How Will You Get Information You Need in a Zombie Apocalypse?

Zombification in the form of neoliberalism has significantly infected our libraries and the information chain, placing the world’s intellectual output at risk. Disaster planning will also be investigated as a response in the information chain to the metaphor of a zombie apocalypse

Sense of coherence predicts post-myocardial infarction trajectory of leisure time physical activity: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Physical activity confers a survival advantage after myocardial infarction (MI), yet the majority of post-MI patients are not regularly active. Since sense of coherence (SOC) has been associated with health outcomes and some health behaviours, we investigated whether it plays a role in post-MI physical activity.</p> <p>We examined the predictive role of SOC in the long-term trajectory of leisure time physical activity (LTPA) after MI using a prospective cohort design.</p> <p>Methods</p> <p>A cohort of 643 patients aged ≤ 65 years admitted to hospital in central Israel with incident MI between February 1992 and February 1993 were followed up for 13 years. Socioeconomic, clinical and psychological factors, including SOC, were assessed at baseline, and LTPA was self-reported on 5 separate occasions during follow-up. The predictive role of SOC in long-term trajectory of LTPA was assessed using generalized estimating equations.</p> <p>Results</p> <p>SOC was consistently associated with engagement in LTPA throughout follow-up. Patients in the lowest SOC tertile had almost twice the odds (odds ratio,1.99; 95% confidence interval,1.52-2.60) of decreasing their engagement in LTPA as those in the highest tertile. A strong association remained after controlling for disease severity, depression, sociodemographic and clinical factors.</p> <p>Conclusion</p> <p>Our evidence suggests that SOC predicts LTPA trajectory post-MI. Assessment of SOC can help identify high-risk MI survivors, who may require additional help in following secondary prevention recommendations which can dramatically improve prognosis.</p

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

The role of the planar cell polarity protein Vangl2 in retinal axon guidance

Van-Gogh-like 2 (Vangl2), a critical player in the establishment of planar cell polarity (PCP), is well known for its crucial role in vertebrate neural tube development. Over time Vangl2 has also been shown to regulate the development and organogenesis of numerous vertebrate tissues. This thesis presents a novel function for Vangl2 in the regulation of retinal development and retinal axon guidance and further expands the field of knowledge regarding Vangl2-mediated development. We initially established a spatial and temporal map of Vangl2 expression and found dynamic, robust expression in the emerging ganglion cell layer (GCL) and optic nerve (ON) of the developing retina. Vangl2 expression persisted in the adult retina and was found prominently in axons of retinal ganglion cells (RGC). Upon examination of mutant Vangl2Lp/Lp retinas, Vangl2 was discovered to be required for retinal and optic nerve development. Specifically, Vangl2Lp/Lp embryos displayed a significantly reduced ocular size, marked thickening of the retina, and striking abnormalities in the morphology of the optic nerve (significant hypoplasia, and aberrant exit trajectory). The latter was due to a severe intraretinal axon guidance defect. To unravel the mechanism behind this newly found Vangl2-mediated retinal axon guidance, we then explored the interaction of Vangl2 with candidate genes that had an ascribed role in axon guidance. We discovered that the heparan sulfate proteoglycan Syndecan4 (Sdc4) was expressed in an overlapping pattern with Vangl2 in the developing retina and the kidney. Furthermore, we discovered that the two proteins were asymmetrically distributed within the cell and could physically interact with one another. These findings led us to propose a mechanism whereby Sdc4 and Vangl2 work together to transduce axon guidance signaling across the cell membrane. Additionally, a novel Vangl2 mouse mutant, Curlybob (Cb) with an I268N mutation displayed both similar and slightly different phenotypes than the known Looptail (Lp) alleles with Vangl2Cb/Cb mutants displaying only a slight retinal axon guidance defect. We sought to biochemically characterize this mutant allele and determined that the I268N variant was a loss-of-function mutation caused by impaired targeting of the protein to the plasma membrane with an associated retention in the endoplasmic reticulum (ER) and decrease in protein stability. This is similar to previously characterized Lp- and neural tube defect (NTD)-associated variants, establishing the I268 residue as crucial for protein function and likely a predictive NTD risk factor in humans.Van-Gogh-like 2 (Vangl2) joue un rôle critique dans l'établissement de la polarité cellulaire planaire (PCP) et dans le développement du tube neural chez les vertébrés. Vangl2 contribue également à l'organogenèse et au développement de nombreux tissus chez les vertébrés. Cette thèse élargit le domaine des connaissances sur le développement médié par Vangl2 en présentant une nouvelle fonction de Vangl2 dans la régulation du développement rétinien et dans le guidage axonal rétinien.Nous avons premièrement établi l'expression spacio-temporelle de Vangl2. Nous avons trouvé une expression dynamique et robuste dans la couche de cellules ganglionnaires de la rétine et dans le nerf optique en développement. Cette expression persiste dans la rétine adulte et elle est prédominante dans les axones des cellules ganglionnaires rétiniennes. Lors de l'examen des rétines Vangl2Lp/Lp, Vangl2 s'est avéré nécessaire pour le développement rétinien et du nerf optique. Spécifiquement, les embryons mutants Vangl2Lp/Lp présentaient une taille oculaire significativement réduite, un épaississement de la rétine et des anomalies dans la morphologie du nerf optique (hypoplasie significative et trajectoire de sortie aberrante). Cette dernière est dû à un grave défaut de guidage axonal intrarétinien. Afin d'élucider le mécanisme derrière le guidage axonal rétinien médié par Vangl2, nous avons exploré l'interaction entre Vangl2 et certains gènes candidats dont le rôle dans le guidage axonal était déjà établi. Nous avons découvert que l'expression de la protéine Syndecan4 (Sdc4) chevauche avec l'expression de Vangl2 dans la rétine en développement et dans le rein. De plus, nous avons découvert que les deux protéines étaient distribuées de façon asymétrique dans la cellule et pouvaient interagir physiquement ensemble. Ces résultats nous ont amenés à proposer un mécanisme par lequel Sdc4 et Vangl2 travaillent ensemble pour transduire la signalisation du guidage axonal à travers la membrane cellulaire. De plus, Curlybob, le nouveau mutant de souris Vangl2 qui a une mutation I268N, présente un défaut de guidage des axones rétiniennes similaire à ce qui a été observé pour les autres allèles Lp connues, mais celui-ci est plus léger. Nous avons caractérisé biochimiquement la mutation I268N et nous avons déterminé que celle-ci est une mutation par perte de fonction qui ne cible pas correctement la protéine à la membrane plasmique. En fait, la protéine mutante est retenue dans le réticulum endoplasmique et affiche une diminution de la stabilité. Ces résultats sont similaires à ce qui a été observé pour les mutations associés à Lp et aux anomalies du tube neural (ATN) caractérisés précédemment. En effet, le résidu I268 est crucial pour la fonction de la protéine et il est probablement un facteur de risque prédictif pour les ATN chez les humains. En effet, toute les mutations connus dans VANGL pourraient un jour aussi être associés à des maladies oculaires humaines

Formic and acetic acid pKa values increase under nanoconfinement.

Organic acids are prevalent in the environment and their acidity and the corresponding dissociation constants can change under varying environmental conditions. The impact of nanoconfinement (when acids are confined within nanometer-scale domains) on physicochemical properties of chemical species is poorly understood and is an emerging field of study. By combining infrared and Raman spectroscopies with molecular dynamics (MD) simulations, we quantified the effect of nanoconfinement in silica nanopores on one of the fundamental chemical reactions-the dissociation of organic acids. The pKa of formic and acetic acids confined within cylindrical silica nanopores with 4 nm diameters were measured. MD models were constructed to calculate the shifts in the pKa values of acetic acid nanoconfined within 1, 2, 3, and 4 nm silica slit pores. Both experiments and MD models indicate a decrease in the apparent acid dissociation constants (i.e., increase in the pKa values) when organic acids are nanoconfined. Therefore, nanoconfinement stabilizes the protonated species. We attribute this observation to (1) a decrease in the average dielectric response of nanoconfined aqueous solutions where charge screening may be decreased; or (2) an increase in proton concentration inside nanopores, which would shift the equilibrium towards the protonated form. Overall, the results of this study provide the first quantification of the pKa values for nanoconfined formic and acetic acids and pave the way for a unifying theory predicting the impact of nanoconfinement on acid-base chemistry

Genetic control of susceptibility to candida albicans in SM/J mice

In the immunocompromised host, invasive infection with the fungal pathogen Candida albicans is associated with high morbidity and mortality. Sporadic cases in otherwise normal individuals are rare, and they are thought to be associated with genetic predisposition. Using a mouse model of systemic infection with C. albicans, we identified the SM/J mouse strain as unusually susceptible to infection. Genetic linkage studies in informative [C57BL/6JxSM/J]F2 mice identified a major locus on distal chromosome 15, given the appellation Carg5, that regulates C. albicans replication in SM/J mice. Cellular and molecular immunophenotyping experiments, as well as functional studies in purified cell populations from SM/J and C57BL/6J, and in [C57BL/ 6JxSM/J]F2 mice fixed for homozygous or heterozygous Carg5 alleles, indicate that Carg5-regulated susceptibility in SM/J is associated with a complex defect in the myeloid compartment of these mice. SM/J neutrophils express lower levels of Ly6G, and importantly, they show significantly reduced production of reactive oxygen species in response to stimulation with fMLF and PMA. Likewise, CD11b+Ly6G2Ly6Chi inflammatory monocytes were present at lower levels in the blood of infected SM/J, recruited less efficiently at the site of infection, and displayed blunted oxidative burst. Studies in F2 mice establish strong correlations between Carg5 alleles, Ly6G expression, production of serum CCL2 (MCP-1), and susceptibility to C. albicans. Genomic DNA sequencing of chromatin immunoprecipitated for myeloid proinflammatory transcription factors IRF1, IRF8, STAT1 and NF-kB, as well as RNA sequencing, were used to develop a "myeloid inflammatory score" and systematically analyze and prioritize potential candidate genes in the Carg5 interval.Peer reviewed: YesNRC publication: Ye