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BACKGROUND: Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. METHODS: In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Düsseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. FINDINGS: The study included 7792 (58·7%) men and 5492 (41·3%) women. 10 906 (82·1%) patients were White, and race was not reported for 2378 (17·9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0·0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0·0062 in the IWG-PM cohort; IDH2 p<0·0001 in EuroMDS vs p=0·042 in IWG-PM; TET2 p=0·031 vs p=0·035; U2AF1 p=0·033 vs p<0·0001) and mutations in two genes were enriched in women (DNMT3A p<0·000

BACKGROUND: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. METHODS: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). RESULTS: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. CONCLUSION: A large change in solar insolation, both between winter and summer and between the minimum an

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Haptic technology is used in the game and media industry to augment a user's presence through touch related sensations. Affective haptic studies haptic feedbacks to elicit human’s emotion but, so far, no shared framework exists that states how to achieve this. By exploiting the correlation between the physiological changes in the body induced by the autonomic nervous system is a promising method but requires expensive and obtrusive devices. Striving for devices that are relatively inexpensive and easy to replicate we focuses our study on the neck. We argue that the neck has the peculiarity of being completely exposed and intimate hence the haptic feedback provided by vibroelectric motors are sufficient to trigger an emotional response in a user. To test our assumption we created a haptic device and a haptic dataset. We proved that our setup was indeed sufficient to elicit different emotional states in a user as meant by the circumplex model of emotion. We found that the intensity of vibration and the sequence in which the actuators are driven affect the arousal but not the valence. Instead the vibration affected both the \textit{arousal} and the valence. We discussed these limitation and offered a set of guidelines on haptic stimuli meant to ease the design of affective feedback for devices that employ an array of actuators.

Haptic technology is used in the game and media industry to augment a user's presence through touch related sensations. Affective haptic studies haptic feedbacks to elicit human’s emotion but, so far, no shared framework exists that states how to achieve this. By exploiting the correlation between the physiological changes in the body induced by the autonomic nervous system is a promising method but requires expensive and obtrusive devices. Striving for devices that are relatively inexpensive and easy to replicate we focuses our study on the neck. We argue that the neck has the peculiarity of being completely exposed and intimate hence the haptic feedback provided by vibroelectric motors are sufficient to trigger an emotional response in a user. To test our assumption we created a haptic device and a haptic dataset. We proved that our setup was indeed sufficient to elicit different emotional states in a user as meant by the circumplex model of emotion. We found that the intensity of vibration and the sequence in which the actuators are driven affect the arousal but not the valence. Instead the vibration affected both the \textit{arousal} and the valence. We discussed these limitation and offered a set of guidelines on haptic stimuli meant to ease the design of affective feedback for devices that employ an array of actuators.

Objective: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. Method: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. Results: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). Conclusion: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Background and Aims The recurrence of wildfires is predicted to increase due to global climate change, resulting in severe impacts on biodiversity and ecosystem functioning. Recurrent fires can drive plant adaptation and reduce genetic diversity; however, the underlying population genetic processes have not been studied in detail. In this study, the neutral and adaptive evolutionary effects of contrasting fire regimes were examined in the keystone tree species Pinus halepensis Mill. (Aleppo pine), a fire-adapted conifer. The genetic diversity, demographic history and spatial genetic structure were assessed at local (within-population) and regional scales for populations exposed to different crown fire frequencies. Methods Eight natural P. halepensis stands were sampled in the east of the Iberian Peninsula, five of them in a region exposed to frequent crown fires (HiFi) and three of them in an adjacent region with a low frequency of crown fires (LoFi). Samples were genotyped at nine neutral simple sequence repeats (SSRs) and at 251 single nucleotide polymorphisms (SNPs) from coding regions, some of them potentially important for fire adaptation. Key Results Fire regime had no effects on genetic diversity or demographic history. Three high-differentiation outlier SNPs were identified between HiFi and LoFi stands, suggesting fire-related selection at the regional scale. At the local scale, fine-scale spatial genetic structure (SGS) was overall weak as expected for a wind-pollinated and wind-dispersed tree species. HiFi stands displayed a stronger SGS than LoFi stands at SNPs, which probably reflected the simultaneous post-fire recruitment of co-dispersed related seeds. SNPs with exceptionally strong SGS, a proxy for microenvironmental selection, were only reliably identified under the HiFi regime. Conclusions An increasing fire frequency as predicted due to global change can promote increased SGS with stronger family structures and alter natural selection in P. halepen

Objective: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. Method: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. Results: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). Conclusion: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Haptic technology is used in the game and media industry to augment a user's presence through touch related sensations. Affective haptic studies haptic feedbacks to elicit human’s emotion but, so far, no shared framework exists that states how to achieve this. By exploiting the correlation between the physiological changes in the body induced by the autonomic nervous system is a promising method but requires expensive and obtrusive devices. Striving for devices that are relatively inexpensive and easy to replicate we focuses our study on the neck. We argue that the neck has the peculiarity of being completely exposed and intimate hence the haptic feedback provided by vibroelectric motors are sufficient to trigger an emotional response in a user. To test our assumption we created a haptic device and a haptic dataset. We proved that our setup was indeed sufficient to elicit different emotional states in a user as meant by the circumplex model of emotion. We found that the intensity of vibration and the sequence in which the actuators are driven affect the arousal but not the valence. Instead the vibration affected both the \textit{arousal} and the valence. We discussed these limitation and offered a set of guidelines on haptic stimuli meant to ease the design of affective feedback for devices that employ an array of actuators.

Metabolic models are the most widespread type of models in systems biology and are currently used in several applications, including metabolic engineering and investigations of pathological states in which metabolic disorders play a relevant role. Once a model has been defined and corroborated, sensitivity analysis techniques can be used to study the model behavior in relation to perturbations of the model parameters. Here, we describe how it is possible to combine regionalized sensitivity analysis and response surface methodology to screen and quantitatively characterize the relation between metabolic phenotypes and biochemical reactions rates. By means of this approach, we identi ̄ed the most important reactions for the citric acid e®lux from mitochondria, one of the key metabolic traits of cancer cells.

CaSR gene is a candidate for calcium nephrolithiasis. Single-nucleotide polymorphisms (SNPs) encompassing its regulatory region were associated with calcium nephrolithiasis.

Membrane Computing is a branch of computer science that was born after the introduction of Membrane Systems (or P systems) by a seminal paper by Gh. Paun. Membrane systems are computing devices inspired by the structure and functioning of living cells as well as from the way the cells are organized in tissues and higher order structures. The aim of membrane computing is to abstract computing ideas and models imitating these products of natural evolution. A typical membrane system is composed by a number of regions surrounded by membranes; regions contains multisets of objects (molecules) and rules (cellular processes) that specify how objects must be re-written and moved among regions. In spite of the fact that the initial primary goal of membrane systems concerned computability theory, the properties of membrane systems such as compartmentalisation, modularity, scalability/extensibility, understandability, programmability and discreteness promoted their use for an important task of the current scientific research: the modelling of biological systems (the topic “systems biology, including modelling of complex systems” has now appeared explicitly in the Seventh Framework Programme of the European Community for research, technological development and demonstration activities). To accomplish this task some features of membrane systems (such as nondeterminism and maximal parallelism) have to be mitigated while other properties have to be considered (e.g. description of the time evolution of the modelled system) to ensure the accurateness of the results gained with the models. Many approaches for the modelling and simulation of biological systems exist and can be classified according to features such as continuous/discrete, deterministic/stochastic, macroscopic/mesoscopic/microscopic, predictive/explorative, quantitative/qualitative and so on. Recently, stochastic methods have gained more attention since many biological processes, such as gene transcription and translati

Systems biology is a multidisciplinary research area aimed at investigating biological systems by developing mathematical models that approach the study and the analysis of both the structure and behaviour of a biological phenomenon from a system perspective. The dynamics described by such mathematical models can be deeply affected by many parameters, and an extensive exploration of the parameters space in order to find crucial factors is most of the time prohibitive since it requires the execution of a huge number of computer simulations. Sensitivity analysis techniques can help in understanding how much the uncertainty in the model outcome is determined by the uncertainties, or by the variations, of the model input factors (components, reactions and respective parameters). In this work we exploit the European Grid Infrastructure to manage the calculations required to perform the SA on a stochastic model of bacterial chemotaxis, using an improved version of the first order screening method of Morris. According to the results achieved in our exploratory analysis, the European Grid Infrastructure is a useful solution for distributing the stochastic simulations required to carry out the SA of a stochastic model. Considering that the more intensive the computation the more scalable the infrastructure, grid computing can be a suitable technology for large scale biological models analysis

BACKGROUND: Calcium-sensing receptor gene (CaSR) is a candidate to explain susceptibility to calcium kidney stones. Thus, we studied CaSR gene single-nucleotide polymorphisms (SNPs) and haplotypes associated with stones. METHODS: Four hundred and sixty-three calcium stone formers and 213 healthy controls were genotyped for 21 SNPs mapping the whole CaSR gene. CaSR gene structure was studied. SNPs and haplotypes were analysed for association with stones. RESULTS: Three haplotype blocks were identified in the CaSR gene. The first block was characterized by six SNPs and included gene promoters. The rs7652589 and rs1501899 SNPs and the CATTCA haplotype of the first block were significantly more frequent in normocitraturic calcium kidney stone formers than controls. The risk of stones was increased in normocitraturic homozygous patients and heterozygotes for the CATTCA haplotype. The rate of stones was higher in stone formers with the CATTCA haplotype. In a three-generation family, calcium stones were associated with the CATTCA haplotype. The bioinformatic analysis identified a new site for the octamer-binding transcription factor 1 in the presence of the variant alleles at the rs7652589 and rs1501899 SNPs. This transcription factor may downregulate the transcription of vitamin D-dependent genes and the CaSR expression. Conclusion. SNPs and CATTCA haplotype of the CaSR gene first block is associated with kidney stones in normocitraturic patients.

Stochastic modelling and simulations play a major role in Systems Biology because, at molecular level, biological systems exhibit noise coming both from within the cell (intrinsic) and from the environment (extrinsic). Stochastic modelling takes into account the effects of noise over the system dynamics, that can strongly affect the behavior of the system in conditions of relatively low amounts of molecular species. Stochastic simulations provide an effective way to describe the system dynamics, and can be applied on systems where specified chemical species are processed by a set of biochemical reactions, each one characterized by a stochastic constant. In the context of stochastic modelling, Parameter Sweep Applications (PSAs) can be a useful way to explore the huge spaces generated by the combinations of variables and parameters values in order to test their effects on systems dynamics. PSAs are common in the scientific community and are structured as sets of instances, each one characterized by a distinct parametrisation. A PSA that aims to sample such large spaces must involve a large number of instances and hence the problem becomes very time consuming. However, the independence of each instance of a particular PSA makes the distributed computing paradigm a very useful solution for large scale PSAs. In this work we present a grid based version of a multi-volume stochastic simulator, tau-DPP, implemented on the EGEE project platform. The aim of the proposed work is to exploit this platform for testing the reliability of PSAs over the grid, pointing out critical factors, bottlenecks and scalability by providing data about our experience in this kind of biological modelling and simulations. As a case study, we present a number of PSAs for a stochastic model of bacterial chemotaxis composed of 59 reactions and 31 chemical species. © 2009 IEEE.