A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Skeletal muscle contraction. The thorough definition of the contractile event requires both load acceleration and load mass to be known

<p>Abstract</p> <p>Background</p> <p>The scope of this work is to show that the correct and complete definition of the system of muscle contraction requires the knowledge of both the mass and the acceleration of the load.</p> <p>Results</p> <p>The aim is achieved by making use of a model of muscle contraction that operates into two phases. The first phase considers the effects of the power stroke in the absence of any hindrance. In the second phase viscous hindrance is introduced to match the experimental speed and yield of the contraction. It is shown that, at constant force of the load, changing load acceleration changes the time course of the pre-steady state of myofibril contraction. The decrease of the acceleration of the load from 9.8 m.s^-2to 1 m.s^-2increases the time length of the pre-steady state of the contraction from a few microseconds to many hundreds of microseconds and decreases the stiffness of the active fibre.</p> <p>Conclusions</p> <p>We urge that in the study of muscle contraction both the mass and the acceleration of the load are specified.</p

DEDICATE: proposal for a conceptual framework to develop dementia-friendly Integrated eCare support

Background: Evidence shows that the implementation of Information and Communication Technologies (ICT) enabled services supporting integrated dementia care represents an opportunity that faces multi-pronged challenges. First, the provision of dementia support is fragmented and often inappropriate. Second, available ICT solutions in this field do not address the full spectrum of support needs arising across an individual’s whole dementia journey. Current solutions fail to harness the potential of available validated e-health services, such as telehealth and telecare, for the purposes of dementia care. Third, there is a lack of understanding of how viable business models in this field can operate. The field comprises both professional and non-professional players that interact and have roles to play in ensuring that useful technologies are developed, implemented and used. Methods: Starting from a literature review, including relevant pilot projects for ICT-based dementia care, we define the major requirements of a system able to overcome the limitations evidenced in the literature, and how this system should be integrated in the socio-technical ecosystem characterizing this disease. From here, we define the DEDICATE architecture of such a system, and the conceptual framework mapping the architecture over the requirements. Results: We identified three macro-requirements, namely the need to overcome: deficient technology innovation, deficient service process innovation, and deficient business models innovation. The proposed architecture is a three level architecture in which the center (data layer) includes patients’ and informal caregivers’ preferences, memories, and other personal data relevant to sustain the dementia journey, is connected through a middleware (service layer), which guarantees core IT services and integration, to dedicated applications (application layer) to sustain dementia care (Formal Support Services, FSS), and to existing formal care infrastructures, in order to guarantee care coordination (Care Coordination Services, CCS). Conclusions: The proposed DEDICATE architecture and framework envisages a feasible means to overcome the present barriers by: (1) developing and integrating technologies that can follow the patient and the caregivers throughout the development of the condition, since the early stages in which the patient is able to build up preferences and memories will be used in the later stages to maximise personalization and thereby improve efficacy and usability (technology innovation); (2) guaranteeing the care coordination between formal and informal caregivers, and giving an active yet supported role to the latter (service innovation); and (3) integrating existing infrastructures and care models to decrease the cost of the overall care pathway, by improving system interoperability (business model innovation)

Postcopulatory Sexual Selection Is Associated with Reduced Variation in Sperm Morphology

The evolutionary role of postcopulatory sexual selection in shaping male reproductive traits, including sperm morphology, is well documented in several taxa. However, previous studies have focused almost exclusively on the influence of sperm competition on variation among species. In this study we tested the hypothesis that intraspecific variation in sperm morphology is driven by the level of postcopulatory sexual selection in passerine birds.Using two proxy measures of sperm competition level, (i) relative testes size and (ii) extrapair paternity level, we found strong evidence that intermale variation in sperm morphology is negatively associated with the degree of postcopulatory sexual selection, independently of phylogeny.Our results show that the role of postcopulatory sexual selection in the evolution of sperm morphology extends to an intraspecific level, reducing the variation towards what might be a species-specific 'optimum' sperm phenotype. This finding suggests that while postcopulatory selection is generally directional (e.g., favouring longer sperm) across avian species, it also acts as a stabilising evolutionary force within species under intense selection, resulting in reduced variation in sperm morphology traits. We discuss some potential evolutionary mechanisms for this pattern

Sequential and Coordinated Actions of c-Myc and N-Myc Control Appendicular Skeletal Development

BACKGROUND: During limb development, chondrocytes and osteoblasts emerge from condensations of limb bud mesenchyme. These cells then proliferate and differentiate in separate but adjacent compartments and function cooperatively to promote bone growth through the process of endochondral ossification. While many aspects of limb skeletal formation are understood, little is known about the mechanisms that link the development of undifferentiated limb bud mesenchyme with formation of the precartilaginous condensation and subsequent proliferative expansion of chondrocyte and osteoblast lineages. The aim of this study was to gain insight into these processes by examining the roles of c-Myc and N-Myc in morphogenesis of the limb skeleton. METHODOLOGY/PRINCIPAL FINDINGS: To investigate c-Myc function in skeletal development, we characterized mice in which floxed c-Myc alleles were deleted in undifferentiated limb bud mesenchyme with Prx1-Cre, in chondro-osteoprogenitors with Sox9-Cre and in osteoblasts with Osx1-Cre. We show that c-Myc promotes the proliferative expansion of both chondrocytes and osteoblasts and as a consequence controls the process of endochondral growth and ossification and determines bone size. The control of proliferation by c-Myc was related to its effects on global gene transcription, as phosphorylation of the C-Terminal Domain (pCTD) of RNA Polymerase II, a marker of general transcription initiation, was tightly coupled to cell proliferation of growth plate chondrocytes where c-Myc is expressed and severely downregulated in the absence of c-Myc. Finally, we show that combined deletion of N-Myc and c-Myc in early limb bud mesenchyme gives rise to a severely hypoplastic limb skeleton that exhibits features characteristic of individual c-Myc and N-Myc mutants. CONCLUSIONS/SIGNIFICANCE: Our results show that N-Myc and c-Myc act sequentially during limb development to coordinate the expansion of key progenitor populations responsible for forming the limb skeleton

Fitness of Escherichia coli during Urinary Tract Infection Requires Gluconeogenesis and the TCA Cycle

Microbial pathogenesis studies traditionally encompass dissection of virulence properties such as the bacterium's ability to elaborate toxins, adhere to and invade host cells, cause tissue damage, or otherwise disrupt normal host immune and cellular functions. In contrast, bacterial metabolism during infection has only been recently appreciated to contribute to persistence as much as their virulence properties. In this study, we used comparative proteomics to investigate the expression of uropathogenic Escherichia coli (UPEC) cytoplasmic proteins during growth in the urinary tract environment and systematic disruption of central metabolic pathways to better understand bacterial metabolism during infection. Using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and tandem mass spectrometry, it was found that UPEC differentially expresses 84 cytoplasmic proteins between growth in LB medium and growth in human urine (P<0.005). Proteins induced during growth in urine included those involved in the import of short peptides and enzymes required for the transport and catabolism of sialic acid, gluconate, and the pentose sugars xylose and arabinose. Proteins required for the biosynthesis of arginine and serine along with the enzyme agmatinase that is used to produce the polyamine putrescine were also up-regulated in urine. To complement these data, we constructed mutants in these genes and created mutants defective in each central metabolic pathway and tested the relative fitness of these UPEC mutants in vivo in an infection model. Import of peptides, gluconeogenesis, and the tricarboxylic acid cycle are required for E. coli fitness during urinary tract infection while glycolysis, both the non-oxidative and oxidative branches of the pentose phosphate pathway, and the Entner-Doudoroff pathway were dispensable in vivo. These findings suggest that peptides and amino acids are the primary carbon source for E. coli during infection of the urinary tract. Because anaplerosis, or using central pathways to replenish metabolic intermediates, is required for UPEC fitness in vivo, we propose that central metabolic pathways of bacteria could be considered critical components of virulence for pathogenic microbes

Divorce, divorce rates, and professional care seeking for mental health problems in Europe: a cross-sectional population-based study

Background: Little is known about differences in professional care seeking based on marital status. The few existing studies show more professional care seeking among the divorced or separated compared to the married or cohabiting. The aim of this study is to determine whether, in a sample of the European general population, the divorced or separated seek more professional mental health care than the married or cohabiting, regardless of self-reported mental health problems. Furthermore, we examine whether two country-level features-the supply of mental health professionals and the country-level divorce rates-contribute to marital status differences in professional care-seeking behavior. Methods: We use data from the Eurobarometer 248 on mental well-being that was collected via telephone interviews. The unweighted sample includes 27,146 respondents (11,728 men and 15,418 women). Poisson hierarchical regression models were estimated to examine whether the divorced or separated have higher professional health care use for emotional or psychological problems, after controlling for mental and somatic health, sociodemographic characteristics, support from family and friends, and degree of urbanization. We also considered country-level divorce rates and indicators of the supply of mental health professionals, and applied design and population weights. Results: We find that professional care seeking is strongly need based. Moreover, the divorced or separated consult health professionals for mental health problems more often than people who are married or who cohabit do. In addition, we find that the gap between the divorced or separated and the married or cohabiting is highest in countries with low divorce rates. Conclusions: The higher rates of professional care seeking for mental health problems among the divorced or separated only partially correlates with their more severe mental health problems. In countries where marital dissolution is more common, the marital status gap in professional care seeking is narrower, partially because professional care seeking is more common among the married or cohabiting

Student public commitment in a school-based diabetes prevention project: impact on physical health and health behavior

<p>Abstract</p> <p>Background</p> <p>As concern about youth obesity continues to mount, there is increasing consideration of widespread policy changes to support improved nutritional and enhanced physical activity offerings in schools. A critical element in the success of such programs may be to involve students as spokespeople for the program. Making such a public commitment to healthy lifestyle program targets (improved nutrition and enhanced physical activity) may potentiate healthy behavior changes among such students and provide a model for their peers. This paper examines whether student's "public commitment"--voluntary participation as a peer communicator or in student-generated media opportunities--in a school-based intervention to prevent diabetes and reduce obesity predicted improved study outcomes including reduced obesity and improved health behaviors.</p> <p>Methods</p> <p>Secondary analysis of data from a 3-year randomized controlled trial conducted in 42 middle schools examining the impact of a multi-component school-based program on body mass index (BMI) and student health behaviors. A total of 4603 students were assessed at the beginning of sixth grade and the end of eighth grade. Process evaluation data were collected throughout the course of the intervention. All analyses were adjusted for students' baseline values. For this paper, the students in the schools randomized to receive the intervention were further divided into two groups: those who participated in public commitment activities and those who did not. Students from comparable schools randomized to the assessment condition constituted the control group.</p> <p>Results</p> <p>We found a lower percentage of obesity (greater than or equal to the 95^thpercentile for BMI) at the end of the study among the group participating in public commitment activities compared to the control group (21.5% vs. 26.6%, p = 0.02). The difference in obesity rates at the end of the study was even greater among the subgroup of students who were overweight or obese at baseline; 44.6% for the "public commitment" group, versus 53.2% for the control group (p = 0.01). There was no difference in obesity rates between the group not participating in public commitment activities and the control group (26.4% vs. 26.6%).</p> <p>Conclusions</p> <p>Participating in public commitment activities during the HEALTHY study may have potentiated the changes promoted by the behavioral, nutrition, and physical activity intervention components.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00458029">NCT00458029</a></p

Lithium and GSK3-β promoter gene variants influence white matter microstructure in bipolar disorder

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections