Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there is little guidance available about their use in clinical practice. Guidelines on which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared to those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalizable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These publicly-available data should provide a basis for informed counselling and clinical decision making

Dynamic Evolution of Pathogenicity Revealed by Sequencing and Comparative Genomics of 19 Pseudomonas syringae Isolates

Closely related pathogens may differ dramatically in host range, but the molecular, genetic, and evolutionary basis for these differences remains unclear. In many Gram- negative bacteria, including the phytopathogen Pseudomonas syringae, type III effectors (TTEs) are essential for pathogenicity, instrumental in structuring host range, and exhibit wide diversity between strains. To capture the dynamic nature of virulence gene repertoires across P. syringae, we screened 11 diverse strains for novel TTE families and coupled this nearly saturating screen with the sequencing and assembly of 14 phylogenetically diverse isolates from a broad collection of diseased host plants. TTE repertoires vary dramatically in size and content across all P. syringae clades; surprisingly few TTEs are conserved and present in all strains. Those that are likely provide basal requirements for pathogenicity. We demonstrate that functional divergence within one conserved locus, hopM1, leads to dramatic differences in pathogenicity, and we demonstrate that phylogenetics-informed mutagenesis can be used to identify functionally critical residues of TTEs. The dynamism of the TTE repertoire is mirrored by diversity in pathways affecting the synthesis of secreted phytotoxins, highlighting the likely role of both types of virulence factors in determination of host range. We used these 14 draft genome sequences, plus five additional genome sequences previously reported, to identify the core genome for P. syringae and we compared this core to that of two closely related non-pathogenic pseudomonad species. These data revealed the recent acquisition of a 1 Mb megaplasmid by a sub-clade of cucumber pathogens. This megaplasmid encodes a type IV secretion system and a diverse set of unknown proteins, which dramatically increases both the genomic content of these strains and the pan-genome of the species

Procyanidin B3 Prevents Articular Cartilage Degeneration and Heterotopic Cartilage Formation in a Mouse Surgical Osteoarthritis Model

Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. Heterotopic ossification (HO) occurs when ectopic masses of endochondral bone form within the soft tissues around the joints and is triggered by inflammation of the soft tissues. Procyanidin B3 (B3) is a procyanidin dimer that is widely studied due to its high abundance in the human diet and antioxidant activity. Here, we evaluated the role of B3 isolated from grape seeds in the maintenance of chondrocytes in vitro and in vivo. We observed that B3 inhibited H2O2-induced apoptosis in primary chondrocytes, suppressed H2O2- or IL-1ß−induced nitric oxide synthase (iNOS) production, and prevented IL-1ß−induced suppression of chondrocyte differentiation marker gene expression in primary chondrocytes. Moreover, B3 treatment enhanced the early differentiation of ATDC5 cells. To examine whether B3 prevents cartilage destruction in vivo, OA was surgically induced in C57BL/6J mice followed by oral administration of B3 or vehicle control. Daily oral B3 administration protected articular cartilage from OA and prevented chondrocyte apoptosis in surgically-induced OA joints. Furthermore, B3 administration prevented heterotopic cartilage formation near the surgical region. iNOS protein expression was enhanced in the synovial tissues and the pseudocapsule around the surgical region in OA mice fed a control diet, but was reduced in mice that received B3. Together, these data indicated that in the OA model, B3 prevented OA progression and heterotopic cartilage formation, at least in a part through the suppression of iNOS. These results support the potential therapeutic benefits of B3 for treatment of human OA and heterotopic ossification

Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants

BACKGROUND: One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age-standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are affecting the number of adults with diabetes. METHODS: We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence—defined as fasting plasma glucose of 7·0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs—in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue. FINDINGS: We used data from 751 studies including 4 372 000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4·3% (95% credible interval 2·4–7·0) in 1980 to 9·0% (7·2–11·1) in 2014 in men, and from 5·0% (2·9–7·9) to 7·9% (6·4–9·7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28·5% due to the rise in prevalence, 39·7% due to population growth and ageing, and 31·8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target. INTERPRETATION: Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults affected, has increased faster in low-income and middle-income countries than in high-income countries. FUNDING: Wellcome Trust

Observation of B(s)0→J/ψpp¯ decays and precision measurements of the B(s)0 masses

The first observation of the decays B 0 ( s ) → J / ψ p ¯ p is reported, using proton-proton collision data corresponding to an integrated luminosity of 5.2     fb − 1 , collected with the LHCb detector. These decays are suppressed due to limited available phase space, as well as due to Okubo-Zweig-Iizuka or Cabibbo suppression. The measured branching fractions are B ( B 0 → J / ψ p ¯ p ) = [ 4.51 ± 0.40 ( stat ) ± 0.44 ( syst ) ] × 10 − 7 , B ( B 0 s → J / ψ p ¯ p ) = [ 3.58 ± 0.19 ( stat ) ± 0.39 ( syst ) ] × 10 − 6 . For the B 0 s meson, the result is much higher than the expected value of O ( 10 − 9 ) . The small available phase space in these decays also allows for the most precise single measurement of both the B 0 mass as 5279.74 ± 0.30 ( stat ) ± 0.10 ( syst )     MeV and the B 0 s mass as 5366.85 ± 0.19 ( stat ) ± 0.13 ( syst )     MeV

Measurement of D s ^± production asymmetry in pp collisions at √s=7 and 8 TeV

The inclusive $D_s^{\pm}$ production asymmetry is measured in $pp$ collisions collected by the LHCb experiment at centre-of-mass energies of $\sqrt{s} =7$ and 8 TeV. Promptly produced $D_s^{\pm}$ mesons are used, which decay as $D_s^{\pm}\to\phi\pi^{\pm}$, with $\phi\to K^+K^-$. The measurement is performed in bins of transverse momentum, $p_{\rm T}$, and rapidity, $y$, covering the range $2.5<p_{\rm T}<25.0$ GeV$/c$ and $2.0<y<4.5$. No kinematic dependence is observed. Evidence of nonzero $D_s^{\pm}$ production asymmetry is found with a significance of 3.3 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2018-010.htm

Observation of the decay Λ _b ⁰ → ψ(2S)pπ⁻

International audienceThe Cabibbo-suppressed decay Λ$_{b}^{0}$  → ψ(2S)pπ$^{−}$ is observed for the first time using a data sample collected by the LHCb experiment in proton-proton collisions corresponding to 1.0, 2.0 and 1.9 fb$^{−1}$ of integrated luminosity at centre-of-mass energies of 7, 8 and 13 TeV, respectively. The ψ(2S) mesons are reconstructed in the μ$^{+}$μ$^{−}$ final state. The branching fraction with respect to that of the Λ$_{b}^{0}$  → ψ(2S)pK$^{−}$ decay mode is measured to b

Evidence for an nc(1S)ff- resonance in B0 yc(1S)K+ decays

A Dalitz plot analysis of B0→ηc(1S)K+π- decays is performed using data samples of pp collisions collected with the LHCb detector at centre-of-mass energies of s=7,8 and 13TeV , corresponding to a total integrated luminosity of 4.7fb-1 . A satisfactory description of the data is obtained when including a contribution representing an exotic ηc(1S)π- resonant state. The significance of this exotic resonance is more than three standard deviations, while its mass and width are 4096±20-22+18MeV and 152±58-35+60MeV , respectively. The spin-parity assignments JP=0+ and JP=1- are both consistent with the data. In addition, the first measurement of the B0→ηc(1S)K+π- branching fraction is performed and gives B(B0→ηc(1S)K+π-)=(5.73±0.24±0.13±0.66)×10-4, where the first uncertainty is statistical, the second systematic, and the third is due to limited knowledge of external branching fractions

Search for CP violation in Λb0→pK− and Λb0→pπ− decays

A search for CP violation in Λb0→pK− and Λb0→pπ− decays is presented using a sample of pp collisions collected with the LHCb detector and corresponding to an integrated luminosity of 3.0fb−1. The CP -violating asymmetries are measured to be ACPpK−=−0.020±0.013±0.019 and ACPpπ−=−0.035±0.017±0.020, and their difference ACPpK−−ACPpπ−=0.014±0.022±0.010, where the first uncertainties are statistical and the second systematic. These are the most precise measurements of such asymmetries to date

Observation of B+c → D0K+ decays

Using proton-proton collision data corresponding to an integrated luminosity of 3.0 fb−1, recorded by the LHCb detector at center-of-mass energies of 7 and 8 TeV, the B+ c → D0K+ decay is observed with a statistical significance of 5.1 standard deviations. By normalizing to B+ → D¯ 0π+ decays, a measurement of the branching fraction multiplied by the production rates for B+ c relative to B+ mesons in the LHCb acceptance is obtained, R D 0 K = ( f c / f u ) × B ( B + c → D 0 K + ) = ( 9. 3 + 2.8 − 2.5 ± 0.6 ) × 10 − 7, where the first uncertainty is statistical and the second is systematic. This decay is expected to proceed predominantly through weak annihilation and penguin amplitudes, and is the first B+ c decay of this nature to be observed