Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease.

Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm

The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis

Engineering JavaScript state persistence of web applications migrating across multiple devices

n/

Service Level Constrained Inventory Systems

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151878/1/poms13060_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151878/2/poms13060.pd

Algebraic service composition for user-centric IoT applications

The Internet of Things (IoT) requires a shift in our way of building applications, as it is aimed at providing many services to society in general. Non-developer people require increasingly complex IoT applications and support for their ever changing run-time requirements. Although service composition allows the combination of functionality into more complex behaviours, current approaches provide support for dealing with one IoT scenario at a time, as they allow the definition of only one workflow. In this paper, we present DX-MAN, an algebraic model for static service composition that allows the definition of composite services that encompass multiple workflows for run-time scenarios. We evaluate our proposal on an example in the domain of smart homes

The capacitated general windy routing problem with turn penalties

In this paper we present the capacitated general windy routing problem with turn penalties. This new problem subsumes many important and well-known arc and node routing problems, and it takes into account turn penalties and forbidden turns, which are crucial in many real-life applications, particularly in downtown areas and for large vehicles. We provide a way to solve this problem both optimally and heuristically by transforming it into a generalized vehicle routing problem. © 2011 Elsevier B.V. All rights reserved.This work has been partially supported by the Ministerio de Educacion y Ciencia of Spain (project TIN2008-06441-C02-01). We are also indebted to the two anonymous referees for their valuable comments.Micó Ruiz, JC.; Soler Fernández, D. (2011). The capacitated general windy routing problem with turn penalties. Operations Research Letters. 39(4):265-271. https://doi.org/10.1016/j.orl.2011.04.007S26527139

Skin rash and response to cetuximab treatment: a retrospective single-center analysis

Background: The standard of care for patients with recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC) not susceptible for surgery or reirradiation is chemotherapy with 5-FU and cisplatin plus cetuximab. Skin rash (SR) is a common adverse event of cetuximab. In patients treated with cetuximab for colorectal cancer there is strong evidence of a better outcome in those who undergo moderate or high grade of SR, and some retrospective data seem to confirm this finding in HNSCC. We report our experience. Materials and methods: We retrospectively reviewed 107 patients treated with cetuximab for R/M HNSCC from January 2014 to December 2016. Patients were divided in two groups by the grade of SR (G0-1 and G2-4), conforming to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Progression-free survival (PFS) was computed as time of progression or death since the date of assessment of recurrent/metastatic disease. Overall response rate (ORR) was computed as the sum of partial and complete responses and evaluated according to RECIST 1.1. PFS and ORR were correlated to the grade of rash. Results: 67 patients were evaluable for PFS: among them PFS was significantly longer (p 0.0014) in those who underwent a G2-4 rash (9,3 months) vs G0-1 (4,9 months). Hazard Ratio was 2,445 (CI 1.412-4.232). 95 patients were evaluable for ORR: among them G0-1 group had 4,2%, while G2-4 group had 36,8% of ORR. Conclusions: Our results support data of literature on improved outcome according to the development of skin rash in HNSCC. SR might be considered a predictive marker of response in these patients; nonetheless further ad hoc studies would be interesting

Sleep/Wake Disruption in a Mouse Model of BLOC-1 Deficiency

Mice lacking a functional Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1), such as those of the pallid line, display cognitive and behavioural impairments reminiscent of those presented by individuals with intellectual and developmental disabilities. Although disturbances in the sleep/wake cycle are commonly lamented by these individuals, the underlying mechanisms, including the possible role of the circadian timing system, are still unknown. In this paper, we have explored sleep/circadian malfunctions and underlying mechanisms in BLOC-1-deficient pallid mice. These mutants exhibited less sleep behaviour in the beginning of the resting phase than wild-type mice with a more broken sleeping pattern in normal light-dark conditions. Furthermore, the strength of the activity rhythms in the mutants were reduced with significantly more fragmentation and lower precision than in age-matched controls. These symptoms were accompanied by an abnormal preference for the open arm in the elevated plus maze in the day and poor performance in the novel object recognition at night. At the level of the central circadian clock (the suprachiasmatic nucleus, SCN), loss of BLOC-1 caused subtle morphological changes including a larger SCN and increased expression of the relative levels of the clock gene Per2 product during the day but did not affect the neuronal activity rhythms. In the hippocampus, the pallid mice presented with anomalies in the cytoarchitecture of the Dentate Gyrus granule cells, but not in CA1 pyramidal neurones, along with altered PER2 protein levels as well as reduced pCREB/tCREB ratio during the day. Our findings suggest that lack of BLOC-1 in mice disrupts the sleep/wake cycle and performance in behavioural tests associated with specific alterations in cytoarchitecture and protein expression

Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101)

Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations