The mental health continuum-short form: The structure and application for cross-cultural studies-A 38 nation study.

OBJECTIVE: The Mental Health Continuum-Short Form (MHC-SF) is a brief scale measuring positive human functioning. The study aimed to examine the factor structure and to explore the cross-cultural utility of the MHC-SF using bifactor models and exploratory structural equation modelling. METHOD: Using multigroup confirmatory analysis (MGCFA) we examined the measurement invariance of the MHC-SF in 38 countries (university students, N = 8,066; 61.73% women, mean age 21.55 years). RESULTS: MGCFA supported the cross-cultural replicability of a bifactor structure and a metric level of invariance between student samples. The average proportion of variance explained by the general factor was high (ECV = .66), suggesting that the three aspects of mental health (emotional, social, and psychological well-being) can be treated as a single dimension of well-being. CONCLUSION: The metric level of invariance offers the possibility of comparing correlates and predictors of positive mental functioning across countries; however, the comparison of the levels of mental health across countries is not possible due to lack of scalar invariance. Our study has preliminary character and could serve as an initial assessment of the structure of the MHC-SF across different cultural settings. Further studies on general populations are required for extending our findings.

(E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists.

A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.

Reduced gravity effects on gait coordinative structures.

Humans have stepped on the Lunar surface for less than 80 h of Extravehicular Activity, providing a narrow understanding of Lunar gait patterns. NASA's Human-crewed Artemis missions are quickly approaching; understanding how fractional gravity affects gait patterns will be critical for the Moon's and Mars' long-term habitation. This study examined gait patterns under 1.0 g (Earth), simulated 0.38 g (Martian), and 0.17 g (Lunar). Participants walked and ran on a treadmill supported by ARGOS (Active Response Gravity Offload System), simulating fractional gravity. Vicon motion capture data and principal component analysis software were used to capture and quantify coordinated gait structures. There were found to be significant differences (p < 0.05) in the coordinative gait structures for ambulation between fractional gravity conditions. Additionally, there were significantly higher asymmetric gait components for Lunar conditions. Finally, a skipping coordinative structure was identified within Lunar and Martian running.

Fragment-Based Screening Identifies New Quinazolinone-Based Inositol Hexakisphosphate Kinase (IP6K) Inhibitors.

A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

Discovery and Evaluation of Novel Angular Fused Pyridoquinazolinonecarboxamides as RNA Polymerase I Inhibitors.

RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.

Fundamental Science and Engineering Questions in Planetary Cave Exploration.

Nearly half a century ago, two papers postulated the likelihood of lunar lava tube caves using mathematical models. Today, armed with an array of orbiting and fly-by satellites and survey instrumentation, we have now acquired cave data across our solar system-including the identification of potential cave entrances on the Moon, Mars, and at least nine other planetary bodies. These discoveries gave rise to the study of planetary caves. To help advance this field, we leveraged the expertise of an interdisciplinary group to identify a strategy to explore caves beyond Earth. Focusing primarily on astrobiology, the cave environment, geology, robotics, instrumentation, and human exploration, our goal was to produce a framework to guide this subdiscipline through at least the next decade. To do this, we first assembled a list of 198 science and engineering questions. Then, through a series of social surveys, 114 scientists and engineers winnowed down the list to the top 53 highest priority questions. This exercise resulted in identifying emerging and crucial research areas that require robust development to ultimately support a robotic mission to a planetary cave-principally the Moon and/or Mars. With the necessary financial investment and institutional support, the research and technological development required to achieve these necessary advancements over the next decade are attainable. Subsequently, we will be positioned to robotically examine lunar caves and search for evidence of life within Martian caves; in turn, this will set the stage for human exploration and potential habitation of both the lunar and Martian subsurface.

A conformational constraint improves a beta-secretase inhibitor but for an unexpected reason.

During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.

Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement.

A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.

Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase.

A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase.

A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.

Microbial succession in an inflated lunar/Mars analog habitat during a 30-day human occupation.

BACKGROUND: For potential future human missions to the Moon or Mars and sustained presence in the International Space Station, a safe enclosed habitat environment for astronauts is required. Potential microbial contamination of closed habitats presents a risk for crewmembers due to reduced human immune response during long-term confinement. To make future habitat designs safer for crewmembers, lessons learned from characterizing analogous habitats is very critical. One of the key issues is that how human presence influences the accumulation of microorganisms in the closed habitat. RESULTS: Molecular technologies, along with traditional microbiological methods, were utilized to catalog microbial succession during a 30-day human occupation of a simulated inflatable lunar/Mars habitat. Surface samples were collected at different time points to capture the complete spectrum of viable and potential opportunistic pathogenic bacterial population. Traditional cultivation, propidium monoazide (PMA)-quantitative polymerase chain reaction (qPCR), and adenosine triphosphate (ATP) assays were employed to estimate the cultivable, viable, and metabolically active microbial population, respectively. Next-generation sequencing was used to elucidate the microbial dynamics and community profiles at different locations of the habitat during varying time points. Statistical analyses confirm that occupation time has a strong influence on bacterial community profiles. The Day 0 samples (before human occupation) have a very different microbial diversity compared to the later three time points. Members of Proteobacteria (esp. Oxalobacteraceae and Caulobacteraceae) and Firmicutes (esp. Bacillaceae) were most abundant before human occupation (Day 0), while other members of Firmicutes (Clostridiales) and Actinobacteria (esp. Corynebacteriaceae) were abundant during the 30-day occupation. Treatment of samples with PMA (a DNA-intercalating dye for selective detection of viable microbial population) had a significant effect on the microbial diversity compared to non-PMA-treated samples. CONCLUSIONS: Statistical analyses revealed a significant difference in community structure of samples over time, particularly of the bacteriomes existing before human occupation of the habitat (Day 0 sampling) and after occupation (Day 13, Day 20, and Day 30 samplings). Actinobacteria (mainly Corynebacteriaceae) and Firmicutes (mainly Clostridiales Incertae Sedis XI and Staphylococcaceae) were shown to increase over the occupation time period. The results of this study revealed a strong relationship between human presence and succession of microbial diversity in a closed habitat. Consequently, it is necessary to develop methods and tools for effective maintenance of a closed system to enable safe human habitation in enclosed environments on Earth and beyond.

Proteinuria en habitantes de una aldea costera de Santa Rosa, Guatemala / Proteinuria in inhabitants of a coastal village of Santa Rosa, Guatemala

Objetivo: determinar la presencia de proteinuria en habitantes de una aldea de la región costera de Santa Rosa, Guatemala, julio del año 2019. Material y métodos: estudio descriptivo y transversal, en una muestra de 575 habitantes de la aldea Casas Viejas, captada por durante cuatro jornadas médicas. Las muestras de orina fueron analizadas con tiras reactivas. Resultados: de los habitantes que participaron, 55.48 % (319) fueron de sexo femenino, la mediana de edad fue de 24 años, el 39.820% (229) estudiante y el 85.2 % (490) sin antecedentes patológicos. De los factores predisponentes de enfermedad renal, el 56.170% (323) consume antiinflamatorios no esteroideo -AINES-, el 82.26 % (473) bebidas carbonatadas, el 13.570% (78) bebidas alcohólicas; la mediana de consumo de agua fue de 6 vasos diarios y 13.22 % (76) han estado expuestos a agroquímicos. Proteinuria se documentó en 8.87 % (51) de los habitantes. Conclusiones: más de la mitad de los sujeto de estudio son de sexo femenino y sin antecedentes patológicos; de los factores predisponentes a enfermedad renal los más frecuentes son el consumo de -AINES-, bebidas carbonatadas y la hidratación inadecuada. Nueve de cada cien sujetos de estudio presentan proteinuria.

Objetive: to establish urine protein presence in inhabitants of a small village of the coastal region in Santa Rosa, Guatemala. July 2019. Material y methods: Descriptive and transversal study performed on 575 persons from Casas Viejas village, using a nonprobabilistic sampling. Proteinuria was determined by urine test strips. Results: Of the persons studied, 55.48% (319) were female, mean age was 24 years old, 39.82% (229) were students and 85.25% had no pathological background. Predisposing factors of kidney disease were noted, 56.17% (323) consumed Non-steroidal Anti-inflammatory Drugs (NSAIDs), 82.26% (473) consumed carbonated drinks, 13.57% (78) alcoholic beverages, the mean water consumption was 6 glasses per day, and 13.22% (76), were exposed to agrochemical pesticides. Proteinuria was found in 8.87% (51) of the sample. Conclutions: more than half of population were female and didn´t showed pathological signs. Predisposing factors to kidney disease were, frequent NSAIDs use, carbonated drinks consumption a no adequate hydration. Nine of each one hundred people studied presented urine protein.

Interface dynamics for copper electrodeposition: the role of organic additives in the growth mode.

An atomistic model for Cu electrodeposition under nonequilibrium conditions is presented. Cu electrodeposition takes place with a height-dependent deposition rate that accounts for fluctuations in the local Cu2+ ions concentration at the interface, followed by surface diffusion. This model leads to an unstable interface with the development of protrusions and grooves. Subsequently the model is extended to account for the presence of organic additives, which compete with Cu2+ for adsorption at protrusions, leading to a stable interface with scaling exponents consistent with those of the Edwards-Wilkinson equation. The model reproduces the interface evolution experimentally observed for Cu electrodeposition in the absence and in the presence of organic additives.

Ansiedad y depresión en pacientes con insuficiencia renal crónica en tratamiento de hemodiálisis / Anxiety and Depression in atients with chronic renal failure in hemodialysis therapy

Objetivo: Determinar la prevalencia de ansiedad y depresión en pacientes con insuficiencia renal crónica en tratamiento sustitutivo de hemodiálisis en la Unidad Nacional de Atención al Enfermo Renal Crónico- UNAERC-Guatemala. Población y Métodos: Estudio descriptivo realizado en una muestra de 86 pacientes, mediante una entrevista elaborada con base al test de Hamilton para ansiedad y depresión. Resultados: De la muestra estudiada 80 (93%) pacientes presentaron ansiedad o depresión; en su mayoría las variantes más severas, 42 (49%) ansiedad mayor, y 34(39%) depresión muy grave; 68 (85%) evidenciaron la presencia de ambos trastornos de forma simultánea. Se observó asociación entre el tiempo mayor a 12 meses en tratamiento de hemodiálisis y la presencia de depresión; (X2):10.23; V de Cramer: 0.34 y P: 0.037. Conclusiones: En la Unidad de Atención al enfermo renal crónico-UNAERC-, según la escala de Hamilton, nueve de cada 10pacientes con insuficiencia renal crónica en tratamiento sustitutivo de hemodiálisis tienen algún grado de ansiedad o depresión, de los cuales más de tres cuartas partes presentan estos dos trastornos afectivos de forma simultánea y en su mayoría padecen sus variantes más severas (AU)

Preliminary results of mental workload and task engagement assessment using electroencephalogram in a space suit.

In this paper, we present preliminary results of subject's mental workload and task engagement assessment in an experimental space suit. We have quantified the mental workload and task engagement based on changes in electroencephalogram (EEG). EEG signals were collected from subjects scalp using a commercial wireless EEG device in two experimental conditions - when subjects did not wear space suit (control condition) and when subjects wore space suit. Brain state changes were estimated and compared with the direct responses for different tasks and different conditions. We found that the spacesuit experiment introduced a greater mental workload where subject's stress levels were higher than control experiment.

Violencia sexual: conocimientos y actitudes en adolescentes / Sexual Violence: Knowledges and attitudes in adolescents

Objetivo: Determinar los conocimientos y actitudes sobre violencia sexual que poseen los adolescentes de Centros Educativos Públicos en el departamento de Chimaltenango en febrero y marzo 2017. Material y métodos: Estudio descriptivo transversal realizado en una muestra aleatoria de 386 sujetos, mediante un cuestionario auto aplicable posterior a consentimiento y asentimiento informado. Resultados: De los sujetos de estudio, 214 (55%) correspondían al sexo femenino, en promedio tenían 12.6 años de edad, 184 (48%) profesaban religión evangélica, 349 (90%) provenían de familias integradas, 292 (76%) pertenecían a la etnia Kaqchiquel. Conocimientos: 132 (34%) refirieron que la violencia sexual se define únicamente como el contacto físico de las partes íntima de otra persona, 116 (30%) identificaron al machismo y el consumo de drogas como factores de riesgo para violencia sexual, 83 (22%) consideraron adecuado el embarazo en menores de edad, 191 (50%) indicaron que en la mayoría de los casos los agresores son personas desconocidas de la víctima; 145 (38%) y 49 (13%) identificaron la calle y el hogar, respectivamente, como los principales lugares en los que se da este fenómeno. Actitudes: 304 (79%) no denunciarían si un compañero/a estuviera sufriendo violencia sexual, 218 (56%) están en desacuerdo con que los padres hablen sobre sexualidad con sus hijos, 202 (52%) no consideran importante que se imparta educación sexual en los centros educativos. Conclusiones: dos terceras partes desconocen conceptos básicos sobre el tema. Se evidencia una marcada indiferencia ante la necesidad de aprender del mismo y apoyar la denuncia de casos de compañeros que sufran algún tipo de violencia sexual.

Objective: To identify the knowledge and attitudes regarding sexual violence of adolescents in public schools of Chimaltenango, between February and March of 2017. Material and Methods: A descriptive cross sectional study conducted in a random sample of 386 subjects, based in a self-applicable questionnaire after student assent and parental consent (from parents or legal guardians). Results: 214 of 386 were female; with an average age of 12.6 years; 184 (48%) profess evangelical religion; 349 (90%) belonged to an integrated household; 292 (76%) belonged to the Kaqchiquel ethnic group. Knowledge: 132 (34%) reported that sexual violence is defined only as physical contact in intimate parts; 116 (30%) identified male chauvinist and drug abuse as risk factors for sexual violence; 83 (22%) considered pregnancy in underage teenagers as adequate; 191 (50%) indicated that in most cases the aggressors are unknown by the victims; students identify the street with 145 (38%) and the house with 49 (13%) as the main places where sexual violence occurs. Attitudes: 304 (79%) of the students would not report if a schoolmate is suffering from sexual violence, 218 (56%) disagree that parents should talk about sexuality with their children, 202 (52%) don't consider important to provide sex education in schools. Conclusions: Two thirds of the students are not aware of basic concepts regarding sexual violence, there is a considerable indifference to the need of learning of this topic and do not support the reporting of cases of classmates who suffer any type of sexual violence.