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Background: A peculiar feature of the hepatitis E virus (HEV) is its reliance on the exosomal route for viral release. Genomic replication is mediated via the viral polyprotein pORF1, yet little is known about its subcellular localization. Methods: Subcellular localization of pORF1 and its subdomains, generated and cloned based on a structural prediciton of the viral replicase, was analyzed via confocal laser scanning microscopy. Exosomes released from cells were isolated via ultracentrifugation and analyzed by isopycnic density gradient centrifugation. This was followed by fluorimetry or Western blot analyses or reverse transcriptase–polymerase chain reaction to analyze separated particles in more detail. Results: We found pORF1 to be accumulating within the endosomal system, most dominantly to multivesicular bodies (MVBs). Expression of the polyprotein’s 7 subdomains revealed that the papain-like cysteine-protease (PCP) is the only domain localizing like the full-length protein. A PCP-deficient pORF1 mutant lost its association to MVBs. Strikingly, both pORF1 and PCP can be released via exosomes. Similarly, genomic RNA still is released via exosomes in the absence of pORF2/3. Conclusions: Taken together, we found that pORF1 localizes to MVBs in a PCP-dependent manner, which is followed by exosomal release. This reveals new aspects of HEV life cycle, because replication and release could be coupled at the endosomal interface. In addition, this may mediate capsid-independent spread or may facilitate the spread of viral infection, because genomes entering the cell during de novo infection readily encounter exosomally transferred pORF1.

Abstract Cardiovascular diseases (CVDs) encompass various conditions affecting the heart and its blood vessels and are often linked with oral microbes. Our data analysis aimed to identify oral bacteria from other non-oral sites (i.e., gut, arterial plaque and cultured blood) that could be linked with CVDs. Taxonomic profiling identified bacteria to the species level and compared with the Human Oral Microbiome Database (HOMD). The oral bacteria in the gut, cultured blood and arterial plaque samples were catalogued, with their average frequency calculated for each sample. Additionally, data were filtered by comparison with the Human Microbiome Project (HMP) database. We identified 17,243 microbial species, of which 410 were present in the HOMD database and further denominated as “oral”, and were found in at least one gut sample, but only 221 and 169 species were identified in the cultured blood and plaque samples, respectively. Of the 410 species, 153 were present solely in oral-associated environments after comparison with the HMP database, irrespective of their presence in other body sites. Our results suggest a potential connection between the presence of specific species of oral bacterial and occurrence of CVDs. Detecting these oral bacterial species in non-oral sites of patients with CVDs could help uncover the link between oral health and general health, including cardiovascular conditions via bacterial translocation.

Three new species, Coenosia circuita sp. n., Coenosia grunowiana sp. n. and Coenosia neaurifa sp. n. are described from Madagascar as new to science. The identification key to the species of the Afrotropical group “Coenosia” created in 1940 by Van Emden has been updated and considers now 14 species.

Abstract Chronic obstructive pulmonary disease (COPD) is associated with smoking and work-related health hazards. Most studies have reported prevalences, and the number of studies examining incidences and social inequalities is small. We analyzed the development of social inequalities of COPD-incidences in terms of income and exacerbations in terms of hospital admissions. Findings were based on claims data from a German statutory health insurance covering 2008 to 2019. Outpatient diagnoses were used for defining COPD-cases, hospital admissions were used for detecting exacerbations. Analyses were performed using Cox-regression. Individual incomes were depicted at three levels defined according to national averages for each year. Data of 3,040,137 insured men and women were available. From 2008 to 2019 COPD-incidences in men decreased by 42% and 47% in women. After stratification by income the reduction at the lowest income level was 41% and 50% in women. Respectively, at the highest income level reductions were 28% and 41%. Disease exacerbations decreased over time, and also social inequalities between income groups emerged. COPD-rates decreased over time at all income levels, but at a faster pace in the lowest income group, thus leading to a positive development of diminishing social gradients in men as well as in women.

Abstract Quantum Chromodynamics, the theory of quarks and gluons, whose interactions can be described by a local SU(3) gauge symmetry with charges called “color quantum numbers”, is reviewed; the goal of this review is to provide advanced Ph.D. students a comprehensive handbook, helpful for their research. When QCD was “discovered” 50 years ago, the idea that quarks could exist, but not be observed, left most physicists unconvinced. Then, with the discovery of charmonium in 1974 and the explanation of its excited states using the Cornell potential, consisting of the sum of a Coulomb-like attraction and a long range linear confining potential, the theory was suddenly widely accepted. This paradigm shift is now referred to as the November revolution. It had been anticipated by the observation of scaling in deep inelastic scattering, and was followed by the discovery of gluons in three-jet events. The parameters of QCD include the running coupling constant, $$\alpha _s(Q^2)$$ α s ( Q 2 ) , that varies with the energy scale $$Q^2$$ Q 2 characterising the interaction, and six quark masses. QCD cannot be solved analytically, at least not yet, and the large value of $$\alpha _s$$ α s at low momentum transfers limits perturbative calculations to the high-energy region where $$Q^2\gg \varLambda _{{\textrm{QCD}}} ^2\simeq $$ Q 2 ≫ Λ QCD 2 ≃ (250 MeV) $$^2$$ 2 . Lattice QCD (LQCD), numerical calculations on a discretized space-time lattice, is discussed in detail, the dynamics of the QCD vacuum is visualized, and the expected spectra of mesons and baryons are displayed. Progress in lattice calculations of the structure of nucleons and of quantities related to the phase diagram of dense and hot (or cold) hadronic matter are reviewed. Methods and examples of how to calculate hadronic corrections to weak matrix elements on a lattice are outlined. The wide variety of analytical approximations currently in use, and the accuracy of these approximations, are reviewed. These methods range from the Bethe–Salpeter, Dyson–Schwinger coupled relativistic equations, which are formulated in both Minkowski or Euclidean spaces, to expansions of multi-quark states in a set of basis functions using light-front coordinates, to the AdS/QCD method that imbeds 4-dimensional QCD in a 5-dimensional deSitter space, allowing confinement and spontaneous chiral symmetry breaking to be described in a novel way. Models that assume the number of colors is very large, i.e. make use of the large $$N_c$$ N c -limit, give unique insights. Many other techniques that are tailored to specific problems, such as perturbative expansions for high energy scattering or approximate calculations using the operator product expansion are discussed. The very powerful effective field theory techniques that are successful for low energy nuclear systems (chiral effective theory), or for non-relativistic systems involving heavy quarks, or the treatment of gluon exchanges between energetic, collinear partons encountered in jets, are discussed. The spectroscopy of mesons and baryons has played an important historical role in the development of QCD. The famous X,Y,Z states – and the discovery of pentaquarks – have revolutionized hadron spectroscopy; their status and interpretation are reviewed as well as recent progress in the identification of glueballs and hybrids in light-meson spectroscopy. These exotic states add to the spectrum of expected $$q{{\bar{q}}}$$ q q ¯ mesons and qqq baryons. The progress in understanding excitations of light and heavy baryons is discussed. The nucleon as the lightest baryon is discussed extensively, its form factors, its partonic structure and the status of the attempt to determine a three-dimensional picture of the parton distribution. An experimental program to study the phase diagram of QCD at high temperature and density started with fixed target experiments in various laboratories in the second half of the 1980s, and then, in this century, with colliders. QCD thermodynamics at high temperature became accessible to LQCD, and numerical results on chiral and deconfinement transitions and properties of the deconfined and chirally restored form of strongly interacting matter, called the Quark–Gluon Plasma (QGP), have become very precise by now. These results can now be confronted with experimental data that are sensitive to the nature of the phase transition. There is clear evidence that the QGP phase is created. This phase of QCD matter can already be characterized by some properties that indicate, within a temperature range of a few times the pseudocritical temperature, the medium behaves like a near ideal liquid. Experimental observables are presented that demonstrate deconfinement. High and ultrahigh density QCD matter at moderate and low temperatures shows interesting features and new phases that are of astrophysical relevance. They are reviewed here and some of the astrophysical implications are discussed. Perturbative QCD and methods to describe the different aspects of scattering processes are discussed. The primary parton–parton scattering in a collision is calculated in perturbative QCD with increasing complexity. The radiation of soft gluons can spoil the perturbative convergence, this can be cured by resummation techniques, which are also described here. Realistic descriptions of QCD scattering events need to model the cascade of quark and gluon splittings until hadron formation sets in, which is done by parton showers. The full event simulation can be performed with Monte Carlo event generators, which simulate the full chain from the hard interaction to the hadronic final states, including the modelling of non-perturbative components. The contribution of the LEP experiments (and of earlier collider experiments) to the study of jets is reviewed. Correlations between jets and the shape of jets had allowed the collaborations to determine the “color factors” – invariants of the SU(3) color group governing the strength of quark–gluon and gluon–gluon interactions. The calculated jet production rates (using perturbative QCD) are shown to agree precisely with data, for jet energies spanning more than five orders of magnitude. The production of jets recoiling against a vector boson, $$W^\pm $$ W ± or Z, is shown to be well understood. The discovery of the Higgs boson was certainly an important milestone in the development of high-energy physics. The couplings of the Higgs boson to massive vector bosons and fermions that have been measured so far support its interpretation as mass-generating boson as predicted by the Standard Model. The study of the Higgs boson recoiling against hadronic jets (without or with heavy flavors) or against vector bosons is also highlighted. Apart from the description of hard interactions taking place at high energies, the understanding of “soft QCD” is also very important. In this respect, Pomeron – and Odderon – exchange, soft and hard diffraction are discussed. Weak decays of quarks and leptons, the quark mixing matrix and the anomalous magnetic moment of the muon are processes which are governed by weak interactions. However, corrections by strong interactions are important, and these are reviewed. As the measured values are incompatible with (most of) the predictions, the question arises: are these discrepancies first hints for New Physics beyond the Standard Model? This volume concludes with a description of future facilities or important upgrades of existing facilities which improve their luminosity by orders of magnitude. The best is yet to come!

Abstract Background Daylength is a key seasonal cue for animals and plants. In cereals, photoperiodic responses are a major adaptive trait, and alleles of clock genes such as PHOTOPERIOD1 (PPD1) and EARLY FLOWERING3 (ELF3) have been selected for in adapting barley and wheat to northern latitudes. How monocot plants sense photoperiod and integrate this information into growth and development is not well understood. Results We find that phytochrome C (PHYC) is essential for flowering in Brachypodium distachyon. Conversely, ELF3 acts as a floral repressor and elf3 mutants display a constitutive long day phenotype and transcriptome. We find that ELF3 and PHYC occur in a common complex. ELF3 associates with the promoters of a number of conserved regulators of flowering, including PPD1 and VRN1. Consistent with observations in barley, we are able to show that PPD1 overexpression accelerates flowering in short days and is necessary for rapid flowering in response to long days. PHYC is in the active Pfr state at the end of the day, but we observe it undergoes dark reversion over the course of the night. Conclusions We propose that PHYC acts as a molecular timer and communicates information on night-length to the circadian clock via ELF3.

Abstract Background There is still a profound lack of efficient therapeutic strategies against pancreatic and other periampullary adenocarcinoma. Surgery is seldom possible, leaving palliative chemotherapy the only option for most patients. Chemotherapy treatment is however often accompanied by serious side-effects, and the identification of biomarkers for early prediction of disease and treatment-associated symptoms could help alleviate patient suffering. This study investigated the dynamic interrelationship between immune-related serum proteins, routine biomarkers, and health-related quality of life (HRQoL) factors during chemotherapy treatment of patients enrolled in the prospective, observational study Chemotherapy, Host response And Molecular dynamics in Periampullary cancer (CHAMP). Methods Proximity extension assay was applied to analyse 92 immune-associated proteins in longitudinal serum samples from 75 patients, 18 treated with curative and 57 with palliative intent. HRQoL data were available from all patients at baseline (BL), from 41 patients at three months, and from 23 patients at six months. Information on routine laboratory parameters albumin, CA19-9, CEA and CRP were collected from medical charts. Results In total nine proteins; chemokine (C–C motif) ligand 23 (CCL23), cluster of differentiation 4 (CD4), cluster of differentiation 28 (CD28), decorin (DCN), galectin-1 (Gal-1), granzyme B (GZMB), granzyme H (GZMH), matrix metallopeptidase 7 (MMP7), and monocyte chemotactic protein-1 (MCP-1) were strongly correlated (Spearman’s Rho ≤ -0.6 or ≥ 0.6) with either cognitive functioning (DCN), emotional functioning (DCN, MCP-1), dyspnoea (CD28, GZMB, GZMH) or insomnia (CCL23, CD4, Gal-1, MMP7) during treatment. Associations between routine laboratory parameters (CA 19–9, CA-125, CRP, CEA and albumin) and HRQoL factors were overall weaker. None of the investigated proteins were associated with pain. Conclusions This is, to our knowledge, the first study exploring associations between serum biomarkers and HRQoL in patients with pancreatic or other periampullary cancer, and some findings merit further validation. The associations of DCN and MCP-1with impaired cognitive and/or emotional functioning are of particular interest, given their established link to various neurodegenerative conditions. Chemotherapy is known to cause persistent cognitive dysfunction with effects on memory and executive function, referred to as “chemo brain”. It would therefore be of great value to identify biomarkers for early detection and management of this debilitating condition. Trial registration Clinical Trial Registration: NCT03724994.

Abstract Background The effect of clinical history on the interpretation of radiographs has been widely researched in human medicine. There is, however, no data on this topic in veterinary medicine. Hypothesis/Objectives Diagnostic accuracy would improve when history was supplied. Animals Thirty client‐owned dogs with abnormal findings on thoracic radiographs and confirmation of the disease, and 30 healthy client‐owned controls were drawn retrospectively. Methods Retrospective case‐control study. Sixty radiographic studies of the thorax were randomized and interpreted by 6 radiologists; first, with no access to the clinical information; and a second time with access to all pertinent clinical information and signalment. Results A significant increase in diagnostic accuracy was noted when clinical information was provided (64.4% without and 75.2% with clinical information; P = .002). There was no significant difference in agreement between radiologists when comparing no clinical information and with clinical information (Kappa 0.313 and 0.300, respectively). Conclusions and Clinical Importance The addition of pertinent clinical information to the radiographic request significantly improves the diagnostic accuracy of thorax radiographs of dogs and is recommended as standard practice.

The Cryogenian period (720–635 million years ago) in the Neoproterozoic era featured two phases of global or near-global ice cover termed “snowball Earth”. Climate models of all kinds indicate that the inception of these phases must have occurred in the course of a self-amplifying ice–albedo feedback that forced the climate from a partially ice-covered to a snowball state within a few years or decades. The maximum concentration of atmospheric carbon dioxide (CO2) allowing such a drastic shift depends on the choice of model, the boundary conditions prescribed in the model, and the amount of climatic variability. Many previous studies reported values or ranges for this CO2 threshold but typically tested only a very few different boundary conditions or excluded variability due to volcanism. Here we present a comprehensive sensitivity study determining the CO2 thresholds in different scenarios for the Cryogenian continental configuration, orbital geometry, and short-term volcanic cooling effects in a consistent model framework using the climate model of intermediate complexity CLIMBER-3α. The continental configurations comprise two palaeogeographic reconstructions for each of both snowball-Earth onsets as well as two idealised configurations with either uniformly dispersed continents or a single polar supercontinent. Orbital geometries are sampled as multiple different combinations of the parameters obliquity, eccentricity, and argument of perihelion. For volcanic eruptions, we differentiate between single globally homogeneous perturbations, single zonally resolved perturbations, and random sequences of globally homogeneous perturbations with realistic statistics. The CO2 threshold lies between 10 and 250 ppm for all simulations. While the thresholds for the idealised continental configurations differ by a factor of up to 19, the CO2 thresholds for the continental reconstructions differ by only 6 %–44 % relative to the lower thresholds. Changes in orbital geometry account for variations in the CO2 threshold of up to 30 % relative to the lowest threshold. The effects of volcanic perturbations largely depend on the orbital geometry and the corresponding structure of coexisting stable states. A very large peak reduction in net solar radiation of 20 or 30 W m−2 can shift the CO2 threshold by the same order of magnitude as or less than the orbital geometry. Exceptionally large eruptions of up to −40 W m−2 shift the threshold by up to 40 % for one orbital configuration. Eruptions near the Equator tend to, but do not always, cause larger shifts than eruptions at high latitudes. The effects of realistic eruption sequences are mostly determined by their largest events. In the presence of particularly intense small-magnitude volcanism, this effect can go beyond the ranges expected from single eruptions.