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KAT6B overexpression in mice causes aggression, anxiety, and epilepsy
No full textLoss of the gene encoding the histone acetyltransferase KAT6B (MYST4/MORF/QKF) causes developmental brain abnormalities as well as behavioral and cognitive defects in mice. In humans, heterozygous variants in the KAT6B gene cause two cognitive disorders, Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM:603736) and genitopatellar syndrome (GTPTS; OMIM:606170). Although the effects of KAT6B homozygous and heterozygous mutations have been documented in humans and mice, KAT6B gain-of-function effects have not been reported. Here, we show that overexpression of the Kat6b gene in mice caused aggression, anxiety, and spontaneous epilepsy. Kat6b overexpression led to an increase in histone H3 lysine 9 acetylation and upregulation of genes driving nervous system development and neuronal differentiation. Kat6b overexpression additionally promoted neural stem cell proliferation and favored neuronal over astrocyte differentiation in vivo and in vitro. Our results suggest that, in addition to loss-of-function alleles, gain-of-function KAT6B alleles may be detrimental for brain development
Coarctation of the aorta and accelerated atherosclerosis: A contemporary review on the burden of atherosclerotic cardiovascular disease
No full textCoarctation of the aorta (CoA) is one of the most common types of congenital heart disease. Unfortunately, there is a high prevalence of hypertension and late cardiovascular mortality in patients with CoA despite successful repair. The growing impact of acquired cardiovascular disease remains a significant concern as the adult congenital heart disease population continues to rapidly expand and age. This review aims to explore (1) the determinants of vascular health and atherosclerosis including endothelial dysfunction and vascular wall abnormalities, (2) the prevalence of atherosclerosis and associated sequelae in repaired CoA including coronary artery disease, coronary artery calcium, aortic calcium, stroke, and peripheral artery disease, and (3) the contributing factors specific to CoA. This review aims to guide optimization of long-term cardiovascular health to ultimately reduce mortality and morbidity in this young high-risk population
The status of care for youth with type 1 diabetes within and coming from humanitarian crises settings: a narrative review
No full textBACKGROUND: Humanitarian crises bring unique, and potentially growing challenges to people with type 1 diabetes (T1D). We aimed to determine, in youth with T1D (mean age (± 1SD) 0-17.9 years) within and coming from humanitarian crises settings (HCS), the reported prevalence that meet international consensus targets for glycaemic, blood pressure and lipid management, and incidence of severe hypoglycaemia or diabetic ketoacidosis. METHODS: A narrative review of quantitative data was conducted, using a systematic process. MEDLINE (Ovid), Global Health, Web of Science, Scopus, Embase, CINAHL, APA PsycINFO, Cochrane trials, and the reference lists of eligible records were searched (January 2014-February 2024); ten records covering ten separate studies were retrieved. RESULTS: Glycaemic management was consistently suboptimal in HCS. However, among individuals coming from HCS, glycaemia varied. Across both groups, data relating to blood pressure, lipids, severe hypoglycaemia or diabetic ketoacidosis were either unavailable or limited. CONCLUSION: Findings expose the dearth of data relating to defined youth with T1D within and coming from HCS, leaving the status of this population largely uncharacterised. With limited data indicating suboptimal T1D management, there is a pressing need for the development of a consensus guideline on, and core indicators relating to such youth within and coming from HCS, plus monitoring systems and outcome data
Exploring the role of splicing in TP53 variant pathogenicity through predictions and minigene assays
No full textBACKGROUND: TP53 variant classification benefits from the availability of large-scale functional data for missense variants generated using cDNA-based assays. However, absence of comprehensive splicing assay data for TP53 confounds the classification of the subset of predicted missense and synonymous variants that are also predicted to alter splicing. Our study aimed to generate and apply splicing assay data for a prioritised group of 59 TP53 predicted missense or synonymous variants that are also predicted to affect splicing by either SpliceAI or MaxEntScan. METHODS: We conducted splicing analyses using a minigene construct containing TP53 exons 2 to 9 transfected into human breast cancer SKBR3 cells, and compared results against different splice prediction methods, including correlation with the SpliceAI-10k calculator. We additionally applied the splicing results for TP53 variant classification using an approach consistent with the ClinGen Sequence Variant Interpretation Splicing Subgroup recommendations. RESULTS: Aberrant transcript profile consistent with loss of function, and for which a PVS1 (RNA) code would be assigned, was observed for 42 (71%) of prioritised variants, of which aberrant transcript expression was over 50% for 26 variants, and over 80% for 15 variants. Data supported the use of SpliceAI ≥ 0.2 cutoff for predicted splicing impact of TP53 variants. Prediction of aberration types using SpliceAI-10k calculator generally aligned with the corresponding assay results, though maximum SpliceAI score did not accurately predict level of aberrant expression. Application of the observed splicing results was used to reclassify 27/59 (46%) test variants as (likely) pathogenic or (likely) benign. CONCLUSIONS: In conclusion, this study enhances the integration of splicing predictions and provides splicing assay data for exonic variants to support TP53 germline classification
Constraining cosmological parameters using the pairwise kinematic Sunyaev-Zel'dovich effect with CMB-S4 and future galaxy cluster surveys
No full textWe present a forecast of the pairwise kinematic Sunyaev-Zel'dovich (kSZ) measurement that will be achievable with the future CMB-S4 experiment. CMB-S4 is the next stage for ground-based cosmic microwave background experiments, with a planned wide-area survey that will observe approximately 50% of the sky. We construct a simulated sample of galaxy clusters that have been optically selected in a Legacy Survey of Space and Time-like survey and have spectroscopic redshifts. For this cluster sample, assuming the likelihood is Gaussian, we predict that CMB-S4 will reject the null hypothesis of zero pairwise kSZ signal at 36σ. We estimate the effects of systematic uncertainties such as scatter in the mass-richness scaling relation and cluster miscentering. We find that these effects can reduce the signal-to-noise ratio of the CMB-S4 pairwise kSZ measurement by 20%. We explore the constraining power of the measured kSZ signal in combination with measurements of the galaxy clusters' thermal SZ emission on two extensions to the standard cosmological model. The first extension allows the dark energy equation of state w to vary. We find the CMB-S4 pairwise kSZ measurement yields a modest reduction in the uncertainty on w by a factor of 1.36 over the Planck's 2018 uncertainty. The second extension tests general relativity by varying the growth index γ. We find that CMB-S4's pairwise kSZ measurement will yield a 28σ constraint on γ and strongly constrain alternative theories of gravity
Simultaneous Measurement of Calciprotein Particles with Different Assays and Clinical Outcomes in CKD
No full textKEY POINTS: Multiple assays are available to measure calciprotein particles (CPP), but a direct comparison of their association with clinical outcomes is lacking. Higher levels of high-density CPP and secondary CPP were independently associated with all-cause mortality in a CKD cohort. Higher levels of low-density CPP, primary CPP, and secondary CPP were each independently associated with progression of CKD. BACKGROUND: Mineral metabolism abnormalities are an almost universal feature of CKD and are believed to contribute to the development of many adverse events. Calciprotein particles (CPP) form spontaneously in biological fluids from calcium and phosphate together with the glycoprotein fetuin-A. While CPP formation is a part of normal mineral homeostasis, levels are chronically elevated in CKD. Several assays have been developed to measure serum CPP, each linking high CPP levels to adverse clinical outcomes in CKD. However, direct comparisons among these assays are lacking. The aim of this exploratory study was to compare these assays to assess their association with CKD progression and mortality. METHODS: We measured baseline CPP levels using various methods on stored serum samples from 189 participants in a prospective observational cohort study of patients with CKD stage 3/4. Three assays were used to measure CPP: (1) ELISA (fetuin-A CPP), (2) low-density CPP (L-CPP) and high-density CPP by gel filtration, and (3) primary CPP and secondary CPP (CPP-II) by flow cytometry. We examined the association of each CPP measure with all-cause mortality and CKD progression using unadjusted and covariate-adjusted Cox proportional hazard regression models. RESULTS: In fully adjusted models, high-density CPP (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.05 to 2.23; P = 0.028) and CPP-II (HR, 3.11; 95% CI, 1.97 to 4.98; P < 0.001) were significantly associated with an increased risk of all-cause mortality. In addition, L-CPP (HR, 1.91; 95% CI, 1.43 to 2.62; P < 0.001), primary CPP (HR, 1.31; 95% CI, 1.04 to 1.65; P = 0.023), and CPP-II (HR, 1.66; 95% CI, 1.20 to 2.29; P = 0.002) were significantly associated with CKD progression. CONCLUSIONS: In a cohort of patients with CKD stages 3 and 4, serum CPP-II levels demonstrated the strongest association with all-cause mortality, while L-CPP levels showed the strongest association with CKD progression
Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models
No full textValproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery
Web-Based Psychoeducational Intervention to Improve Family Caregiver Preparedness in Specialized Palliative Home Care: A Randomized Controlled Trial
No full textOBJECTIVE: Preparedness for caregiving refers to how ready family caregivers perceive themselves for caregiving tasks and stress of the caregiving role. This study investigated whether a web-based psychoeducational intervention could improve preparedness for caregiving among family caregivers of patients receiving specialized palliative home care. METHODS: The intervention "narstaende.se" was provided via a website featuring 23 short videos in which healthcare professionals and family caregivers (actors) discussed key care-related issues. Family caregivers were randomized to the intervention or control group and completed the Preparedness for Caregiving Scale (PCS) at baseline, 4 weeks, and 8 weeks. Data were analyzed using linear mixed models. The intervention effect was assessed based on PCS scores of the entire sample, followed by subgroup analyses based on level of baseline preparedness for caregiving, participation in physical care, and active intervention use, as determined by responses to single-item questions. RESULTS: A total of 205 family caregivers were recruited (103 intervention, 102 control). The intervention had no significant effect on preparedness for caregiving, including in subgroups based on level of baseline preparedness for caregiving, participation in physical care, or active intervention use. However, all subgroups reported higher levels of preparedness for caregiving at both follow-up assessments than at baseline. CONCLUSIONS: Preparedness for caregiving improved over time in both the intervention and control groups, suggesting other contributing factors. Limited participant engagement may explain the lack of intervention effect. Future studies should evaluate the intervention with more structured and clinically integrated use
Costs of transitioning the livestock sector to net-zero emissions under future climates
No full textLand managers are challenged with the need to balance priorities in production, greenhouse gas (GHG) abatement, biodiversity and social license to operate. Here, we develop a transdisciplinary approach for prioritising land use, illustrated by co-designing pathways for transitioning farming systems to net-zero emissions. We show that few interventions enhanced productivity and profitability while reducing GHG emissions. Antimethanogenic feed supplements and planting trees afforded the greatest mitigation, while revenue diversification with wind turbines and adoption of livestock genotypes with enhanced feed-conversion efficiency (FCE) were most conducive to improving profit. Serendipitously, the intervention with the lowest social licence-continuing the status quo and purchasing carbon credits to offset emissions-was also the most costly pathway to transition to net-zero. In contrast, stacking several interventions to mitigate enteric methane, improve FCE and sequester carbon entirely negated enterprise emissions in a profitable way. We conclude that costs of transitioning to net-zero are lower when interventions are bundled and/or evoke productivity co-benefits
Predicting changes in agricultural yields under climate change scenarios and their implications for global food security
No full textClimate change has direct impacts on current and future agricultural productivity. Statistical meta-analysis models can be used to generate expectations of crop yield responses to climatic factors by pooling data from controlled experiments. However, methodological challenges in performing these meta-analyses, together with combined uncertainty from various sources, make it difficult to validate model results. We present updates to published estimates of crop yield responses to projected temperature, precipitation, and CO2 patterns and show that mixed effects models perform better than pooled OLS models on root mean squared error (RMSE) and explained deviance, despite the common usage of pooled OLS in previous meta-analyses. Based on our analysis, the use of pooled OLS may underestimate yield losses. We also use a block-bootstrapping approach to quantify uncertainty across multiple dimensions, including modeler choices, climate projections from the sixth Coupled Model Intercomparison Project (CMIP6), and emissions scenarios from Shared Socioeconomic Pathways (SSP). Our estimates show projected yield responses of - 22% (maize), - 9% (rice), - 15% (soy), and - 14% (wheat) from 2015 to 2080-2100 under the business-as-usual scenario of SSP5-8.5, which reduce to - 3.8%, - 2.7%, 1.4%, and - 1.5% respectively under the lower emissions scenario of SSP1-2.6. Without mitigation and adaptation, countries in South Asia, sub-Saharan Africa, North America, and Oceania could become at risk of being unable to meet national calorie demand by the end of the century under the most severe emissions scenario