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This randomized, double-blind, single- and multiple-ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small-molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half-life of 8-15 h, and 1.4-1.9-fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)-12/IL-18-induced interferon (IFN)γ production ex vivo in a dose- and concentration-dependent manner. Following in vivo challenge with IFNα-2a, deucravacitinib demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IFN-regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first-in-human study, deucravacitinib inhibited IL-12/IL-23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune-mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus.

Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.

Olivine is the most abundant mineral in Earth’s mantle, and its rheology is likely to control upper-mantle convection. While the rheology of olivine is widely studied, little is known about the rheology of olivine grain boundaries and their effect on deformation in the mantle. Forsterite bicrystals, synthesized by direct bonding of highly polished single-crystal plates, were tested in this study to investigate sliding along the single grain boundary at high temperature (1300°C). Prior to deformation, the bicrystals were polished and scratch markers were scribed perpendicular to the grain boundary to track grain-boundary sliding. Bicrystals were deformed in shear loading between two alumina pistons in a uniaxial creep apparatus at 1 atm with applied axial stress ranging from 1 to 30 MPa. The specimen deformation was measured in real time using a high-resolution (~1 μm) linear variable differential transducer. Each test was carried out until attainment of a quasi-steady state deformation rate to determine the creep parameters. Post-deformation microstructural analysis was conducted using a scanning electron microscope (SEM) and electron backscattered diffraction. Our study established that the creep-rate law for bicrystals is different than single and polycrystalline forsterite. Bicrystals are weaker and shows up to 1 order of magnitude higher deformation rates. SEM microstructures reveal the sliding of scratch markers, which is direct evidence of grain-boundary sliding in forsterite. However, the strain geometry is complex, and further experiments are necessary to determine the overall strain distribution in the sample. Here we present the rationale of our research, and we compare our results on grain-boundary sliding in forsterite with the earlier literature.

Lattice preferred orientation (LPO) of olivine crystals occurs due to deformation in the mantle. Different parts of the upper mantle can undergo a large variety of deformation paths. During simple processes, such as simple shearing below oceans due to the movement of tectonic plates, the LPO will reflect the direction of the movement of tectonic plates. On the other hand, in areas, such as around subduction zones, the mantle undergoes more complex deformation paths, resulting in a less easily predictable LPO. Seismic anisotropy has been used as a proxy for mantle flows and the LPO formed in the mantle. To interpret the seismic anisotropy observations more accurately, we need to understand how LPO forms in different regions of subduction.LPO has been implemented in many numerical modelling tools to predict seismic anisotropy, which places constraints on mantle dynamics. However, a few recent studies have linked olivine texture development to viscous anisotropy, resulted from the summed effect of individual crystals that are deforming anisotropically. Anisotropic viscosity can affect deformation and in turn the resulting LPO. To study the effect of anisotropic viscosity (AV) and LPO evolution in geodynamics processes, it is important to know the role of AV on LPO and the differences between the numerical methods that calculate them.We choose three methods of olivine texture development to examine in this study. D-Rex is a polycrystal LPO model that is relatively balanced in computational efficiency and accuracy. From previous studies, D-Rex has been shown to produce faster texture development and stronger texture compared to other methods, including our second choice, the modified director method (MDM). The MDM parameterizes the olivine LPO formation as relative rotation rates along the slip systems that participate in the rotation of olivine grains due to finite deformation. We also couple the MDM with a micromechanical model for olivine AV (which makes our third choice MDM+AV), to allow the anisotropic texture to modify the viscosity and in turn affect the formation of LPO.Here we compare the LPO evolution under subduction settings with a slowly advancing trench and a retreating trench, with and without the effect of AV. Since the mantle flow pattern in subduction zones is not homogeneous, different particles experience a variety of deformation paths. We place 60 particles in each subduction model around the slab to track the deformation and resulting olivine texture. We compute olivine texture using the above-mentioned three different methods (D-Rex, MDM, MDM+AV). With the particles, we can identify characteristic textures developed in key regions such as the mantle wedge, sub-slab area, and lateral slab edge. We then run a statistical analysis on the texture parameter and anisotropic properties of the particles from both retreating and advancing subduction models, to study where anisotropic viscosity has the largest effect on the mantle flow. We expect AV to have a larger effect in a retreating slab setting since the mantle flows feeding material to the sub-slab region is more intensive.

Transient creep controls the behavior of Earth’s mantle at human timescales. Transient creep occurs during postseismic creep, glacial isostatic adjustment, and tidal deformation of planetary interiors experiencing large tidal stresses, such as Jupiter’s moon Io or various identified exoplanets. Unfortunately, laboratory data of transient creep of olivine, the most abundant mineral in Earth’s upper mantle, remain limited, and at present we lack the microphysical understanding of transient creep required to extrapolate experimental data to geological grain sizes and time scales. Several mechanisms for transient creep have been proposed, both intergranular mechanisms such as plastic anisotropy and elastically or diffusionally-assisted grain boundary sliding, and intragranular mechanisms including long-range dislocation interactions and various other dislocation damping mechanisms. Each mechanism produces distinct rheological behavior, presenting a hurdle for modeling geodynamic processes occurring on timescales of hours to years.To distinguish among the various proposed microphysical mechanisms for transient creep, we performed compressional load-reduction experiments on cylindrical, isostatically hot-pressed aggregates of San Carlos olivine in a gas-medium Paterson apparatus at confining pressures of 300 MPa and temperatures of 1200°C. Samples were subjected to a constant differential stress of 200 MPa, which resulted in a steady-state strain rate of ~10-5 s-1. After steady state was achieved, the samples were subjected to a near-instantaneous load reduction of 10–70% of the original load. For load reductions exceeding ~50%, the samples exhibited a period of transient anelastic relaxation with zero or negative strain rate before continuing to strain at a positive strain rate lower than the previous steady state. The duration of relaxation increased with the magnitude of the load reduction. Multiple load reductions from the same steady-state strain rate were performed during a single experiment to test for reproducibility. We interpret our results to indicate that, at these conditions, the backstress stored in polycrystalline olivine is approximately half of the differential stress applied to the material. The magnitude of backstress is compatible with long-range dislocation interactions on the [100](010) and [100](001) or [001](100) slip systems previously observed for single crystals of olivine. If transient creep is controlled by such dislocation interactions then it may be inappropriate to apply the traditional Burgers rheology based exclusively on intergranular dissipation processes or power-law flow laws calibrated for steady-state creep to model transient creep and transient viscosity evolution in the upper mantle.

Dyslexia is a common learning disability exhibited as a delay in acquiring reading skills despite adequate intelligence, and reading single real words are impaired in many dyslexics. Reading disability or developmental dyslexia (DD) is a neurodevelopmental disorder affecting children globally, and the molecular mechanisms underlying it are largely underdetermined, while loci and susceptibility genes are suggested by genetic mapping in families or cohorts and by genome wide association studies (GWAS). To identify a possible genetic cause, we genotyped and performed genome wide linkage analysis employing the programs LIPED and SNP6-LINK of six multigenerational families with autosomal dominant inherited dyslexia. The linkage analyses resulted in informative haplotypes segregating with the dyslectic trait in all families and a LOD score of Z>4 at 13q12.3 and 19p13.3, and a LOD score of Z>3 at 15q23-q24.1, 18q11.21, and 21q22.3. The five mapped regions are supported by previous linkage or associations studies of dyslexia. Whole genome sequencing (WGS) of affected individuals in the six family’s revealed rare regulatory variants in the mapped regions.

Causes of suicide are complex indicating a nation's psycho-socio-economic well-being hence this population-based study explores whether USA suicides worsened compared to nineteen Other Western Countries (OWC) being possibly related to gun ownership in theTotal suicide data are drawn from the latest WHO Age-Standardised-Death-Rates per million (pm) controlled for age, sex, and population, along with suicides in the five age- bands 15-34 years to 75 + years. National gun ownership data from the international Small Arms Survey. Chi-square tests any significant difference between American and OWC suicides during the century. Spearman Rank Order correlations are used to determine comparability of suicides and gun ownership per thousand person rates over the period 2000-15.USA had the highest gun ownership, treble the rate of the next highest country. American Total suicides rose 27%, significantly more than eight other countries (The key finding is whilst most countries reduced suicides American rates rose substantially this century, raising questions about US society. Importantly the easy access to firearms in the USA makes Young Adult suicide more likely when facing psycho-social stress. This study exposes the vulnerability of distressed young American adults in a permissive gun culture, with its sequel, life-long grieving parents.HighlightsDuring 21st Century USA suicides rose substantially more than other Western nations.Only USA suicides rose20% amongst Total suicides and in those aged 15-to-74years.USA Young Adult suicides 150,099 in 21st century, 12,438 in 2015, 6,702 were gun-related.

In Schleswig-Holstein müssen die Mentoren und Mentorinnen als sogenannte Ausbildungslehrkräfte ein Zertifikat für die Ausbildungstätigkeit erwerben. Der Erwerb dieses Zertifikats bedingt Qualifikationen, die in speziellen Fortbildungen erworben werden. Damit entsteht ein Qualitätsmanagement zur Ausbildung, welches nicht der einzelnen Ausbildungslehrkraft überlassen wird, sondern insgesamt Maßstäbe setzt.

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1+/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.

The mechanics of olivine deformation play a key role in long-term planetary processes, such as the response of the lithosphere to tectonic loading or the response of the solid Earth to tidal forces, and in short-term processes, such as the evolution of roughness on oceanic fault surfaces or postseismic creep within the upper mantle. Many previous studies have emphasized the importance of grain-size effects in the deformation of olivine. However, most of our understanding of the role of grain boundaries in the deformation of olivine is inferred from comparison of experiments on single crystals to experiments on polycrystalline samples.To directly observe and quantify the mechanical properties of olivine grain boundaries, we use high-precision mechanical testing of synthetic forsterite bicrystals with well characterised interfaces. We conduct in-situ micropillar compression tests at high-temperature (700°C) on low-angle (13° tilt about [100] on (015)) and high-angle (60° tilt about [100] on (011)) grain boundaries. In these experiments, the boundary is contained within the micropillar and oriented at 45° to the loading direction to promote shear along the boundary. In these in-situ tests, we observe differences in deformation style between the pillars containing the grain boundary and the pillars in the crystal interior. In-situ observations and analysis of the mechanical data indicate that pillars containing the grain boundary consistently support elastic loading to higher stresses than pillars without a grain boundary. Moreover, only the pillars without a grain boundary display evidence of sustained plasticity and slip-band formation. Post-deformation advanced microstructural characterization (STEM) confirms that under the conditions of these deformation experiments, sliding did not occur along the grain boundary. These observations support the hypothesis that grain boundaries are stronger than the crystal interior. These experiments on small deformation volumes allow us to qualitatively explore the differences between the crystal interior and regions containing grain boundaries. Overall, the variation in strain and temperature in our small scale experiments allows fundamental investigation of the response of well characterised forsterite grain boundaries to deformation.

The development of olivine texture, or lattice preferred orientation (LPO), has been implemented in many numerical modelling tools to predict seismic anisotropy, which places constraints on mantle dynamics. However, a few recent studies have linked olivine texture development to its mechanical anisotropy, which in turn can affect deformation rates and also the resulting texture. To study the effect of anisotropic viscosity (AV) and LPO evolution in geodynamics processes, it is important to know the role of AV and LPO and the differences between the numerical methods that calculate them.The modified director method parameterizes the olivine LPO formation as relative rotation rates along the slip systems that participate in the rotation of olivine grains due to finite deformation. When it is coupled with a micromechanical model for olivine AV, it allows the anisotropic texture to modify the viscosity. We compare the olivine textures predicted by the modified director method both with and without a coupled micromechanical model and textures predicted by the D-Rex LPO evolution model. To do this, we recalculate the texture observed in simple 3D models such as a shear box model and two other well-understood models: a corner flow model and a subduction model. In general, we observed that the D-Rex models predict a stronger anisotropic texture compared to the texture predicted by the modified director method both with and without the micromechanical model, in agreement with previous studies. When including the micromechanical model, the anisotropic texture changes the observed strain rates, which allows for a slightly faster texture evolution that is more similar to the D-Rex predictions than it is to those produced by the modified director method alone. We found that even for the simplest settings there is an increase of 10~15% in strain rate during deformation until a strain of 2.5. When shearing the asthenosphere over ~10 Myr, such anisotropy could modify the effective viscosity of the mantle,causing an up to 40% increase in plate velocity for the same applied stress. The anisotropy can also induce deformation in planes other than the initial shear plane, which can change the direction of the primary deformation.Our ultimate goal is to understand the role of AV and LPO evolution in geodynamic processes by looking at deformation paths predicted by geodynamic models in ASPECTWith this initial test, we will gain a basic understanding of olivine AV behavior and LPO evolution under different deformation settings calculated with different numerical methods, which we will carry onto our next step of implementing anisotropic viscosity of olivine in 3D into ASPECT.

Increasingly, volcanologists model mature volcanic systems as being fed by stratified magma reservoirs, that is, small lenses of eruptible magma suspended within a larger volume of non-eruptible, crystal-rich mush. Erupted lavas record geochemical evidence for long-term deep storage of distinct magma bodies followed by their ascent and coalescence shortly before eruption. Conditions and flow mechanisms that allow deep-seated magmas to rise quickly in reservoirs despite the high viscosity and low permeability of crystal-rich mushes are a subject of debate. We present results of melt migration experiments conducted in a triaxial, gas-medium apparatus. We prepared multiple crystal-rich mushes by hot pressing crushed borosilicate glass mixed with different amounts of subrounded quartz sand (44-106 μm diameter). Prepared mushes have crystal fractions from 0.59 to 0.83. A single disk of mush is stacked on a disk of soda lime glass, representing the intruding crystal-free magma, then heated to 900°C (above the glass transitions) and pressurized to 100-300 MPa. The bottom and circumference of the mush experience the confining pressure, but the top is at room pressure, resulting in a pore pressure gradient (~33-100 MPa/mm) that could drive the underlying melt into the mush. After several hours samples are cooled, decompressed, cut and imaged to determine the distribution of the soda lime glass that migrated in to the mush while at the experimental conditions. High crystal fraction samples (>0.80; Hi X) have glass filling intergranular space. In low crystal fraction samples (-1.7 to 10-8.6). The observed increase in the amount of melt migration with decreasing crystal fraction is coincident with the onset of mush deformation. Applied to natural systems, these results suggest small changes in mush crystal fraction significantly influence the amount of melt migration that occurs and that melt migration in magma reservoirs peaks near the transition from deformable mush to partially-molten rock (i.e., at the rheologically critical melt fraction).

Aim: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease.Materials and Methods: In this phase 2a study (NCT03550378), patients with body mass index 25-45 kg/m2, estimated glomerular filtration rate 30-59 ml/min/1.73 m2 and type 2 diabetes [glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once-daily subcutaneous cotadutide (50-300 μg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed-meal tolerance test.Results: Participants receiving cotadutide (n = 21) had significant reductions in the mixed-meal tolerance test area under the glucose concentration-time curve (–26.71% vs. +3.68%, p Conclusions: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin-to-creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer-term clinical trials.

At low-temperature and high-stress conditions, quartz deformation is controlled by the kinetics of dislocation glide, that is, low-temperature plasticity (LTP). To investigate the relationship between intracrystalline H2O content and the yield strength of quartz LTP, we have integrated spherical and Berkovich nanoindentation tests at room temperature on natural quartz with electron backscatter diffraction and secondary-ion mass spectrometry measurements of intracrystalline H2O content. Dry (, Geophysical Research Letters, 49 (2), ISSN:0094-8276, ISSN:1944-8007

Aims: To examine whether increased neurological deaths during 21st Century are predominately due to elderly demographics, or major influences of interactive-multiple environmental contributory factors? We examine WHO Early-Adult-Deaths (55-74yearolds), which is below Western life-expectancy, and total Age-Standardised-Death-Rates (ASDR) controlled by age, sex, and population, to challenge the demographic assumption. Method. Based upon WHO latest global neurological mortality categories, Nervous-Disease-Deaths and Alzheimer’s & Other Dementias, which provides the Combined Neurological Death, rates per million (pm), for the twenty-one West-Developed-Nations (WDN) over the period. Early-Adult-Death rates based upon numbers of deaths, divided by 55-74 population and WHO total ASDR during the 21st Century. Increases between Over 75’s population and Over 75’s neurological mortality is compared using Odds Ratios. Numbers of deaths are indicative of family and services pressures. Results: Every country’s 55-74yearolds Nervous-Disease-Deaths rates were higher than Alzheimer’s & Dementia Deaths, ten countries Nervous-Disease-Deaths rose higher than Alzheimer’s & Dementias during Century. Highest Combined Deaths and increases were Finland 1006 per million (pm) up 44%, USA 710pm, rose 39% and UK 653pm a rise of 32%, countries average of 25%, though Belgium, Canada and France rates fell. Highest ASDR were Finland 973pm, up 104%, USA 592pm, rose 76%, UK 553pm, increase 170%. Lowest were Japan 112pm, yet up 90%, Greece 184pm, rose 64% and Austria 214pm increased 102%, average nation’s 62%. Belgium at 387pm up 34%, Canada 401pm, increased 13% and France ASDR 336pm up 11%. Population compared with total neurological amongst Early-Adult-Deaths and Over 75’s, ratios of change, were respectively 1:1.34 and 1:2.21, yielding an Odds ratios of 1:1.65 French total neurological numbers were 40,594 rose to 71,543, up 76%, UK 24,601 to 103,550 increased 321% and the USA 174,708 to 436,438 rising 150%. Discussion: We reject the hypothesis that neurological increases were mainly dues to demographics. Our results support by new studies across the continents, with their findings of significant causal multiple-interactive-environmental pollutants, including, endocrine disruptive chemicals, air pollution, organophosphates, plastics, petrochemicals, impact of low ubiquitous prolonged electro-magnetism, etc, associated with neuro-degenerative disease, especially Early-Onset-Dementia, below Western life-expectancy. Conclusions: Governments should seek urgent research to explain this new epidemic.

Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics.Key pointsD2 partial agonists share many pharmacological and clinical propertiesD2 partial agonists differ in several important respects from D2 antagonistsD2 partial agonists should be considered a discrete class of antipsychotics D2 partial agonists share many pharmacological and clinical properties D2 partial agonists differ in several important respects from D2 antagonists D2 partial agonists should be considered a discrete class of antipsychotics