Analytical modeling of HSUPA-enabled UMTS networks for capacity planning

In recent years, mobile communication networks have experienced significant evolution. The 3G mobile communication system, UMTS, employs WCDMA as the air interface standard, which leads to quite different mobile network planning and dimensioning processes compared with 2G systems. The UMTS system capacity is limited by the received interference at NodeBs due to the unique features of WCDMA, which is denoted as `soft capacity'. Consequently, the key challenge in UMTS radio network planning has been shifted from channel allocation in the channelized 2G systems to blocking and outage probabilities computation under the `cell breathing' effects which are due to the relationship between network coverage and capacity. The interference characterization, especially for the other-cell interference, is one of the most important components in 3G mobile networks planning. This monograph firstly investigates the system behavior in the operation of UMTS uplink, and develops the analytic techniques to model interference and system load as fully-characterized random variables, which can be directly applicable to the performance modeling of such networks. When the analysis progresses from single-cell scenario to multi-cell scenario, as the target SIR oriented power control mechanism is employed for maximum capacity, more sophisticated system operation, `feedback behavior', has emerged, as the interference levels at different cells depend on each other. Such behaviors are also captured into the constructed interference model by iterative and approximation approaches. The models are then extended to cater for the features of the newly introduced HSUPA, which provides enhanced dedicated channels for the packet switched data services such that much higher bandwidth can be achieved for best-effort elastic traffic, which allows network operators to cope with the coexistence of both circuit-switched and packet-switched traffic and guarantee the QoS requirements. During the derivation, we consider various propagation models, traffic models, resource allocation schemes for many possible scenarios, each of which may lead to different analytical models. All the suggested models are validated with either Monte-Carlo simulations or discrete event simulations, where excellent matches between results are always achieved. Furthermore, this monograph studies the optimization-based resource allocation strategies in the UMTS uplink with integrated QoS/best-effort traffic. Optimization techniques, both linear-programming based and non-linear-programming based, are used to determine how much resource should be assigned to each enhanced uplink user in the multi-cell environment where each NodeB possesses full knowledge of the whole network. The system performance under such resource allocation schemes are analyzed and compared via Monte-Carlo simulations, which verifies that the proposed framework may serve as a good estimation and optimal reference to study how systems perform for network operators

I primi passi dell'igiene industriale e della tossicologia occupazionale presso la Clinica del Lavoro di Milano sotto la guida di Luigi Devoto

INTRODUCTION: The Clinica del Lavoro, the first clinic for occupational diseases of the world, was inaugurated in Milan on 20 March 1910; its first director was Luigi Devoto, who was in charge until 1935. The purpose of this work is to review the activities of industrial hygiene and toxicology carried out at the Clinica del Lavoro under the guidance of Devoto. METHODS: Documents published by the Istituti Clinici di Perfezionamento, a group of clinics of which the Clinica del Lavoro was part, record the birth and organization of this structure and the presence of a laboratory of chemistry; documents by Devoto and other authors were also retrieved to extrapolate specific information on activities of industrial hygiene and toxicology. RESULTS: The Clinica del Lavoro, at the time of its inauguration, included four laboratories: of chemistry, clinical physics, histopathology and bacteriology. The chemistry lab was located on the first floor and was composed of 6 well-lit rooms, modernly equipped with work benches that could accommodate 12 people. In Devoto's view, the chemistry laboratory, supported by that of clinical physics, had to assess the toxicological properties of chemicals commonly found in the workplace and to reveal the mechanisms of induction of damage to humans. In the first 30 years of activity, the Clinica del Lavoro investigated various diseases deriving from exposure to chemical agents, including saturnism, or lead intoxication, mercurialism, phosphorism, benzolism, sulfocarbonism, dust diseases. Several assays were developed and applied to measure toxicants in different biological and environmental mean as evidenced by scientific publications starting from 1920. CONCLUSION: In Devoto's view, industrial hygiene and toxicology were essential tools for the research and prevention of occupational diseases since the first years of activity of the Clinica del Lavoro

Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment

Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverb\u3b2 and Ppar\u3b1. Interestingly, chronic treatment with the multi receptor modulator lurasidone (3 mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus. We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders

Sex-Specific Effects of Prenatal Stress on Bdnf Expression in Response to an Acute Challenge in Rats : a Role for Gadd45β

Exposure to early adversities represents a major risk factor for psychiatric disorders. We have previously shown that exposure to prenatal stress (PNS) in rats alters the developmental expression of brain-derived neurotrophic factor (Bdnf) with a specific temporal profile. However, exposure to early-life stress is known to alter the ability to cope with challenging events later in life, which may contribute to the enhanced vulnerability to stress-related disorders. Since Bdnf is also an important player for activity-dependent plasticity, we investigated whether the exposure to PNS in rats could alter Bdnf responsiveness to an acute challenge at adulthood. We found that exposure to PNS produces significant changes in Bdnf responsiveness with brain region- and gender-specific selectivity. Indeed, exposure to an acute stress upregulates Bdnf expression in the prefrontal cortex, but not in the hippocampus, of control animals. Moreover, such modulatory activity is selectively impaired in PNS female rats, an effect that was associated with changes in the modulation of the DNA demethylase Gadd45\u3b2. Our results suggest that exposure to PNS may reprogram gene transcription through epigenetic mechanisms reducing the ability to cope under adverse conditions, a trait that is disrupted in psychiatric diseases

Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders

Background Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution. Methods Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring (n = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and quantitative real-time polymerase chain reaction analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. Gene ontology term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation. Results Adult offspring of immune-challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for gamma-aminobutyric acidergic differentiation and signaling (e.g., Dlx1, Lhx5, Lhx8), Wnt signaling (Wnt3, Wnt8a, Wnt7b), and neural development (e.g., Efnb3, Mid1, Nlgn1, Nrxn2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring\u2019s age and were markedly influenced by the precise timing of prenatal immune activation. Conclusions Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories

Peak shape clustering reveals biological insights

Background: ChIP-seq experiments are widely used to detect and study DNA-protein interactions, such as transcription factor binding and chromatin modifications. However, downstream analysis of ChIP-seq data is currently restricted to the evaluation of signal intensity and the detection of enriched regions (peaks) in the genome. Other features of peak shape are almost always neglected, despite the remarkable differences shown by ChIP-seq for different proteins, as well as by distinct regions in a single experiment. Results: We hypothesize that statistically significant differences in peak shape might have a functional role and a biological meaning. Thus, we design five indices able to summarize peak shapes and we employ multivariate clustering techniques to divide peaks into groups according to both their complexity and the intensity of their coverage function. In addition, our novel analysis pipeline employs a range of statistical and bioinformatics techniques to relate the obtained peak shapes to several independent genomic datasets, including other genome-wide protein-DNA maps and gene expression experiments. To clarify the meaning of peak shape, we apply our methodology to the study of the erythroid transcription factor GATA-1 in K562 cell line and in megakaryocytes. Conclusions: Our study demonstrates that ChIP-seq profiles include information regarding the binding of other proteins beside the one used for precipitation. In particular, peak shape provides new insights into cooperative transcriptional regulation and is correlated to gene expression

Characterization of a decrease in muscarinic m2 mRNA in cerebellar granule cells by carbachol

Studies involving carbachol (100 microM) treatment of cerebellar granule cells for 1, 3, 6, 9, 12 and 24 hr show a decrease in the mRNA encoding for the muscarinic m2 receptor. The response was transient, decreasing m2 mRNA by 25 to 50% in 6 and 9 hr, respectively. The data presented in this work were quantified by ribonuclease protection assay, using a [32P]-cRNA probe corresponding to nucleotide +1138 to 1650 of the rat m2 muscarinic receptor. Because cerebellar granule cells express muscarinic m2 and m3 receptors, we tested whether the carbachol-mediated decrease in m2 mRNA resulted from a homologous or heterologous activation of muscarinic receptors. At a 1 microM concentration, methoctramine specifically blocked the muscarinic m2 receptor and reversed carbachol's action. These data suggested that carbachol acts via a possible homologous activation of muscarinic m2 receptors. The half-life of the receptor mRNA measured in the presence of actinomycin D with and without carbachol were similar. Because carbachol treatments decrease the steady-state levels of m2 mRNA without changing the half-life of the message, we suggest that a carbachol treatment induces a decrease in the transcription of the gene for the muscarinic m2 receptor

Blood biomarkers and treatment response in major depression

Introduction: Millions of people worldwide suffer from depression, but despite advances in pharmacological therapies, many patients do not experience symptomatic remission or treatment response, even after treatments with several medications. As such, there is an urgent need to identify biomarkers that can not only predict the treatment response but also allow a rational selection of optimal therapy for each patient. Areas covered: This review examines the recent findings, coming from different \u2018omic sciences,\u2019 in human blood-based biomarkers associated with antidepressant treatment response with particular attention on genetic/epigenetic and biochemical biomarkers. Specific emphasis will be placed on key molecules related to neuroplasticity and inflammation because of their involvement in the pathophysiology of depression and antidepressant response. Expert commentary: Biomarker identification is still an ongoing work. Indeed, to date, no biomarkers have sufficiently proven specificity, sensitivity, and reproducibility to be used in the clinical setting. However, \u2018omic\u2019 approaches hold great promise in identifying multiple features for predicting antidepressant response, making a personalized treatment strategy possible for each patient, and thereby assist with quick and efficacious responsiveness. It is thus necessary that future studies take an integrative approach that includes clinical assessment, environment influences, and molecular and biological biomarkers

Morc1 knockout evokes a depression-like phenotype in mice

Morc1 gene has recently been identified by a DNA methylation and genome-wide association study as a candidate gene for major depressive disorder related to early life stress in rodents, primates and humans. So far, no transgenic animal model has been established to validate these findings on a behavioral level. In the present study, we examined the effects of a Morc1 loss of function mutation in female C57BL/6N mice on behavioral correlates of mood disorders like the Forced Swim Test, the Learned Helplessness Paradigm, O-Maze and Dark-Light-Box. We could show that Morc1(-/-) mice display increased depressive-like behavior whereas no behavioral abnormalities regarding locomotor activity or anxiety-like behavior were detectable. CORT plasma levels did not differ significantly between Morc1(-/-) mice and their wildtype littermates, yet - surprisingly - total Bdnf mRNA-levels in the hippocampus were up-regulated in Morc1(-/-) animals. Although further work would be clarifying, Morc1(-/-) mice seem to be a promising epigenetically validated mouse model for depression associated with early life stress

The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. The human BDNF gene consists of 11 exons, and distinct BDNF transcripts are produced through the use of alternative promoters and splicing events. The majority of the BDNF transcripts can be detected not only in the brain but also in the blood cells, although no study has yet investigated the differential expression of BDNF transcripts at the peripheral level. This review provides a description of the human BDNF gene structure as well as a summary of clinical and preclinical evidence supporting the role of BDNF in the pathogenesis of psychiatric disorders. We will discuss several mechanisms as possibly underlying BDNF modulation, including epigenetic mechanisms. We will also discuss the potential use of peripheral BDNF as a biomarker for psychiatric disorders, focusing on the factors that can influence BDNF gene expression and protein levels. Within this context, we have also characterized, for we believe the first time, the expression of BDNF transcripts in the blood, with the aim to provide novel insights into the molecular mechanisms and signaling that may regulate peripheral BDNF gene expression levels