Synthesis, spectroscopic properties, and photoinduced CO-release studies of functionalized ruthenium(II) polypyridyl complexes: versatile building blocks for development of CORM-peptide nucleic acid bioconjugates.
A series of ruthenium(II) dicarbonyl complexes of formula [RuCl2(L)(CO)2] (L = bpy(CH3,CH3) = 4,4'-dimethyl-2,2'-bipyridine, bpy(CH3,CHO) = 4'-methyl-2,2'-bipyridine-4-carboxyaldehyde, bpy(CH3,COOH) = 4'-methyl-2,2'-bipyridine-4-carboxylic acid, CppH = 2-(pyridin-2-yl)pyrimidine-4-carboxylic acid, dppzcH = dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylic acid), and [RuCl(L)(CO)2](+) (L = tpy(COOH) = 6-(2,2':6',2″-terpyridine-4'-yloxy)hexanoic acid) has been synthesized. In addition, a high-yield synthesis of a peptide nucleic acid (PNA) monomer containing the 2-(pyridin-2-yl)pyrimidine ligand was also developed, and this compound was used to prepare the first Ru(II) dicarbonyl complex, [RuCl2(Cpp-L-PNA)(CO)2],(Cpp-L-PNA = tert-butyl-N-[2-(N-9-fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoyl]glycinate) attached to a PNA monomer backbone. Such metal-complex PNA-bioconjugates are attracting profound interest for biosensing and biomedical applications. Characterization of all complexes has been undertaken by IR and NMR spectroscopy, mass spectrometry, elemental analysis, and UV-vis spectroscopy. Investigation of the CO-release properties of the Ru(II) complexes in water/dimethyl sulfoxide (49:1) using the myoglobin assay showed that they are stable under physiological conditions in the dark for at least 60 min and most of them even for up to 15 h. In contrast, photoinduced CO release was observed upon illumination at 365 nm, the low-energy shoulder of the main absorption maximum centered around 300 nm, establishing these compounds as a new class of PhotoCORMs. While the two 2,2'-bipyridine complexes release 1 equiv of CO per mole of complex, the terpyridine, 2-(2'-pyridyl)pyrimidine, and dipyrido[3,2-a:2',3'-c]phenazine complexes are less effective CO releasers. Attachment of the 2-(2'-pyridyl)pyrimidine complex to a PNA backbone as in [RuCl2(Cpp-L-PNA)CO2] did not significantly change the spectroscopic or CO-release properties compared to the parent complex. Thus, a novel class of Ru(II)-based PhotoCORMs has been established which can be coupled to carrier delivery vectors such as PNA to facilitate cellular uptake without loss of the inherent CORM properties of the parent compound.


Exercise interventions on health-related quality of life for cancer survivors.
Cancer survivors experience numerous disease and treatment-related adverse outcomes and poorer health-related quality of life (HRQoL). Exercise interventions are hypothesized to alleviate these adverse outcomes. HRQoL and its domains are important measures for cancer survivorship. To evaluate the effectiveness of exercise on overall HRQoL and HRQoL domains among adult post-treatment cancer survivors. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE, EMBASE, CINAHL, PsycINFO, PEDRO, LILACS, SIGLE, SportDiscus, OTSeeker, and Sociological Abstracts from inception to October 2011 with no language or date restrictions. We also searched citations through Web of Science and Scopus, PubMed's related article feature, and several websites. We reviewed reference lists of included trials and other reviews in the field. We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing exercise interventions with usual care or other nonexercise intervention to assess overall HRQoL or at least one HRQoL domain in adults. Included trials tested exercise interventions that were initiated after completion of active cancer treatment. We excluded trials including people who were terminally ill, or receiving hospice care, or both, and where the majority of trial participants were undergoing active treatment for either the primary or recurrent cancer. Five paired review authors independently extracted information on characteristics of included trials, data on effects of the intervention, and assessed risk of bias based on predefined criteria. Where possible, meta-analyses results were performed for HRQoL and HRQoL domains for the reported difference between baseline values and follow-up values using standardized mean differences (SMD) and a random-effects model by length of follow-up. We also reported the SMDs between mean follow-up values of exercise and control group. Because investigators used many different HRQoL and HRQoL domain instruments and often more than one for the same domain, we selected the more commonly used instrument to include in the SMD meta-analyses. We also report the mean difference for each type of instrument separately. We included 40 trials with 3694 participants randomized to an exercise (n = 1927) or comparison (n = 1764) group. Cancer diagnoses in study participants included breast, colorectal, head and neck, lymphoma, and other. Thirty trials were conducted among participants who had completed active treatment for their primary or recurrent cancer and 10 trials included participants both during and post cancer treatment. Mode of the exercise intervention included strength training, resistance training, walking, cycling, yoga, Qigong, or Tai Chi. HRQoL and its domains were measured using a wide range of measures.The results suggested that exercise compared with control has a positive impact on HRQoL and certain HRQoL domains. Exercise resulted in improvement in: global HRQoL at 12 weeks' (SMD 0.48; 95% confidence interval (CI) 0.16 to 0.81) and 6 months' (0.46; 95% CI 0.09 to 0.84) follow-up, breast cancer concerns between 12 weeks' and 6 months' follow-up (SMD 0.99; 95% CI 0.41 to 1.57), body image/self-esteem when assessed using the Rosenberg Self-Esteem scale at 12 weeks (MD 4.50; 95% CI 3.40 to 5.60) and between 12 weeks' and 6 months' (mean difference (MD) 2.70; 95% CI 0.73 to 4.67) follow-up, emotional well-being at 12 weeks' follow-up (SMD 0.33; 95% CI 0.05 to 0.61), sexuality at 6 months' follow-up (SMD 0.40; 95% CI 0.11 to 0.68), sleep disturbance when comparing follow-up values by comparison group at 12 weeks' follow-up (SMD -0.46; 95% CI -0.72 to -0.20), and social functioning at 12 weeks' (SMD 0.45; 95% CI 0.02 to 0.87) and 6 months' (SMD 0.49; 95% CI 0.11 to 0.87) follow-up. Further, exercise interventions resulted in decreased anxiety at 12 weeks' follow-up (SMD -0.26; 95% CI -0.07 to -0.44), fatigue at 12 weeks' (SMD -0.82; 95% CI -1.50 to -0.14) and between 12 weeks' and 6 months' (SMD -0.42; 95% CI -0.02 to -0.83) follow-up, and pain at 12 weeks' follow-up (SMD -0.29; 95% CI -0.55 to -0.04) when comparing follow-up values by comparison group.Positive trends and impact of exercise intervention existed for depression and body image (when analyzing combined instruments); however, because few studies measured these outcomes the robustness of findings is uncertain.No conclusions can be drawn regarding the effects of exercise interventions on HRQoL domains of cognitive function, physical functioning, general health perspective, role function, and spirituality.Results of the review need to be interpreted cautiously owing to the risk of bias. All the trials reviewed were at high risk for performance bias. In addition, the majority of trials were at high risk for detection, attrition, and selection bias. This systematic review indicates that exercise may have beneficial effects on HRQoL and certain HRQoL domains including cancer-specific concerns (e.g. breast cancer), body image/self-esteem, emotional well-being, sexuality, sleep disturbance, social functioning, anxiety, fatigue, and pain at varying follow-up periods. The positive results must be interpreted cautiously due to the heterogeneity of exercise programs tested and measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials. Further research is required to investigate how to sustain positive effects of exercise over time and to determine essential attributes of exercise (mode, intensity, frequency, duration, timing) by cancer type and cancer treatment for optimal effects on HRQoL and its domains.


International variations in associations of allergic markers and diseases in children: ISAAC Phase Two.
Circulating allergen-specific IgE (sIgE) and skin prick tests (SPT) are used to define atopy. Downregulation of local inflammatory responsiveness has been proposed to explain a low prevalence of positive SPTs in less affluent countries. We analysed the association between SPTs, total and allergen-specific IgE and their relationships to allergic symptoms in centres with diverse living conditions. Cross-sectional studies of stratified random samples of 8 to 12-year-old children (n = 7461) used the standardized methodology of Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC). Symptoms of asthma, rhinitis and eczema were ascertained by parental questionnaires. Skin examination, hypertonic saline bronchial challenge, six aeroallergen SPTs and measurements of serum total IgE and sIgE were performed. In nonaffluent countries, a higher proportion of children with positive SPT had no detectable sIgE (range 37-61%) than in affluent countries (0-37%). Total serum IgE was associated with all disease outcomes among children with both positive SPT and sIgE (P < 0.001), but only with self-reported eczema in children with negative SPTs and negative sIgE. The international pattern of discordance between SPT and sIgE results did not support the downregulation hypothesis. Among children with no evidence of sensitization to common aeroallergens, increased total IgE contributes little to the risk of wheeze and rhinitis in the general population but may play a role in eczema.


In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer's disease.
Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging. Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195. Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66-0.76, t=3.90-5.58, FDR-corrected p (pFDR)=<0.001-0.002) and orbitofrontal cortex (β=0.51-0.57, t=3.53-4.30, pFDR=0.001-0.004). Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.


Automated laboratory reporting of infectious diseases in a climate of bioterrorism.
While newly available electronic transmission methods can increase timeliness and completeness of infectious disease reports, limitations of this technology may unintentionally compromise detection of, and response to, bioterrorism and other outbreaks. We reviewed implementation experiences for five electronic laboratory systems and identified problems with data transmission, sensitivity, specificity, and user interpretation. The results suggest a need for backup transmission methods, validation, standards, preserving human judgment in the process, and provider and end-user involvement. As illustrated, challenges encountered in deployment of existing electronic laboratory reporting systems could guide further refinement and advances in infectious disease surveillance.


Association between off-label use of drug-eluting stents and subsequent stent thrombosis: a case-control analysis.
We sought to examine the association between off-label drug-eluting stent (DES) use and stent thrombosis (ST) in unselected patients undergoing percutaneous coronary intervention (PCI). DES are frequently used in clinical and angiographic scenarios not initially tested and approved by the FDA (off-label use) resulting in lingering concerns about the higher risk of ST in these situations. Out of 5,383 patients undergoing PCI at a single center between 2004 and 2006, 380 had death or myocardial infarction within 1 year. After adjudication using Academic Research Consortium definitions, patients with possible, probable or definite ST were termed cases. Cases were matched with controls, free of ST at 1 year, using geographic and temporal similarities. Off-label usage was defined using manufacturer's instructions and other standard criteria. Overall, the proportion of off-label usage was higher among cases than controls (58% vs. 43%; p = 0.002) and both cases with definite/probable ST (77% vs. 59%; p = 0.08) and possible ST (54% vs. 37%; p = 0.002) had a higher off-label use than respective controls. Off-label use among cases with ST remained higher within the following subgroups: off-label by manufacturer's criteria (36% vs. 27%; p = 0.05), left main stent implantation (2% vs. 0%; p = 0.01), ostial (12% vs. 6%; p = 0.04) and bifurcated lesions (26% vs. 9%; p < 0.001). In multivariate analysis, being a case independently predicted off-label use (OR 1.68, 95% CI: 1.10-2.57; p = 0.02). In this case-control analysis, off-label use of DES was independently associated with ST within 1 year, although the increased risk was moderate.


ICON 2019-International Scientific Tendinopathy Symposium Consensus: There are nine core health-related domains for tendinopathy (CORE DOMAINS): Delphi study of healthcare professionals and patients.
The absence of any agreed-upon tendon health-related domains hampers advances in clinical tendinopathy research. This void means that researchers report a very wide range of outcome measures inconsistently. As a result, substantial synthesis/meta-analysis of tendon research findings is almost futile despite researchers publishing busily. We aimed to determine options for, and then define, core health-related domains for tendinopathy. We conducted a Delphi study of healthcare professionals (HCP) and patients in a three-stage process. In stage 1, we extracted candidate domains from clinical trial reports and developed an online survey. Survey items took the form: 'The 'candidate domain' is important enough to be included as a core health-related domain of tendinopathy'; response options were: agree, disagree, or unsure. In stage 2, we administered the online survey and reported the findings. Stage 3 consisted of discussions of the findings of the survey at the ICON (International Scientific Tendinopathy Symposium Consensus) meeting. We set 70% participant agreement as the level required for a domain to be considered 'core'; similarly, 70% agreement was required for a domain to be relegated to 'not core' (see Results next). Twenty-eight HCP (92% of whom had >10 years of tendinopathy experience, 71% consulted >10 cases per month) and 32 patients completed the online survey. Fifteen HCP and two patients attended the consensus meeting. Of an original set of 24 candidate domains, the ICON group deemed nine domains to be core. These were: (1) patient rating of condition, (2) participation in life activities (day to day, work, sport), (3) pain on activity/loading, (4) function, (5) psychological factors, (6) physical function capacity, (7) disability, (8) quality of life and (9) pain over a specified time. Two of these (2, 6) were an amalgamation of five candidate domains. We agreed that seven other candidate domains were not core domains: range of motion, pain on clinician applied test, clinical examination, palpation, drop out, sensory modality pain and pain without other specification. We were undecided on the other five candidate domains of physical activity, structure, medication use, adverse effects and economic impact. Nine core domains for tendon research should guide reporting of outcomes in clinical trials. Further research should determine the best outcome measures for each specific tendinopathy (ie, core outcome sets).


Synthesis and anticancer activity of new [(Indolyl)pyrazolyl]-1,3,4-oxadiazole thioglycosides and acyclic nucleoside analogs.
New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.


Wetting properties of poultry litter and derived hydrochar.
Detailed assessment of hydrochar wetting properties, which could provide an essential understanding of underlying mechanisms during its application to soils, is lacking. We characterized hydrochar produced from hydrothermal carbonization (HTC) performed on poultry litter at various temperatures and for different times in terms of hydrophobicity and surface free energy properties. Hydrochar was more hydrophobic than untreated poultry litter, and its hydrophobicity increased with increasing HTC temperature (contact angle > 130°). These changes were correlated with degradation of hemicellulose and cellulose. Hydrochar produced at 250°C contained mostly lignin and displayed high hydrophobicity over both prolonged wetting periods and repeated wetting cycles. Surface free energy was calculated using the Owens-Wendt-Rabel-Kaelble and Wu models, with the latter resulting in lower standard errors. The surface free energy decreased as HTC treatment severity increased from 26 mJ/m2 in the poultry litter to 8 mJ/m2 after treatment at 250°C for 60 min. The dispersive component fraction of the surface free energy increased with increasing treatment severity. This study demonstrated that changes in the physical composition of hydrochar due to increased treatment severity increase its hydrophobicity and decrease its surface free energy. Moreover, due to non-persistent hydrophobicity, hydrochar produced at temperatures lower than 250°C will likely not show adverse effects on soils.


Spectral composition of concurrent noise affects neuronal sensitivity to interaural time differences of tones in the dorsal nucleus of the lateral lemniscus.
We are regularly exposed to several concurrent sounds, producing a mixture of binaural cues. The neuronal mechanisms underlying the localization of concurrent sounds are not well understood. The major binaural cues for localizing low-frequency sounds in the horizontal plane are interaural time differences (ITDs). Auditory brain stem neurons encode ITDs by firing maximally in response to "favorable" ITDs and weakly or not at all in response to "unfavorable" ITDs. We recorded from ITD-sensitive neurons in the dorsal nucleus of the lateral lemniscus (DNLL) while presenting pure tones at different ITDs embedded in noise. We found that increasing levels of concurrent white noise suppressed the maximal response rate to tones with favorable ITDs and slightly enhanced the response rate to tones with unfavorable ITDs. Nevertheless, most of the neurons maintained ITD sensitivity to tones even for noise intensities equal to that of the tone. Using concurrent noise with a spectral composition in which the neuron's excitatory frequencies are omitted reduced the maximal response similar to that obtained with concurrent white noise. This finding indicates that the decrease of the maximal rate is mediated by suppressive cross-frequency interactions, which we also observed during monaural stimulation with additional white noise. In contrast, the enhancement of the firing rate to tones at unfavorable ITD might be due to early binaural interactions (e.g., at the level of the superior olive). A simple simulation corroborates this interpretation. Taken together, these findings suggest that the spectral composition of a concurrent sound strongly influences the spatial processing of ITD-sensitive DNLL neurons.


An update on ECARUCA, the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations.
The European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA, www.ecaruca.net) is an online database initiated in 2003 that collects and provides detailed, curated clinical and molecular information on rare unbalanced chromosome aberrations. ECARUCA now contains over 4800 cases with a total of more than 6600 genetic aberrations and has over 3000 account holders worldwide. Recently, the ECARUCA web site was renewed, including the presentation of interesting case reports in collaboration with the European Journal of Medical Genetics. This article gives an overview of the current status and future plans of the online ECARUCA database.


MitoTool: a web server for the analysis and retrieval of human mitochondrial DNA sequence variations.
MitoTool, a web-based bioinformatics platform, is designed for deciphering human mitochondrial DNA (mtDNA) data in batch mode. The platform has advantages in (i) parsing diverse types of mtDNA data; (ii) automatically classifying haplogroup according to mtDNA sequences or variants; (iii) discovering possibly missing variants of the samples with claimed haplogroups status; (iv) estimating the evolutionary conservation index, protein coding effect and potential pathogenicity of certain substitutions; (v) performing statistical analysis for haplogroup distribution frequency between case and control groups. Furthermore, it offers an integrated database for retrieving five types of mitochondrion-related information. The MitoTool is freely accessed at http://www.mitotool.org.


Costunolide Inhibits the Growth of OAW42-A Multidrug-Resistant Human Ovarian Cancer Cells by Activating Apoptotic and Autophagic Pathways, Production of Reactive Oxygen Species (ROS), Cleaved Caspase-3 and Cleaved Caspase-9.
BACKGROUND Worldwide, ovarian cancer has a high mortality rate due to the difficulty in diagnosing early-stage disease and resistance to chemotherapy agents. Costunolide is a plant-derived sesquiterpene lactone with anti-oxidant properties. This study aimed to investigate the effects of costunolide on cell growth, apoptosis, autophagy, the production of reactive oxygen species (ROS), cleaved caspase-3, and cleaved caspase-9 on the multidrug-resistant ovarian cancer cell line, OAW42-A. MATERIAL AND METHODS The MTT assay determined the proliferation rate of OAW42-A multidrug-resistant ovarian cancer cells and the apoptosis rate was determined using propidium iodide (PI) staining. Autophagy was detected by measuring the expression of LC3 II. Fluorescence flow cytometry was used to measure the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. Protein expression of LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9 were measured by Western blot. RESULTS Costunolide treatment inhibited the growth of OAW42-A cells with an IC₅₀ of 25 µM, resulted in apoptotic cell death, increased the expression of Bax, and decreased the expression of Bcl-2. Confocal electron microscopy showed that costunolide induced autophagy in the OAW42-A cells. Western blot showed that costunolide treatment of OAW42-A cells increased the expression of the LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9. Costunolide treatment significantly increased the levels of ROS and reduced the OAW42-A cell mitochondrial membrane potential. CONCLUSIONS Costunolide inhibited growth, apoptosis, ROS generation, and was associated with loss of mitochondrial membrane potential of OAW42-A multidrug-resistant ovarian cancer cells.


Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation.
Recent attention has been focused on the long-term impact of cannabis exposure, for which experimental animal studies have validated causal relationships between neurobiological and behavioral alterations during the individual's lifetime. Here, we show that adolescent exposure to Δ(9)-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, results in behavioral and neurobiological abnormalities in the subsequent generation of rats as a consequence of parental germline exposure to the drug. Adult F1 offspring that were themselves unexposed to THC displayed increased work effort to self-administer heroin, with enhanced stereotyped behaviors during the period of acute heroin withdrawal. On the molecular level, parental THC exposure was associated with changes in the mRNA expression of cannabinoid, dopamine, and glutamatergic receptor genes in the striatum, a key component of the neuronal circuitry mediating compulsive behaviors and reward sensitivity. Specifically, decreased mRNA and protein levels, as well as NMDA receptor binding were observed in the dorsal striatum of adult offspring as a consequence of germline THC exposure. Electrophysiologically, plasticity was altered at excitatory synapses of the striatal circuitry that is known to mediate compulsive and goal-directed behaviors. These findings demonstrate that parental history of germline THC exposure affects the molecular characteristics of the striatum, can impact offspring phenotype, and could possibly confer enhanced risk for psychiatric disorders in the subsequent generation.


Different sham procedures for rats in traumatic brain injury experiments induce corresponding increases in levels of trauma markers.
In traumatic brain injury animal models, sham or naïve control groups are often used for the analysis of injured animals; however, the existence and/or significance of differences in the control groups has yet to be studied. In addition, recent controversies regarding the decompressive craniectomy trial in which decompressive craniectomies in patients with severe traumatic brain injury and refractory increased intracranial pressure remains unsettled. Although the report demonstrated that the procedure may result in less favorable long-term outcomes despite the decrease in intracranial pressure and shorter length of intensive care unit stay, the study has been criticized, and the debate is still inconclusive partly because of a lack of mechanistic explanation. We have recently discovered epithelial and endothelial tyrosine kinase (Etk) to exhibit upregulation after traumatic neural injury and will compare the effects of craniectomy procedure with those of other procedures inducing different levels of severity. Four groups of rats receiving different procedures (controlled cortical impact, craniectomy, bicortical drilling, and unicortical drilling [UD]) were compared. Polymerase chain reaction, Western blot analysis, and immunoflorescence staining of Etk, S100, and glial fibrillary acidic protein levels were used to analyze the results and compare the different groups. Etk upregulation was statistically significant between craniectomy and UD groups. The level of change for glial fibrillary acidic protein and S100 was only significant when cortex was impacted. UD may be preferable as a sham control procedure over craniectomy or bicortical drilling. Increases in the expression of Etk in the craniectomy group suggest a possible mechanism by which unfavorable outcome occurs in patients receiving craniectomy procedures.


Involvement of CD226+ NK cells in immunopathogenesis of systemic lupus erythematosus.
Dysfunction of immune systems, including innate and adaptive immunity, is responsible for the immunopathogenesis of systemic lupus erythematosus (SLE). NK cells are a major part of the innate immune system, and diminished populations of NK cells have been reported in SLE patients. However, the mechanisms behind this decrease and the role of NK cells in SLE pathogenesis remain poorly understood. In this study, we found that a deficiency of NK cells, especially CD226(+) NK cells, is prominent in patients with active SLE. Meanwhile, expression of the CD226 ligands CD112 and CD155 on plasmacytoid dendritic cells is observed in SLE patients; thus, activation of CD226(+) NK cells may be induced by CD226-ligand interactions. Furthermore, IFN-α, which is mainly produced by plasmacytoid dendritic cells, can mediate the activation-induced cell death of NK cells. Therefore, these processes likely contribute to the loss of NK cells in patients with active SLE. Despite the impaired cytotoxicity of peripheral NK cells in human SLE patients and mouse SLE models, we provide evidence that CD226(+) NK cells infiltrate the kidneys of predisease MRL-lpr/lpr mice. Kidney-infiltrating NK cells displayed an activated phenotype and a marked ability to produce cytotoxic granules. These results suggest that, before apoptosis, activated NK cells can infiltrate tissues and, to some extent, mediate tissue injury by producing cytotoxic granules and immunoregulatory cytokines.


Microsecond sub-domain motions and the folding and misfolding of the mouse prion protein.
Protein aggregation appears to originate from partially unfolded conformations that are sampled through stochastic fluctuations of the native protein. It has been a challenge to characterize these fluctuations, under native like conditions. Here, the conformational dynamics of the full-length (23-231) mouse prion protein were studied under native conditions, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS). The slowest fluctuations could be associated with the folding of the unfolded state to an intermediate state, by the use of microsecond mixing experiments. The two faster fluctuations observed by PET-FCS, could be attributed to fluctuations within the native state ensemble. The addition of salt, which is known to initiate the aggregation of the protein, resulted in an enhancement in the time scale of fluctuations in the core of the protein. The results indicate the importance of native state dynamics in initiating the aggregation of proteins.


Hysteresis effects of the subjective visual vertical during continuous quasi-static whole-body roll rotation.
Healthy human subjects, when roll tilted in darkness, make systematic errors in estimating subjective visual vertical (SVV). Typically, roll tilt underestimation occurs at angles beyond 60 degrees (A-effect). At smaller tilt angles, overestimation may occur (E-effect). At approximately 135 degrees whole-body roll tilt, Kaptein and Van Gisbergen (2004, 2005) found an abrupt A/E transition, the exact location of which depended on the preceding rotation direction indicating hysteresis. Since this was observed using relatively fast roll velocity, it remains unclear whether the described hysteresis is dynamic or static. To clarify this uncertainty, we continuously rotated nine healthy subjects about the earth-horizontal naso-occipital axis, while they performed SVV adjustments every 2 s. Starting from the upright position, three full quasi-static constant velocity rotations (2 degrees/s) were completed in both directions (CW: clockwise; CCW: counterclockwise). SVV deviation from earth-verticality was plotted as a function of whole-body roll position. A bimodal Gaussian distribution function was fitted to SVV differences between CW and CCW rotations. A-effects (peaks at 88 degrees and 257 degrees chair position) at identical whole-body positions were larger after rotations from upside-down than after rotations from upright (average peak difference: 26 degrees). These results demonstrate static hysteresis for SVV estimation.


Bereavement in the Time of Coronavirus: Unprecedented Challenges Demand Novel Interventions.
COVID-19 fatalities exemplify "bad deaths" and are distinguished by physical discomfort, difficulty breathing, social isolation, psychological distress, and care that may be discordant with the patient's preferences. Each of these death attributes is a well-documented correlate of bereaved survivors' symptoms of depression, anxiety, and anger. Yet the grief experienced by survivors of COVID-related deaths is compounded by the erosion of coping resources like social support, contemporaneous stressors including social isolation, financial precarity, uncertainty about the future, lack of routine, and the loss of face-to-face mourning rituals that provide a sense of community and uplift. National efforts to enhance advance care planning may help dying patients to receive care that is concordant with the preferences of them and their families. Virtual funeral services, pairing bereaved elders with a telephone companion, remote counseling, and encouraging "continuing bonds" may help older adults adapt to loss in the time of pandemic.


Synthesis of piroxicam loaded novel electrospun biodegradable nanocomposite scaffolds for periodontal regeneration.
Development of biodegradable composites having the ability to suppress or eliminate the pathogenic micro-biota or modulate the inflammatory response has attracted great interest in order to limit/repair periodontal tissue destruction. The present report includes the development of non-steroidal anti-inflammatory drug encapsulated novel biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) electro-spun (e-spun) composite nanofibrous mats and films and study of the effect of heat treatment on fibers and films morphology. It also describes comparative in-vitro drug release profiles from heat treated and control (non-heat treated) nanofibrous mats and films containing varying concentrations of piroxicam (PX). Electrospinning was used to obtain drug loaded ultrafine fibrous mats. The physical/chemical interactions were evaluated by Fourier Transform Infrared (FT-IR) spectroscopy. The morphology, structure and pore size of the materials were investigated by scanning electron microscopy (SEM). The thermal behavior of the materials was investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Control (not heat treated) and heat treated e-spun fibers mats and films were tested for in vitro drug release studies at physiological pH7.4 and initially, as per requirement burst release patterns were observed from both fibers and films and later sustained release profiles were noted. In vitro cytocompatibility was performed using VERO cell line of epithelial cells and all the synthesized materials were found to be non-cytotoxic. The current observations suggested that these materials are potential candidates for periodontal regeneration.


Considerations of the Principles of Resistance Training in Exercise Studies for the Management of Knee Osteoarthritis: A Systematic Review.
To evaluate the methodologic quality of resistance training interventions for the management of knee osteoarthritis. A search of the literature for studies published up to August 10, 2015, was performed on MEDLINE (OVID platform), PubMed, Embase, and Physiotherapy Evidence Database databases. Search terms associated with osteoarthritis, knee, and muscle resistance exercise were used. Studies were included in the review if they were published in the English language and met the following criteria: (1) muscle resistance training was the primary intervention; (2) randomized controlled trial design; (3) treatment arms included at least a muscle conditioning intervention and a nonexercise group; and (4) participants had osteoarthritis of the knee. Studies using preoperative (joint replacement) interventions with only postoperative outcomes were excluded. The search yielded 1574 results. The inclusion criteria were met by 34 studies. Two reviewers independently screened the articles for eligibility. Critical appraisal of the methodology was assessed according to the principles of resistance training and separately for the reporting of adherence using a specially designed scoring system. A rating for each article was assigned. There were 34 studies that described a strength training focus of the intervention; however, the principles of resistance training were inconsistently applied and inadequately reported across all. Methods for adherence monitoring were incorporated into the design of 28 of the studies, but only 13 reported sufficient detail to estimate average dose of exercise. These findings affect the interpretation of the efficacy of muscle resistance exercise in the management of knee osteoarthritis. Clinicians and health care professionals cannot be confident whether nonsignificant findings are because of the lack of efficacy of muscle resistance interventions, or occur through limitations in treatment prescription and patient adherence. Future research that seeks to evaluate the effects of muscle strength training interventions on symptoms of osteoarthritis should be properly designed and adherence diligently reported.


Psychological distress by type of fertility barrier.
We examined fertility-specific distress (FSD) and general distress by type of fertility barrier (FB). In a random sample telephone survey, 580 US women reported their fertility intentions and histories. Six groups of women were identified: (i) no FBs, (ii) infertile with intent, (iii) infertile without intent, (iv) other fertility problems, (v) miscarriages and (vi) situational barriers. Multiple regression analyses were used to compare groups with FBs. Sixty-one percent reported FBs and 28% reported an inability to conceive for at least 12 months. The infertile with intent group had the highest FSD, which was largely explained by (a) self-identification as infertile and (b) seeking medical help for fertility. The no FB group had a mean Center for Epidemiological Studies Depression scale score above the commonly used cut-off of 16, although 23% of the women with FBs did score above 16. FBs are common. Self-identification as infertile is the largest source of FSD. More women with FBs had elevated general distress than women without FBs; mean general distress was below 16 for all FB groups. It may be that, for some women (even those with children), FBs can have lasting emotional consequences, but many women do heal from the emotional distress that may accompany fertility difficulties.


Interleukin-2 enhancement of cytotoxicity by humanized monoclonal antibody M195 (anti-CD33) in myelogenous leukemia.
Humanized M195 (HuM195) is a genetically engineered, human IgG1 version of the parent M195, a mouse immunoglobulin G2a, anti-CD33 monoclonal antibody which reacts with early myeloid progenitor cells and myelogenous leukemia cells. In Phase I studies in patients with relapsed and refractory myelogenous leukemia, HuM195 safely targeted to sites of disease and was nonimmunogenic. HuM195 shows only modest capability of antibody-dependent cellular cytotoxicity (ADCC) against target HL60 cells and minimal cytolytic activity mediated by human complement. Therefore, efforts were made to enhance ADCC using cytokines. gamma-Interferon, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor did not promote neutrophil-mediated ADCC with HuM195. However, interleukin-2 (IL-2) showed a range of 2-6-fold increases in ADCC against fresh myelogenous leukemia cells and HL60 cells over that seen with HuM195 or low-dose IL-2 alone. ADCC potency was not improved further by the use of homodimeric HuM195. Flow cytometry and Fc receptor-blocking experiments showed that CD16(+) cells were essential for IL-2-enhanced ADCC. As compared to HL60 cells, a multidrug-resistant line of HL60 cells was at least as susceptible to killing by IL-2 or HuM195 or in combination, suggesting that the mechanism of killing may be active against cells surviving and resistant to chemotherapy. Since these in vitro levels of IL-2 and HuM195 can be safely achieved in patients, the enhancement of HuM195 ADCC with low-dose IL-2 is a possible strategy that may be used in vivo to eliminate minimal disease in future trials of patients with myeloid leukemias.


How are Substance Use Disorder Treatment Programs Adjusting to Value-Based Payment? A Statewide Qualitative Study.
Healthcare systems are implementing value-based payment (VBP) arrangements in efforts to incentivize cost-effective, high quality of care. These arrangements represent a major shift for substance use disorder (SUD) treatment providers who may need to make changes to their clinical and business operations to meet new demands for quality under value-based contracts. This qualitative study was conducted in the context of New York State's efforts to implement VBP among SUD treatment providers to understand their experiences, challenges, and needs. Five focus groups were conducted across the State with a total of 68 treatment professionals. Content analysis was conducted and five themes emerged. First, competing demands, limited workforce and technology infrastructure, and perceived lack of information were leading to overwhelmed administrators. Second, confusion and financial fear was being driven by the need for new clinical roles, business practices, and external partnerships. Third, providers were undertaking a number of measures to address workforce needs. Fourth, providers were building new business models and clinical practices. Fifth, providers desired more support and information. As VBP models are being adopted, healthcare systems should identify ways to mitigate challenges and support SUD treatment providers that may have limited resources to address complex workforce, client, and infrastructure needs.


Longitudinal modeling in developmental neuroimaging research: Common challenges, and solutions from developmental psychology.
Hypotheses about change over time are central to informing our understanding of development. Developmental neuroscience is at critical juncture: although the majority of longitudinal imaging studies have observations with two time points, researchers are increasingly obtaining three or more observations of the same individuals. The goals of the proposed manuscript are to draw upon the long history of methodological and applied literature on longitudinal statistical models to summarize common problems and issues that arise in their use. We also provide suggestions and solutions to improve the design, analysis and interpretation of longitudinal data, and discuss the importance of matching the theory of change with the appropriate statistical model used to test the theory. Researchers should articulate a clear theory of change and to design studies to capture that change and use appropriately sensitive measures to assess that change during development. Simulated data are used to demonstrate several common analytic approaches to longitudinal analyses. We provide the code for our simulations and figures in an online supplement to aid researchers in exploring and plotting their data. We provide brief examples of best practices for reporting such models. Finally, we clarify common misunderstandings in the application and interpretation of these analytic approaches.


Inhibitive Effects of FGF2/FGFR1 Pathway on Astrocyte-Mediated Inflammation in vivo and in vitro After Infrasound Exposure.
Infrasound, a kind of ambient noise, can cause severe disorders to various human organs, specially to central nervous system (CNS). Our previous studies have shown that infrasound-induced CNS injury was closely related with astrocytes activation and astrocytes-mediated neuroinflammation, but the underlying molecular mechanisms are still largely unclear. FGF2/FGFR1 (Fibroblast growth factor 2/Fibroblast growth factor receptor 1) pathway was reported to play an important role in anti-inflammation in CNS disorders. To further study the possible roles of FGF2/FGFR1 pathway in infrasound-induced CNS injury, here we exposed Sprague-Dawley rats or cultured astrocytes to 16 Hz, 150 dB infrasound, and explored the effects of FGF2 on infrasound-induced astrocytes activation and neuroinflammation. Western blotting, immunofluorescence and liquid chip method were used in this experiment. Our results showed that after 3- or 7-day exposure (2 h/day) of rats as well as 2 h exposure of cultured astrocytes to 16 Hz, 150 dB infrasound, astrocyte-expressed FGFR1 was downregulated in vivo and in vitro. FGF2 pretreatment not only inhibited infrasound-induced astrocyte activation in rat hippocampal CA1 region, but also reduced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-18, IL-6, and IFN-γ in vitro and in vivo. However, FGF2 significantly upregulated the expression of FGFR1. Furthermore, we showed that FGF2 could attenuate IκBα phosphorylation, NF-κB p65 translocation, pro-inflammatory cytokines levels, and neuronal loss in the CA1 region induced by infrasound. On the contrary, PD173074, a special antagonist of FGFR1, could reverse the effects above in vitro and in vivo. Taken together, our findings showed that FGF2/FGFR1 pathway may exert inhibitive effects on astrocyte-mediated neuroinflammation in vitro and in vivo after infrasound exposure.


Obesity during childhood is associated with higher cancer mortality rate during adulthood: the i3C Consortium.
In high-income countries, cancer is the leading cause of death among middle-aged adults. Prospective data on the effects of childhood risk exposures on subsequent cancer mortality are scarce. We examined whether childhood body mass index (BMI), blood pressure, glucose and lipid levels were associated with adult cancer mortality, using data from 21,012 children enrolled aged 3-19 years in seven prospective cohort studies from the U.S., Australia, and Finland that have followed participants from childhood into adulthood. Cancer mortality (cancer as a primary or secondary cause of death) was captured using registries. 354 cancer deaths occurred over the follow-up. In age-, sex, and cohort-adjusted analyses, childhood BMI (Hazard ratio [HR], 1.13; 95% confidence interval [CI] 1.03-1.24 per 1-SD increase) and childhood glucose (HR 1.22; 95%CI 1.01-1.47 per 1-SD increase), were associated with subsequent cancer mortality. In a multivariable analysis adjusted for age, sex, cohort, and childhood measures of fasting glucose, total cholesterol, triglycerides, and systolic blood pressure, childhood BMI remained as an independent predictor of subsequent cancer mortality (HR, 1.24; 95%CI, 1.03-1.49). The association of childhood BMI and subsequent cancer mortality persisted after adjustment for adulthood BMI (HR for childhood BMI, 1.35; 95%CI 1.12-1.63). Higher childhood BMI was independently associated with increased overall cancer mortality.


[Understanding the elderly user of auditory prostheses].
The main goal was to identify the factors involved in the application for and use of auditory prostheses by the elderly as well as their awareness of the Policy of Care to Auditory Health. 25 elderly people of both sexes using auditory prostheses in Vitória (Espírito Santo, Brazil) were selected. They were contacted by telephone to participate in the research by answering a questionnaire. The results demonstrated that most of the elderly people interviewed (52%) use the device all day which suggests good adaptation to the process. Thirteen elderly people reported that they contacted the prosthesis company of their own accord. The advantages involved better communication and listening to TV (64%) while the difficulties were due to noisy environments; 56% were unable to understand what was being said at lectures, in church, and on the telephone, 72% reported no improvement with the prosthesis. 88% of the elderly participants are unaware of donation policies for auditory devices and 100% are unaware of this kind of service. Research and practices in health services about auditory issues still have far to go. There is a need for a change in management with the objective of putting into action policies which define the responsibilities of the State.


Forensic mental health services: Current service provision and planning for a prison mental health service in the Eastern Cape.
No research data exists on forensic psychiatric service provision in the Eastern Cape, Republic of South Africa. The objective of this research was to assess current forensic psychiatric service provision and utilisation rates at Fort England Hospital. This is important in improving and strengthening the service. A related objective was to develop a model for a provincial prison mental health service. This study is a situational analysis of an existing forensic psychiatric service in the Eastern Cape. The design of the study was cross sectional. An audit questionnaire was utilised to collate quantitative data, which was submitted to Fort England Hospital, Grahamstown. A proposed prison mental health service was developed utilising prevalence rates of mental illness among prisoners to calculate bed and staff requirements for an ambulatory and in-patient service. During the study period a total of 403 remand detainees were admitted to the forensic psychiatry division of Fort England Hospital. The average length of stay was 494 days and the bed utilisation rate was determined at 203.54%. We estimate that to provide a provincial prison mental health service to treat psychotic illnesses and major depression the province requires a 52 bedded facility and a total staff complement of approximately 31. Forensic psychiatric services include the assessment, management and treatment of mentally disordered persons in conflict with the law and prisoners requiring psychiatric assessments. The Eastern Cape Province does not have plans or policies to assess and manage mentally ill offenders, resulting in an increased load on available services. We recommend that an inter-departmental task team, which includes Health, Justice and Constitutional Development and Correctional Services, should be established in the province, to develop a strategy to assist in the development of an effective and efficient forensic psychiatric service. This should be driven by the provincial Department of Health.


Clinical utility of circulating tumor cells in patients with non-small-cell lung cancer.
Several different studies have addressed the role of the circulating tumor cells (CTC) in non-small-cell lung cancer (NSCLC). In particular, the potential of CTC analysis in the early diagnosis of NSCLC and in the prediction of the outcome of patients with early and advanced NSCLC have been explored. A major limit of these studies is that they used different techniques for CTC isolation and enumeration, they employed different thresholds to discriminate between high- and low-risk patients, and they enrolled heterogeneous and often small cohort of patients. Nevertheless, the results of many studies are concordant in indicating a correlation between high CTC count and poor prognosis in both early and advanced NSCLC. The reduction of CTC number following treatment might also represent an important indicator of sensitivity to therapy in patients with metastatic disease. Preliminary data also suggest the potential for CTC analysis in the early diagnosis of NSCLC in high-risk individuals. However, these findings need to be confirmed in large prospective trials in order to be transferred to the clinical practice. The molecular profiling of single CTC in NSCLC might provide important information on tumor biology and on the mechanisms involved in tumor dissemination and in acquired resistance to targeted therapies. In this respect, xenografts derived from CTC might represent a valuable tool to investigate these phenomena and to develop novel therapeutic strategies.


Arabidopsis thaliana AUCSIA-1 regulates auxin biology and physically interacts with a kinesin-related protein.
Aucsia is a green plant gene family encoding 44-54 amino acids long miniproteins. The sequenced genomes of most land plants contain two Aucsia genes. RNA interference of both tomato (Solanum lycopersicum) Aucsia genes (SlAucsia-1 and SlAucsia-2) altered auxin sensitivity, auxin transport and distribution; it caused parthenocarpic development of the fruit and other auxin-related morphological changes. Here we present data showing that the Aucsia-1 gene of Arabidopsis thaliana alters, by itself, root auxin biology and that the AtAUCSIA-1 miniprotein physically interacts with a kinesin-related protein. The AtAucsia-1 gene is ubiquitously expressed, although its expression is higher in roots and inflorescences in comparison to stems and leaves. Two allelic mutants for AtAucsia-1 gene did not display visible root morphological alterations; however both basipetal and acropetal indole-3-acetic acid (IAA) root transport was reduced as compared with wild-type plants. The transcript steady state levels of the auxin efflux transporters ATP BINDING CASSETTE subfamily B (ABCB) ABCB1, ABCB4 and ABCB19 were reduced in ataucsia-1 plants. In ataucsia-1 mutant, lateral root growth showed an altered response to i) exogenous auxin, ii) an inhibitor of polar auxin transport and iii) ethylene. Overexpression of AtAucsia-1 inhibited primary root growth. In vitro and in vivo protein-protein interaction experiments showed that AtAUCSIA-1 interacts with a 185 amino acids long fragment belonging to a 2712 amino acids long protein of unknown function (At4g31570). Bioinformatics analysis indicates that the AtAUCSIA-1 interacting protein (AtAUCSIA-1IP) clusters with a group of CENP-E kinesin-related proteins. Gene ontology predictions for the two proteins are consistent with the hypothesis that the AtAUCSIA-1/AtAUCSIA-1IP complex is involved in the regulation of the cytoskeleton dynamics underlying auxin biology.


[Natural interferon-beta in the treatment of relapsing-remitting multiple sclerosis: a multicenter, randomized, MRI-based, phase II clinical trial].
The ability of natural human interferon beta (n-hIFN beta) to reduce multiple sclerosis (MS) activity was investigated in 60 patients with relapsing-remitting MS (RRMS). Patients were randomized to receive either 9 MIU (33 micrograms) of n-hIFN beta by subcutaneous route, three times per week, on alternate days, during one year, or no treatment (control group) during the first six months and then switched to the same treatment for the following six months. Disease activity was monitored monthly by both magnetic resonance imaging (MRI) and clinical parameters. An intergroup analysis (first 6 months of the study) showed fewer active lesions and lower exacerbation rate in the treatment group than in the control group. Similarly, there were more exacerbation-free patients in the treatment group during this time. When switched to treatment, the control group showed a significant reduction in the number of active lesions (p = 0.00001) and the exacerbation rate decreased by half. Exacerbation-free patients more than doubled (p = 0.006) and the median time to first exacerbation was significantly prolonged (96 vs > 180 days; p = 0.019). Treatment was extended for 12 additional months at a dose of 6 MIU (22 micrograms) once a week and disease activity persisted under control in 88% of patients. Treatment with n-hIFN beta was well tolerated, adverse events being mild and self-limiting. Sera were analyzed for anti-IFN beta antibodies and neutralizing activity was found in 12% of the patients after two years. The results of this phase II study show, that n-hIFN beta promotes a significant reduction of disease activity in RRMS as shown by both MRI and clinical variables, and that the treatment is well tolerated, with low antigenicity.


The enhanced peroxidase one step method increases sensitivity for detection of Ki-67 in pituitary tumours.
To compare the Ki-67 labelling index determined using the enhanced peroxidase one step (EPOS) method with that using the standard ABC technique in pituitary tumours. Adjacent sections were immunostained using the EPOS and ABC techniques with the same Ki-67 antibody and same antigen retrieval method. The labelling index measurements with the EPOS Ki-67 antibody were significantly higher than when using the traditional ABC method, and there was a positive correlation between the two techniques when performed on the same cases. This suggests that a higher proportion of cells are within the cell cycle than previously thought, although it gives no direct information on the rate of proliferation of the tumour. It appears that the EPOS system is not only more convenient but may be more sensitive than traditional techniques for detecting Ki-67 in the nuclei of cells, thus demonstrating more accurately which cells have entered the cell cycle.


The hematopoietic stem cell diet.
Hematopoietic stem cells (HSCs) are responsible for sustaining life-long blood formation or hematopoiesis and are also used clinically in a form of bone marrow transplantation, a curative cellular therapy for a range of hematological diseases. HSCs are maintained throughout adult life by a complex biological niche or microenvironment, which is thought to be composed of a range of cellular, molecular, and metabolic components. The metabolic components of the HSC niche have become of increasing interest over the past few years. It is now well-recognized that metabolic activity is intimately linked to HSC function, and dysregulation of these metabolic pathways result in hematological pathologies such as leukemia. Here, we review the recent progress in this field including our current understanding of the "dietary" requirements of HSCs and how nutrition influences HSC activity. These recent findings have suggested promising new metabolic approaches to improve clinical HSC transplantation and leukemia therapies.


Enzymatic characterization of organic phosphorus in animal manure.
Information on the forms of P present in animal manure may improve our ability to manage manure P. In most investigations of manure P composition, only inorganic and total P are determined, and the difference between them is assigned as organic P. In this study, we explored the possibility of identifying and quantifying more specific organic P forms in animal manure with orthophosphate-releasing enzymes. Pig (Sus scrofa) manure and cattle (Bos taurus) manure were first sequentially fractionated into water-soluble P, NaHCO3-soluble P, NaOH-soluble P, HCl-soluble P, and residual P. The fractions were separately incubated with wheat phytase, alkaline phosphatase, nuclease P1, nucleotide pyrophosphatase, or their combinations. The released orthophosphate was determined by a molybdate blue method. Part of the organic P in those fractions could be identified by the enzymatic treatments as phytate (i.e., 39% for pig manure and 17% for cattle manure in water-soluble organic P), simple phosphomonoesters (i.e., 43% for pig manure and 15% for cattle manure in NaOH-soluble organic P), nucleotide-like phosphodiesters (2-12%), and nucleotide pyrophosphate (0-4%). Our data indicate that the enzymatic treatment is an effective approach to identify and quantify the organic P forms present in animal manures.


BC-819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers.
BC-819 (DTA-H19), in development by BioCancell Therapeutics Inc, under license from the Hebrew University of Jerusalem, is a double-stranded DNA plasmid carrying the gene for the A subunit of diphtheria toxin under the regulation of the H19 gene promoter. H19, a paternally imprinted, oncofetal gene, encodes an RNA that acts as a riboregulator. Expressed at substantial levels in embryonic and malignant tissues, but minimally or not expressed in adult tissues, elevated H19 RNA expression has been observed in over 30 malignancies prompting investigation into its utility as a targeted therapeutic agent. While most in vivo studies have investigated BC-819 for the treatment of bladder cancer, recent studies have also yielded encouraging results in NSCLC,colon, pancreatic and ovarian cancers. A phase I/IIa clinical trial in patients with non-muscle invasive bladder cancer receiving intravesical BC-819 reported mild local toxicity and complete and partial response rates of 22 and 44%, respectively. At the time of publication, a phase IIb trial was ongoing in patients with bladder cancer, while phase I/II clinical trials in patients with ovarian and pancreatic cancer were accruing participants. This review provides a focused summary of the existing experimental evidence demonstrating the effectiveness of the plasmid construct, early clinical outcomes and a discussion of the potential role of BC-819 as a targeted cancer therapy.


Everything should be as simple as possible, but no simpler: towards a protocol for accumulating evidence regarding the active content of health behaviour change interventions.
There is a need to consolidate the evidence base underlying our toolbox of methods of behaviour change. Recent efforts to this effect have conducted meta-regressions on evaluations of behaviour change interventions, deriving each method's effectiveness from its association to intervention effect size. However, there are a range of issues that raise concern about whether this approach is actually furthering or instead obstructing the advancement of health psychology theories and the quality of health behaviour change interventions. Using examples from theory, the literature and data from previous meta-analyses, these concerns and their implications are explained and illustrated. An iterative protocol for evidence base accumulation is proposed that integrates evidence derived from both experimental and applied behaviour change research, and combines theory development in experimental settings with theory testing in applied real-life settings. As evidence gathered in this manner accumulates, a cumulative science of behaviour change can develop.


Time trends in utilization of G-CSF prophylaxis and risk of febrile neutropenia in a Medicare population receiving adjuvant chemotherapy for early-stage breast cancer.
The purpose of this study is to assess temporal trends in the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis and risk of febrile neutropenia (FN) among older women receiving adjuvant chemotherapy for early-stage breast cancer. Women aged ≥ 66 years with diagnosis of early-stage breast cancer who initiated selected adjuvant chemotherapy regimens were identified using the SEER-Medicare data from 2002 to 2012. Adjusted, calendar-year-specific proportions were estimated for use of G-CSF primary prophylaxis (PP) and secondary prophylaxis and FN risk in the first and the second/subsequent cycles during the first course of chemotherapy, using logistic regression models. calendar-year-specific mean probabilities were estimated with covariates set to modal values. Among 11,107 eligible patients (mean age 71.7 years), 74% received G-CSF in the first course of chemotherapy. Of all patients, 5819 (52%) received G-CSF PP, and among those not receiving G-CSF PP, only 5% received G-CSF secondary prophylaxis. The adjusted proportion using G-CSF PP increased from 6% in 2002 to 71% in 2012. During the same period, the adjusted risk of FN in the first cycle increased from 2% to 3%; the adjusted risk increased from 1.5% to 2.9% among those receiving G-CSF PP and from 2.3% to 3.5% among those not receiving G-CSF PP. The use of G-CSF PP increased substantially during the study period. Although channeling of higher-risk patients to treatment with G-CSF PP is expected, the adjusted risk of FN among patients treated with G-CSF PP tended to be lower than among those not receiving G-CSF PP.


Antagonistic actions of ecdysone and insulins determine final size in Drosophila.
All animals coordinate growth and maturation to reach their final size and shape. In insects, insulin family molecules control growth and metabolism, whereas pulses of the steroid 20-hydroxyecdysone (20E) initiate major developmental transitions. We show that 20E signaling also negatively controls animal growth rates by impeding general insulin signaling involving localization of the transcription factor dFOXO and transcription of the translation inhibitor 4E-BP. We also demonstrate that the larval fat body, equivalent to the vertebrate liver, is a key relay element for ecdysone-dependent growth inhibition. Hence, ecdysone counteracts the growth-promoting action of insulins, thus forming a humoral regulatory loop that determines organismal size.


On-demand concentration of an analyte on laser-printed polytetrafluoroethylene.
Controllable targeted deposition of an analyte dissolved in a liquid drop evaporating on a superhydrophobic surface has recently emerged as a promising concentrator approach with various applications ranging from ultrasensitive bioidentification to DNA molecule sorting. Here, we demonstrate that surface textures with non-uniform wettability fabricated using direct easy-to-implement femtosecond-pulse filament-assisted ablation of polytetrafluoroethylene substrates can be used to concentrate and deposit an analyte at a designated location out of a water droplet. The proposed surface textures contain a central superhydrophilic trap surrounded by superhydrophobic periodically arranged pillars with a hierarchical roughness. By optimizing the arrangement and geometry of the central trap and the surrounding superhydrophobic textures, the analyte dissolved in a 5 μL water drop was fixed onto a 90 × 90 μm2 target. The proposed textures provide a concentration factor of 103, an order of magnitude higher than those for the previously reported surface textures. This promising ultrasensitive versatile platform allows the detection of fingerprints of the deposited analyte via surface-enhanced spectroscopy techniques (Raman scattering or photoluminescence) at an estimated detection threshold better than 10-15 mol L-1.


Congenital Ewing's Sarcoma, a Rare and Difficult Diagnosis: A Case Report.
We have interestedly read the article written by Thalia Wong BS in July 2015, which is about Pediatric Blood Cancer, including clinical findings and results of infants <1 year of age with Ewing sarcoma. We report a case with congenital Ewing's sarcoma that easily interfered with rabdomyosarcoma in a pregnant woman. A 32-year-old multigravida with a big neck mass at 35 weeks was referred to our clinic. The final diagnosis of extraskeletal Ewing's sarcoma was made. Hepatic metastasis was detected and treatment by chemotherapy was initiated. Ewing's sarcoma is usually noted among adolescents or young adults and more rarely than among newborns. This case is important because of its rarity.


Falling Plasmodium knowlesi Malaria Death Rate among Adults despite Rising Incidence, Sabah, Malaysia, 2010-2014.
Deaths from Plasmodium knowlesi malaria have been linked to delayed parenteral treatment. In Malaysia, early intravenous artesunate is now recommended for all severe malaria cases. We describe P. knowlesi fatalities in Sabah, Malaysia, during 2012-2014 and report species-specific fatality rates based on 2010-2014 case notifications. Sixteen malaria-associated deaths (caused by PCR-confirmed P. knowlesi [7], P. falciparum [7], and P. vivax [1] and microscopy-diagnosed "P. malariae" [1]) were reported during 2012-2014. Six patients with severe P. knowlesi malaria received intravenous artesunate at hospital admission. For persons ≥15 years of age, overall fatality rates during 2010-2014 were 3.4, 4.2, and 1.0 deaths/1,000 P. knowlesi, P. falciparum, and P. vivax notifications, respectively; P. knowlesi-associated fatality rates fell from 9.2 to 1.6 deaths/1,000 notifications. No P. knowlesi-associated deaths occurred among children, despite 373 notified cases. Although P. knowlesi malaria incidence is rising, the notification-fatality rate has decreased, likely due to improved use of intravenous artesunate.


High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice.
The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients. Mice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies. The increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogenic-like/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted. Our data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.


Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.
The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.


A Laplacian approach to multi-oriented text detection in video.
In this paper, we propose a method based on the Laplacian in the frequency domain for video text detection. Unlike many other approaches which assume that text is horizontally-oriented, our method is able to handle text of arbitrary orientation. The input image is first filtered with Fourier-Laplacian. K-means clustering is then used to identify candidate text regions based on the maximum difference. The skeleton of each connected component helps to separate the different text strings from each other. Finally, text string straightness and edge density are used for false positive elimination. Experimental results show that the proposed method is able to handle graphics text and scene text of both horizontal and nonhorizontal orientation.


A positive turning point in life--how persons with late effects of polio experience the influence of an interdisciplinary rehabilitation programme.
To describe and enhance our understanding of how persons with late effects of polio experience the influence of an interdisciplinary rehabilitation programme. Twelve persons with clinically verified late effects of polio who had participated in an individualized, goal-oriented, comprehensive interdisciplinary rehabilitation programme. Qualitative research interviews analysed using the constant comparative method of grounded theory. The rehabilitation programme was experienced as a turning point in the participants' lives. Before rehabilitation they felt they were on a downward slope without control. Rehabilitation was the start of a process of change whereby they acquired new skills, which, over time, contributed to a different but good life. After approximately a year, they had a sense of control and had accepted life with late effects of polio. They had also established new habits, taken on a changed valued self and could look to the future with confidence. This qualitative study has shown that persons with late effects of polio can benefit from an individualized, goal-oriented, comprehensive interdisciplinary rehabilitation programme and experience positive changes in their management of daily activities and in their view of their late effects of polio, their future and their self.


DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma.
The significance of chromosome 3p gene alterations in lung cancer is poorly understood. This study set out to investigate promoter methylation in the deleted in lung and oesophageal cancer 1 (DLEC1), MLH1 and other 3p genes in 239 non-small cell lung carcinomas (NSCLC). DLEC1 was methylated in 38.7%, MLH1 in 35.7%, RARbeta in 51.7%, RASSF1A in 32.4% and BLU in 35.3% of tumours. Any two of the gene alterations were associated with each other except RARbeta. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P=0.025) and in squamous cell carcinoma (P=0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P=0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P=0.009). However, microsatellite instability and loss of MLH1 expression was rare, suggesting that MLH1 promoter methylation does not usually lead to gene silencing in lung cancer. This is the first study describing the prognostic value of DLEC1 and MLH1 methylation in NSCLC. The concordant methylation is possibly a consequence of a long-range epigenetic effect in this region of chromosome 3p, which has recently been described in other cancers.


Movement of the hyoid bone and the epiglottis during swallowing in patients with dysphagia from different etiologies.
(1) To compare the kinematic motion of the hyoid bone and the epiglottis in healthy controls and a sample of patients with dysphagia of different etiologies, and (2) to evaluate the potential value of kinematic swallowing analysis to differentiate the mechanism of dysphagia. We performed two-dimensional video motion analysis of the hyoid bone using videofluoroscopic images in nine controls without any swallowing difficulty, and seven patients with supratentorial stroke, three patients with inflammatory myopathy who showed dysphagia. Main outcome measures were: (1) horizontal and vertical excursion of the hyoid bone, and rotation of the epiglottis, and (2) trajectory of the hyoid bone and epiglottis during swallowing. Horizontal excursion of the hyoid bone and rotation of the epiglottis were reduced in patients with myopathy as compared to control and patients with stroke (P<0.05). Patients with dysphagia showed different patterns as compared to control in trajectory analysis according to their etiology. We conclude that extent and pattern of movement of the hyoid bone and the epiglottis during swallowing were different according to etiology of dysphagia, and swallowing motion analysis could be applied to differentiate the mechanism of dysphagia.


Combined use of fluorescence with a magnetic tracer and dilution effect upon sentinel node localization in a murine model.
Sentinel node biopsy using radioisotope and blue dye remains a gold standard for axillary staging in breast cancer patients with low axillary burden. However, limitations in the use of radioisotopes have resulted in emergence of novel techniques. This is the first in vivo study to assess the feasibility of combining the two most common novel techniques of using a magnetic tracer and indocyanine green (ICG) fluorescence. A total of 48 mice were divided into eight groups. Groups 1 and 2, the co-localization groups, received an injection of magnetic tracers (Resovist® and Sienna+®, respectively) and ICG fluorescence; distilled water was used as the solvent of ICG. Groups 3 and 4, the diluted injection groups, received an injection of magnetic tracers (Resovist and Sienna+, respectively) and saline for dilution. Groups 5, 6, and 7, the control groups, received magnetic tracer (Resovist, Sienna+) and ICG alone, respectively. Fluorescent intensity assessment and iron quantification of excised popliteal lymph nodes were performed. Group 1', a co-localization group, received an injection of magnetic tracers (Resovist) and ICG' fluorescence: saline was used as the solvent for ICG. Lymphatic uptake of all tracers was confined to the popliteal nodes only, with co-localization confirmed in all cases and no significant difference in fluorescent intensity or iron content of ex vivo nodes between the groups (except for Group 1'). There was no impact of dilution on the iron content in the diluted Sienna+ group, but it significantly enhanced Resovist uptake (P=0.005). In addition, there was a significant difference in iron content (P=0.003) in Group 1'. The combination of a magnetic tracer (Resovist or Sienna+) and ICG fluorescence is feasible for sentinel node biopsy and will potentially allow for precise transcutaneous node identification, in addition to accurate intraoperative assessment. This radioisotope-free "combined technique" warrants further assessment within a clinical trial.


Isoprene synthesis in plants: lessons from a transgenic tobacco model.
Isoprene is a highly reactive gas, and is emitted in such large quantities from the biosphere that it substantially affects the oxidizing potential of the atmosphere. Relatively little is known about the control of isoprene emission at the molecular level. Using transgenic tobacco lines harbouring a poplar isoprene synthase gene, we examined control of isoprene emission. Isoprene synthase required chloroplastic localization for catalytic activity, and isoprene was produced via the methyl erythritol (MEP) pathway from recently assimilated carbon. Emission patterns in transgenic tobacco plants were remarkably similar to naturally emitting plants under a wide variety of conditions. Emissions correlated with photosynthetic rates in developing and mature leaves, and with the amount of isoprene synthase protein in mature leaves. Isoprene synthase protein levels did not change under short-term increase in heat/light, despite an increase in emissions under these conditions. A robust circadian pattern could be observed in emissions from long-day plants. The data support the idea that substrate supply and changes in enzyme kinetics (rather than changes in isoprene synthase levels or post-translational regulation of activity) are the primary controls on isoprene emission in mature transgenic tobacco leaves.


Catalytic Hydrogenation of a Manganese(V) Nitride to Ammonia.
The catalytic hydrogenation of a metal nitride to produce free ammonia using a rhodium hydride catalyst that promotes H2 activation and hydrogen-atom transfer is described. The phenylimine-substituted rhodium complex (η5-C5Me5)Rh(MePhI)H (MePhI = N-methyl-1-phenylethan-1-imine) exhibited higher thermal stability compared to the previously reported (η5-C5Me5)Rh(ppy)H (ppy = 2-phenylpyridine). DFT calculations established that the two rhodium complexes have comparable Rh-H bond dissociation free energies of 51.8 kcal mol-1 for (η5-C5Me5)Rh(MePhI)H and 51.1 kcal mol-1 for (η5-C5Me5)Rh(ppy)H. In the presence of 10 mol% of the phenylimine rhodium precatalyst and 4 atm of H2 in THF, the manganese nitride (tBuSalen)Mn≡N underwent hydrogenation to liberate free ammonia with up to 6 total turnovers of NH3 or 18 turnovers of H• transfer. The phenylpyridine analogue proved inactive for ammonia synthesis under identical conditions owing to competing deleterious hydride transfer chemistry. Subsequent studies showed that the use of a non-polar solvent such as benzene suppressed formation of the cationic rhodium product resulting from the hydride transfer and enabled catalytic ammonia synthesis by proton-coupled electron transfer.


Rumen distension and contraction influence feed preference by sheep.
Distension of the rumen limits feed intake by livestock. Ruminal dysfunctions due to bloat, which causes distension by accumulation of excessive gas within the rumen, also reduce feeding. We hypothesized that excessive levels of rumen distension cause feed aversions and that preference increases for feeds eaten in association with recovery from bloat. To test these hypotheses, we determined whether 12 commercial crossbred lambs (average initial BW of 43 +/- 2 kg) could associate ingestion of specific feeds with the consequences of increased intraruminal pressure and its subsidence. Six of the lambs were fitted with rumen cannulas and offered ground alfalfa for 30 min after a rubber balloon was inserted into the rumen of each animal and distended with air to volumes of 1.8, 2.5, or 4.5 L. Subsequently, balloons were deflated and alfalfa was offered again for a second period of 30 min. Feed intake was not affected when the balloon was not distended (P = 0.45 to 0.93), but distension reduced feed intake (P < 0.001) in direct proportion to the magnitude of distension at all 3 volumes (R(2) = 0.70). Relief from distension promoted a compensatory increase in feed intake (P = 0.006). During conditioning to determine if lambs acquired a preference for a feed associated with recovery from distension, fistulated lambs were offered novel feeds: wheat bran (group 1; n = 3) and beet pulp (group 2; n = 3), and the balloon was distended for 30 min. Feeds were then switched and the balloons were deflated (recovery). Control lambs (n = 6) received the same feeding protocol without the balloons. Lambs formed strong aversions to feeds associated with distension and preferred feeds associated with recovery (P = 0.001 to P = 0.10). No preferences or avoidances were observed in control lambs conditioned without rumen distension (P = 0.17 to P = 0.87). Thus, rumen distension and recovery from distension induced feed aversions and preferences, respectively, which may be critical in learning avoidance of bloat-inducing plants and preferences for plants and supplements that relieve the incidence of bloat.


Flow cytometric basophil activation test: a review.
Flow cytometry is a technique enabling the analysis of physical and biological characteristics of cells or other biological particles when labeled with antibodies coupled to fluorochromes or other dyes. The basophil activation test (BAT), also called flow-cytometric allergen stimulation test (FAST) [commercially available under the name of Flow CAST (Bühlmann Laboratories) or BASOTEST (Beckton-Dickinson)] is based on the in vitro allergen-induced specific activation of basophils. This assay rests on the demonstration of some membrane protein markers that appear after exposure to the allergen. This paper reviews some of the literature about the use of this technique in the investigation of immediate-type allergies to inhalant allergens, drugs, and foods, as well as our own experience with this diagnostic technique. Flow cytometry is a reliable method for the quantification of basophil activation after allergenic stimulus in vitro and in vivo. It also enables us to detect allergic and pseudoallergic reactions because of other mechanisms than allergen-specific IgE antibodies. Further clinical evaluation of this technique will allow validation and better establishment of its diagnostic value in allergy.


Fork-tailed drongos use deceptive mimicked alarm calls to steal food.
Despite the prevalence of vocal mimicry in animals, few functions for this behaviour have been shown. I propose a novel hypothesis that false mimicked alarm calls could be used deceptively to scare other species and steal their food. Studies have previously suggested that animals use their own species-specific alarm calls to steal food. However none have shown conclusively that these false alarms are deceptive, or that mimicked alarm calls are used in this manner. Here, I show that wild fork-tailed drongos (Dicrurus adsimilis) make both drongo-specific and mimicked false alarm calls when watching target species handling food, in response to which targets flee to cover abandoning their food. The drongo-specific and mimicked calls made in false alarms were structurally indistinguishable from calls made during true alarms at predators by drongos and other species. Furthermore, I demonstrate by playback experiments that two of these species, meerkats (Suricata suricatta) and pied babblers (Turdoides bicolor), are deceived by both drongo-specific and mimicked false alarm calls. These results provide the first conclusive evidence that false alarm calls are deceptive and demonstrate a novel function for vocal mimicry. This work also provides valuable insight into the benefits of deploying variable mimetic signals in deceptive communication.


Processing of speech and non-speech sounds in the supratemporal plane: auditory input preference does not predict sensitivity to statistical structure.
The supratemporal plane contains several functionally heterogeneous subregions that respond strongly to speech. Much of the prior work on the issue of speech processing in the supratemporal plane has focused on neural responses to single speech vs. non-speech sounds rather than focusing on higher-level computations that are required to process more complex auditory sequences. Here we examined how information is integrated over time for speech and non-speech sounds by quantifying the BOLD fMRI response to stochastic (non-deterministic) sequences of speech and non-speech naturalistic sounds that varied in their statistical structure (from random to highly structured sequences) during passive listening. Behaviorally, the participants were accurate in segmenting speech and non-speech sequences, though they were more accurate for speech. Several supratemporal regions showed increased activation magnitude for speech sequences (preference), but, importantly, this did not predict sensitivity to statistical structure: (i) several areas showing a speech preference were sensitive to statistical structure in both speech and non-speech sequences, and (ii) several regions that responded to both speech and non-speech sounds showed distinct responses to statistical structure in speech and non-speech sequences. While the behavioral findings highlight the tight relation between statistical structure and segmentation processes, the neuroimaging results suggest that the supratemporal plane mediates complex statistical processing for both speech and non-speech sequences and emphasize the importance of studying the neurocomputations associated with auditory sequence processing. These findings identify new partitions of functionally distinct areas in the supratemporal plane that cannot be evoked by single stimuli. The findings demonstrate the importance of going beyond input preference to examine the neural computations implemented in the superior temporal plane.


Present and previous psychopathology of juvenile onset migraine: a pilot investigation by Child Behavior Checklist.
The objective was to describe the premorbid state of migraine with juvenile onset. Thirty subjects with migraine and 30 healthy subjects were enrolled in a case-control study. A structured questionnaire (Child Behavior Checklist, CBCL) was administered to the mothers and ratings were obtained for the past two age periods (0-3 and 4-6 years) and for the present state. CBCL scores of the migraine group (MG) were compared to those of the control group (CG) during the three periods. A longitudinal study was performed to evaluate the evolution of psychopathology comparing CBCL scores of MG in the three age periods. During the premorbid period MG showed significantly higher mean scores on total, internalising, anxious-depressive scales. In the longitudinal perspective, internalising traits were present in the premorbid period in MG. Children later diagnosed as having migraine differ from CG in several scales during different age periods. Migraine could be considered as the expression of a previous vulnerability.


Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate.
The goal of this study was to find the most favorable injection interval of norethisterone enanthate (NETE) plus testosterone undecanoate (TU) in terms of gonadotropin, sperm suppression, and prostatic effects. Fifty normal men were randomly assigned to receive NETE 200 mg plus TU 1000 mg every 8 wk (n = 10), every 12 wk (n = 10), every 6 wk for 12 wk and then every 12 wk (n = 10), and every 6 wk for 12 wk and thereafter TU 1000 mg plus placebo every 12 wk (n = 10), and placebo plus placebo every 6 wk for 12 wk and then every 12 wk (n = 10) for 48 wk. Semen analyses, blood drawings, physical examinations, and prostate ultrasounds were performed throughout the study. Of the men in the 8-wk injection group, 90% (nine of 10) achieved azoospermia, compared with 37.5% (three of eight) in the 12-wk injection group (P = 0.019). TU plus placebo injected every 12 wk did not maintain sperm suppression. Prostate volumes did not change significantly in either group. In conclusion, these data suggest that the combined administration of NETE and TU at 8-wk intervals represents an effective hormonal contraceptive regimen.


Whole genome sequence of Auricularia heimuer (Basidiomycota, Fungi), the third most important cultivated mushroom worldwide.
Heimuer, Auricularia heimuer, is one of the most famous traditional Chinese foods and medicines, and it is the third most important cultivated mushroom worldwide. The aim of this study is to develop genomic resources for A. heimuer to furnish tools that can be used to study its secondary metabolite production capability, wood degradation ability and biosynthesis of polysaccharides. The genome was obtained from single spore mycelia of the strain Dai 13782 by using combined high-throughput Illumina HiSeq 4000 system with the PacBio RSII long-read sequencing platform. Functional annotation was accomplished by blasting protein sequences with different public available databases to obtain their corresponding annotations. It is 49.76Mb in size with a N50 scaffold size of 1,350,668bp and encodes 16,244 putative predicted genes. This is the first genome-scale assembly and annotation for A. heimuer, which is the third sequenced species in Auricularia.


A bacterial pathogen uses dimethylsulfoniopropionate as a cue to target heat-stressed corals.
Diseases are an emerging threat to ocean ecosystems. Coral reefs, in particular, are experiencing a worldwide decline because of disease and bleaching, which have been exacerbated by rising seawater temperatures. Yet, the ecological mechanisms behind most coral diseases remain unidentified. Here, we demonstrate that a coral pathogen, Vibrio coralliilyticus, uses chemotaxis and chemokinesis to target the mucus of its coral host, Pocillopora damicornis. A primary driver of this response is the host metabolite dimethylsulfoniopropionate (DMSP), a key element in the global sulfur cycle and a potent foraging cue throughout the marine food web. Coral mucus is rich in DMSP, and we found that DMSP alone elicits chemotactic responses of comparable intensity to whole mucus. Furthermore, in heat-stressed coral fragments, DMSP concentrations increased fivefold and the pathogen's chemotactic response was correspondingly enhanced. Intriguingly, despite being a rich source of carbon and sulfur, DMSP is not metabolized by the pathogen, suggesting that it is used purely as an infochemical for host location. These results reveal a new role for DMSP in coral disease, demonstrate the importance of chemical signaling and swimming behavior in the recruitment of pathogens to corals and highlight the impact of increased seawater temperatures on disease pathways.


Post-translational control of occludin membrane assembly in mouse trophectoderm: a mechanism to regulate timing of tight junction biogenesis and blastocyst formation.
The mouse blastocyst forms during the 32-cell stage with the emergence of the blastocoelic cavity. This developmental transition is dependent upon the differentiation and transport function of the trophectoderm epithelium which forms the wall of the blastocyst and exhibits functional intercellular tight junctions (TJs) to maintain epithelial integrity during blastocoele expansion. To investigate mechanisms regulating the timing of blastocyst formation, we have examined the dynamics of expression of occludin, an integral membrane protein of the TJ. Confocal microscopy of intact embryos and synchronised cell clusters revealed that occludin first assembles at the apicolateral membrane contact site between nascent trophectoderm cells usually during the early 32-cell stage, just prior to the time of blastocoele cavitation. This is a late event in the assembly of TJ-associated proteins within trophectoderm which, from our previous data, spans from 8- to 32-cell stages. Occludin membrane assembly is dependent upon prior E-cadherin-mediated cell-cell adhesion and is sensitive to brefeldin A, an inhibitor of Golgi-to-membrane transport. Occludin is delivered to the TJ site in association with the TJ plaque protein, ZO-1(&agr;)+, which we have shown previously is newly transcribed and translated during late cleavage. Immediately after assembly and before cavitation, occludin localised at the TJ site switches from a Triton X-100-soluble to -insoluble form indicative of actin cytoskeletal and/or membrane anchorage. Occludin mRNA and protein are detectable throughout cleavage by RT-PCR and immunoblotting, respectively, indicating that timing of membrane assembly is not controlled by expression alone. Rather, we have identified changes in the pattern of different occludin forms expressed during cleavage which, using phosphatase treatment of embryo lysates, include post-translational modifications. We propose that the phosphorylation of one form of occludin (band 2, 65-67 kDa) during late cleavage, which leads to its exclusive conversion from a Triton X-100-soluble to -insoluble pool, may regulate occludin association with ZO-1(&agr;)+ and membrane assembly, and thereby act to control completion of TJ biogenesis and the timing of blastocyst formation.


The Bcl-2 gene is differentially regulated by IL-2 and IL-4: role of the transcription factor NF-AT.
The murine TS1alphabeta T cell line expresses the anti-apoptotic protein Bcl-2 upon IL-2 stimulation, whereas IL-4-mediated growth of this cell line proceeds in the absence of Bcl-2 expression. In addition, IL-4 stimulation inhibits Bcl-2 expression and modulates its mRNA level. IL-2-induced DNA binding activity for these transcription factors is sensitive to phosphatidylinositol 3 kinase inhibitor wortmannin and to Rho inhibitor Clostridium difficile toxin B, which inhibit IL-2-induced Bcl-2 expression. NF-AT transcription factor appears to be the most important in the control Bcl-2 expression, since inhibition of the calcium-calmodulin-dependent phosphatase calcineurin, which regulates NF-AT activity, downregulates Bcl-2 expression in IL-2-stimulated cells. Constitutive expression of this phosphatase also upregulates Bcl-2 expression in IL-4-stimulated cells. In addition, a dominant negative NF-AT expression vector downregulates Bcl-2 expression in IL-2-stimulated cells. These results suggest that IL-2 induction of Bcl-2 expression may be directly or indirectly mediated by NF-AT.