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Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. © 2013 The American Society of Human Genetics.

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P> 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

The results of gamma-ray observations of the binary system HESS J0632 + 057 collected during 450 hr over 15 yr, between 2004 and 2019, are presented. Data taken with the atmospheric Cherenkov telescopes H.E.S.S., MAGIC, and VERITAS at energies above 350 GeV were used together with observations at X-ray energies obtained with Swift-XRT, Chandra, XMM-Newton, NuSTAR, and Suzaku. Some of these observations were accompanied by measurements of the H�� emission line. A significant detection of the modulation of the very high-energy gamma-ray fluxes with a period of 316.7 �� 4.4 days is reported, consistent with the period of 317.3 �� 0.7 days obtained with a refined analysis of X-ray data. The analysis of data from four orbital cycles with dense observational coverage reveals short-timescale variability, with flux-decay timescales of less than 20 days at very high energies. Flux variations observed over a timescale of several years indicate orbit-to-orbit variability. The analysis confirms the previously reported correlation of X-ray and gamma-ray emission from the system at very high significance, but cannot find any correlation of optical H�� parameters with fluxes at X-ray or gamma-ray energies in simultaneous observations. The key finding is that the emission of HESS J0632 + 057 in the X-ray and gamma-ray energy bands is highly variable on different timescales. The ratio of gamma-ray to X-ray flux shows the equality or even dominance of the gamma-ray energy range. This wealth of new data is interpreted taking into account the insufficient knowledge of the ephemeris of the system, and discussed in the context of results reported on other gamma-ray binary systems. The astrophysical journal 923(2), 241 (2021). doi:10.3847/1538-4357/ac29b7 Published by Univ., Chicago, Ill. [u.a.]

Background: Allergic rhinitis (AR) management has changed in recent years following the switch from the concept of disease severity to the concept of disease control, publication of the AR clinical decision support system (CDSS) and development of mobile health (m-health) tools for patients (eg Allergy Diary). The Allergy Diary Companion app for healthcare providers is currently being developed and will be launched in 2018. It incorporates the AR CDSS to provide evidence-based treatment recommendations, linking all key stakeholders in AR management. Objective: To produce an electronic version of the AR CDSS (e-CDSS) for incorporation into the Allergy Diary Companion, to describe the app interfaces used to collect information necessary to inform the e-CDSS and to summarize some key features of the Allergy Diary Companion. Methods: The steps involved in producing the e-CDSS and incorporating it into the Allergy Diary Companion were (a) generation of treatment management scenarios; (b) expert consensus on treatment recommendations; (c) generation of electronic decisional algorithms to describe all AR CDSS scenarios; (d) digitization of these algorithms to form the e-CDSS; and (e) embedding the e-CDSS into the app to permit easy user e-CDSS interfacing. Results: Key experts in the AR field agreed on the AR CDSS approach to AR management and on specific treatment recommendations provided by Allergy Diary Companion. Based on this consensus, decision processes were developed and programmed into the Allergy Diary Companion using Titanium Appcelerator (JavaScript) for IOS tablets. To our knowledge, this is the first time the development of any m-health tool has been described in this transparent and detailed way, providing confidence, not only in the app, but also in the provided management recommendations. Conclusion: The Allergy Diary Companion for providers provides guideline and expert-endorsed AR management recommendations. [MASK paper No 32]. © 2018 John Wiley & Sons Ltd

The nonapeptide bradykinin (BK) is involved in the genesis of inflammation, edema and in pain mediation. As such, much effort has gone into the development of peptide/non-peptide antagonists to counteract these processes. However, there is an increasing awareness of the potential value of chemically stable BK agonists in the treatment of diabetes and cardiovascular diseases. In this study, a structure-activity relationship study of BK was performed to develop potent and stable peptide mimetics active at the human B2 receptors (hB2R). Twenty-three analogues were produced with substitutions at positions 1, 3, 5, 7, 8 and/or 9 of BK. In vitro binding (on transiently transfected HEK-293T cells) and biological activities (vasomotricity tests on human umbilical veins, MAPK assays on HEK-293T cells) of novel BK peptide derivatives at hB2R were determined alongside with previously reported synthetic agonists (e.g. RMP-7, JMV1609, FR190997). Some peptides were also tested in vivo in rats and rabbits using blood pressure assays. Two compounds, [Hyp(3), Thi(5), Cha(8)]-BK and [Hyp(3), Thi(5), (N)Chg(7), Thi(8)]-BK, exhibited equivalent (or even greater) in vitro affinities and potencies to BK at the naturally expressed and recombinant hB2R. Their potency and duration of action in vivo were highly superior to BK, thus inferring that they can withstand intravascular proteolysis. These novel compounds show promise as candidates for investigating the pharmacology of BK receptors and developing potential therapeutical applications.

7000 Background: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. Methods: Pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg →15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee. Results: 283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/29%. Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤ 1% BCR-ABL1IS; 30 mg→15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations. Clinical trial information: NCT02467270. [Table: see text]

Abstract In this work, with the help of the rescaled Hinge loss, we propose a twin support vector regression (TSVR) model that is robust to noise. The corresponding optimization problem turns out to be non-convex with smooth l2 regularizer. To solve the problem efficiently, we convert it to its dual form, thereby transforming it into a convex optimization problem. An algorithm, named Res-TSVR, is provided to solve the formulated dual problem. The proof of the convergence of the algorithm is given. It is shown that the maximum number of iterations to achieve an e-precision solution to the dual problem is O ( log ( 1 e ) ) . We conduct a set of numerical experiments to compare the proposed method with the recently proposed robust approaches of TSVR and the standard SVR. Experimental results reveal that the proposed approach outperforms other robust methods of TSVR in terms of generalization performance and robustness to noise with comparable training time. This claim is based on the experiments performed using seven real-world data sets and three synthetic data sets.

Many extensions of the Standard Model posit the existence of heavy particles with long lifetimes. This article presents the results of a search for events containing at least one long-lived particle that decays at a significant distance from its production point into two leptons or into five or more charged particles. This analysis uses a data sample of proton-proton collisions at root s = 8 TeV corresponding to an integrated luminosity of 20.3 fb(-1) collected in 2012 by the ATLAS detector operating at the Large Hadron Collider. No events are observed in any of the signal regions, and limits are set on model parameters within supersymmetric scenarios involving R-parity violation, split supersymmetry, and gauge mediation. In some of the search channels, the trigger and search strategy are based only on the decay products of individual long-lived particles, irrespective of the rest of the event. In these cases, the provided limits can easily be reinterpreted in different scenarios.

Aim Species-area relationships (SARs) are fundamental scaling laws in ecology although their shape is still disputed. At larger areas, power laws best represent SARs. Yet, it remains unclear whether SARs follow other shapes at finer spatial grains in continuous vegetation. We asked which function describes SARs best at small grains and explored how sampling methodology or the environment influence SAR shape. Location Palaearctic grasslands and other non-forested habitats. Taxa Vascular plants, bryophytes and lichens. Methods We used the GrassPlot database, containing standardized vegetation-plot data from vascular plants, bryophytes and lichens spanning a wide range of grassland types throughout the Palaearctic and including 2,057 nested-plot series with at least seven grain sizes ranging from 1 cm(2) to 1,024 m(2). Using nonlinear regression, we assessed the appropriateness of different SAR functions (power, power quadratic, power breakpoint, logarithmic, Michaelis-Menten). Based on AICc, we tested whether the ranking of functions differed among taxonomic groups, methodological settings, biomes or vegetation types. Results The power function was the most suitable function across the studied taxonomic groups. The superiority of this function increased from lichens to bryophytes to vascular plants to all three taxonomic groups together. The sampling method was highly influential as rooted presence sampling decreased the performance of the power function. By contrast, biome and vegetation type had practically no influence on the superiority of the power law. Main conclusions We conclude that SARs of sessile organisms at smaller spatial grains are best approximated by a power function. This coincides with several other comprehensive studies of SARs at different grain sizes and for different taxa, thus supporting the general appropriateness of the power function for modelling species diversity over a wide range of grain sizes. The poor performance of the Michaelis-Menten function demonstrates that richness within plant communities generally does not approach any saturation, thus calling into question the concept of minimal area. We thank all vegetation scientists who carefully collected multi‐ scale plant diversity data from Palaearctic Grasslands available in GrassPlot. The Eurasian Dry Grassland Group (EDGG) and the International Association for Vegetation Science (IAVS) sup‐ ported the EDGG Field Workshops, which generated a core part of the GrassPlot data. The Bavarian Research Alliance (grant BayIntAn_UBT_2017_58) and the Bayreuth Center of Ecology and Environmental Research (BayCEER) funded the initial GrassPlot workshop during which the database was established and the cur‐ rent paper was initiated. A.N. acknowledges support by the Center for International Scientific Studies and Collaboration (CISSC), Iran. C.M., I.B., I.G.‐M and J.A.C. were funded by the Basque Government (IT936‐16). D.V. carried out the research supported by a grant of the State Fund For Fundamental Research Ф83/53427. G.F. carried out the research in the frame of the MIUR initiative ‘Department of excellence' (Law 232/2016). I.D. was supported by the Polish National Science Centre (grant DEC‐2013/09/N/NZ8/03234). J.Do. was supported by the Czech Science Foundation (GA 17‐19376S). M.J. was supported by grant by Slovak Academy of Sciences (VEGA 02/0095/19). W.U. ac‐ knowledges support from the Polish National Science Centre (grant 2017/27/B/NZ8/00316).

Abstract Aims Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants. Methods and results Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7–8.3] overall [male 8.1% (7.8–8.5); female 7.6% (7.0–8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9–12.9) vs. 8.2% (95% CI 7.8–8.7) in patients with no angina, P < 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4–7.3)] or without angina [6.4% (95% CI 5.9–7.0)], P > 0.99. Prescription rates of evidence-based secondary prevention therapies were high. Conclusion This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment. Clinical registry ISRCTN43070564