Cosmogenic Nuclide Systematics and the CRONUScalc Program

As cosmogenic nuclide applications continue to expand, the need for a common basis for calculation becomes increasingly important. In order to accurately compare between results from different nuclides, a single method of calculation is necessary. Calculators exist in numerous forms with none matching the needs of the CRONUS-Earth project to provide a simple and consistent method to interpret data from most commonly used cosmogenic nuclides. A new program written for this purpose, CRONUScalc, is presented here. This unified code presents a method applicable to 10Be, 26Al, 36Cl, 3He, and 14C, with 21Ne in testing. The base code predicts the concentration of a sample at a particular depth for a particular time in the past, which can be used for many applications. The multi-purpose code already includes functions for performing production rate calibrations as well as calculating erosion rates and surface exposure ages for single samples and depth profiles. The code is available under the GNU General Public License agreement and can be downloaded and modified to deal with specific atypical scenarios

Canadian Initiatives to Prevent Hypertension by Reducing Dietary Sodium

Hypertension is the leading risk for premature death in the world. High dietary sodium is an important contributor to increased blood pressure and is strongly associated with other important diseases (e.g., gastric cancer, calcium containing kidney stones, osteoporosis, asthma and obesity). The average dietary sodium intake in Canada is approximately 3400 mg/day. It is estimated that 30% of hypertension, more than 10% of cardiovascular events and 1.4 billion dollars/year in health care expenses are caused by this high level of intake in Canada. Since 2006, Canada has had a focused and evolving effort to reduce dietary sodium based on actions from Non Governmental Organizations (NGO), and Federal and Provincial/Territorial Government actions. NGOs initiated Canadian sodium reduction programs by developing a policy statement outlining the health issue and calling for governmental, NGO and industry action, developing and disseminating an extensive health care professional education program including resources for patient education, developing a public awareness campaign through extensive media releases and publications in the lay press. The Federal Government responded by striking a Intersectoral Sodium Work Group to develop recommendations on how to implement Canada’s dietary reference intake values for dietary sodium and by developing timelines and targets for foods to be reduced in sodium, assessing key research gaps with funding for targeted dietary sodium based research, developing plans for public education and for conducting evaluation of the program to reduce dietary sodium. While food regulation is a Federal Government responsibility Provincial and Territorial governments indicated reducing dietary sodium needed to be a priority. Federal and Provincial Ministers of Health have endorsed a target to reduce the average consumption of sodium to 2300 mg/day by 2016 and the Deputy Ministers of Health have tasked a joint committee to review the recommendations of the Sodium Work Group and report back to them

Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma

Shows Single Nucleotide Substitutions in the MAPK Pathway. (XLSX 43 kb

Salud mental y democracia participativa en Colombia periodo 2010 – 2014

Tesis¿Por qué hablar de salud mental y democracia en Colombia? Realmente fue la pregunta inicial por la cual se dio el inicio a esta investigación, tratando de entender la enredada realidad por la cual se ha venido materializando el sujeto como actor político en un ecosistema complejo y distorsionado. Por ejemplo, según el plan Decenal de Salud Pública 2012 – 2021, planteó una reforma al Sistema General de Seguridad Social en Salud del país, que, mediante la conocida ley 1438 del 2011 (ley que fue sancionada en el periodo de observación de la presente investigación), buscó promover mecanismos de participación colectiva e individual, orientada hacia la Atención Primaria en Salud, buscando tener una marca importante en los determinantes sociales y económicos de la salud dentro del territorio colombiano. Para esta investigación, se utilizó un enfoque de corte cualitativo exploratoria, con un diseño hermeneútico. De igual forma, se utilizó el muestreo por expertos.1. LINEAMIENTOS GENERALES DE LA INVESTIGACIÓN 2. SALUD MENTAL 3. DEMOCRACIA 4. MÉTODO 5. RESULTADOS Y DISCUSIÓN 6. CONCLUSIONES 7. RECOMENDACIONES 8. REFERENCIASMaestríaMagister en Ciencia Polític

Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease etiology in this population, most notably at NOD2, in which three causal, uncommon, and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to a non-Jewish population (145 haplotypes and no haplotypes with P-value < 10−3, respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established Crohn’s disease loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare Crohn’s disease-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association

In situ cosmogenic nuclide production rate calibration for the CRONUS-Earth project from Lake Bonneville, Utah, shoreline features

Well-dated bedrock surfaces associated with the highstand and subsequent catastrophic draining of Pleistocene Lake Bonneville, Utah, during the Bonneville flood are excellent locations for in situ cosmogenic nuclide production rate calibration. The CRONUS-Earth project sampled wave-polished bedrock and boulders on an extensive wave-cut bench formed during the Bonneville-level highstand that was abandoned almost instantaneously during the Bonneville flood. CRONUS-Earth also sampled the Tabernacle Hill basalt flow that erupted into Lake Bonneville soon after its stabilization at the Provo level, following the flood. New radiocarbon dating results from tufa at the margins of Tabernacle Hill as part of this study have solidified key aspects of the exposure history at both sites. Both sites have well-constrained exposure histories in which factors such as potential prior exposure, erosion, and shielding are either demonstrably negligible or quantifiable. Multi-nuclide analyses from multiple labs serve as an ad hoc inter-laboratory comparison that supplements and expands on the formalized CRONUS-Earth and CRONUS-EU inter-laboratory comparisons (Blard et al., 2015; Jull et al., 2015; Vermeesch et al., 2015). Results from 10Be, 26Al, and 14C all exhibit scatter comparable to that observed in the CRONUS-Earth effort. Although a 36Cl inter-laboratory comparison was not completed for Jull et al. (2015), 36Cl from plagioclase mineral separates exhibits comparable reproducibility. Site production rates derived from these measurements provide valuable input to the global production rate calibration described by Borchers et al. (2015). Whole-rock 36Cl concentrations, however, exhibit inter-laboratory variation exceeding analytical uncertainty and outside the ranges observed for the other nuclides (Jull et al., 2015). A rigorous inter-laboratory comparison studying the systematics of whole-rock 36Cl extraction techniques is currently underway with the goals of delineating the source(s) of this discrepancy and standardizing these procedures going forward

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P =.01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery

De novo mutations in histone modifying genes in congenital heart disease

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. By analysis of exome sequencing of parent-offspring trios, we compared the incidence of de novo mutations in 362 severe CHD cases and 264 controls. CHD cases showed a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging mutations. Similar odds ratios were seen across major classes of severe CHD. We found a marked excess of de novo mutations in genes involved in production, removal or reading of H3K4 methylation (H3K4me), or ubiquitination of H2BK120, which is required for H3K4 methylation2–4. There were also two de novo mutations in SMAD2; SMAD2 signaling in the embryonic left-right organizer induces demethylation of H3K27me5. H3K4me and H3K27me mark `poised' promoters and enhancers that regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundred genes that collectively contribute to ~10% of severe CHD

Phosphorylation of Kif26b Promotes Its Polyubiquitination and Subsequent Proteasomal Degradation during Kidney Development

Kif26b, a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. Kif26b expression is restricted to the metanephric mesenchyme, and its transcription is regulated by a zinc finger transcriptional regulator Sall1. However, the mechanism(s) by which Kif26b protein is regulated remain unknown. Here, we demonstrate phosphorylation and subsequent polyubiquitination of Kif26b in the developing kidney. We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway. Furthermore, Kif26b lacks ATPase activity but does associate with microtubules. Nocodazole treatment not only disrupts the localization of Kif26b to microtubules but also promotes phosphorylation and polyubiquitination of Kif26b. These results suggest that the function of Kif26b is microtubule-based and that Kif26b degradation in the metanephric mesenchyme via the ubiquitin-proteasome pathway may be important for proper kidney development