Hamptonpaul8329
Self-assembly associated with shape-tunable oblate colloidal allergens in to orientationally ordered uric acid, glassy deposits as well as plastic material crystals.
Defect-Rich High-Entropy Oxide Nanosheets with regard to Effective 5-Hydroxymethylfurfural Electrooxidation.
We apply this methodology to the online recruitment platform of the Swiss public employment service and find that rates of contact by recruiters are 4-19% lower for individuals from immigrant and minority ethnic groups, depending on their country of origin, than for citizens from the majority group. Women experience a penalty of 7% in professions that are dominated by men, and the opposite pattern emerges for men in professions that are dominated by women. We find no evidence that recruiters spend less time evaluating the profiles of individuals from minority ethnic groups. Our methodology provides a widely applicable, non-intrusive and cost-efficient tool that researchers and policy-makers can use to continuously monitor hiring discrimination, to identify some of the drivers of discrimination and to inform approaches to counter it.Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. selleck compound The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. link= selleck compound Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. selleck compound Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation.
Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts.
The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding.
Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.
Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.
Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.
Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.
We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. link2 Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.
This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation.
Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions.
Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). link2 Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p < 0.001) and accounted for 9% of the variation of a full mutation expansion.
Apart from significant differences regarding the number of CGG repeats and AGG interruptions between Ashkenazi and non-Ashkenazi heterozygotes, ethnicity independently affects the risk of a full mutation.
Apart from significant differences regarding the number of CGG repeats and AGG interruptions between Ashkenazi and non-Ashkenazi heterozygotes, ethnicity independently affects the risk of a full mutation.
To investigate the effectiveness of phenotype-based search approaches using publicly available online databases.
We included consecutively solved cases from our exome database. For each case, the combination of Human Phenotype Ontology terms reported by the referring clinician was used to perform a search in three commonly used databases OMIM (first 300 results), Phenolyzer (first 300 results), and Mendelian (all 100 results).
One hundred cases were included (43 females; mean age 10 years). The actual molecular diagnosis identified through exome sequencing was not included in the search results of any of the queried databases in 33% of cases. In 85% of cases it was not found within the top five search results. When included, its median rank was 61 (range 1-295), 21 (1-270), and 29 (1-92) in OMIM, Phenolyzer and Mendelian, respectively.
This study demonstrates that, in most cases, phenotype-based search approaches using public online databases is ineffective in providing a probable diagnosis for Mendelian conditions. Genotype-first approach through molecular-guided diagnostics with backward phenotyping may be a more appropriate approach for these disorders, unless a specific diagnosis is considered a priori based on highly unique phenotypic features or a specific facial gestalt.
This study demonstrates that, in most cases, phenotype-based search approaches using public online databases is ineffective in providing a probable diagnosis for Mendelian conditions. Genotype-first approach through molecular-guided diagnostics with backward phenotyping may be a more appropriate approach for these disorders, unless a specific diagnosis is considered a priori based on highly unique phenotypic features or a specific facial gestalt.
Genetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics.
We retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children's hospitals in Texas, 2017-2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield.
The majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis.
Though there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.
Though there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.Sepsis is the life-threatening organ dysfunction caused by a dysregulated host response to infection and is the leading cause of death in intensive care units. Cardiac dysfunction caused by sepsis, usually termed sepsis-induced cardiomyopathy, is common and has long been a subject of interest. In this Review, we explore the definition, epidemiology, diagnosis and pathophysiology of septic cardiomyopathy, with an emphasis on how best to interpret this condition in the clinical context. link3 Advances in diagnostic techniques have increased the sensitivity of detection of myocardial abnormalities but have posed challenges in linking those abnormalities to therapeutic strategies and relevant clinical outcomes. Sophisticated methodologies have elucidated various pathophysiological mechanisms but the extent to which these are adaptive responses is yet to be definitively answered. link3 Although the indications for monitoring and treating septic cardiomyopathy are clinical and directed towards restoring tissue perfusion, a better understanding of the course and implications of septic cardiomyopathy can help to optimize interventions and improve clinical outcomes.
