Functional dynamics of PDZ binding domains: a normal-mode analysis.

Postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domains are relatively small (80-120 residues) protein binding modules central in the organization of receptor clusters and in the association of cellular proteins. Their main function is to bind C-terminals of selected proteins that are recognized through specific amino acids in their carboxyl end. Binding is associated with a deformation of the PDZ native structure and is responsible for dynamical changes in regions not in direct contact with the target. We investigate how this deformation is related to the harmonic dynamics of the PDZ structure and show that one low-frequency collective normal mode, characterized by the concerted movements of different secondary structures, is involved in the binding process. Our results suggest that even minimal structural changes are responsible for communication between distant regions of the protein, in agreement with recent NMR experiments. Thus, PDZ domains are a very clear example of how collective normal modes are able to characterize the relation between function and dynamics of proteins, and to provide indications on the precursors of binding/unbinding events.

Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry.

To measure the average length of telomere repeats at chromosome ends in individual cells we developed a flow cytometry method using fluorescence in situ hybridization (flow FISH) with labeled peptide nucleic acid (PNA) probes. Results of flow FISH measurements correlated with results of conventional telomere length measurements by Southern blot analysis (R = 0.9). Consistent differences in telomere length in CD8+ T-cell subsets were identified. Naive and memory CD4+ T lymphocytes in normal adults differed by around 2.5 kb in telomere length, in agreement with known replicative shortening of telomeres in lymphocytes in vivo. T-cell clones grown in vitro showed stabilization of telomere length after an initial decline and rare clones capable of growing beyond 100 population doublings showed variable telomere length. These results show that flow FISH can be used to measure specific nucleotide repeat sequences in single cells and indicate that the very large replicative potential of lymphocytes is only indirectly related to telomere length.

Performance of blood pressure-to-height ratio at a single screening visit for the identification of hypertension in children.

BACKGROUND: The diagnosis of hypertension in children is difficult because of the multiple sex-, age-, and height-specific thresholds to define elevated blood pressure (BP). Blood pressure-to-height ratio (BPHR) has been proposed to facilitate the identification of elevated BP in children. OBJECTIVE: We assessed the performance of BPHR at a single screening visit to identify children with hypertension that is sustained elevated BP. METHOD: In a school-based study conducted in Switzerland, BP was measured at up to three visits in 5207 children. Children had hypertension if BP was elevated at the three visits. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the identification of hypertension were assessed for different thresholds of BPHR. The ability of BPHR at a single screening visit to discriminate children with and without hypertension was evaluated with receiver operating characteristic (ROC) curve analyses. RESULTS: The prevalence of systolic/diastolic hypertension was 2.2%. Systolic BPHR had a better performance to identify hypertension compared with diastolic BPHR (area under the ROC curve: 0.95 vs. 0.84). The highest performance was obtained with a systolic BPHR threshold set at 0.80 mmHg/cm (sensitivity: 98%; specificity: 85%; PPV: 12%; and NPV: 100%) and a diastolic BPHR threshold set at 0.45 mmHg/cm (sensitivity: 79%; specificity: 70%; PPV: 5%; and NPV: 99%). The PPV was higher among tall or overweight children. CONCLUSION: BPHR at a single screening visit had a high performance to identify hypertension in children, although the low prevalence of hypertension led to a low PPV.

Suitability of GRIND-based principal properties for the description of molecular similarity and ligand-based virtual screening

The information provided by the alignment-independent GRid Independent Descriptors (GRIND) can be condensed by the application of principal component analysis, obtaining a small number of principal properties (GRIND-PP), which is more suitable for describing molecular similarity. The objective of the present study is to optimize diverse parameters involved in the obtention of the GRIND-PP and validate their suitability for applications, requiring a biologically relevant description of the molecular similarity. With this aim, GRIND-PP computed with a collection of diverse settings were used to carry out ligand-based virtual screening (LBVS) on standard conditions. The quality of the results obtained was remarkable and comparable with other LBVS methods, and their detailed statistical analysis allowed to identify the method settings more determinant for the quality of the results and their optimum. Remarkably, some of these optimum settings differ significantly from those used in previously published applications, revealing their unexplored potential. Their applicability in large compound database was also explored by comparing the equivalence of the results obtained using either computed or projected principal properties. In general, the results of the study confirm the suitability of the GRIND-PP for practical applications and provide useful hints about how they should be computed for obtaining optimum results.

The role of computational fluid dynamics in the management of unruptured intracranial aneurysms: a clinicians' view

Objective: The importance of hemodynamics in the etiopathogenesis of intracranial aneurysms (IAs) is widely accepted.Computational fluid dynamics (CFD) is being used increasingly for hemodynamic predictions. However, alogn with thecontinuing development and validation of these tools, it is imperative to collect the opinion of the clinicians. Methods: A workshopon CFD was conducted during the European Society of Minimally Invasive Neurological Therapy (ESMINT) Teaching Course,Lisbon, Portugal. 36 delegates, mostly clinicians, performed supervised CFD analysis for an IA, using the @neuFuse softwaredeveloped within the European project @neurIST. Feedback on the workshop was collected and analyzed. The performancewas assessed on a scale of 1 to 4 and, compared with experts’ performance. Results: Current dilemmas in the management ofunruptured IAs remained the most important motivating factor to attend the workshop and majority of participants showedinterest in participating in a multicentric trial. The participants achieved an average score of 2.52 (range 0–4) which was 63% (range 0–100%) of an expert user. Conclusions: Although participants showed a manifest interest in CFD, there was a clear lack ofawareness concerning the role of hemodynamics in the etiopathogenesis of IAs and the use of CFD in this context. More effortstherefore are required to enhance understanding of the clinicians in the subject.

Leveraging explicitly disclosed location information to understand tourist dynamics: a case study

In recent years, the large deployment of mobile devices has led to a massiveincrease in the volume of records of where people have been and when they were there.The analysis of these spatio-temporal data can supply high-level human behaviorinformation valuable to urban planners, local authorities, and designer of location-basedservices. In this paper, we describe our approach to collect and analyze the history ofphysical presence of tourists from the digital footprints they publicly disclose on the web.Our work takes place in the Province of Florence in Italy, where the insights on thevisitors’ flows and on the nationalities of the tourists who do not sleep in town has beenlimited to information from survey-based hotel and museums frequentation. In fact, mostlocal authorities in the world must face this dearth of data on tourist dynamics. In thiscase study, we used a corpus of geographically referenced photos taken in the provinceby 4280 photographers over a period of 2 years. Based on the disclosure of the locationof the photos, we design geovisualizations to reveal the tourist concentration and spatiotemporalflows. Our initial results provide insights on the density of tourists, the points ofinterests they visit as well as the most common trajectories they follow.

Bilinear models for spatio-temporal point distribution analysis: application to extrapolation of left ventricular, biventricular and whole heart cardiac dynamics

In this work we describe the usage of bilinear statistical models as a means of factoring the shape variability into two components attributed to inter-subject variation and to the intrinsic dynamics of the human heart. We show that it is feasible to reconstruct the shape of the heart at discrete points in the cardiac cycle. Provided we are given a small number of shape instances representing the same heart atdifferent points in the same cycle, we can use the bilinearmodel to establish this. Using a temporal and a spatial alignment step in the preprocessing of the shapes, around half of the reconstruction errors were on the order of the axial image resolution of 2 mm, and over 90% was within 3.5 mm. From this, weconclude that the dynamics were indeed separated from theinter-subject variability in our dataset.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

Dynamics of diversity within the Mossos d’Esquadra

This chapter offers a case-study of diversity and diversity policies withinthe Mossos d’Esquadra, the police force of the Catalan autonomous communityin Spain. The case is described in a comprehensive way (includingpolicies in all relevant policy areas: recruitment, retention, and promotion)and at the same time analyzed with a new analytical framework (includingthe definition of diversity, the motivation for diversity within the organisation,and the facilitation of diversity within the organisation with policies).The goal of the chapter is twofold. First, offer a deeper understanding ofthe dynamics of diversity within this police force. Second, demonstrate theacademic potential of this new analytical framework.

Cost-effectiveness of opportunistic versus organised mammography screening in Switzerland

BACKGROUND: Various centralised mammography screening programmes have shown to reduce breast cancer mortality at reasonable costs. However, mammography screening is not necessarily cost-effective in every situation. Opportunistic screening, the predominant screening modality in several European countries, may under certain circumstances be a cost-effective alternative. In this study, we compared the cost-effectiveness of both screening modalities in Switzerland. METHODS: Using micro-simulation modelling, we predicted the effects and costs of biennial mammography screening for 50-69 years old women between 1999 and 2020, in the Swiss female population aged 30-70 in 1999. A sensitivity analysis on the test sensitivity of opportunistic screening was performed. RESULTS: Organised mammography screening with an 80% participation rate yielded a breast cancer mortality reduction of 13%. Twenty years after the start of screening, the predicted annual breast cancer mortality was 25% lower than in a situation without screening. The 3% discounted cost-effectiveness ratio of organised mammography screening was euro11,512 per life year gained. Opportunistic screening with a similar participation rate was comparably effective, but at twice the costs: euro22,671-24,707 per life year gained. This was mainly related to the high costs of opportunistic mammography and frequent use of imaging diagnostics in combination with an opportunistic mammogram. CONCLUSION: Although data on the performance of opportunistic screening are limited, both opportunistic and organised mammography screening seem effective in reducing breast cancer mortality in Switzerland. However, for opportunistic screening to become equally cost-effective as organised screening, costs and use of additional diagnostics should be reduced.

The dynamics of the Swiss electricity market : three essays

Executive Summary Electricity is crucial for modern societies, thus it is important to understand the behaviour of electricity markets in order to be prepared to face the consequences of policy changes. The Swiss electricity market is now in a transition stage from a public monopoly to a liberalised market and it is undergoing an "emergent" liberalisation - i.e. liberalisation taking place without proper regulation. The withdrawal of nuclear capacity is also being debated. These two possible changes directly affect the mechanisms for capacity expansion. Thus, in this thesis we concentrate on understanding the dynamics of capacity expansion in the Swiss electricity market. A conceptual model to help understand the dynamics of capacity expansion in the Swiss electricity market is developed an explained in the first essay. We identify a potential risk of imports dependence. In the second essay a System Dynamics model, based on the conceptual model, is developed to evaluate the consequences of three scenarios: a nuclear phase-out, the implementation of a policy for avoiding imports dependence, and the combination of both. We conclude that the Swiss market is not well prepared to face unexpected changes of supply and demand, and we identify a risk of imports dependence, mainly in the case of a nuclear phase-out. The third essay focus on the opportunity cost of hydro-storage power generation, one of the main generation sources in Switzerland. We use and extended version of our model to test different policies for assigning an opportunity cost to hydro-storage power generation. We conclude that the preferred policies are different for different market participants and depend on market structure.

Late bloomer or language impaired? Screening the speech of a Spanish-English bilingual toddler for early signs of language impairment

This case study presents corpus data gathered from a Spanish-English bilingual child with expressive language delay. Longitudinal data on the child’s linguistic development was collected from the onset of productive speech at age 1;1 until age 4 over the course of 28 video-taped sessions with the child’s principal caregivers. A literature review focused on the relationship between language delay and persisting disorders—including a discussion of the frequent difficulty in distinguishing between the two at early stages of bilingual development—is followed by an analysis of the child’s productive development in 2 distinct phases. An attempt is made to assess the child’s speech at age 4 for preliminary signs of SLI and to consider techniques for identifying ‘at risk’ bilingual children (that is, those with productive language delay, poor oral fluency, and family history of language problems) based on samples of recorded and transcribed speech.

MRSA screening by the Xpert MRSA PCR assay: pooling samples of the nose, throat, and groin increases the sensitivity of detection without increasing the laboratory costs.

The performance of the Xpert MRSA polymerase chain reaction (PCR) assay on pooled nose, groin, and throat swabs (three nylon flocked eSwabs into one tube) was compared to culture by analyzing 5,546 samples. The sensitivity [0.78, 95 % confidence interval (CI) 0.73-0.82] and specificity (0.99, 95 % CI 0.98-0.99) were similar to the results from published studies on separated nose or other specimens. Thus, the performance of the Xpert MRSA assay was not affected by pooling the three specimens into one assay, allowing a higher detection rate without increasing laboratory costs, as compared to nose samples alone.