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Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication. [ABSTRACT FROM AUTHOR]

Arteriviruses are a family of positive-stranded RNA viruses that includes the prototypic equine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV). Although several vaccines against these viruses are commercially available there is room for improvement, especially in the case of PRRSV. The ability of arteriviruses to counteract the immune response is thought to decrease the efficacy of the current modified live virus vaccines. We have recently shown that the deubiquitinase (DUB) activity of EAV papain-like protease 2 (PLP2) is important for the inhibition of innate immune activation during infection. A vaccine virus lacking PLP2 DUB activity may therefore be more immunogenic and provide improved protection against subsequent challenge than its DUB-competent counterpart. To test this hypothesis, twenty Shetland mares were randomly assigned to one of three groups. Two groups were vaccinated, either with DUB-positive ( n = 9) or DUB-negative ( n = 9) recombinant EAV. The third group ( n = 2) was not vaccinated. All horses were subsequently challenged with the virulent KY84 strain of EAV. Both vaccine viruses proved to be replication competent in vivo . In addition, the DUB-negative virus provided a similar degree of protection against clinical disease as its DUB-positive parental counterpart. Owing to the already high level of protection provided by the parental virus, a possible improvement due to inactivation of PLP2 DUB activity could not be detected under these experimental conditions. Taken together, the data obtained in this study warrant further in vivo investigations into the potential of using DUB-mutant viruses for the improvement of arterivirus vaccines. [ABSTRACT FROM AUTHOR]

Simon Stevin's (1548–1620) treatises had an influence on the construction of settlements in Southeast Asia as well as on the settlement of Malacca. In the treatise ‘Ideal Plan for a City’, published in 1649, Stevin developed a city design in which he was influenced by ideas of an ideal town according to the principles of the Italian Renaissance (fourteenth century until the sixteenth century). This treatise had an influence on the development of settlements in Southeast Asia. The settlement of Malacca was influenced, apart from the Dutch, by Portuguese design and architecture. The influence of Simon Stevin's treatise was also noticable on the Verenigde Oostindische Compagnie (United East Indies Company – VOC) settlement of Jayakarta (Batavia). VOC architecture and town planning in general was influenced by the ideas of Simon Stevin. The findings are that the three requirements, defence, agriculture and location, are met as mentioned by Stevin in ‘Ideal Plan for a City’. The other requirements of design (as mentioned in his treatise Vande Oirdeningh der Steden of 1599) – arithmetic, symmetry, placement of buildings and a system of streets – are not met. [ABSTRACT FROM PUBLISHER]

The COVID-19 pandemic has disrupted economic activity in India. Adjusting policies to contain transmission while mitigating the economic impact requires an assessment of the economic situation in near real-time and at high spatial granularity. This paper shows that daily electricity consumption and monthly nighttime light intensity can proxy for economic activity in India. Energy consumption is compared with the predictions of a consumption model that explains 90 percent of the variation in normal times. Energy consumption declined strongly after a national lockdown was implemented on March 25, 2020 and remained a quarter below normal levels throughout April. It recovered subsequently, but electricity consumption remained lower even in September. Not all states and union territories have been affected equally. While electricity consumption halved in some, it declined very little in others. Part of the heterogeneity is explained by the prevalence of COVID-19 infections, the share of manufacturing, and return migration. During the national lockdown, higher COVID-19 infection rates at the district level were associated with larger declines in nighttime light intensity. Without effectively reducing the risk of a COVID-19 infection, voluntary reductions of mobility will hence prevent a return to full economic potential even when restrictions are relaxed. Together, daily electricity consumption and nighttime light intensity allow monitoring economic activity in near real-time and high spatial granularity. [ABSTRACT FROM AUTHOR]

Background: Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident.Methods: We performed a nested case control study of samples obtained before and after noncardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT-PCR) relative microRNA expression (cycle quantification [Cq] threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO).Results: MicroRNAs were detectable in all 59 patients (median age 67 yr [61-75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95-8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94-10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia.Conclusions: Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury. [ABSTRACT FROM AUTHOR]

Background: Myocardial injury is more frequent after noncardiac surgery in patients with preoperative cardiac vagal dysfunction, as quantified by delayed heart rate (HR) recovery after cessation of cardiopulmonary exercise testing. We hypothesised that serial and dynamic measures of cardiac vagal activity are also associated with myocardial injury after noncardiac surgery.Methods: Serial autonomic measurements were made before and after surgery in patients undergoing elective noncardiac surgery. Cardiac vagal activity was quantified by HR variability and HR recovery after orthostatic challenge (supine to sitting). Revised cardiac risk index (RCRI) was calculated for each patient. The primary outcome was myocardial injury (high-sensitivity troponin ≥15 ng L-1) within 48 h of surgery, masked to investigators. The exposure of interest was cardiac vagal activity (high-frequency power spectral analysis [HFLn]) and HR recovery 90 s from peak HR after the orthostatic challenge.Results: Myocardial injury occurred in 48/189 (25%) patients, in whom 41/48 (85%) RCRI was <2. In patients with myocardial injury, vagal activity (HFLn) declined from 5.15 (95% confidence interval [CI]: 4.58-5.72) before surgery to 4.33 (95% CI: 3.76-4.90; P<0.001) 24 h after surgery. In patients who remained free of myocardial injury, HFLn did not change (4.95 [95% CI: 4.64-5.26] before surgery vs 4.76 [95% CI: 4.44-5.08] after surgery). Before and after surgery, the orthostatic HR recovery was slower in patients with myocardial injury (5 beats min-1 [95% CI: 3-7]), compared with HR recovery in patients who remained free of myocardial injury (10 beats min-1 [95% CI: 7-12]; P=0.02).Conclusions: Serial HR measures indicating loss of cardiac vagal activity are associated with perioperative myocardial injury in lower-risk patients undergoing noncardiac surgery. [ABSTRACT FROM AUTHOR]

Objective Experimental animal models demonstrate that autonomic activity regulates systemic inflammation. By contrast, human studies are limited in number and exclusively use heart rate variability (HRV) as an index of cardiac autonomic regulation. HRV measures are primarily dependent on, and need to be corrected for, heart rate. Thus, independent autonomic measures are required to confirm HRV-based findings. Here, the authors sought to replicate the findings of preceding HRV-based studies by using HRV-independent, exercise-evoked sympathetic and parasympathetic measures of cardiac autonomic regulation to examine the relationship between autonomic function and systemic inflammation. Methods Sympathetic function was assessed by measuring heart rate changes during unloaded pedaling prior to onset of exercise, divided into quartiles; an anticipatory heart rate (AHRR) rise during this period is evoked by mental stress in many individuals. Parasympathetic function was assessed by heart rate recovery (HRR) 60 s after finishing cardiopulmonary exercise testing, divided into quartiles. Parasympathetic dysfunction was defined by delayed heart rate recovery (HRR) ≤12.beats.min −1 , a threshold value associated with higher cardiovascular morbidity/mortality in the general population. Systemic inflammation was primarily assessed by neutrophil-lymphocyte ratio (NLR), where a ratio >4 is prognostic across several inflammatory diseases and correlates strongly with elevated plasma levels of pro-inflammatory cytokines. High-sensitivity C-reactive protein (hsCRP) was also measured. Results In 1624 subjects (65 ± 14 y; 67.9% male), lower HRR (impaired vagal activity) was associated with progressively higher NLR (p = 0.004 for trend across quartiles). Delayed HRR, recorded in 646/1624 (39.6%) subjects, was associated with neutrophil-lymphocyte ratio >4 (relative risk: 1.43 (95%CI: 1.18–1.74); P = 0.0003). Similar results were found for hsCRP (p = 0.045). By contrast, AHRR was not associated with NLR (relative risk: 1.24 (95%CI: 0.94–1.65); P = 0.14). Conclusions Delayed HRR, a robust measure of parasympathetic dysfunction, is independently associated with leukocyte ratios indicative of systemic inflammation. These results further support a role for parasympathetic modulation of systemic inflammation in humans. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Total hip/knee replacement surgery (THR/TKR respectively) is associated with an increased risk of venous thromboembolism. Dabigatran is recommended as a thromboprophylactic agent post orthopaedic surgery. The aim of this study was to assess the post-operative (Day-1 and Day-2) effect of prophylactic Dabigatran on: the thrombin generation (TG) assay; prothrombin fragment 1.2 (F1.2); thrombin-antithrombin complexes (TAT); D-dimer (D-D); and other coagulation parameters. Methods and samples: Nineteen patients (12 THR, 7 TKR) who received 110mg dabigatran 4hours post-operatively, then 220mg the following day, were recruited. Blood was collected: pre-operatively (Pre-); peri-operatively (Peri-); 19hours after 110mg dabigatran (Day-1); and 17hours after 220mg dabigatran (Day-2). The TG assay was measured using the Calibrated Automated Thrombogram and a low concentration of tissue factor. Other coagulation parameters measured included activated partial thromboplastin time (APTT), thrombin-time (TT), ecarin-clotting time (ECT) and Hemoclot tests. Results: From Pre- to Peri-, ETP/peak-thrombin, F1.2, TAT and D-D increased significantly. From Peri- to Day-1 and Day-2: TAT reduced progressively; D-D increased; F1.2 did not change significantly; lag-time and time-to-peak prolonged; ETP/Peak-thrombin increased spuriously, due to Dabigatran interfering with the α-2 macroglobulin:thrombin complex in the TG assay. APTT, TT, ECT and Hemoclot increased progressively post-operatively; good correlations were seen between these tests. Conclusion: The effect of dabigatran on the TG assay, showed a spurious increase in ETP and Peak-thrombin due to its interference with the TG assay. Dabigatran reduced TAT, but not F1.2, suggesting that thrombin was still being generated after surgery, but was blocked by Dabigatran. [Copyright &y& Elsevier]