The „heritability” of a phenotype measures the proportion of trait variance due to genetic factors in a population. In the past 50 years, studies with monozygotic and dizygotic twins have estimated heritability for 17 804 traits; thus twin studies are popular for estimating heritability. However, overestimation of heritability in twin studies is one suggested cause of the „missing-heritability phenomena” (estimates from empirical genetic studies are often smaller than twin studies). Developing more accurate methods for estimating heritability may be warranted. Therefore, we propose a robust framework for estimating heritability in twin studies using generalized estimating equations (GEE2). Two popular methods for estimating heritability, the normal ACE model (NACE) and Falconer’s method, are derived within this unified GEE2 framework, which additionally provides robust standard errors. Although the traditional Falconer’s method cannot adjust for covariates, the corresponding „GEE2-Falconer” can incorporate mean and variance-level covariate effects (eg, let heritability vary by sex or age). Given nonnormal data, the GEE2 models are shown to attain better coverage of the true heritability compared to traditional methods. Finally, a scenario is demonstrated where NACE produces biased estimates of heritability while Falconer remains unbiased. Therefore, we recommend the more robust GEE2-Falconer method for estimating heritability in twin studies.Ovaries and oviducts of the adult African Clawed Toad (Xenopus laevis DAUDIN, 1802) were studied by light microscopy (LM) of paraplast embedded tissue sections and scanning electron microscopy (SEM) of vascular corrosion casts (VCCs). Histomorphology revealed that ovarian vessels located in the thecal layers. Ovarian and interlobar arteries displayed a horse-shoe shaped longitudinally running bundle of vascular smooth muscle cells. Follicular blood vessels showed flattened profiles, which were confirmed by scanning electron microscopy in vascular corrosion casts. The flattened profiles obviously led to high intravasal pressures, which locally prevented filling of the follicular capillary bed. Oviduct arteries pierced the fibrous stroma surrounding the oviduct mucosa. In the pars convoluta, the mucosa consisted of a ciliated simple columnar epithelium and tubular oviduct glands that opened between ciliated epithelial cells into the oviduct lumen. Oviduct arteries branched at the basolateral surfaces of tubular glands. After a short tangential course, arterioles branched into capillaries which ran radially between oviduct glands towards the subepithelium. Anastomoses at different heights connected capillaries of neighbouring glands. Subepithelially, capillaries ran longitudinally and undulated. Postcapillary venules radiated centrifugally towards the stroma to finally drain into oviduct veins located in the stroma. Oviduct vascular densities clearly reflected non-ovulatory and ovulatory states.Objective To evaluate the impact of lasmiditan, an oral, centrally-penetrant, selective serotonin 1F (5-HT1F ) receptor agonist developed for the acute treatment of migraine, on simulated driving. Methods Healthy adult volunteers enrolled in two randomized, placebo and active comparator-controlled, crossover studies. Study 1 (N = 90) tested lasmiditan (50-, 100-, 200-mg), alprazolam (1-mg), and placebo at 1.5 hr post-dose. Study 2 (N = 68) tested lasmiditan (100-, 200-mg), diphenhydramine (50-mg, administered 2 hr pre-assessments), and placebo at 8, 12 and 24 hr post-dose. Driving performance was assessed using a validated driving simulator employing a 100 km driving scenario. Standard deviation of lateral position (SDLP), a measure of lane position control, was the primary endpoint. Results Assay sensitivity was confirmed by increased SDLP for active comparators at 1.5- and 8-hr time points. Lasmiditan doses showed significant driving impairment versus placebo at 1.5 hr post-dose. Lasmiditan doses were non-inferior to placebo at 8 hr. Driving impairment was concentration-dependent at 1.5 hr but not at 8 hr. Common adverse events were central nervous system-related and mild-to-moderate in severity. Conclusions Lasmiditan was associated with impaired simulated driving performance at 1.5 hr post-dose, but showed no clinically meaningful impairment at 8 hr post-dose.The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin-producing β-cells by islet-specific autoreactive T cells. Inhibition of islet-specific autoreactive T cells to rescue β-cells is a promising approach to treat new-onset T1D. The immune checkpoint signal axis programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD-L1 to produce immunosuppressive platelets. The PD-L1-overexpressing platelets (designated PD-L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non-obese diabetic (NOD) mice, protecting the insulin-producing β-cells from destruction. Moreover, PD-L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of β-cells by PD-L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.Oxyfunctionalization of fatty acids (FAs) is a key step in the design of novel synthetic pathways for bio-based/bio-degradable polymers, surfactants and fuels. Here, we show the isolation and characterization of a robust FA α-hydroxylase (P450 Jα ) which catalyses the selective conversion of a broad range of FAs (C60-C160) and oleic acid (C181) with H 2 O 2 as oxidant. selleck inhibitor Under optimized reaction conditions P450 Jα yields α-hydroxy acids all with >95% regioselectivity, high specific activity (up to 15.2 U mg -1 ) and efficient coupling of oxidant to product (up to 85%). Lauric acid (C120) turned out to be an excellent substrate with respect to productivity (TON = 394 min -1 ). On preparative scale, conversion of C120 reached 83% (0.9 g L -1 ) when supplementing H 2 O 2 in fed-batch mode. Under similar conditions P450 Jα allowed further the first biocatalytic α-hydroxylation of oleic acid (88% conversion on 100 mL scale) at high selectivity and in good yields (1.1 g L -1 ; 79% isolated yield). Unexpectedly, P450 Jα displayed also 1-alkene formation from shorter chain FAs (≤ C100) showing that oxidative decarboxylation is more widely distributed across this enzyme family than reported previously.Almost all highly efficient perovskite solar cells (PVSCs) with power conversion efficiencies (PCEs) of greater than 22% currently contain the thermally unstable methylammonium (MA) molecule. MA-free perovskites are an intrinsically more stable optoelectronic material for use in solar cells but compromise the performance of PVSCs with relatively large energy loss. Here, the open-circuit voltage (Voc ) deficit is circumvented by the incorporation of β-guanidinopropionic acid (β-GUA) molecules into an MA-free bulk perovskite, which facilitates the formation of quasi-2D structure with face-on orientation. The 2D/3D hybrid perovskites embed at the grain boundaries of the 3D bulk perovskites and are distributed through half the thickness of the film, which effectively passivates defects and minimizes energy loss of the PVSCs through reduced charge recombination rates and enhanced charge extraction efficiencies. A PCE of 22.2% (certified efficiency of 21.5%) is achieved and the operational stability of the MA-free PVSCs is improved.QTc interval prolongation can lead to life-threatening complications such as torsade de pointes (TdP), ventricular tachycardia (VT), and sudden cardiac death (SCD). link2 It can occur with tyrosine kinase inhibitors (TKIs) but comparative real-world analyses on the incidence and complication rates are scarce. We retrospectively reviewed all cancer patients treated with TKI at Mayo Clinic between 01/2005 and 12/2018 and had at least two ECGs (before and after TKI). For each TKI type, we determined the administration rate and incidence of QTc prolongation. QTc prolongation was defined as corrected QT interval (by Fridericia formula) ≥ 450 ms in men and ≥ 470 ms in women. A total of 618 cancer patients were included with 902 TKI administrations, of which 654 (72.5%) were accounted for pazopanib, sunitinib, imatinib, nilotinib, and dasatinib. QTc prolongation (any grade) was reported in 28.8%, most commonly with nilotinib (38.7%) and dasatinib (41.7%). A QTc interval ≥ 500 ms and a QTc increase ≥ 60 ms was documented in 46 and 63 administrations, respectively. Life-threatening toxicity was seen in 14 cases (5.4% of QTc prolongation cases) including VT in 9, SCD in 3 and TdP in 2 administrations. The response to QTc prolongation was discontinuation in 68%, dose reduction in 13.5%, temporary hold in 8.1 %, and no action in 10.4%. In conclusion, QTc prolongation with TKI therapy is very common (approximately 1/3 of cases) and in 5% (1.7% overall) associated with life-threatening complications. These data support recommendations for careful ECG monitoring in cancer patients undergoing TKI therapy. This article is protected by copyright. All rights reserved.Background We aimed to evaluate cyclophosphamide efficacy in the treatment of idiopathic membranous nephropathy (IMN) and explore the efficacy of phospholipase-A2 receptor antibody (PLA2R-Ab), 24 hours proteinuria, and serum albumin in predicting 6- and 12-month treatment effects. link3 Methods A retrospective analysis was performed on 135 patients with IMN who followed up after treatment. The observation points were before, and after 3, 6, and 12 months of treatment. We collected clinical indicator data at each observation point and measured PLA2R-Ab levels before and after 3-month treatment. Results The remission rates at 3, 6, and 12 months of cyclophosphamide therapy for patients with IMN were 41.4, 74.8, and 76.1%, respectively. Patients in whom PLA2R-Ab turned negative within 3 months had high remission rates at 3, 6, and 12 months after treatment (P less then .05). PLA2R-Ab change at 3 months had a strong correlation with 24 hours proteinuria change at 6 months. The change in albumin concentration before and after 3-month treatment was an independent variable related to remission rate at 6 months, and 24 hours proteinuria change before and after 6-month treatment was an independent variable related to remission rate at 12 months after treatment. Conclusion Cyclophosphamide showed good efficacy at 3, 6, and 12 months for patients with IMN. Serum albumin change and PLA2R-Ab change at 3 months can be used as indicators to predict remission at 6 months, respectively. Moreover, 24 hours proteinuria change at 6 months can predict remission at 12 months.Paediatric morphoea is a debilitating fibrosing disorder of uncertain aetiology, affecting the skin and subcutaneous tissues. Defining optimum management strategies in paediatric morphoea remains an ongoing challenge, owing to the varied presentations and a relative paucity of paediatric-specific studies. We performed a literature search on PubMed, MEDLINE and Google Scholar, using keywords such as 'pediatric morphea’, 'juvenile localised scleroderma’ and 'juvenile systemic sclerosis’. Relevant studies, including randomized trials, reviews of standard current guidelines and original research articles, were selected and results analysed before summarizing them. In Part 1 of this review, we described the epidemiology, aetiopathogenesis and clinical classification; in this part, we discuss the diagnosis, markers of disease activity, management and natural history in paediatric morphoea.