OGFOD1 modulates the transcriptional and proteomic landscapes to alter isoproterenol-induced hypertrophy susceptibility.

Cardiac hypertrophy is associated with increased translation. However, little is known of the mechanisms that regulate translation in hypertrophy. Members of the 2-oxoglutarate-dependent dioxygenase family regulate several aspects of gene expression, including translation. An important member of this family is OGFOD1. Here, we show OGFOD1 accumulates in failing human hearts. Upon OGFOD1 deletion, murine hearts showed transcriptomic and proteomic changes, with only 21 proteins and mRNAs (0.6%) changing in the same direction. Additionally, OGFOD1-KO mice were protected from induced hypertrophy, supporting a role for OGFOD1 in the cardiac response to chronic stress.

Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis.

By the age of 40, one in five adults without symptoms of cardiovascular disease are at risk for developing congestive heart failure. Within this population, dilated cardiomyopathy (DCM) remains one of the leading causes of disease and death, with nearly half of cases genetically determined. Though genetic and high throughput sequencing-based approaches have identified sporadic and inherited mutations in a multitude of genes implicated in cardiomyopathy, how combinations of asymptomatic mutations lead to cardiac failure remains a mystery. Since a number of studies have implicated mutations of the transcription factor TBX20 in congenital heart diseases, we investigated the underlying mechanisms, using an unbiased systems-based screen to identify novel, cardiac-specific binding partners. We demonstrated that TBX20 physically and genetically interacts with the essential transcription factor CASZ1. This interaction is required for survival, as mice heterozygous for both Tbx20 and Casz1 die post-natally as a result of DCM. A Tbx20 mutation associated with human familial DCM sterically interferes with the TBX20-CASZ1 interaction and provides a physical basis for how this human mutation disrupts normal cardiac function. Finally, we employed quantitative proteomic analyses to define the molecular pathways mis-regulated upon disruption of this novel complex. Collectively, our proteomic, biochemical, genetic, and structural studies suggest that the physical interaction between TBX20 and CASZ1 is required for cardiac homeostasis, and further, that reduction or loss of this critical interaction leads to DCM. This work provides strong evidence that DCM can be inherited through a digenic mechanism.

High Frequency of Ovarian Cyst Development in Vhl2B/+;Snf5+/- Mice.

The new paradigm of mutations in chromatin-modifying genes as driver events in the development of cancers has proved challenging to resolve the complex influences over disease phenotypes. In particular, impaired activities of members of the SWI/SNF chromatin remodeling complex have appeared in an increasing variety of tumors. Mutations in SNF5, a member of this ubiquitously expressed complex, arise in almost all cases of malignant rhabdoid tumor in the absence of additional genetic alterations. Therefore, we studied how activation of additional oncogenic pathways might shift the phenotype of disease driven by SNF5 loss. With the use of a genetically engineered mouse model, we examined the effects of a hypomorphic Vhl2B allele on disease phenotype, with a modest up-regulation of the hypoxia response pathway. Snf5+/-;Vhl2B/+ mice did not demonstrate a substantial difference in overall survival or a change in malignant rhabdoid tumor development. However, a high percentage of female mice showed complex hemorrhagic ovarian cysts, a phenotype rarely found in either parental mouse strain. These lesions also showed mosaic expression of SNF5 by immunohistochemistry. Therefore, our studies implicate that modest changes in angiogenic regulation interact with perturbations of SWI/SNF complex activity to modulate disease phenotypes.

Deleting the ribosomal prolyl hydroxylase OGFOD1 protects mice against diet-induced obesity and insulin resistance.

Type 2 diabetes predisposes patients to heart disease, which is the primary cause of death across the globe. Type 2 diabetes often accompanies obesity and is defined by insulin resistance and abnormal glucose handling. Insulin resistance impairs glucose uptake and results in hyperglycemia, which damages tissues such as kidneys, liver, and heart. 2-oxoglutarate (2-OG)- and iron-dependent oxygenases (2-OGDOs), a family of enzymes regulating various aspects of cellular physiology, have been studied for their role in obesity and diet-induced insulin resistance. However, nothing is known of the 2-OGDO family member 2-oxoglutarate and iron-dependent prolyl hydroxylase domain containing protein 1 (OGFOD1) in this setting. OGFOD1 deletion leads to protection in cardiac ischemia-reperfusion injury and cardiac hypertrophy, which are two cardiac events that can lead to heart failure. Considering the remarkable correlation between heart disease and diabetes, the cardioprotection observed in OGFOD1-knockout mice led us to challenge these knockouts with high-fat diet. Wildtype mice fed a high-fat diet developed diet-induced obesity, insulin resistance, and glucose intolerance, but OGFOD1 knockout mice fed this same diet were resistant to diet-induced obesity and insulin resistance. These results support OGFOD1 down-regulation as a strategy for preventing obesity and insulin handling defects.

A Gro/TLE-NuRD corepressor complex facilitates Tbx20-dependent transcriptional repression.

The cardiac transcription factor Tbx20 has a critical role in the proper morphogenetic development of the vertebrate heart, and its misregulation has been implicated in human congenital heart disease. Although it is established that Tbx20 exerts its function in the embryonic heart through positive and negative regulation of distinct gene programs, it is unclear how Tbx20 mediates proper transcriptional regulation of its target genes. Here, using a combinatorial proteomic and bioinformatic approach, we present the first characterization of Tbx20 transcriptional protein complexes. We have systematically investigated Tbx20 protein-protein interactions by immunoaffinity purification of tagged Tbx20 followed by proteomic analysis using GeLC-MS/MS, gene ontology classification, and functional network analysis. We demonstrate that Tbx20 is associated with a chromatin remodeling network composed of TLE/Groucho corepressors, members of the Nucleosome Remodeling and Deacetylase (NuRD) complex, the chromatin remodeling ATPases RUVBL1/RUVBL2, and the T-box repressor Tbx18. We determined that the interaction with TLE corepressors is mediated via an eh1 binding motif in Tbx20. Moreover, we demonstrated that ablation of this motif results in a failure to properly assemble the repression network and disrupts Tbx20 function in vivo. Importantly, we validated Tbx20-TLE interactions in the mouse embryonic heart, and identified developmental genes regulated by Tbx20-TLE binding, thereby confirming a primary role for a Tbx20-TLE repressor complex in embryonic heart development. Together, these studies suggest a model in which Tbx20 associates with a Gro/TLE-NuRD repressor complex to prevent inappropriate gene activation within the forming heart.

Geo-spatial risk factor analysis for drug overdose death in South Florida from 2014 to 2019, and the independent contribution of social determinants of health.

PURPOSE: The physical environment and social determinants of health have been shown to influence health behaviors including drug use and fatal drug overdose. The current research examines the effects of the built environment, social determinants of health measures and aggregated risk from the built environment at neighborhood-level on drug overdose death locations in Miami-Dade County, Florida. METHODS: Risk Terrain Modeling (RTM) was used to assess the place features risk factors that significantly increase the risk of drug overdose death spatially in Miami-Dade County ZIP Code Tabulation Areas, Florida from 2014 to 2019. An aggregated neighborhood risk of fatal drug overdose measure was developed by averaging the risk per grid cell from the RTM within census block groups each year. Six logistic and zero-inflated regression models were built to examine the effects of three indices of incident-specific social determinants of health (IS-SDH) measures and aggregated risk measures separately, and simultaneously on drug overdose death locations each year. RESULTS: Seven place features including parks, bus stops, restaurants and grocery stores were significantly related to the occurrence of fatal drug overdoses. When examined separately, one or more indices of the IS-SDH were significant covariates of drug overdose locations in some years. When examined simultaneously, the three indices of the IS-SDH and aggregated risk of fatal drug overdose measure could be all significant in certain years. CONCLUSIONS: The patterns of high-risk areas and place features identified from the RTM related to drug overdose deaths may be used to inform the placement of treatment and prevention resources. A multi-factor approach that combines an aggregated neighborhood risk measure reflecting the risk from the built environment and the incident-specific social determinants of health measures can be used to identify the drug overdose death locations in certain years.

Leading causes of unintentional and intentional injury mortality: United States, 2000-2009.

OBJECTIVES: We have described national trends for the 5 leading external causes of injury mortality. METHODS: We used negative binomial regression and annual underlying cause-of-death data for US residents for 2000 through 2009. RESULTS: Mortality rates for unintentional poisoning, unintentional falls, and suicide increased by 128%, 71%, and 15%, respectively. The unintentional motor vehicle traffic crash mortality rate declined 25%. Suicide ranked first as a cause of injury mortality, followed by motor vehicle traffic crashes, poisoning, falls, and homicide. Females had a lower injury mortality rate than did males. The adjusted fall mortality rate displayed a positive age gradient. Blacks and Hispanics had lower adjusted motor vehicle traffic crash and suicide mortality rates and higher adjusted homicide rates than did Whites, and a lower unadjusted total injury mortality rate. CONCLUSIONS: Mortality rates for suicide, poisoning, and falls rose substantially over the past decade. Suicide has surpassed motor vehicle traffic crashes as the leading cause of injury mortality. Comprehensive traffic safety measures have successfully reduced the national motor vehicle traffic crash mortality rate. Similar efforts will be required to diminish the burden of other injury.

Ogfod1 deletion increases cardiac beta-alanine levels and protects mice against ischaemia- reperfusion injury.

AIMS: Prolyl hydroxylation is a post-translational modification that regulates protein stability, turnover, and activity. The proteins that catalyze prolyl hydroxylation belong to the 2-oxoglutarate- and iron-dependent oxygenase family of proteins. 2-oxoglutarate- and iron-dependent oxygenase domain-containing protein 1 (Ogfod1), which hydroxylates a proline in ribosomal protein s23 is a newly described member of this family. The aims of this study were to investigate roles for Ogfod1 in the heart, and in the heart's response to stress. METHODS AND RESULTS: We isolated hearts from wild-type (WT) and Ogfod1 knockout (KO) mice and performed quantitative proteomics using tandem mass Tag labelling coupled to liquid chromatography and tandem mass spectrometry (LC-MS/MS) to identify protein changes. Ingenuity pathway analysis identified 'Urate Biosynthesis/Inosine 5'-phosphate Degradation' and 'Purine Nucleotides Degradation II (Aerobic)' as the most significantly enriched pathways. We performed metabolomics analysis and found that both purine and pyrimidine pathways were altered with the purine nucleotide inosine 5'-monophosphate showing a 3.5-fold enrichment in KO hearts (P = 0.011) and the pyrimidine catabolism product beta-alanine showing a 1.7-fold enrichment in KO hearts (P = 0.014). As changes in these pathways have been shown to contribute to cardioprotection, we subjected isolated perfused hearts to ischaemia and reperfusion (I/R). KO hearts showed a 41.4% decrease in infarct size and a 34% improvement in cardiac function compared to WT hearts. This protection was also evident in an in vivo I/R model. Additionally, our data show that treating isolated perfused WT hearts with carnosine, a metabolite of beta-alanine, improved protection in the context of I/R injury, whereas treating KO hearts with carnosine had no impact on recovery of function or infarct size. CONCLUSIONS: Taken together, these data show that Ogfod1 deletion alters the myocardial proteome and metabolome to confer protection against I/R injury.

Cholera deaths in Soho, London, 1854: Risk Terrain Modeling for epidemiological investigations.

Risk Terrain Modeling (RTM) is a spatial analysis technique used to diagnose environmental conditions that lead to hazardous outcomes. Originally developed for applications to violent crime analysis, RTM is utilized here to analyze Dr. John Snow's data from the 1854 cholera outbreak in London to demonstrate its potential value to contemporary epidemiological investigations. Dr. Snow saved countless lives when he traced the source of the cholera outbreak to a specific water pump through inductive reasoning, which he communicated through maps and spatial evidence. His methods have since inspired several fields of scientific inquiry. Informed by the extant research on RTM, we speculated that it could have helped test Dr. Snow's hypothesis about cholera and empirically identified the sole source of contaminated well water. We learned that it could and, although it was not available to Dr. Snow in the 1800s, we discuss RTM's implications for present-day research and practice as it relates to the analysis, prevention and treatment of cholera and other public health threats around the world.

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism.

Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation-induced necrosis, but its function and substrates remain unclear. Herein, we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.

The ribosomal prolyl-hydroxylase OGFOD1 decreases during cardiac differentiation and modulates translation and splicing.

The mechanisms regulating translation and splicing are not well understood. We provide insight into a new regulator of translation, OGFOD1 (2-oxoglutarate and iron dependent oxygenase domain-containing protein 1), which is a prolyl-hydroxylase that catalyzes the posttranslational hydroxylation of Pro-62 in the small ribosomal protein S23. We show that deletion of OGFOD1 in an in vitro model of human cardiomyocytes decreases translation of specific proteins (e.g., RNA-binding proteins) and alters splicing. RNA sequencing showed poor correlation between changes in mRNA and protein synthesis, suggesting that posttranscriptional regulation was the primary cause for the observed differences. We found that loss of OGFOD1 and the resultant alterations in protein translation modulates the cardiac proteome, shifting it towards higher protein amounts of sarcomeric proteins such as cardiac troponins, titin and cardiac myosin binding protein C. Furthermore, we found a decrease of OGFOD1 during cardiomyocyte differentiation. These results suggest that loss of OGFOD1 modulates protein translation and splicing, thereby leading to alterations in the cardiac proteome and highlight the role of altered translation and splicing in regulating the proteome..

Is counter-terrorism policy evidence-based? What works, what harms, and what is unknown.

Is counter-terrorism policy evidence-based? What works, what harms, and what is unknown. One of the central concerns surrounding counter-terrorism interventions today, given the attention and money spent on them, is whether such interventions are effective. To explore this issue, we conducted a general review of terrorism literature as well as a Campbell systematic review on counter-terrorism strategies. In this article, we summarize some of our findings from these works. Overall, we found an almost complete absence of evaluation research on counter-terrorism strategies and conclude that counter-terrorism policy is not evidence-based. The findings of this review emphasise the need for government leaders, policy makers, researchers, and funding agencies to include and insist on evaluations of the effectiveness of these programs in their agendas.

Closing the immunization gap.

Current vaccination rates are falling with a new group of unimmunized children. Since some parents are unaware of the diseases and potential health threats, many are often influenced by the media and myths, choosing to delay or avoid vaccinations. NP providers must be prepared to confront these myths with facts to help parents make informed decisions. Vaccine-preventable diseases, popular myths, and evidence-based research findings are reviewed in this manuscript.

Is counter-terrorism policy evidence-based? What works, what harms, and what is unknown / ¿Está basada la política antiterrorista en la evidencia? Lo que es efectivo, lo que es perjudicial, y lo desconocido

One of the central concerns surrounding counter-terrorism interventions today, given the attention and money spent on them, is whether such interventions are effective. To explore this issue, we conducted a general review of terrorism literature as well as a Campbell systematic review on counter-terrorism strategies. In this article, we summarize some of our findings from these works. Overall, we found an almost complete absence of evaluation research on counter-terrorism strategies and conclude that counter-terrorism policy is not evidence-based. The findings of this review emphasise the need for government leaders, policy makers, researchers, and funding agencies to include and insist on evaluations of the effectiveness of these programs in their agendas (AU)

Una de las mayores preocupaciones de las políticas antiterroristas es su efectividad, dado el gasto enorme que suponen. Para explorar este punto llevamos a cabo una revisión sobre la literatura en general del terrorismo, así como una revisión Campbell sobre las estrategias antiterroristas. En conjunto hallamos casi una ausencia completa de evidencia sobre estos programas, y concluimos que la política antiterrorista no está basada en la evidencia. Esta revisión enfatiza la necesidad de que los políticos, los investigadores y los responsables de la gestión de estas políticas acentúen la necesidad de promover la evaluación de la efectividad de esos programas (AU)