Orientation and directed migration of cultured corneal epithelial cells in small electric fields are serum dependent.
Reorientation and migration of cultured bovine corneal epithelial cells (CECs) in an electric field were studied. Electric field application was designed to model the laterally directed, steady direct current electric fields which arise in an injured corneal epithelium. Single cells cultured in media containing 10% foetal bovine serum showed significant galvanotropism, reorienting to lie perpendicular to electric field vector with a threshold field strength of less than 100 mV/mm. Cells cultured in serum-free medium showed no reorientation until 250 mV/mm. Addition of EGF, bFGF or TGF-beta 1 singly or in combination to serum free medium significantly restored the reorientation response at low field strengths. Both the mean translocation rate and directedness of cell migration were serum dependent. Cultured in medium with serum or serum plus added EGF, single cells showed obvious cathodal migration at 100 mV/mm. Increasing electric field strength enhanced the cathodal directedness of single cell migration. Supplementing serum free medium with growth factors restored the cathodal directed migration of single cells and highest directedness was found for the combination of EGF and TGF-beta 1. Corneal epithelial sheets also migrated towards the cathode in electric fields. Serum or individual growth factors stimulated CEC motility (randomly directed). Applied fields did not further augment migration rates but added a vector to stimulated migration. Electric fields which are present in wounded cornea interact with other environmental factors and may impinge on CECs migration during wound healing. Therapies which combine the application of growth factors and electric fields may be useful clinically.


Common genes contribute to depressive symptoms and heart rate variability: the Twins Heart Study.
Depression and reduced heart rate variability (HRV) are predictors of coronary artery disease (CAD), and highly correlated with each other. However, little is known to what extend this correlation can be explained by common genetic components. We examined 198 middle-aged male twins (121 monozygotic and 77 dizygotic) from the Vietnam Era Twin Registry. Current depressive symptoms were assessed using the Beck Depression Inventory-II and HRV was assessed on 24-hour electrocardiographic Holter recordings. Five frequency domain variables were used, including ultra low frequency (ULF), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TPow). Structural equation modeling was used to estimate shared genetic effects for depressive symptoms and the HRV frequency domains. Both depressive symptoms (h(2)=.5) and all measurements of HRV showed high heritability (h(2)=.43-.63). A significant inverse correlation was found between depressive symptoms and all HRV indices except LF and HF, with the highest coefficient (r) for TPow (r = -.24, P = .01) and ULF (r = -.24, P = .01). Bivariate genetic modeling revealed significant genetic correlations between depressive symptoms and TPow (r(A) = -.21, P = .04), as well as ULF (r(A) = -.23, P = .02). Of the total covariance between depressive symptoms and these two HRV indices, over 80% was due to the same genetic factors. In conclusion, depressive symptoms are associated with decreased HRV and this association is due, in large part, to a shared genetic effect. These results suggest that a common neurobiological dysfunction links depression and autonomic dysregulation.


Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol.
Six novel aminoalkylindole analogs, related structurally to the dual cyclooxygenase inhibitor and nonopioid analgesic pravadoline, were evaluated in the mouse to determine whether their pharmacological profile of activity was similar to that exhibited by delta 9-tetrahydrocannabinol (delta 9-THC). Analog I (C2-H; C3-methoxy-benzoyl) reduced locomotion, but had no other effects (hypothermia, antinociception or ring-immobility) up to 21 mumol/kg. Analogs II and III (C3-naphthoyl; C2-H and C2-methyl, respectively) possessed all properties exhibited by delta 9-THC with ED50 values ranging from 0.68 to 18 mumol/kg. Analog IV (C2-methyl; C3-anthroyl) was devoid of activity. Stereoselectivity was demonstrated by the fact that (+)-WIN-55,212 (one isomer of a semirigid derivative possessing C2-H and C3-naphthoyl substituents) was moderately potent in all tests (ED50 values ranging from 0.25-23 mumol/kg), but (-)-WIN-55,212 was inactive up to 57 mumol/kg. Active aminoalkylindole compounds were generally least effective in the production of hypothermia. Analogs were also evaluated for their ability to produce delta 9-THC-like discriminative stimulus effects in rats. The ED50 for delta 9-THC as a discriminative stimuli for this model was 1.9 mumol/kg. Analog II and III and (+)-WIN-55,212 produced delta 9-THC-like discriminative effects with ED50 values ranging from 0.33 to 4.3 mumol/kg, whereas analogs I, IV and (-)-WIN-55,212 did not. Although reported to be cannabinoid receptor antagonists in vitro, neither analog I, analog IV nor (-)-WIN-55,212 (at 20 mumol/kg) antagonized the in vivo pharmacological effects of delta 9-THC in the mouse or rat.(ABSTRACT TRUNCATED AT 250 WORDS)


Mapping future fire probability under climate change: Does vegetation matter?
Understanding where and how fire patterns may change is critical for management and policy decision-making. To map future fire patterns, statistical correlative models are typically developed, which associate observed fire locations with recent climate maps, and are then applied to maps of future climate projections. A potential source of uncertainty is the common omission of static or dynamic vegetation as predictor variables. We therefore assessed the sensitivity of future fire projections to different combinations of vegetation maps used as explanatory variables in a statistically based fire modeling framework. We compared models without vegetation to models that incorporated static vegetation maps and that included output from a dynamic vegetation model that imposed three scenarios of fire and one scenario of land use change. We mapped projected future probability of all and large fires (> = 40 ha) under two climate scenarios in a heterogeneous study area spanning a large elevational gradient in the Sierra Nevada, California, USA. Results showed high model sensitivity to the treatment of vegetation as a predictor variable, particularly for models of large fire probability and for models accounting for wildfire effects on vegetation, which lowered future fire probability. Some scenarios resulted in opposite directional trends in the extent and probability of future fire, which could have serious implications for policy and management resource allocation. Model sensitivity resulted from high relative importance of vegetation variables in the baseline models and from large predicted changes in vegetation, particularly when simulating wildfire. Although statistical fire models often omit vegetation due to uncertainty, model sensitivity demonstrated here suggests a need to account for that uncertainty. Coupling statistical and processed based models may be a promising approach to reflect a more plausible range of scenarios.


Interobserver variation in the reporting of cervical colposcopic biopsy specimens: comparison of grading systems.
To assess interobserver variation in reporting cervical colposcopic biopsy specimens and to determine whether a modified Bethesda grading system results in better interobserver agreement than the traditional cervical intraepithelial neoplasia (CIN) grading system. One hundred and twenty five consecutive cervical colposcopic biopsy specimens were assessed independently by six histopathologists. Specimens were classified using the traditional CIN grading system as normal, koilocytosis, CIN I, CIN II, or CIN III. The specimens were also classified using a modified Bethesda grading system as either normal, low grade squamous intraepithelial lesion (LSIL) or high grade squamous intraepithelial lesion (HSIL). Participants were also asked to categorise biopsy specimens by the CIN system with the addition of the recently proposed category "basal abnormalities of uncertain significance (BAUS)". The degree of agreement between participants was assessed by kappa statistics. Using the CIN system, interobserver agreement was generally poor: unweighted and weighted kappa values between individual pairs of observers ranging from 0.05 to 0.34 (average 0.20) and from 0.20 to 0.54 (average 0.36), respectively. With the modified Bethesda system, interobserver agreement was better but still poor: unweighted and weighted kappa values ranging from 0.15 to 0.58 (average 0.30) and from 0.21 to 0.61 (average 0.36), respectively. There was little or no agreement between observers in the diagnosis of BAUS. Interobserver agreement in the reporting of cervical colposcopic biopsy specimens using the CIN grading system is poor. Agreement, while still poor, is better when a modified Bethesda grading system is used. There is little or no consensus in the diagnosis of BAUS.


Lung cancer risk in welders and foundry workers with a history of heavy smoking in the USA: The National Lung Screening Trial.
Foundry work is a risk factor for lung cancer; however, the association with welding is unclear, as smoking is common among metalworkers and may mask the relationship. We evaluated whether history of welding and foundry work, independently and jointly, and employment duration were associated with lung cancer risk in heavy smokers. We analysed data from the National Lung Screening Trial, a prospective randomised trial of 53 454 heavy smokers (>30 pack-years) in the USA. Cox regression models were used to estimate the HRs and 95% CIs of medically/histologically confirmed incident lung cancer during the follow-up period (2002-2009) in relation to history and duration of welding and foundry work assessed via questionnaires, adjusted for screening arm, component study, sex, age, race/ethnicity, education, smoking status and pack-years, body mass index and personal/family medical history. There were 2034 incident lung cancer cases throughout the follow-up. Increasing years of employment in welding (p-trend =0.039) and foundry work (p-trend =0.005) were related to increased lung cancer risk among heavy smokers. Having ever been employed (≥1 yr) as either a welder or foundry worker alone was associated with non-significant increased risks of lung cancer (HR=1.12 (95% CI 0.91 to 1.37) and HR=1.09 (95% CI 0.85 to 1.39), respectively). Further, there was a joint-effect in that those who were ever employed in both occupations had significantly increased risks (HR=1.48 (95% CI 1.08 to 2.04)). Our findings provide further evidence that exposure to welding/metal fumes may be associated with elevated lung cancer risk. NCT00047385.


Whole genome resequencing of black Angus and Holstein cattle for SNP and CNV discovery.
One of the goals of livestock genomics research is to identify the genetic differences responsible for variation in phenotypic traits, particularly those of economic importance. Characterizing the genetic variation in livestock species is an important step towards linking genes or genomic regions with phenotypes. The completion of the bovine genome sequence and recent advances in DNA sequencing technology allow for in-depth characterization of the genetic variations present in cattle. Here we describe the whole-genome resequencing of two Bos taurus bulls from distinct breeds for the purpose of identifying and annotating novel forms of genetic variation in cattle. The genomes of a Black Angus bull and a Holstein bull were sequenced to 22-fold and 19-fold coverage, respectively, using the ABI SOLiD system. Comparisons of the sequences with the Btau4.0 reference assembly yielded 7 million single nucleotide polymorphisms (SNPs), 24% of which were identified in both animals. Of the total SNPs found in Holstein, Black Angus, and in both animals, 81%, 81%, and 75% respectively are novel. In-depth annotations of the data identified more than 16 thousand distinct non-synonymous SNPs (85% novel) between the two datasets. Alignments between the SNP-altered proteins and orthologues from numerous species indicate that many of the SNPs alter well-conserved amino acids. Several SNPs predicted to create or remove stop codons were also found. A comparison between the sequencing SNPs and genotyping results from the BovineHD high-density genotyping chip indicates a detection rate of 91% for homozygous SNPs and 81% for heterozygous SNPs. The false positive rate is estimated to be about 2% for both the Black Angus and Holstein SNP sets, based on follow-up genotyping of 422 and 427 SNPs, respectively. Comparisons of read depth between the two bulls along the reference assembly identified 790 putative copy-number variations (CNVs). Ten randomly selected CNVs, five genic and five non-genic, were successfully validated using quantitative real-time PCR. The CNVs are enriched for immune system genes and include genes that may contribute to lactation capacity. The majority of the CNVs (69%) were detected as regions with higher abundance in the Holstein bull. Substantial genetic differences exist between the Black Angus and Holstein animals sequenced in this work and the Hereford reference sequence, and some of this variation is predicted to affect evolutionarily conserved amino acids or gene copy number. The deeply annotated SNPs and CNVs identified in this resequencing study can serve as useful genetic tools, and as candidates in searches for phenotype-altering DNA differences.


Molecular dynamics simulations of the structure and the morphology of graphene/polymer nanocomposites.
The structure and morphology of three polymer/graphene nanocomposites have been studied using classical molecular dynamics (MD) simulations. The simulations use 10-monomer oligomeric chains of three polymers: polyethylene (PE), polystyrene (PS) and polyvinylidene fluoride (PVDF). The structure of the polymer chains at the graphene surface has been investigated and characterized by pair correlation functions (PCF), g(r), g(θ) and g(r,θ). In addition, the influence of the temperature on the graphene/polymer interactions has been analysed for each of the three polymer/graphene nanocomposite systems. The results indicate that graphene induces order in both the PE and PVDF systems by providing a nucleation site for crystallisation, steering the growth of oligomer crystals according to the orientation of the graphene sheet, whereas the PS system remains disordered in the presence of graphene. The overall results are in line with the findings in a recent quantumchemical study by some of the present authors.


Intrinsic functional architecture in the anaesthetized monkey brain.
The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain's energy consumption is devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour. Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks. Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the 'default' system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.


Haemocyanin mRNA from arthropod and mollusc origin. Evidence for a multi-unit structure in mollusc haemocyanin mRNA.
mRNA from two molluscs, the snail Levantina hierosolima and the cuttlefish Sepia officinalis, and one arthropod, the scorpion Leiurus quinquestriatus, were found to contain species that hybridize with an oligodeoxynucleotide sequence corresponding to the six-amino-acid sequence His-His-Trp-His-Trp-His postulated to carry binuclear copper in arthropod haemocyanins. The duplexes formed between the oligodeoxynucleotide and mRNA from Leiurus and Levantina had similar 'melting' temperatures, namely 46.5 and 44.5 degrees C respectively. The hybridizable mRNA species were identified with mRNA that codes for haemocyanin, Hc mRNA. Electrophoresis under denaturing conditions of Leiurus Hc mRNA gave a single band corresponding to 2.3 kb (kilobases), consistent with the value of 75 000 reported for the Mr of the polypeptide chain of arthropod haemocyanin. Electrophoresis of mollusc Hc mRNA yielded RNA bands corresponding to 9.4, 6.7, 4.0 and 1.7 kb for Levantina and 9.5, 2.8 and 1.7 kb for Sepia. The 9.4 and 9.5 kb species represent authentic Hc mRNA and are consistent with an Mr of 350 000 for molluscan haemocyanin polypeptide chain. The faster-moving RNA bands are attributed to Hc mRNA cleavage by nucleases during isolation of mRNA. Analysis of the electrophoretic band pattern indicates a multi-unit structure for mollusc Hc mRNA.


Mutation of a conserved cysteine in the X-linked cone opsins causes color vision deficiencies by disrupting protein folding and stability.
To test the effects of disruption of a conserved cysteine in the green cone opsin molecule on light-activated isomerization, transducin activation, folding, transport, and protein half-life. Stable cell lines were established by transfecting 293-EBNA cells with a plasmid containing wild-type or mutant (C203R, C203S, C126S, C126S/C203S) green opsin cDNA molecules. The proteins were induced by culturing the cells in the presence of cadmium chloride and analyzed by spectra, transducin activation, Western blotting, pulse-labeling with immunoprecipitation, and immunocytochemistry. The C203R mutation disrupts the folding and half-life of the green opsin molecule and its abilities to absorb light at the appropriate wavelength and to activate transducin. Similar disruption of folding, half-life, and light activation occurs when Cys203 or its presumed partner for formation of a disulfide bond (Cys126) is replaced by serine residues. Like rhodopsin, the folding of the cone opsins appears to be dependent on the formation of a disulfide bond between the third transmembrane helix and the second extracellular loop. Disruption of this disulfide bond represents a cause of color vision deficiencies that is unrelated to spectral shifts of the photopigment.


Body perception disturbance: a contribution to pain in complex regional pain syndrome (CRPS).
In spite of pain in the CRPS limb, clinical observations show patients pay little attention to, and fail to care for, their affected limb as if it were not part of their body. Literature describes this phenomenon in terms of neurological neglect-like symptoms. This qualitative study sought to explore the nature of the phenomenon with a view to providing insights into central mechanisms and the relationship with pain. Twenty-seven participants who met the IASP CRPS classification were interviewed using qualitative methods to explore feelings and perceptions about their affected body parts. These semi-structured interviews were analysed utilising principles of grounded theory. Participants revealed bizarre perceptions about a part of their body and expressed a desperate desire to amputate this part despite the prospect of further pain and functional loss. A mismatch was experienced between the sensation of the limb and how it looked. Anatomical parts of the CRPS limb were erased in mental representations of the affected area. Pain generated a raised consciousness of the limb yet there was a lack of awareness as to its position. These feelings were about the CRPS limb only as the remaining unaffected body was felt to be normal. Findings suggest that there is a complex interaction between pain, disturbances in body perception and central remapping. Clinically, findings support the use of treatments that target cortical areas, which may reduce body perception disturbance and pain. We propose that body perception disturbance is a more appropriate term than 'neglect-like' symptoms to describe this phenomenon.


Changes in Sexual Functioning in Women and Men in the 5 Years After Bariatric Surgery.
Short-term improvements in sexual functioning are reported after bariatric surgery, but to our knowledge, little is known about the durability of these improvements. To determine the percentage of adults with impairment in sexual functioning who experience durable improvements in sexual functioning after bariatric surgery and to identify factors associated with improvements. The Longitudinal Assessment of Bariatric Surgery-2 is an observational cohort study conducted at 10 hospitals in 6 US clinical centers. Adults undergoing their first bariatric procedure were recruited from 2005 through 2009, data were collected through August 2014. Data analysis was conducted from 2016 to April 2018. Participants completed assessments before the procedure and annually thereafter for 5 years. A self-administered questionnaire was used to assess clinically meaningful differences before and after surgery in past-month sexual satisfaction, desire, and activity and physical health limitations to sexual activity among subgroups who reported sexual functioning at less than domain-specific thresholds before surgery. Of 2215 participants eligible for sexual function follow-up, 2036 (91.9%) completed 1 or more follow-up assessment (1431 [64.6%] at year 5), of whom 1607 (78.9%) were women. At the presurgery assessment, median (interquartile range) age was 47 (37-55) years, and the median (interquartile range) body mass index was 45.8 (41.7-51.3). Among those who were not satisfied with their sexual life before surgery (1015 of 1456 women [69.7%]; 304 of 409 men [74.3%]), 56.0% of women (95% CI, 52.5%-59.5%) and 49.2% of men (95% CI, 42.4%-55.9%) experienced clinically meaningful improvements at year 1; these percentages did not significantly differ during further follow-up. Among those who reported physical limitations to sexual activity at baseline (892 of 1490 women [59.9%] and 267 of 406 men [65.8%]), the percentage experiencing improvement in this domain decreased during follow-up, but 73.6% (95% CI, 69.3%-78.0%) of women and 67.6% (95% CI, 59.6%-75.6%) of men continued to report improvements at year 5. Greater postsurgical reduction in depressive symptoms was independently associated with improvement in 4 domains of sexual life among women (frequency of sexual desire: adjusted relative risk [aRR] per 5-point decrease in Beck Depression Inventory score, 1.12 [95% CI, 1.07-1.18]; P < .001; frequency of sexual activity: aRR, 1.13 [95% CI, 1.08-1.18]; P < .001; the degree to which physical health limited sexual activity: aRR, 1.19 [95% CI, 1.14-1.23]; P < .001; and satisfaction with sexual life: aRR, 1.25 [95% CI, 1.19-1.31]; P < .001) and 2 domains among men (physical health limitations: aRR, 1.14 [95% CI, 1.04-1.26]; P = .008 and satisfaction with sexual life: aRR, 1.55 [95% CI, 1.33-1.81]; P < .001). Surgical procedure was not associated with improvement. Per this study, approximately half of women and men who were not satisfied with their sexual life prior to bariatric surgery experienced improvements in satisfaction in 5 years of follow-up. ClinicalTrials.gov Identifier: NCT00465829.


Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective, randomized, double-blind, controlled trial.
Animal models and clinical studies suggest that intraventricular thrombolysis improves clot resolution and clinical outcomes among patients with intraventricular hemorrhage. However, this intervention may increase the rates of rebleeding and infection. To assess the safety and efficacy of intraventricular thrombolysis, we conducted a pilot, randomized, double-blind, controlled, multicenter study. Patients with intraventricular hemorrhage requiring ventriculostomy were randomized to receive intraventricular injections of normal saline solution or urokinase (25000 international units) at 12-hour intervals. Injections continued until ventricular drainage was discontinued according to prespecified clinical criteria. Head computed tomographic scans were obtained daily, for quantitative determinations of intraventricular hemorrhage volumes. The rate of clot resolution was estimated for each group. Twelve subjects were enrolled (urokinase, seven patients; placebo, five patients). Commercial withdrawal of urokinase precluded additional enrollment. The urokinase and placebo groups were similar with respect to age (49.6 versus 55.2 yr, P = 0.43) and presenting Glasgow Coma Scale scores (7.14 versus 8.00, P = 0.72). Randomization to the urokinase treatment arm (P = 0.02) and female sex (P = 0.008) favorably affected the clot resolution rate. The sex-adjusted clot half-life for the urokinase-treated group was reduced 44.6%, compared with the value for the placebo group (4.69 versus 8.48 d). Intraventricular thrombolysis with urokinase speeds the resolution of intraventricular blood clots, compared with treatment with ventricular drainage alone.


Reference ranges for fetal ventricular width: a non-normal approach.
Normal ranges for fetal cerebral ventricular width are usually based on parametric methods, which define cut-off values based on means and standard deviations. We aimed to construct reference charts based on a large sample and using a method that better fits with skewed measurements. In November 2001-December 2005, a single operator, who was unaware of the subsequent analysis, performed prospectively and routinely fetal cerebral ventricular width measurements. We used the LMS method (which summarizes the changing distribution of a variable of interest according to a covariate (gestational age) using three curves representing the median (M), the coefficient of variation (S) and skewness (L)) to describe the distribution of measurements with gestational age. The LMS method provides a general method for fitting smooth centile curves to reference data. It utilizes the power transformation family of Box and Cox to allow the skewness of the measurement distribution, as well as the median and variability, to vary with age. The theoretical proportion of fetal ventricular widths > or = 10 mm based on the LMS method and on methods based on the assumption of normality were compared with the actual proportion using binomial tests. The influence on ventricular size of gestational age and fetal gender and presentation was assessed using robust regression methods. Included in the study were 4769 ventricular measurements, 42 (0.88%) of which were > or = 10 mm. The LMS method allowed us to fit the skewness of the measurements and identified slight changes throughout gestation. The actual proportion of measurements > or = 10 mm was not different from that expected according to the LMS method (0.88% vs. 1%, P = 0.25), whereas it was significantly different from that based on the classical normal approximation (0.88% vs. 0.4%, P < 0.0001). There was a significant difference with gender (males: + 0.29 +/- 0.042 mm as compared to females, P < 0.0001), but there was no difference with fetal presentation (P = 0.4). We present new reference values for fetal ventricular width based on the LMS method. A fixed cut-off value of 10 mm identifies around 1% of the population throughout gestation, which is more than that calculated in previous studies.


Identifying novel QTLs for submergence tolerance in rice cultivars IR72 and Madabaru.
Short-term submergence is a recurring problem in many rice production areas. The SUB1 gene, derived from the tolerant variety FR13A, has been transferred to a number of widely grown varieties, allowing them to withstand complete submergence for up to 2 weeks. However, in areas where longer-term submergence occurs, improved varieties having higher tolerance levels are needed. To search for novel quantitative trait loci (QTLs) from other donors, an F(2:3) population between IR72 and Madabaru, both moderately tolerant varieties, was investigated. After a repeated phenotyping of 466 families under submergence stress, a subset of 80 families selected from the two extreme phenotypic tails was used for the QTL analysis. Phenotypic data showed transgressive segregation, with several families having an even higher survival rate than the FR13A-derived tolerant check (IR40931). Four QTLs were identified on chromosomes 1, 2, 9, and 12; the largest QTL on chromosome 1 had a LOD score of 11.2 and R (2) of 52.3%. A QTL mapping to the SUB1 region on chromosome 9, with a LOD score of 3.6 and R (2) of 18.6%, had the tolerant allele from Madabaru, while the other three QTLs had tolerant alleles from IR72. The identification of three non-SUB1 QTLs from IR72 suggests that an alternative pathway may be present in this variety that is independent of the ethylene-dependent pathway mediated by the SUB1A gene. These novel QTLs can be combined with SUB1 using marker assisted backcrossing in an effort to enhance the level of submergence tolerance for flood-prone areas.


Outcome of early breast cancer treated in an urban and a rural breast cancer unit in Germany.
Conflicting evidence has been published concerning survival disadvantages in the outcome of breast cancer patients in relationship to their residency in urban or rural communities. The primary aim of this study was to evaluate differences in patients and treatment characteristics between an urban and a rural breast cancer unit. Therefore, all early breast cancer patients treated consecutively between 1999 and 2007 in a rural and an urban breast cancer unit were included. Patient and tumor characteristics, treatment strategies, and guideline adherence were included to evaluate the prognoses of both populations. Overall, data from 2,566 patients were included in this analysis. The 610 patients treated in the rural unit showed significantly more negative prognostic criteria than the 1,956 patients treated in the urban center. No differences were observed with respect to surgical and systemic treatment after adjustment for prognostic parameters. Adherence to national guidelines did not differ significantly between both settings and ranged between 78.0 and 95.6%. Furthermore, no differences regarding recurrence-free and overall survival were observed. The stage-adjusted pattern of care was similar in 2 German breast care units in a rural region and an urban area. Nevertheless, an earlier diagnosis of breast cancer should be enforced in rural areas to avoid extended treatment burden.


Macrophage plasticity in experimental atherosclerosis.
As in human disease, macrophages (MØ) are central players in the development and progression of experimental atherosclerosis. In this study we have evaluated the phenotype of MØ associated with progression of atherosclerosis in the apolipoprotein E (ApoE) knockout (KO) mouse model.We found that bone marrow-derived MØ submitted to M1 and M2 polarization specifically expressed arginase (Arg) II and Arg I, respectively. This distinct arginase expression was used to evaluate the frequency and distribution of M1 and M2 MØ in cross-sections of atherosclerotic plaques of ApoE KO mice. Early lesions were infiltrated by Arg I(+) (M2) MØ. This type of MØ favored the proliferation of smooth muscle cells, in vitro. Arg II(+) (M1) MØ appeared and prevailed in lesions of aged ApoE KO mice and lesion progression was correlated with the dominance of M1 over the M2 MØ phenotype. In order to address whether the M2->M1 switch could be due to a phenotypic switch of the infiltrated cells, we performed in vitro repolarization experiments. We found that fully polarized MØ retained their plasticity since they could revert their phenotype. The analysis of the distribution of Arg I- and Arg II-expressing MØ also argued against a recent recruitment of M1 MØ in the lesion. The combined data therefore suggest that the M2->M1 switch observed in vivo is due to a conversion of cells already present in the lesion. Our study suggests that interventional tools able to revert the MØ infiltrate towards the M2 phenotype may exert an atheroprotective action.


Inactivation of tensin3 in mice results in growth retardation and postnatal lethality.
Tensin family is a group of focal adhesion proteins that interact with integrins, actin, and phosphotyrosine-containing proteins. To explore the in vivo functions of a new member of the family, tensin3, we have generated mutant mice with a disrupted tensin3 gene. Inactivation of tensin3 resulted in growth retardation and postnatal lethality in one third of the homozygous mutants. Histological analysis of those mutants showed incomplete development of the small intestine, lung, and bone. Villus formation in the small intestine was affected and cells migrated slower in the runt mutants. Their lungs also displayed enlarged air space suggesting defects in alveogenesis. In addition, the resting zone was thicker and fewer proliferating cells were present in the growth plates of tensin3(-/-) tibiae. These observations indicate that tensin3 is essential for normal development and functions of the small intestine, lung, and bone. These phenotypes of the runt tensin3(-/-) mice are similar to some clinical features of Silver-Russell syndrome (SRS) which is a genetically inherited defect. About 10% of SRS cases have been linked to abnormality in chromosome 7p11.2-13, where human tensin3 gene is located, suggesting a potential link between tensin3 and SRS.


The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade.
Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.


Prospective Risk for Incapacitated Rape Among Sexual Minority Women: Hookups and Drinking.
Sexual minority women (SMW), including lesbian and bisexual women, are at greater risk for heavy drinking and sexual victimization than heterosexual women. Risk factors for alcohol-related sexual victimization, such as incapacitated rape (IR), include frequent heavy drinking and hookups among heterosexual women, but it is less clear whether these risk factors extend to SMW. This current study was designed to address this gap. In a national sample of SMW (N = 1,057), logistic regressions were used to test whether heavy drinking and hookups in the first year of the study were risk factors for IR during the second year. After controlling for history of prior sexual victimization, subsequent IR was predicted by an interaction between heavy drinking and the number of male hookup partners. Specifically, more frequent heavy drinking was associated with increased risk for subsequent IR, but only among SMW who reported more than one male hookup partner, indicating exposure to more potential perpetrators. When examined separately, this finding held for bisexual women, but was not significant for lesbian women, likely because they reported fewer male hookup partners. Overall, findings from this longitudinal study highlight that in combination, heavy drinking and hookups with multiple men elevate risk for IR.


Measurement properties of a novel survey to assess stages of organizational readiness for evidence-based interventions in community chronic disease prevention settings.
There is a great deal of variation in the existing capacity of primary prevention programs and policies addressing chronic disease to deliver evidence-based interventions (EBIs). In order to develop and evaluate implementation strategies that are tailored to the appropriate level of capacity, there is a need for an easy-to-administer tool to stage organizational readiness for EBIs. Based on theoretical frameworks, including Rogers' Diffusion of Innovations, we developed a survey instrument to measure four domains representing stages of readiness for EBI: awareness, adoption, implementation, and maintenance. A separate scale representing organizational climate as a potential mediator of readiness for EBIs was also included in the survey. Twenty-three questions comprised the four domains, with four to nine items each, using a seven-point response scale. Representatives from obesity, asthma, diabetes, and tobacco prevention programs serving diverse populations in the United States were surveyed (N=243); test-retest reliability was assessed with 92 respondents. Confirmatory factor analysis (CFA) was used to test and refine readiness scales. Test-retest reliability of the readiness scales, as measured by intraclass correlation, ranged from 0.47-0.71. CFA found good fit for the five-item adoption and implementation scales and resulted in revisions of the awareness and maintenance scales. The awareness scale was split into two two-item scales, representing community and agency awareness. The maintenance scale was split into five- and four-item scales, representing infrastructural maintenance and evaluation maintenance, respectively. Internal reliability of scales (Cronbach's α) ranged from 0.66-0.78. The model for the final revised scales approached good fit, with most factor loadings >0.6 and all >0.4. The lack of adequate measurement tools hinders progress in dissemination and implementation research. These preliminary results help fill this gap by describing the reliability and measurement properties of a theory-based tool; the short, user-friendly instrument may be useful to researchers and practitioners seeking to assess organizational readiness for EBIs across a variety of chronic disease prevention programs and settings.


Topical Brazilian propolis improves corneal wound healing and inflammation in rats following alkali burns.
The objective of this study was to investigate the effects of the Brazilian Scaptotrigona sp propolis, a widely used folk medicine, in corneal wound healing and inflammation. Corneal epithelial defects of 1 mm in diameter were made in the right eyes of Wistar male adult rats by cauterization with silver nitrate sticks. Subsequently, they were divided in two groups (n = 40 rats/group): Brazilian propolis (BP) group was topically treated with a microemulsion containing 1% Brazilian propolis; vehicle (VH) group received the same formulation without propolis. The epithelial defect area was photographed and measured at t = 0 (wound induction), and after 12, 24, 48 and 120 h of treatment. The inflammatory response was evaluated based on counting of neutrophils. Epithelial regeneration rates were determined based on Ki-67 expression in basal epithelial cells. Comparisons were made using the Kruskal-Wallis and the Mann-Whitney U test. The BP group presented both smaller epithelial defect areas at 12, 24 and 48 h and fewer corneal infiltrating neutrophils at 24 and 48 h (P < 0.01) than the VH group. These effects were associated with more pervasive Ki-67 staining in the BP group at 12 and 24 h (P < 0.05). Topically applied BP accelerated wound healing and reduced the inflammatory response to silver nitrate-induced corneal alkali burns in rats.


Long-term prognosis of steroid-dependent sensorineural hearing loss.
We report on the long-term follow-up of 15 patients with steroid-dependent sensorineural hearing loss (SDSNHL), which was steroid dose dependent. We classified the patients into 2 groups: group A consisted of 6 patients with systemic SDSNHL, and group B consisted of 9 patients with inner-ear-specific SDSNHL without systemic disease. Group B patients were further classified as patients with slowly or rapidly progressive hearing loss. The yearly rate of hearing deterioration was greater in group B than in group A. Thus, the long-term hearing prognosis of patients in group B was worse than those in group A. Although SDSNHL may have immune-related origins, we hypothesize that hearing deterioration may be caused by proinflammatory cytokines because many of our cases exhibited abnormal immunological laboratory values and because many of these cases responded favorably to steroid treatment.


Opportunities for the application of advanced remotely-sensed data in ecological studies of terrestrial animal movement.
Animal movement patterns in space and time are a central aspect of animal ecology. Remotely-sensed environmental indices can play a key role in understanding movement patterns by providing contiguous, relatively fine-scale data that link animal movements to their environment. Still, implementation of newly available remotely-sensed data is often delayed in studies of animal movement, calling for a better flow of information to researchers less familiar with remotely-sensed data applications. Here, we reviewed the application of remotely-sensed environmental indices to infer movement patterns of animals in terrestrial systems in studies published between 2002 and 2013. Next, we introduced newly available remotely-sensed products, and discussed their opportunities for animal movement studies. Studies of coarse-scale movement mostly relied on satellite data representing plant phenology or climate and weather. Studies of small-scale movement frequently used land cover data based on Landsat imagery or aerial photographs. Greater documentation of the type and resolution of remotely-sensed products in ecological movement studies would enhance their usefulness. Recent advancements in remote sensing technology improve assessments of temporal dynamics of landscapes and the three-dimensional structures of habitats, enabling near real-time environmental assessment. Online movement databases that now integrate remotely-sensed data facilitate access to remotely-sensed products for movement ecologists. We recommend that animal movement studies incorporate remotely-sensed products that provide time series of environmental response variables. This would facilitate wildlife management and conservation efforts, as well as the predictive ability of movement analyses. Closer collaboration between ecologists and remote sensing experts could considerably alleviate the implementation gap. Ecologists should not expect that indices derived from remotely-sensed data will be directly analogous to field-collected data and need to critically consider which remotely-sensed product is best suited for a given analysis.


Association of amino acids with common complications of prematurity.
Tandem mass spectrometry has been proposed as a method of diagnosing or predicting the development of common complex neonatal diseases. Our objective was to identify metabolites associated with common complications of prematurity. We performed a retrospective analysis of medical data and metabolite measurements from routine neonatal screening on 689 preterm (<37 wk of gestational age) neonates. We observed higher levels of phenylalanine (PHE) in infants with respiratory distress syndrome (RDS; P = 1.7 × 10(-5)), the only association that was significant after correction for multiple testing. We found suggestive significance (P < 0.001) of higher essential amino acids in infants with patent ductus arteriosus (PDA). Functionality of these findings was explored in the ductus arteriosus (DA) isolated from term and preterm mouse pups. None of the amino acids had a direct vasodilatory effect on the isolated DA. We found that newborns with RDS had higher levels of PHE that may be a result of impaired PHE hydroxylase activity. We also detected marginally higher levels of all measured essential amino acids in infants with PDA. We did not find dilation of the mouse ductus for these metabolites, indicating that instead of potentially causing PDA, they are probably serving as markers of catabolism.


Efficacy of Pre- and Postinoculation Application of Fungicides to Expanding Young Citrus Leaves for Control of Melanose, Scab, and Alternaria Brown Spot.
In greenhouse trials, copper hydroxide, pyraclostrobin, and famoxadone were applied to actively growing young citrus seedlings to determine the duration of protection of young leaves provided by these fungicides against melanose, caused by Diaporthe citri, citrus scab, caused by Elsinoe fawcettii, and Alternaria brown spot, caused by Alternaria alternata. Fungicides were applied to different sets of potted plants of grapefruit for control of melanose, of rough lemon for control of scab, and of Dancy tangerine for control of Alternaria brown spot 1 to 6 days prior to inoculation, as well as on the day of inoculation. Leaf area of treated shoots was estimated on the day of fungicide application and the day of inoculation and disease severity evaluated subsequently. In most cases, copper hydroxide and famoxadone provided at least 50% control of all three diseases for only about 2 days after application. Generally, there was little or no disease control when the products were applied 4 or more days before inoculation. In contrast, pyraclostrobin usually provided a high level of control of all three diseases when applied up to 5 days prior to inoculation. The level of disease control decreased as the interval between a fungicide application and inoculation increased and the relationship between disease control and leaf expansion best fit a quadratic equation. Effective disease control was observed with copper hydroxide and famoxadone until leaf area had increased by 100 to 200%, whereas control with pyraclostrobin was observed up to 400 to 500% increase in leaf area. In postinoculation tests with scab and melanose, pyraclostrobin provided high levels of disease control (>75%) when applied up to 2 days after inoculation, whereas copper hydroxide and famoxadone had minimal postinoculation activity. Applications of pyraclostrobin to the spring flush growth of citrus trees are much more likely to provide control of melanose, scab, and Alternaria brown spot than those of famoxadone or copper hydroxide.


The phase shift of light scattering at sub-wavelength dielectric structures.
We present a new theoretical analysis for the light scattering at sub-wavelength dielectric structures. This analysis can provide new intuitive insights into the phase shift of the scattered light that cannot be obtained from the existing approaches. Unlike the traditional analytical (e.g. Mie formalism) and numerical (e.g. FDTD) approaches, which simulate light scattering by rigorously matching electromagnetic fields at boundaries, we consider sub-wavelength dielectric structures as leaky resonators and evaluate the light scattering as a coupling process between incident light and leaky modes of the structure. Our analysis indicates that the light scattering is fundamentally dictated by the eigenvalue of the leaky modes. It indicates that the upper limit for the scattering efficiency of a cylindrical cylinder in free space is 4n, where n is the refractive index. It also indicates that the phase shift of the forward scattered light at dielectric structures can only cover half of the phase space [0, 2π], but backward scattering can provide a full phase coverage.


Plasmodium vivax: clinical spectrum, risk factors and pathogenesis.
Vivax malaria was historically described as 'benign tertian malaria' because individual clinical episodes were less likely to cause severe illness than Plasmodium falciparum. Despite this, Plasmodium vivax was, and remains, responsible for major morbidity and significant mortality in vivax-endemic areas. Single infections causing febrile illness in otherwise healthy individuals rarely progress to severe disease. Nevertheless, in the presence of co-morbidities, P. vivax can cause severe illness and fatal outcomes. Recurrent or chronic infections in endemic areas can cause severe anaemia and malnutrition, particularly in early childhood. Other severe manifestations include acute lung injury, acute kidney injury and uncommonly, coma. Multiorgan failure and shock are described but further studies are needed to investigate the role of bacterial and other co-infections in these syndromes. In pregnancy, P. vivax infection can cause maternal anaemia, miscarriage, low birth weight and congenital malaria. Compared to P. falciparum, P. vivax has a greater capacity to elicit an inflammatory response, resulting in a lower pyrogenic threshold. Conversely, cytoadherence of P. vivax to endothelial cells is less frequent and parasite sequestration is not thought to be a significant cause of severe illness in vivax malaria. With a predilection for young red cells, P. vivax does not result in the high parasite biomass associated with severe disease in P. falciparum, but a four to fivefold greater removal of uninfected red cells from the circulation relative to P. falciparum is associated with a similar risk of severe anaemia. Mechanisms underlying the pathogenesis of severe vivax syndromes remain incompletely understood.


Use of the mice passive protection test to evaluate the humoral response in goats vaccinated with Sterne 34F2 live spore vaccine.
The Sterne live spore vaccine (34F2) is the most widely used veterinary vaccine against anthrax in animals. Antibody responses to several antigens of Bacillus anthracis have been described with a large focus on those against protective antigen (PA). The focus of this study was to evaluate the protective humoral immune response induced by the live spore anthrax vaccine in goats. Boer goats vaccinated twice (week 0 and week 12) with the Sterne live spore vaccine and naive goats were used to monitor the anti-PA and toxin neutralizing antibodies at week 4 and week 17 (after the second vaccine dose) post vaccination. A/J mice were passively immunized with different dilutions of sera from immune and naive goats and then challenged with spores of B. anthracis strain 34F2 to determine the protective capacity of the goat sera. The goat anti-PA ELISA titres indicated significant sero-conversion at week 17 after the second doses of vaccine (p = 0.009). Mice receiving undiluted sera from goats given two doses of vaccine (twice immunized) showed the highest protection (86%) with only 20% of mice receiving 1:1000 diluted sera surviving lethal challenge. The in vitro toxin neutralization assay (TNA) titres correlated to protection of passively immunized A/J mice against lethal infection with the vaccine strain Sterne 34F2 spores using immune goat sera up to a 1:10 dilution (rs ≥ 0.522, p = 0.046). This study suggests that the passive mouse protection model could be potentially used to evaluate the protective immune response in livestock animals vaccinated with the current live vaccine and new vaccines.


Dorsal Root Ganglion Stimulation for the Treatment of Chronic Neuropathic Knee Pain.
To elucidate the efficacy of dorsal root ganglion stimulation in the treatment of chronic neuropathic pain confined to the knee. Retrospective analysis of prospectively collected data of 14 consecutive patients undergoing dorsal root ganglion stimulation for chronic knee pain, in a single center. The primary outcome measure was pain reduction assessed by numeric pain rating scale score preoperatively and postoperatively. Secondary outcomes included quantification of percentage of pain area covered by stimulation, and reduction in usage of opioid medications. Responders were defined as patients that experienced a greater than or equal to 50% improvement in their preoperative pain score. Fourteen patients were implanted with dorsal root ganglion stimulator electrodes; 8 had a single L3 lead implanted, 1 patient had a single L4 lead implanted, and 3 patients had 2 leads implanted (L3 and L4). Two patients had their leads explanted: 1 for non-efficacy, and 1 for repeated electrode displacement. The most common indication for surgery was type 2 complex regional pain syndrome, secondary to either trauma or postoperative chronic pain (either knee replacement or arthroscopy). Median preoperative numeric rating scale score was 8.5, median postoperative numeric rating scale score was 2 (P = 0.002, Wilcoxon signed rank test). The median improvement in pain score was 80%. All 12 patients undergoing chronic stimulation were responders. Median coverage of pain area was 85%. All but 1 patient who was on opioid medication prior to surgery had reduced the dosage of regular opioid. In selected patients, dorsal root ganglion stimulation is an extremely efficacious means of treating otherwise refractory chronic knee pain.


Simplified versus standard regimen for focal radiofrequency ablation of dysplastic Barrett's oesophagus: a multicentre randomised controlled trial.
For focal radiofrequency ablation of Barrett's oesophagus, a simplified regimen (3 × 15 J/cm2, without cleaning) has proven to be as effective as the standard regimen (2 × 15 J/cm2, followed by cleaning, followed by 2 × 15 J/cm2). However, this simplified regimen seemed to be associated with a higher stenosis rate. Therefore, we lowered the radiofrequency energy and hypothesised that this new simplified regimen would be as effective and safe as the standard regimen. This randomised non-inferiority trial included patients with dysplastic Barrett's oesophagus or residual Barrett's oesophagus after endoscopic resection or circumferential radiofrequency ablation, in five European tertiary referral centres. Patients were randomly assigned (1:1) to the new simplified regimen (3 × 12 J/cm2, without cleaning) or the standard regimen, with variable block sizes of four, six, and eight patients, stratified by participating hospital. Focal radiofrequency ablation was done every 3 months, up to a maximum of three treatments, until all Barrett's oesophagus was eradicated. The primary outcome was complete endoscopic and histological regression of dysplasia and intestinal metaplasia after two focal radiofrequency ablation treatments, assessed in the intention-to-treat population. Non-inferiority was assessed on the basis of the difference between groups in the median percentage of Barrett's oesophagus surface regression, with a non-inferiority margin of -15%. This study is registered with www.trialregister.nl, number NTR4994, and is completed. Between March 25, 2015, and July 25, 2016, 84 patients were randomly assigned to treatment: 44 to receive the simplified regimen and 40 to receive the standard regimen. One patient assigned to the simplified regimen and four assigned to the standard regimen were excluded because they weree found not to be eligible; therefore the final intention-to-treat population consisted of 43 patients in the simplified ablation group and 36 in the standard ablation group. Complete endoscopic and histological regression of dysplasia and intestinal metaplasia after two focal radiofrequency ablation treatments was achieved in 32 (74%, 95% CI 59-87) patients treated with the simplified protocol, versus 30 (83%, 95% CI 67-94) patients treated with the standard protocol (p=0·34). Median Barrett's oesophagus surface regression after two focal radiofrequency ablation sessions was 98% (IQR 95-100) in the simplified regimen group and 100% (97-100) in the standard regimen group. The difference between medians was 2% (95% CI -0·562 to 3·162); thus the simplified regimen was deemed non-inferior to the standard regimen. Stenoses requiring dilatation were observed in four (9%) of 43 patients in the simplified regimen group and four (11%) of 36 in the standard regimen group. Post-procedural bleeding requiring repeat endoscopy occurred in one (2%) patient in the simplified ablation group and three (8%) patients in the standard ablation group. One patient (2%) in the simplified treatment group died 36 days after the second radiofrequency ablation procedure, due to an unknown cause. Based on the results of this study, we conclude that the simplified regimen is the preferred regimen for focal radiofrequency ablation of Barrett's oesophagus. None.


A universally conserved residue in the SUR1 subunit of the KATP channel is essential for translating nucleotide binding at SUR1 into channel opening.
The sulphonylurea receptor (SUR1) subunit of the ATP-sensitive potassium (KATP) channel is a member of the ATP-binding cassette (ABC) protein family. Binding of MgADP to nucleotide-binding domain 2 (NBD2) is critical for channel activation.We identified a residue in NBD2 (G1401) that is fully conserved among ABC proteins and whose functional importance is unknown. Homology modelling places G1401 on the outer surface of the protein, distant from the nucleotide-binding site. The ATPase activity of purified SUR1-NBD2-G1410R (bound to maltose-binding protein) was slightly inhibited when compared to the wild-type protein, but its inhibition by MgADP was unchanged, indicating that MgADP binding is not altered. However, MgADP activation of channel activity was abolished. This implies that the G1401R mutation impairs the mechanism by which MgADP binding to NBD2 is translated into opening of the KATP channel pore. The location of G1401 would be consistent with interaction of this residue with the pore-forming Kir6.2 subunit. Channel activity in the presence of MgATP reflects the balance between the stimulatory (at SUR1) and inhibitory (at Kir6.2) effects of nucleotides. Mutant channels were 2.5-fold less sensitive to MgATP inhibition and not activated by MgATP. This suggests that ATP block of the channel is reduced by the SUR1 mutation. Interestingly, this effect was dependent on the functional integrity of the NBDs. These results therefore suggest that SUR1 modulates both nucleotide inhibition and activation of the KATP channel.


Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma.
Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.


Effects of low-level lead exposure on blood pressure and function of the rat isolated heart.
Exposure to low levels of lead acetate can induce hypertension in both humans and experimental animals. The exact mechanisms of lead-induced hypertension are not well understood, but its pathogenesis could be explained by the changes in heart rate and contractility. In the present study, the effects of exposure to 100 ppm of lead in drinking water (for periods of 4, 8, and 12 weeks) on blood pressure and some physiologic parameters (eg, electrocardiography [ECG], heart rate [HR], cardiac contractility, and coronary flow) of isolated beating rat heart was investigated using the Langendorff isolated heart apparatus. The isolated hearts were perfused with Krebs-Henseleit solution (37°C; pH 7.4; gassed with 95% O(2) + 5% CO(2)). All data were digitized by a software program for further analysis. The blood pressure in the 8- and 12-week lead-exposed groups was significantly increased as compared to the control group. The ECG showed arrhythmias and conduction abnormalities only in the late phases of exposure (12 weeks). The HR and contractility were significantly higher in the 8- and 12-week lead-treated rats but not in the 4-week group. No significant changes were observed in coronary flow. THESE RESULTS INDICATE THAT: 1) low levels of lead exposure do not significantly affect the ECG in the early phase, 2) low levels of lead exposure causes ECG changes in the late phases of exposure, and 3) this level of lead exposure can increase HR and cardiac contractility but has no effect on coronary flow.


Effect of Agouti-related protein in regulation of the hypothalamic-pituitary-thyroid axis in the melanocortin 4 receptor knockout mouse.
Agouti-related protein (AGRP) is thought to be one of the neuropeptides mediating the effects of leptin on appetite and satiety. The central administration of AGRP not only stimulates food intake, but also inhibits the hypothalamic-pituitary-thyroid axis (HPT) axis, closely replicating the central hypothyroid state induced by fasting. AGRP binds as an endogenous antagonist or inverse agonist of the central melanocortin receptors but has also been hypothesized to have melanocortin receptor-independent effects. Thus, we determined whether the central effects of AGRP on the HPT axis are altered in mice with selective deletion of the melanocortin 4 receptor (MC4-R). AGRP or artificial cerebrospinal fluid was administered daily into the lateral ventricle of adult, male MC4-R knockout and wild-type (WT) mice for 3 d. AGRP significantly increased the cumulative food intake and weight of white and brown adipose tissue, suppressed circulating levels of T(4) [control vs. AGRP in WT (microg/dl): 4.54 +/- 0.16 vs. 3.87 +/- 21], and inhibited proTRH mRNA content in the hypothalamic paraventricular nucleus of WT mice (control vs. AGRP in WT (density units +/- sem): 4.65 +/- 0.50 vs. 2.47 +/- 0.17). In contrast, no significant effects of AGRP were observed in any of these parameters in the MC4-R knockout mice. These data suggest that AGRP signaling to TRH hypophysiotropic neurons in the paraventricular nucleus is primarily mediated by the MC4-R and therefore, binding to the MC3-R or other putative AGRP receptors may have only a minor role.


Predicting the bioavailability of sediment-associated spiked compounds by using the polyoxymethylene passive sampling and tenax extraction methods in sediments from three river basins in Europe.
This study presents the bioavailability of four spiked compounds to Lumbriculus variegatus, in sediment samples from three river basins in Europe: the Elbe, the Llobregat, and the Scheldt. Twenty sediment samples differing in physical and chemical properties were spiked with chlorpyrifos, pyrene, tetrachloribiphenyl, and tetrabromo diphenyl ether. The main focus of this study was to compare the suitability of two chemical approaches-the rapidly desorbing fraction method based on the Tenax extraction and the freely dissolved chemical concentration method based on polyoxymethylene passive sampling-for predicting the bioavailability of sediment-associated hydrophobic compounds. It appears that accessible concentration estimated by Tenax extraction does not result in equal freely dissolved concentrations based on polyoxymethylene passive sampling results. The present data show that freely dissolved concentration in pore water mainly determines the uptake by organisms and, therefore, the polyoxymethylene passive sampling method was a successful approach to estimating the bioavailability of sediment-associated lipophilic contaminants (log octanol-water partitioning coefficient >6). The sediment characteristics or river basin differences had only a minor effect on the bioavailability estimates. Overall, passive samplers have not been tested to a sufficient extent in various chemicals or exposure matrixes. For this reason, bioassays are still needed in the risk assessment process in order to verify results based on passive sampling methods.


Physical therapy and chiropractic use among childhood cancer survivors with chronic disease: impact on health-related quality of life.
The use of rehabilitation services to address musculoskeletal, neurological and cardiovascular late effects among childhood cancer survivors could improve physical function and health-related quality-of-life (HRQL). We describe physical therapy (PT) and chiropractic utilization among childhood cancer survivors and their association with HRQL. The sample included 5+ year survivors from the Childhood Cancer Survivor Study (N = 9,289). Questions addressing use of PT or chiropractic services and HRQL (Medical Outcomes Survey Short Form (SF-36)) were evaluated. Multivariable regression models compared PT and/or chiropractic utilization between survivors and siblings, and by diagnosis, treatment and demographic characteristics; associations between chronic disease, PT/chiropractic use, and HRQL were similarly evaluated. Survivors were not more likely to use PT (OR 1.0; 95% CI 0.8-1.2) or chiropractic (OR 0.8; 95% CI 0.7-1.0) services than siblings. More survivors reported using chiropractic (12.4%) than PT (9.2%) services. Older age and having health insurance were associated with utilization of either PT or chiropractic services. Grade 3-4 chronic conditions and a CNS tumor or sarcoma history were associated with PT but not with chiropractic service utilization. Survivors with musculoskeletal (OR 1.8; 95% CI 1.1-2.9), neurological (OR 3.4; 95% CI 1.6-6.9), or cardiovascular (OR 3.3; 95% CI 1.6-6.9) chronic conditions who used PT/chiropractic services were more likely to report poor physical health than survivors who did not use services. The reported prevalence of PT/chiropractic among survivors is consistent with that reported by siblings. Severity of late effects is associated with service use and with reporting poor physical health. Long-term childhood cancer survivors do not appear to utilize rehabilitation services to optimize physical function and support increased HRQL.


Levels of SARS-CoV-2 population exposure are considerably higher than suggested by seroprevalence surveys.
Accurate knowledge of prior population exposure has critical ramifications for preparedness plans for future SARS-CoV-2 epidemic waves and vaccine prioritization strategies. Serological studies can be used to estimate levels of past exposure and thus position populations in their epidemic timeline. To circumvent biases introduced by the decay in antibody titers over time, methods for estimating population exposure should account for seroreversion, to reflect that changes in seroprevalence measures over time are the net effect of increases due to recent transmission and decreases due to antibody waning. Here, we present a new method that combines multiple datasets (serology, mortality, and virus positivity ratios) to estimate seroreversion time and infection fatality ratios (IFR) and simultaneously infer population exposure levels. The results indicate that the average time to seroreversion is around six months, IFR is 0.54% to 1.3%, and true exposure may be more than double the current seroprevalence levels reported for several regions of England.


Mechanistic insights into nitrogen fixation by nitrogenase enzymes.
Biological nitrogen fixation by nitrogenase enzymes is a process that activates dinitrogen (N2) one of the most inert molecules in nature, within the confines of a living organism and at ambient conditions. Despite decades of study, there are still no complete explanations as to how this is possible. Here we describe a model of N2 reduction using the Mo-containing nitrogenase (FeMoco) that can explain the reactivity of the active site via a series of electrochemical steps that reversibly unseal a highly reactive Fe edge site. Our model can explain the 8 proton-electron transfers involved in biological ammonia synthesis within the kinetic scheme of Lowe and Thorneley, the obligatory formation of one H2 per N2 reduced, and the behavior of known inhibitors.


Systems biology of the modified branched Entner-Doudoroff pathway in Sulfolobus solfataricus.
Sulfolobus solfataricus is a thermoacidophilic Archaeon that thrives in terrestrial hot springs (solfatares) with optimal growth at 80°C and pH 2-4. It catabolizes specific carbon sources, such as D-glucose, to pyruvate via the modified Entner-Doudoroff (ED) pathway. This pathway has two parallel branches, the semi-phosphorylative and the non-phosphorylative. However, the strategy of S.solfataricus to endure in such an extreme environment in terms of robustness and adaptation is not yet completely understood. Here, we present the first dynamic mathematical model of the ED pathway parameterized with quantitative experimental data. These data consist of enzyme activities of the branched pathway at 70°C and 80°C and of metabolomics data at the same temperatures for the wild type and for a metabolic engineered knockout of the semi-phosphorylative branch. We use the validated model to address two questions: 1. Is this system more robust to perturbations at its optimal growth temperature? 2. Is the ED robust to deletion and perturbations? We employed a systems biology approach to answer these questions and to gain further knowledge on the emergent properties of this biological system. Specifically, we applied deterministic and stochastic approaches to study the sensitivity and robustness of the system, respectively. The mathematical model we present here, shows that: 1. Steady state metabolite concentrations of the ED pathway are consistently more robust to stochastic internal perturbations at 80°C than at 70°C; 2. These metabolite concentrations are highly robust when faced with the knockout of either branch. Connected with this observation, these two branches show different properties at the level of metabolite production and flux control. These new results reveal how enzyme kinetics and metabolomics synergizes with mathematical modelling to unveil new systemic properties of the ED pathway in S.solfataricus in terms of its adaptation and robustness.


Attentional selection of multiple goal positions before rapid hand movement sequences: an event-related potential study.
A dot-probe paradigm was used to provide physiological evidence for the parallel selection of multiple movement goals before rapid hand movement sequences. Participants executed a sequence of manual pointing movements to two out of three possible goal positions. During movement preparation, a task-irrelevant visual transient (a dot probe) was flashed either at one of both movement goals, or at the third, movement-irrelevant location. The results revealed that the N1 component induced by the presentation of the dot was enhanced if the dot was flashed at one of the movement goals, indicating that both target positions were attended before the initialization of the movement sequence. A second experiment showed that movement-irrelevant locations between the movement goals were not attended, suggesting that attention splits into spatially distinct foci.


"Falling off the wagon": older adults' experiences of living with frailty in rural arctic communities.
Most populations around the world are ageing. The proportion of older adults in the population is larger and is growing more rapidly in rural communities than in urban areas. Longevity increases the risk of frailty. Our aim was to explore how single-living frail older adults experience living with frailty in everyday life in rural Arctic areas. Over eight months, we conducted a series of three interviews with eight older adults identified as frail by home care services in two rural municipalities in northern Norway. We conducted a thematic analysis. We generated three themes. Frailty as a dynamic phenomenon indicated that the participants' experiences of frailty varied over time. Frailty as part of old age referred to the findings that many participants tried to adapt to the changing circumstances, while others found it more challenging to accept the experienced limitations. Frailty in a rural Arctic context concerned the findings that the rural Arctic environment affected the participants' experiences of frailty due to its long, snowy winters; long distances between communities and municipal centres; and out-migration. Our results demonstrate that frailty is a consequence of the interplay between ageing persons and their physical and social environments.


Intravenous recombinant secretory leukoprotease inhibitor augments antineutrophil elastase defense.
Secretory leukoprotease inhibitor (SLPI), a 12-kDa serine antiprotease, normally protects the upper airway epithelial surface from attack by neutrophil elastase (NE). In the context that a variety of inflammatory lung diseases are characterized by large neutrophil burdens with resultant high levels of NE in the lung, recombinant SLPI (rSLPI), a molecule identical to natural SLPI, may be an effective means to augment the anti-NE protective screen of the lung. To determine whether intravenous rSLPI will augment respiratory tract and epithelial surface levels of SLPI and anti-NE capacity, rSLPI was administered intravenously to sheep and SLPI levels were quantified in plasma, lung lymph (as a measure of lung interstitial levels), lung epithelial lining fluid (ELF), and urine. rSLPI (1 g) was administered over 10 min, and after 30 min plasma levels of SLPI were 8 microM and decreased with a half-life of 1.8 h. Lymph SLPI levels paralleled the plasma levels: 4 h after infusion the lymph-to-plasma ratio was 0.8. ELF SLPI levels paralleled the lymph levels: 4 h after infusion the ELF-to-lymph ratio was 0.3. Western analysis demonstrated intact SLPI in lymph and ELF, and functional analysis showed increases in lymph and ELF anti-NE capacity that paralleled the levels of SLPI. As might be expected from a protein with a molecular mass of 12 kDa, urine excretion was high, with 20% of the SLPI excreted over 5 h. However, if the rate of infusion was slowed, SLPI excretion decreased significantly, with a 3-h infusion associated with 9% excretion and a 12-h infusion associated with less than 0.2% excretion.(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic myeloid leukemia and second-generation tyrosine kinase inhibitors: when, how, and which one?
Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation due to toxicity (intolerance). For patients who fail with standard-dose imatinib therapy, imatinib dose escalation is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse-event tolerance level, and risk factors.


Acidogenic fermentation of municipal solid waste and its application to bio-electricity production via microbial fuel cells (MfCs).
Acidogenic fermentation of organic municipal solid waste (MSW) and the bio-electricity production potential from its volatile fatty acid (VFA)-rich leachate using an air-cathode microbial fuel cell (MFC) was investigated in this study. The acidogenic fermentation of 2 kg of MSW has been carried out in a 6 L anaerobic leach-bed reactor (LBR) under mesophilic conditions (30 degrees C). Total production of 92 g VFA expressed as chemical oxygen demand (COD) in 3 L leachate mainly containing acetic, propionic, butyric, and valeric acids has been achieved with manual leachate recirculation and without pH control in 74 days of incubation. Leachate collected on day 32 was used as a feed to an air-cathode MFC after being diluted and supplemented with NaCl or NaHCO3. The maximum power density in the diluted leachate was only 5.9 W/m3, but reached up to 8.6 W/m3 upon the addition of 7 mmol/L NaCl. Increase in coulombic efficiency from 6 to 22% was also observed as a result of NaCl supplementation. On the other hand, NaHCO3 addition did not improve the power output.


Addressing Survivorship in Cancer Care.
As a disease, cancer can affect an individual's well-being, from physical to psychological, social, and even spiritual wellness. The cancer survivor population must navigate a complex, constantly evolving field, with the assistance of their care team, to conquer the disease. To address the unmet needs of the cancer survivorship community, NCCN conducted an environmental scan of existing and emerging aspects of survivorship cancer care through stakeholder meetings with survivors and patient advocacy groups to discuss needs, opportunities, and challenges in providing high-quality, patient-centered cancer survivorship care. The findings of this environmental scan directly informed the corresponding NCCN Patient Advocacy Summit: Addressing Survivorship in Cancer Care, held in Washington, DC, on December 1, 2017. In addition to the many patient advocacy groups, the summit featured stakeholders from all relevant areas of survivorship care. This article encapsulates the findings of the thorough environmental scan and the discussion from the NCCN Patient Advocacy Summit, including identified gaps and needs in addressing survivorship in cancer care.


Acetylation of the p53 DNA-binding domain regulates apoptosis induction.
The ability of p53 to induce apoptosis plays an important role in tumor suppression. Here, we describe a previously unknown posttranslational modification of the DNA-binding domain of p53. This modification, acetylation of lysine 120 (K120), occurs rapidly after DNA damage and is catalyzed by the MYST family acetyltransferases hMOF and TIP60. Mutation of K120 to arginine, as occurs in human cancer, debilitates K120 acetylation and diminishes p53-mediated apoptosis without affecting cell-cycle arrest. The K120R mutation selectively blocks the transcription of proapoptotic target genes such as BAX and PUMA while the nonapoptotic targets p21 and hMDM2 remain unaffected. Consistent with this, depletion of hMOF and/or TIP60 inhibits the ability of p53 to activate BAX and PUMA transcription. Furthermore, the acetyllysine 120 (acetyl-K120) form of p53 specifically accumulates at proapoptotic target genes. These data suggest that K120 acetylation may help distinguish the cell-cycle arrest and apoptotic functions of p53.


Risk Factors for Youth E-Cigarette "Vape Trick" Behavior.
Some adolescent users of e-cigarettes and other electronic vaping products (EVPs) report performing "vape tricks" (exhaling aerosol to make shapes). However, little is known about this behavior. We examined the frequency of performing and watching vape tricks and the characteristics of those most likely to perform vape tricks among a sample of adolescent EVP users. We used social media ads to recruit a national convenience sample of U.S. adolescents (n = 1,729) to participate in an online survey in September 2016. Inclusion criteria required participants to be aged 15-17 years and to have used EVPs at least once in the past 30 days. The majority of EVP-using adolescents reported trying (77.8%) and watching vape tricks in person (83.7%) or online (74.0%). Risk factors for performing tricks included using advanced vaping devices, vaping every day, white race, moderate levels of seeing and sharing vaping information on social media, and believing that EVP use is more normative among peers. Likelihood of trying vape tricks decreased as beliefs about the harmfulness of EVPs increased. Vape tricks pose a potential threat to adolescent health if they encourage nonusers to initiate or current EVP users to use more frequently or switch to advanced devices that produce more harmful chemical emissions. Further research should examine the possible health effects of performing vape tricks, and future public health campaigns should be informed by an understanding of the appeal of this activity for adolescents.


The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study.
Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX. In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) once-monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24. In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade. In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.


Evaluation of Intense Androgen Deprivation Before Prostatectomy: A Randomized Phase II Trial of Enzalutamide and Leuprolide With or Without Abiraterone.
Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer. Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored. Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP. Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.


Cryptosporidium parvum Subtilisin-Like Serine Protease (SUB1) Is Crucial for Parasite Egress from Host Cells.
Despite the severity and global burden of Cryptosporidium infection, treatments are less than optimal, and there is no effective vaccine. Egress from host cells is a key process for the completion of the life cycle of apicomplexan parasites. For Plasmodium species, subtilisin-like serine protease (SUB1) is a key mediator of egress. For Toxoplasma species, calcium-dependent protein kinases (CDPKs) are critical. In this study, we characterized Cryptosporidium SUB1 expression and evaluated its effect using an infection model. We found increased expression between 12 and 20 h after in vitro infection, prior to egress. We induced silencing of SUB1 (ΔSUB1) mRNA using SUB1 single-stranded antisense RNA coupled with human Argonaute 2. Silencing of SUB1 mRNA expression did not affect parasite viability, excystation, or invasion of target cells. However, knockdown led to a 95% decrease in the proportion of released merozoites in vitro (P < 0.0001). In contrast, silencing of CDPK5 had no effect on egress. Overall, our results indicate that SUB1 is a key mediator of Cryptosporidium egress and suggest that interruption of the life cycle at this stage may effectively inhibit the propagation of infection.


Bupivacaine-induced apoptosis independently of WDR35 expression in mouse neuroblastoma Neuro2a cells.
Bupivacaine-induced neurotoxicity has been shown to occur through apoptosis. Recently, bupivacaine was shown to elicit reactive oxygen species (ROS) production and induce apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) in a human neuroblastoma cell line. We have reported that WDR35, a WD40-repeat protein, may mediate apoptosis through caspase-3 activation. The present study was undertaken to test whether bupivacaine induces apoptosis in mouse neuroblastoma Neuro2a cells and to determine whether ROS, p38 MAPK, and WDR35 are involved. Our results showed that bupivacaine induced ROS generation and p38 MAPK activation in Neuro2a cells, resulting in apoptosis. Bupivacaine also increased WDR35 expression in a dose- and time-dependent manner. Hydrogen peroxide (H(2)O(2)) also increased WDR35 expression in Neuro2a cells. Antioxidant (EUK-8) and p38 MAPK inhibitor (SB202190) treatment attenuated the increase in caspase-3 activity, cell death and WDR35 expression induced by bupivacaine or H(2)O(2). Although transfection of Neuro2a cells with WDR35 siRNA attenuated the bupivacaine- or H(2)O(2)-induced increase in expression of WDR35 mRNA and protein, in contrast to our previous studies, it did not inhibit the increase in caspase-3 activity in bupivacaine- or H(2)O(2)-treated cells. In summary, our results indicated that bupivacaine induced apoptosis in Neuro2a cells. Bupivacaine induced ROS generation and p38 MAPK activation, resulting in an increase in WDR35 expression, in these cells. However, the increase in WDR35 expression may not be essential for the bupivacaine-induced apoptosis in Neuro2a cells. These results may suggest the existence of another mechanism of bupivacaine-induced apoptosis independent from WDR35 expression in Neuro2a cells.


Changes in the volatile profile of skim milk powder prepared under different processing conditions and the effect on the volatile flavor profile of model white chocolate.
The objective of this work is to determine the extent to which changes in the skim milk powder (SMP) manufacturing process alter the volatile profile of SMP, and whether these changes are carried through to a final product when the SMP is used as an ingredient and subjected to further processing. The manufacture of SMP is a multistage process involving a preliminary concentration step, heat treatment, and a drying stage. However, the methods and conditions used by the industry are not standardized, and the inherent variability in the production of SMP has consequences for the end-users, such as the confectionery industry, where the SMP is used as an ingredient during the production of milk chocolate, white chocolate, and caramel. This study investigates the effect of each stage of the manufacturing process on the concentration of reducing sugars and available amino groups (as precursors of the Maillard reaction) as well as on the volatile products of the Maillard reaction and lipid degradation. Eight types of SMP were produced using combinations of different processing conditions: concentration (by evaporation or reverse osmosis), heat treatment (low heat or high heat), and drying (spray-drying or freeze-drying). Maillard precursors were quantified after each processing stage and volatile compounds were extracted using solid-phase microextraction, and analyzed by gas chromatography-mass spectrometry. The resulting SMP were incorporated into a model white chocolate system, produced under varying conching conditions. We demonstrate not only that changes in the SMP manufacturing conditions affect the volatile profile of SMP, but also that these differences can be carried through to a final product when the SMP is used to prepare a model white chocolate. Understanding these differences is important to the industry for controlling the flavor of the end product.


Tranilast suppresses the disease development of the adjuvant- and streptococcal cell wall-induced arthritis in rats.
This study explores the effects of the anti-allergic and anti-fibrotic agent tranilast on adjuvant- and streptococcal cell wall-induced arthritis in rats, animal models of rheumatoid arthritis in humans. Tranilast (150 or 300 mg/kg, twice daily) or vehicle only was administered orally to the two arthritis models, from 17 days before sensitization. As a comparative control, methotrexate (0.1 mg/kg, once daily) was given to another group. Tranilast suppressed the increase in foot volumes, paw thicknesses, clinical scores, and histopathological scores of the ankle joints in both models dose-dependently. In addition, the fibrosis indices of the ankles were dramatically decreased by tranilast in both of the models. Compared to the effects of methotrexate, tranilast seemed to work more effectively in the streptococcal cell wall-induced arthritis model than in the adjuvant-induced arthritis model. From these observations, it can be concluded that tranilast suppresses the development of arthritis in multiple models and is potentially a novel therapeutic agent for human rheumatoid arthritis.


Modern Electronic Devices: An Increasingly Common Cause of Skin Disorders in Consumers.
: The modern conveniences and enjoyment brought about by electronic devices bring with them some health concerns. In particular, personal electronic devices are responsible for rising cases of several skin disorders, including pressure, friction, contact dermatitis, and other physical dermatitis. The universal use of such devices, either for work or recreational purposes, will probably increase the occurrence of polymorphous skin manifestations over time. It is important for clinicians to consider electronics as potential sources of dermatological ailments, for proper patient management. We performed a literature review on skin disorders associated with the personal use of modern technology, including personal computers and laptops, personal computer accessories, mobile phones, tablets, video games, and consoles.


Energy transfer from colloidal nanocrystals to strongly absorbing perovskites.
Integration of colloidal nanocrystal quantum dots (NQDs) with strongly absorbing semiconductors offers the possibility of developing optoelectronic and photonic devices with new functionalities. We examine the process of energy transfer (ET) from photoactive CdSe/ZnS core/shell NQDs into lead-halide perovskite polycrystalline films as a function of distance from the perovskite surface using time-resolved photoluminescence (TRPL) spectroscopy. We demonstrate near-field electromagnetic coupling between vastly dissimilar excitation in two materials that can reach an efficiency of 99% at room temperature. Our experimental results, combined with electrodynamics modeling, reveal the leading role of non-radiative ET at close distances, augmented by the waveguide emission coupling and light reabsorption at separations >10 nm. These results open the way to combining materials with different dimensionalities to achieve novel nanoscale architectures with improved photovoltaic and light emitting functionalities.


Can Brown Fat Win the Battle Against White Fat?
A rapid growth in the overweight and obese population in the last few decades suggest that the current diet, exercise, awareness or drug strategies are still not effectively restraining the obesity epidemic. Obesity results from increased energy intake, and the body's energy balance shifts towards energy abundance. Therefore, current research is focused on developing new strategies aimed at increasing energy expenditure. As a result, brown adipose tissue (BAT) is receiving tremendous attention since the major function of BAT is to dissipate energy as heat. For example, mouse models that have increased BAT activity or increased numbers of brown-like adipocytes within the white adipose tissue (WAT) are lean and protected from obesity. Alternatively, mouse models that lack BAT activity are more susceptible to age and diet-induced obesity. However, a significant loss of BAT mass during the natural growth process in humans has created enormous challenges in effectively utilizing this tissue to increase energy expenditure. New strategies are primarily focused on expanding the BAT mass and/or activating the existing BAT. In this regard, recent finding that expression of early B cell factor-2 (Ebf2) reprograms the white pre-adipocytes into brown adipocytes is a significant break-through in developing BAT-mediated strategies to treat obesity. Here we review the major biological functions of WAT and BAT, which play critical but opposing roles in the energy spectrum, energy storage versus energy expenditure, and we evaluate whether activation and/or expansion of BAT is practically achievable to treat obesity in humans.


Similar levels of emotional contagion in male and female rats.
Emotional contagion, the ability to feel what other individuals feel without necessarily understanding the feeling or knowing its source, is thought to be an important element of social life. In humans, emotional contagion has been shown to be stronger in women than men. Emotional contagion has been shown to exist also in rodents, and a growing number of studies explore the neural basis of emotional contagion in male rats and mice. Here we explore whether there are sex differences in emotional contagion in rats. We use an established paradigm in which a demonstrator rat receives footshocks while freezing is measured in both the demonstrator and an observer rat. The two rats can hear, smell and see each other. By comparing pairs of male rats with pairs of female rats, we found (i) that female demonstrators froze less when submitted to footshocks, but that (ii) the emotional contagion response, i.e. the degree of influence across the rats, did not depend on the sex of the rats. This was true whether emotional contagion was quantified based on the slope of a regression linking demonstrator and observer average freezing, or on Granger causality estimates of moment-to-moment freezing. The lack of sex differences in emotional contagion is compatible with an interpretation of emotional contagion as serving selfish danger detection.