Pseudomorphic and partially relaxed layers of corundum phase (Al, Ga)2O3 epilayers on (01.2)-oriented Al2O3 fabricated by pulsed laser deposition (PLD) are investigated. An exact analytical ...(continuum elasticity) strain theory for rhombohedral heterostructures as a function of the two substrate orientation angles fits the strain state of pseudomorphic and relaxed samples very well. From reciprocal space maps and a quantitative analysis of x-ray diffraction peaks and tilts using the strain theory, it is concluded that in the present samples grown below 800 °C, plastic strain relaxation above the critical thickness occurs first through slip on the prismatic a-plane glide system and subsequently via the basal c-plane system. We also present a general PLD stoichiometry transfer model simultaneously explaining the epilayer alloy composition and growth rate in the entire composition range.
Summary
In addition to their detection in typical X‐linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)‐2 receptor common gamma chain gene (IL2RG) have been ...described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4‐year‐old boy with lethal Epstein–Barr virus‐related lymphoma and his asymptomatic 8‐month‐old brother with a TlowB+natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL‐2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription‐1 (STAT‐5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc), which showed partially preserved function. Co‐immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc. Here, we describe how the R328X mutation in IL‐2RG may allow partial phosphorylation of STAT‐5 through a JAK3‐independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.
We report the biochemical and functional characterization of a nonsense mutation (p.R328X) in IL2RG present in two brothers with atypical clinical and immunological phenotype. The mutant allows partial STAT5 phosphorylation through a JAK3 independent pathway identifying a critical region for stabilization of receptors and facilitating this alternative signalling.
Research was done during 2012 to evaluate the potential exposure of pollinators to neonicotinoid insecticides used as seed treatments on corn, cotton, and soybean. Samples were collected from small ...plot evaluations of seed treatments and from commercial fields in agricultural production areas in Arkansas, Mississippi, and Tennessee. In total, 560 samples were analyzed for concentrations of clothianidin, imidacloprid, thiamethoxam, and their metabolites. These included pollen from corn and cotton, nectar from cotton, flowers from soybean, honey bees, Apis mellifera L., and pollen carried by foragers returning to hives, preplanting and in-season soil samples, and wild flowers adjacent to recently planted fields. Neonicotinoid insecticides were detected at a level of 1 ng/g or above in 23% of wild flower samples around recently planted fields, with an average detection level of about 10 ng/g. We detected neonicotinoid insecticides in the soil of production fields prior to planting at an average concentration of about 10 ng/g, and over 80% of the samples having some insecticide present. Only 5% of foraging honey bees tested positive for the presence of neonicotinoid insecticides, and there was only one trace detection (< 1 ng/g) in pollen being carried by those bees. Soybean flowers, cotton pollen, and cotton nectar contained little or no neonicotinoids resulting from insecticide seed treatments. Average levels of neonicotinoid insecticides in corn pollen ranged from less than 1 to 6 ng/g. The highest neonicotinoid concentrations were found in soil collected during early flowering from insecticide seed treatment trials. However, these levels were generally not well correlated with neonicotinoid concentrations in flowers, pollen, or nectar. Concentrations in flowering structures were well below defined levels of concern thought to cause acute mortality in honey bees. The potential implications of our findings are discussed.
Attaining control over life and death decisions facilitates the identification of new therapeutic strategies for diseases affected by early cell loss or resistance to cell death. In this context, ...ferroptosis, a prevailing form of non-apoptotic cell death marked by the iron-dependent oxidative destruction of lipid bilayers and metabolic aberrations, has attracted overwhelming interest among basic researchers and clinicians due to its relevance for a number of degenerative diseases, such as neurodegeneration, ischemia/reperfusion injury (IRI), and organ failure, as well as therapy-resistant tumors. As the ferroptotic death pathway offers various druggable nodes, it is anticipated that the preclinical and clinical development of ferroptosis modulators will unleash unprecedented opportunities for the treatment of as-yet-incurable diseases.
Ferroptosis is a pervasive, disease-relevant metabolic cell death pathway, entirely distinct from other known forms of regulated cell death.Ferroptosis is the root cause of a number of degenerative diseases and emerges as a liability for difficult-to-treat tumors.Ferroptosis modulation may unleash unprecedented opportunities for pharmacological intervention.
To analyze and compare perspectives on antenatal consultation and decision-making from participants with varying degrees of prematurity experience and clinician-experts.
Open-ended interviews ...structured around topics previously identified by recognized clinician-experts were conducted with participants having different levels of prematurity experience. Analysis used mixed methods (thematic and mental models analysis). Secondary sub-group comparisons were performed, based on degree of experience.
Non-clinician participants' (n = 80) perspectives differed regarding: amount and content of information desired, decision-making strategies, and who - parent or clinician - should direct consultations. Most wanted to retain decisional authority, all recognized their emotional limitations and many advocated for deliberation support. Participants worried parents' would regret choosing palliative care contrary to clinicians. Bereaved parents often saw issues differently.
Parents approach risk and decision-making for extremely premature infants in a personal fashion. They need personalized support tailored to their unique circumstances, decision-making preferences, and emotions.
High-throughput screening (HTS) is a well-established process in lead discovery for pharma and biotech companies and is now also being set up for basic and applied research in academia and some ...research hospitals. Since its first advent in the early to mid-1990s, the field of HTS has seen not only a continuous change in technology and processes but also an adaptation to various needs in lead discovery. HTS has now evolved into a quite mature discipline of modern drug discovery. Whereas in previous years, much emphasis has been put toward a steady increase in capacity ("quantitative increase") via various strategies in the fields of automation and miniaturization, the past years have seen a steady shift toward higher content and quality ("quality increase") for these biological test systems. Today, many experts in the field see HTS at the crossroads with the need to decide either toward further increase in throughput or more focus toward relevance of biological data. In this article, the authors describe the development of HTS over the past decade and point out their own ideas for future directions of HTS in biomedical research. They predict that the trend toward further miniaturization will slow down with the implementation of 384-well, 1536-well, and 384 low-volume-well plates. The authors predict that, ultimately, each hit-finding strategy will be much more project related, tailor-made, and better integrated into the broader drug discovery efforts.
The availability of nutrients from mosquito blood meals accelerates the development of Plasmodium falciparum laboratory strains in artificially infected Anopheles gambiae mosquitoes. The impact of ...multiple blood meals on the number of P. falciparum genotypes developing from polyclonal natural human malaria infections (field-isolates) remains unexplored. Here, we experimentally infect An. gambiae with P. falciparum field-isolates and measure the impact of an additional non-infectious blood meal on parasite development. We also assess parasite genetic diversity at the blood stage level of the parasite in the human host and of the sporozoites in the mosquito. Additional blood meals increase the sporozoite infection prevalence and intensity, but do not substantially affect the genetic diversity of sporozoites in the mosquito. The most abundant parasite genotypes in the human blood were transmitted to mosquitoes, suggesting that there was no preferential selection of specific genotypes. This study underlines the importance of additional mosquito blood meals for the development of parasite field-isolates in the mosquito host.
Background
Metabolic syndrome with its key components insulin resistance, central obesity, dyslipidaemia, and hypertension is associated with a high risk for cardiovascular events and all‐cause ...mortality in the general population. However, evidence that these findings apply to patients with chronic kidney disease (CKD) with moderately reduced estimated glomerular filtration rate and/or albuminuria is limited.
Objectives
We aimed to investigate the association between metabolic syndrome and its components with all‐cause mortality and cardiovascular outcomes in CKD patients.
Methods
Prospective observation of a cohort of 5110 CKD patients from the German Chronic Kidney Disease study with 3284 (64.3%) of them having a metabolic syndrome at baseline.
Results
During the follow‐up of 6.5 years, 605 patients died and 650 patients experienced major cardiovascular events. After extended data adjustment, patients with a metabolic syndrome had a higher risk for all‐cause mortality (hazard ratio HR = 1.26, 95% confidence interval CI: 1.04–1.54) and cardiovascular events (HR = 1.48, 95% CI: 1.22–1.79). The risk increased steadily with a growing number of metabolic syndrome components (increased waist circumference, glucose, triglycerides, hypertension and decreased HDL cholesterol): HR per component = 1.09 (95% CI: 1.02–1.17) for all‐cause mortality and 1.23 (95% CI: 1.15–1.32) for cardiovascular events. This resulted in hazard ratios between 1.50 and 2.50 in the case when four or five components are present. An analysis of individual components of metabolic syndrome showed that the glucose component led to the highest increase in risk for all‐cause mortality (HR = 1.68, 95% CI: 1.38–2.03) and cardiovascular events (HR = 1.81, 95% CI: 1.51–2.18), followed by the HDL cholesterol and triglyceride components.
Conclusions
We observed a high prevalence of metabolic syndrome among patients with moderate CKD. Metabolic syndrome increases the risk for all‐cause mortality and cardiovascular events. The glucose and lipid components seem to be the main drivers for the association with outcomes.
Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), ...which regulates cholesterol homeostasis, has recently emerged as an approach to reduce cholesterol levels. The development of humanized animal models is an important step to validate and study human drug targets, and use of genome and base editing has been proposed as a mean to target disease alleles.
To address the lack of validated models to test the safety and efficacy of techniques to target human PCSK9, we generated a liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI). We showed that plasma concentrations of total cholesterol were higher in hPCSK9-KI than in wildtype mice and increased with age. Treatment with evolocumab, a monoclonal antibody that targets human PCSK9, reduced cholesterol levels in hPCSK9-KI but not in wildtype mice, showing that the hypercholesterolemic phenotype was driven by overexpression of human PCSK9. CRISPR-Cas9-mediated genome editing of human PCSK9 reduced plasma levels of human and not mouse PCSK9, and in parallel reduced plasma concentrations of total cholesterol; genome editing of mouse Pcsk9 did not reduce cholesterol levels. Base editing using a guide RNA that targeted human and mouse PCSK9 reduced plasma levels of human and mouse PCSK9 and total cholesterol. In our mouse model, base editing was more precise than genome editing, and no off-target editing nor chromosomal translocations were identified.
Here, we describe a humanized mouse model with liver-specific expression of human PCSK9 and a human-like hypercholesterolemia phenotype, and demonstrate that this mouse can be used to evaluate antibody and gene editing-based (genome and base editing) therapies to modulate the expression of human PCSK9 and reduce cholesterol levels. We predict that this mouse model will be used in the future to understand the efficacy and safety of novel therapeutic approaches for hypercholesterolemia.
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