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Multi-targeting zinc finger nuclease vector unsilences paternal UBE3A in a mouse model of Angelman syndrome
Get PDFAngelman syndrome (AS) is a severe neurodevelopmental disorder most often caused by deletion of the maternally inherited UBE3A allele (matUBE3A). In neurons, a long non-coding antisense RNA (Ube3a-ATS) silences the paternally-inherited UBE3A allele (patUBE3A). Here, we find that delivery of a zinc finger nuclease (ZFN) pair targeted to 86 Snord115 genes within Ube3a-ATS (ZFN17/18) using adeno-associated virus (AAV) can unsilence patUBE3A in primary neuron cultures and in the brain of a mouse model of AS for at least 9 weeks. The AAV vector genome integrated at ZFN17/18 on-target sites in cultured neurons and, as evidence of specificity, did not integrate at predicted off-target sites. AAV vectors carrying nickase and catalytically inactive ZFN17/18 variants failed to appreciably unsilence patUbe3a and did not integrate at on-target sites. In vivo, we observed significant knockdown of Ube3a-ATS in AS-model mice, resulting in some neurons reaching UBE3A levels like those of wild-type mice. ZFN17/18 did not downregulate Snrpn, Snord116, or IPW in vivo, genes that are associated with Prader-Willi syndrome. Overall, our findings demonstrate the potential use of multi-target ZFNs as therapeutics for AS
Seeing Discrimination: How Different Definitions of Discrimination Relate to Health in U.S. Adults.
Get PDFResearch demonstrates that perceived discrimination negatively impacts health. Yet there is conflicting evidence about how an individual's definition of discrimination-separate from their experience of discrimination-shapes health disparities. Using a nationally representative survey experiment in which participants (N = 2,000) are asked to evaluate nine different scenarios of potential discrimination, we find that how a person labels these discrimination scenarios is significantly related to their self-rated health, even after controlling for sociodemographic factors. U.S. adults who are more likely to label the event as discrimination in cases where it is intentional have comparatively worse self-rated health, whereas those who are more likely to label discrimination in cases where it affects more powerful groups (White people, men, and the wealthy) have comparatively better self-rated health-even though they are not experiencing the discrimination themselves. We argue that these findings have important implications for how health researchers measure discrimination's health effects
Analysis of left ventricular mass for African American individuals using multi-ancestry polygenic risk scores: the Jackson Heart Study
Get PDFBACKGROUND: Left ventricular mass (LVM) is suggested to be a sensitive predictor of adverse cardiovascular outcomes, such as heart failure. In recent years, genome-wide association studies have discovered loci that associate with outcomes related to LVM, providing an opportunity for the development of genetic risk scores. However, the relevance of these genetic variants to non-European ancestry groups requires additional testing. Here, we examined if variants that have been associated with heart failure and LVM in multi-ancestry populations are associated with LVM among African American individuals in the Jackson Heart Study (JHS). METHODS: Heart failure and LVM associated variants were identified from two published multi-ancestry studies. Two polygenic risk scores (PRSs) were computed for 2175 African American participants (mean age 53, 63% female). We assessed the linear association of both PRSs with LVM indexed to height (LVMh) and indexed to body surface area (LVMbsa) and fit a multivariate general linear model to LVM containing both PRS and covariates (age, sex, body mass index (BMI), diabetes and hypertension). Type III MANOVA Pillai tests were run to assess the effects of the PRS on the log LVM values. RESULTS: Linear correlation analysis showed positive associations between age and LVMh (r=0.278) and LVMbsa (r=0.296) as well as BMI with LVMh (r=0.320). A strong linear correlation was observed between LVMh and LVMbsa (r=0.894). Elevated LVM among individuals with diabetes and hypertension was observed. When accounting for age, sex, BMI, diabetes and hypertension, we found insufficient evidence to suggest that the heart failure PRS affected either measure of LVM; the same can be said for the LVM PRS. CONCLUSION: We find insufficient evidence to suggest that heart failure and LVM genetic variants derived from predominantly European multi-ancestry populations are linearly associated with log LVM among African American participants in the JHS
Prediction of antipsychotic medication inception in antipsychotic-naive youth at clinical high risk for psychosis
Get PDFAntipsychotic (AP) medication in individuals at clinical high risk for psychosis (CHR-P) is not routinely recommended by clinical guidelines but is commonly prescribed. Since little is known about the predictors of AP inception in CHR-P, we analyzed data from two observational cohorts. To avoid baseline predictors being confounded by previous treatment, participants were selected for analysis from the 764 participants at CHR-P enrolled in NAPLS-2 and the 710 enrolled in NAPLS-3 by excluding those with lifetime histories of AP use. Baseline clinical variables available in both studies were employed as predictors of subsequent AP inception over the next 6 months in univariable and multivariable analyses. Preliminary analyses indicated no important effects of sample. The final combined population included 79 AP inception participants and 580 participants who did not have AP inception. The AP medications most commonly prescribed were risperidone, aripiprazole, and quetiapine. Univariable analyses identified seven significant predictors of AP inception. The final logistic regression model including these variables was highly significant (χ2 = 36.53, df = 7, p = <0.001). Three variables (current major depression, fewer education years, and current benzodiazepine use) emerged as significant independent predictors of AP inception. This study is the first to determine baseline characteristics that predict subsequent AP initiation in CHR-P. Some AP use in CHR-P appears to be intended as augmentation of antidepressant treatment for comorbid major depression. Some prescribers may not have detected the attenuated positive symptoms characteristic of CHR-P since their severity did not significantly predict AP inception
Evidence That Intervention Dosage Is Associated With Better Outcomes in Autism—Reply
Get PDFIn Reply In response to our recent study, rather than reproduce
our analytic approach, Frazier and colleagues made the
following analytic choices without justification
DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders
Get PDFBCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins
Switching to the CKD-EPI but Not Modified FAS eGFR Formula Underdetects CKD Among Adolescents and Young Adults in México
Get PDFBackground: Guidelines recommend switching the glomerular filtration rate (eGFR) estimation from the CKiD-U25 to the CKD-EPI formula at age 18. We investigated how this would affect chronic kidney disease (CKD) classification. Methods: Serum creatinine was enzymatically measured in 1061 samples from 914 community-based 10–23-year-olds from Tlaxcala, Mexico, a region where urinary biomarkers demonstrated early kidney damage associated with exposure to inorganic toxins in a pediatric population. We calculated their eGFR using CKiD-U25, modified Schwartz, the first and modified Pottel full-age spectrum (FAS), and CKD-EPI formulae. Correlation analysis characterized the CKD stage stratified by age and sex. Results: At baseline, the median age was 13 (IQR: 12, 15) years, and 55% were female. Median CKiD-U25 eGFR was 96.9 (IQR: 83.3, 113.3) mL/min/1.73 m2, significantly lower than the CKD-EPI eGFR, which was 140.8 (IQR: 129.9, 149.3) mL/min/1.73 m2 (p < 0.0001, Wilcoxon rank test). The mean bias was 36.99 ± 12.89 mL/min/1.73 m2. Pearson correlation was r = 0.8296 (95% confidence interval 0.0898–0.8474). There was a better correlation between the modified Schwartz (r = 0.9421 (0.9349, 0.9485)) and the Pottel FAS (r = 0.9299 (0.9212, 0.9376)) formulae. Agreement was deficient when the eGFR was >75 mL/min/1.73 m2 in younger age and female sex. Modified Schwartz identified 281 (26.4%) measurements as having CKD 2 and 3 (2+), U25 identified 401 (37.7%) measurements as having CKD 2+, FAS identified 267 (25.1%) and modified FAS identified 282 (30%) measurements as having CKD 2+, and CKD-EPI identified 51 (4.8%) measurements as having CKD 2+, respectively. Conclusions: In this population, there needed to be better agreement between the various eGFR formulae. CKD-EPI identifies substantially fewer at-risk participants as having CKD
P-Distill: Efficient and Effective Prompt Tuning Using Knowledge Distillation
Get PDFIn the field of natural language processing (NLP), prompt-based learning is widely used for efficient parameter learning. However, this method has the drawback of shortening the input length by the extent of the attached prompt, leading to the inefficient utilization of the input space. In this study, we propose P-Distill, a novel prompt compression method that mitigates the aforementioned limitation of prompt-based learning while maintaining performance via knowledge distillation. The knowledge distillation process of P-Distill consists of two methods, namely prompt initialization and prompt distillation. Experiments on various NLP tasks demonstrated that P-Distill exhibited comparable or superior performance compared to other state-of-the-art prompt-based learning methods, even with significantly shorter prompts. Specifically, we achieved a peak improvement of 1.90% even with the prompt lengths compressed to one-eighth. An additional study further provides insights into the distinct impact of each method on the overall performance of P-Distill. Our code will be released upon acceptance
Dynamic Landscape of Mpox Importation Risks Driven by Heavy-Tailed Sexual Contact Networks Among Men Who Have Sex With Men in 2022
Get PDFBackground. During the 2022 global mpox outbreak, the cumulative number of countries reporting their first imported case quickly rose in the early phase, but the importation rate subsequently slowed down, leaving many countries reporting no cases by the 2022 year-end. Methods. We developed a mathematical model of international dissemination of mpox infections incorporating sexual networks and global mobility data. We used this model to characterize the mpox importation patterns observed in 2022 and to discuss the potential of further international spread. Results. Our proposed model better explained the observed importation patterns than models not assuming heterogeneity in sexual contacts. Estimated importation hazards decreased in most countries, surpassing the global case count decline, suggesting a reduced per-case risk of importation. We assessed each country’s potential to export mpox cases until the end of an epidemic, identifying countries capable of contributing to the future international spread. Conclusions. The accumulation of immunity among high-risk individuals over highly heterogeneous sexual networks may have contributed to the slowdown in the rate of mpox importations. Nevertheless, the existence of countries with the potential to contribute to the global spread of mpox highlights the importance of equitable resource access to prevent the global resurgence of mpox
