Teratozoospermia: spotlight on the main genetic actors in the human

BACKGROUND Male infertility affects >20 million men worldwide and represents a major health concern. Although multifactorial, male infertility has a strong genetic basis which has so far not been extensively studied. Recent studies of consanguineous families and of small cohorts of phenotypically homogeneous patients have however allowed the identification of a number of autosomal recessive causes of teratozoospermia. Homozygous mutations of aurora kinase C (AURKC) were first described to be responsible for most cases of macrozoospermia. Other genes defects have later been identified in spermatogenesis associated 16 (SPATA16) and dpy-19-like 2 (DPY19L2) in patients with globozoospermia and more recently in dynein, axonemal, heavy chain 1 (DNAH1) in a heterogeneous group of patients presenting with flagellar abnormalities previously described as dysplasia of the fibrous sheath or short/stump tail syndromes, which we propose to call multiple morphological abnormalities of the flagella (MMAF). METHODS A comprehensive review of the scientific literature available in PubMed/Medline was conducted for studies on human genetics, experimental models and physiopathology related to teratozoospermia in particular globozoospermia, large headed spermatozoa and flagellar abnormalities. The search included all articles with an English abstract available online before September 2014. RESULTS Molecular studies of numerous unrelated patients with globozoospermia and large-headed spermatozoa confirmed that mutations in DPY19L2 and AURKC are mainly responsible for their respective pathological phenotype. In globozoospermia, the deletion of the totality of the DPY19L2 gene represents ∼81% of the pathological alleles but point mutations affecting the protein function have also been described. In macrozoospermia only two recurrent mutations were identified in AURKC, accounting for almost all the pathological alleles, raising the possibility of a putative positive selection of heterozygous individuals. The recent identification of DNAH1 mutations in a proportion of patients with MMAF is promising but emphasizes that this phenotype is genetically heterogeneous. Moreover, the identification of mutations in a dynein strengthens the emerging point of view that MMAF may be a phenotypic variation of the classical forms of primary ciliary dyskinesia. Based on data from human and animal models, the MMAF phenotype seems to be favored by defects directly or indirectly affecting the central pair of axonemal microtubules of the sperm flagella. CONCLUSIONS The studies described here provide valuable information regarding the genetic and molecular defects causing infertility, to improve our understanding of the physiopathology of teratozoospermia while giving a detailed characterization of specific features of spermatogenesis. Furthermore, these findings have a significant influence on the diagnostic strategy for teratozoospermic patients allowing the clinician to provide the patient with informed genetic counseling, to adopt the best course of treatment and to develop personalized medicine directly targeting the defective gene product

Pressurized solid oxide fuel cell testing

The Pressurized SOFC Test Program is an integral part of the Cooperative Agreement between Westinghouse and DOE and was put into place to evaluate the effects of pressurization on SOFC performance. The goals of the SOFC pressurized test program are to obtain cell voltage versus current (VI) performance data as a function of pressure; to evaluate the effects of operating parameters such as temperature, air stoichiometry, and fuel utilization on cell performance, and to demonstrate long term stability of the SOFC materials at elevated pressures

Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella.

International audienceTen to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum

Borcherds symmetries in M-theory

It is well known but rather mysterious that root spaces of the $E_k$ Lie groups appear in the second integral cohomology of regular, complex, compact, del Pezzo surfaces. The corresponding groups act on the scalar fields (0-forms) of toroidal compactifications of M theory. Their Borel subgroups are actually subgroups of supergroups of finite dimension over the Grassmann algebra of differential forms on spacetime that have been shown to preserve the self-duality equation obeyed by all bosonic form-fields of the theory. We show here that the corresponding duality superalgebras are nothing but Borcherds superalgebras truncated by the above choice of Grassmann coefficients. The full Borcherds' root lattices are the second integral cohomology of the del Pezzo surfaces. Our choice of simple roots uses the anti-canonical form and its known orthogonal complement. Another result is the determination of del Pezzo surfaces associated to other string and field theory models. Dimensional reduction on $T^k$ corresponds to blow-up of $k$ points in general position with respect to each other. All theories of the Magic triangle that reduce to the $E_n$ sigma model in three dimensions correspond to singular del Pezzo surfaces with $A_{8-n}$ (normal) singularity at a point. The case of type I and heterotic theories if one drops their gauge sector corresponds to non-normal (singular along a curve) del Pezzo's. We comment on previous encounters with Borcherds algebras at the end of the paper.Comment: 30 pages. Besides expository improvements, we exclude by hand real fermionic simple roots when they would naively aris

Characterizing the Near-infrared Spectra of Flares from TRAPPIST-1 During JWST Transit Spectroscopy Observations

We present the first analysis of JWST near-infrared spectroscopy of stellar flares from TRAPPIST-1 during transits of rocky exoplanets. Four flares were observed from 0.6--2.8 $\mu$m with NIRISS and 0.6--3.5 $\mu$m with NIRSpec during transits of TRAPPIST-1b, f, and g. We discover P$\alpha$ and Br$\beta$ line emission and characterize flare continuum at wavelengths from 1--3.5 $\mu$m for the first time. Observed lines include H$\alpha$, P$\alpha$-P$\epsilon$, Br$\beta$, He I $\lambda$0.7062$\mu$m, two Ca II infrared triplet (IRT) lines, and the He I IRT. We observe a reversed Paschen decrement from P$\alpha$-P$\gamma$ alongside changes in the light curve shapes of these lines. The continuum of all four flares is well-described by blackbody emission with an effective temperature below 5300 K, lower than temperatures typically observed at optical wavelengths. The 0.6--1 $\mu$m spectra were convolved with the TESS response, enabling us to measure the flare rate of TRAPPIST-1 in the TESS bandpass. We find flares of 10$^{30}$ erg large enough to impact transit spectra occur at a rate of 3.6$\substack{+2.1 \\ -1.3}$ flare d$^{-1}$, $\sim$10$\times$ higher than previous predictions from K2. We measure the amount of flare contamination at 2 $\mu$m for the TRAPPIST-1b and f transits to be 500$\pm$450 and 2100$\pm$400 ppm, respectively. We find up to 80% of flare contamination can be removed, with mitigation most effective from 1.0--2.4 $\mu$m. These results suggest transits affected by flares may still be useful for atmospheric characterization efforts.Comment: 29 pages, 17 figures, 3 tables, accepted to The Astrophysical Journa

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans

Vortices in Superfluid Films on Curved Surfaces

We present a systematic study of how vortices in superfluid films interact with the spatially varying Gaussian curvature of the underlying substrate. The Gaussian curvature acts as a source for a geometric potential that attracts (repels) vortices towards regions of negative (positive) Gaussian curvature independently of the sign of their topological charge. Various experimental tests involving rotating superfluid films and vortex pinning are first discussed for films coating gently curved substrates that can be treated in perturbation theory from flatness. An estimate of the experimental regimes of interest is obtained by comparing the strength of the geometrical forces to the vortex pinning induced by the varying thickness of the film which is in turn caused by capillary effects and gravity. We then present a non-perturbative technique based on conformal mappings that leads an exact solution for the geometric potential as well as the geometric correction to the interaction between vortices. The conformal mapping approach is illustrated by means of explicit calculations of the geometric effects encountered in the study of some strongly curved surfaces and by deriving universal bounds on their strength.Comment: 50 pages, 38 figure

MINDS. JWST-MIRI Reveals a Dynamic Gas-Rich Inner Disk Inside the Cavity of SY Cha

SY Cha is a T Tauri star surrounded by a protoplanetary disk with a large cavity seen in the millimeter continuum but has the spectral energy distribution (SED) of a full disk. Here we report the first results from JWST-MIRI Medium Resolution Spectrometer (MRS) observations taken as part of the MIRI mid-INfrared Disk Survey (MINDS) GTO Program. The much improved resolution and sensitivity of MIRI-MRS compared to Spitzer enables a robust analysis of the previously detected H2O, CO, HCN, and CO2 emission as well as a marginal detection of C2H2. We also report the first robust detection of mid-infrared OH and ro-vibrational CO emission in this source. The derived molecular column densities reveal the inner disk of SY Cha to be rich in both oxygen and carbon bearing molecules. This is in contrast to PDS 70, another protoplanetary disk with a large cavity observed with JWST, which displays much weaker line emission. In the SY Cha disk, the continuum, and potentially the line, flux varies substantially between the new JWST observations and archival Spitzer observations, indicative of a highly dynamic inner disk.Comment: 19 pages, 10 figures, 5 tables, accepted for publication in Ap

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio