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Mercury concentration measurements were compiled from 72 sites located throughout seven departments of Colombia using field information gathered from 2016–2021 by Pure Earth, an international non-profit organization, and secondary information from previously conducted studies. These measurements and other data such as type of contaminated resource (water, soil), resource use (fishing, agricultural, residential, and industrial), estimated at-risk population, and permissible contamination limits were entered into Pure Earth’s Toxic Site Identification Program (TSIP) database. Using information from the TSIP database, the Blacksmith Index, a contaminated site intervention prioritization index, was calculated for all 72 sites. After applying exclusion criteria to the sites for this study, the results show that approximately 55,095 people are affected by mercury contamination in 44 sites. Of these study sites, the site with the highest Blacksmith Index value and therefore, the highest health risk due to mercury contamination, is La Bocana in the department of Valle del Cauca.

Mercury concentration measurements were compiled from 72 sites located throughout seven departments of Colombia using field information gathered from 2016-2021 by Pure Earth, an international non-profit organization, and secondary information from previously conducted studies. These measurements and other data such as type of contaminated resource (water, soil), resource use (fishing, agricultural, residential, and industrial), estimated at-risk population, and permissible contamination limits were entered into Pure Earth's Toxic Site Identification Program (TSIP) database. Using information from the TSIP database, the Blacksmith Index, a contaminated site intervention prioritization index, was calculated for all 72 sites. After applying exclusion criteria to the sites for this study, the results show that approximately 55,095 people are affected by mercury contamination in 44 sites. Of these study sites, the site with the highest Blacksmith Index value and therefore, the highest health risk due to mercury contamination, is La Bocana in the department of Valle del Cauca. KEYWORDS: Mercury; mining; gold; tailings; contaminated sites El presente articulo busca mostrar el panorama de las concentraciones de mercurio estimadas por Pure Earth en Colombia con informacion de campo desde el ano 2016 y ejecutado bajo la metodologia TSIP (Toxic Site Investigation Program), identificando el recurso contaminado (agua o suelo) y el uso dado (agua-pesca, suelo-agropecuario, suelo-residencial, suelo-industrial); luego de la identificacion de concentraciones, se realiza una caracterizacion de priorizacion de zonas por medio de la ecuacion desarrollada por el Blacksmith Institute llamada Indice Blacksmith, que contempla variables como poblacion en riesgo estimada, concentracion de mercurio y lmnites permisibles segun normas ambientales que rigen cada pais. A partir de lo anterior, dentro de 72 sitios identificados se estima que la contaminacion por mercurio afecta aproximadamente de 55,095 personas y que el departamento con el mayor riesgo por contaminacion con mercurio se ubica en La Bocana, en Valle del Cauca. Mercurio; mineria; oro; relaves; sitios contaminados

A critical review of past theories on dielectric breakdown of water is presented. It is shown that past models do not agree qualitatively with empirical experiments. A new model based on protonic conduction and on dipole ordering is presented and found to agree with experiments both qualitatively and quantitatively.

Objective To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism.Design Retrospective cohort study.Setting Large US administrative database between 1 January 2010 and 31 December 2014.Participants 5405 pregnant women with subclinical hypothyroidism, defined as untreated thyroid stimulating hormone (TSH) concentration 2.5-10 mIU/L.Exposure Thyroid hormone therapy.Main outcome measure Pregnancy loss and other pre-specified maternal and fetal pregnancy related adverse outcomes.Results Among 5405 pregnant women with subclinical hypothyroidism, 843 with a mean pre-treatment TSH concentration of 4.8 (SD 1.7) mIU/L were treated with thyroid hormone and 4562 with a mean baseline TSH concentration of 3.3 (SD 0.9) mIU/L were not treated (P<0.01). Pregnancy loss was significantly less common among treated women (n=89; 10.6%) than among untreated women (n=614; 13.5%) (P<0.01). Compared with the untreated group, treated women had lower adjusted odds of pregnancy loss (odds ratio 0.62, 95% confidence interval 0.48 to 0.82) but higher odds of preterm delivery (1.60, 1.14 to 2.24), gestational diabetes (1.37, 1.05 to 1.79), and pre-eclampsia (1.61, 1.10 to 2.37); other pregnancy related adverse outcomes were similar between the two groups. The adjusted odds of pregnancy loss were lower in treated women than in untreated women if their pre-treatment TSH concentration was 4.1-10 mIU/L (odds ratio 0.45, 0.30 to 0.65) but not if it was 2.5-4.0 mIU/L (0.91, 0.65 to 1.23) (P<0.01).Conclusion Thyroid hormone treatment was associated with decreased risk of pregnancy loss among women with subclinical hypothyroidism, especially those with pre-treatment TSH concentrations of 4.1-10 mIU/L. However, the increased risk of other pregnancy related adverse outcomes calls for additional studies evaluating the safety of thyroid hormone treatment in this patient population.

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n  = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b + sepsis neutrophils inhibited proliferation and activation of CD4 + T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n  = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2 + immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection. Knight and colleagues report altered granulopoiesis and increased frequency of immature neutrophil subsets with immunosuppressive properties in a subset of patients with sepsis with poor outcome.

We discovered that Enterococcus faecium (E. faecium), a ubiquitous commensal bacterium, and its secreted peptidoglycan hydrolase (SagA) were sufficient to enhance intestinal barrier function and pathogen tolerance, but the precise biochemical mechanism was unknown. Here we show E. faecium has unique peptidoglycan composition and remodeling activity through SagA, which generates smaller muropeptides that more effectively activates nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in mammalian cells. Our structural and biochemical studies show that SagA is a NlpC/p60-endopeptidase that preferentially hydrolyzes crosslinked Lys-type peptidoglycan fragments. SagA secretion and NlpC/p60-endopeptidase activity was required for enhancing probiotic bacteria activity against Clostridium difficile pathogenesis in vivo. Our results demonstrate that the peptidoglycan composition and hydrolase activity of specific microbiota species can activate host immune pathways and enhance tolerance to pathogens.

There is mounting anecdotal and empirical evidence that gardening and art-making afford therapeutic benefits. This randomly controlled pilot study tested the hypothesis that participation in group-based indoor gardening or art-making activities for one hour twice a week for four weeks would provide quantifiably different therapeutic benefits to a population of healthy women ages 26-49. A population of 42 volunteers was randomly assigned to parallel gardening or art-making treatment groups. A total of 36 participants initiated the treatment protocol and 32 (Gardening n = 15 and Art n = 17) received the interventions and completed all assessments. Treatments included eight one-hour group-based gardening or art intervention sessions. Self-report psychometric assessments were conducted for anxiety, depression symptomatology, mood disturbance, stress, satisfaction with discretionary social activities, and quality of life measures. Cardiac physiological data were also collected. Outcomes were measured at baseline, during, and post-intervention. Engaging in both gardening and art-making activities resulted in apparent therapeutic improvements for self-reported total mood disturbance, depression symptomatology, and perceived stress with different effect sizes following eight one-hour treatment sessions. Gardening also resulted in improvements for indications of trait anxiety. Based on time-course evidence, dosage responses were observed for total mood disturbance, perceived stress, and depression symptomatology for both gardening and art-making. However, gardening or art-making did not have an apparent influence on heart rate or blood pressure or result in marked improvement for satisfaction with discretionary leisure activities. The data did not support the hypothesis of differential therapeutic benefits of gardening and art-making for healthy women. When taken together, group-based gardening or art-making can provide quantitatively measurable improvements in healthy women's psychosocial health status that imply potentially important public health benefits.

Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We used chemoproteomic profiling and structure-based design to develop a selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC organoid models and use a combination of RNA-sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in cancer. A highly selective inhibitor of the DCLK1/2 kinases is used to uncover the consequences of DCLK1 inhibition on viability, phosphosignaling and the transcriptome in patient-derived organoid models of pancreatic ductal adenocarcinoma.

Background Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. Methods In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student’s T-tests for simple comparisons and two-factor ANOVA for evaluating significance. Results The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Conclusions Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.