Epidemiology of human adenoviruses: a 20-year retrospective observational study in hospitalized patients in Bern, Switzerland.

Background: Human adenovirus (HAdV) is an important pathogen seen in clinical practice. Long-term studies may help better understand epidemiological trends and changes in circulating genotypes over time. Purpose: Using a large biobank of samples from hospitalized, adenovirus-positive patients over a 20-year period, we aimed to analyze long-term epidemiological trends and genotypic relatedness among circulating HAdV strains. Methods: Based on samples from hospitalized patients confirmed to be HAdV positive in Bern, Switzerland, from 1998 to 2017, and on their associated demographic and clinical data, we identified epidemiological trends and risk factors associated with HAdV infection. HAdV genotyping was performed by PCR amplification and sequencing of the hypervariable hexon gene. The obtained sequences were phylogenetically compared with sequences from international HAdV strains. Results: HAdV was identified in 1302 samples tested. Cases of HAdV infection were reported throughout the years with no clear seasonality. Upper respiratory tract samples, conjunctivitis swabs, and stool had the highest positivity rate (56.2%, 18.7%, and 14.2% of the cases, respectively). HAdV infection was highest among children ≤4 years old. Increased number of HAdV cases were observed in years 2009 (n = 110) and 2010 (n =112). HAdV8 was the predominant genotype among patients older than 20 years, and was mostly associated with ophthalmic infection. Predominant genotypes among children ≤4 years old were HAdV1, HAdV2, and HAdV3, which were mostly associated with respiratory tract infections. Recurring peaks of increased HAdV cases were evidenced every 4 years among children ≤4 years old. Conclusion: Our study gives novel insights on long-term epidemiological trends and phylogenetic relatedness among circulating HAdV strains in Switzerland, country in which little data on HAdV prevalence and diversity was so far available

Observation of anomalous Meissner screening in Cu/Nb and Cu/Nb/Co thin films

We have observed the spatial distribution of magnetic flux in Nb, Cu/Nb and Cu/Nb/Co thin films using muon-spin rotation. In an isolated 50 nm thick Nb film we find a weak flux expulsion (Meissner effect) which becomes significantly enhanced when adding an adjacent 40 nm layer of Cu. The added Cu layer exhibits a Meissner effect (due to induced superconducting pairs) and is at least as effective as the Nb to expel flux. These results are confirmed by theoretical calculations using the quasiclassical Green’s function formalism. An unexpected further significant enhancement of the flux expulsion is observed when adding a thin (2.4 nm) ferromagnetic Co layer to the bottom side of the Nb. This observed cooperation between superconductivity and ferromagnetism, by an unknown mechanism, forms a key ingredient for developing superconducting spintronics

Intrinsic paramagnetic meissner effect due to s-wave odd-frequency superconductivity

In 1933, Meissner and Ochsenfeld reported the expulsion of magnetic flux, the diamagnetic Meissner effect, from the interior of superconducting lead. This discovery was crucial in formulating the Bardeen-Cooper-Schrieffer (BCS) theory of superconductivity. In exotic superconducting systems BCS theory does not strictly apply. A classical example is a superconductor-magnet hybrid system where magnetic ordering breaks time-reversal symmetry of the superconducting condensate and results in the stabilisation of an odd-frequency superconducting state. It has been predicted that under appropriate conditions, odd-frequency superconductivity should manifest in the Meissner state as fluctuations in the sign of the magnetic susceptibility meaning that the superconductivity can either repel (diamagnetic) or attract (paramagnetic) external magnetic flux. Here we report local probe measurements of faint magnetic fields in a Au/Ho/Nb trilayer system using low energy muons, where antiferromagnetic Ho (4.5 nm) breaks time-reversal symmetry of the proximity induced pair correlations in Au. From depth-resolved measurements below the superconducting transition of Nb we observe a local enhancement of the magnetic field in Au that exceeds the externally applied field, thus proving the existence of an intrinsic paramagnetic Meissner effect arising from an odd-frequency superconducting state.J.W.A.R. acknowledges financial support from the Royal Society through a University Research Fellowship. J.W.A.R. and A.D.B. acknowledge financial support from the UK EPSRC through NanoDTC EP/G037221/1 and the Leverhulme Trust through an International Network Grant (IN-2013-033). A.D.B. also acknowledges additional financial support from the Schiff Foundation. X.L.W. and J.H.Z. acknowledge support from the MOST of China (2015CB921500). J.L. acknowledges support from the Outstanding Academic Fellows programme at NTNU, the Norwegian Research Council Grant (205591, FRINAT, 216700). J. L., J.W.A.R, and A.D.B. finally acknowledge support from the COST Action MP-1201 'Novel Functionalities through Optimized Confinement of Condensate and Fields.' S.L. and M.G.F. acknowledge the support of the EPSRC through Grant No. EP/J01060X. The muSR measurements were performed at the Swiss Muon Source (SµS), at the Paul Scherrer Institute in Villigen, Switzerland. The project has also received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under the NMI3-II Grant number 283883.This is the final version of the article. It first appeared from APS via http://dx.doi.org/10.1103/PhysRevX.5.04102

BicaudalD Actively Regulates Microtubule Motor Activity in Lipid Droplet Transport

A great deal of sub-cellular organelle positioning, and essentially all minus-ended organelle transport, depends on cytoplasmic dynein, but how dynein's function is regulated is not well understood. BicD is established to play a critical role in mediating dynein function-loss of BicD results in improperly localized nuclei, mRNA particles, and a dispersed Golgi apparatus-however exactly what BicD's role is remains unknown. Nonetheless, it is widely believed that BicD may act to tether dynein to cargos. Here we use a combination of biophysical and biochemical studies to investigate BicD's role in lipid droplet transport during Drosophila embryogenesis.Functional loss of BicD impairs the embryo's ability to control the net direction of droplet transport; the developmentally controlled reversal in transport is eliminated. We find that minimal BicD expression (near-BicD(null)) decreases the average run length of both plus and minus end directed microtubule (MT) based transport. A point mutation affecting the BicD N-terminus has very similar effects on transport during cellularization (phase II), but in phase III (gastrulation) motion actually appears better than in the wild-type.In contrast to a simple static tethering model of BicD function, or a role only in initial dynein recruitment to the cargo, our data uncovers a new dynamic role for BicD in actively regulating transport. Lipid droplets move bi-directionally, and our investigations demonstrate that BicD plays a critical-and temporally changing-role in balancing the relative contributions of plus-end and minus-end motors to control the net direction of transport. Our results suggest that while BicD might contribute to recruitment of dynein to the cargo it is not absolutely required for such dynein localization, and it clearly contributes to regulation, helping activation/inactivation of the motors

Controlling the electromagnetic proximity effect by tuning the mixing between superconducting and ferromagnetic order

We present low-energy muon-spin rotation measurements on Cu/Nb/AlOx/Co thin films that probe the newly described electromagnetic (EM) proximity effect. By varying the thickness of the insulating AlOx layer we control the degree of coupling between the superconductor and ferromagnet and thus the EM proximity effect. For barrier thicknesses up to 4 nm we find both a small contact-dependent reduction in the standard Meissner effect and a larger diamagnetic contribution originating at the Nb/AlOx/Co interface which decays away over a lengthscale far exceeding the superconducting coherence length. This second component we attribute to the EM proximity effect. Our analysis provides compelling experimental evidence for previously neglected electromagnetic effects within proximity coupled systems

Systematic Functional Analysis of Bicaudal-D Serine Phosphorylation and Intragenic Suppression of a Female Sterile Allele of BicD

Protein phosphorylation is involved in posttranslational control of essentially all biological processes. Using mass spectrometry, recent analyses of whole phosphoproteomes led to the identification of numerous new phosphorylation sites. However, the function of most of these sites remained unknown. We chose the Drosophila Bicaudal-D protein to estimate the importance of individual phosphorylation events. Being involved in different cellular processes, BicD is required for oocyte determination, for RNA transport during oogenesis and embryogenesis, and for photoreceptor nuclei migration in the developing eye. The numerous roles of BicD and the available evidence for functional importance of BicD phosphorylation led us to identify eight phosphorylation sites of BicD, and we tested a total of 14 identified and suspected phosphoserine residues for their functional importance in vivo in flies. Surprisingly, all these serines turned out to be dispensable for providing sufficient basal BicD activity for normal growth and development. However, in a genetically sensitized background where the BicDA40V protein variant provides only partial activity, serine 103 substitutions are not neutral anymore, but show surprising differences. The S103D substitution completely inactivates the protein, whereas S103A behaves neutral, and the S103F substitution, isolated in a genetic screen, restores BicDA40V function. Our results suggest that many BicD phosphorylation events may either be fortuitous or play a modulating function as shown for Ser103. Remarkably, amongst the Drosophila serines we found phosphorylated, Ser103 is the only one that is fully conserved in mammalian BicD

Clinical significance of cardiovascular dysmetabolic syndrome

Although diabetes mellitus is predominantly a metabolic disorder, recent data suggest that it is as much a vascular disorder. Cardiovascular complications are the leading cause of death and disability in patients with diabetes mellitus. A number of recent reports have emphasized that many patients already have atherosclerosis in progression by the time they are diagnosed with clinical evidence of diabetes mellitus. The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction. The evolving knowledge regarding the variety of metabolic, hormonal, and hemodynamic abnormalities in patients with diabetes mellitus has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that insulin resistance, the key abnormality in type II diabetes, often precedes clinical features of diabetes by 5–6 years. Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome should help identify those at risk at an early stage. The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus by improving insulin sensitivity and related abnormalities. Early identification and implementation of appropriate therapeutic strategies would be necessary to contain the emerging new epidemic of cardiovascular disease related to diabetes

Rapid Transcriptional Pulsing Dynamics of High Expressing Retroviral Transgenes in Embryonic Stem Cells

Single cell imaging studies suggest that transcription is not continuous and occurs as discrete pulses of gene activity. To study mechanisms by which retroviral transgenes can transcribe to high levels, we used the MS2 system to visualize transcriptional dynamics of high expressing proviral integration sites in embryonic stem (ES) cells. We established two ES cell lines each bearing a single copy, self-inactivating retroviral vector with a strong ubiquitous human EF1α gene promoter directing expression of mRFP fused to an MS2-stem-loop array. Transfection of MS2-EGFP generated EGFP focal dots bound to the mRFP-MS2 stem loop mRNA. These transcription foci colocalized with the transgene integration site detected by immunoFISH. Live tracking of single cells for 20 minutes detected EGFP focal dots that displayed frequent and rapid fluctuations in transcription over periods as short as 25 seconds. Similarly rapid fluctuations were detected from focal doublet signals that colocalized with replicated proviral integration sites by immunoFISH, consistent with transcriptional pulses from sister chromatids. We concluded that retroviral transgenes experience rapid transcriptional pulses in clonal ES cell lines that exhibit high level expression. These events are directed by a constitutive housekeeping gene promoter and may provide precedence for rapid transcriptional pulsing at endogenous genes in mammalian stem cells

How do NHS organisations plan research capacity development? Strategies, strengths, and opportunities for improvement

Research that is integral into a 'learning healthcare system' can promote cost effective services and knowledge creation. As such, research is defined as a 'core function' in UK health service organisations, and is often planned through research and development (R&D) strategies that aim to promote research activity and research capacity development (RCD). The discussion focuses around the content of ten R&D strategies for healthcare organisations in England and Scotland, with respect to RCD. These organisations were engaged with a research interest network called ACORN (Addressing Organisational Capacity to do Research Network) that included two Scottish Health Boards, four community and mental health trusts, two provincial district hospitals, and two teaching hospitals. We undertook a thematic documentary analysis of the R&D strategies which identified 11 'core activities' of RCD. The potential for building research capacity in these 'core activities' was established by reviewing them through the lens of a RCD framework. Core activities aimed to 'hard wire' RCD into health organisations. They demonstrated a complex interplay between developing a strong internal organisational infrastructure, and supporting individual career planning and skills development, in turn enabled by organisational processes. They also included activities to build stronger inter-organisational relationships and networks. Practitioner, manager and patient involvement was a cross cutting theme. The potential to demonstrate progress was included in plans through monitoring activity across all RCD principles. Strategies were primarily aimed at research production rather than research use. Developing 'actionable dissemination' was poorly addressed in the strategies, and represents an area for improvement. We describe strengths of RCD planning activities, and opportunities for improvement. We explore how national policy and research funders can influence health systems' engagement in research