidates with bioassay and structure–activity relationship data found in the scientific literature and patents for COVID-19 or related virus infections. Highlighted are several sets of small molecules and biologics that act on specific targets, including 3CLpro, PLpro, RdRp, S-protein–ACE2 interaction, helicase/NTPase, TMPRSS2, and furin, which are involved in the viral life cycle or in other aspects of the disease pathophysiology. We hope this report will be valuable to the ongoing drug repurposing efforts and the discovery of new therapeutics with the potential for treating COVID-19.

Inflammation is a defensive response in the living tissue of the vascular system that acts against damage factors and involves various types of immune cells, including macrophages, neutrophils, endothelial cells and other associated immune molecules. If the release of inflammatory mediators is excessive, systemic inflammatory response syndrome may develop. Sepsis is the most common complication of severe burns and is a systemic inflammatory response syndrome that is caused by infectious factors and is capable of leading to multiple organ dysfunction and potentially death. Research concerning the mechanism and treatment of sepsis is crucial. Macrophages are an important type of immune cell that remove invasive pathogens and are involved in innate and adaptive immune responses. It has been previously reported that bone marrow mesenchymal stem cells (BMSCs) affect macrophages by regulating immunity. The present study aimed to investigate the effect of BMSCs on macrophage polarization in vivo and in vitro, in addition to the potential therapeutic effect of these cells on experimental sepsis. BMSCs and peritoneal macrophages were isolated from Sprague-Dawley rats and co-cultured overnight as a mixed culture or Transwell system, and subsequently stimulated with 100 ng/ml lipopolysaccharide (LPS). After 12 h, the medium was replaced with normal complete medium for various durations and supernatants were collected to extract proteins and cells for ELISA, western blot and flow cytometry analysis to investigate different aspects of macrophages. Sepsis was induced in Sprague-Dawley rats by injection of LPS (5 mg/kg), followed by tail vein injection of BMSCs or PBS 1 h later. After 6, 12, 24 and 48 h, lung tissues were harvested for pathological observation and peritoneal macrophages were collected for flow cytometry analysis to assess the expression of markers, including cluster of differentiation (CD)68 (used for gating), CD11c and CD206. The results demonstrated that, in the culture medium, LPS stimulation increased the expression of CD11c in macrophages, and the levels of tumor necrosis factor-α and inducible nitric oxide synthase were also increased. By contrast, in macrophages treated with BMSCs directly, the expression of CD11c was reduced compared with the LPS-stimulated macrophage alone group. However, the secretion of interleukin-10, transforming growth factor-β and arginase-1 was increased in the direct co-culture group, compared with the LPS-stimulated macrophage alone group. BMSCs reduced the inflammation in lung tissues and inhibited macrophage expression of CD11c in the rat model of sepsis. The results of the present study demonstrated that BMSCs co-cultured with macrophages directly inhibited macrophage differentiation into the M1 phenotype and reduced inflammation in macrophages stimulated by LPS. In vivo, BMSCs decreased the expression of CD11c in peritoneal macrophages and reduced the pathological inflammatory response in the lungs. The findings of the present study demonstrated that BMSCs may reduce the e...

In response to the ongoing COVID-19 pandemic, there is a worldwide effort being made to identify potential anti-SARS-CoV-2 therapeutics. Here, we contribute to these efforts by building machine-learning predictive models to identify novel drug candidates for the viral targets 3 chymotrypsin-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp). Chemist-curated training sets of substances were assembled from CAS data collections and integrated with curated bioassay data. The best-performing classification models were applied to screen a set of FDA-approved drugs and CAS REGISTRY substances that are similar to, or associated with, antiviral agents. Numerous substances with potential activity against 3CLpro or RdRp were found, and some were validated by published bioassay studies and/or by their inclusion in upcoming or ongoing COVID-19 clinical trials. This study further supports that machine learning-based predictive models may be used to assist the drug discovery process for COVID-19 and other diseases.

The developing brain is susceptible to hypoxic damage because of its high oxygen and energy requirements. Hypoxia-induced inflammatory response has been recognized as one of the main culprits in the development of hypoxic brain injury. In this regard, a hallmark feature is microglial activation which results in overproduction of inflammatory cytokines, free radicals and nitric oxide. Concomitantly, activated microglia exhibit enhanced expression of ion channels such as Kv1.2, Kv1.1 and Nav which further promote the release of inflammatory cytokines, chemokines and reactive oxygen species. Through the above-mentioned inflammatory mediators, activated microglia induce neuronal loss, axonal damage and oligodendroglial death along with myelination disturbances. Our recent studies have extended that tumor necrosis factor-alpha, interleukin-1beta, monocyte chemoattractant protein-1 and macrophage colony stimulating factor produced by activated microglia are linked to the pathogenesis of periventricular white matter damage in the hypoxic brain. It is envisaged that a better understanding of the interactions between microglia and neurons, axons and oligodendrocytes is key to the development of effective preventive and therapeutic strategies for mitigation of hypoxic brain injury.