Multimetallic clusters can be described as building blocks in intermetallics, compounds prepared from all metals and/or semi-metals, and in Zintl phases, a subset of intermetallics containing metals ...with large differences in electronegativity. In many cases, these intermetallic and Zintl phases provide the first clue for the possibilities of bond formation between metals and semi-metals. Recent advances in multimetallic clusters found in Zintl phases and nanoparticles focusing on Ge with transition metals and semi-metals is presented. Colloidal routes to Ge nanocrystals provide an opportunity for kinetically stabilized Ge-metal and Ge-semi-metal bonding. These routes provide crystalline nanoclusters of Ge, hereafter referred to as nanocrystals, that can be structurally characterized. Compositions of Ge nanocrystals containing transition metals, and the semi-metals, Sb, Bi, and Sn, whose structures have recently been elucidated through EXAFS, will be presented along with potential applications.
This review connects seemingly disparate fields of intermetallics and Zintl phases with nanocluster (nanocrystal) chemistry to inform on multimetallic bonding within nanoclusters through advances in structural characterization.
Current base editors (BEs) catalyze only base transitions (C to T and A to G) and cannot produce base transversions. Here we present BEs that cause C-to-A transversions in Escherichia coli and C-to-G ...transversions in mammalian cells. These glycosylase base editors (GBEs) consist of a Cas9 nickase, a cytidine deaminase and a uracil-DNA glycosylase (Ung). Ung excises the U base created by the deaminase, forming an apurinic/apyrimidinic (AP) site that initiates the DNA repair process. In E. coli, we used activation-induced cytidine deaminase (AID) to construct AID-nCas9-Ung and found that it converts C to A with an average editing specificity of 93.8% ± 4.8% and editing efficiency of 87.2% ± 6.9%. For use in mammalian cells, we replaced AID with rat APOBEC1 (APOBEC-nCas9-Ung). We tested APOBEC-nCas9-Ung at 30 endogenous sites, and we observed C-to-G conversions with a high editing specificity at the sixth position of the protospacer between 29.7% and 92.2% and an editing efficiency between 5.3% and 53.0%. APOBEC-nCas9-Ung supplements the current adenine and cytidine BEs (ABE and CBE, respectively) and could be used to target G/C disease-causing mutations.
Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been ...previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Objective
Our objective was to evaluate the efficacy of the Sitting Together and Reaching to Play (START-Play) intervention in young infants with neuromotor disorders.
Method
This randomized ...controlled trial compared usual care early intervention (UC-EI) with START-Play plus UC-EI. Analyses included 112 infants with motor delay (55 UC-EI, 57 START-Play) recruited at 7 to 16 months of age across 5 sites. START-Play included twice-weekly home visits with the infant and caregiver for 12 weeks provided by physical therapists trained in the START-Play intervention; UC-EI was not disrupted. Outcome measures were the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley); the Gross Motor Function Measure; reaching frequency; and the Assessment of Problem Solving in Play (APSP). Comparisons for the full group as well as separate comparisons for infants with mild motor delay and infants with significant motor delay were conducted. Piecewise linear mixed modeling estimated short- and long-term effects.
Results
For infants with significant motor delay, positive effects of START-Play were observed at 3 months for Bayley cognition, Bayley fine motor, and APSP and at 12 months for Bayley fine motor and reaching frequency outcomes. For infants with mild motor delay, positive effects of START-Play for the Bayley receptive communication outcome were found. For the UC-EI group, the only difference between groups was a positive effect for the APSP outcome, observed at 3 months.
Conclusion
START-Play may advance reaching, problem solving, cognitive, and fine motor skills for young infants with significant motor delay over UC-EI in the short term. START-Play in addition to UC-EI may not improve motor/cognitive outcomes for infants with milder motor delays over and above usual care.
Impact
Concepts of embodied cognition, applied to early intervention in the START-Play intervention, may serve to advance cognition and motor skills in young infants with significant motor delays over usual care early intervention.
Lay Summary
If you have a young infant with significant delays in motor skills, your physical therapist can work with you to develop play opportunities to enhance your child’s problem solving, such as that used in the START-Play intervention, in addition to usual care to help your child advance cognitive and motor skills.
Policy Points
This article reconceptualizes our understanding of the opioid epidemic and proposes six strategies that address the epidemic's social roots.
In order to successfully reduce drug‐related ...mortality over the long term, policymakers and public health leaders should develop partnerships with people who use drugs, incorporate harm reduction interventions, and reverse decades of drug criminalization policies.
Context
Drug overdose is the leading cause of injury‐related death in the United States. Synthetic opioids, predominantly illicit fentanyl and its analogs, surpassed prescription opioids and heroin in associated mortality rates in 2016. Unfortunately, interventions fail to fully address the current wave of the opioid epidemic and often omit the voices of people with lived experiences regarding drug use. Every overdose death is a culmination of a long series of policy failures and lost opportunities for harm reduction.
Methods
In this article, we conducted a scoping review of the opioid literature to propose a novel framework designed to foreground social determinants more directly into our understanding of this national emergency. The “continuum of overdose risk” framework is our synthesis of the global evidence base and is grounded in contemporary theories, models, and policies that have been successfully applied both domestically and internationally.
Findings
De‐escalating overdose risk in the long term will require scaling up innovative and comprehensive solutions that have been designed through partnerships with people who use drugs and are rooted in harm reduction.
Conclusions
Without recognizing the full drug‐use continuum and the role of social determinants, the current responses to drug overdose will continue to aggravate the problem they are trying to solve.
Background
Enthusiasm for precision oncology may obscure the psychosocial and ethical considerations associated with the implementation of tumor genetic sequencing.
Methods
Patients with advanced ...cancer undergoing tumor‐only genetic sequencing in the National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) trial were randomized to a web‐based genetic education intervention or usual care. The primary outcomes were knowledge, anxiety, depression, and cancer‐specific distress collected at baseline (T0), posteducation (T1) and after results (T2). Two‐sided, 2‐sample t tests and univariate and multivariable generalized linear models were used.
Results
Five hundred ninety‐four patients (80% from NCI Community Oncology Research Program sites) were randomized to the web intervention (n = 293) or usual care (n = 301) before the receipt of results. Patients in the intervention arm had greater increases in knowledge (P for T1‐T0 < .0001; P for T2‐T0 = .003), but there were no significant differences in distress outcomes. In unadjusted moderator analyses, there was a decrease in cancer‐specific distress among women (T0‐T1) in the intervention arm but not among men. Patients with lower health literacy in the intervention arm had greater increases in cancer‐specific distress and less decline in general anxiety (T0‐T1) and greater increases in depression (T0‐T2) in comparison with those receiving usual care.
Conclusions
Web‐based genetic education before tumor‐only sequencing results increases patient understanding and reduces distress in women. Refinements to the intervention could benefit low‐literacy groups and men.
In the Communication and Education in Tumor Profiling (COMET) study, patients with advanced cancer undergoing tumor genetic sequencing in the National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) trial have been randomized to a web‐based genetic education intervention or usual care. Web‐based genetic education has resulted in increased patient understanding and reduced distress in female patients with cancer.
•DMDD is a rare mental disorder in the community, with a prevalence of 0.3-0.76%.•More than 90% of children with DMDD had at least one other psychiatric disorder.•Increasing internalizing (DMDD only) ...and externalizing problems in DMDD and ODD.•DMDD influenced mainly peer relationships but not academic performance.•DMDD comorbid with ODD brought more impairment than ODD alone.
We examined correlates, psychiatric comorbidities, and social adjustment difficulties in children with disruptive mood dysregulation disorder (DMDD) from a national epidemiological study in Taiwan.
The sample consisted of 4816 children, who were 3rd, 5th, and 7th graders from schools randomly chosen based on the urbanization level in a recent national survey of childhood mental disorders. Among the 4816 children (2520 boys, 52.3%) interviewed using the Kiddie epidemiologic version of the Schedule for Affective Disorders and Schizophrenia (K-SADS-E) for the DSM-5, 30 children were diagnosed as DMDD (23 boys, 76.7%). They and their parents also reported on the Social Adjustment Inventory for Children and Adolescents (SAICA). We conducted regressions for survey data that controlled for stratification and clustering.
The weighted prevalence of DMDD was 0.3~0.76% in Taiwanese children. Lower parental educational levels, male predominance, higher psychiatric comorbidities, and worse self-report school functions (e.g., more behavioral problems with peers) were observed in children with DMDD than those without. Additional analyses revealed that oppositional defiant disorder (ODD) but not DMDD was related to conduct disorder. Children with ODD with or without DMDD had more problems regarding attitudes toward school, academic performance, and parent-child interaction at home than those with DMDD-only.
Small sample size of DMDD.
DMDD is a rare disorder in the community. Children with DMDD had more psychiatric comorbidities, and subjectively experienced more difficulties than those without. DMDD and ODD both resulted in severe impairment yet in different domains.
Introduction
Our understanding of the genetic predisposition for age‐at‐onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any ...have sex‐specific effects.
Methods
Genome‐wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome.
Results
We identified 11 genome‐wide significant loci (P < 5 × 10−8), including six known AD‐risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex‐specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males.
Discussion
Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD.
Thermoelectric materials convert heat energy into electricity, hold promising capabilities for energy waste harvesting, and may be the future of sustainable energy utilization. In this work, we ...successfully synthesized core–shell Bi2Te3/Sb2Te3 (BTST) nanostructured heterojunctions via a two-step solution route. Samples with different Bi2Te3 core to Sb2Te3 shell ratios could be synthesized by controlling the reaction precursors. Scanning electron microscopy images show well-defined hexagonal nanoplates and the distinct interfaces between Bi2Te3 and Sb2Te3. The similarity of the area ratios with the precursor ratios indicates that the growth of the Sb2Te3 shell mostly took place on the lateral direction rather than the vertical. Transmission electron microscopy revealed the crystalline nature of the as-synthesized Bi2Te3 core and Sb2Te3 shell. Energy-dispersive X-ray spectroscopy verified the lateral growth of a Sb2Te3 shell on the Bi2Te3 core. Thermoelectric properties were measured on pellets obtained from powders via spark plasma sintering with two different directions, in-plane and out-of-plane, showing anisotropic properties due to the nanostructure alignment in the pellets. All samples showed a degenerate semiconducting character with the electrical resistivity increasing with the temperature. Starting from Sb2Te3, the electrical resistivity increases with the increase in amounts of Bi2Te3. Thermal conductivity is lowered due to the increase in interfaces and additional phonon scattering. We show that the out-of-plane direction of the BTST 1-3 sample (where 1-3 indicates the ratio of BT to ST) demonstrates a high Seebeck value of 145 μV/K at 500 K which may be attributed to an energy filtering effect across the heterojunction interfaces. The highest overall zT is observed for the BTST 1-3 sample in the out-of-plane direction at 500 K. The zT values increase continuously over the measured temperature range, indicating a probable higher value at increased temperatures.
Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 ...(GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.
Observational cohort study.
Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study).
Circulating GDF-15, Gal-3, and sST2 measured at baseline.
Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident.
Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function.
Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m2. Higher GDF-15 (adjusted HR aHR per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events.
Event rates for heart failure and atherosclerotic CVD were low.
Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.
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