Helicobacter pylori: cellular immunity and protection from Multiple Sclerosis

Helicobacter pylori colonises the stomachs of almost half the world’s population, subverting host immunity to usually establish a life-long infection. Although asymptomatic in most cases, peptic ulcer disease and gastric cancer develop in a minority of those colonised. Recently, more evidence is emerging that the reducing prevalence of infections in developed countries is linked with the stark rise of allergy, asthma, and autoimmune diseases such as multiple sclerosis (MS). The ‘Old friend’s hypothesis’, suggests that the lack of exposure to certain microbes, likely by increasing antibiotic use and improved sanitation, causes dysregulated immunity leading to immune and inflammatory conditions. The microbiota also regulates host immunity, during homeostasis and in the response to infection and susceptibility for disease development. The induction of tolerogenic dendritic cells and IL-10-producing regulatory T-cells, is an important H. pylori persistence mechanism. In the literature, these responses are also linked to the mitigation of extra-gastric diseases. Inadequate Treg responses are associated with a negative prognosis, especially in MS. This is the most common neurological condition affecting young adults, causing chronic progressive disability with a devastating impact on quality of life. Using the mouse model experimental autoimmune encephalomyelitis (EAE), the research group previously reported a reduced severity of EAE when infected with H. pylori. For the current studies, it was hypothesised that protection from MS may be mediated through H. pylori modulation of the T-helper response. Gastric mucosal inflammation induced by H. pylori may alter lymphocyte homing patterns and reduce infiltration to the central nervous system. The regulatory T-cell response has previously been shown to facilitate repair in a demyelinated central nervous system by the secreted factor CCN3. This was proposed as a potential mechanism for H. pylori to mediate a protective effect in EAE or MS. Murine glia were cultured with CD4 supernatants to investigate the myelinating capacity of oligodendrocytes. Firstly, differences in the peripheral blood T-helper and cytokine responses were investigated between infected and uninfected patients, and infected patients before and after H. pylori eradication therapy. Differences in IL-17A, IL-12p70 and IL-10 concentrations were detected according to presence of H. pylori infection and gastro-duodenal pathology. The CD4+ T-helper cytokines IL10 and IL17A were differentially expressed at the mRNA level in PBMCs between infected and uninfected patients. IL10 mRNA was elevated following H. pylori eradication, concurrent with a reducing anti-Hp humoral IgG response. This indicates that the infection exerts important effects on the immune system. Using the EAE model, a strain-specific mitigation of disease severity was observed when infected with H. pylori strain SS1 compared to PMSS1, independently of the CD4 T-helper subsets quantified. A fluorescence-based technique was developed for in vivo imaging of EAE CD4+ T-cells adoptively transferred to infected or uninfected recipient mice. The CD4+ T-cell populations from the spleens and mesenteric lymph nodes of H. pylori infected mice contained higher frequencies of both pro- and anti-inflammatory T-helper subsets. CCN3 mRNA was markedly elevated in cells from infected mice. There was a marked increase in myelin production from glia treated with supernatants from CD4 cells, and this was slightly higher using the cell supernatants from infected mice. The differences observed were modest, and further work is required to confirm and expand on these preliminary findings

Shocks in supersonic sand

We measure time-averaged velocity, density, and temperature fields for steady granular flow past a wedge and calculate a speed of granular pressure disturbances (sound speed) equal to 10% of the flow speed. The flow is supersonic, forming shocks nearly identical to those in a supersonic gas. Molecular dynamics simulations of Newton's laws and Monte Carlo simulations of the Boltzmann equation yield fields in quantitative agreement with experiment. A numerical solution of Navier-Stokes-like equations agrees with a molecular dynamics simulation for experimental conditions excluding wall friction.Comment: 4 pages, 5 figure

Onset of Patterns in an Ocillated Granular Layer: Continuum and Molecular Dynamics Simulations

We study the onset of patterns in vertically oscillated layers of frictionless dissipative particles. Using both numerical solutions of continuum equations to Navier-Stokes order and molecular dynamics (MD) simulations, we find that standing waves form stripe patterns above a critical acceleration of the cell. Changing the frequency of oscillation of the cell changes the wavelength of the resulting pattern; MD and continuum simulations both yield wavelengths in accord with previous experimental results. The value of the critical acceleration for ordered standing waves is approximately 10% higher in molecular dynamics simulations than in the continuum simulations, and the amplitude of the waves differs significantly between the models. The delay in the onset of order in molecular dynamics simulations and the amplitude of noise below this onset are consistent with the presence of fluctuations which are absent in the continuum theory. The strength of the noise obtained by fit to Swift-Hohenberg theory is orders of magnitude larger than the thermal noise in fluid convection experiments, and is comparable to the noise found in experiments with oscillated granular layers and in recent fluid experiments on fluids near the critical point. Good agreement is found between the mean field value of onset from the Swift-Hohenberg fit and the onset in continuum simulations. Patterns are compared in cells oscillated at two different frequencies in MD; the layer with larger wavelength patterns has less noise than the layer with smaller wavelength patterns.Comment: Published in Physical Review

Transport Coefficients for Granular Media from Molecular Dynamics Simulations

Under many conditions, macroscopic grains flow like a fluid; kinetic theory pred icts continuum equations of motion for this granular fluid. In order to test the theory, we perform event driven molecular simulations of a two-dimensional gas of inelastic hard disks, driven by contact with a heat bath. Even for strong dissipation, high densities, and small numbers of particles, we find that continuum theory describes the system well. With a bath that heats the gas homogeneously, strong velocity correlations produce a slightly smaller energy loss due to inelastic collisions than that predicted by kinetic theory. With an inhomogeneous heat bath, thermal or velocity gradients are induced. Determination of the resulting fluxes allows calculation of the thermal conductivity and shear viscosity, which are compared to the predictions of granular kinetic theory, and which can be used in continuum modeling of granular flows. The shear viscosity is close to the prediction of kinetic theory, while the thermal conductivity can be overestimated by a factor of 2; in each case, transport is lowered with increasing inelasticity.Comment: 14 pages, 17 figures, 39 references, submitted to PRE feb 199

Performance evaluation of a non-invasive one-step multiplex RT-qPCR assay for detection of SARS-CoV-2 direct from saliva

Polymerase chain reaction (PCR) has proven to be the gold-standard for SARS-CoV-2 detection in clinical settings. The most common approaches rely on nasopharyngeal specimens obtained from swabs, followed by RNA extraction, reverse transcription and quantitative PCR. Although swab-based PCR is sensitive, swabbing is invasive and unpleasant to administer, reducing patient compliance for regular testing and resulting in an increased risk of improper sampling. To overcome these obstacles, we developed a non-invasive one-step RT-qPCR assay performed directly on saliva specimens. The University of Nottingham Asymptomatic Testing Service protocol simplifies sample collection and bypasses the need for RNA extraction, or additives, thus helping to encourage more regular testing and reducing processing time and costs. We have evaluated the assay against the performance criteria specified by the UK regulatory bodies and attained accreditation (BS EN ISO/IEC 17,025:2017) for SARS-CoV-2 diagnostic testing by the United Kingdom Accreditation Service. We observed a sensitivity of 1 viral copy per microlitre of saliva, and demonstrated a concordance of > 99.4% between our results and those of other accredited testing facilities. We concluded that saliva is a stable medium that allows for a highly precise, repeatable, and robust testing method

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.Swedish Research Council et al.Manuscrip

First measurement of the Hubble Constant from a Dark Standard Siren using the Dark Energy Survey Galaxies and the LIGO/Virgo Binary–Black-hole Merger GW170814

International audienceWe present a multi-messenger measurement of the Hubble constant H 0 using the binary–black-hole merger GW170814 as a standard siren, combined with a photometric redshift catalog from the Dark Energy Survey (DES). The luminosity distance is obtained from the gravitational wave signal detected by the Laser Interferometer Gravitational-Wave Observatory (LIGO)/Virgo Collaboration (LVC) on 2017 August 14, and the redshift information is provided by the DES Year 3 data. Black hole mergers such as GW170814 are expected to lack bright electromagnetic emission to uniquely identify their host galaxies and build an object-by-object Hubble diagram. However, they are suitable for a statistical measurement, provided that a galaxy catalog of adequate depth and redshift completion is available. Here we present the first Hubble parameter measurement using a black hole merger. Our analysis results in , which is consistent with both SN Ia and cosmic microwave background measurements of the Hubble constant. The quoted 68% credible region comprises 60% of the uniform prior range [20, 140] km s−1 Mpc−1, and it depends on the assumed prior range. If we take a broader prior of [10, 220] km s−1 Mpc−1, we find (57% of the prior range). Although a weak constraint on the Hubble constant from a single event is expected using the dark siren method, a multifold increase in the LVC event rate is anticipated in the coming years and combinations of many sirens will lead to improved constraints on H 0

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Population of Merging Compact Binaries Inferred Using Gravitational Waves through GWTC-3

We report on the population properties of compact binary mergers inferred from gravitational-wave observations of these systems during the first three LIGO-Virgo observing runs. The Gravitational-Wave Transient Catalog 3 (GWTC-3) contains signals consistent with three classes of binary mergers: binary black hole, binary neutron star, and neutron star-black hole mergers. We infer the binary neutron star merger rate to be between 10 and 1700 Gpc-3 yr-1 and the neutron star-black hole merger rate to be between 7.8 and 140 Gpc-3 yr-1, assuming a constant rate density in the comoving frame and taking the union of 90% credible intervals for methods used in this work. We infer the binary black hole merger rate, allowing for evolution with redshift, to be between 17.9 and 44 Gpc-3 yr-1 at a fiducial redshift (z=0.2). The rate of binary black hole mergers is observed to increase with redshift at a rate proportional to (1+z)κ with κ=2.9-1.8+1.7 for z≲1. Using both binary neutron star and neutron star-black hole binaries, we obtain a broad, relatively flat neutron star mass distribution extending from 1.2-0.2+0.1 to 2.0-0.3+0.3M⊙. We confidently determine that the merger rate as a function of mass sharply declines after the expected maximum neutron star mass, but cannot yet confirm or rule out the existence of a lower mass gap between neutron stars and black holes. We also find the binary black hole mass distribution has localized over- and underdensities relative to a power-law distribution, with peaks emerging at chirp masses of 8.3-0.5+0.3 and 27.9-1.8+1.9M⊙. While we continue to find that the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above approximately 60M⊙, which would indicate the presence of a upper mass gap. Observed black hole spins are small, with half of spin magnitudes below χi≈0.25. While the majority of spins are preferentially aligned with the orbital angular momentum, we infer evidence of antialigned spins among the binary population. We observe an increase in spin magnitude for systems with more unequal-mass ratio. We also observe evidence of misalignment of spins relative to the orbital angular momentum