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INTRODUCTION: Opioid agonist treatment (OAT) is the only treatment for opioid use disorder (OUD) proven to reduce overdose mortality, yet access to this evidence-based treatment remains poor. The purpose of this cross-sectional audit study was to assess OAT availability at residential substance use services in North Carolina. METHODS: We conducted a state-wide inventory of residential substance use service providers in North Carolina and subsequently called all providers identified, posing as uninsured persons who use heroin, seeking treatment services. Program characteristics, as reported in phone calls, were systematically recorded. We used Fisher's exact tests to assess what program characteristics were associated with OAT availability and with staff making discouraging comments about OAT. We used unsupervised agglomerative clustering to identify facilities with similar characteristics. RESULTS: Of the 94 treatment providers identified, we successfully contacted and collected data from 66. Of those, only 7 (10.6 %) provide OAT on site; an additional 9 (13.6 %) allow OAT through an outside or community-based prescriber. Only 8 (12.1 %) providers were licensed to provide residential substance use treatment. Staff from 33 (50.0 %) providers made negative, discouraging, or stigmatizing remarks about OAT-for example, that OAT substitutes one addiction for another or does not constitute "true recovery." OAT availability was positively associated with a provider holding a state license for any substance use-related service (41.9 % vs 8.6 %, p = 0.002) and offering 12-step programming (36.1 % vs. 10/0 %, p = 0.020). OAT availability was negatively associated with faith-based programming (6.1 % vs 42.4 %, p = 0.001), dress codes (5.3 % vs 50.0 %, p < 0.001), and mandates that residents work in a provider-owned and -operated commercial enterprise (5.0 % vs 32.6 %, p = 0.026). Cluster analysis revealed that the most common (n = 21) type of service provider in North Carolina is an unlicensed, faith-based organization that prohibits OAT, imposes a dress code, and mandates that residents work, often in provider-owned and -operated commercial enterprises. CONCLUSION: Evidence-based treatments for OUD are largely unavailable at providers of residential substance use services in North Carolina. The prohibition of OAT occurs most often among providers who are unlicensed and impose labor and/or 12-step mandates on residents. Changes to state licensure requirements and exemptions may help improve OAT availability.
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Background: Despite the development of patient-centred or patient-reported outcome measures (PCOMs or PROMs) in palliative and end-of-life care over recent years, their routine use in practice faces continuing challenges. Objective: To update a highly cited literature review, identify and synthesise new evidence on facilitators, barriers, lessons learned, PCOMs used, models of implementation, implementation outcomes, costs, and consequences of implementing PCOMs in palliative care clinical practice. Methods: We will search MEDLINE, PsycINFO, CINAHL, Embase, Emcare, SCI-Expanded, SSCI, ESCI, and BNI. The database search will be supplemented by a list of studies from the expert advisory committee, hand-searching of reference lists for included articles, and citations of the original review. We will include primary studies using a PCOM during clinical care of adult patients with advanced disease in palliative care settings and extract data on reported models of implementation, PCOMs, facilitators, barriers, lessons learned, costs, and implementation outcomes. Gough's Weight of Evidence Framework will be used to assess the robustness and relevance of the studies. We will narratively synthesise and tabulate the findings. This review will follow PRISMA, PRISMA-Abstract, PRISMA-P, and PRISMA-Search as the reporting guidelines. Source of funding: Marie Curie. The funder is not involved in designing or conducting this study. Protocol registration: CRD42023398653 (13/02/2023).
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Evaluación de Resultado en la Atención de Salud , Cuidados Paliativos , Humanos , Adulto , Cuidados Paliativos/métodos , Revisiones Sistemáticas como Asunto , Metaanálisis como Asunto , Literatura de Revisión como AsuntoRESUMEN
PURPOSE: Accurate segmentation (separating diseased portions of the lung from normal appearing lung) is a challenge in radiomic studies of non-neoplastic diseases, such as pulmonary tuberculosis (PTB). In this study, we developed a segmentation method, applicable to chest X-rays (CXR), that can eliminate the need for precise disease delineation, and that is effective for constructing radiomic models for automatic PTB cavity classification. METHODS: This retrospective study used a dataset of 266 posteroanterior CXR of patients diagnosed with laboratory confirmed PTB. The lungs were segmented using a U-net-based in-house automatic segmentation model. A secondary segmentation was developed using a sliding window, superimposed on the primary lung segmentation. Pyradiomics was used for feature extraction from every window which increased the dimensionality of the data, but this allowed us to accurately capture the spread of the features across the lung. Two separate measures (standard-deviation and variance) were used to consolidate the features. Pearson's correlation analysis (with a 0.8 cut-off value) was then applied for dimensionality reduction followed by the construction of Random Forest radiomic models. RESULTS: Two almost identical radiomic signatures consisting of 10 texture features each (9 were the same plus 1 other feature) were identified using the two separate consolidation measures. Two well performing random forest models were constructed from these signatures. The standard-deviation model (AUC = 0.9444 (95% CI, 0.8762; 0.9814)) performed marginally better than the variance model (AUC = 0.9288 (95% CI, 0.9046; 0.9843)). CONCLUSION: The introduction of the secondary sliding window segmentation on CXR could eliminate the need for disease delineation in pulmonary radiomic studies, and it could improve the accuracy of CXR reporting currently regaining prominence as a high-volume screening tool as the developed radiomic models correctly classify cavities from normal CXR.
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Enfermedades Pulmonares , Tuberculosis Pulmonar , Humanos , Estudios Retrospectivos , Tuberculosis Pulmonar/diagnóstico por imagen , Pulmón/diagnóstico por imagen , RadiografíaAsunto(s)
Contusiones , Hematología , Niño , Contusiones/etiología , Familia , Hemorragia/diagnóstico , Hemorragia/etiología , Hemorragia/prevención & control , HumanosRESUMEN
Omega (n)-3 polyunsaturated fatty acids (PUFA) are known to regulate lipid metabolism and inflammation; however, the regulation of maternal lipid metabolism and cytokines profile by n-3 PUFA during different gestation stages, and its impact on fetal sustainability is not known. We investigated the effects of maternal diet varying in n-3 PUFA prior to, and during gestation, on maternal metabolic profile, placental inflammatory cytokines, and fetal outcomes. Female C57BL/6 mice were fed either a high, low or very low (9, 3 or 1% w/w n-3 PUFA) diet, containing n-6:n-3 PUFA of 5:1, 20:1 and 40:1, respectively for two weeks before mating, and throughout pregnancy. Animals were sacrificed prior to mating (NP), and during pregnancy at gestation days 6.5, 12.5 and 18.5. Maternal metabolic profile, placental cytokines and fetal outcomes were determined. Our results show for the first time that a maternal diet high in n-3 PUFA prevented dyslipidemia in NP mice, and maintained the expected lipid profile during pregnancy. However, females fed the very low n-3 PUFA diet became hyperlipidemic prior to pregnancy, and carried this profile into pregnancy. Maternal diet high in n-3 PUFA maintained maternal plasma progesterone and placental pro-inflammatory cytokines profile, and sustained fetal numbers throughout pregnancy, while females fed the low and very-low n-3 PUFA diet had fewer fetuses. Our findings demonstrate the importance of maternal diet before, and during pregnancy, to maintain maternal metabolic profile and fetus sustainability. These findings are important when designing dietary strategies to optimize maternal metabolism during pregnancy for successful pregnancy outcome.
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Citocinas/sangre , Ácidos Grasos Omega-3/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Dieta/métodos , Dislipidemias/prevención & control , Ácidos Grasos Insaturados/farmacología , Femenino , Feto/efectos de los fármacos , Feto/metabolismo , Inflamación/metabolismo , Lípidos/sangre , Ratones , Ratones Endogámicos C57BL , Placenta/metabolismo , Embarazo , Resultado del EmbarazoRESUMEN
Cohesin's association with and translocation along chromosomal DNAs depend on an ATP hydrolysis cycle driving the association and subsequent release of DNA. This involves DNA being 'clamped' by Scc2 and ATP-dependent engagement of cohesin's Smc1 and Smc3 head domains. Scc2's replacement by Pds5 abrogates cohesin's ATPase and has an important role in halting DNA loop extrusion. The ATPase domains of all SMC proteins are separated from their hinge dimerisation domains by 50-nm-long coiled coils, which have been observed to zip up along their entire length and fold around an elbow, thereby greatly shortening the distance between hinges and ATPase heads. Whether folding exists in vivo or has any physiological importance is not known. We present here a cryo-EM structure of the apo form of cohesin that reveals the structure of folded and zipped-up coils in unprecedented detail and shows that Scc2 can associate with Smc1's ATPase head even when it is fully disengaged from that of Smc3. Using cysteine-specific crosslinking, we show that cohesin's coiled coils are frequently folded in vivo, including when cohesin holds sister chromatids together. Moreover, we describe a mutation (SMC1D588Y) within Smc1's hinge that alters how Scc2 and Pds5 interact with Smc1's hinge and that enables Scc2 to support loading in the absence of its normal partner Scc4. The mutant phenotype of loading without Scc4 is only explicable if loading depends on an association between Scc2/4 and cohesin's hinge, which in turn requires coiled coil folding.
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Proteínas de Ciclo Celular/química , Proteínas Cromosómicas no Histona/química , Cromosomas/química , Proteínas de Saccharomyces cerevisiae/química , Adenosina Trifosfatasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromátides , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas/metabolismo , Microscopía por Crioelectrón , ADN/metabolismo , Dimerización , Regulación Fúngica de la Expresión Génica , Hidrólisis , Dominios Proteicos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , CohesinasRESUMEN
BACKGROUND: Medical education, residency training, and the structure of child neurology residency training programs are evolving. We sought to evaluate how training program selection priorities of child neurology residency applicants have changed over time. METHODS: An electronic survey was sent to child neurology residents and practicing child neurologists via the Professors of Child Neurology distribution list in the summer of 2018. It was requested that the survey be disseminated to current trainees and alumni of the programs. The survey consisted of seven questions assessing basic demographics and a list of factors applicants consider when choosing a residency. RESULTS: There were 284 responses with a higher representation of individuals matriculating into residency in the last decade. More recent medical school graduates had a lower probability of considering curriculum as an important factor for residency selection (odds ratio [OR], 0.746; 95% confidence interval [95% CI], 0.568 to 0.98; P = 0.035) and higher priority placed on interaction with current residents over the course of the interview day (OR, 2.207; 95% CI, 1.486 to 3.278; P < 0.0001), sense of resident happiness and well-being (OR, 2.176; 95% CI, 1.494 to 3.169; P < 0.0001), and perception of city or geography of the residency program (OR, 1.710; 95% CI, 1.272 to 2.298; P < 0.001). CONCLUSIONS: Over time, child neurology residency applicants are putting more emphasis on quality of life factors over curriculum. To accommodate these changes, child neurology residency programs should prioritize interactions with residents during the interview process and resident wellness initiatives throughout residency training.
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Curriculum/normas , Internado y Residencia/normas , Neurólogos/estadística & datos numéricos , Calidad de Vida , Adulto , Encuestas de Atención de la Salud , Humanos , Masculino , Neurología/educación , Pediatría/educación , Estados UnidosRESUMEN
Here, we demonstrate that the upregulation of catalase is required to compensate for the loss of nicotinamide nucleotide transhydrogenase (NNT) to maintain hydrogen peroxide (H2O2) steady-state levels in C57BL/6J liver mitochondria. Our investigations using the closely related mouse strains C57BL/6NJ (6NJ; +NNT) and C57BL/6J (6J; -NNT) revealed that NNT is required for the provision of NADPH and that the upregulation of isocitrate dehydrogenase-2 (IDH2) activity is not enough to compensate for the absence of NNT, which is consistent with previous observations. Intriguingly, despite the absence of NNT, 6J mitochondria had rates of H2O2 production (58.56⯱â¯3.79â¯pmolâ¯mg-1 min-1) that were similar to samples collected from 6NJ mice (72.75⯱â¯14.26â¯pmolâ¯mg-1 min-1) when pyruvate served as the substrate. However, 6NJ mitochondria energized with succinate produced significantly less H2O2 (59.95⯱â¯2.13â¯pmolâ¯mg-1 min-1) when compared to samples from 6J mice (116.39⯱â¯20.74â¯pmolâ¯mg-1 min-1), an effect that was attributed to the presence of NNT. Further investigations into the H2O2 eliminating capacities of these mitochondria led to the novel observation that 6J mitochondria compensate for the loss of NNT by upregulating catalase. Indeed, 6NJ and 6J mitochondria energized with pyruvate or succinate displayed similar rates for H2O2 elimination, quenching ~84% and ~86% of the H2O2, respectively, in the surrounding medium within 30â¯s. However, inclusion of palmitoyl-CoA, an NNT inhibitor, significantly limited H2O2 degradation by 6NJ mitochondria only (~55% of H2O2 eliminated in 30â¯s). Liver mitochondria from 6J mice treated with palmitoyl-CoA still cleared ~80% of the H2O2 from the surrounding environment. Inhibition of catalase with triazole compromised the capacity of 6J mitochondria to maintain H2O2 steady-state levels. By contrast, disabling NADPH-dependent antioxidant systems had a limited effect on the H2O2 clearing capacity of 6J mitochondria. Liver mitochondria collected from 6NJ mice, on the other hand, were more reliant on the GSH and TRX systems to clear exogenously added H2O2. However, catalase still played an integral in eliminating H2O2 in 6NJ liver mitochondria. Immunoblot analyses demonstrated that catalase protein levels were ~7.7-fold higher in 6J mitochondria. Collectively, our findings demonstrate for the first time that 6J liver mitochondria compensate for the loss of NNT by increasing catalase levels for the maintenance of H2O2 steady-state levels. In general, our observations reveal that catalase is an integral arm of the antioxidant response in liver mitochondria.
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Peróxido de Hidrógeno , Mitocondrias Hepáticas , Animales , Catalasa/genética , Catalasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias , Mitocondrias Hepáticas/metabolismoAsunto(s)
Enfermedades del Ano/virología , Abuso Sexual Infantil , Condiloma Acuminado , Niño , Condiloma Acuminado/diagnóstico , Condiloma Acuminado/terapia , Condiloma Acuminado/virología , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Guías de Práctica Clínica como Asunto , Derivación y Consulta , Salud Sexual , Reino Unido/epidemiologíaRESUMEN
PURPOSE: Adolescents in rural areas have higher unmet medical needs and receive fewer preventive health care visits than their urban counterparts. This community health assessment aimed to describe adolescent experiences of key components of a medical home in rural Washington. METHODS: A cross-sectional survey using questions from two validated measures was created with input from a community advisory group using community-based participatory research principles. The survey was administered to a convenience sample of high-school students in one rural town. Responses within each medical home domain were grouped to create composite scores. Linear and logistic regression analyses identified characteristics associated with receiving medical home services. RESULTS: A total of 217 adolescents aged 13-19 years completed the survey. Eighty-five percent identified as Latino/Hispanic. Respondents described usually or always feeling listened to by providers (80%), respected by providers (89%), and welcomed at their clinic (79%). Fewer reported having a personal health provider (56%), meeting alone with a provider (56%), or knowing the visit was confidential (60%). Those who identified having a primary provider had 2.48 greater odds (95% confidence interval = 1.13-5.45) of reporting a well visit in the previous year and had higher composite scores for compassionate and patient-centered care. CONCLUSIONS: This sample of rural adolescents reported receiving many characteristics of a medical home but had limited experience with personal providers and confidential services. Improving adolescent access to confidential care may be especially important in small, rural communities. The association of a primary provider with improved medical home experience highlights this key characteristic in an adolescent medical home.
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Servicios de Salud del Adolescente/estadística & datos numéricos , Investigación Participativa Basada en la Comunidad/métodos , Atención Dirigida al Paciente , Servicios de Salud Rural , Adolescente , Confidencialidad , Estudios Transversales , Etnicidad , Femenino , Humanos , Masculino , Encuestas y Cuestionarios , Washingtón , Adulto JovenRESUMEN
INTRODUCTION The efficacy and cost-effectiveness of exercise treadmill testing for patients with low cardiovascular risk is unclear. This is due to the low incidence of coronary artery disease in this population and the potential for false-positive results leading to additional invasive and expensive investigation. AIM To investigate the value of exercise treadmill testing (ETT) as a predictor of coronary artery disease in patients with different levels of cardiovascular risk. METHODS An observational study was completed on an outpatient population from a chest pain clinic (n = 529). Cross-tabulations and binary logistic regressions were used to examine relationships between variables. RESULTS A negative ETT result was recorded for 72.5% of patients with low cardiovascular risk compared to 54.3% of those with moderate or high risk. Within the low cardiovascular risk group, patients with symptoms atypical for cardiac ischaemia were 11.1-fold more likely to have a negative ETT result. Of the patients with positive or equivocal ETT results, coronary artery disease was subsequently confirmed in only 23.1% of the low cardiovascular risk group compared to 77.2% of those with moderate or high cardiovascular risk. DISCUSSION Results show low cardiovascular risk patients are significantly more likely to return negative ETT results, particularly when associated with atypical symptoms. Similarly, positive or equivocal ETTs in this group are significantly more likely to be false positives. This suggests the ETT is not efficacious in predicting coronary artery disease in patients with low cardiovascular risk. Is it therefore appropriate to offer exercise testing to this cohort or should alternative management strategies be considered?
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Understanding athletes' attitudes to doping continues to be of interest for its potential to contribute to an international anti-doping system. However, little is known about the relationship between elite athletes' attitudes to drug use and potential explanatory factors, including achievement goals and the motivational climate. In addition, despite specific World Anti-Doping Agency Code relating to team sport athletes, little is known about whether sport type (team or individual) is a risk or protective factor in relation to doping. Elite athletes from Scotland (N = 177) completed a survey examining attitudes to performance-enhancing drug (PED) use, achievement goal orientations and perceived motivational climate. Athletes were generally against doping for performance enhancement. Hierarchical regression analysis revealed that task and ego goals and mastery motivational climate were predictors of attitudes to PED use (F (4, 171) = 15.81, P < .01). Compared with individual athletes, team athletes were significantly lower in attitude to PED use and ego orientation scores and significantly higher in perceptions of a mastery motivational climate (Wilks' lambda = .76, F = 10.89 (5, 170), P < .01). The study provides insight into how individual and situational factors may act as protective and risk factors in doping in sport.
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Logro , Atletas/psicología , Actitud , Doping en los Deportes/psicología , Objetivos , Motivación , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sustancias para Mejorar el Rendimiento , Escocia , Adulto JovenRESUMEN
Climate change is recognised as a significant public health issue that will impact on food security. One of the major contributors to global warming is the livestock industry, and, relative to plant-based agriculture, meat production has a much higher environmental impact in relation to freshwater use, amount of land required, and waste products generated. Promoting increased consumption of plant-based foods is a recommended strategy to reduce human impact on the environment and is also now recognised as a potential strategy to reduce the high rates of some chronic diseases such as cardiovascular disease and certain cancers. Currently there is a scant evidence base for policies and programs aiming to increase consumption of plant-based diets and little research on the necessary conditions for that change to occur and the processes involved in such a change. This paper reviews some of the environmental and health consequences of current dietary practices, reviews literature on the determinants of consuming a plant-based diet, and provides recommendations for further research in this area.
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Dieta/efectos adversos , Ambiente , Alimentos/efectos adversos , Conducta de Elección , Cambio Climático , Femenino , Abastecimiento de Alimentos , Estado de Salud , Humanos , Masculino , Política Nutricional , Plantas Comestibles , Cambio SocialRESUMEN
Cohesin's structural maintenance of chromosome 1 (Smc1) and Smc3 are rod-shaped proteins with 50-nm long intra-molecular coiled-coil arms with a heterodimerization domain at one end and an ABC-like nucleotide-binding domain (NBD) at the other. Heterodimerization creates V-shaped molecules with a hinge at their centre. Inter-connection of NBDs by Scc1 creates a tripartite ring within which, it is proposed, sister DNAs are entrapped. To investigate whether cohesin's hinge functions as a possible DNA entry gate, we solved the crystal structure of the hinge from Mus musculus, which like its bacterial counterpart is characterized by a pseudo symmetric heterodimeric torus containing a small channel that is positively charged. Mutations in yeast Smc1 and Smc3 that together neutralize the channel's charge have little effect on dimerization or association with chromosomes, but are nevertheless lethal. Our finding that neutralization reduces acetylation of Smc3, which normally occurs during replication and is essential for cohesion, suggests that the positively charged channel is involved in a major conformational change during S phase.
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Proteínas de Ciclo Celular/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Cromátides/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Modelos Moleculares , Animales , Western Blotting , Calorimetría , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/aislamiento & purificación , Proteoglicanos Tipo Condroitín Sulfato/aislamiento & purificación , Inmunoprecipitación de Cromatina , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/aislamiento & purificación , Cristalización , Dimerización , Inmunoprecipitación , Ratones , Microscopía Fluorescente , Reacción en Cadena de la Polimerasa , CohesinasRESUMEN
Human saliva not only helps control oral health (with anti-microbial proteins), but it may also play a role in chemical communication. As is the case with other mammalian species, human saliva contains peptides, proteins, and numerous volatile organic compounds (VOCs). A high-throughput analytical method is described for profiling a large number of saliva samples to screen the profiles of VOCs. Saliva samples were collected in a non-stimulated fashion. The method utilized static stir bar extraction followed by gas chromatography-mass spectrometry (GC-MS). The method provided excellent reproducibility for a wide range of salivary compounds, including alcohols, aldehydes, ketones, carboxylic acids, esters, amines, amides, lactones, and hydrocarbons. Furthermore, substantial overlap of salivary VOCs and the previously reported skin VOCs in the same subject group was found in this study by using pattern recognition analyses. Sensitivity, precision, and reproducibility of the method suggest that this technique has potential in physiological, metabolomic, pharmacokinetic, forensic, and toxicological studies of small organic compounds where a large number of human saliva samples are involved.
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Fraccionamiento Químico/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Compuestos Orgánicos/análisis , Compuestos Orgánicos/aislamiento & purificación , Saliva/química , Femenino , Humanos , Masculino , Compuestos Orgánicos/química , Reproducibilidad de los Resultados , VolatilizaciónRESUMEN
Body fluids such as urine potentially contain a wealth of information pertaining to age, sex, social and reproductive status, physiologic state, and genotype of the donor. To explore whether urine could encode information regarding environment, physiology, and development, we compared the volatile compositions of mouse urine using solid-phase microextraction and gas chromatography-mass spectrometry (SPME-GC/MS). Specifically, we identified volatile organic compounds (VOCs) in individual urine samples taken from inbred C57BL/6J-H-2(b) mice under several experimental conditions-maturation state, diet, stress, and diurnal rhythms, designed to mimic natural variations. Approximately 1000 peaks (i.e., variables) were identified per comparison and of these many were identified as potential differential biomarkers. Consistent with previous findings, we found groups of compounds that vary significantly and consistently rather than a single unique compound to provide a robust signature. We identified over 49 new predictive compounds, in addition to identifying several published compounds, for maturation state, diet, stress, and time-of-day. We found a considerable degree of overlap in the chemicals identified as (potential) biomarkers for each comparison. Chemometric methods indicate that the strong group-related patterns in VOCs provide sufficient information to identify several parameters of natural variations in this strain of mice including their maturation state, stress level, and diet.
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Biomarcadores/orina , Ritmo Circadiano/fisiología , Dieta , Maduración Sexual , Estrés Fisiológico , Animales , Cromatografía de Gases y Espectrometría de Masas , Masculino , Ratones , Ratones Endogámicos C57BL , Método de Montecarlo , Análisis de Componente Principal , Microextracción en Fase Sólida , Compuestos Orgánicos Volátiles/química , Compuestos Orgánicos Volátiles/aislamiento & purificación , Compuestos Orgánicos Volátiles/orinaRESUMEN
BACKGROUND: The cohesin complex that mediates sister chromatid cohesion contains three core subunits: Smc1, Smc3, and Scc1. Heterotypic interactions between Smc1 and Smc3 dimerization domains create stable V-shaped Smc1/Smc3 heterodimers with a hinge at the center and nucleotide-binding domains (NBDs) at the ends of each arm. Interconnection of each NBD through their association with the N- and C-terminal domains of Scc1 creates a tripartite ring, within which sister DNAs are thought to be entrapped (the ring model). Crystal structures show that the Smc1/Smc3 hinge has a toroidal shape, with independent "north" and "south" interaction surfaces on an axis of pseudosymmetry. The ring model predicts that sister chromatid cohesion would be lost by transient hinge opening. RESULTS: We find that mutations within either interface weaken heterodimerization of isolated half hinges in vitro but do not greatly compromise formation of cohesin rings in vivo. They do, however, reduce the residence time of cohesin on chromosomes and cause lethal defects in sister chromatid cohesion. This demonstrates that mere formation of rings is insufficient for cohesin function. Stable cohesion requires cohesin rings that cannot easily open. CONCLUSIONS: Either the north or south hinge interaction surface is sufficient for the assembly of V-shaped Smc1/Smc3 heterodimers in vivo. Any tendency of Smc proteins with weakened hinges to dissociate will be suppressed by interconnection of their NBDs by Scc1. We suggest that transient hinge dissociation caused by the mutations described here is incompatible with stable sister chromatid cohesion because it permits chromatin fibers to escape from cohesin rings.
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Proteínas de Ciclo Celular/metabolismo , Cromátides/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Modelos Moleculares , Estructura Terciaria de Proteína/fisiología , Proteínas de Schizosaccharomyces pombe/metabolismo , Secuencia de Aminoácidos , Proteínas de Ciclo Celular/genética , Cromatografía en Gel , Proteínas Cromosómicas no Histona/genética , Cristalización , Dimerización , Datos de Secuencia Molecular , Mutación/genética , Proteínas de Schizosaccharomyces pombe/genética , Especificidad de la Especie , Levaduras , CohesinasRESUMEN
House mice (Mus domesticus) communicate using scent-marks, and the chemical and microbial composition of these 'extended phenotypes' are both influenced by genetics. This study examined how the genes of the major histocompatibility complex (MHC) and background genes influence the volatile compounds (analysed with Gas Chromatography Mass Spectrometry or GC/MS) and microbial communities (analysed using Denaturating Gradient Gel Electrophoresis or DGGE) in scent-marks produced by congenic strains of mice. The use of Consensus Principal Components Analysis is described and shows relationships between the two types of fingerprints (GC/MS and DGGE profiles). Classification methods including Support Vector Machines and Discriminant Partial Least Squares suggest that mice can be classified according to both background strain and MHC-haplotype. As expected, the differences among the mice were much greater between strains that vary at both MHC and background loci than the congenics, which differ only at the MHC. These results indicate that the volatiles in scent-marks provide information about genetic similarity of the mice, and support the idea that the production of these genetically determined volatiles is influenced by commensal microflora. This paper describes the application of consensus methods to relate two blocks of analytical data.
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Electroforesis en Gel de Poliacrilamida/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Complejo Mayor de Histocompatibilidad , Ratones Congénicos , Odorantes/análisis , Procesamiento de Señales Asistido por Computador , Animales , Biomarcadores/análisis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
ISSUE ADDRESSED: This paper describes results of a survey comparing people's knowledge of health and environmental impacts of dietary choices. Dietary choice is one of the key ways in which individuals can reduce their environmental impact in relation to water use and greenhouse gas emissions but this may not be widely known amongst the public due to limited press coverage. METHODS: A street intercept survey was conducted asking open ended questions on how people can help the environment, maintain or improve health and basic demographics. The sample size was 107 with a refusal rate of 51%. RESULTS: Only 3.2% of the sample made a link between dietary choice and environmental impact whereas 85.6% of the sample referred to dietary choice in relation to personal health. Transport options and keeping active were popular responses to both health and environmental categories. CONCLUSIONS: It seems that very few people are aware that the livestock sector is the second largest contributor to equivalent greenhouse gas emissions and one of the largest users of fresh water. Reduction in red meat consumption could have both important positive health and environmental impacts.
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The majority of works in metabolomics employ approaches based on principal components analysis (PCA) and partial least-squares, primarily to determine whether samples fall within large groups. However, analytical chemists rarely tackle the problem of individual fingerprinting, and in order to do this effectively, it is necessary to study a large number of small groups rather than a small number of large groups and different approaches are required, as described in this paper. Furthermore, many metabolomic studies on mammals and humans involve analyzing compounds (or peaks) that are present in only a certain portion of samples, and conventional approaches of PCA do not cope well with sparse matrices where there may be many 0s. There is, however, a large number of qualitative similarity measures available for this purpose that can be exploited via principal coordinates analysis (PCO). It can be shown that PCA scores are a specific case of PCO scores, using a quantitative similarity measure. A large-scale study of human sweat consisting of nearly 1000 gas chromatography/mass spectrometry analyses from the sweat of an isolated population of 200 individuals in Carinthia (Southern Austria) sampled once per fortnight over 10 weeks was employed in this study and grouped into families. The first step was to produce a peak table requiring peak detection, alignment, and integration. Peaks were reduced from 5080 to 373 that occurred in at least 1 individual over 4 out of 5 fortnights. Both qualitative (presence/absence) and quantitative (equivalent to PCA) similarity measures can be computed. PCO and the Kolomorogov-Smirnoff (KS) rank test are applied to these similarity matrices. It is shown that for this data set there is a reproducible individual fingerprint, which is best represented using the qualitative similarity measure as assessed both by the Hotelling t2 statistic as applied to PCO scores and the probabilities associated with the KS rank test.