Exact Occupation Time Distribution in a Non-Markovian Sequence and Its Relation to Spin Glass Models

We compute exactly the distribution of the occupation time in a discrete {\em non-Markovian} toy sequence which appears in various physical contexts such as the diffusion processes and Ising spin glass chains. The non-Markovian property makes the results nontrivial even for this toy sequence. The distribution is shown to have non-Gaussian tails characterized by a nontrivial large deviation function which is computed explicitly. An exact mapping of this sequence to an Ising spin glass chain via a gauge transformation raises an interesting new question for a generic finite sized spin glass model: at a given temperature, what is the distribution (over disorder) of the thermally averaged number of spins that are aligned to their local fields? We show that this distribution remains nontrivial even at infinite temperature and can be computed explicitly in few cases such as in the Sherrington-Kirkpatrick model with Gaussian disorder.Comment: 10 pages Revtex (two-column), 1 eps figure (included

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection

To unravel the strategy by which Brucella abortus establishes chronic infections, we explored its early interaction with innate immunity. Methodology/Principal Findings Brucella did not induce proinflammatory responses as demonstrated by the absence of leukocyte recruitment, humoral or cellular blood changes in mice. Brucella hampered neutrophil (PMN) function and PMN depletion did not influence the course of infection. Brucella barely induced proinflammatory cytokines and consumed complement, and was strongly resistant to bactericidal peptides, PMN extracts and serum. Brucella LPS (BrLPS), NH-polysaccharides, cyclic glucans, outer membrane fragments or disrupted bacterial cells displayed low biological activity in mice and cells. The lack of proinflammatory responses was not due to conspicuous inhibitory mechanisms mediated by the invading Brucella or its products. When activated 24 h post-infection macrophages did not kill Brucella, indicating that the replication niche was not fusiogenic with lysosomes. Brucella intracellular replication did not interrupt the cell cycle or caused cytotoxicity in WT, TLR4 and TLR2 knockout cells. TNF-α-induction was TLR4- and TLR2-dependent for live but not for killed B. abortus. However, intracellular replication in TLR4, TLR2 and TLR4/2 knockout cells was not altered and the infection course and anti-Brucella immunity development upon BrLPS injection was unaffected in TLR4 mutant mice. Conclusion/Significance We propose that Brucella has developed a stealth strategy through PAMPs reduction, modification and hiding, ensuring by this manner low stimulatory activity and toxicity for cells. This strategy allows Brucella to reach its replication niche before activation of antimicrobial mechanisms by adaptive immunity. This model is consistent with clinical profiles observed in humans and natural hosts at the onset of infection and could be valid for those intracellular pathogens phylogenetically related to Brucella that also cause long lasting infections

The lipopolysaccharide of Brucella abortus BvrS/BvrR mutants contains lipid A modifications and has higher affinity for bactericidal cationic peptides

The two-component BvrS/BvrR system is essential for Brucella abortus virulence. It was shown previously that its dysfunction abrogates expression of some major outer membrane proteins and increases bactericidal peptide sensitivity. Here, we report that BvrS/BvrR mutants have increased surface hydrophobicity and susceptibility to killing by nonimmune serum. The bvrS and bvrR mutant lipopolysaccharides (LPSs) bound more polymyxin B, chimeras constructed with bvrS mutant cells and parental LPS showed augmented polymyxin B resistance, and, conversely, parental cells and bvrS mutant LPS chimeras were more sensitive and displayed polymyxin B-characteristic outer membrane lesions, implicating LPS as being responsible for the phenotype of the BvrS/BvrR mutants. No qualitative or quantitative changes were detected in other envelope and outer membrane components examined: periplasmic beta(1-2) glucans, native hapten polysaccharide, and phospholipids. The LPS of the mutants was similar to parental LPS in O-polysaccharide polymerization and fine structure but showed both increased underacylated lipid A species and higher acyl-chain fluidity that correlated with polymyxin B binding. These lipid A changes did not alter LPS cytokine induction, showing that in contrast to other gram-negative pathogens, recognition by innate immune receptors is not decreased by these changes in LPS structure. Transcription of Brucella genes required for incorporating long acyl chains into lipid A (acpXL and lpxXL) or implicated in lipid A acylation control (bacA) was not affected. We propose that in Brucella the outer membrane homeostasis depends on the functioning of BvrS/BvrR. Accordingly, disruption of BvrS/BvrR damages the outer membrane, thus contributing to the severe attenuation manifested by bvrS and bvrR mutants

Clarifications on the Design and Interpretation of Conclusions from Health Canada’s Study on Wind Turbine Noise and Health

It has been extensively communicated that Health Canada’s Community Noise and Health Study (CNHS) did not find positive associations between wind turbine noise (WTN) levels and any of the evaluated health outcomes, beyond an increase in the prevalence of high annoyance toward several wind turbine features. The authors emphasize that this general conclusion remains bound by the study strengths and limitations. Following the publication of the CNHS findings, there has been interest among some individuals to present alternative interpretations of the results originally reported by Michaud et al. (J Acoust Soc Am 139(3):1443–1454, 2016. https://doi.org/10.1121/1.4942391). While recognizing the importance of independent scientific re-evaluation and/or reinterpretation, this commentary serves to clarify and, where necessary, correct some of the information put forward by others. One factor that has been re-evaluated by external stakeholders is the subsample of participants that comprise the lowest WTN category. In their reanalysis, they have eliminated this category, or introduced alternative comparative data. This paper identifies substantial issues associated with the re-evaluation put forth. To thoroughly address these issues and to avoid further confusion or misinterpretation, the authors of the CNHS provide a comparison between the CNHS health condition prevalence data and nationally representative health-based surveys conducted in Canada during the same calendar year. In addition, this paper responds to comments received to date on the CNHS, including the study’s age range, the generalization of findings, the provision of raw data, and conclusions on the association between WTN level and health