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Huntingtin-lowering approaches that target huntingtin expression are a major focus for therapeutic intervention for Huntington’s disease. When the cytosine, adenine and guanine repeat is expanded, the huntingtin pre-mRNA is alternatively processed to generate the full-length huntingtin and HTT1a transcripts. HTT1a encodes the aggregation-prone and highly pathogenic exon 1 huntingtin protein. In evaluating huntingtin-lowering approaches, understanding how the targeting strategy modulates levels of both transcripts and the huntingtin protein isoforms that they encode will be essential. Given the aggregation-propensity of exon 1 huntingtin, the impact of a given strategy on the levels and subcellular location of aggregated huntingtin will need to be determined. We have developed and applied sensitive molecular approaches to monitor the levels of aggregated and soluble huntingtin isoforms in tissue lysates. We have used these, in combination with immunohistochemistry, to map the appearance and accumulation of aggregated huntingtin throughout the CNS of zQ175 mice, a model of Huntington’s disease frequently chosen for preclinical studies. Aggregation analyses were performed on tissues from zQ175 and wild-type mice at monthly intervals from 1 to 6 months of age. We developed three homogeneous time-resolved fluorescence assays to track the accumulation of aggregated huntingtin and showed that two of these were specific for the exon 1 huntingtin protein. Collectively, the homogeneous time-resolved fluorescence assays detected huntingtin aggregation in the 10 zQ175 CNS regions by 1–2 months of age. Immunohistochemistry with the polyclonal S830 anti-huntingtin antibody showed that nuclear huntingtin aggregation, in the form of a diffuse nuclear immunostain, could be visualized in the striatum, hippocampal CA1 region and layer IV of the somatosensory cortex by 2 months. That this diffuse nuclear immunostain represented aggregated huntingtin was confirmed by immunohistochemistry with a polyglutamine-specific antibody, which required formic acid antigen retrieval to expose its epitope. By 6 months of age, nuclear and cytoplasmic inclusions were widely distributed throughout the brain. Homogeneous time-resolved fluorescence analysis showed that the comparative levels of soluble exon 1 huntingtin between CNS regions correlated with those for huntingtin aggregation. We found that soluble exon 1 huntingtin levels decreased over the 6-month period, whilst those of soluble full-length mutant huntingtin remained unchanged, data that were confirmed for the cortex by immunoprecipitation and western blotting. These data support the hypothesis that exon 1 huntingtin initiates the aggregation process in knock-in mouse models and pave the way for a detailed analysis of huntingtin aggregation in response to huntingtin-lowering treatments.

Alcanzar los objetivos de desarrollo sostenible requiere el impulso de los gobiernos y la unión de diferentes sectores de la sociedad en beneficio de los países y, en consecuencia, del mundo entero. La divulgación de los propósitos y temas asociados debe ser asumida como una tarea obligatoria para lograr una mayor integración de fuerzas. Por ello, esta investigación, de tipo documental, se planteó como propósito identificar las estrategias de comunicación que permiten promover la educación ambiental con base en los objetivos de desarrollo sostenible, para tal fin se hizo una revisión de documentos publicados durante los últimos 5 años en base de datos tales como Redalyc, Latindex y repositorios universitarios. La búsqueda de información evidencia un interés por el tema; principalmente, desde el compromiso de crear conciencia en niños y adolescentes sobre del impacto de las acciones humanas en el futuro del planeta. Se puede concluir, que la educación ambiental está presente en la formación académica y en la agenda de los medios de comunicación; no obstante, su incorporación en la académico se limita a materias o temas, y en lo periodístico o informativo, se restringe a noticias más que a programas o actividades de formación; por ello, se hace necesario la implementación de estrategias comunicacionales, a través de todos los medios de comunicación, especialmente digitales y el cara a cara, para consolidar una conciencia y comportamientos más ambientalista en los ciudadanos como un asunto de interés mundial.

Graphical abstract, Highlights • PA and SAR are both related to heart failure. • The authors describe “phantom systole,” a remarkable finding of FE. • PVCs play a key role in worsening systolic heart failure.

Supplemental Material, sj-pdf-1-het-10.1177_09603271211063161 for Methylation patterns of the CDKN2B and CDKN2A genes in an indigenous population exposed to pesticides by Diana M Paredes-C��spedes, Yael Yvette Bernal-Hern��ndez, Jos�� Francisco Herrera-Moreno, Aurora Elizabeth Rojas-Garc��a, Irma Martha Medina-D��az, Cyndia A Gonz��lez-Arias and Briscia Socorro Barr��n-Vivanco in Human & Experimental Toxicology

El objetivo de la presente investigación es determinar la relación entre el clima organizacional y satisfacción laboral en una empresa industrial peruana durante el año 2020. La investigación se desarrolló bajo el enfoque cuantitativo, de diseño y nivel no experimental correlacional, de tipo básica, en la que se empleó el método descriptivo; la muestra estuvo constituida por los 316 empleados o colaboradores de una empresa industrial peruana ubicada en Lima. Se aplicaron los instrumentos de clima laboral y de satisfacción laboral de 20 y 16 ítems, respectivamente. Los resultados descriptivos indican que el 71.20% de los trabajadores perciben el clima organizacional como regular, mientras que la satisfacción laboral es percibida por el 80.70% de los trabajadores con un nivel regular. Se concluye, que existen evidencias suficientes para afirmar que la variable clima organizacional tiene relación positiva media (Rho = 0,559) y significativa (p= 0,000 < 0,05) con la variable satisfacción laboral de una empresa industrial peruana durante el año 2020.

Huntington's disease is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington’s disease, that were known to abrogate somatic instability in Huntington’s disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the HTT gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 HTT with 90 CAGs, a mutation that causes juvenile Huntington’s disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington’s disease patient’s blood, but which has been detected in post mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG)(90) mice and that this correlated with the onset of transcriptional dysregulation in these lines. Whereas in R6/2(CAG)(200) mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG)(90) brains have different properties to those in the R6/2(CAG)(200) mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilised by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG)(200) brains polymerise into larger structures that appear as inclusion bodies. These data emphasise that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.

3 Figuras.-- 2 Tablas, El objetivo de este trabajo fue estudiar la valorización del extrusionado de frambuesa residual generado en la industria agroalimentaria de frutos rojos en la zona de Huelva (Andalucía). Para ello, se aplicaron diferentes tratamientos mecánicos, con los que se pretendió estudiar el grado de rotura de los aquenios, que componen aproximadamente el 95 % de este residuo, y con ello, liberar y posteriormente extraer compuestos de alto valor añadido. Estos tratamientos fueron: tratamiento con molino de bolas (TMB); tratamiento con molino de martillo (TMM); tratamiento con molino de cuchillas (TMC); tratamiento con mortero (TMO); la combinación de los tratamientos con molino de cuchillas + mortero (TCM) y un tratamiento control con el extrusionado de frambuesa residual sin moler (EFR). También, los materiales de los tratamientos EFR, TMB, TMM y TMC (sin extracción previa de compuestos de alto valor añadido) se valorizaron mediante digestión anaeróbica a través de la prueba de BMP (Biochemical Methane Potential) para estudiar la biodegradabilidad de este residuo. El tratamiento mecánico produjo la rotura de la estructura de los aquenios, y con ello, la reducción del tamaño de las partículas, especialmente con los tratamientos TMC y TCM. Entre los compuestos de alto valor añadido extraídos los más importantes fueron las antocianinas y el ácido elágico, debido a su efecto positivo en la salud humana. La extracción de ácido elágico libre fue mayor en los materiales de los trata mientos TMC y TCM, aumentándose en un 32% la extracción de este compuesto en comparación con el extrusionado de frambuesa residual sin tratar (EFR). Sin embargo, el contenido de las antocianinas fue mayor en el EFR, debido a que su extracción disminuyó con el aumento del número de partículas. Finalmente, la digestión anaerobia de los materiales de los tratamientos EFR, TMB, TMM y TMC condujo a una producción de metano entre 18 y 236 mL CH4/g SV, consiguiéndose una mejora del 1.211% de producción de metano con TMC respecto al EFR., The objective of this work was to study the valorisation of the residual raspberry extrudate from the berry agri-food industry in the area of Huelva (Andalusia). For this, different mechanical treatments were applied to study the degree of breakage of the achenes, which compose approximately 95 % of the residual raspberry extrudate, and thus release and subsequently extract high added-value compounds. These treatments were: treatment with a ball mill (TMB); treatment with a hammer mill (TMM); treatment with a blade mill (TMC); treatment with a mortar (TMO); treatment with the combination of blade mill + mortar (TCM) and a control treatment with the residual raspberry extrudate without grinding (EFR). Also, the materials from EFR, TMB, TMM and TMC trea tments (without previous extraction of high added-value compounds) were valorised by anaerobic digestion through the BMP test (Biochemical Methane Potential) to study the biodegradability of this waste. The mechanical treatment produced the rupture of the achene structure and consequently the reduction of the particle size, especially with TMC and TCM treatments. Among the high added-value compounds extracted, the most important were anthocyanins and ellagic acid, due to their positive effect on suman health. The extraction of free ellagic acid was higher in the materials of the TMC and TCM treatments, increasing the extraction of this compound with these treatments in a 32% compared to the residual raspberry extrudate without grinding (EFR). However, the content of anthocyanins was higher in the EFR, because their extraction decreased with the increase in the number of particles. Finally, the anaerobic digestion of the materials from EFR, TMB, TMM and TMC treatments led to a methane production between 18 and 236 mL CH4/ g VS, achieving a 1,211% improvement in methane production with TMC compared to the EFR., Esta investigación fue financiada por el Ministerio de Economía, Industria y Competitividad de España para financiar esta investigación a través del proyecto CTM2017-83870-R.

Patients with asthma need uninterrupted supplies of affordable, quality-assured essential medicines. However, access in many low- and middle-income countries (LMICs) is limited. The World Health Organization (WHO) Non-Communicable Disease (NCD) Global Action Plan 2013–2020 sets an 80% target for essential NCD medicines’ availability. Poor access is partly due to medicines not being included on the national Essential Medicines Lists (EML) and/or National Reimbursement Lists (NRL) which guide the provision of free/subsidised medicines. We aimed to determine how many countries have essential asthma medicines on their EML and NRL, which essential asthma medicines, and whether surveys might monitor progress. A cross-sectional survey in 2013–2015 of Global Asthma Network principal investigators generated 111/120 (93%) responses—41 high-income countries and territories (HICs); 70 LMICs. Patients in HICs with NRL are best served (91% HICs included ICS (inhaled corticosteroids) and salbutamol). Patients in the 24 (34%) LMICs with no NRL and the 14 (30%) LMICs with an NRL, however no ICS are likely to have very poor access to affordable, quality-assured ICS. Many LMICs do not have essential asthma medicines on their EML or NRL. Technical guidance and advocacy for policy change is required. Improving access to these medicines will improve the health system’s capacity to address NCDs.

No demographic characteristics identified who might benefit most from pretravel counseling., Among travelers, rabies cases are rare, but animal bites are relatively common. To determine which travelers are at highest risk for rabies, we studied 2,697 travelers receiving care for animal-related exposures and requiring rabies postexposure prophylaxis at GeoSentinel clinics during 1997–2012. No specific demographic characteristics differentiated these travelers from other travelers seeking medical care, making it challenging to identify travelers who might benefit from reinforced pretravel rabies prevention counseling. Median travel duration was short for these travelers: 15 days for those seeking care after completion of travel and 20 days for those seeking care during travel. This finding contradicts the view that preexposure rabies vaccine recommendations should be partly based on longer travel durations. Over half of exposures occurred in Thailand, Indonesia, Nepal, China, and India. International travelers to rabies-endemic regions, particularly Asia, should be informed about potential rabies exposure and benefits of pretravel vaccination, regardless of demographics or length of stay.

The assessment of patients with a suspected cardiac failure aims to an early and precise diagnosis and risk stratification. Only natriuretic peptides have demonstrated to be clinically useful. Brain natriuretic peptide stands out due to its diagnostic and prognostic value. However its results should be cautiously interpreted in the clinical context, bearing in mind possible confounders. The combination of markers can provide a better risk stratification and compensates the limitations of individual markers. Each new marker gives a new insight on the underlying physiopathology of cardiac failure and proposes new therapeutic approaches.