Short-period volcanic gas precursors to phreatic eruptions: Insights from Poás Volcano, Costa Rica

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Worst case and probabilistic analysis of the 2-Opt algorithm for the TSP

2-Opt is probably the most basic local search heuristic for the TSP. This heuristic achieves amazingly good results on “real world” Euclidean instances both with respect to running time and approximation ratio. There are numerous experimental studies on the performance of 2-Opt. However, the theoretical knowledge about this heuristic is still very limited. Not even its worst case running time on 2-dimensional Euclidean instances was known so far. We clarify this issue by presenting, for every p∈N , a family of L p instances on which 2-Opt can take an exponential number of steps. Previous probabilistic analyses were restricted to instances in which n points are placed uniformly at random in the unit square [0,1]2, where it was shown that the expected number of steps is bounded by O~(n10) for Euclidean instances. We consider a more advanced model of probabilistic instances in which the points can be placed independently according to general distributions on [0,1] d , for an arbitrary d≥2. In particular, we allow different distributions for different points. We study the expected number of local improvements in terms of the number n of points and the maximal density ϕ of the probability distributions. We show an upper bound on the expected length of any 2-Opt improvement path of O~(n4+1/3⋅ϕ8/3) . When starting with an initial tour computed by an insertion heuristic, the upper bound on the expected number of steps improves even to O~(n4+1/3−1/d⋅ϕ8/3) . If the distances are measured according to the Manhattan metric, then the expected number of steps is bounded by O~(n4−1/d⋅ϕ) . In addition, we prove an upper bound of O(ϕ√d) on the expected approximation factor with respect to all L p metrics. Let us remark that our probabilistic analysis covers as special cases the uniform input model with ϕ=1 and a smoothed analysis with Gaussian perturbations of standard deviation σ with ϕ∼1/σ d

Students benefit from developing their own emergency medicine OSCE stations: a comparative study using the matched-pair method

Background: Students can improve the learning process by developing their own multiple choice questions. If a similar effect occurred when creating OSCE (objective structured clinical examination) stations by themselves it could be beneficial to involve them in the development of OSCE stations. This study investigates the effect of students developing emergency medicine OSCE stations on their test performance. Method: In the 2011/12 winter semester, an emergency medicine OSCE was held for the first time at the Faculty of Medicine at the University of Leipzig. When preparing for the OSCE, 13 students (the intervention group) developed and tested emergency medicine examination stations as a learning experience. Their subsequent OSCE performance was compared to that of 13 other students (the control group), who were parallelized in terms of age, gender, semester and level of previous knowledge using the matched-pair method. In addition, both groups were compared to 20 students who tested the OSCE prior to regular emergency medicine training (test OSCE group). Results: There were no differences between the three groups regarding age (24.3 +/- 2.6; 24.2 +/- 3.4 and 24 +/- 2.3 years) or previous knowledge (29.3 +/- 3.4; 29.3 +/- 3.2 and 28.9 +/- 4.7 points in the multiple choice {[} MC] exam in emergency medicine). Merely the gender distribution differed (8 female and 5 male students in the intervention and control group vs. 3 males and 17 females in the test OSCE group). In the exam OSCE, participants in the intervention group scored 233.4 +/- 6.3 points (mean +/- SD) compared to 223.8 +/- 9.2 points (p < 0.01) in the control group. Cohen's effect size was d = 1.24. The students of the test OSCE group scored 223.2 +/- 13.4 points. Conclusions: Students who actively develop OSCE stations when preparing for an emergency medicine OSCE achieve better exam results

Attachment and Mentalization in Female Patients With Comorbid Narcissistic and Borderline Personality Disorder

We investigated attachment representations and the capacity for mentalization in a sample of adult female borderline patients with and without comorbid narcissistic personality disorder (NPD). Participants were 22 borderline patients diagnosed with comorbid NPD (NPD/BPD) and 129 BPD patients without NPD (BPD) from 2 randomized clinical trials. Attachment and mentalization were assessed on the Adult Attachment Interview (AAI; George

Cost-effectiveness of nurse-delivered cognitive behavioural therapy (CBT) compared to supportive listening (SL) for adjustment to multiple sclerosis

Background: Cognitive Behavioural Therapy (CBT) reduces distress in multiple sclerosis, and helps manage adjustment, but cost-effectiveness evidence is lacking. Methods: An economic evaluation was conducted within a multi-centre trial. 94 patients were randomised to either eight sessions of nurse-led CBT or supportive listening (SL). Costs were calculated from the health, social and indirect care perspectives, and combined with additional quality-adjusted life years (QALY) or improvement on the GHQ-12 score, to explore cost-effectiveness at 12 months. Results: CBT had higher mean health costs (£1610, 95% CI, −£187 to 3771) and slightly better QALYs (0.0053, 95% CI, −0.059 to 0.103) compared to SL but these differences were not statistically significant. This yielded £301,509 per QALY improvement, indicating that CBT is not cost-effective according to established UK NHS thresholds. The extra cost per patient improvement on the GHQ-12 scale was £821 from the same perspective. Using a £20,000, threshold, CBT in this format has a 9% probability of being cost effective. Although subgroup analysis of patients with clinical levels of distress at baseline showed an improvement in the position of CBT compared to SL, CBT was still not cost-effective. Conclusion: Nurse delivered CBT is more effective in reducing distress among MS patients compared to SL, but is highly unlikely to be cost-effective using a preference-based measure of health (EQ-5D). Results from a diseasespecif ic measure (GHQ-12) produced comparatively lower Incremental Cost-Effectiveness Ratios, but there is currently no acceptable willingness-to-pay threshold for this measure to guide decision-making

Decreased hydrocortisone sensitivity of T cell function in multiple sclerosis-associated major depression

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS with a high prevalence of depression. Both MS and depression have been linked to elevated cortisol levels and inflammation, indicating disturbed endocrine-immune regulation. An imbalance in mineralocorticoid versus glucocorticoid signaling in the CNS has been proposed as a pathogenetic mechanism of depression. Intriguingly, both receptors are also expressed in lymphocytes, but their role for ‘escape’ of the immune system from endocrine control is unknown. Using steroid sensitivity of T cell function as a read-out system, we here investigate a potential role of mineralocorticoid receptor (MR) versus glucocorticoid receptor (GR) regulation in the immune system as a biological mechanism underlying MS-associated major depression. Twelve female MS patients meeting diagnostic criteria for current major depressive disorder (MDD) were compared to twelve carefully matched MS patients without depression. We performed lymphocyte phenotyping by flow cytometry. In addition, steroid sensitivity of T cell proliferation was tested using hydrocortisone as well as MR (aldosterone) and GR (dexamethasone) agonists. Sensitivity to hydrocortisone was decreased in T cells from depressed MS patients. Experiments with agonists suggested disturbed MR regulation, but intact GR function. Importantly, there were no differences in lymphocyte composition and frequency of T cell subsets, indicating that the differences in steroid sensitivity are unlikely to be secondary to shifts in the immune compartment. To our knowledge, this study provides first evidence for altered steroid sensitivity of T cells from MS patients with comorbid MDD possibly due to MR dysregulation

Mechanochemical Coupling in the Myosin Motor Domain. II. Analysis of Critical Residues

An important challenge in the analysis of mechanochemical coupling in molecular motors is to identify residues that dictate the tight coupling between the chemical site and distant structural rearrangements. In this work, a systematic attempt is made to tackle this issue for the conventional myosin. By judiciously combining a range of computational techniques with different approximations and strength, which include targeted molecular dynamics, normal mode analysis, and statistical coupling analysis, we are able to identify a set of important residues and propose their relevant function during the recovery stroke of myosin. These analyses also allowed us to make connections with previous experimental and computational studies in a critical manner. The behavior of the widely used reporter residue, Trp501, in the simulations confirms the concern that its fluorescence does not simply reflect the relay loop conformation or active-site open/close but depends subtly on its microenvironment. The findings in the targeted molecular dynamics and a previous minimum energy path analysis of the recovery stroke have been compared and analyzed, which emphasized the difference and complementarity of the two approaches. In conjunction with our previous studies, the current set of investigations suggest that the modulation of structural flexibility at both the local (e.g., active-site) and domain scales with strategically placed “hotspot” residues and phosphate chemistry is likely the general feature for mechanochemical coupling in many molecular motors. The fundamental strategies of examining both collective and local changes and combining physically motivated methods and informatics-driven techniques are expected to be valuable to the study of other molecular motors and allosteric systems in general

2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease

Previously, we demonstrated that mitochondrial bioenergetic deficits preceded Alzheimer's disease (AD) pathology in the female triple-transgenic AD (3xTgAD) mouse model. In parallel, 3xTgAD mice exhibited elevated expression of ketogenic markers, indicating a compensatory mechanism for energy production in brain. This compensatory response to generate an alternative fuel source was temporary and diminished with disease progression. To determine whether this compensatory alternative fuel system could be sustained, we investigated the impact of 2-deoxy-D-glucose (2-DG), a compound known to induce ketogenesis, on bioenergetic function and AD pathology burden in brain. 6-month-old female 3xTgAD mice were fed either a regular diet (AIN-93G) or a diet containing 0.04% 2-DG for 7 weeks. 2-DG diet significantly increased serum ketone body level and brain expression of enzymes required for ketone body metabolism. The 2-DG-induced maintenance of mitochondrial bioenergetics was paralleled by simultaneous reduction in oxidative stress. Further, 2-DG treated mice exhibited a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers, which was paralleled by significantly increased α-secretase and decreased γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway. In addition, 2-DG increased expression of genes involved in Aβ clearance pathways, degradation, sequestering, and transport. Concomitant with increased bioenergetic capacity and reduced β-amyloid burden, 2-DG significantly increased expression of neurotrophic growth factors, BDNF and NGF. Results of these analyses demonstrate that dietary 2-DG treatment increased ketogenesis and ketone metabolism, enhanced mitochondrial bioenergetic capacity, reduced β-amyloid generation and increased mechanisms of β-amyloid clearance. Further, these data link bioenergetic capacity with β-amyloid generation and demonstrate that β-amyloid burden was dynamic and reversible, as 2-DG reduced activation of the amyloidogenic pathway and increased mechanisms of β-amyloid clearance. Collectively, these data provide preclinical evidence for dietary 2-DG as a disease-modifying intervention to delay progression of bioenergetic deficits in brain and associated β-amyloid burden

Short-term fatty acid intervention elicits differential gene expression responses in adipose tissue from lean and overweight men

The goal of this study was to investigate the effect of a short-term nutritional intervention on gene expression in adipose tissue from lean and overweight subjects. Gene expression profiles were measured after consumption of an intervention spread (increased levels of polyunsaturated fatty acids, conjugated linoleic acid and medium chain triglycerides) and a control spread (40 g of fat daily) for 9 days. Adipose tissue gene expression profiles of lean and overweight subjects were distinctly different, mainly with respect to defense response and metabolism. The intervention resulted in lower expression of genes related to energy metabolism in lean subjects, whereas expression of inflammatory genes was down-regulated and expression of lipid metabolism genes was up-regulated in the majority of overweight subjects. Individual responses in overweight subjects were variable and these correlated better to waist–hip ratio and fat percentage than BMI

Satellite Cells Derived from Obese Humans with Type 2 Diabetes and Differentiated into Myocytes In Vitro Exhibit Abnormal Response to IL-6

Obesity and type 2 diabetes are associated with chronically elevated systemic levels of IL-6, a pro-inflammatory cytokine with a role in skeletal muscle metabolism that signals through the IL-6 receptor (IL-6Rα). We hypothesized that skeletal muscle in obesity-associated type 2 diabetes develops a resistance to IL-6. By utilizing western blot analysis, we demonstrate that IL-6Rα protein was down regulated in skeletal muscle biopsies from obese persons with and without type 2 diabetes. To further investigate the status of IL-6 signaling in skeletal muscle in obesity-associated type 2 diabetes, we isolated satellite cells from skeletal muscle of people that were healthy (He), obese (Ob) or were obese and had type 2 diabetes (DM), and differentiated them in vitro into myocytes. Down-regulation of IL-6Rα was conserved in Ob myocytes. In addition, acute IL-6 administration for 30, 60 and 120 minutes, resulted in a down-regulation of IL-6Rα protein in Ob myocytes compared to both He myocytes (P<0.05) and DM myocytes (P<0.05). Interestingly, there was a strong time-dependent regulation of IL-6Rα protein in response to IL-6 (P<0.001) in He myocytes, not present in the other groups. Assessing downstream signaling, DM, but not Ob myocytes demonstrated a trend towards an increased protein phosphorylation of STAT3 in DM myocytes (P = 0.067) accompanied by a reduced SOCS3 protein induction (P<0.05), in response to IL-6 administration. Despite this loss of negative control, IL-6 failed to increase AMPKα2 activity and IL-6 mRNA expression in DM myocytes. There was no difference in fusion capacity of myocytes between cell groups. Our data suggest that negative control of IL-6 signaling is increased in myocytes in obesity, whereas a dysfunctional IL-6 signaling is established further downstream of IL-6Rα in DM myocytes, possibly representing a novel mechanism by which skeletal muscle function is compromised in type 2 diabetes