Long-Range Autocorrelations of CpG Islands in the Human Genome

In this paper, we use a statistical estimator developed in astrophysics to study the distribution and organization of features of the human genome. Using the human reference sequence we quantify the global distribution of CpG islands (CGI) in each chromosome and demonstrate that the organization of the CGI across a chromosome is non-random, exhibits surprisingly long range correlations (10 Mb) and varies significantly among chromosomes. These correlations of CGI summarize functional properties of the genome that are not captured when considering variation in any particular separate (and local) feature. The demonstration of the proposed methods to quantify the organization of CGI in the human genome forms the basis of future studies. The most illuminating of these will assess the potential impact on phenotypic variation of inter-individual variation in the organization of the functional features of the genome within and among chromosomes, and among individuals for particular chromosomes

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Formation of CO₂ and Ethane from Propionyl over Platinum: A Density Functional Theory Study

The conversion of propionyl, the most stable dehydrogenation product of 1-propanol on flat and stepped Pt(111) surfaces is explored computationally as a model for the transformation of alcohols on Pt to CO₂ and hydrocarbons. We studied a reaction network in which dehydrogenation steps or hydroxyl insertion may precede the desired C–C cleavage, via either decarboxylation or decarbonylation. In the latter case, CO₂ will be obtained via a subsequent water-gas-shift reaction. On a flat surface, the decarbonylation pathway with the highest barrier of 91 kJ mol^–1 was calculated to be preferred, as the decarboxylation reactions are inaccessible because of high barriers of the preceding dehydrogenations, 129 kJ mol^–1, or the C–C bond scission itself, 204 kJ mol^–1. At step defects the highest barrier for decarboxylation was determined to be notably lower, at 86 kJ mol^–1, making this pathway competitive for C–C scission

Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis.

The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis

The lipid-sensor TREM2 aggravates disease in a model of LCMV-induced hepatitis

textabstractLipid metabolism is increasingly being appreciated to affect immunoregulation, inflammation and pathology. In this study we found that mice infected with lymphocytic choriomeningitis virus (LCMV) exhibit global perturbations of circulating serum lipids. Mice lacking the lipid-sensing surface receptor triggering receptor expressed on myeloid cells 2 (Trem2 -/-) were protected from LCMV-induced hepatitis and showed improved virus control despite comparable virus-specific T cell responses. Non-hematopoietic expression of TREM2 was found to be responsible for aggravated hepatitis, indicating a novel role for TREM2 in the non-myeloid compartment. These results suggest a link between virus-perturbed lipids and TREM2 that modulates liver pathogenesis upon viral infection. Targeted interventions of this immunoregulatory axis may ameliorate tissue pathology in hepatitis

Characteristics, predictors and outcomes among 99 patients hospitalised with COVID-19 in a tertiary care centre in Switzerland: an observational analysis

AIMS OF THE STUDY To describe admission characteristics, risk factors and outcomes of patients with coronavirus disease 2019 (COVID-19) hospitalised in a tertiary care hospital in Switzerland during the early phase of the pandemic. METHODS This retrospective cohort study included adult patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) testing and hospitalised at the cantonal hospital Aarau (Switzerland) between 26 February 2020 and 30 April 2020. Our primary endpoint was severe COVID-19 progression defined as a composite of transfer to the intensive care unit (ICU) and in-hospital mortality. RESULTS A total of 99 patients (median age 67 years [interquartile range 56–76], 37% females) were included and 35% developed severe COVID-19 progression (24% needed ICU treatment, 19% died). Patients had a high burden of comorbidities with a median Charlson comorbidity index of 3 points and a high prevalence of hypertension (57%), chronic kidney disease (28%) and obesity (27%). Baseline characteristics with the highest prognostic value for the primary endpoint by means of area under the receiver operating characteristic curve were male gender (0.63) and initial laboratory values including shock markers (lactate on ambient air 0.67; lactate with O2 supply 0.70), markers of inflammation (C-reactive protein 0.72, procalcitonin 0.80) and markers of compromised oxygenation (pO2 0.75 on ambient air), whereas age and comorbidities provided little prognostic information. CONCLUSION This analysis provides insights into the first consecutively hospitalised patients with confirmed COVID-19 at a Swiss tertiary care hospital during the initial period of the pandemic. Markers of disease progression such as inflammatory markers, markers for shock and impaired respiratory function provided the most prognostic information regarding severe COVID-19 progression in our sample

Comparison of characteristics, predictors and outcomes between the first and second COVID-19 waves in a tertiary care centre in Switzerland: an observational analysis

AIM OF THE STUDY To compare admission characteristics, predictors and outcomes of patients with confirmed coronavirus disease 2019 (COVID-19) hospitalised in a tertiary care hospital in Switzerland during the first and second waves of the pandemic. METHODS This retrospective observational analysis included adult patients with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection confirmed by a real-time reverse transcriptase polymerase chain reaction (RT-PCR) or rapid antigen test and hospitalised at the Cantonal Hospital Aarau from 26 February to 30 April 2020 (first wave) and from 1 October to 31 December 2020 (second wave). The primary endpoint was all-cause in-hospital mortality. The secondary endpoints were transfer to the intensive care unit (ICU) and length of hospital stay (LOS). RESULTS Overall, 486 patients (mean age 65.9 years ± 14.7 SD, 65% male) were included. Ninety-two patients (19%) died during the hospital stay and 92 patients (19%) were transferred to the ICU. Admission characteristics, including comorbidities and frailty, were similar for patients of the first (n = 100) and second wave (n = 386). However, during the second wave the median time from symptom onset to presentation to the emergency department (ED) was shorter (7 days, interquartile range [IQR] 4–9 vs 8 days, IQR 4–11; p = 0.02). In the second wave, most patients received high-dose glucocorticoid treatment (0% vs 76%, p <0.01). In-hospital mortality was similar among COVID-19 patients in the first (19/100, 19%) and second wave (73/386, 19%); this finding persisted after full adjustment in multiple regression models (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI] 0.49–2.80; p = 0.71). Risk for ICU admission was also similar (24% vs 18%; aOR 0.98, 95% CI 0.46–2.06; p = 0.95). More patients were transferred to rehabilitation facilities in the second wave (18% vs 31%; aOR 2.06, 95% CI 1.04–4.07; p = 0.04) and LOS was 2.5 days shorter (9.0 vs 6.5 days; adjusted difference −2.53 days, 95%-CI −4.51 to −0.54; p = 0.01). Main predictors for in-hospital death were patient age (aOR 1.07, 95% CI 1.02–1.11; p <0.01), male sex (aOR 2.41, 95% CI 1.05–5.55; p = 0.04) and the age-adjusted Charlson comorbidity index (aOR 1.27, 95% CI 1.09–1.48 p <0.01). CONCLUSION Despite differing treatment regimens, mortality and ICU admission remained largely unchanged for COVID-19 patients admitted during the second wave of the pandemic in our tertiary care hospital. However, discharge processes were optimised with patients leaving the hospital earlier and going to rehabilitation facilities more often

CD8+ T cells induce cachexia during chronic viral infection

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8 T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8 T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8 T cell response and required T cell–intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8 T cells in IAC