The role of neuronal NLRP1 inflammasome in Alzheimer's disease : bringing neurons into the neuroinflammation game

The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer’s disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates, and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β (IL-1β) and interleukin-18 (IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the Nlrp1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD

Assessment of phytochemical content, polyphenolic composition, antioxidant and antibacterial activities of Leguminosae medicinal plants in Peninsular Malaysia

Background: Many medicinal plants from Leguminosae family can be found easily in Malaysia. These plants have been used as traditional medicines by local ethnic groups, where they are prepared as decoction, pastes for wound infections, and some have been eaten as salad. This paper focused on the assessment of antioxidant potential, antibacterial activity and classes of phytochemicals of nine plants from the Leguminosae family. Methods: Acacia auriculiformis, Bauhinia kockiana, Bauhinia purpurea, Caesalpinia pulcherrima, Calliandra tergemina, Cassia surattensis, Leucaena leucocephala, Peltophorum pterocarpum, and Samanea saman were extracted with aqueous methanol and dichloromethane:methanol mixture to test for antioxidant and antibacterial activities. The Folin-Ciocalteu assay was conducted to quantify the total phenolic content and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the free radical quenching capacity. Antibacterial activity was assessed using disc diffusion (Kirby-Bauer) assay. Screening for major classes of phytochemical was done using standard chemical tests. Results: B. kockiana flowers and C. pulcherrima leaves contained high total phenolic content (TPC) and strong DPPH radical scavenging ability with TPC of 8280 ± 498 mg GAE/100 g, IC50 of 27.0 ± 5.0 μg/mL and TPC of 5030 ± 602 mg GAE/100 g, IC50 of 50.0 ± 5.0 μg/mL respectively. Positive correlation was observed between TPC and free radical scavenging ability. Most extracts showed antibacterial activity against Gram positive bacteria at 1 mg, while none showed activity against Gram negative bacteria at the same dose. All extracts (except Samanea saman flower) showed antibacterial activity against two strains of methicillin resistant Staphylococcus aureus (MRSA) with MID values ranging between 100 μg/disc and 500 μg/disc. Conclusion: The potential source of antioxidant and antibacterial agents, especially for MRSA infection treatments were found in B. kockiana, C. pulcherrima, C. tergemina and P. pterocarpum. These preliminary results would be a guide in the selection of potential candidates for further pharmacological study and in search of new drug candidate in treating MRSA infections

On the Amortized Communication Complexity of Byzantine Broadcast

Designing an efficient solution for Byzantine broadcast is an important problem for many distributed computing and cryptographic tasks. There have been many attempts to achieve sub-quadratic communication complexity in several directions, both in theory and practice, all with pros and cons. This paper initiates the study of another attempt: improving the amortized communication complexity of multi-shot Byzantine broadcast. Namely, we try to improve the average cost when we have sequential multiple broadcast instances. We present a protocol that achieves optimal amortized linear complexity under an honest majority. Our core technique is to efficiently form a network for disseminating the sender\u27s message by keeping track of dishonest behaviors over multiple instances. We also generalize the technique for the dishonest majority to achieve amortized quadratic communication complexity

Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease

Huntington’s disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general

Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology

Cardiac arrhythmias in patients with COVID-19.

The emergence of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major global public health concern. Although SARS-CoV-2 causes primarily respiratory problems, concurrent cardiac injury cannot be ignored since it may be an independent predictor for adverse outcomes. Cardiac arrhythmias are often observed in patients with COVID-19, especially in severe cases, and more likely contribute to the high risk of adverse outcomes. Arrhythmias should be regarded as one of the main complications of COVID-19. Mechanistically, a number of ion channels can be adversely affected in COVID-19, leading to alterations in cardiac conduction and/or repolarization properties, as well as calcium handling, which can predispose to cardiac arrhythmogenesis. In addition, several antimicrobials that are currently used as potential therapeutic agents for COVID-19, such as chloroquine, hydroxychloroquine and azithromycin, have uncertain benefit, and yet may induce electrocardiographic QT prolongation with potential ventricular pro-arrhythmic effects. Continuous electrocardiogram monitoring, accurate and prompt recognition of arrhythmias are important. The present review focuses on cardiac arrhythmias in patients with COVID-19, its underlying mechanisms, and proposed preventive and therapeutic strategies

Results from the centers for disease control and prevention's predict the 2013-2014 Influenza Season Challenge

Background: Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013-14 Unites States influenza season. Methods: Challenge contestants were asked to forecast the start, peak, and intensity of the 2013-2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013-March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). Results: Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. Conclusion: Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts. © 2016 The Author(s)

Improved Outcomes Associated With the Use of Intravenous Acetaminophen for Management of Acute Post-Surgical Pain in Cesarean Sections and Hysterectomies

Background: Post-surgical pain impacts many patient outcomes. Effective pain management increasingly relies on multimodal analgesia regimens in which acetaminophen (APAP) is a key component. The aim of our study was to examine the impact of oral APAP versus intravenous (IV) APAP as a component of post-surgical pain management after Cesarean sections and hysterectomies. Methods: A retrospective analysis of the Cerner HealthFacts® database (from January, 2011 to December, 2015) was conducted to compare outcomes of Cesarean section and hysterectomy surgery patients who received oral APAP to those who received IV APAP post-surgically. Length of stay (LOS), daily morphine milligram equivalent (MME) consumption, the presence of potential opioid-related adverse events (ORADEs), and total pharmacy costs were assessed. Adjusted results were derived using inverse probability weighted regression adjustment (IPW-RA) estimators based on covariates that included demographics, comorbidities, patient clinical characteristics, and hospital characteristics. Results: The study identified 29,124 Cesarean section patients (24,612 oral APAP; 4,512 IV APAP) and 9,767 hysterectomy surgery patients (5,586 oral APAP; 4,181 IV APAP). Compared to the oral APAP group, the IV APAP group had reductions in adjusted LOS (Cesarean section: -11.7% days (P < 0.001), hysterectomy: -11.8% days (P = 0.005)), lowered adjusted daily MME consumption from day 0 to day 3 (Cesarean section: -1.6 mg (P < 0.001), hysterectomy: -1.7 mg (P = 0.014)), and reduced risk of ORADEs for Cesarean sections (relative risk of 0.45, P < 0.001). Total pharmacy costs were not significantly different between the two APAP groups. Conclusions: Post-surgical pain managed with IV APAP in patients undergoing Cesarean section or hysterectomy was associated with shorter LOS, reduced risk of ORADEs, and lower opioid consumption compared to patients managed with oral APAP, without adversely impacting total pharmacy costs