Thermococcus fumicolans sp. nov., a new hyperthermophilic archaeon isolated from a deep-sea hydrothermal vent in the north Fiji Basin.
An extremely thermophilic archaeon, strain ST557T (T = type strain), was isolated from a deep-sea hydrothermal vent in the North Fiji Basin. This strain is a strictly anaerbic coccus whose cells are about 0.8 to 2 microns in diameter. The optimum temperature, pH and sea salt concentration for growth are 85 degrees C, 8.5, and 20 to 40 g/liter, respectively. Strain ST557T grows preferentially in the presence of elemental sulfur on proteinaceous substrates and on a mixture of 20 amino acids. It grows slowly on pyruvate and maltose. Growth is inhibited by rifampin. The DNA G + C content is 54 to 55 mol%. Sequencing of the 16S rRNA gene revealed that strain ST557T belongs to the genus Thermococcus. We propose that this organism should be placed in a new species, Thermococcus fumicolans.


The bioprocess TEA calculator: An online technoeconomic analysis tool to evaluate the commercial competitiveness of potential bioprocesses.
Techno-economic analysis connects R&D, engineering, and business. By linking process parameters to financial metrics, it allows researchers to understand the factors controlling the potential success of their technologies. In particular, metabolic and bioprocess engineering, as disciplines, are aimed at engineering cells to synthesize products with an ultimate goal of commercial deployment. As a result it is critical to be able to understand the potential impact of strain engineering strategies and lab scale results on commercial potential. To date, while numerous techno-economic models have been developed for a wide variety of bioprocesses, they have either required process engineering expertise to adapt and/or use or do not directly connect financial outcomes to potential strain engineering results. Despite the clear value of techno-economic analysis, these challenges have made it inaccessible to many researchers. I have developed this online calculator (https://bioprocesstea.com OR http://bioprocess-tea-calculator.herokuapp.com/) to make the basic capabilities of early-stage techno-economic analysis of bioprocesses readily accessible. The tool, currently focused on aerobic fermentation processes, can be used to understand the impact of fermentation level metrics on the commercial potential of a bioprocess for the production of a wide variety of organic molecules. Using the calculator, I review the commercially relevant targets for an aerobic bioprocess for the production of diethyl malonate.


Design of a static Fourier-transform spectrometer with increased field of view.
We present several novel designs of static Fourier-transform spectrometers based on Wollaston prisms. By numerical modeling we show the increased field of view that can be obtained when an achromatic half-wave plate is included between the prisms or when prisms fabricated from positive and negative birefringent materials are combined. In addition, we model how a single Wollaston prism with an inclined optic axis produces a fringe plane localized behind its exit face, thus enabling the design of a static Fourier-transform spectrometer based on a single Wollaston prism.


Impact of electrode design and surgical approach on scalar location and cochlear implant outcomes.
Three surgical approaches: cochleostomy (C), round window (RW), and extended round window (ERW); and two electrodes types: lateral wall (LW) and perimodiolar (PM), account for the vast majority of cochlear implantations. The goal of this study was to analyze the relationship between surgical approach and electrode type with final intracochlear position of the electrode array and subsequent hearing outcomes. Comparative longitudinal study. One hundred postlingually implanted adult patients were enrolled in the study. From the postoperative scan, intracochlear electrode location was determined and using rigid registration, transformed back to the preoperative computed tomography which had intracochlear anatomy (scala tympani and scala vestibuli) specified using a statistical shape model based on 10 microCT scans of human cadaveric cochleae. Likelihood ratio chi-square statistics were used to evaluate for differences in electrode placement with respect to surgical approach (C, RW, ERW) and type of electrode (LW, PM). Electrode placement completely within the scala tympani (ST) was more common for LW than were PM designs (89% vs. 58%; P < 0.001). RW and ERW approaches were associated with lower rates of electrode placement outside the ST than was the cochleostomy approach (9%, 16%, and 63%, respectively; P < 0.001). This pattern held true regardless of whether the implant was LW or PM. When examining electrode placement and hearing outcome, those with electrode residing completely within the ST had better consonant-nucleus-consonant word scores than did patients with any number of electrodes located outside the ST (P = 0.045). These data suggest that RW and ERW approaches and LW electrodes are associated with an increased likelihood of successful ST placement. Furthermore, electrode position entirely within the ST confers superior audiological outcomes. 2b.


Frequency of trauma exposure and Post-Traumatic Stress Disorder in Italy: analysis from the World Mental Health Survey Initiative.
Epidemiological studies have examined the relative importance of Traumatic Events (TEs) in accounting for the societal burden of post-traumatic stress disorder (PTSD). However, most studies used the worst trauma experienced, which can lead to an overestimation of the conditional risk of PTSD. Although a number of epidemiological surveys on PTSD have been carried out in the United States, only a few studies in limited sample have been conducted in Italy. This study, carried out in the framework of the World Mental Health Survey Initiative, is a cross-sectional household survey of a representative sample of the Italian adult population. Lifetime prevalence of TEs and 12-month prevalence of PTSD were evaluated using the Composite International Diagnostic Interview (CIDI). Reports of PTSD associated with randomly selected TEs were weighted by the individual-level probabilities of TE selection to generate estimates of population-level PTSD risk associated with each TE. Network events was the most commonly reported class of TEs (29.4%). War events had the highest conditional risk of PTSD (12.2%). The TEs that contributed most to societal PTSD burden were unexpected death of a loved one (24.1%) and having seen atrocities (18.2%). Being female was related to high risk of PTSD after experiencing a TE. Exposure to network events is commonly reported among Italian adults, but two TEs are responsible for the highest burden associated with PTSD: the unexpected death of someone close and sexual assault. These results can help designing public health interventions to reduce the societal PTSD burden.


In vivo demonstration that human parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene.
Osteoprotegerin (OPG) is a potent inhibitor of osteoclast formation and function. To elucidate how OPG is regulated in bone, we examined (1) the expression and localization of OPG protein in bone tissue, (2) the effect of human parathyroid hormone 1-38 (hPTH 1-38) on OPG messenger RNA (mRNA) levels in rat femur metaphyseal and diaphyseal bone, and (3) the effect of hPTH(1-38) on expression of OPG mRNA in cultured osteoblast-like cells derived from the metaphysis and diaphysis, and in ROS 17/2.8 osteosarcoma cells. Because PTH has been shown to stimulate osteoblast activity via the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signal transduction pathway we also investigated whether PTH action on OPG in vivo is dependent on activation of cAMP/PKA pathway. Immunohistochemistry was used to evaluate OPG protein expression and Northern blot hybridization was used to analyze OPG mRNA expression both in vivo and in vitro. Immunohistochemistry of OPG protein expression in the rat distal femur metaphysis revealed that it was localized predominantly in preosteoblasts, osteoblasts, lining cells, and the osteoid layer, with occasional immunoreactivity in osteocytes and cells of the bone marrow. Subcutaneous (sc) administration of a single injection of hPTH(1-38) at 80 microg/kg induced a rapid and transient decrease in OPG mRNA expression in both metaphyseal and diaphyseal bone. The decrease in OPG message was evident by 1 h and mRNA levels returned to baseline after 3 h. PTH analog PTH(1-31), which stimulates intracellular cAMP accumulation, inhibited OPG expression, whereas PTH analogs (3-34 and 7-34) that do not stimulate cAMP production had no effect on expression. In contrast to PTH, prostaglandin E2 (PGE2) had no effect on OPG mRNA expression in vivo in the metaphyseal bone cells, under conditions in which PGE2 does promote expression of the c-fos gene. The in vivo effects of hPTH(1-38) on OPG mRNA were confirmed in isolated primary osteoblast cultures derived from either metaphyseal or diaphyseal bone as well as in ROS 17/2.8 osteosarcoma cells. We propose that the rapid and transient decrease in OPG expression may initiate a cascade of events resulting in the differentiation of osteoclast progenitor. Such a spatially and temporally programmed effect of PTH might contribute to bone turnover.


Feasibility and utility of telephone-based psychological support for people with brain tumor: a single-case experimental study.
Rates of psychological distress are high following diagnosis and treatment of brain tumor. There can be multiple barriers to accessing psychological support, including physical and cognitive impairments and geographical limitations. Tele-based support could provide an effective and more flexible option for delivering psychological interventions. The present study aimed to investigate the feasibility and utility of a telephone-based psychotherapy intervention for people with brain tumor. A single-case multiple-baseline design was employed with a 4-7-week baseline phase, 10-week treatment phase, and 5-week maintenance phase including a booster session. Four participants with a benign or malignant brain tumor (three males and one female; aged 34-49 years), received 10 sessions of tele-based therapy and a booster session at 4 weeks post-treatment. Levels of depression, anxiety, and illness cognitions were monitored on a weekly basis throughout each phase whilst measures of quality of life, stress, and self-concept were administered at the start and end of each phase. Weekly measures were analyzed using a combination of both visual analysis and Tau-U statistics. Of the four participants, two of them demonstrated significant gains in mental health (depression and/or anxiety) and a significant decrease in their levels of helplessness (p < 0.05). The other two participants did not show gains in mental health or change in illness cognitions. All participants reported improvement in quality of life post-treatment. The results of the study provide preliminary support concerning the feasibility and utility of tele-based therapy for some people with brain tumor. Further research examining factors influencing the outcomes of tele-based psychological support is needed.


Bioenergetic consequences of sex-specific mitochondrial DNA evolution.
Doubly uniparental inheritance (DUI) represents a notable exception to the general rule of strict maternal inheritance (SMI) of mitochondria in metazoans. This system entails the coexistence of two mitochondrial lineages (F- and M-type) transmitted separately through oocytes and sperm, thence providing an unprecedented opportunity for the mitochondrial genome to evolve adaptively for male functions. In this study, we explored the impact of a sex-specific mitochondrial evolution upon gamete bioenergetics of DUI and SMI bivalve species, comparing the activity of key enzymes of glycolysis, fermentation, fatty acid metabolism, tricarboxylic acid cycle, oxidative phosphorylation and antioxidant metabolism. Our findings suggest reorganized bioenergetic pathways in DUI gametes compared to SMI gametes. This generally results in a decreased enzymatic capacity in DUI sperm with respect to DUI oocytes, a limitation especially prominent at the terminus of the electron transport system. This bioenergetic remodelling fits a reproductive strategy that does not require high energy input and could potentially link with the preservation of the paternally transmitted mitochondrial genome in DUI species. Whether this phenotype may derive from positive or relaxed selection acting on DUI sperm is still uncertain.


Evaluation of bisubstrate secondary utilization kinetics by biofilms.
A bisubstrate system having S(s1) > S(min 1) was tested with phenol and acetate as model compounds in completely mixed biofilm reactors. Two series of experiments compared the kinetics of phenol removal as a single substrate and as part of a bisubstrate system having a fixed total feed COD. Experimental results showed that, although the rate of utilization of either substrate was almost the same in a bisubstrate system as in a single substrate system, the utilization rate of either compound always was slightly greater in a bisubstrate system than in a single-substrate system. This slight enhanced removal of an individual compound in a bisubstrate system was attributed to the extra biomass accumulated from the utilization of the other substrate. As the fraction of the feed COD contributed by an individual compound decreased in a bisubstrate system, the effluent concentration of that compound decreased and its fractional removal efficiency increased. The bisubstrate secondary-utilization model successfully described the experimental results and explained the differences that occurred as phenol became a smaller fraction of the fixed total feed COD.


[Comparative analysis of the latent periods of adjacent neurons in microareas of the visual cortex].
Latencies of responses to heteromodal stimuli were determined for neurones of the cat visual cortex recorded with different amplitudes of action potentials (AP). Latencies of responses of three neighbouring neurones recorded with one microelectrode were compared. It was shown that in the case of light stimulation, the neurone recorded with a smaller AP amplitude, as a rule entered the reaction before the neurone recorded with a greater AP amplitude; in response to acoustic stimulation, the reverse relationship was observed. In most of the microareas in which response latencies of the neighbouring cells differed slightly, crosscorrelograms revealed action of "the common input". Comparative analysis has shown that an afferent wave excites each of the microarea cells separately.


An investigation of the safety of oral calcium formate in dairy cows using clinical, biochemical and histopathological parameters.
To investigate the safety of orally administered calcium formate in dairy cows fed adequate amounts of good quality pasture. Twelve mixed-age pasture-fed lactating dairy cows were randomly allocated to three groups (n=4 cows/ group). Group 1 served as untreated controls. Group 2 was treated orally with 400 ml of 13.4% (w/w) calcium as calcium chloride gel, four times at approximately 12-h intervals. Group 3 was treated orally with 350 ml of 11.4 % (w/w) calcium as a 48.6% aqueous suspension of calcium formate, four times at approximately 12-h intervals. Cows grazed good quality autumn ryegrass and white clover pasture throughout the trial. All cows were examined clinically each evening and a blood sample collected. Cows were slaughtered 75 h after the last treatment and viscera examined visually for lesions. Samples from the mid-fundic area of the abomasum of each cow were collected for histopathological examination. Blood samples collected pre and 90-h post-first treatment were analysed for serum haptoglobin and pepsinogen concentrations. No evidence of abnormality was detected by observation or clinical examination in any of the trial cows. Serum haptoglobin concentrations were basal for all groups pre-treatment and remained basal for Groups 1 and 3 post-treatment, but were elevated post-treatment for Group 2 (p=0.016). No differences in serum pepsinogen concentrations were detected between sampling times or treatment groups. One cow from Group 2 had several small (5 mm) abomasal ulcers present at necropsy. Another cow from the same group had histopathology suggestive of thrombosis and re-endothelialisation. Oral administration of calcium formate (350 ml of 48.6% aqueous suspension) administered on four occasions at 12-h intervals had no adverse effects on the four cows examined, and as such is considered a safe form of calcium supplementation in adult dairy cows.


In situ interactions between photosynthetic picoeukaryotes and bacterioplankton in the Atlantic Ocean: evidence for mixotrophy.
Heterotrophic bacterioplankton, cyanobacteria and phototrophic picoeukaryotes (< 5 μm in size) numerically dominate planktonic oceanic communities. While feeding on bacterioplankton is often attributed to aplastidic protists, recent evidence suggests that phototrophic picoeukaryotes could be important bacterivores. Here, we present direct visual evidence from the surface mixed layer of the Atlantic Ocean that bacterioplankton are internalized by phototrophic picoeukaryotes. In situ interactions of phototrophic picoeukaryotes and bacterioplankton (specifically Prochlorococcus cyanobacteria and the SAR11 clade) were investigated using a combination of flow cytometric cell sorting and dual tyramide signal amplification fluorescence in situ hybridization. Using this method, we observed plastidic Prymnesiophyceae and Chrysophyceae cells containing Prochlorococcus, and to a lesser extent SAR11 cells. These microscopic observations of in situ microbial trophic interactions demonstrate the frequency and likely selectivity of phototrophic picoeukaryote bacterivory in the surface mixed layer of both the North and South Atlantic subtropical gyres and adjacent equatorial region, broadening our views on the ecological role of the smallest oceanic plastidic protists.


A chemical approach for the synthesis of the DNA-binding domain of the oncoprotein MYC.
We describe the first chemical synthesis of a functional mutant of the DNA binding domain of the oncoprotein MYC, using two alternative strategies which involve either one or two Native Chemical Ligations (NCLs). Both routes allowed the efficient synthesis of a miniprotein which is capable of heterodimerizing with MAX, and replicate the DNA binding of the native protein. The versatility of the reported synthetic approach enabled the straightforward preparation of MYC and Omomyc analogues, as well as fluorescently labeled derivatives.


Mitochondrial dysfunction in genetic animal models of Parkinson's disease.
Mitochondria are highly dynamic, multifunctional organelles. Aside from their major role in energy metabolism, they are also crucial for many cellular processes including neurotransmission, synaptic maintenance, calcium homeostasis, cell death, and neuronal survival. Increasing evidence supports a role for abnormal mitochondrial function in the molecular pathophysiology of Parkinson's disease (PD). For three decades we have known that mitochondrial toxins are capable of producing clinical parkinsonism in humans. PD is the most common neurodegenerative movement disorder that is characterized by the progressive loss of substantia nigra dopaminergic neurons leading to a deficiency of striatal dopamine. Although the neuropathology underlying the disease is well defined, it remains unclear why nigral dopaminergic neurons degenerate and die. Most PD cases are idiopathic, but there are rare familial cases. Mutations in five genes are known to unambiguously cause monogenic familial PD: α-synuclein, parkin, DJ-1, PTEN-induced kinase 1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2). These key molecular players are proteins of seemingly diverse function, but with potentially important roles in mitochondrial maintenance and function. Cell and animal-based genetic models have provided indispensable tools for understanding the molecular basis of PD, and have provided additional evidence implicating mitochondrial dysfunction as a primary pathogenic pathway leading to the demise of dopaminergic neurons in PD. Here, we critically discuss the evidence for mitochondrial dysfunction in genetic animal models of PD, and evaluate whether abnormal mitochondrial function represents a cause or consequence of disease pathogenesis. Mitochondria may represent a potential target for the development of disease-modifying therapies.


Sodium-hydrogen exchange system in LLC-PK1 epithelium.
Sodium influx into LLC-PK1 cells has been characterized. The main amiloride-sensitive pathway for sodium entry through the apical membrane in this cell line is sodium-hydrogen exchange with an apparent Km for sodium of 19 mM. Influx is pH dependent and is amiloride sensitive with K1/2 of 30 microM. Inhibition of the sodium transport by protons (at 1 mM external sodium) is consistent with an interaction of H+ ions at a single site having an apparent pKH of 7.2. These data are similar to those reported previously for brush border membrane (BBM) isolated from kidney proximal tubule. However, in contrast to previously published reports, H+ does not compete with amiloride in blocking Na+ influx and exhibits a mixed inhibition with sodium ions. The latter, together with a direct and independent assessment of amiloride and sodium interaction, indicates that amiloride does not compete with sodium for the same site. Possible explanations for the discrepancy in the literature concerning the interaction of Na+, H+, and amiloride with the Na+-H+ exchanger and the characteristics of the Na+-H+ exchange system in LLC-PK1 are discussed.


APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42.
Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-β (Aβ) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aβ plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.


Loss of tryptophan associated with photo-polymerization and yellowing of proteins exposed to light over 300nm.
S-Carboxymethyl-lysozyme and S-carboxymethyl-ribonuclease A were irradiated with light of wavelength greater than 300nm. Photo-oxidative loss of tryptophan from the S-carboxymethyl-lysozyme was accompanied by yellowing of the protein and the formation of covalently cross-linked polymers. S-Carboxymethyl-ribonuclease, which contains no tryptophan, showed little yellowing and no polymer formation. The irradiated S-carboxymethyl-lysozyme was similar to the proteins of the brown cataractous human lens nucleus and to bovine lens proteins exposed to sunlight in vitro in that it (1) was insoluble in non-denaturing solvents, (2) contained a new fluorescence, (3) was brown in colour, and (4) contained covalent cross-links that are not disulphide bonds.


Accuracy of serological tests for bovine brucellosis: A systematic review and meta-analysis.
The direct methods for diagnosis of bovine brucellosis have several limitations, therefore serological tests are the basis for the diagnosis of the disease. However, a meta-analysis estimating the diagnostic sensitivity (DSe) and diagnostic specificity (DSp) on the main tests used in bovine brucellosis control programs worldwide has not been performed. This systematic review and meta-analysis aimed to estimate the DSe, DSp and thereby accuracy of serological tests individually used in the diagnosis of bovine brucellosis. The databases CABI, Cochrane Library, PubMed/MEDLINE, SciELO, Scopus and Web of Science were used to select articles. The search resulted in 5308 studies, of which 71 were selected for systematic review using quality assessment tools and 65 studies were included in the meta-analysis. For the meta-analysis, 178 assays and 11 different serological tests were considered. To estimate DSe and DSp of the tests, studies were divided according to animal selection for the studies: (1) studies that carried out a random or consecutive selection of participants (noncasecontrol studies) and (2) all studies, including casecontrol studies. Considering only the non-case-control studies to estimate the DSe, the tests that exhibited the best and worst performance were the iELISA test (indirect enzyme immunoassay - bacterial suspension as antigen - BS) (96.5%, 95% CI: 94.1-97.9%) and 2ME (2- mercaptoethanol test) (85.0%, 95% CI: 79.6-89.1%), respectively; while for DSp, the FPA (fluorescence polarization assay) (99, 7%, 95% CI: 99.5-99.8%) and PCFIA tests (protein concentration fluorescence immunoassay) (78.5%, 95% CI: 70.0-85.1%) showed better and worse performance, respectively. Overall, our results showed an overestimation in the DSe and DSp of the eleven serological tests assessed when casecontrol studies were included in the meta-analysis, which is a concern considering its impacts on the time and costs associated with populational diagnosis of the diseases, since several of these tests are routinely used in the control and eradication programs of bovine brucellosis worldwide. Furthermore, the tests that exhibited the best DSe and DSp, iELISA (BS) and FPA, respectively, are relatively easy to perform and interpret and the test which showed the best overall accuracy was FPA.


A genetic linkage map of the baboon (Papio hamadryas) genome based on human microsatellite polymorphisms.
A first-generation genetic linkage map of the baboon (Papio hamadryas) genome was developed for use in biomedical and evolutionary genetics. Pedigreed baboons (n = 694) were selected from the breeding colony maintained by the Southwest Foundation for Biomedical Research. To facilitate comparison with the human genome, the baboon linkage map consists primarily of human microsatellite loci amplified using published human PCR primers. Genotypes for 325 human microsatellites and 6 novel baboon microsatellites were used in linkage analyses performed with the MultiMap expert system. The resulting sex-averaged meiotic recombination map covers all 20 baboon autosomes, with average spacing among loci of 7.2 cM. Direct comparison among homologous (orthologous) loci reveals that, for 7 human autosomes, locus order is conserved between humans and baboons. For the other 15 autosomes, one or more rearrangements distinguish the two genomes. The total centimorgan distances among homologous markers are 28.0% longer in the human genome than in the baboon, suggesting that rates of recombination may be higher in humans. This baboon linkage map is the first reported for any nonhuman primate species and creates opportunities for mapping quantitative trait loci in baboons, as well as for comparative evolutionary analyses of genome structure.


The Prognostic Role of CD73/A2AR Expression and Tumor Immune Response in Periampullary Carcinoma Subtypes.
Periampullary adenocarcinoma (PAAC) is a rare, lethal heterogeneous group of malignancy that differs in their molecular phenotypes. Ecto-5'-nucleotidase (CD73)/adenosine A2A Receptor (A2AR) pathway has shown an emerging role in cancer therapy through modulating the immune response. Therefore, this study aimed to explore the functional role of CD73 and A2AR in pancreatic ductal adenocarcinoma (PDAC) and ampullary carcinoma (AC). An immunohistochemical study for CD73 and A2AR carried on 48 PDAC cases, 21 AC cases and 34 adjacent non-tumor tissues that were taken from the farthest point of normal pancreatic tissue away from the tumor. CD73 was overexpressed in the PDAC (p < 0.001), and AC (p = 0.004) groups compared to their non-tumor tissues. However, A2AR was overexpressed in the PDAC group (p = 0.003) but not in the AC group (p = 0.359) compared to non-tumor tissue. In the PDAC group, CD73 overexpression was significantly associated with longer overall survival (p = 0.018). In contrary, A2AR overexpression was significantly associated with high grade (p = 0.001) and late- stage (p = 0.01). Both markers had no prognostic impact on AC. In the meantime, tumor immune response showed a negative prognostic role in PDAC and AC. The prognostic role of tumor immune response in the PDAC group was strongly modulated by CD73 and A2AR expression. PDAC and AC shared CD73 Overexpression while A2AR was overexpressed in PDAC only. In PDAC, CD73 and A2AR showed an opposed prognostic effect but both had no prognostic impact on AC. In addition, tumor immune response showed a controversial impact on the prognosis of PDAC and AC.


Polarization-Independent Silicon Metadevices for Efficient Optical Wavefront Control.
We experimentally demonstrate a functional silicon metadevice at telecom wavelengths that can efficiently control the wavefront of optical beams by imprinting a spatially varying transmittance phase independent of the polarization of the incident beam. Near-unity transmittance efficiency and close to 0-2π phase coverage are enabled by utilizing the localized electric and magnetic Mie-type resonances of low-loss silicon nanoparticles tailored to behave as electromagnetically dual-symmetric scatterers. We apply this concept to realize a metadevice that converts a Gaussian beam into a vortex beam. The required spatial distribution of transmittance phases is achieved by a variation of the lattice spacing as a single geometric control parameter.


Dual Interface Compatibility Enabled via Composite Solid Electrolyte with High Transference Number for Long-Life All-Solid-State Lithium Metal Batteries.
The development of solid-state electrolytes (SSEs) effectively solves the safety problem derived from dendrite growth and volume change of lithium during cycling. In the meantime, the SSEs possess non-flammability compared to conventional organic liquid electrolytes. Replacing liquid electrolytes with SSEs to assemble all-solid-state lithium metal batteries (ASSLMBs) has garnered significant attention as a promising energy storage/conversion technology for the future. Herein, a composite solid electrolyte containing two inorganic components (Li6.25 Al0.25 La3 Zr2 O12 , Al2 O3 ) and an organic polyvinylidene difluoride matrix is designed rationally. X-ray photoelectron spectroscopy and density functional theory calculation results demonstrate the synergistic effect among the components, which results in enhanced ionic conductivity, high lithium-ion transference number, extended electrochemical window, and outstanding dual interface compatibility. As a result, Li||Li symmetric battery maintains a stable cycle for over 2500 h. Moreover, all-solid-state lithium metal battery assembled with LiNi0.6 Co0.2 Mn0.2 O2 cathode delivers a high discharge capacity of 168 mAh g-1 after 360 cycles at 0.1 C at 25 °C, and all-solid-state lithium-sulfur battery also exhibits a high initial discharge capacity of 912 mAh g-1 at 0.1 C. This work demonstrates a long-life flexible composite solid electrolyte with excellent interface compatibility, providing an innovative way for the rational construction of next-generation high-energy-density ASSLMBs.


The delicate balance of phase speciation in bimetallic nickel cobalt nanoparticles.
Bimetallic nickel-cobalt nanoparticles are highly sought for their potential as catalytic and magnetic nanoparticles. These are typically prepared in organic solvents in the presence of strong stabilizing ligands such as tri-n-octylphosphine (TOP). Due to the variety of cobalt crystallographic phases and to the strong interaction of the ligands with the metallic surfaces, forming fcc nanoparticles rather than a phase mixture is a challenging endeavor. Here, using a two-step synthesis strategy that aims at a core-shell nickel-cobalt morphology, we demonstrated that many parameters have to be adjusted: concentration of the metal precursors, stoichiometry of TOP, and heating program from room temperature to 180 °C. We found optimized conditions to form size-controlled fcc NiCo nanoparticles from preformed Ni nanoparticles, and the phase attribution was confirmed with a combination of X-Ray diffraction on powder and X-Ray absorption spectroscopy at the Co K edge. We then investigated the early stages of Co nucleation on the nickel using a lower stoichiometry of Co, down to 0.05 equiv. vs. Ni. Using X-ray photoelectron spectroscopy and scanning transmission electron microscopy coupled to energy-dispersive X-Ray spectroscopy and electron energy loss spectroscopy, we showed that cobalt reacts first on the nickel nanoparticles but easily forms cobalt-rich larger aggregates in the further steps of the reaction.


NIMROD: a program for inference via a normal approximation of the posterior in models with random effects based on ordinary differential equations.
Models based on ordinary differential equations (ODE) are widespread tools for describing dynamical systems. In biomedical sciences, data from each subject can be sparse making difficult to precisely estimate individual parameters by standard non-linear regression but information can often be gained from between-subjects variability. This makes natural the use of mixed-effects models to estimate population parameters. Although the maximum likelihood approach is a valuable option, identifiability issues favour Bayesian approaches which can incorporate prior knowledge in a flexible way. However, the combination of difficulties coming from the ODE system and from the presence of random effects raises a major numerical challenge. Computations can be simplified by making a normal approximation of the posterior to find the maximum of the posterior distribution (MAP). Here we present the NIMROD program (normal approximation inference in models with random effects based on ordinary differential equations) devoted to the MAP estimation in ODE models. We describe the specific implemented features such as convergence criteria and an approximation of the leave-one-out cross-validation to assess the model quality of fit. In pharmacokinetics models, first, we evaluate the properties of this algorithm and compare it with FOCE and MCMC algorithms in simulations. Then, we illustrate NIMROD use on Amprenavir pharmacokinetics data from the PUZZLE clinical trial in HIV infected patients.


Myricetin protects cells against oxidative stress-induced apoptosis via regulation of PI3K/Akt and MAPK signaling pathways.
Recently, we demonstrated that myricetin exhibits cytoprotective effects against H(2)O(2)-induced cell damage via its antioxidant properties. In the present study, myricetin was found to inhibit H(2)O(2)-induced apoptosis in Chinese hamster lung fibroblast (V79-4) cells, as shown by decreased apoptotic bodies, nuclear fragmentation, sub-G(1) cell population, and disruption of mitochondrial membrane potential (Δψ(m)), which are increased in H(2)O(2)-treated cells. Western blot data showed that in H(2)O(2)-treated cells, myricetin increased the level of Bcl-2, which is an anti-apoptotic factor, and decreased the levels of Bax, active caspase-9 and -3, which are pro-apoptotic factors. And myricetin inhibited release of cytochrome c from mitochondria to cytosol in H(2)O(2)-treated cells. Myricetin-induced survival correlated with Akt activity, and the rescue of cells by myricetin treatment against H(2)O(2)-induced apoptosis was inhibited by the specific PI3K (phosphoinositol-3-kinase) inhibitor. Myricetin-mediated survival also inhibited the activation of p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which are members of MAPK. Our studies suggest that myricetin prevents oxidative stress-induced apoptosis via regulation of PI3K/Akt and MAPK signaling pathways.


Atg18 function in autophagy is regulated by specific sites within its β-propeller.
Autophagy is a conserved degradative transport pathway. It is characterized by the formation of double-membrane autophagosomes at the phagophore assembly site (PAS). Atg18 is essential for autophagy but also for vacuole homeostasis and probably endosomal functions. This protein is basically a β-propeller, formed by seven WD40 repeats, that contains a conserved FRRG motif that binds to phosphoinositides and promotes Atg18 recruitment to the PAS, endosomes and vacuoles. However, it is unknown how Atg18 association with these organelles is regulated, as the phosphoinositides bound by this protein are present on the surface of all of them. We have investigated Atg18 recruitment to the PAS and found that Atg18 binds to Atg2 through a specific stretch of amino acids in the β-propeller on the opposite surface to the FRRG motif. As in the absence of the FRRG sequence, the inability of Atg18 to interact with Atg2 impairs its association with the PAS, causing an autophagy block. Our data provide a model whereby the Atg18 β-propeller provides organelle specificity by binding to two determinants on the target membrane.


Thalamic single neuron activity in patients with dystonia: dystonia-related activity and somatic sensory reorganization.
Indirect evidence suggests that the thalamus contributes to abnormal movements occurring in patients with dystonia (dystonia patients). The present study tested the hypothesis that thalamic activity contributes to the dystonic movements that occur in such patients. During these movements, spectral analysis of electromyographic (EMG) signals in flexor and extensor muscles of the wrist and elbow exhibited peak EMG power in the lowest frequency band [0-0.78 Hz (mean: 0.39 Hz) dystonia frequency] for 60-85% of epochs studied during a pointing task. Normal controls showed low-frequency peaks for <16% of epochs during pointing. Among dystonia patients, simultaneous contraction of antagonistic muscles (cocontraction) at dystonia frequency during pointing was observed for muscles acting about the wrist (63% of epochs) and elbow (39%), but cocontraction was not observed among normal controls during pointing. Thalamic neuronal signals were recorded during thalamotomy for treatment of dystonia and were compared with those of control patients without motor abnormality who were undergoing thalamic procedures for treatment of chronic pain. Presumed nuclear boundaries of a human thalamic cerebellar relay nucleus (ventral intermediate, Vim) and a pallidal relay nucleus (ventral oral posterior, Vop) were estimated by aligning the anterior border of the principal sensory nucleus (ventral caudal, Vc) with the region where the majority of cells have cutaneous receptive fields (RFs). The ratio of power at dystonia frequency to average spectral power was >2 (P < 0.001) for cells in presumed Vop often for dystonia patients (81%) but never for control patients. The percentage of such cells in presumed Vim of dystonia patients (32%) was not significantly different from that of controls (31%). Many cells in presumed Vop exhibited dystonia frequency activity that was correlated with and phase-advanced on EMG activity during dystonia, suggesting that this activity was related to dystonia. Thalamic somatic sensory activity also differed between dystonia patients and controls. The percentage of cells responding to passive joint movement or to manipulation of subcutaneous structures (deep sensory cells) in presumed Vim was significantly greater in patients with dystonia than in control patients undergoing surgery for treatment of pain or tremor. Dystonia patients had a significantly higher proportion of deep sensory cells responding to movement of more than one joint (26%, 13/52) than did "control" patients (8%, 4/49). Deep sensory cells in patients with dystonia were located in thalamic maps that demonstrated increased representations of parts of the body affected by dystonia. Thus dystonia patients showed increased receptive fields and an increased thalamic representation of dystonic body parts. The motor activity of an individual sensory cell was related to the sensory activity of that cell by identification of the muscle apparently involved in the cell's receptive field. Specifically, we defined the effector muscle as the muscle that, by contraction, produced the joint movement associated with a thalamic neuronal sensory discharge, when the examiner passively moved the joint. Spike X EMG correlation functions during dystonia indicated that thalamic cellular activity less often was related to EMG in effector muscles (52%) than in other muscles (86%). Thus there is a mismatch between the effector muscle for a thalamic cell and the muscles with EMG correlated with activity of that cell during dystonia. This mismatch may result from the reorganization of sensory maps and may contribute to the simultaneous activation of multiple muscles observed in dystonia. Microstimulation in presumed Vim in dystonia patients produced simultaneous contraction of multiple forearm muscles, similar to the simultaneous muscle contractions observed in dystonia. (ABSTRACT TRUNCATED)


Ankle and toe muscle strength characteristics in runners with a history of medial tibial stress syndrome.
A high proportion of flexor digitorum longus attachment is found at the posteromedial border of the tibia, which is the most common location of medial tibial stress syndrome (MTSS). Therefore, plantar flexion strength of the lesser toes could be related to MTSS; however, the relationship between MTSS and muscle strength of the hallux and lesser toes is not yet evaluated due to the lack of quantitative methods. This study investigated the muscle strength characteristics in runners with a history of MTSS by using a newly developed device to measure the muscle strength of the hallux, lesser toes, and ankle. This study comprised 27 collegiate male runner participants (20.0 ± 1.6 years, 172.1 ± 5.1 cm, 57.5 ± 4.0 kg). Maximal voluntary isometric contraction (MVIC) torque of the plantar flexion, dorsiflexion, inversion, and eversion of the ankle were measured by using an electric dynamometer. MVIC torque of the 1st metatarsophalangeal joint (MTPJ) and 2nd-5th MTPJ were measured by using a custom-made torque-measuring device. MVIC torques were compared between runners with and without a history of MTSS. MVIC torque of the 1st MTPJ plantar flexion was significantly higher in runners with a history of MTSS than in those without it. In contrast, there were no significant differences in the MVIC torque values of the 2nd-5th MTPJ plantar flexion and each MVIC torque of the ankle between runners with and without a history of MTSS. A history of MTSS increased the isometric FHL strength.


Cystic fibrosis sputum DNA has NETosis characteristics and neutrophil extracellular trap release is regulated by macrophage migration-inhibitory factor.
Neutrophils are the main proinflammatory cell type in chronically infected lungs of cystic fibrosis (CF) patients; however, they fail to effectively clear the colonizing pathogens. Here, we investigated the molecular composition of non-mucoid and mucoid Pseudomonas aeruginosa-induced neutrophil extracellular traps (NETs) in vitro and compared them to the DNA-protein complexes present in the CF sputum. The protein composition of P. aeruginosa-induced NET fragments revealed that irrespective of the inducing stimuli, NET fragments were decorated with a conserved set of proteins. The DNA-protein complexes derived from CF sputum were consistent with NETosis and shared a similar protein signature, suggesting that the majority of the extracellular DNA was NET derived. The ability of polymorphonuclear leukocytes to produce NETs in response to P. aeruginosa was driven by macrophage migration-inhibitory factor (MIF) by promoting mitogen-activated protein kinase. Analysis of 132 CF patient samples revealed that elevated MIF protein levels correlated with poorer lung function. We suggest that targeting MIF by small molecular inhibitors might reduce the presence of extracellular DNA and serve as an adjunct to the use of antimicrobial drugs that could ultimately reduce bacterial fitness in the lungs during the later stages of CF disease.


Zonation of total and plasma protein turnover in rat liver: effects of chronic ethanol treatment.
To study the acinar distribution of protein turnover, rats were given a tracer dose of 14C-valine intraperitoneally. At 30 min or 20 hr later, livers were perfused in situ and periportal (pp) or perivenous (pv) cell lysates were collected after digitonin pulse infusion. In control rats the post-label radioactivity of cell lysates showed no zonation. The radioactivity of the pp and pv cell lysates was significantly higher in livers of chronically ethanol-fed rats than in the controls, and the increase was more prominent in the pp region. Furthermore, after chronic ethanol feeding, an enrichment of plasma protein in the pv region was observed. The results support the view that in the control rats liver protein turnover is not zonated. Chronic ethanol feeding may, however, induce such zonation, as evidenced by both a slower rate of protein turnover in the pp cells and preferential pv accumulation of plasma proteins.


Importance of a Potential Protein Kinase A Phosphorylation Site of Na+,K+-ATPase and Its Interaction Network for Na+ Binding.
The molecular mechanism underlying PKA-mediated regulation of Na(+),K(+)-ATPase was explored in mutagenesis studies of the potential PKA site at Ser-938 and surrounding charged residues. The phosphomimetic mutations S938D/E interfered with Na(+) binding from the intracellular side of the membrane, whereas Na(+) binding from the extracellular side was unaffected. The reduction of Na(+) affinity is within the range expected for physiological regulation of the intracellular Na(+) concentration, thus supporting the hypothesis that PKA-mediated phosphorylation of Ser-938 regulates Na(+),K(+)-ATPase activity in vivo Ser-938 is located in the intracellular loop between transmembrane segments M8 and M9. An extended bonding network connects this loop with M10, the C terminus, and the Na(+) binding region. Charged residues Asp-997, Glu-998, Arg-1000, and Lys-1001 in M10, participating in this bonding network, are crucial to Na(+) interaction. Replacement of Arg-1005, also located in the vicinity of Ser-938, with alanine, lysine, methionine, or serine resulted in wild type-like Na(+) and K(+) affinities and catalytic turnover rate. However, when combined with the phosphomimetic mutation S938E only lysine substitution of Arg-1005 was compatible with Na(+),K(+)-ATPase function, and the Na(+) affinity of this double mutant was reduced even more than in single mutant S938E. This result indicates that the positive side chain of Arg-1005 or the lysine substituent plays a mechanistic role as interaction partner of phosphorylated Ser-938, transducing the phosphorylation signal into a reduced affinity of Na(+) site III. Electrostatic interaction of Glu-998 is of minor importance for the reduction of Na(+) affinity by phosphomimetic S938E as revealed by combining S938E with E998A.


Regulated expression of nullo is required for the formation of distinct apical and basal adherens junctions in the Drosophila blastoderm.
During cellularization, the Drosophila embryo undergoes a large-scale cytokinetic event that packages thousands of syncytial nuclei into individual cells, resulting in the de novo formation of an epithelial monolayer in the cortex of the embryo. The formation of adherens junctions is one of the many aspects of epithelial polarity that is established during cellularization: at the onset of cellularization, the Drosophila beta-catenin homologue Armadillo (Arm) accumulates at the leading edge of the cleavage furrow, and later to the apicolateral region where the zonula adherens precursors are formed. In this paper, we show that the basal accumulation of Arm colocalizes with DE-cadherin and Dalpha-catenin, and corresponds to a region of tight membrane association, which we refer to as the basal junction. Although the two junctions are similar in components and function, they differ in their response to the novel cellularization protein Nullo. Nullo is present in the basal junction and is required for its formation at the onset of cellularization. In contrast, Nullo is degraded before apical junction formation, and prolonged expression of Nullo blocks the apical clustering of junctional components, leading to morphological defects in the developing embryo. These observations reveal differences in the formation of the apical and basal junctions, and offer insight into the role of Nullo in basal junction formation.


Heterotrimeric G protein-independent signaling of a G protein-coupled receptor. Direct binding of ARNO/cytohesin-2 to the carboxyl terminus of the A2A adenosine receptor is necessary for sustained activation of the ERK/MAP kinase pathway.
The A2A adenosine receptor is a prototypical G(s)-coupled receptor, but it also signals, e.g. to mitogen-activated protein (MAP) kinase, via a pathway that is independent of heterotrimeric G proteins. Truncation of the carboxyl terminus affects the strength of the signal through these alternative pathways. In a yeast two-hybrid interaction hunt, we screened a human brain library for proteins that bound to the juxtamembrane portion of the carboxyl terminus of the A2A receptor. This approach identified ARNO/cytohesin-2, a nucleotide exchange factor for the small (monomeric) G proteins of the Arf (ADP-ribosylation factor) family, as a potential interaction partner. We confirmed a direct interaction by mutual pull down (of fusion proteins expressed in bacteria) and by immunoprecipitation of the proteins expressed in mammalian cells. To circumvent the long term toxicity associated with overexpression of ARNO/cytohesin-2, we created stable cell lines that stably expressed the A2A receptor and where ARNO/cytohesin-2 or the dominant negative version E156K-ARNO/cytohesin-2 was inducible by mifepristone. Cyclic AMP accumulation induced by an A2A-specific agonist was neither altered by ARNO/cytohesin-2 nor by the dominant negative version. This was also true for agonist-induced desensitization. In contrast, expression of dominant negative E156K-ARNO/cytohesin-2 and of dominant negative T27N-Arf6 abrogated the sustained phase of MAP kinase stimulation induced by the A2A receptor. We therefore conclude that ARNO/cytohesin-2 is required to support the alternative, heterotrimeric G protein-independent, signaling pathway of A2A receptor, which is stimulation of MAP kinase.


Exploring the efficacy of psychological treatments for depression: a multiverse meta-analysis protocol.
In the past four decades, over 700 randomised controlled trials (RCTs) and 80 meta-analyses have examined the efficacy of psychological treatments for depression. Overwhelming evidence suggests that all types of psychological treatments are effective. Yet, many aspects are still unexplored. Meta-analysts could perform hundreds of potential meta-analyses with the current literature, and a comprehensive bird's-eye view of all published studies is missing. This protocol outlines how a multiverse meta-analysis can evaluate the entire body of the literature on psychological treatments of depression in a single analysis. Thereby, gaps of evidence and areas of robustness are highlighted. We will conduct systematic literature searches in bibliographical databases (PubMed, Embase, PsycINFO and Cochrane Register of Controlled Trials) up until 1 January 2021. We will include all RCTs comparing a psychological treatment with a control condition. We will include studies published in English, German, Spanish or Dutch, and exclude trials on maintenance and relapse prevention as well as dissertations. Two independent researchers will check all records. All self-reported and clinician-rated instruments measuring depression are included. We will extract information on recruitment settings, target groups, age groups, comorbidity, intervention formats, psychotherapy types, number of sessions, control conditions and country. Two independent researchers will assess risk of bias using the Cochrane Risk of Bias assessment tool. As part of the multiverse meta-analysis, unweighted, fixed effect and random effects models will be calculated. As we will not collect any primary data, an ethical approval of this protocol is not required. We will publish the results in a peer-review journal and present them at international conferences. We will follow open science practices and provide our code and data.


Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10.
In an attempt to develop effective vaccines against central nervous system (CNS) tumors, we evaluated the ability of vaccines with standard dendritic cells (DC) versus type 1 polarizing DCs (DC1) to induce glioma-specific type 1 CTLs with CNS tumor-relevant homing properties and the mechanism of their action. C57BL/6 mouse-derived bone marrow cells were cultured with mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) for 6 days, and CD11c(+) cells were subsequently cultured with GM-CSF, rmIFN-gamma, rmIFN-alpha, rmIL-4, and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for 24 hours to generate DC1s. In analogy to their human counterparts, mouse DC1s exhibited surface marker profiles of mature DCs and produced high levels of IL-12 and CXCL10. Importantly for their application as cancer vaccines, such DC1s stably retained their type 1 phenotype even when exposed to type 2-promoting or regulatory T cell (Treg)-promoting environments. Consistently, mouse DC1s induced antigen-specific type 1 CTLs more efficiently than nonpolarized DCs in vitro. DC1s given s.c. migrated into draining lymph nodes, induced antigen-specific CTLs, and suppressed Treg accumulation. In addition, s.c. immunization with DC1s loaded with glioma-associated antigen (GAA)-derived CTL epitope peptides prolonged the survival of CNS GL261 glioma-bearing mice, which was associated with efficient CNS glioma homing of antigen-specific CTLs. Intratumoral injections of GAA peptide-loaded DC1s further enhanced the anti-CNS glioma effects of DC1-based s.c. immunization. Interestingly, the antitumor functions were abrogated with CXCL10(-/-) mouse-derived DC1s. Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines.


A system divided: the state of neurosurgical training in modern-day Vietnam.
The current report is the first of its kind in describing the neurosurgical training in modern-day Vietnam. Starting with in-depth face-to-face interviews, followed by electronically distributed questionnaires, a detailed picture of the training systems emerged.Neurosurgical training in Vietnam is multifaceted and dichotomous. The country of nearly 100 million people currently has only one neurosurgery-specific residency program, at the University of Medicine and Pharmacy at Ho Chi Minh City (UMPHCMC). This program lasts for 3 years, and Westerners might recognize many similarities to programs native to their countries. A similar training program exists in the north, at the Hanoi Medical University, but at this institution, trainees focus on neurosurgery only in the final year of their 3-year training. Neurosurgical training that resembles the program in Hanoi permeates the rest of the country, and the goal for all of the programs is to rapidly produce surgeons who can be dispersed throughout the country to treat patients requiring urgent neurosurgical procedures who are medically unsuitable for transfer to large urban centers and multispecialty hospitals. For the privilege of practicing elective neurosurgery, trainees around the country are required to acquire further training in Ho Chi Minh City or Hanoi or during fellowships abroad.A clear description of the neurosurgical training systems in Vietnam is hard to achieve, as there exist many diverse pathways and no standard definition of the endpoint for training. Unification and a clearer certification standard will likely help to elevate the standards of training and the state of neurosurgical practice in Vietnam.


Reperfusion Times for Radial Versus Femoral Access in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Observations From the Cardiac Care Network Provincial Primary PCI Registry.
Radial access is associated with less bleeding and vascular complications. However, it may delay reperfusion during primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction. A provincial database prospectively collected clinical and procedural characteristics for all urgent percutaneous coronary intervention procedures performed between June 2010 and September 2011 in Ontario for ST-segment-elevation myocardial infarction, including time of arrival in the catheterization laboratory and time of first balloon inflation. After excluding patients with cardiogenic shock, with previous bypass surgery, or who received fibrinolysis, 2947 patients were included in the analysis. Propensity score matching was used to minimize difference in clinical characteristics between radial and femoral access procedures. Predictors of radial access included younger age and male sex. After propensity score matching, the median time from arrival in the cardiac catheterization laboratory to first balloon was 27 minutes (25th%-75th%, 21-34) for the femoral group and 30 minutes (25th%-75th %, 24-39) for the radial group (P<0.001). When hospitals were stratified based on the proportion of primary percutaneous coronary intervention cases that were performed using radial access, there was no difference in treatment times between radial and femoral access in the tercile of hospitals that used radial access most frequently. There were no significant differences in the rates of death or myocardial infarction at 30 days. This contemporary multicenter registry demonstrates that the time to first balloon inflation is slightly longer with radial access than with femoral access, although the 3 minute difference is unlikely to be clinically relevant. There is no difference in treatment times at hospitals that frequently use radial access for primary percutaneous coronary intervention. Short-term mortality and reinfarction rates are similar with radial and femoral access.


Levosimendan improves cardiac function and myocardial efficiency in rats with right ventricular failure.
Levosimendan is an inotropic and vasodilator drug, which is known to improve cardiac function in animal models of right ventricular (RV) failure. The effects of levosimendan on oxygen consumption and myocardial efficiency in the failing RV is unknown. We investigated the effects of levosimendan on RV function, myocardial oxygen consumption, myocardial external efficiency (MEE), and myocardial metabolism in rats with RV hypertrophy and failure. RV hypertrophy and failure were induced by pulmonary trunk banding in rats. Rats were randomized to seven weeks of treatment with vehicle (n = 16) or levosimendan (3 mg/kg/day) (n = 13). Control animals without pulmonary banding received vehicle treatment (n = 11). RV MEE and RV metabolism were evaluated by echocardiography, 11C-acetate positron emission tomography (PET), 18F-FDG PET, and invasive pressure measurements. We found that levosimendan improved RV MEE (26 ± 3 vs. 14 ± 1%, P < 0.01) by increasing RV external work (0.62 ± 0.06 vs. 0.30 ± 0.03 mmHgċmL, P < 0.001) without affecting RV myocardial oxygen consumption ( P = 0.64). The improvement in RV MEE was not associated with a change in RV myocardial glucose uptake (1.3 ± 0.1 vs. 1.0 ± 0.1 µmol/g/min, P = 0.44). In conclusion, in the hypertrophic and failing RV of the rat, levosimendan improves RV function without increasing myocardial oxygen consumption leading to improved MEE. The improvement in RV MEE was not associated with a change in myocardial glucose uptake. This study emphasizes the potential therapeutic value of chronic levosimendan treatment RV failure. It extends previous observations on the effect profile of levosimendan and motivates clinical testing of levosimendan in RV failure.


Maternal perceptions of childhood vaccination: explanations of reasons for and against vaccination.
Understanding reasons for and against vaccination from the parental perspective is critical for designing vaccination campaigns and informing other interventions to increase vaccination uptake in Canada. The objective of this study was to understand maternal vaccination decision making for children. Mothers participating in a longitudinal community-based pregnancy cohort, the All Our Babies study in Calgary, Alberta, completed open-ended survey questions providing explanations for the vaccination status of their child by 24 months postpartum. Qualitative responses were linked to administrative vaccination records to examine survey responses and recorded child vaccination status. There were 1560 open-ended responses available; 89% (n = 1391) provided explanations for vaccinating their children, 5% (n = 79) provided explanations for not vaccinating/delaying, and 6% (n = 90) provided explanations for both. Themes were similar for those vaccinating and not vaccinating/delaying; however, interpretations were different. Two broad themes were identified: Sources of influence and Deliberative Processes. Sources of influence on decision making included personal, family, and external experiences. Deliberative Processes included risk, research, effectiveness, and balancing risks/benefits. Under Deliberative Processes, responsibility was a category for those vaccinating; while choice, instrumental/practical, and health issues were categories for those not vaccinating/delaying. Mothers' levels of conviction and motivation provided a Context for understanding their decision making perspectives. Vaccination decision making is complex and impacted by many factors that are similar but contribute to different decisions depending on mothers' perspectives. The results of this study indicate the need to examine new intervention approaches to increase uptake that recognize and address feelings of pressure and parental commitment to choice.


The Burwell roadmap.
In January 2015 the current Secretary of the Department of Health and Human Services (HHS) outlined a bold initiative to shape the delivery of healthcare through a set of strategies aimed at improving the quality of care and reducing the growth of healthcare costs. The strategies include increasing payment incentives tied to higher value care, increasing care coordination and integration, and increasing access to information to guide patients and clinicians. Significantly, the proposal includes specific goals for alternative payment models and value-based payments for the first time in the history of the Medicare program.


A hybrid Bayesian hierarchical model combining cohort and case-control studies for meta-analysis of diagnostic tests: Accounting for partial verification bias.
To account for between-study heterogeneity in meta-analysis of diagnostic accuracy studies, bivariate random effects models have been recommended to jointly model the sensitivities and specificities. As study design and population vary, the definition of disease status or severity could differ across studies. Consequently, sensitivity and specificity may be correlated with disease prevalence. To account for this dependence, a trivariate random effects model had been proposed. However, the proposed approach can only include cohort studies with information estimating study-specific disease prevalence. In addition, some diagnostic accuracy studies only select a subset of samples to be verified by the reference test. It is known that ignoring unverified subjects may lead to partial verification bias in the estimation of prevalence, sensitivities, and specificities in a single study. However, the impact of this bias on a meta-analysis has not been investigated. In this paper, we propose a novel hybrid Bayesian hierarchical model combining cohort and case-control studies and correcting partial verification bias at the same time. We investigate the performance of the proposed methods through a set of simulation studies. Two case studies on assessing the diagnostic accuracy of gadolinium-enhanced magnetic resonance imaging in detecting lymph node metastases and of adrenal fluorine-18 fluorodeoxyglucose positron emission tomography in characterizing adrenal masses are presented.


Neonatal Bartter syndrome.
A pre-term baby girl was born following a pregnancy complicated by severe polyhydramnios at a gestational age of 36 weeks. She was initially suffering from respiratory distress consistent with idiopathic respiratory distress syndrome, and altered electrolyte imbalance with hyponatremia, hypokalemia and hypochloremic metabolic alkalosis. However, during the third week of life when she had dehydration along with significant electrolyte imbalance, Bartter's syndrome was considered which was supported by findings of high renin and aldosterone levels. Treatment was done by correction of electrolytes and dehydration along with indomethacin. The drug was well tolerated. The infant showed correction of electrolyte imbalance. The features of this case suggest an extreme form of Bartter's syndrome presenting from the early days of life. The syndrome is reported because of it's rarity and alerts pediatricians to the antenatal and neonatal variant of Bartter's syndrome.


Childhood anxiety trajectories and adolescent disordered eating: findings from the NICHD Study of Early Child Care and Youth Development.
The goal of the present article was to examine whether childhood anxiety trajectories predict eating psychopathology. We predicted that girls with trajectories of increasing anxiety across childhood would have significantly greater risk of disordered eating in adolescence in comparison to girls with stable or decreasing trajectories of anxiety over childhood. Data were collected as part of the prospective longitudinal NICHD Study of Early Child Care and Youth Development (N = 450 girls). Childhood anxiety was assessed yearly (54 months through 6th grade) via maternal report on the Child Behavior Checklist. Disordered eating behaviors were assessed at age 15 via adolescent self-report on the Eating Attitudes Test (EAT-26). We conducted latent growth mixture modeling to define girls' childhood anxiety trajectories. Maternal sensitivity, maternal postpartum depression, maternal anxiety, and child temperament were included as predictors of trajectory membership. The best fitting model included three trajectories of childhood anxiety, the low-decreasing class (22.9% of girls), the high-increasing class (35.4%), and the high-decreasing class (41.6%). Mothers with more symptoms of depression and separation anxiety had girls who were significantly more likely to belong to the high-increasing anxiety trajectory. There were no significant differences in adolescent disordered eating for girls across the three childhood anxiety trajectories. Childhood anxiety, as captured by maternal report, may not be the most robust predictor of adolescent disordered eating and may be of limited utility for prevention programs that aim to identify children in the community at greatest risk for disordered eating.


Feasibility of spirometry in preschool children.
To determine the rate at which satisfactory spirometry results are obtained (spirometry success rate) in preschool children. We analyzed the spirometry results of children ≤ 6 years of age. All tests were conducted between June of 2009 and February of 2010 in the Pulmonary Function Laboratory of the Hospital Infantil Jeser Amarante Faria, located in the city of Joinville, Brazil. The spirometry program employed features an animated incentive (soap bubbles). The procedures were performed by a pediatric pulmonologist, in accordance with the reproducibility and acceptability criteria recommended by the American Thoracic Society. We attempted to achieve an expiratory time of at least 1 s. The following parameters were measured: FVC, FEV0.5, FEV1, and the FEV1/FVC ratio. Our sample comprised 74 children. The spirometry success rate was 82%. Although the performance improved with age, the difference between younger and older children was not significant (p > 0.05). An average of 6.6 attempts/test were needed in order to achieve acceptable, reproducible curves. All 61 successful tests produced satisfactory FEV0.5 and FEV1 values. By calculating Z scores, we found that 21.6% of the children presented with an obstructive pattern. In our sample, the spirometry success rate was high, showing that spirometry is a valid method for assessing pulmonary function in preschool children. The high success rate in our sample might be attributable to the use of an incentive and to the fact that the tests were performed by professionals specializing in pediatrics.


Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Elderly Japanese Patients with Atherosclerotic Risk Factors: Subanalysis of a Randomized Clinical Trial (JPPP-70).
This post hoc subanalysis of the randomized Japanese Primary Prevention Project investigated whether once-daily low-dose aspirin versus no aspirin reduced the risk of cardiovascular events (CVEs) in patients aged ≥ 70 years with atherosclerotic risk factors. Patients aged < 70 years (young-old) or ≥ 70 years (old) with hypertension, dyslipidemia, or diabetes participated between 2005 and 2007. Patients were randomized 1:1 to receive 100 mg enteric-coated aspirin once daily or no aspirin plus standard of care. The primary outcome was a composite of death from cardiovascular causes plus nonfatal stroke and nonfatal myocardial infarction. The secondary outcome was a composite of the primary outcome plus transient ischemic attack, angina pectoris, and arteriosclerotic disease requiring medical or surgical intervention. Old (n = 7971) and young-old (n = 6493) patients were followed up for a median 5.02 years. Aspirin did not reduce the risk of primary (hazard ratio [HR] 0.92 [95% confidence interval {CI} 0.74-1.16]; P = 0.50) or secondary (0.85 [0.70-1.04]; P = 0.11) outcomes in patients aged ≥ 70 years. In old men with high-density lipoprotein < 40 mg/dL, treatment with low-dose aspirin was associated with a reduction in the incidence of the primary endpoint compared with the group not receiving aspirin (10/260 vs 22/250; HR 0.44 [95% CI 0.20-0.93]; P = 0.03). This subgroup was also found to contain significant larger proportions of patients with elevated body mass index, patients with diabetes mellitus, and smokers (P < 0.001). Old patients also showed differences in bleeding outcomes. Serious extracranial hemorrhage requiring transfusion or hospitalization occurred significantly more frequently in the aspirin-treated group than in the non-aspirin-treated group (35 [0.88%] vs 18 [0.45%]; HR 1.96 [1.11-3.46]; P = 0.020). Gastrointestinal hemorrhage occurred significantly more frequently in the aspirin-treated group than the non-aspirin-treated group (63 [1.58%] vs 18 [0.45%]; relative risk [RR] 3.5 [2.08-5.90]; P < 0.0001). Cerebral hemorrhage (intracranial hemorrhage) tended to occur more frequently in the aspirin-treated group than the non-aspirin-treated group (22 [0.55%] vs 11 [0.28%]; RR 2.01 [0.97-4.14]; P = 0.058). Cerebral hemorrhage occurred significantly more frequently in old patients than in young-old patients (33 [0.41%] vs 10 [0.15%]; HR 2.7 [1.34-5.53]; P = 0.0055). Gastrointestinal hemorrhage occurred in a slightly higher proportion of old patients compared with young-old patients (81 [1.02%] vs 53 [0.82%]; RR 1.2 [0.88-1.76]; P = 0.21). Aspirin did not reduce the risk of the primary or secondary outcomes in old patients. Aspirin treatment may have reduced CVEs within a high CVE risk elderly population subgroup. Aspirin treatment in such a group requires caution, because of the increased risk of intracranial hemorrhage, severe extracranial hemorrhage requiring hospitalization or transfusion, and gastrointestinal bleeding in old patients receiving aspirin therapy. The study is registered at ClinicalTrials.gov [NCT00225849].


Incorrect needle position during lumbar epidural steroid administration: inaccuracy of loss of air pressure resistance and requirement of fluoroscopy and epidurography during needle insertion.
Loss of air pressure resistance leads to a high rate (25.7%) of inaccurate needle-tip placement in the posterior soft tissues of the back during lumbar epidural steroid administration employing a 20-gauge Tuohy needle. Imaging and epidurogram are essential for confident identification of the lumbar epidural space to enable accurate location of steroid administration. Studies assessing efficacy of lumbar epidural steroid injection and individual patient treatments should ensure location of administration with epidurogram to enhance the validity of results.


Compliance with barrier precautions during paediatric trauma resuscitations.
Barrier precautions protect patients and providers from blood-borne pathogens. Although barrier precaution compliance has been shown to be low among adult trauma teams, it has not been evaluated during paediatric resuscitations in which perceived risk of disease transmission may be low. The purpose of this study was to identify factors associated with compliance with barrier precautions during paediatric trauma resuscitations. Video recordings of resuscitations performed on injured children (<18 years old) were reviewed to determine compliance with an established policy requiring gowns and gloves. Depending on activation level, trauma team members included up to six physicians, four nurses, and a respiratory therapist. Multivariate logistic regression was used to determine the effect of team role, resuscitation factors, and injury mechanism on barrier precaution compliance. Over twelve weeks, 1138 trauma team members participated in 128 resuscitations (4.7% penetrating injuries, 9.4% highest level activations). Compliance with barrier precautions was 81.3%, with higher compliance seen among roles primarily at the bedside compared to positions not primarily at the bedside (90.7% vs. 65.1%, p<0.001). Bedside residents (98.4%) and surgical fellows (97.6%) had the highest compliance, while surgical attendings (20.8%) had the lowest (p<0.001). Controlling for role, increased compliance was observed during resuscitations of patients with penetrating injuries (OR=3.97 [95% CI: 1.35-11.70], p=0.01), during resuscitations triaged to the highest activation level (OR=2.61 [95% CI: 1.34-5.10], p=0.005), and among team members present before patient arrival (OR=4.14 [95% CI: 2.29-7.39], p<0.001). Compliance with barrier precautions varies by trauma team role. Team members have higher compliance when treating children with penetrating and high acuity injuries and when arriving before the patient. Interventions integrating barrier precautions into the workflow of team members are needed to reduce this variability and improve compliance with universal precautions during paediatric trauma resuscitations.


Long-distance movement of cherry leaf roll virus in infected tobacco plants.
The long-distance movement of cherry leaf roll virus (CLRV) in tobacco plants was studied using a tissue printing technique with non-isotopic RNA probes. Time-course analysis revealed that CLRV RNA accumulated in the inoculated leaf at an early stage, such as 20 h post-inoculation. The virus accumulation reached a peak at 8-10 days post-inoculation (d.p.i.) and then progressively decreased. The virus RNA signal was detected before the appearance of symptoms. The virus invaded stem vascular tissues at 3 d.p.i., moving towards the roots before moving to the upper leaves. In systemically infected leaves, the virus appeared first in the basal regions and then moved to the distal parts through the vascular system. The distribution pattern of the virus coat protein in systemically infected leaves was parallel to that observed for the virus RNA, suggesting that CLRV requires the coat protein for long-distance movement. The movement of the virus was influenced by the phyllotactic position of the leaves. The viral symptoms and the virus RNA signal in older systemically infected leaves were asymmetrically distributed, being localized in the side of the lamina closest to the inoculated leaf. Virus distribution in infected plants as well as the susceptibility of the plant to systemic infection were also influenced by the developmental stage of the inoculated leaves. Inoculation of leaves at 95% of their final size resulted in virus replication but no systemic infection. In fully mature leaves the virus did not replicate.


[Efferent methods of the treatment of cerebrospinal fluid hypertension in exacerbation of multiple sclerosis].
Analysis is made of the efficacy of the treatment of CSF hypertension in 40 patients in the phase of exacerbation of multiple sclerosis. Use was made of sorption detoxication methods: hemoperfusion (the author's certificate No.1466754) and enterosorption (the priority certificate No.4465054/14 (115542) dated July 22, 1988). SKH-IK and SKH-2K sorbents were employed as hemoperfusion, using the venovenous scheme of perfusion, the volumetric rate of the blood flow being 100-120 ml/min during 2-3 hours. Altogether 2-3 sessions were carried out, with an interval of 5 to 7 days. For enterosorption, use was made of a crumbled up filamentous carbonic sorbent in a dose of 50-60 mg per kg bw 3 times a day for 20 days in 2 hourly intervals between food intake. Regression of the neurological symptoms began 2-3 hours after the first session of hemoperfusion and 5-6 days after the beginning of the intake of the filamentous carbonic sorbent, increasing throughout the whole treatment course. That coincided with the disappearance of CSF hypertension and normalization of the immunological spectrum of the blood serum. Sorption detoxication brought about no complications and is a method of choice in the treatment of CSF hypertension in patients in the phase of multiple sclerosis exacerbation.


Inhibition of proteasome by MG-132 treatment causes extra phragmoplast formation and cortical microtubule disorganization during M/G1 transition in synchronized tobacco cells.
The 26S proteasome plays essential roles in cell cycle progression in various types of cell. We previously reported that the inhibition of 26S proteasome activities by a proteasome inhibitor, MG-132, exclusively caused cell cycle arrest in synchronized tobacco BY-2 cells. Here we report a further observation of 26S proteasome involvement during M/G1 transition utilizing a transgenetic BY-2 cell line that stably expresses a GFP-alpha-tubulin fusion protein (BY-GT16). Interestingly, MG-132 treatment caused the arrest of cell cycle progression prior to entering the G1 phase. Indeed, phragmoplast-like structures were formed and cortical microtubules were not organized after the collapse of the original phragmoplasts. Additionally, actin microfilaments showed irregular rearrangements when further incubated with MG-132 and as the phragmoplast-like structures developed. Since these phragmoplast-like structures had a similar configuration and ability to form cell plates to that of the original phragmoplasts, we designated these phragmoplast-like structures as extra phragmoplasts. Furthermore, we showed that a tobacco kinesin-related polypeptide of 125 kDa (TKRP125) localized in the extra phragmoplasts and that its protein level remained unchanged during MG-132 treatment. We propose that TKRP125 might be one of the possible targets of the ubiquitin-proteasome degradation pathway during M/G1 transition.


Survivin as a therapeutic target for radiation sensitization in lung cancer.
Expression of survivin is elevated in most malignancies, especially in radiation-resistant cell lines. In this study, we investigated how radiation affects survivin expression in primary endothelial cells as well as in malignant cell lines. We found that 3 Gy significantly reduced survivin protein level in human umbilical vein endothelial cells (HUVECs) but not in tumor cell lines. Flow cytometry studies suggest that the down-regulation of survivin is independent of cell cycle. In addition, survivin mRNA level was also down-regulatable by irradiation. However, it was abrogated by actinomycin D-mediated inhibition of gene transcription. Luciferase reporter gene assays suggest that irradiation suppressed the survivin promoter. p53 overexpression reduced survivin expression, but overexpression of a p53 mutant failed to abolish the radiation-induced down-regulation in HUVECs. Alteration of p53 status in Val138 lung cancer cell line also failed to restore the radiation-inducible down-regulation. Overexpression of survivin in 293 cells prevented apoptosis induced by irradiation and increased cell viability after irradiation. The inhibition of survivin using antisense oligonucleotides caused a significant decrease in cell viability of irradiated H460 lung cancer cells. These data suggest that radiation transcriptionally down-regulates survivin in HUVECs. This regulatory mechanism is defective in malignancies and is not mediated by p53. Survivin overexpression may lead to resistance to radiotherapy by inhibiting apoptosis and enhancing cell viability. The inhibition of survivin results in sensitization of H460 lung cancer cells to radiation. These studies suggest that survivin may be a target for cancer therapy.


Mental Stress Detection and Mitigation using Machine Learning and Binaural Beat Stimulation.
Stress is an inevitable problem experienced by people worldwide. Continuous exposure to stress can greatly impact mental activity as well as physical health thereby leading to several diseases. In this study, we investigate the effectiveness of audio binaural beat stimulation (BBs) in mitigating mental stress. We developed an experimental protocol to induce four mental states: rest, control, stress, and stress mitigation. The stress was induced by utilizing Stroop Color Word Test (SCWT) with time constraints and mitigated, by listening to 16 Hz of BBs. The four mental states were assessed using behavioral responses (accuracy of target detection), a perceived stress state questionnaire (PSS-10), and electroencephalography (EEG). The mean spectral power of four frequency bands was estimated using Power Spectral Density (PSD), and five different machine learning classifiers were used to classify the four mental states. Our results show that SCWT reduced the detection accuracy by 59.58% while listening to 16-Hz BBs significantly increased the accuracy of detection by 27.08%, (p = .00392). Furthermore, the support vector machine (SVM) significantly outperformed other classifiers achieving the highest accuracy of 82.5 ± 2.0 % using the beta band information. Similarly, the PSD topographical maps showed different patterns between the four mental states, where the temporal region's PSD was mostly affected by stress. Nevertheless, under mitigation, there was a noticeable restoration in the temporal activity. Overall, our results demonstrate that BBs at 16 Hz can be used to mitigate stress levels.


PARIS: protocol for a prospective single arm, theory-based, group-based feasibility intervention study to increase Physical Activity and reduce sedentary behaviouR after barIatric Surgery.
Increased physical activity and reduced sedentary behaviour can encourage favourable outcomes after bariatric surgery. However, there is a lack of evidence as to how to support patients with behaviour change. The aim of this study is to assess the feasibility of a physiotherapist led, online group-based behaviour change intervention to increase physical activity and reduce sedentary behaviour following bariatric surgery. Single arm feasibility study of a theory and evidence-based group behaviour change intervention based on the Behaviour Change Wheel and Theoretical Domains Framework using behaviour change techniques from the Behaviour Change Technique Taxonomy v1. The intervention has eight objectives and specifies behaviour change techniques that will be used to address each of these. Groups of up to eight participants who have had surgery within the previous 5 years will meet weekly over 6 weeks for up to 1½ hours. Groups will be held online led by a physiotherapist and supported by an intervention handbook. Feasibility study outcomes include: rate of recruitment, retention, intervention fidelity, participant engagement and acceptability. Secondary outcomes include: physical activity, sedentary behaviour, body composition, self-reported health status and will be analysed descriptively. Change in these outcomes will be used to calculate the sample size for a future evaluation study. Qualitative interviews will explore participants' views of the intervention including its acceptability. Data will be analysed according to the constant comparative approach of grounded theory. This study has National Health Service Research Ethics Committee approval; Haydock 20/NW/0472. All participants will provide informed consent and can withdraw at any point. Findings will be disseminated through peer-reviewed journals, conference and clinical service presentations. ISRCTN31524689.


Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models.
Spontaneous (novel) object recognition (SOR) is one of the most widely used rodent behavioural tests. The opportunity for rapid data collection has made SOR a popular choice in studies that explore cognitive impairment in rodent models of schizophrenia, and that test the efficacy of drugs intended to reverse these deficits. We provide an overview of the many recent studies that have used SOR to explore the mnemonic effects of manipulation of the key transmitter systems relevant to schizophrenia-the dopamine, glutamate, GABA, acetylcholine, serotonin and cannabinoid systems-alone or in combination. We also review the use of SOR in studying memory in genetically modified mouse models of schizophrenia, as well as in neurodevelopmental and lesion models. We end by discussing the construct and predictive validity, and translational relevance, of SOR with respect to cognitive impairment in schizophrenia. Perturbation of the dopamine or glutamate systems can generate robust and reliable impairment in SOR. Impaired performance is also seen following antagonism of the muscarinic acetylcholine system, or exposure to cannabinoid agonists. Cognitive enhancement has been reported using alpha7-nicotinic acetylcholine receptor agonists and 5-HT(6) antagonists. Among non-pharmacological models, neonatal ventral hippocampal lesions and maternal immune activation can impair SOR, while mixed results have been obtained with mice carrying mutations in schizophrenia risk-associated genes, including neuregulin and COMT. While SOR is not without its limitations, the task represents a useful method for studying manipulations with relevance to cognitive impairment in schizophrenia, as well as the interactions between them.


Single C8-Arylguanine modifications render oligonucleotides in the Z-DNA conformation under physiological conditions.
Z-DNA is the only DNA conformation that has a left-handed helical twist. Although Z-DNA has been implicated in both carcinogenesis and mutagenesis, its specific biological role remains uncertain. We have demonstrated that the formation of C8-arylguanine DNA adducts, derived from arylhydrazines, shifts the B/Z-DNA equilibrium toward the Z-DNA conformation in d(CG)5 sequences. However, our previous work examined the effect of two adducts in the duplex, and it was unclear whether the two base modifications were working together to cause the equilibrium shift toward the Z-DNA conformation. Here we report the synthesis and characterization of a hairpin oligonucleotide sequence (d(CG)5T4(CG)5) containing only one C8-arylguanine modified base. The unmodified hairpin and the previously studied unmodified double-stranded oligonucleotide were conformationally similar, and each required ∼3 M NaCl to yield a B-/Z-DNA ratio of 1:1. The introduction of a single C8-arylguanine modification significantly reduced the NaCl concentration needed to produce a 1:1 B-/Z-DNA ratio in the hairpin. Further, the addition of MgCl2 and spermine to the C8-arylguanine-modified hairpin shifts the B/Z-DNA equilibrium such that the Z form predominated under physiological conditions. NMR and molecular modeling indicated the conformational effects produced by the C8-arylguanine modification occurred locally at the site of modification while CD data demonstrated that the C8-arylguanine-modified base destabilized the B form. Additionally, our data show that adopting the Z-DNA conformation is preferred over denaturation to the single-stranded form. Finally, the conformational effects of the C8-arylguanine modifications were not additive and the introduction of any such modifications drive Z-DNA formation under physiological conditions, which may provide a novel carcinogenesis mechanism where DNA adducts confer their carcinogenicity through a Z-DNA-mediated mechanism.


Comments on Cavanagh and Mather (1989): coming up short (and long)
Cavanagh and Mather (1989) reviewed literature concerning the possible distinction between short- and long-range processes in motion perception and concluded that the distinction cannot be supported. Instead, they proposed that motion perception be considered on the basis of detectors for first-order (luminance, color) and second-order (first-order motion, texture, stereo) stimulus attributes. They supported their position with studies of motion based on second-order stimuli. The present paper contends that when experiments permitting the investigation of both processes in the same display are included and when criteria are examined in their totality rather than one-by-one, the original short-range/long-range distinction can be retained. Furthermore, it is argued that the first-order/second-order distinction does not represent a theoretical advancement and that studies of second-order motion can be interpreted in terms of the older distinction. It is concluded that the short-range/long-range distinction is useful and should not be abandoned.


Proteolytic cleavage of bacteriophage lambda repressor in induction.
The bacteriophage lambda repressor, a protein that maintains the lysogenic state of a bacterium containing a lambda prophage, is cleaved when the lysogen is induced by mitomycin C or ultraviolet light. This cleavage does not occur when induction is prevented by mutational alteration either of the phage repressor or of the host recA gene product. Proteolytic cleavage may be the primary mechanism of repressor inactivation in this induction pathway, or it may follow a different event which causes the initial inactivation.


Random forest modeling can predict infectious complications following trauma laparotomy.
Identifying clinical and biomarker profiles of trauma patients may facilitate the creation of models that predict postoperative complications. We sought to determine the utility of modeling for predicting severe sepsis (SS) and organ space infections (OSI) following laparotomy for abdominal trauma. Clinical and molecular biomarker data were collected prospectively from patients undergoing exploratory laparotomy for abdominal trauma at a Level I trauma center between 2014 and 2017. Machine learning algorithms were used to develop models predicting SS and OSI. Random forest (RF) was performed, and features were selected using backward elimination. The SS model was trained on 117 records and validated using the leave-one-out method on the remaining 15 records. The OSI model was trained on 113 records and validated on the remaining 19. Models were assessed using areas under the curve. One hundred thirty-two patients were included (median age, 30 years [23-42 years], 68.9% penetrating injury, median Injury Severity Score of 18 [10-27]). Of these, 10.6% (14 of 132) developed SS and 13.6% (18 of 132) developed OSI. The final RF model resulted in five variables for SS (Penetrating Abdominal Trauma Index, serum epidermal growth factor, monocyte chemoattractant protein-1, interleukin-6, and eotaxin) and four variables for OSI (Penetrating Abdominal Trauma Index, serum epidermal growth factor, monocyte chemoattractant protein-1, and interleukin-8). The RF models predicted SS and OSI with areas under the curve of 0.798 and 0.774, respectively. Random forests with RFE can help identify clinical and biomarker profiles predictive of SS and OSI after trauma laparotomy. Once validated, these models could be used as clinical decision support tools for earlier detection and treatment of infectious complications following injury. Prognostic, level III.


Machine vision based alternative testing approach for physical purity, viability and vigour testing of soybean seeds (Glycine max).
The conventional methods for seed quality testing have several limitations as they involve visual assessment and are destructive. In this context, a study was performed to assess the suitability of non-contact, non-destructive type imaging techniques such as visible imaging and X-ray imaging for conducting physical purity, viability and vigour tests of soybean seeds. The seeds that appeared healthy in external surface examination using visible tests as well as in internal assessment using X-ray tests were classified as sound seeds while the other seeds were marked as not-sound seeds. The obtained results were then correlated with the results of the standard germination tests. The high correlation results between the imaging tests and the standard conventional germination tests indicate the effectiveness and usability of the proposed image analysis based technique as an attractive alternative to the existing quality assessment methods for soybean seeds.


Blood pressure documentation in the emergency department.
To analyze the frequency of blood pressure documentation performed by nursing professionals in an emergency department. This is a cross-sectional, observational, descriptive, and analytical study, which included medical records of adult patients admitted to the observation ward of an emergency department, between March and May 2014. Data were obtained through a collection instrument divided into three parts: patient identification, triage data, and blood pressure documentation. For statistical analysis, Pearson's correlation coefficient was used, with a significance level of α<0.05. One hundred fifty-seven records and 430 blood pressure measurements were analyzed with an average of three measurements per patient. Of these measures, 46.5% were abnormal. The mean time from admission to documentation of the first blood pressure measurement was 2.5 minutes, with 42 minutes between subsequent measures. There is no correlation between the systolic blood pressure values and the mean time interval between blood pressure documentations: 0.173 (p=0.031). The present study found no correlation between frequency of blood pressure documentation and blood pressure values. The frequency of blood pressure documentation increased according to the severity of the patient and decreased during the length of stay in the emergency department.


An Operator's Experience of the Loss-of-Resistance Technique in Epidural Injections: An Observational Study.
A successful interlaminar epidural injection relies on correct epidural space needle placement. Most interlaminar epidural steroid injection (ESI) procedures are performed with a blind technique known as loss-of-resistance (LOR) without an imaging guide. This study aims to evaluate the success rate of the LOR technique in interlaminar epidural steroid injection under fluoroscopic control. Patients who underwent interlaminar ESI owing to a history of at least 3 months of chronic low back and leg pain not responding to medications and physical therapies were included in an observational trial. Participants' age was between 27 and 88 years, and they had an American Society of Anesthesiologists physical status of I-III. The patients were placed in a prone position, and a Tuohy needle was introduced at the level of the L5-S1 interlaminar foramen using fluoroscopic image with an anteroposterior view. A lateral view was obtained when the LOR was felt. The procedures that achieved epidural spread by contrast agent in the first attempt were deemed successful. Those that did not and those that had false positive LOR were regarded as unsuccessful. Interlaminar ESİ was administered to 150 patients. The procedure's success and failure rates were 76% (114 patients) and 24% (36 patients), respectively. A total of 58.3% (21 patients) of patients who underwent an unsuccessful procedure had a false LOR, whereas 41.6% (15 patients) of the same group exhibited other causes. Sex, age, and body mass index (BMI) showed no statistical significance in terms of procedural success. There were statistically significant differences in the distance between the skin and the epidural space according to the body mass index groups. The LOR technique identified the epidural space in most epidural procedures. However, in some cases, LOR was shown to be inadequate. Therefore, we suggest that the LOR technique must be supported by imaging such as fluoroscopy during epidural injections.