GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men.
Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR). Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH2. The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 μg), GLP-2 (800 μg), GIP(3-30)NH2 (800 pmol/kg/min) + GLP-2 (800 μg), and placebo. The main outcomes were bone resorption measured as collagen type 1 C-terminal telopeptide (CTX) and bone formation measured as procollagen type 1 N-terminal propeptide (P1NP). CTX (mean ± SEM) significantly decreased after both GIP (to 55.3 ± 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 ± 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30)NH2 + GLP-2 (to 63.2 ± 3.1% of baseline) did not differ from GLP-2 alone (p = 0.95) nor did net AUC0-240 (-6801 ± 879%*min vs -6027 ± 648%*min, p = 0.56). At t = 30 min, GIP significantly (p < 0.0001) increased P1NP to 115.1 ± 2.2% of baseline compared with 103.1 ± 1.5% after placebo. Both GLP-2 and GIP(3-30)NH2 + GLP-2 significantly (p < 0.0001) decreased P1NP to 91.3 ± 1.1% and 88.1 ± 3.0% of baseline, respectively (at t = 45 min) compared with placebo. GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans. ClinicalTrials.gov (NCT03159741).


Low-algorithmic-complexity entropy-deceiving graphs.
In estimating the complexity of objects, in particular, of graphs, it is common practice to rely on graph- and information-theoretic measures. Here, using integer sequences with properties such as Borel normality, we explain how these measures are not independent of the way in which an object, such as a graph, can be described or observed. From observations that can reconstruct the same graph and are therefore essentially translations of the same description, we see that when applying a computable measure such as the Shannon entropy, not only is it necessary to preselect a feature of interest where there is one, and to make an arbitrary selection where there is not, but also more general properties, such as the causal likelihood of a graph as a measure (opposed to randomness), can be largely misrepresented by computable measures such as the entropy and entropy rate. We introduce recursive and nonrecursive (uncomputable) graphs and graph constructions based on these integer sequences, whose different lossless descriptions have disparate entropy values, thereby enabling the study and exploration of a measure's range of applications and demonstrating the weaknesses of computable measures of complexity.


Obsessive-compulsive disorder: Insights from animal models.
Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.


Evaluation of TB Case Finding through Systematic Contact Investigation, Chhattisgarh, India.
Rationale. Contact investigation is an established tool for early case detection of tuberculosis (TB). In India, contact investigation is not often conducted, despite national policy, and the yield of contact investigation is not well described. Objective. To determine the yield of evaluating household contacts of sputum smear-positive TB cases in Rajnandgaon district, Chhattisgarh, India. Methods. Among 14 public health care facilities with sputum smear microscopy services, home visits were conducted to identify household contacts of all registered sputum smear-positive TB cases. We used a standardized protocol to screen for clinical symptoms suggestive of active TB with additional referral for chest radiograph and sputa collection. Results. From December 2010 to May 2011, 1,556 household contacts of 312 sputum smear-positive TB cases were identified, of which 148 (9.5%) were symptomatic. Among these, 109 (73.6%) were evaluated by sputum examination resulting in 11 cases (10.1%) of sputum smear-positive TB and 4 cases (3.6%) of smear-negative TB. Household visits contributed additional 63% TB cases compared to passive case detection alone. Conclusion. A standard procedure for conducting household contact investigation identified additional TB cases in the community and offered an opportunity to initiate isoniazid chemoprophylaxis among children.


A songbird inhibits blinking behaviour in flight.
Visual attention plays a fundamental role in avian flight but attention is likely limited whenever birds blink. Because blinks are necessary to maintaining proper vision, this study tested the hypothesis that birds strategically inhibit their blinks in flight. The blinks of captive great-tailed grackles (Quiscalus mexicanus) were recorded before, during and after they flew a short distance in an open environment. The grackles spent the least amount of time blinking in flight (take-off, during flight and landing) and the most amount of time blinking at impact. Their blinking behaviour was similar before and after flight. These results suggest that grackles strategically inhibit their blinking behaviour in flight, potentially because blinks impose costs to avian flight.


Quantitative evaluation of bioorthogonal chemistries for surface functionalization of nanoparticles.
We present here a highly efficient and chemoselective liposome functionalization method based on oxime bond formation between a hydroxylamine and an aldehyde-modified lipid component. We have conducted a systematic and quantitative comparison of this new approach with other state-of-the-art conjugation reactions in the field. Targeted liposomes that recognize overexpressed receptors or antigens on diseased cells have great potential in therapeutic and diagnostic applications. However, chemical modifications of nanoparticle surfaces by postfunctionalization approaches are less effective than in solution and often not high-yielding. In addition, the conjugation efficiency is often challenging to characterize and therefore not addressed in many reports. We present here an investigation of PEGylated liposomes functionalized with a neuroendocrine tumor targeting peptide (TATE), synthesized with a variety of functionalities that have been used for surface conjugation of nanoparticles. The reaction kinetics and overall yield were quantified by HPLC. Reactions were conducted in solution as well as by postfunctionalization of liposomes in order to study the effects of steric hindrance and possible affinity between the peptide and the liposome surface. These studies demonstrate the importance of choosing the correct chemistry in order to obtain a quantitative surface functionalization of liposomes.


Small employers and health benefits: findings from the 2002 small employer health benefits survey.
Overall, 19 percent of small employers offering health benefits made changes to their health plan between 2001 and 2002. Sixty-five percent increased deductibles and co-pays; 35 percent switched insurers; 30 percent increased the employee share of the premium; and 29 percent cut back on the scope of benefits. Twenty-six percent increased the scope of benefits offered. Nearly one-quarter of small employers offering health benefits think their firm would change coverage and 3 percent think it would drop coverage if the cost were to increase an additional 5 percent. Most small employers offer sound business reasons for offering health benefits to workers. Many report that it helps with employee recruitment and retention, and increases productivity. More than three-quarters report that offering health benefits is "the right thing to do." Most small employers that do offer health benefits report that it has a positive impact on various aspects of the business, such as recruitment, retention, employee attitude and performance, employee health status, and the overall success of the business. Most small employers that do not offer health benefits tend to think that not offering them has no negative impact on the above aspects of their business or the overall success of the business. However, those not offering benefits are more likely than those offering them to report that most of their employees are high-turnover and stay on the job only a few months. Small employers that offer health benefits tend to be distinctly different from those not offering them. Worker income in firms not offering health benefits tends to be considerably lower than in firms that do offer them. Employers not offering health benefits are more likely than those offering them to have a smaller proportion of full-time employees, and employers that do not offer health benefits have a larger proportion of females, workers under age 30, and minority employees. Of small employers that offer dependent coverage, more than 40 percent report that workers do not take coverage for their dependents because the dependents have coverage from somewhere else, but 35 percent report that employees decline dependent coverage because they cannot afford the premiums. Many small employers that do not offer health benefits are potential purchasers. Eleven percent are either extremely or very likely to start offering health benefits in the next two years, and 22 percent are somewhat likely to start offering health benefits.


Outbreak of pruritic rashes associated with mites--Kansas, 2004.
In late August 2004, the Kansas Department of Health and Environment (KDHE) received reports from the Crawford County Health Department (CCHD) of approximately 300 residents of Pittsburg, Kansas (2000 population: 19,243), seeking care for a pruritic rash of unknown etiology. In early September, three neighboring counties in Kansas and two neighboring states (Missouri and Nebraska) also reported such cases. These events prompted KDHE to request assistance from CDC. Additional cases subsequently were reported in Oklahoma and Texas. This report describes the investigation in Crawford County, Kansas, by public health agencies and entomologists to identify the etiology of the pruritic rash and to assess the extent of the outbreak. A microscopic itch mite (Pyemotes herfsi) was identified as the likely cause of the outbreak, which affected an estimated 54% of the Crawford County population (2000 population: 38,242). Entomologists confirmed the return of P. herfsi in Kansas in August 2005 and have recommended prevention measures, such as use of DEET-containing products, to help minimize exposure for persons outdoors.


Integrated Diagnosis Project for Inflammatory Myopathies: An association between autoantibodies and muscle pathology.
Inflammatory myopathies are a heterogeneous group of immune-mediated diseases that involve skeletal muscle as well as many other organs. The classification of inflammatory myopathies has been based on clinical diagnoses, pathological diagnoses, and autoantibodies, independently. The clinical phenotypes of inflammatory myopathies are characterized by various autoantibodies that are originally detected by RNA or protein immunoprecipitation. However, since the correlation between histological features and autoantibodies had not been fully elucidated, we created the "Integrated Diagnosis Project for Inflammatory Myopathies" in October 2010. Based on our work and previous studies, the three major subsets of inflammatory myopathies defined by autoantibodies are immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome, and dermatomyositis. IMNM is the pathological entity, characterized by significant necrotic and regeneration muscle fibers with minimal or no inflammatory cell infiltration. The detection of autoantibodies against signal recognition particles or 3-hydroxy-3-methylglutaryl-coenzyme A reductase is important for the diagnosis of IMNM. Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is the clinical entity based on the presence of aminoacyl transfer RNA synthetase antibodies. Perifascicular necrosis is a distinctive hallmark of antisynthetase syndrome in muscle pathology. The diagnosis of dermatomyositis is usually based on clinical features of typical skin rash. Several autoantibodies are associated with specific subsets of dermatomyositis. Myxovirus resistance A expression in the myofiber cytoplasm has a better sensitivity for the diagnosis of dermatomyositis compared to perifascicular atrophy. The screening of autoantibodies has clinical relevance for managing patients with inflammatory myopathies.


Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.


Proteomics in globe artichoke: protein extraction and sample complexity reduction by PEG fractionation.
Here, we report the first leaf proteome analysis for globe artichoke. Three protein extraction protocols were tested and a reproducible Mg/NP-40-based method was established. Ribulose-1,5-biphosphate carboxylase-oxygenase (RuBisCO) is a highly abundant leaf protein, and its presence masks co-localizing, less abundant proteins. To remove RuBisCO from the sample, and thereby improve spot resolution, a PEG fractionation approach was elaborated. 2-DE profiles of various PEG fractions showed that the fractionation procedure was successful in excluding most of the RuBisCO, allowing for the detection of many low-abundance proteins. Western blot analysis was able to confirm the reduction in RuBisCO content achieved by PEG fractionation. In all, 841 distinct protein spots were detected, and 40 of these, selected from the RuBisCO region of the 2-DE profile, were successfully identified by MS. A number of homologues of these proteins also co-localize with RuBisCO in Arabidopsis thaliana.


The mechanism of stereospecific C-H oxidation by Fe(Pytacn) complexes: bioinspired non-heme iron catalysts containing cis-labile exchangeable sites.
A detailed mechanistic study of the hydroxylation of alkane C-H bonds using H2O2 by a family of mononuclear non heme iron catalysts with the formula [Fe(II)(CF3SO3)2(L)] is described, in which L is a tetradentate ligand containing a triazacyclononane tripod and a pyridine ring bearing different substituents at the α and γ positions, which tune the electronic or steric properties of the corresponding iron complexes. Two inequivalent cis-labile exchangeable sites, occupied by triflate ions, complete the octahedral iron coordination sphere. The C-H hydroxylation mediated by this family of complexes takes place with retention of configuration. Oxygen atoms from water are incorporated into hydroxylated products and the extent of this incorporation depends in a systematic manner on the nature of the catalyst, and the substrate. Mechanistic probes and isotopic analyses, in combination with detailed density functional theory (DFT) calculations, provide strong evidence that C-H hydroxylation is performed by highly electrophilic [Fe(V)(O)(OH)L] species through a concerted asynchronous mechanism, involving homolytic breakage of the C-H bond, followed by rebound of the hydroxyl ligand. The [Fe(V)(O)(OH)L] species can exist in two tautomeric forms, differing in the position of oxo and hydroxide ligands. Isotopic-labeling analysis shows that the relative reactivities of the two tautomeric forms are sensitively affected by the α substituent of the pyridine, and this reactivity behavior is rationalized by computational methods.


Activation of neural cell fate programs toward direct conversion of adult human fibroblasts into tri-potent neural progenitors using OCT-4.
Several transcription factors and methods have been used to convert fibroblasts directly to neural fate and have provided insights into molecular mechanisms as to how each of these required factors orchestrate neural fate conversion. Here, we provide evidence and detailed characterization of the direct conversion process of primary adult human fibroblasts (hFib) to neural progenitor cells (NPC) using OCT4 alone. Factors previously associated with neural cell fate conversion were induced during hFib-NPC(OCT-4) generation, where OCT-4 alone was sufficient to induce neural fate conversion without the use of promiscuous small-molecule manipulation. Human Fib-NPC(OCT-4) proliferate, express neural stem/progenitor markers, and possess developmental potential that gives rise to all three major subtypes of neural cells: astrocytes, oligodendrocytes, and neurons with functional capacity. We propose a de-convoluted reprogramming approach for neural fate conversion in which OCT4 is sufficient for inducing neural conversion from hFib for disease modeling as well as the fundamental study of early neural fate induction.


Transaminases for chiral amine synthesis.
Amine transaminases are important biocatalysts for the synthesis of chiral primary amines. Unlike many enzymes that have been employed for the synthesis of optically active amines, amine transaminases are capable of asymmetric synthesis and do not rely on costly cofactors that must be regenerated in situ. However, their application as general catalysts for the preparation of amines is hampered by a limited substrate scope, substrate and (co)product inhibition and difficulties associated with displacing challenging reaction equilibrium. There has been important progress made to overcome these challenges, including the development of enzymes with broader substrate scope and the design of methodology to effectively displace the reaction equilibrium. Amine transaminases are also being applied in an increasing range of (chemo)enzymatic cascades and immobilized for applications in flow.


Surfactants as microbicides and contraceptive agents: a systematic in vitro study.
The urgent need for cheap and easy-to-use protection against both unwanted pregnancies and sexually transmitted diseases has stimulated considerable interest in the use of surfactants as microbicides, anti-viral, and contraceptive agents in recent years. In the present study we report a systematic in vitro evaluation of the microbicidal, anti-viral and contraceptive potential of cationic, anionic, zwitterionic, and non-ionic surfactants. Toxicity was evaluated in mammalian columnar epithelial (MDCK) cells, human sperm cells, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Streptococcus agalactiae and Enterococcus faecalis. The inhibition of adenovirus and lentivirus infection of MDCK cells was also tested. A homologous series of cationic surfactants, alkyl-N,N,N-trimethylammonium bromides (C(n)TAB), with varying alkyl chains were shown to be bactericidal and fungicidal at doses that were related to the surfactant critical micelle concentrations (CMC), all of them at concentrations significantly below the CMC. In general, bacteria were more susceptible to this surfactant group than C. albicans and this organism, in turn, was more susceptible than MDCK cells. This suggests that the C(n)TAB may be useful as vaginal disinfectants only in so far as bacterial and fungal infections are concerned. None of the surfactants examined, including those that have been used in pre-clinical studies, showed inhibition of adenovirus or lentivirus infection of MDCK cells or spermicidal activity at doses that were sub-toxic to MDCK cells. The results of this study lead us to propose that systematic analysis of surfactant toxicity, such as we report in the present work, be made a mandatory pre-condition for the use of these substances in pre-clinical animal and/or human studies.


Anxiety control of dental patients by clinical combination of acupuncture, Bi-Digital O-Ring Test, and eye movement desensitization with sedation via submucosal route.
The data presented in this article was collected after reviewing clinical findings gathered from using various anxiety control methods on apprehensive patients. We examined clinical applications of the eye movement (EM) component of Eye Movement Desensitization (EMD) on fearful dental patients who have histories of traumatic dental experiences. We also used Bi-Digital O-Ring Test (BDORT) to select the proper dosage of sedative to minimize the adverse side effects. For patients who did not respond well to EM, we used BDORT to select the proper sedative medication and its dosage. In certain difficult cases, we supplemented these techniques with acupuncture to augment the sedative effects. Findings were based on the clinical impressions and assessments of both the patients and the operating team. Results showed that EM, although effective in enabling patients to undergo non-invasive dental procedures such as clinical examination and simple prophylaxis, had only limited beneficial effect with invasive procedures such as extraction, drilling, and injections, etc. We also found that BDORT greatly reduced adverse side effects of sedatives such as hypertension, hypotension, hypoxia, tachycardia, bradycardia, nausea, and vomiting. For most apprehensive patients, we found that EMD and acupuncture combined with BDORT predetermined dosage for the submucosal sedation enabled these patients to undergo the complete dental treatment. The authors try to explain the mechanism of BDORT and EM in terms of visual awareness (or consciousness) and preferred patterns, where neurons in the brain respond to the actions and/or direction of movement. The authors believe that BDORT and EM could have better results if the persons performing BDORT have visual awareness and are focused on the task; whereas in EM, the patient's eye on the therapist's hand movements. A more focused approach via visual pathway will result in more favorable results in EM. Likewise, performing BDORT absentmindedly could lead to false results if visual awareness (or consciousness) is absent. "Preferred pattern" will arouse neurons in the brain to cause conscientiousness, and performing BDORT with 'open eyes' arouse the necessary visual awareness that is necessary for the successful performance of BDORT tasks.


Dietary Supplements and Young Teens: Misinformation and Access Provided by Retailers.
Despite the American Academy of Pediatrics' recommendations against pediatric use of creatine and testosterone boosters, research suggests that many young teenagers take these dietary supplements. Our objective was to determine to what extent health food stores would recommend and/or sell creatine and testosterone boosters to a 15-year-old boy customer. Research personnel posing as 15-year-old high school athletes seeking to increase muscle strength contacted 244 health food stores in the United States via telephone. Researchers asked the sales attendant what supplements he/she would recommend. If a sales attendant did not mention creatine or testosterone boosters initially, each of these supplements was then specifically asked about. Supplement recommendations were recorded. Sales attendants were also asked if a 15-year-old could purchase these products on his own in the store. A total of 67.2% (164/244) of sales attendants recommended creatine: 38.5% (94/244) recommended creatine without prompting, and an additional 28.7% (70/244) recommended creatine after being asked specifically about it. A total of 9.8% (24/244) of sales attendants recommended a testosterone booster. Regarding availability for sale, 74.2% (181/244) of sales attendants stated a 15-year-old was allowed to purchase creatine, whereas 41.4% (101/244) stated one could purchase a testosterone booster. Health food store employees frequently recommend creatine and testosterone boosters for boy high school athletes. In response to these findings, pediatricians should inform their teenage patients, especially athletes, about safe, healthy methods to improve athletic performance and discourage them from using creatine or testosterone boosters. Retailers and state legislatures should also consider banning the sale of these products to minors.


ADCK4 "reenergizes" nephrotic syndrome.
Steroid-resistant nephrotic syndrome has a poor prognosis and often leads to end-stage renal disease development. In this issue of the JCI, Ashraf and colleagues used exome sequencing to identify mutations in the aarF domain containing kinase 4 (ADCK4) gene that cause steroid-resistant nephrotic syndrome. Patients with ADCK4 mutations had lower coenzyme Q10 levels, and coenzyme Q10 supplementation ameliorated renal disease in a patient with this particular mutation, suggesting a potential therapy for patients with steroid-resistant nephrotic syndrome with ADCK4 mutations.


Age-related differences in mind-wandering in daily life.
In recent years, several laboratory studies have indicated that healthy older adults exhibit a reduction in mind-wandering frequency compared with young adults. However, it is unclear if these findings extend to daily life settings. In the current study, using experience sampling over the course of a week in the daily life of 31 young and 20 older adults, we assessed age-related differences in: (a) mind-wandering frequency, (b) the relationship between affect and mind-wandering frequency, and (c) content of mind wandering. Older adults mind wandered less than young adults in daily life. Across age groups, negative affect was positively associated with mind-wandering occurrence. Finally, older adults reported that their thoughts were more pleasant, interesting, and clear compared with young adults, who had thoughts that were more dreamlike, novel, strange, and racing. Our results provide the first demonstration using thought sampling that older adults exhibit a reduction in mind-wandering frequency in daily life. Implications for current theories of age-related reductions in mind-wandering frequency are discussed. (PsycINFO Database Record


Wet cooling systems as a source of sporadic Legionnaires' disease: a geographical analysis of data for England and Wales, 1996-2006.
The source of infection for most sporadic cases of Legionnaires' disease remains unknown. This study aims quantify the relationship between cases and wet cooling systems (WCS), a potential source of aerosolised legionella bacteria. The study analysed data on 1163 sporadic, community-acquired cases of Legionnaires' disease in England and Wales with onset between 1996 and 2006, and 11630 postcode controls randomly sampled in proportion to population size and matched on region, age group and sex. The relationship between risk of Legionnaires' disease and distance from a WCS was analysed by conditional logistic regression. Cases and controls had a mean age of 56.3 years; 79.3% were male. Cases lived appreciably closer to WCS than their controls (mean distance of cases=2.11 km, controls=2.58 km; mean difference 0.47 km (95% CI 0.28 to 0.65)). The OR for disease within 1 km of a WCS compared with over 6 km (a distance taken to reflect background rates of Legionnaires' disease) was 1.59 (95% CI 1.26 to 2.01) when adjusted for socio-economic deprivation, and 1.33 (95% CI 1.04 to 1.71) when additionally adjusted for population density. The results suggest that residential proximity to a WCS may account for 19.6% of sporadic community-acquired cases. WCS may be an important source of sporadic, community-acquired cases of Legionnaires' disease, an observation that has important implications for health protection, especially given the likely increase in such systems as a component of strategies to improve energy efficiency in buildings.


Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry.
Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity.


The adipokines and inflammatory marker in young type 2 diabetics with metabolic syndrome: A pilot study.
The purpose of the metabolic syndrome (MetS) concept was to early identify subjects having risk for developing cardiovascular diseases and diabetes, which of both are involved in low grade inflammation and obesity. We wish to explore the role of adipokines and inflammatory marker in young type 2 diabetics (YDM) with MetS. Forty-eight YDM patients were divided to 2 and 3 groups according to the presence of the MetS (MetS+ and MetS-), and the numbers of MetS component (MetS-2 to MetS-4 with 1-2, 3, and 4-5 components) respectively. Plasma adipokines (tumor necrosis factor-α; TNF-α and adiponectin) and C-reactive protein (CRP) were measured and compared among groups. Blood pressure (BP), body mass index (BMI), and plasma triglyceride (TG) levels were higher in the group with MetS+ than that of MetS-. Except for diastolic BP, BMI, waist, and plasma TG levels, which were generally lower in the MetS-2 group, the rest demographic characteristics were not different among these three groups. Finally, the plasma adiponectin, CRP and TNF-αlevels were not different between both groups with or without MetS; and also among these three groups regardless the component numbers they had. YDM with MetS might have non-significant lower adiponectin and higher CRP levels compared to subjects without MetS. It needs prospective study with larger scale to explicit the role of cytokines and inflammatory markers in YDM with MetS.


Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin.
Proliferation of Ag-specific T cells is central to the development of protective immunity. The concomitant stimulation of the TCR and CD28 programs resting T cells to IL-2-driven clonal expansion. We report that a prolonged occupancy of the TCR and CD28 bypasses the need for autocrine IL-2 secretion and sustains IL-2-independent lymphocyte proliferation. In contrast, a short engagement of the TCR and CD28 only drives the expansion of cells capable of IL-2 production. TCR/CD28- and IL-2-driven proliferation revealed a different requirement for PI3K and for the mammalian target of rapamycin (mTOR). Thus, both PI3K and mTOR activities were needed for T cells to proliferate to TCR/CD28-initiated stimuli and for optimal cyclin E expression. In contrast, either PI3K or mTOR were sufficient for IL-2-driven cell proliferation as they independently mediated cyclin E induction. Interestingly, rapamycin delayed cell cycle entry of IL-2-sufficient T cells, but did not prevent their expansion. Together, our findings indicate that the TCR, CD28, and IL-2 independently control T cell proliferation via distinct signaling pathways involving PI3K and mTOR. These data suggest that Ag persistence and the availability of costimulatory signals and of autocrine and paracrine growth factors individually shape T lymphocyte expansion in vivo.


Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors.
Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.


The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer.
Ovarian cancer (OC) is one of the three types of malignant tumors in the female reproductive system, and epithelial ovarian cancer (EOC) is its most typical form. Due to the asymptomatic nature of the early stages and resistance to chemotherapy, EOC has both a poor prognosis and a high fatality rate. Current treatments for OC are very limited, and the 5-years survival rate is approximately 30%. Exosomes, which are microvesicles ranging from approximately 30-100 nm in size that are secreted by living cells, can be produced from different cell types and detected in various body fluids. Cancer cells can secrete more exosomes than healthy cells, and more importantly, the content of cancer cell-derived exosomes is distinct. The exosomes shedding from tumor cells are considered to be involved in tumor progression and metastasis. As such, exosomes are expected to be potential tools for tumor diagnosis and treatment. In this review, we briefly present the emerging roles of exosomes in OC and summarize related articles about their roles as diagnostic or prognostic biomarkers and in the treatment and drug resistance of OC.


Indigenous food security revival strategies at the village level: The gender factor implications.
This article is based on an evaluation concerning the practice of the Zunde raMambo concept (commonly referred to as Zunde) in four of Zimbabwe's 52 districts; (Mangwe, Lupane, Guruve and Hwedza). Zunde is a social security system providing protection against food shortages to vulnerable families and is coordinated by chiefs. The Zunde concept identifies with Ndebele and Shona rural communities in Zimbabwe. Thus, this evaluation sought to determine the relevance and fulfilment of the Zunde project objectives, namely: efficiency, effectiveness, impact and sustainability. The revived Zunde practice extends a long way in reducing food insecurity in vulnerable communities. Although the concept may be as old as the Zimbabwean culture, it had been abandoned as communities became urbanised. The Chief's Council of Zimbabwe, in collaboration with the Nutrition Unit of the Ministry of Health and Child Welfare have rekindled it. However, to revive this indigenous knowledge practice, there is need to assess the nature of existing social and economic structures, leadership, gender roles and the availability of resources such as land, inputs and implements. This article, which is based on both qualitative and quantitative data, collected between September 2013 and March 2014, goes on to reflect on policy issues surrounding disaster risk reduction (DRR) and survival strategies used by vulnerable communities in rural areas of Zimbabwe. It recommends that the gender factor approach offers the best means possible to understand peoples' needs and challenges as well as how these can be satisfied and resolved respectively.


The relationship of hip muscle performance to leg, ankle and foot injuries: a systematic review.
Hip control affects movement and muscle firing patterns in the leg, ankle and foot, and may contribute to overuse injuries. Muscle performance can be measured as strength, endurance or muscle activation patterns. Our objective was to systematically review whether hip muscle performance is associated with leg, ankle and foot injuries. A structured and comprehensive search of six medical literature databases was combined with forward and backward citation tracking (AMED, CINAHL, EMBASE, Medline, Scopus and SportDiscus). Eligible studies measured hip muscle performance in individuals with musculoskeletal injuries below the tibial tuberosity, using dynamometry or electromyography (EMG). All studies compared an injured group with a control group or compared the injured and non-injured limb in the same individual. Data was extracted from each study independently by two authors. Twenty case-control and four prospective studies (n = 24) met the inclusion criteria. Injury classifications included chronic ankle instability (n = 18), Achilles tendinopathy (n = 2), medial tibial stress syndrome and tibial stress fracture (n = 1), posterior tibial tendon dysfunction (n = 1), and exertional medial tibial pain (n = 2). Eleven of the studies revealed differences in hip muscle performance indicating less strength, delayed onset activation and decreased duration of activation in the injured groups. Two studies found evidence for differences between groups only in some of their measurements. Three out of the four prospective studies revealed that hip muscle performance was not a risk factor for leg, ankle and foot injuries. This review provides limited evidence that hip muscle performance variables are related to leg, ankle and foot injuries. Emerging evidence indicates this might be a result of the injury rather than a contributor to the injury.


Experimental basis for a stable plasmid, pLS30, to shuttle between Bacillus subtilis species by conjugational transfer.
The use of Bacillus subtilis 168 as the initial host for molecular cloning and subsequent delivery of the engineered DNA to other Bacillus hosts appears attractive, and would lead to an efficient DNA manipulation system. However, methods of delivery to other Bacillus species are limited due to their inability to develop natural competence. An alternative, unexplored conjugational transfer method drew our attention and a B. subtilis native plasmid, pLS30, isolated from B. subtilis (natto) strain IAM1168 was characterized for this aim. The nucleotide sequence (6,610 bp) contained the mob gene and its recognition sequence, oriT, that features pLS30 as a mobile plasmid between Bacillus species on conjugational transfer. Plasmid pLS3001, a chimera with a pBR322-based plasmid prepared in Escherichia coli to confer an antibiotic resistance marker, showed apparent mobilizing activity in the pLS20-mediated conjugational transfer system recently established. The rep gene and associated palT1-like sequence common to all other pLS plasmids previously sequenced indicated that pLS30 is a typical rolling circle replicating (RCR) type plasmid. Due to the significant stability of pLS30 in IAM1168, application of a mobile plasmid would allow quick propagation to Bacillus species.


Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus.
Many patients with insulin-dependent diabetes mellitus have an increase in the glomerular filtration rate and renal enlargement early in the course of their disease. Both these changes may be risk factors for the later development of diabetic nephropathy. Their cause is not known, but they could be due to augmented renal responses to the increase in plasma amino acid concentrations that occurs when dietary protein intake is high, a factor known to increase glomerular filtration and renal blood flow in normal subjects. We measured the glomerular filtration rate and renal plasma flow after an overnight fast and during an infusion of amino acids in 12 patients with insulin-dependent diabetes mellitus and 9 normal subjects. The diabetic patients were studied when they were hyperglycemic, when they were euglycemic after an insulin infusion for 36 hours, and after intensive insulin therapy for 3 weeks. Kidney volume was measured by ultrasonography before and after the period of intensive insulin therapy. The glomerular filtration rate and renal plasma flow were normal after fasting when the patients were hyperglycemic (mean [+/- SE] fasting plasma glucose level, 11.5 +/- 0.7 mmol per liter). After the amino acid infusion, these values increased more in the patients (glomerular filtration rate, 2.65 +/- 0.07 ml per second per 1.73 m2 of body-surface area; renal plasma flow, 13.30 +/- 0.68 ml per second per 1.73 m2; P less than 0.05 for both) than in the normal subjects (2.25 +/- 0.08 and 11.20 +/- 0.65 ml per second per 1.73 m2, respectively). The 36-hour infusion of insulin in the diabetic patients did not alter the glomerular filtration rate or renal plasma flow either before or during the amino acid infusion. After three weeks of intensive insulin therapy (fasting plasma glucose level, 5.3 +/- 0.2 mmol per liter), the glomerular filtration rate and renal plasma flow after the amino acid infusion (2.33 +/- 0.03 and 11.30 +/- 0.43 ml per second per 1.73 m2, respectively) were similar to those in the normal subjects. The kidney volumes in the normal subjects and the patients with diabetes were 219 +/- 14 and 312 +/- 14 ml per 1.73 m2, respectively (P less than 0.01); the volume decreased to 267 +/- 22 ml per 1.73 m2 (P less than 0.001) in the diabetic patients after three weeks of intensive insulin therapy, which was not significantly different from the volume in the normal subjects (P = 0.1). Conventionally treated diabetic patients who have normal renal function while fasting have augmented renal hemodynamic responses to increased plasma amino acid concentrations. The concomitant decrease in these hemodynamic responses and in kidney size with strict glycemic control suggests that these phenomena are related and influenced by the metabolic state.


Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse.
To determine whether loss of beta-cell mass and function in the NOD mouse occurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, beta-cell mass and rates of beta-cell proliferation and insulin secretory responses from the perfused pancreas were measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age, respectively. Beta-cell mass in 8-week-old NOD mice was 69% of control mice (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a compensatory proliferative response to ongoing autoimmune beta-cell destruction. Despite an increase in the rate of beta-cell proliferation, beta-cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than beta-cell mass, suggesting the presence of beta-cell dysfunction in addition to reduced mass. These results suggest that in the NOD mouse, beta-cell destruction begins soon after the onset of insulitis. Despite a compensatory beta-cell proliferative response, beta-cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be present when residual beta-cell mass represents 30% of control levels.


Experimental observation and analysis of the 3ν(1)(Σ(g)) stretching vibrational state of acetylene using continuous-wave infrared stimulated emission.
We present a sensitive experimental method for molecular spectroscopy that can be used to determine ro-vibrational states using mid-infrared stimulated emission. Our infrared stimulated emission probing (IRSEP) experiment is based on using a narrow-line, continuous-wave Ti:sapphire laser beam (pump) to excite the molecules to an upper vibrational state and a continuous-wave, mid-infrared beam from an optical parametric oscillator (probe) to detect the stimulated emission by the excited molecules. Spectroscopic data are gathered by tuning the wavelengths of the beams. The molecules are probed before their velocity distribution is disturbed by collisions, which leads to a sub-Doppler resolution. The full width at half maximum of the emission peaks is below 10 MHz. The stimulated emission lines are measured with an accuracy of at least 0.005 cm(-1). We use the IRSEP experiment to observe and analyze the symmetric ro-vibrational state [21+] (3ν1(Σg)) of acetylene (C2H2). This state is not accessible via one photon transitions from the ground vibrational state. We use the least-squares method to determine that the band center is at 9991.9725 (12) cm(-1) and the rotational parameters are B = 1.156145 (22) and D = 1.608 (87) × 10(-6) cm(-1), where the uncertainties in parentheses are one-standard errors in the least significant digit.


Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms: a case series and literature review.
Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behaviour compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours, and guidance for surveillance and treatment strategies are lacking. To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behaviour and outcomes of malignant OANs. A retrospective clinicopathological review of 10 histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas. We reviewed all the cases of malignant OAN reported in the literature and compared to our case series. Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin-Weiss-Bisceglia criteria, LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1. In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signalling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.


Incident-angle-controlled semitransparent colored perovskite solar cells with improved efficiency exploiting a multilayer dielectric mirror.
See-through perovskite solar cells with high efficiency and iridescent colors are demonstrated by employing a multilayer dielectric mirror. A certain amount of visible light is used for wide color gamut semitransparent color generation, which can be easily tuned by changing an angle of incidence, and a wide range of visible light is efficiently reflected back toward a photoactive layer of the perovskite solar cells by the dielectric mirror for highly efficient light-harvesting performance, thus achieving 10.12% power conversion efficiency. We also rigorously examine how the number of pairs in the multilayer dielectric mirror affects optical properties of the colored semitransparent perovskite solar cells. The described approach can open the door to a large number of applications such as building-integrated photovoltaics, self-powered wearable electronics and power-generating color filters for energy-efficient display systems.


Impact of complex genetic variation in COMT on human brain function.
Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.


Reversible dementia, psychotic symptoms and epilepsy in a patient with vitamin B12 deficiency.
Vitamin B12 deficiency is a common condition, typically associated with megaloblastic anaemia, glossitis and neuropsychiatric symptoms. We report the case of a patient presenting with progressive cognitive and functional deterioration, psychosis and seizures, later found to be secondary to pernicious anaemia. Importantly, the diagnosis of pernicious anaemia was only established 5 years after symptom onset and was overlooked even when the patient was under medical care, in part due to the lack of classic neurological and haematological signs associated with the condition. The patient had a remarkable neuropsychiatric recovery after vitamin replacement and psychopharmacological management. We discuss similar presentations of vitamin B12 deficiency found in the literature, symptom reversibility and the importance of its early recognition and treatment.


Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes.
The monocytic leukemia zinc finger protein MOZ and the related factor MORF form tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3. To gain new insights into the structure, function, and regulation of these complexes, we reconstituted them and performed various molecular analyses. We found that BRPF proteins bridge the association of MOZ and MORF with ING5 and EAF6. An N-terminal region of BRPF1 interacts with the acetyltransferases; the enhancer of polycomb (EPc) homology domain in the middle part binds to ING5 and EAF6. The association of BRPF1 with EAF6 is weak, but ING5 increases the affinity. These three proteins form a trimeric core that is conserved from Drosophila melanogaster to humans, although authentic orthologs of MOZ and MORF are absent in invertebrates. Deletion mapping studies revealed that the acetyltransferase domain of MOZ/MORF is sufficient for BRPF1 interaction. At the functional level, complex formation with BRPF1 and ING5 drastically stimulates the activity of the acetyltransferase domain in acetylation of nucleosomal histone H3 and free histones H3 and H4. An unstructured 18-residue region at the C-terminal end of the catalytic domain is required for BRPF1 interaction and may function as an "activation lid." Furthermore, BRPF1 enhances the transcriptional potential of MOZ and a leukemic MOZ-TIF2 fusion protein. These findings thus indicate that BRPF proteins play a key role in assembling and activating MOZ/MORF acetyltransferase complexes.


Experiences of Healthcare Professionals to the Introduction in Sweden of a Public eHealth Service: Patients' Online Access to their Electronic Health Records.
Patients' increasing demands for medical information, the digitization of health records and the fast spread of Internet access form a basis of introducing new eHealth services. An international trend is to provide access for patients to health information of various kind. In Sweden, access by patients to their proper electronic health record (EHR) has been provided in a pilot county since November 2012. This eHealth service is controversial and criticism has arised from the clinical professions, mainly physicians. Two web surveys were conducted to discover whether the opinions of healthcare professionals differ; between staff that have had experience with patients accessing their own EHR and those who have no such expericence. Experienced nurses found the EHR more important for the patients and a better reform, compared to unexperienced nurses in the rest of the country. Similarly, physicians with their own experience had a more positive attitude compared to non-experienced physicians. The conclusion of this study is that healthcare professionals must be involved in the implementation of public eHealth services such as EHRs and that real experiences of the professionals should be better disseminated to their inexperienced peers.


Hercules: a profile HMM-based hybrid error correction algorithm for long reads.
Choosing whether to use second or third generation sequencing platforms can lead to trade-offs between accuracy and read length. Several types of studies require long and accurate reads. In such cases researchers often combine both technologies and the erroneous long reads are corrected using the short reads. Current approaches rely on various graph or alignment based techniques and do not take the error profile of the underlying technology into account. Efficient machine learning algorithms that address these shortcomings have the potential to achieve more accurate integration of these two technologies. We propose Hercules, the first machine learning-based long read error correction algorithm. Hercules models every long read as a profile Hidden Markov Model with respect to the underlying platform's error profile. The algorithm learns a posterior transition/emission probability distribution for each long read to correct errors in these reads. We show on two DNA-seq BAC clones (CH17-157L1 and CH17-227A2) that Hercules-corrected reads have the highest mapping rate among all competing algorithms and have the highest accuracy when the breadth of coverage is high. On a large human CHM1 cell line WGS data set, Hercules is one of the few scalable algorithms; and among those, it achieves the highest accuracy.


Subduction and slab detachment in the Mediterranean-Carpathian region.
Seismic tomography models of the three-dimensional upper mantle velocity structure of the Mediterranean-Carpathian region provide a better understanding of the lithospheric processes governing its geodynamical evolution. Slab detachment, in particular lateral migration of this process along the plate boundary, is a key element in the lithospheric dynamics of the region during the last 20 to 30 million years. It strongly affects arc and trench migration, and causes along-strike variations in vertical motions, stress fields, and magmatism. In a terminal-stage subduction zone, involving collision and suturing, slab detachment is the natural last stage in the gravitational settling of subducted lithosphere.


Regional differences in the association between land cover and West Nile virus disease incidence in humans in the United States.
West Nile virus (WNV) is generally considered to be an urban pathogen in the United States, but studies associating land cover and disease incidence, seroprevalence, or infection rate in humans, birds, domesticated and wild mammals, and mosquitoes report varying and sometimes contradictory results at an array of spatial extents. Human infection can provide insight about basic transmission activity; therefore, we analyzed data on the incidence of WNV disease in humans to obtain a comprehensive picture of how human disease and land cover type are associated across the United States. Human WNV disease incidence in Northeastern regions was positively associated with urban land covers, whereas incidence in the Western United States was positively associated with agricultural land covers. We suggest that these regional associations are explained by the geographic distributions of prominent WNV vectors: Culex pipiens complex (including Cx. pipiens and Cx. quinquefasciatus) in the Northeast and Cx. tarsalis in the Western United States.


Is alcohol beneficial or harmful for cardioprotection?
While the effects of chronic ethanol consumption on liver have been well studied and documented, its effect on the cardiovascular system is bimodal. Thus, moderate drinking in many population studies is related to lower prevalence of coronary artery disease (CAD). In contrast, heavy drinking correlates with higher prevalence of CAD. In several other studies of cardiovascular mortalities, abstainers and heavy drinkers are at higher risk than light or moderate drinkers. The composite of this disparate relation in several population studies of cardiovascular mortality has been a "U-" or "J-"shaped curve. Apart from its ability to eliminate cholesterol from the intima of the arteries by reverse cholesterol transport, another major mechanism by which HDL may have this cardioprotective property is by virtue of the ability of its component enzyme paraoxonase1 (PON1) to inhibit LDL oxidation and/or inactivate OxLDL. Therefore, PON1 plays a central role in the disposal of OxLDL and thus is antiatherogenic. Furthermore, PON1 is a multifunctional antioxidant enzyme that can also detoxify the homocysteine metabolite, homocysteine thiolactone (HTL), which can pathologically cause protein damage by homocysteinylation of the lysine residues, thereby leading to atherosclerosis. We demonstrated that moderate alcohol up regulates liver PON1 gene expression and serum activity, whereas heavy alcohol consumption had the opposite effects in both animal models and in humans. The increase in PON1 activity in light drinkers was not due to preferential distribution of high PON1 genotype in this group. It is well known that wine consumption in several countries shows a remarkable inverse correlation to local rates of CAD mortality. Significantly, apart from its alcohol content, red wine also has polyphenols such as quercetin and resveratrol that are also known to have cardioprotective effects. We have shown that quercetin also up regulates PON1 gene in rats and in human liver cells. The action of quercetin seems to be mediated via the active form of the nuclear lipogenic transcription factor, sterol-regulatory element-binding protein 2 (SREBP2) that is translocated from endoplasmic reticulum to the nucleus. However, the mechanism of action of ethanol-mediated up-regulation of PON1 gene remains to be elucidated. We conclude that both moderate ethanol and quercetin, the two major components of red wine, exhibit cardioprotective properties via the up-regulation of the antiatherogenic gene PON1.


Boron distributions in individual core-shell Ge/Si and Si/Ge heterostructured nanowires.
Ge/Si and Si/Ge core-shell nanowires (NWs) have substantial potential for application in many kinds of devices. Because impurity distributions in Ge/Si and Si/Ge core-shell NWs strongly affect their electrical properties, which in turn affect device performance, this issue needs urgent attention. Here we report an atom probe tomographic study of the distribution of boron (B), one of the most important impurities, in two kinds of NWs. B atoms were doped into the Si regions of Ge/Si and Si/Ge core-shell NWs. It was found that the B atoms were randomly distributed in the Si shell of the Ge/Si core-shell NWs. In the Si/Ge core-shell NWs, on the other hand, the B distributions depended on the growth temperature and the B2H6 flux. With a higher growth temperature and an increased B2H6 flux, the B atoms piled up in the outer region of the Si core. However, the B atoms were observed to be randomly distributed in the Si core after decreasing both the growth temperature and the B2H6 flux.


Pitch memory and exposure effects.
Recent studies indicate that the ability to represent absolute pitch values in long-term memory, long believed to be the possession of a small minority of trained musicians endowed with "absolute pitch," is in fact shared to some extent by a considerable proportion of the population. The current study examined whether this newly discovered ability affects aspects of music and auditory cognition, particularly pitch learning and evaluation. Our starting points are two well-established premises: (1) frequency of occurrence has an influence on the way we process stimuli; (2) in Western music, some pitches and musical keys are much more frequent than others. Based on these premises, we hypothesize that if absolute pitch values are indeed represented in long-term memory, pitch frequency of occurrence in music would significantly affect cognitive processes, in particular pitch learning and evaluation. Two experiments were designed to test this hypothesis in participants with no absolute pitch, most with little or no musical training. Experiment 1 demonstrated a faster response and a learning advantage for frequent pitches over infrequent pitches in an identification task. In Experiment 2, participants evaluated infrequent pitches as more pleasing than frequent pitches when presented in isolation. These results suggest that absolute pitch representation in memory may play a substantial, hitherto unacknowledged role in auditory (and specifically musical) cognition.


Structure of Escherichia coli inorganic pyrophosphatase at 2.2 A resolution.
The refined crystal structures of hexameric soluble inorganic pyrophosphatase from E. coli (E-PPase) are reported to R factors of 18.7 and 18.3% at 2.15 and 2.2 A, respectively. The first contains one independent monomer; the other, two independent monomers, in an R32 unit cell. Because the E-PPase monomer is small with a large open active site, there are relatively few hydrophobic interactions that connect the active-site loops to the five-stranded twisted beta-barrel that is the hydrophobic core of the molecule. The active-site loops are, however, held in place by interactions between monomers around the threefold and twofold symmetry axes of the D(3) hexamer. Consequently, mutations of active-site residues (such as Glu20 and Lysl04) often affect protein stability and oligomeric structure. Conversely, mutations of residues in the interface between monomers (such as His136 and Hisl40) not only affect oligomeric structure but also affect active-site function. The effects of the H136Q and H140Q variants can be explained by the extended ionic interaction between H140, D143 and H136' of the neighbouring monomer. This interaction is further buttressed by an extensive hydrogen-bonding network that appears to explain why the E-PPase hexamer is so stable and also why the H136Q and H140Q variant proteins are less stable as hexamers.


Automated analysis of angle closure from anterior chamber angle images.
To evaluate a novel software capable of automatically grading angle closure on EyeCam angle images in comparison with manual grading of images, with gonioscopy as the reference standard. In this hospital-based, prospective study, subjects underwent gonioscopy by a single observer, and EyeCam imaging by a different operator. The anterior chamber angle in a quadrant was classified as closed if the posterior trabecular meshwork could not be seen. An eye was classified as having angle closure if there were two or more quadrants of closure. Automated grading of the angle images was performed using customized software. Agreement between the methods was ascertained by κ statistic and comparison of area under receiver operating characteristic curves (AUC). One hundred forty subjects (140 eyes) were included, most of whom were Chinese (102/140, 72.9%) and women (72/140, 51.5%). Angle closure was detected in 61 eyes (43.6%) with gonioscopy in comparison with 59 eyes (42.1%, P = 0.73) using manual grading, and 67 eyes (47.9%, P = 0.24) with automated grading of EyeCam images. The agreement for angle closure diagnosis between gonioscopy and both manual (κ = 0.88; 95% confidence interval [CI), 0.81-0.96) and automated grading of EyeCam images was good (κ = 0.74; 95% CI, 0.63-0.85). The AUC for detecting eyes with gonioscopic angle closure was comparable for manual and automated grading (AUC 0.974 vs. 0.954, P = 0.31) of EyeCam images. Customized software for automated grading of EyeCam angle images was found to have good agreement with gonioscopy. Human observation of the EyeCam images may still be needed to avoid gross misclassification, especially in eyes with extensive angle closure.


Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis.
To date, there are no inhibitors that directly and specifically target activated STAT3 and c-Myc in the clinic. Although peptide-based inhibitors can selectively block activated targets, their clinical usage is limited because of low cell penetration and/or serum stability. Here, we generated cell-penetrating acetylated (acet.) STAT3, c-Myc, and Gp130 targeting peptides by attaching phosphorothioated (PS) polymer backbone to peptides. The cell-penetrating peptides efficiently penetrated cells and inhibited activation of the intended targets and their downstream genes. Locally or systemically treating tumor-bearing mice with PS-acet.-STAT3 peptide at low concentrations effectively blocked STAT3 in vivo, resulting in significant antitumor effects in 2 human xenograft models. Moreover, PS-acet.-STAT3 peptide penetrated and activated splenic CD8+ T cells in vitro. Treating immune-competent mice bearing mouse melanoma with PS-acet.-STAT3 peptide inhibited STAT3 in tumor-infiltrating T cells, downregulating tumor-infiltrating CD4+ T regulatory cells while activating CD8+ T effector cells. Similarly, systemic injections of the cell-penetrating c-Myc and Gp130 peptides prevented pancreatic tumor growth and induced antitumor immune responses. Taken together, we have developed therapeutic peptides that effectively and specifically block challenging cancer targets, resulting in antitumor effects through both direct tumor cell killing and indirectly through antitumor immune responses.


High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin: a possible mechanism for reestablishing satellite cell quiescence in vivo.
Skeletal muscle regeneration and work-induced hypertrophy rely on molecular events responsible for activation and quiescence of resident myogenic stem cells, satellite cells. Recent studies demonstrated that hepatocyte growth factor (HGF) triggers activation and entry into the cell cycle in response to mechanical perturbation, and that subsequent expression of myostatin may signal a return to cell quiescence. However, mechanisms responsible for coordinating expression of myostatin after an appropriate time lag following activation and proliferation are not clear. Here we address the possible role of HGF in quiescence through its concentration-dependent negative-feedback mechanism following satellite cell activation and proliferation. When activated/proliferating satellite cell cultures were treated for 24 h beginning 48-h postplating with 10-500 ng/ml HGF, the percentage of bromodeoxyuridine-incorporating cells decreased down to a baseline level comparable to 24-h control cultures in a HGF dose-dependent manner. The high level HGF treatment did not impair the cell viability and differentiation levels, and cells could be reactivated by lowering HGF concentrations to 2.5 ng/ml, a concentration that has been shown to optimally stimulate activation of satellite cells in culture. Coaddition of antimyostatin neutralizing antibody could prevent deactivation and abolish upregulation of cyclin-dependent kinase (Cdk) inhibitor p21. Myostatin mRNA expression was upregulated with high concentrations of HGF, as demonstrated by RT-PCR, and enhanced myostatin protein expression and secretion were revealed by Western blots of the cell lysates and conditioned media. These results indicate that HGF could induce satellite cell quiescence by stimulating myostatin expression. The HGF concentration required (over 10-50 ng/ml), however, is much higher than that for activation, which is initiated by rapid release of HGF from its extracellular association. Considering that HGF is produced by satellite cells and spleen and liver cells in response to muscle damage, local concentrations of HGF bathing satellite cells may reach a threshold sufficient to induce myostatin expression. This time lag may delay action of the quiescence signaling program in proliferating satellite cells during initial phases of muscle regeneration followed by induction of quiescence in a subset of cells during later phases.


Enactment of home practice following mindfulness-based relapse prevention and its association with substance-use outcomes.
Mindfulness-based treatments have received increasing interest and empirical support in the clinical psychology literature. There are, however, no studies to date that have systematically examined treatment enactment, which is the amount and type of home practice participants incorporate into their daily lives. Because treatment enactment has been cited as a key aspect of treatment fidelity, this study examined the relationships between treatment enactment (i.e., home mindfulness practice) and alcohol and other drug (AOD) use and craving in the context of a larger study of mindfulness-based relapse prevention (MBRP). Participants (N=93) in this secondary analysis had been randomized in the parent study to receive MBRP. AOD use, craving, and home mindfulness practice were assessed at baseline, post-treatment, 2-month and 4-month follow-up time points. MBRP participants significantly increased the amount of time spent in home mindfulness practice over the course of the study. Further, greater time spent in home practice was associated with less AOD use and craving at the 2- and 4-month follow-ups. Of note, the significant treatment gains in home practice faded somewhat at the 2- and 4-month follow-ups as participants returned to standard aftercare, which did not involve mindfulness-based practice. Participation in MBRP was associated with a significant increase in home mindfulness practice, and increased involvement in home practice was associated with significantly lower AOD use and craving over the course of the study. This suggests that treatment enactment, which entails building mindfulness practice into one's daily life, plays a key role in ongoing recovery following MBRP treatment. Teaching mindfulness skills for daily use versus for only in high-risk situations has the potential to boost the longevity of MBRP treatment effects. These findings also suggest that MBRP clinicians should target the post-intervention decline in home practice (e.g., with ongoing mindfulness practice groups) to maximize the benefits of mindfulness meditation in decreasing AOD use and craving.


Nursing home administrators' perspectives on a study feedback report: a cross sectional survey.
This project is part of the Translating Research in Elder Care (TREC) program of research, a multi-level and longitudinal research program being conducted in 36 nursing homes in three Canadian Prairie Provinces. The overall goal of TREC is to improve the quality of care for older persons living in nursing homes and the quality of work life for care providers. The purpose of this paper is to report on development and evaluation of facility annual reports (FARs) from facility administrators' perspectives on the usefulness, meaningfulness, and understandability of selected data from the TREC survey. A cross sectional survey design was used in this study. The feedback reports were developed in collaboration with participating facility administrators. FARs presented results in four contextual areas: workplace culture, feedback processes, job satisfaction, and staff burnout. Six weeks after FARs were mailed to each administrator, we conducted structured telephone interviews with administrators to elicit their evaluation of the FARs. Administrators were also asked if they had taken any actions as a result of the FAR. Descriptive and inferential statistics, as well as content analysis for open-ended questions, were used to summarize findings. Thirty-one facility administrators (representing thirty-two facilities) participated in the interviews. Six administrators had taken action and 18 were planning on taking action as a result of FARs. The majority found the four contextual areas addressed in FAR to be useful, meaningful, and understandable. They liked the comparisons made between data from years one and two and between their facility and other TREC study sites in their province. Twenty-two indicated that they would like to receive information on additional areas such as aggressive behaviours of residents and information sharing. Twenty-four administrators indicated that FARs contained enough information, while eight found FARs 'too short'. Administrators who reported that the FAR contained enough information were more likely to take action within their facilities than administrators who reported that they needed more information. Although the FAR was brief, the presentation of the four contextual areas was relevant to the majority of administrators and prompted them to plan or to take action within their facility.


Two-Dimensional Electronic Spectroscopy Reveals Excitation Energy-Dependent State Mixing during Singlet Fission in a Terrylenediimide Dimer.
Singlet fission (SF) is a spin-allowed process in which a singlet exciton, 1(S1S0), within an assembly of two or more chromophores spontaneously down-converts into two triplet excitons via a multiexciton correlated triplet pair state, 1(T1T1). To elucidate the involvement of charge transfer (CT) states and vibronic coupling in SF, we performed 2D electronic spectroscopy (2DES) on dilute solutions of a covalently linked, slip-stacked terrylene-3,4:11,12-bis(dicarboximide) (TDI) dimer. This dimer undergoes efficient SF in nonpolar 1,4-dioxane and symmetry-breaking charge separation in polar dichloromethane. The various 2DES spectral features in 1,4-dioxane show different pump wavelength dependencies, supporting the presence of mixed states with variable 1(S1S0), 1(T1T1) and CT contributions that evolve with time. Analysis of the 2DES spectra in dichloromethane reveals the presence of a state having largely 1(T1T1) character during charge separation. Therefore, the 1(T1T1) multiexciton state plays an important role in the photophysics of this TDI dimer irrespective of solvent polarity.


Differentiation capacity and maintenance of differentiated phenotypes of human mesenchymal stromal cells cultured on two distinct types of 3D polymeric scaffolds.
Many studies have shown the influence of soluble factors and material properties on the differentiation capacity of mesenchymal stromal cells (MSCs) cultured as monolayers. These types of two-dimensional (2D) studies can be used as simplified models to understand cell processes related to stem cell sensing and mechano-transduction in a three-dimensional (3D) context. For several other mechanisms such as cell-cell signaling, cell proliferation and cell morphology, it is well-known that cells behave differently on a planar surface compared to cells in 3D environments. In classical tissue engineering approaches, a combination of cells, 3D scaffolds and soluble factors are considered as the key ingredients for the generation of mechanically stable 3D tissue constructs. However, when MSCs are used for tissue engineering strategies, little is known about the maintenance of their differentiation potential in 3D scaffolds after the removal of differentiation soluble factors. In this study, the differentiation potential of human MSCs (hMSCs) into the chondrogenic and osteogenic lineages on two distinct 3D scaffolds, additive manufactured electrospun scaffolds, was assessed and compared to conventional 2D culture. Human MSCs cultured in the presence of soluble factors in 3D showed to differentiate to the same extent as hMSCs cultured as 2D monolayers or as scaffold-free pellets, indicating that the two scaffolds do not play a consistent role in the differentiation process. In the case of phenotypic changes, the achieved differentiated phenotype was not maintained after the removal of soluble factors, suggesting that the plasticity of hMSCs is retained in 3D cell culture systems. This finding can have implications for future tissue engineering approaches in which the validation of hMSC differentiation on 3D scaffolds will not be sufficient to ensure the maintenance of the functionality of the cells in the absence of appropriate differentiation signals.


China's health care system reform: Progress and prospects.
This paper discusses the progress and prospects of China's complex health care reform beginning in 2009. The Chinese government's undertaking of systemic reform has achieved laudable achievements, including the expansion of social health insurance, the reform of public hospitals, and the strengthening of primary care. An innovative policy tool in China, policy experimentation under hierarchy, played an important role in facilitating these achievements. However, China still faces gaps and challenges in creating a single payer system, restructuring the public hospitals, and establishing an integrated delivery system. Recently, China issued the 13th 5-year plan for medical reform, setting forth the goals, policy priorities, and strategies for health reform in the following 5 years. Moreover, the Chinese government announced the "Healthy China 2030" blueprint in October 2016, which has the goals of providing universal health security for all citizens by 2030. By examining these policy priorities against the existing gaps and challenges, we conclude that China's health care reform is heading in the right direction. To effectively implement these policies, we recommend that China should take advantage of policy experimentation to mobilize bottom-up initiatives and encourage innovations.


The ISCB Student Council Internship Program: Expanding computational biology capacity worldwide.
Education and training are two essential ingredients for a successful career. On one hand, universities provide students a curriculum for specializing in one's field of study, and on the other, internships complement coursework and provide invaluable training experience for a fruitful career. Consequently, undergraduates and graduates are encouraged to undertake an internship during the course of their degree. The opportunity to explore one's research interests in the early stages of their education is important for students because it improves their skill set and gives their career a boost. In the long term, this helps to close the gap between skills and employability among students across the globe and balance the research capacity in the field of computational biology. However, training opportunities are often scarce for computational biology students, particularly for those who reside in less-privileged regions. Aimed at helping students develop research and academic skills in computational biology and alleviating the divide across countries, the Student Council of the International Society for Computational Biology introduced its Internship Program in 2009. The Internship Program is committed to providing access to computational biology training, especially for students from developing regions, and improving competencies in the field. Here, we present how the Internship Program works and the impact of the internship opportunities so far, along with the challenges associated with this program.


Collision cross section calibrants for negative ion mode traveling wave ion mobility-mass spectrometry.
Unlike traditional drift-tube ion mobility-mass spectrometry, traveling-wave ion mobility-mass spectrometry typically requires calibration in order to generate collision cross section (CCS) values. Although this has received a significant amount of attention for positive-ion mode analysis, little attention has been paid for CCS calibration in negative ion mode. Here, we provide drift-tube CCS values for [M - H](-) ions of two calibrant series, polyalanine and polymalic acid, and evaluate both types of calibrants in terms of the accuracy and precision of the traveling-wave ion mobility CCS values that they produce.


[Survival factors in 152 patients with gastrointestinal stromal tumors].
The gastrointestinal stromal tumor (GIST) is the designation for a specific type of mesenchymal tumor of the digestive tract that is origin in the interstitial cells of Cajal (ICC) or its precursor multipotentials, its presentation is rare and therefore its best knowledge must affect a proper diagnosis and treatment. To evaluate the clinical characteristics and to identify factors influencing survival of patients with gastrointestinal stromal tumor. This study design is quantitative, non experimental, descriptive, retrospective and transversal. The study has been performed in 152 patients with gastrointestinal stromal tumor who were treated at the National Institute of Neoplastic Diseases (INEN), Lima, Peru, from January 1999 through December 2009. For the final diagnosis was registered the outcome of the surgical and histology was complemented by immunohistochemical test. To assess the normal distribution of the population was used the Shapiro-Wolk, Anderson-Darling, Lilliefors, regarding the use of inferential statistical tables for survival and to assess its significance in the univariate analysis (p <0.05 significance), was used the Wilcoxon test, Tarone-Ware Log-rank and also to evaluate the difference between groups in contingency tables used the chi square and Fisher's test. Multivariate analysis was performed using the proportional hazards model of Cox. The group of 152 patients included 78 women (51%) and 74 men (49%) with age range from 16 to 92 years, with an average age of 54. The frequency presentation was increased from the fourth decade of life and reaches its highest expression between 50 and 70. The initial presentation was with localized disease to 79 patients (52%) and primary metastases in 73 patients (48%), with an average time of disease 14 months. The prevalence of GIST tumor in the different organs was as follows: stomach with 77 patients (50.65%), jejunum with 21 patients (13.82%), retroperitoneum with 17 patients (11.18%), duodenum 11 patients (7.24%), colon 11 patients (7.24%), ileum 8 patients (5.26%),pancreas, 3 patients (1.97%), rectum, 3 patients (1.97%) and esophagus with 1 patient (0.66%). The most common symptoms of GIST tumors in general were gastrointestinal bleeding, abdominal tumor and abdominal pain. There are organ-specific symptoms such as jaundice in pancreas, dysphagia in esophagus and obstruction in the ileum. The tumor size greater than 10 centimeters was found in 92 patients (60.51%), 39 patients had size between 5 and 10 centimeters (25.65%) and 20 patients had lesions smaller than 5 centimeters (13.15%). Immunohistochemistry tests performed in 75 patients show that for all locations, the expression of KIT (CD117) is 94.8%, followed by CD34 to 70.35%; on the other hand, actin (61.68%) and S-100 (57.56%) have a smaller range of expression. Retroperitoneal GIST tumors had an expression of CD117 of 92.86% and CD34 of 60%, and GIST tumors of the pancreas had an expression of CD117 of 100% and CD34 of 100%. We evaluated 27 patients with low mitotic index, of which 10 had primary metastases (37%), in turn, of 25 patients with high mitotic index, 8 had primary metastases (32%). Of the 152 patients, 93 had complete resection of the disease, 28 had partial resection, 24 were unresectable and 07 did not undergo surgery, the more aggressive behavior was observed in ileum, 03 patients were unresectable, 02 patients had partial resection and only 02 could be completely resected, the rest of the series in general, for each location, the GIST tumors completely resected outscored the unresectable and partially resected. Of 93 patients that had completely resected, recurrence was found in 32 of these patients (34.4%), recurrence was local in 8 patients, metastases in 18 patients and local recurrence + metastases in 6 patients, with an average time of recurrence 22 months. The overall cumulative survival at 5 years was 81.35%. The survival of patients under and over 50 expressed a p = 0.08, cumulative survival rates by tumor size expressed p = 0.56, cumulative survival rates for stomach and intestinal location shows a p = 0.056. The 5-year survival of completely resected patients was 87.70%. Overall survival of patients with and without metastasis expressed p = 0.001, the cumulative survival function completely resected patients, the resected and partially resected, expresses with p <0.0001. Multivariate analysis showed that the most significant factor for disease progression was the primary metastases with p = 0.007, and that survival was directly related to complete resection of the disease which is expressed with p <0.0001. The most important prognostic factor of survival for gastrointestinal stromal tumors (GIST) is the complete resection of the disease. The factor that is associated with progression of the disease is the presence of metastases. In our series of 152 patients, tumor locations tend to relate better survival in gastric GIST that in intestinal GIST. Similarly, we found a tendency to express a lower survival in patients younger than 50 years. Differentiated tumor size in three size categories expressed no more related to survival. The low mitotic index associated with metastasis, not reflected a good prognosis of disease.


The influence of ridge migration on the magmatic segmentation of mid-ocean ridges.
The Earth's mid-ocean ridges display systematic changes in depth and shape, which subdivide the ridges into discrete spreading segments bounded by transform faults and smaller non-transform offsets of the axis. These morphological changes have been attributed to spatial variations in the supply of magma from the mantle, although the origin of the variations is poorly understood. Here we show that magmatic segmentation of ridges with fast and intermediate spreading rates is directly related to the migration velocity of the spreading axis over the mantle. For over 9,500 km of mid-ocean ridge examined, leading ridge segments in the 'hotspot' reference frame coincide with the shallow magmatically robust segments across 86 per cent of all transform faults and 73 per cent of all second-order discontinuities. We attribute this relationship to asymmetric mantle upwelling and melt production due to ridge migration, with focusing of melt towards ridge segments across discontinuities. The model is consistent with variations in crustal structure across discontinuities of the East Pacific Rise, and may explain variations in depth of melting and the distribution of enriched lavas.


Impact of anatase and rutile titanium dioxide nanoparticles on uptake carriers and efflux pumps in Caco-2 gut epithelial cells.
TiO2 microparticles are widely used in food products, where they are added as a white food colouring agent. This food additive contains a significant amount of nanoscale particles; still the impact of TiO2 nanoparticles (TiO2-NPs) on gut cells is poorly documented. Our study aimed at evaluating the impact of rutile and anatase TiO2-NPs on the main functions of enterocytes, i.e. nutrient absorption driven by solute-liquid carriers (SLC transporters) and protection against other xenobiotics driven by efflux pumps from the ATP-binding cassette (ABC) family. We show that acute exposure of Caco-2 cells to both anatase (12 nm) and rutile (20 nm) TiO2-NPs induce early upregulation of a battery of efflux pumps and nutrient transporters. In addition they cause overproduction of reactive oxygen species and misbalance redox repair systems, without inducing cell mortality or DNA damage. Taken together, these data suggest that TiO2-NPs may increase the functionality of gut epithelial cells, particularly their property to form a protective barrier against exogenous toxicants and to absorb nutrients.


The Good, the bad, and the just: justice sensitivity predicts neural response during moral evaluation of actions performed by others.
Morality is a fundamental component of human cultures and has been defined as prescriptive norms regarding how people should treat one another, including concepts such as justice, fairness, and rights. Using fMRI, the current study examined the extent to which dispositions in justice sensitivity (i.e., how individuals react to experiences of injustice and unfairness) predict behavioral ratings of praise and blame and how they modulate the online neural response and functional connectivity when participants evaluate morally laden (good and bad) everyday actions. Justice sensitivity did not impact the neuro-hemodynamic response in the action-observation network but instead influenced higher-order computational nodes in the right temporoparietal junction (rTPJ), right dorsolateral and dorsomedial prefrontal cortex (rdlPFC, dmPFC) that process mental states understanding and maintain goal representations. Activity in these regions predicted praise and blame ratings. Further, the hemodynamic response in rTPJ showed a differentiation between good and bad actions 2 s before the response in rdlPFC. Evaluation of good actions was specifically associated with enhanced activity in dorsal striatum and increased the functional coupling between the rTPJ and the anterior cingulate cortex. Together, this study provides important knowledge in how individual differences in justice sensitivity impact neural computations that support psychological processes involved in moral judgment and mental-state reasoning.


Prediction and Outcome of Intensive Care Unit-Acquired Paresis.
Intensive care unit-acquired paresis (ICUAP) is associated with poor outcomes. Our objective was to evaluate predictors for ICUAP and the short-term outcomes associated with this condition. A secondary analysis of a prospective study including 4157 mechanically ventilated adults in 494 intensive care units from 39 countries. After sedative interruption, patients were screened for ICUAP daily, which was defined as the presence of symmetric and flaccid quadriparesis associated with decreased or absent deep tendon reflexes. A multinomial logistic regression was used to create a predictive model for ICUAP. Propensity score matching was used to estimate the relationship between ICUAP and short-term outcomes (ie, weaning failure and intensive care unit [ICU] mortality). Overall, 114 (3%) patients had ICUAP. Variables associated with ICUAP were duration of mechanical ventilation (relative risk ratio [RRR] per day, 1.10; 95% confidence interval [CI] 1.08-1.12), steroid therapy (RRR 1.8; 95% CI, 1.2-2.8), insulin therapy (RRR 1.8; 95% CI 1.2-2.7), sepsis (RRR 1.9; 95% CI: 1.2 to 2.9), acute renal failure (RRR 2.2; 95% CI 1.5-3.3), and hematological failure (RRR 1.9; 95% CI: 1.2-2.9). Coefficients were used to generate a weighted scoring system to predict ICUAP. ICUAP was significantly associated with both weaning failure (paired rate difference of 22.1%; 95% CI 9.8-31.6%) and ICU mortality (paired rate difference 10.5%; 95% CI 0.1-24.0%). Intensive care unit-acquired paresis is relatively uncommon but is significantly associated with weaning failure and ICU mortality. We constructed a weighted scoring system, with good discrimination, to predict ICUAP in mechanically ventilated patients at the time of awakening.


A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.
Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process.