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1.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502534

RESUMO

Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient's myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations.

2.
Biochem J ; 478(14): 2793-2809, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34232285

RESUMO

Growth factor receptor-bound protein 2 (GRB2) is a trivalent adaptor protein and a key element in signal transduction. It interacts via its flanking nSH3 and cSH3 domains with the proline-rich domain (PRD) of the RAS activator SOS1 and via its central SH2 domain with phosphorylated tyrosine residues of receptor tyrosine kinases (RTKs; e.g. HER2). The elucidation of structural organization and mechanistic insights into GRB2 interactions, however, remain challenging due to their inherent flexibility. This study represents an important advance in our mechanistic understanding of how GRB2 links RTKs to SOS1. Accordingly, it can be proposed that (1) HER2 pYP-bound SH2 potentiates GRB2 SH3 domain interactions with SOS1 (an allosteric mechanism); (2) the SH2 domain blocks cSH3, enabling nSH3 to bind SOS1 first before cSH3 follows (an avidity-based mechanism); and (3) the allosteric behavior of cSH3 to other domains appears to be unidirectional, although there is an allosteric effect between the SH2 and SH3 domains.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34299794

RESUMO

The development of motor competencies is necessary for participation in the culture of sport, exercise, and physical activity, which in turn supports the development of a healthy lifestyle. A lack of physical activity in childhood and deficits in motor performance emphasize the relevance of interventions for promoting basic motor competencies. However, there are research desiderata with regard to such interventions. This article describes an intervention program for promoting basic motor competencies in middle childhood (around 6 to 10 years of age). The intervention was investigated in a longitudinal study from June 2019 to January 2020 (n = 200; 58% girls, M = 8.84 years, SD = 0.63) at three primary schools. The intervention was conducted once a week in physical education (PE). The comparison group participated in regular PE. The intervention showed significant effects on basic motor competencies in object movement but not in self-movement. The results demonstrate that positive effects on basic motor competencies can be achieved with the help of a relatively simple intervention. Further longitudinal studies are desirable as a means of substantiating the results and developing evidence-based concepts to support children in their development in the best possible way.


Assuntos
Educação Física e Treinamento , Esportes , Criança , Exercício Físico , Feminino , Humanos , Estudos Longitudinais , Masculino , Destreza Motora , Instituições Acadêmicas
4.
Support Care Cancer ; 29(11): 6259-6269, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33847829

RESUMO

PURPOSE: Aside from urological and sexual problems, long-term (≥5 years after initial diagnosis) prostate cancer (PC) survivors might suffer from pain, fatigue, and depression. These concurrent symptoms can form a cluster. In this study, we aimed to investigate classes of this symptom cluster in long-term PC survivors, to classify PC survivors accordingly, and to explore associations between classes of this cluster and health-related quality of life (HRQoL). METHODS: Six hundred fifty-three stage T1-T3N0M0 survivors were identified from the Prostate Cancer Survivorship in Switzerland (PROCAS) study. Fatigue was assessed with the EORTC QLQ-FA12, depressive symptoms with the MHI-5, and pain with the EORTC QLQ-C30 questionnaire. Latent class analysis was used to derive cluster classes. Factors associated with the derived classes were determined using multinomial logistic regression analysis. RESULTS: Three classes were identified: class 1 (61.4%) - "low pain, low physical and emotional fatigue, moderate depressive symptoms"; class 2 (15.1%) - "low physical fatigue and pain, moderate emotional fatigue, high depressive symptoms"; class 3 (23.5%) - high scores for all symptoms. Survivors in classes 2 and 3 were more likely to be physically inactive, report a history of depression or some other specific comorbidity, be treated with radiation therapy, and have worse HRQoL outcomes compared to class 1. CONCLUSION: Three distinct classes of the pain, fatigue, and depression cluster were identified, which are associated with treatment, comorbidities, lifestyle factors, and HRQoL outcomes. Improving classification of PC survivors according to severity of multiple symptoms could assist in developing interventions tailored to survivors' needs.


Assuntos
Sobreviventes de Câncer , Neoplasias da Próstata , Depressão/epidemiologia , Depressão/etiologia , Fadiga/epidemiologia , Fadiga/etiologia , Humanos , Masculino , Dor/epidemiologia , Dor/etiologia , Neoplasias da Próstata/epidemiologia , Qualidade de Vida , Inquéritos e Questionários , Sobrevivência , Suíça/epidemiologia , Síndrome
5.
Neuro Oncol ; 23(10): 1765-1776, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33738488

RESUMO

BACKGROUND: Global variations in survival for brain tumors are very wide when all histological types are considered together. Appraisal of international differences should be informed by the distribution of histology, but little is known beyond Europe and North America. METHODS: The source for the analysis was the CONCORD database, a program of global surveillance of cancer survival trends, which includes the tumor records of individual patients from more than 300 population-based cancer registries. We considered all patients aged 0-99 years who were diagnosed with a primary brain tumor during 2000-2014, whether malignant or nonmalignant. We presented the histology distribution of these tumors, for patients diagnosed during 2000-2004, 2005-2009, and 2010-2014. RESULTS: Records were submitted from 60 countries on 5 continents, 67 331 for children and 671 085 for adults. After exclusion of irrelevant morphology codes, the final study population comprised 60 783 children and 602 112 adults. Only 59 of 60 countries covered in CONCORD-3 were included because none of the Mexican records were eligible. We defined 12 histology groups for children, and 11 for adults. In children (0-14 years), the proportion of low-grade astrocytomas ranged between 6% and 50%. Medulloblastoma was the most common subtype in countries where low-grade astrocytoma was less commonly reported. In adults (15-99 years), the proportion of glioblastomas varied between 9% and 69%. International comparisons were made difficult by wide differences in the proportion of tumors with unspecified histology, which accounted for up to 52% of diagnoses in children and up to 65% in adults. CONCLUSIONS: To our knowledge, this is the first account of the global histology distribution of brain tumors, in children and adults. Our findings provide insights into the practices and the quality of cancer registration worldwide.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Adulto , Neoplasias Encefálicas/epidemiologia , Criança , Bases de Dados Factuais , Europa (Continente) , Humanos , Sistema de Registros
6.
J Sports Sci ; 39(16): 1903-1909, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33787463

RESUMO

Dual process theories suggest that the decision to be physically active is influenced by reflective and automatic processes. However, associations of automatic (affective) evaluations of exercise with physical activity and underlying basic motor competencies have not yet been investigated in children and young adolescents. Ninety-one participants (52 male; age: 10-14 years) were recruited from academic high schools in Germany and Switzerland. Automatic evaluations of exercise were measured with the Single-Target Implicit Association Test (ST-IAT) and a D-score was calculated. Moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA) per day were determined via wrist-worn actigraphy over the course of seven days. Basic motor competencies were measured using the MOBAK-5 test battery. Pearson correlations showed non-significant associations of automatic evaluations of exercise with MVPA, but significant associations with VPA. Basic motor competencies were associated with automatic evaluations of exercise, and the MOBAK subscale of object movement was associated with both MVPA and VPA. Our results underscore the relevance of affective processes for physical activity behaviour. This could potentially be relevant for interventions targeting physical activity promotion. Longitudinal investigations and intervention studies are necessary to verify causal relationships and potential underlying mechanisms.


Assuntos
Exercício Físico/fisiologia , Exercício Físico/psicologia , Atividade Motora/fisiologia , Destreza Motora/fisiologia , Actigrafia , Adolescente , Criança , Estudos Transversais , Feminino , Alemanha , Humanos , Masculino , Suíça
7.
BMC Cancer ; 21(1): 229, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676446

RESUMO

BACKGROUND: A recent study found an influence of organized mammography screening programmes (MSPs) on geographical and temporal variation of mastectomy rates. We aimed to quantify the effect on the example of one of the cantonal programmes in Switzerland. METHODS: We used incidence data for the years 2010-2017 from the cancer registry of Eastern Switzerland. We included women with invasive-non-metastatic breast cancer (BC) in the screening age group 50-69-year-olds in the canton of St.Gallen. We compared mastectomy rates among cancer patients detected through the organised screening programme (MSP) vs. otherwise detected by stage. RESULTS: MSP-detected patients in St.Gallen presented with lower stages. 95% of MSP-detected had stages I-II vs 76% of Non-MSP-detected. Within all non-metastatic stage, tumour size and nodal status groups, MSP-detected patients had lower mastectomy rates, overall 10% vs 24% in 50-69-year-old non-participants. Their odds of receiving a mastectomy are about half of the Non-MSP-detected (OR = 0.48, p = 0.002). CONCLUSIONS: Our study showed that MSPs have a positive effect on lowering mastectomy rates. Screening participants are significantly less likely to receive a mastectomy compared to non-participants, which must be attributed to additional factors than just lower stages. Lower mastectomy rates lead to a higher quality of life for many patients.


Assuntos
Neoplasias da Mama/cirurgia , Detecção Precoce de Câncer/estatística & dados numéricos , Mamografia/estatística & dados numéricos , Programas de Rastreamento/organização & administração , Mastectomia/estatística & dados numéricos , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Feminino , Geografia , Humanos , Incidência , Programas de Rastreamento/estatística & dados numéricos , Mastectomia/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Programas e Projetos de Saúde , Qualidade de Vida , Sistema de Registros/estatística & dados numéricos , Suíça/epidemiologia
8.
FEBS J ; 288(13): 4098-4114, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33405388

RESUMO

Human guanylate-binding protein 1 (hGBP1) is a key player in innate immunity and fights diverse intracellular microbial pathogens. Its antimicrobial functions depend on hGBP1's GTP binding- and hydrolysis-induced abilities to form large, structured polymers and to attach to lipid membranes. Crucial for both of these biochemical features is the nucleotide-controlled release of the C terminally located farnesyl moiety. Here, we address molecular details of the hGBP1 membrane binding mechanism by employing recombinant, fluorescently labeled hGBP1, and artificial membranes. We demonstrate the importance of the GTPase activity and the resulting structural rearrangement of the hGBP1 molecule, which we term the open state. This open state is supported and stabilized by homodimer contacts involving the middle domain of the protein and is further stabilized by binding to the lipid bilayer surface. We show that on the surface of the lipid bilayer a hGBP1 monolayer is built in a pins in a pincushion-like arrangement with the farnesyl tail integrated in the membrane and the N-terminal GTPase domain facing outwards. We suggest that similar intramolecular contacts between neighboring hGBP1 molecules are responsible for both polymer formation and monolayer formation on lipid membranes. Finally, we show that tethering of large unilamellar vesicles occurs after the vesicle surface is fully covered by the monolayer. Both hGBP1 polymer formation and hGBP1-induced vesicle tethering have implications for understanding the molecular mechanism of combating bacterial pathogens. DATABASES: Structural data are available in RCSB Protein Data Bank under the accession numbers: 6K1Z, 2D4H.


Assuntos
Membrana Celular/metabolismo , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/metabolismo , Guanosina Trifosfato/metabolismo , Multimerização Proteica , Estabilidade Enzimática , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/metabolismo , Humanos , Hidrólise , Cinética , Bicamadas Lipídicas/metabolismo , Ligação Proteica , Domínios Proteicos
9.
Children (Basel) ; 8(1)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477320

RESUMO

In preschool, children build new contacts and social relationships with other people. They learn to cooperate with their peers and communicate in groups. In addition to social relationships, basic motor competencies (in German: Motorische Basiskompetenzen (MOBAK)) are also seen as a central developmental goal in early childhood and are necessary for participation in the culture of sports and movement. The aim of this paper is to describe the connection between social relationships and basic motor competencies in early childhood. In this present study, the motor competencies of N = 548 preschool children (51% girls, M = 68.0 months, SD = 6.8) were tested in the competence areas of self-movement and object movement. The children's perceived social relationships were recorded from teacher and parent perspectives. The results clearly show a connection between social relationships and motor competencies in early childhood, with a stronger connection observed in boys. This finding is relevant both from a developmental and a health-oriented perspective, as it points to a link between physical and mental health, as well as technical and interdisciplinary competencies, in early childhood.

10.
FEBS J ; 288(2): 582-599, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32352209

RESUMO

Human guanylate-binding protein 1 (hGBP-1) shows a dimer-induced acceleration of the GTPase activity yielding GDP as well as GMP. While the head-to-head dimerization of the large GTPase (LG) domain is well understood, the role of the rest of the protein, particularly of the GTPase effector domain (GED), in dimerization and GTP hydrolysis is still obscure. In this study, with truncations and point mutations on hGBP-1 and by means of biochemical and biophysical methods, we demonstrate that the intramolecular communication between the LG domain and the GED (LG:GED) is crucial for protein dimerization and dimer-stimulated GTP hydrolysis. In the course of GTP binding and γ-phosphate cleavage, conformational changes within hGBP-1 are controlled by a chain of amino acids ranging from the region near the nucleotide-binding pocket to the distant LG:GED interface and lead to the release of the GED from the LG domain. This opening of the structure allows the protein to form GED:GED contacts within the dimer, in addition to the established LG:LG interface. After releasing the cleaved γ-phosphate, the dimer either dissociates yielding GDP as the final product or it stays dimeric to further cleave the ß-phosphate yielding GMP. The second phosphate cleavage step, that is, the formation of GMP, is even more strongly coupled to structural changes and thus more sensitive to structural restraints imposed by the GED. Altogether, we depict a comprehensive mechanism of GTP hydrolysis catalyzed by hGBP-1, which provides a detailed molecular understanding of the enzymatic activity connected to large structural rearrangements of the protein. DATABASE: Structural data are available in RCSB Protein Data Bank under the accession numbers: 1F5N, 1DG3, 2B92.


Assuntos
Proteínas de Ligação ao GTP/química , Guanosina Difosfato/química , Guanosina Trifosfato/química , Domínios e Motivos de Interação entre Proteínas , Sítios de Ligação , Biocatálise , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Cinética , Modelos Moleculares , Mutação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
11.
J Phys Chem B ; 125(1): 24-35, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33382616

RESUMO

Molecular simulations of intrinsically disordered proteins (IDPs) are challenging because they require sampling a very large number of relevant conformations, corresponding to a multitude of shallow minima in a flat free energy landscape. However, in the presence of a binding partner, the free energy landscape of an IDP can be dominated by few deep minima. This characteristic imposes high demands on the accuracy of the force field used to describe the molecular interactions. Here, as a model system for an IDP that is unstructured in solution but folds upon binding to a structured interaction partner, the transactivation domain of c-Myb was studied both in the unbound (free) form and when bound to the KIX domain. Six modern biomolecular force fields were systematically tested and compared in terms of their ability to describe the structural ensemble of the IDP. The protein force field/water model combinations included in this study are AMBER ff99SB-disp with its corresponding water model that was derived from TIP4P-D, CHARMM36m with TIP3P, ff15ipq with SPC/Eb, ff99SB*-ILDNP with TIP3P and TIP4P-D, and FB15 with TIP3P-FB water. Comparing the results from REST2-enhanced sampling simulations with experimental CD spectra and secondary chemical shifts reveals that the ff99SB-disp force field can realistically capture the broad and mildly helical structural ensemble of free c-Myb. The structural ensembles yielded by CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15 are also mildly helical; however, each of these force fields can be assigned a specific subset of c-Myb residues for which the simulations could not reproduce the experimental secondary chemical shifts. In addition, microsecond-timescale MD simulations of the KIX/c-Myb complex show that most force fields used preserve a stable helix fold of c-Myb in the complex. Still, all force fields predict a KIX/c-Myb complex interface that differs slightly from the structures provided by NMR because several NOE-derived distances between KIX and c-Myb were exceeded in the simulations. Taken together, the ff99SB-disp force field in the first place but also CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15 can be suitable choices for future simulation studies of the coupled folding and binding mechanism of the KIX/c-Myb complex and potentially also other IDPs.


Assuntos
Proteínas Intrinsicamente Desordenadas , Simulação por Computador , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Água
12.
Phys Chem Chem Phys ; 22(47): 27903-27911, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33284914

RESUMO

A common feature of intrinsically disordered proteins (IDPs) is a disorder-to-order transition upon binding to other proteins, which has been tied to multiple benefits, including accelerated association rates or binding with low affinity, yet high specificity. Given the balanced equilibrium concentrations of folded and unfolded state of an IDP we asked the question if changes in the chemical environment, such as the presence of osmolytes or crowding agents, have a strong influence on the interaction of an IDP. Here, we demonstrate the impact of cosolutes on the interaction of the intrinsically disordered transcription factor c-Myb and its binding partner, the kinase-inducible interaction domain (KIX) of the CREB-binding protein. Temperature jump relaxation kinetics and microscale thermophoresis were employed in order to quantify the rate constants and the binding affinity of the c-Myb/KIX complex, respectively, in the presence of various cosolutes. We find the binding free energy of the c-Myb/KIX complex only marginally modulated by cosolutes, whereas the enthalpy and entropy of the interaction are very sensitive to the respective solvent conditions. For different cosolutes we observe substantial changes in enthalpy, both favorable and unfavorable, which are going with entropy changes largely compensating the enthalpy effects in each case. These characteristics might reflect a potential mechanism by which c-Myb offsets changes in the physico-chemical environment to maintain a roughly unaltered binding affinity.


Assuntos
Proteína de Ligação a CREB/metabolismo , Proteínas Intrinsicamente Desordenadas/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Betaína/química , Proteína de Ligação a CREB/química , Entropia , Glicina/química , Humanos , Proteínas Intrinsicamente Desordenadas/química , Cinética , Metilaminas/química , Ligação Proteica , Domínios Proteicos , Proteínas Proto-Oncogênicas c-myb/química , Temperatura , Ureia/química
13.
Artigo em Inglês | MEDLINE | ID: mdl-33375134

RESUMO

Lack of physical activity is a global public health problem causing not only morbidity and premature mortality, but it is also a major economic burden worldwide. One of the cornerstones of a physically active lifestyle is Motor Competence (MC). MC is a complex biocultural attribute and therefore, its study requires a multi-sectoral, multi-, inter- and transdisciplinary approach. MC is a growing area of research, especially in children and adolescents due to its positive association with a plethora of health and developmental outcomes. Many questions, however, remain to be answered in this field of research, with regard to: (i) Health and Developmental-related Associations of MC; (ii) Assessment of MC; (iii) Prevalence and Trends of MC; (iv) Correlates and Determinants of MC; (v) MC Interventions, and (vi) Translating MC Research into Practice and Policy. This paper presents a narrative review of the literature, summarizing current knowledge, identifying key research gaps and presenting questions for future investigation on MC in children and adolescents. This is a collaborative effort from the International Motor Competence Network (IMCNetwork) a network of academics and researchers aiming to promote international collaborative research and knowledge translation in the expansive field of MC. The knowledge and deliverables generated by addressing and answering the aforementioned research questions on MC presented in this review have the potential to shape the ways in which researchers and practitioners promote MC and physical activity in children and adolescents across the world.


Assuntos
Exercício Físico , Destreza Motora , Adolescente , Criança , Promoção da Saúde , Humanos , Estilo de Vida , Prevalência
14.
J Phys Act Health ; 17(11): 1083-1090, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839350

RESUMO

BACKGROUND: The relationship between engagement in physical activity and the development of motor competence (MC) is considered to be reciprocal and dynamic throughout childhood and adolescence. The 10-month follow-up study aimed to explore this reciprocal relationship and investigated whether the relationship is mediated by the corresponding self-perception of MC (PMC). METHODS: A total of 51 children aged between 10 and 11 years (M = 10.27 [0.45]) participated in the study (52.9% boys, 47.1% girls). As an indicator for physical activity, the average vigorous physical activity (VPA) per day was measured by ActiGraph accelerometers. Two aspects of MC and PMC were recorded: self-movement and object movement. Saturated pathway models in a cross-lagged panel design with 2 measurement points were analyzed. RESULTS: Reciprocal and direct relationships between VPA and MC object movement respectively MC self-movement were not found in longitudinal analyses with PMC as a mediator. Indirect effects of MC at t1 on VPA at t2 via PMC were identified (self-movement: ß = 0.13, 95% confidence interval, 0.04 to 0.26; object movement: ß = 0.14, 95% confidence interval, 0.01 to 0.49). CONCLUSION: The results highlight the importance of MC and PMC in promoting children's VPA. However, VPA does not drive the development of MC.

15.
Front Psychiatry ; 11: 594, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670116

RESUMO

High levels of cardiorespiratory fitness have the potential to buffer against physical and mental health impairments, which can result from exposure to occupational stress. Police officers are especially at risk of high psychosocial stress; therefore, effective intervention strategies are warranted. Given this background, the purpose of the present study was to examine whether police officers with different levels of cardiorespiratory fitness differ with regard to their (a) physiological stress reactivity during acute real-life stress situations, and (b) physiological recovery related to acute and chronic work stress. In total, 201 police officers took part in this study (M = 38.6 years, SD = 10.1, 35.8% females). Officers were contacted eight times on a smartphone during their workday, and asked to report their current level of positive and negative affect, as well as feelings of stress and anger. Physiological stress responses and recovery (heart rate variability) were assessed using Movisens EcgMove3 devices. The Åstrand bicycle ergometer test was used to assess participants' cardiorespiratory fitness. Chronic work stress was assessed using the effort-reward imbalance model and the job strain model. Multilevel modeling was used to test buffering effects of cardiorespiratory fitness on physiological stress reactivity. Linear regression was applied to test stress-buffering effects of cardiorespiratory fitness on physiological recovery. Results showed lowered physiological stress reactivity to acute work stress in officers with higher levels of cardiorespiratory fitness. However, these results were not consistent, with no effects occurring for feelings of anger, positive affect, and negative affect. Chronic work stress (effort-reward imbalance) was related to lower physiological recovery. Cardiorespiratory fitness was positively related to physiological recovery. Data did not support interactions between work stress and cardiorespiratory fitness on physiological recovery. To some extent, cardiorespiratory fitness seems to have the potential to buffer stress reactivity in police officers in acute stress situations. Therefore, we encourage promoting fitness programs which aim to enhance cardiorespiratory fitness in stressful occupations such as law enforcement. Improvements in cardiorespiratory fitness might further enhance physiological recovery from chronic work stress, which is thought to improve cardiovascular health.

16.
Cancer Med ; 9(15): 5416-5424, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32524704

RESUMO

BACKGROUND: Nerve-sparing (NS) surgery was developed to improve postoperative sexual and potentially urological outcomes after radical prostatectomy (RP). However, it is largely unknown how NSRP affects health-related quality of life (HRQoL) including urinary and sexual outcomes in prostate cancer (PC) survivors 5-10 years after diagnosis in comparison with Non-NSRP. METHODS: The study population included 382 stage pT2-T3N0M0 PC survivors 5-10 years post diagnosis, who were identified from the multiregional Prostate Cancer Survivorship in Switzerland (PROCAS) study. Briefly, in 2017/2018, PC survivors were identified via six population-based cancer registries based in both German- and French-speaking Switzerland. HRQoL and PC-specific symptom burden was assessed using the EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Differences in HRQoL outcomes between survivors treated with NSRP (uni- & bilateral) and Non-NSRP were analyzed with multivariable linear regression adjusted for age, years since diagnosis, cancer stage, comorbidities at diagnosis, and further therapies, if appropriate. Multiple imputation was performed to minimize the bias due to missing data. RESULTS: Five to ten years after diagnosis, PC survivors treated with NSRP and Non-NSRP reported similar symptom burden and comparable HRQoL function scores. The only significant differences were reported for sexual activity, whereas PC survivors who underwent NSRP reported statistically significant (P = .031) higher sexual activity than those on Non-NSRP. NSRP and Non-NSRP reported similar scores for urinary symptoms and all other HRQoL outcomes. CONCLUSIONS: Our results support nerve-sparing techniques as an option to improve postoperative sexual, but not urinary outcomes after RP in long-term PC survivors.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Idoso , Sobreviventes de Câncer , Humanos , Masculino , Neoplasias da Próstata/mortalidade , Qualidade de Vida
17.
EMBO J ; 39(13): e104926, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32510692

RESUMO

In the outer membrane of gram-negative bacteria, O-antigen segments of lipopolysaccharide (LPS) form a chemomechanical barrier, whereas lipid A moieties anchor LPS molecules. Upon infection, human guanylate binding protein-1 (hGBP1) colocalizes with intracellular gram-negative bacterial pathogens, facilitates bacterial killing, promotes activation of the lipid A sensor caspase-4, and blocks actin-driven dissemination of the enteric pathogen Shigella. The underlying molecular mechanism for hGBP1's diverse antimicrobial functions is unknown. Here, we demonstrate that hGBP1 binds directly to LPS and induces "detergent-like" LPS clustering through protein polymerization. Binding of polymerizing hGBP1 to the bacterial surface disrupts the O-antigen barrier, thereby unmasking lipid A, eliciting caspase-4 recruitment, enhancing antibacterial activity of polymyxin B, and blocking the function of the Shigella outer membrane actin motility factor IcsA. These findings characterize hGBP1 as an LPS-binding surfactant that destabilizes the rigidity of the outer membrane to exert pleiotropic effects on the functionality of gram-negative bacterial cell envelopes.


Assuntos
Proteínas de Ligação ao GTP/química , Lipídeo A/química , Antígenos O/química , Shigella/química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Lipídeo A/metabolismo , Antígenos O/metabolismo , Ligação Proteica , Shigella/metabolismo
18.
Methods Mol Biol ; 2159: 67-81, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32529364

RESUMO

The human guanylate-binding protein 1 (hGBP1) is the best characterized isoform of the seven human GBPs belonging to the superfamily of dynamin-like proteins (DLPs). As known for other DLPs, hGBP1 also exhibits antiviral and antimicrobial activity within the cell. hGBP 1, like hGBPs 2 and 5, carries a CAAX motive at the C-terminus leading to isoprenylation in the living cells. The attachment of a farnesyl anchor and its unique GTPase cycle provides hGBP1 the ability of a nucleotide- stimulated polymerization and membrane binding. In this chapter, we want to show how to prepare farnesylated hGBP1 (hGBP1fn) by bacterial synthesis and by enzymatic modification, respectively, and how to purify the non-farnesylated, as well as the farnesylated hGBP1, by chromatographic procedures. Furthermore, we want to demonstrate how to investigate the special features of polymerization by a UV-absorption-based turbidity assay and the binding to artificial membranes by means of fluorescence energy transfer.


Assuntos
Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/isolamento & purificação , Multimerização Proteica , Membrana Celular/metabolismo , Ativação Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Transferência Ressonante de Energia de Fluorescência , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Humanos , Prenilação , Ligação Proteica , Proteínas Recombinantes , Análise Espectral
19.
Artigo em Inglês | MEDLINE | ID: mdl-32422866

RESUMO

(1) Background: The association between actual and perceived motor competence (MC) is one of the underlying mechanisms that influence the practice of physical activity. This study mainly aimed to analyze the structure and correlations between actual and perceived MC in schoolchildren and to compare actual and perceived MC between girls and boys. (2) Methods: A total of 467 fifth and sixth graders (43.9% girls, M = 11.26, SD = 0.70) participated. Actual and perceived MC were assessed. To examine the proposed four factor models, structural equation models (factor analyses, latent correlations, invariance testing for gender) were conducted. Student t-test for independent samples was used to compare boys and girls. (3) Results: Proposed models achieved acceptable fit values with moderate correlation between the factors according to the type of MC in actual and perceived MC. Invariant factor structure in boys and girls was revealed. Boys performed and perceived themselves higher in object control than girls; whereas girls showed higher actual and perceived self-movement than boys. (4) Conclusions: The association between actual and perceived MC exists both globally and separately by gender, despite the differences between boys and girls. It is important to consider the role of gender and type of MC in the development of motor competencies, as well as in the strengthening of the children's sense of competence.


Assuntos
Exercício Físico , Destreza Motora , Criança , Análise Fatorial , Feminino , Humanos , Masculino , Movimento , Autoimagem
20.
BMC Cancer ; 20(1): 87, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013907

RESUMO

Following publication of the original article [1], an error was reported in the author group. The correct author group should read as follows.

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