Towards ideal magnetofluorescent nanoparticles for bimodal detection of breast-cancer cells.
An increasing number of novel molecular markers based on nanomaterials for tumor diagnostics have been developed in recent years. Many efforts have focused on the achievement of site-targeted bioconjugated nanoparticles. In contrast, the mechanisms of toxicity, endocytosis, and degradation pathways are still poorly understood, despite their primary importance for clinical translation. In this study, three different model nanoscale magnetofluorescent particle systems (MFNs) are designed and fabricated. These nanoparticles are evaluated in terms of size, morphology, zeta potential, fluorescence efficiency, capability of enhancing T(2) relaxivity of water protons, and stability. Accordingly, two are developed and the mechanism of internalization, the intracellular fate, and the toxicity in MCF-7 adenocarcinoma cells are studied. Besides the well-documented size effect, the anionic charge seems to be a crucial factor for particle internalization, as MFN penetration through the cell membrane could be modulated by surface charge. Ultrastructural analysis of transmission electron micrographs combined with evidence from confocal microscopy reveals that MFNs are internalized by clathrin-mediated endocytosis and macropinocytosis. Moreover, MFNs are found in EEA1-positive endosomes and in lysosomes, indicating that they follow a physiological pathway of endocytosis. Magnetorelaxometric analysis demonstrates that MFNs enable the detection of 5 x 10(5) cells mL(-1) after treatment with particle dosages as low as 30 microg mL(-1). Hence, MFNs appear to be a valuable and safe bimodal contrast agent that can be developed for the noninvasive diagnosis of breast cancer.


Relationships between mercury burden, sex, and sexually selected feather ornaments in crested auklet (Aethia cristatella).
Individuals with higher contaminant burdens are expected to be in poorer physical health and be of lower individual body condition and energetic status, potentially resulting in reduced ornamentation or increased asymmetry in bilateral features. The degree and magnitude of this effect also would be expected to vary by sex, as female birds depurate contaminants into eggs. We tested for relationships among mercury in feathers, sex, and elaborate feather ornaments that relate to individual quality in crested auklets (Aethia cristatella), small planktivorous seabirds in the North Pacific Ocean. We found no relationships between mercury and the size of individuals' forehead crest or degree of measurement asymmetry in auricular plumes, both of which are favoured by intersexual selection. Females had significantly greater mercury concentrations than males (females. 1.02 ± 0.39 μg/g; males, 0.75 ± 0.32 μg/g); but concentrations were below that known to have physiological effects, as expected for a secondary consumer. Sex differences in overwintering area for this long-distance migrant species (more females in the Kuroshio Current Large Marine Ecosystem than males) could be the reason for this seemingly counterintuitive result between sexes. Further research relating mercury burden to overwintering ecology and diet contents would build on our results and further elucidate interrelationships between sex, sexually selected feather ornaments and contaminant burden.


Intraspecific variation in semicircular canal morphology-A missing element in adaptive scenarios?
Recent evidence suggests that the amount of intraspecific variation in semicircular canal morphology may, itself, be evidence for varying levels of selection related to locomotor demands. To determine the extent of this phenomenon across taxa, we expand upon previous work by examining intraspecific variation in canal radii and canal orthogonality in a broad sample of strepsirrhine and platyrrhine primates. Patterns of interspecific variation are re-examined in light of intraspecific variation to better understand the resolution at which locomotion can be reconstructed from single individuals. Data was collected from high-resolution CT scans of 14 size-matched, related species. Six of these taxa have existing data on rotational head speeds. The level of intraspecific variation was found to differ in strepsirrhine and in platyrrhine species pairs, with larger ranges of variation generally observed for the slower moving taxon than the faster moving one. Taxa that are classified as relatively agile can to some extent be separated from those who are slower-moving, but only when comparing similarly sized, closely related species with more extreme forms of locomotion. Our findings agree with previous research showing that canal intraspecific variation can fluctuate according to species-specific locomotor behavior and extends this further by identifying behaviors that may be under unusual selective pressure. It also demonstrates the complexity of interpreting inner ear morphology in the context of broadly applicable locomotor "categories" of the kind commonly used in behavioral studies. We suspect that simplified models predicting vestibular sensitivity may be unable to differentiate behaviors when only a single specimen is available.


Recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in nonhuman primates.
The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses an individual filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). The main concern with all replication-competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV) GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV) GP; three animals received rVSV-wild type (wt) vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use.


American Academy of Pediatrics. Committee on Infectious Diseases. Severe invasive group A streptococcal infections: a subject review.
The course of severe invasive group A beta-hemolytic streptococcal (GABHS) infections is often precipitous, requiring prompt diagnosis and rapid initiation of appropriate therapy. Therefore, physicians must have a high index of suspicion of this disease, particularly in patients at increased risk (e.g., those with varicella or diabetes mellitus). Although a relationship between the use of nonsteroidal antiinflammatory drugs and severe invasive GABHS infections has been suggested, at present data on which to base a clinical decision about the use or restriction of nonsteroidal antiinflammatory drugs in children with varicella are insufficient. When necrotizing fasciitis is suspected, prompt surgical drainage, debridement, fasciotomy, or amputation often is necessary. Many experts recommend intravenously administered penicillin G and clindamycin for the treatment of invasive GABHS infections on the basis of animal studies. Some evidence exists that intravenous immunoglobulin given in addition to appropriate antimicrobial and surgical therapy may be beneficial. Although chemoprophylaxis for household contacts of persons with invasive GABHS infections has been considered by some experts, the limited available data indicate that the risk of secondary cases is low (2.9 per 1000) and data about the effectiveness of any drug are insufficient to make recommendations. Because of the low risk of secondary cases of invasive GABHS infections in schools or child care facilities, chemoprophylaxis is not indicated in these settings. Routine immunization of all healthy children against varicella is recommended and is an effective means to decrease the risk of invasive GABHS infections.


The paradox of readmission: effect of a quality improvement program in hospitalized patients with heart failure.
Congestive heart failure (CHF) is an increasingly common condition associated with significant hospital resource utilization. Initiating better disease management at the time of initial hospital admission has the potential to reduce readmissions. To evaluate the impact of a multifaceted quality improvement program on 12-month hospital utilization in patients admitted to hospital with CHF. Prospective longitudinal study comparing baseline and intervention cohorts. All consecutive patients with CHF discharged alive from 3 metropolitan hospitals during the baseline (October 1, 2000 to April 17, 2001) and intervention (February 15, 2002 to August 31, 2002) study periods. Active prospective case-finding identified 220 baseline and 235 intervention participants; full data was available on 197 baseline and 219 intervention participants. Education and performance feedback for hospital and primary care practitioners; clinical decision support tools; individualized, guideline-based treatment plans; patient education and self-management support; and improved hospital-community integration. Twelve-month all-cause hospital readmission, 12-month mortality, readmission-free survival, heart failure-specific readmission, and total hospital days over 12 months. Intervention patients had a higher rate of all-cause readmission (odds ratio [OR] = 1.65; 95% confidence interval [CI] = 1.10-2.46) but a trend to reduction in mortality (OR = 0.68; 95% CI = 0.44-1.07). There was no difference in frequency of hospitalizations per year, number of hospital days, or the composite outcome of death or readmission. The intervention improved care processes and may have reduced mortality, but at the cost of higher readmission rates. Better understanding of intervention components, intensity, and targeting may optimize the effectiveness of disease management programs.


Profile of Metabolic Syndrome in Newly Detected Hypertensive Patients in India: An Hospital-Based Study.
Metabolic syndrome (MetS) is recognized as an emerging threat and interest of public health because the factors defining syndrome are associated with increased risk of mortality and morbidity. Hypertension further adds to risk factor leading to target organ damage. Recognizing the MetS in patients with hypertension provides a great opportunity for more aggressive treatment. The objective of the study is to estimate the prevalence and evaluate the metabolic profile of MetS in newly diagnosed adult hypertensive participants. This is an hospital-based cross-sectional study. A total of 400 participants with newly detected essential hypertension were included in the study after detailed medical and laboratory investigations done to exclude the secondary hypertension. After the informed consent, a structured proforma was filled containing the demographic data; medical history; physiological parameters such as blood pressure, height, weight, and waist circumference; some laboratory investigations such as lipid profile and fasting blood glucose. Descriptive statistics such as mean and proportion were used. To compare the proportions, Chi-square test was used. Kappa agreement was utilized to know the level of agreement between various criteria defining MetS. The prevalence of MetS according to the International Diabetes Federation criteria in the new hypertensive study participants was 50.5% more common in females. One-fourth of young hypertensives was having MetS. Hypertensive patients with MetS show risk factors at significantly higher range than their counterparts. High-density lipoprotein was the most common risk factor present apart from increased waist circumference. There was a wide variation in the prevalence of MetS in the Indian population by different criteria. Half of the new hypertensive patients had MetS and thus it becomes very important to screen all the hypertensives at the onset for MetS and treat them aggressively to decrease the cardiovascular events.


Concentration-independent MRI of pH with a dendrimer-based pH-responsive nanoprobe.
The measurement of extracellular pH (pHe ) has significant clinical value for pathological diagnoses and for monitoring the effects of pH-altering therapies. One of the major problems of measuring pHe with a relaxation-based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH-unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation-based dendritic MRI contrast agent in a concentration-independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA-4AmP)44 -G5, a G5-PAMAM dendrimer-based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r1 ) increased from 7.91 to 9.65 mM(-1) s(-1) (on a per Gd(3+) basis) on changing pH from 8.84 to 6.35. At 7 T, r1 relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r2 ) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA-4AmP)44 -G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R2 /R1 also showed a linear relationship in a pH-responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA-4AmP)44 -G5 agent. Importantly, the nanoprobe (GdDOTA-4AmP)44 -G5 shows pH response in the range commonly found in the microenvironment of solid tumors.


A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis.
Pioglitazone is used effectively to treat non-alcoholic steatohepatitis (NASH), but there is marked variability in response. This study examined whether genetic variation contributes to pioglitazone response variability in patients with NASH. This genetic substudy includes 55 participants of a randomized controlled trial designed to determine the efficacy of long-term pioglitazone treatment in patients with NASH. The primary outcome of the clinical trial was defined as ≥2-point reduction in the non-alcoholic fatty liver disease activity score (NAS). In this substudy, single nucleotide polymorphisms (SNPs) in putative candidate genes were tested for association with primary and secondary outcomes. A genetic response score was constructed based on the sum of response alleles for selected genes. The genetic response score was significantly associated with achievement of the primary outcome (odds ratio 1.74; 95% CI 1.27-2.54; p = 0.0015). ADORA1 rs903361 associated with resolution of NASH (p = 0.0005) and change in the ballooning score among Caucasian and Hispanic patients (p = 0.0005). LPL rs10099160 was significantly associated with change in ALT (p = 0.0005). The CYP2C8∗3 allele, which confers faster pioglitazone clearance in allele carriers, was associated with change in fibrosis score (p = 0.026). This study identified key genetic factors that explain some of the inter-individual variability in response to pioglitazone among patients with NASH.


Prothrombin gene G20210A mutation and obstetric complications.
To estimate whether maternal carriage of the prothrombin gene G20210A mutation is associated with pregnancy loss, preeclampsia, placental abruption, or small for gestational age (SGA) neonates in a low-risk, prospective cohort. This was a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development factor V Leiden study, a multicenter, prospective, observational cohort of 5,188 unselected singleton gestations. A total of 4,167 first-trimester samples were available for analysis and were tested for the prothrombin G20210A mutation. Obstetric complications were compared between women with and without the prothrombin G20210A mutation by univariable and multivariable analysis. A total of 157 (3.8%) women had the prothrombin gene mutation (156 heterozygous and one homozygous). Carriers of the prothrombin G20210A mutation had similar rates of pregnancy loss, preeclampsia, SGA neonates, and abruption compared with noncarriers. Results were similar in a multivariable analysis controlling for age, race, prior pregnancy loss, prior SGA neonates, and family history of thromboembolism. Three thromboembolic events occurred in women testing negative for the mutation. There was no association between the prothrombin G20210A mutation and pregnancy loss, preeclampsia, abruption, or SGA neonates in a low-risk, prospective cohort. These data raise questions about the practice of screening women without a history of thrombosis or adverse pregnancy outcomes for this mutation. II.


Preparation, Characterization and in vivo Evaluation of Parenteral Sustained Release Microsphere Formulation of Zopiclone.
The aim of this study was to prepare zopiclone-loaded polycaprolactone microspheres by emulsion solvent evaporation technique with different drug-to-carrier ratios {MP 1 (1:1), MP 2 (1:2), MP 3 (1:3), and MP 4 (1:4)}, characterize and evaluate the in vivo performance. The microspheres were characterized for particle size, surface morphology, drug excipient compatibility, percentage yield, drug entrapment, and in vitro release kinetics. Pharmacokinetics and pharmacodynamics were evaluated after parenteral administration so as to determine the sustained action of the drug after one-time administration of the formulation in a rat model. Of four formulations prepared, MP 2, i.e., 1:2 (drug-polymer) ratio was selected as the optimized formulation based on particle size, particle shape, and the release behavior. The size of microspheres was found to be ranging from 5.4 to 12.1 µm. The shape of microspheres was found to be spherical by SEM. Among the four formulations, MP 2 (1:2) showed maximum percentage yield of 75% ± 2.68%. There was no interaction between drug and polymer by FT-IR study. In the in vitro release study, formulation MP 2 (1:2) showed 86.5% drug release and was found to be sustained for 10 days. The microsphere formulations were able to sustain the release of drug both in vitro and in vivo. Pharmacodynamic study (Maze apparatus) indicated that the anxiolytic activity shown by zopiclone microspheres was significant when compared to the zopiclone solution given daily.


Immunochemical identity of peroxisomal enoyl-CoA hydratase with the peroxisome-proliferation-associated 80,000 mol wt polypeptide in rat liver.
Peroxisome proliferators, which induce proliferation of hepatic peroxisomes, have been shown previously to cause a marked increase in an 80,000 mol wt polypeptide predominantly in the light mitochondrial and microsomal fractions of liver of rodents. We now present evidence to show that this hepatic peroxisome-proliferation-associated polypeptide, referred to as polypeptide PPA-80, is immunochemically identical with the multifunctional peroxisome protein displaying heat-labile enoyl-CoA hydratase activity. This conclusion is based on the following observations: (a) the purified polypeptide PPA-80 and the heat- labile enoyl-CoA hydratase from livers of rats treated with the peroxisome proliferators Wy-14,643 {[4-chloro-6(2,3-xylidino)-2-pyrimidinylthio]acetic acid} exhibit identical minimum molecular weights of approximately 80,000 on SDS polyacrylamide gel electrophoresis; (b) these two proteins are immunochemically identical on the basis of ouchterlony double diffusion, immunotitration, rocket immunoelectrophoresis, and crossed immunoelectrophoresis analysis; and (c) the immunoprecipitates formed by antibodies to polypeptide PPA-80 when dissociated on a sephadex G-200 column yield enoyl-CoA hydratase activity. Whether the polypeptide PPA-80 exhibits the activity of other enzyme(s) of the peroxisomal beta-oxidation system such as fatty acyl-CoA oxidase activity or displays immunochemical identity with such enzymes remains to be determined. The availability of antibodies to polypeptide PPA-80 and enoyl-CoA hydratase facilitated immunofluorescent and immunocytochemical localization of the polypeptide PPA- 80 and enoyl-CoA hydratase in the rat liver. The indirect immunofluorescent studies with these antibodies provided direct visual evidence for the marked induction of polypeptide PPA-80 and enoyl-CoA hydratase in the livers of rats treated with Wy-14,643. The present studies also provide immunocytochemical evidence for the localization of polypeptide PPA- 80 and the heat-labile enoyl-CoA hydratase in the peroxisome, but not in the mitochondria, of hepatic parenchymal cells. These studies, therefore, provide morphological evidence for the existence of fatty acyl-CoA oxidizing system in peroxisomes. An increase of polypeptide PPA-80 on SDS polyacrylamide gel electrophoretic analysis of the subcellular fractions of liver of rodents treated with lipid-lowering drugs should serve as a reliable and sensitive indicator of enhanced peroxisomal beta- oxidation system.


Stool antigen test for diagnosis of Helicobacter pylori infection in children with symptomatic disease: a prospective study.
Noninvasive tests for the diagnosis of Helicobacter pylori (Hp) infection in children are limited by low accuracy rates and lack of validation. Existing studies indicate that the stool antigen test (HpSA) has an acceptable level of accuracy for the diagnosis of Hp infection in adults but not children. The aim of this study was to evaluate the accuracy of the HpSA test for the detection of Hp infection in U.S. children. Children requiring upper endoscopic procedures were prospectively recruited from two pediatric gastroenterology clinics. Stool samples were collected from each participant before endoscopy. The presence of Hp infection was determined by positive histologic findings and positive rapid urease test (RUT). The presence of Hp organisms in stool was determined by an enzyme-linked immunosorbent assay using a commercially available polyclonal antibody kit (Meridian Diagnostics, Cincinnati, OH, U.S.A.). Results of the stool antigen test were compared with histology findings and RUT results. One hundred twenty-one children (mean age, 10.1 +/- 3.7 years) participated, of whom 9 (7.4%) had Hp infection. Histologic findings and RUT results were concordant in 95% of the children. Per study protocol, HpSA had a sensitivity, specificity, positive and negative predictive value, and accuracy rate of 67%, 99%, 86%, 97%, and 96.5%, respectively. HpSA, a polyclonal antibody test, had a low sensitivity for infection in children in the United States and at present cannot replace histologic findings as the gold standard for the diagnosis of Hp infection in the pediatric population.


Premedication before intubation in UK neonatal units: a decade of change?
To ascertain the prevalence of premedication before intubation and the choice of drugs used in UK neonatal units in 2007 and assess changes in practice since 1998. A structured telephone survey of 221 eligible units was performed. 214 of the units surveyed completed the telephone questionnaire. The units were subdivided into those that routinely intubated and ventilated neonates (routine group) and those that intubated neonates prior to transfer to a regional unit (transfer group). A similar study was performed by one of the authors in 1998. The same telephone methodology was used in both studies. Premedication for newborn intubations was provided by 93% (198/214) of all UK units and 76% (162/214) had a written policy or guideline concerning premedication prior to elective intubation. Of those 198 units which premedicate, morphine was the most widely used sedative for newborn intubations with 80% (158/198) using either morphine alone or in combination with other drugs. The most widely used combination was morphine and suxamethonium+/-atropine, which was used by 21% (41/198) of all units. 78% (154/198) of all units administered a paralytic agent. There has been substantial growth over the last decade in the number of UK neonatal units that provide some premedication for non-emergent newborn intubation, increasing from 37% in 1998 to 93% in 2007. This includes a concomitant increase in the use of paralytic drugs from 22% to 78%. However, the variety of drugs used merits further research.


Ten years of experience from interactive ergonomics projects.
This paper highlights experiences from ergonomics projects, applying an interactive research approach. The aim of this paper is to summarise experiences from seven interactive ergonomics projects with the aim to improve ergonomics and organizational performance jointly. Results from these seven projects were analysed with a model for assessing sustainable change, including the factors active ownership, professional management, competent project leadership, and involved participants. All factors were found giving support to impact and sustainability of the change projects. However, the role of the researcher is difficult and demanding.


Folding and unfolding phylogenetic trees and networks.
Phylogenetic networks are rooted, labelled directed acyclic graphswhich are commonly used to represent reticulate evolution. There is a close relationship between phylogenetic networks and multi-labelled trees (MUL-trees). Indeed, any phylogenetic network N can be "unfolded" to obtain a MUL-tree U(N) and, conversely, a MUL-tree T can in certain circumstances be "folded" to obtain aphylogenetic network F(T) that exhibits T. In this paper, we study properties of the operations U and F in more detail. In particular, we introduce the class of stable networks, phylogenetic networks N for which F(U(N)) is isomorphic to N, characterise such networks, and show that they are related to the well-known class of tree-sibling networks. We also explore how the concept of displaying a tree in a network N can be related to displaying the tree in the MUL-tree U(N). To do this, we develop aphylogenetic analogue of graph fibrations. This allows us to view U(N) as the analogue of the universal cover of a digraph, and to establish a close connection between displaying trees in U(N) and reconciling phylogenetic trees with networks.


Ultra-high throughput detection (1 million droplets per second) of fluorescent droplets using a cell phone camera and time domain encoded optofluidics.
Droplet-based assays-in which ultra-sensitive molecular measurements are made by performing millions of parallel experiments in picoliter droplets-have generated enormous enthusiasm due to their single molecule resolution and robustness to reaction conditions. These assays have great untapped potential for point of care diagnostics but are currently confined to laboratory settings due to the instrumentation necessary to serially generate, control, and measure tens of millions of droplets. To address this challenge, we have developed the microdroplet megascale detector (μMD) that can generate and detect the fluorescence of millions of droplets per second (1000× faster than conventional approaches) using only a conventional cell phone camera. The key innovation of our approach is borrowed from the telecommunications industry, wherein we modulate the excitation light with a pseudorandom sequence that enables individual droplets to be resolved that would otherwise overlap due to the limited frame rate of digital cameras. Using this approach, the μMD measures droplets at a rate of 106 droplets per sec (ϕ = 166 mL h-1) in 120 parallel microfluidic channels and achieves a limit of detection LOD = 1 μM Rhodamine dye, sufficient for typical droplet based assays. We incorporate this new droplet detection technology with our previously reported parallelized droplet production strategy, incorporating 200 parallel droplet makers and only one set of continuous and droplet phase inputs and one output line. By miniaturizing and integrating droplet based diagnostics into a handheld format, the μMD platform can translate ultra-sensitive droplet based assays into a self-contained platform for practical use in clinical and industrial settings.


Development of methodologies for identification and quantification of hazardous air pollutants from turbine engine emissions.
Aircraft turbine engines are a significant source of particulate matter (PM) and gaseous emissions in the vicinity of airports and military installations. Hazardous air pollutants (HAPs) (e.g., formaldehyde, benzene, naphthalene and other compounds) associated with aircraft emissions are an environmental concern both in flight and at ground level. Therefore, effective sampling, identification, and accurate measurement of these trace species are important to assess their environmental impact. This effort evaluates two established ambient air sampling and analysis methods, U.S. Environmental Protection Agency (EPA) Method TO-11A and National Institute for Occupational Safety and Health (NIOSH) Method 1501, for potential use to quantify HAPs from aircraft turbine engines. The techniques were used to perform analysis of the exhaust from a T63 turboshaft engine, and were examined using certified gas standards transferred through the heated sampling systems used for engine exhaust gaseous emissions measurements. Test results show that the EPA Method TO-11A (for aldehydes) and NIOSH Method 1501 (for semivolatile hydrocarbons) were effective techniques for the sampling and analysis of most HAPs of interest. Both methods showed reasonable extraction efficiencies of HAP species from the sorbent tubes, with the exception of acrolein, styrene, and phenol, which were not well quantified. Formaldehyde measurements using dinitrophenylhydrazine (DNPH) tubes (EPA method TO-11A) were accurate for gas-phase standards, and compared favorably to measurements using gas-phase Fourier-transform infrared (FTIR) spectroscopy. In general, these two standard methodologies proved to be suitable techniques for field measurement of turbine engine HAPs within a reasonable (5-10 minutes) sampling period. Details of the tests, the analysis methods, calibration procedures, and results from the gas standards and T63 engine tested using a conventional JP-8 jet fuel are provided. HAPs from aviation-related sources are important because of their adverse health and environmental impacts in and around airports and flight lines. Simpler, more convenient techniques to measure the important HAPs, especially aldehydes and volatile organic HAPs, are needed to provide information about their occurrence and assist in the development of engines that emit fewer harmful emissions.


Structure-guided insights on the role of NS1 in flavivirus infection.
We highlight the various domains of the flavivirus virulence factor NS1 and speculate on potential implications of the NS1 3D structure in understanding its role in flavivirus pathogenesis. Flavivirus non-structural protein 1 (NS1) is a virulence factor with dual functions in genome replication and immune evasion. Crystal structures of NS1, combined with reconstructions from electron microscopy (EM), provide insight into the architecture of dimeric NS1 on cell membranes and the assembly of a secreted hexameric NS1-lipid complex found in patient sera. Three structural domains of NS1 likely have distinct roles in membrane association, replication complex assembly, and immune system avoidance. A conserved hydrophobic inner face is sequestered either on the membrane or in the interior of the secreted hexamer and contains regions implicated in viral replication. The exposed variable outer face is presented to cellular and secreted components of the immune system in infected patients and contains candidate regions for immune system modulation. We anticipate that knowledge of the distinct NS1 domains and assembly will lead to advances in elucidating virus-host interactions mediated through NS1 and in dissecting the role of NS1 in viral genome replication.


Assembly of Hepatocyte Spheroids Using Magnetic 3D Cell Culture for CYP450 Inhibition/Induction.
There is a significant need for in vitro methods to study drug-induced liver injury that are rapid, reproducible, and scalable for existing high-throughput systems. However, traditional monolayer and suspension cultures of hepatocytes are difficult to handle and risk the loss of phenotype. Generally, three-dimensional (3D) cell culture platforms help recapitulate native liver tissue phenotype, but suffer from technical limitations for high-throughput screening, including scalability, speed, and handling. Here, we developed a novel assay for cytochrome P450 (CYP450) induction/inhibition using magnetic 3D cell culture that overcomes the limitations of other platforms by aggregating magnetized cells with magnetic forces. With this platform, spheroids can be rapidly assembled and easily handled, while replicating native liver function. We assembled spheroids of primary human hepatocytes in a 384-well format and maintained this culture over five days, including a 72 h induction period with known CYP450 inducers/inhibitors. CYP450 activity and viability in the spheroids were assessed and compared in parallel with monolayers. CYP450 activity was induced/inhibited in spheroids as expected, separate from any toxic response. Spheroids showed a significantly higher baseline level of CYP450 activity and induction over monolayers. Positive staining in spheroids for albumin and multidrug resistance-associated protein (MRP2) indicates the preservation of hepatocyte function within spheroids. The study presents a proof-of-concept for the use of magnetic 3D cell culture for the assembly and handling of novel hepatic tissue models.


Understanding selectin counter-receptor binding from electrostatic energy computations and experimental binding studies.
Higher organisms defend themselves against invading micro-organisms and harmful substances with their immune system. Key players of the immune system are the white blood cells (WBC), which in case of infection move in an extravasation process from blood vessels toward infected tissue promoting inflammation. This process starts with the attachment of the WBC to the blood vessel wall, mediated by protein pair interactions of selectins and counter-receptors (C-R). Individual selectin C-R binding is weak and varies only moderately between the three selectin types. Multivalency enhances such small differences, rendering selectin-binding type specific. In this work, we study selectin C-R binding, the initial step of extravasation. We performed electrostatic energy computations based on the crystal structure of one selectin type co-crystallized with the ligating part of the C-R. The agreement with measured free energies of binding is satisfactory. Additionally, we modeled selectin mutant structures in order to explain differences in binding of the different selectin types. To verify our modeling procedures, surface plasmon resonance data were measured for several mutants and compared with computed binding affinities. Binding affinities computed with soaked rather than co-crystallized selectin C-R structures do not agree with measured data. Hence, these structures are inappropriate to describe the binding mode. The analysis of selectin/C-R binding unravels the role played by individual molecular components in the binding event. This opens new avenues to prevent immune system malfunction, designing drugs that can control inflammatory processes by moderating selectin C-R binding.


The role of echocardiography in SARS-CoV-2 pandemic: a compromise among appropriateness, safety and clinical impact.
SARS-CoV-2 infection, responsible for COVID-19, can determine cardiac events, which require a quick diagnosis and management, and should not be overlooked due to the presence of COVID-19 infection. In some cases, cardiovascular symptoms can also be the first and only manifestation of SARS-CoV-2 infection. In patients with COVID-19, the full cardiovascular disease diagnostic algorithm can be hindered by logistic restrain mainly derived from the difficulty of transporting patients in critical conditions to Radiology or Hemodynamics wards. The echocardiography in SARS-CoV-2 pandemic can help for differential diagnosis of cardiac events, which can be related or unrelated by the infection and can likely impact on short-term prognosis. Indeed, transthoracic echocardiography plays a key role in the screen for CV complications of COVID-19 infection: it must be focused cardiac ultrasound study (FoCUS) performed at bedside. All transthoracic, transesophageal and stress echocardiograms in patients in which test results are unlikely to change the management strategy should be postponed.


Psychometric evaluation of the Danish version of Satisfaction with Daily Occupations (SDO).
The Satisfaction with Daily Occupations (SDO) scale assesses satisfaction within the domains of work, leisure, domestic tasks, and self-care. The aim was to investigate the psychometric properties of the Danish version of the SDO when used with asylum seekers. The participants were 93 Danes without known ill health and 43 asylum seekers. They completed the SDO and rated their perceived health, activity level, and general satisfaction with daily occupations. Translation into Danish and back-translation into Swedish was made by professional interpreters. Internal consistency was α = 0.75 for the Danish sample and α = 0.79 for the asylum seekers. The SDO distinguished between asylum seekers and the Danish sample, suggesting criterion validity. Concurrent validity, analysed against general satisfaction with daily occupations, was indicated for both samples. Discriminant validity was indicated against self-rated health for both samples and against activity level for the Danish sample. There was, however, a correlation of 0.65 between the SDO satisfaction score and activity level for the asylum seekers. The SDO exhibited satisfactory internal consistency and criterion and concurrent validity. The findings regarding discriminant validity were somewhat inconclusive. The Danish SDO may be regarded as psychometrically sound but further psychometric testing is needed.


New permanent teeth from Gran Dolina-TD6 (Sierra de Atapuerca). The bearing of Homo antecessor on the evolutionary scenario of Early and Middle Pleistocene Europe.
Here we analyze the unpublished hominin dental remains recovered from the late Early Pleistocene Gran Dolina-TD6.2 level of the Sierra de Atapuerca (northern Spain), as well as provide a reassessment of the whole TD6.2 hominin dental sample. Comparative descriptions of the outer enamel surface (OES) and the enamel-dentine junction (EDJ) are provided. Overall, the data presented here support the taxonomic validity of Homo antecessor, since this species presents a unique mosaic of traits. Homo antecessor displays several primitive features for the genus Homo as well as some traits exclusively shared with Early and Middle Pleistocene Eurasian hominins. Some of these Eurasian traits were retained by the Middle Pleistocene hominins of Europe, and subsequently became the typical condition of the Neanderthal lineage. Although other skeletal parts present resemblances with Homo sapiens, TD6.2 teeth do not show any synapomorphy with modern humans. In addition, TD6.2 teeth can be well differentiated from those of Asian Homo erectus. The dental evidence is compatible with previous hypothesis about H. antecessor belonging to the basal population from which H. sapiens, Homo neanderthalensis, and Denisovans emerged. Future findings and additional research may help to elucidate the precise phylogenetic link among them.


Providing Services During Times of Change: Can Employees Maintain Their Levels of Empowerment, Work Engagement and Service Quality Through a Job Crafting Intervention?
By means of a quasi-experimental study, the effects of a tailor-made job crafting intervention for employees of a Dutch unemployment agency were evaluated. The intervention was designed to prevent a decrease in employee empowerment, work engagement and employee performance (i.e., the provision of services) due to organizational changes. Seventy-four employees received a 1-day training in which they set four job crafting goals for the subsequent weeks. After 6 weeks a reflection session was organized. Repeated measures ANOVA's showed that the intervention prevented a decrease in employees' feelings of empowerment. Furthermore, pre-post comparison tests showed that the control group (N = 89) experienced a significant decrease in work engagement, whereas the intervention group did not. Results showed no effect on customer-rated employee service quality. However, 1 year after the intervention, customer ratings of employee service quality were significantly higher for the intervention group compared to the control group. Although further research is needed, our results demonstrate that a job crafting intervention may be a promising tool to combat a decline in employee empowerment and work engagement during times of organizational change.


Characterization of regional heterogeneity in cerebrovascular reactivity dynamics using novel hypocapnia task and BOLD fMRI.
We offer a new method for characterizing the magnitude and dynamics of the vascular response to changes in arterial gas tensions using non-invasive blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) and paradigms appropriate for clinical settings. A novel respiratory task, "Cued Deep Breathing" (CDB), consisting of two consecutive cycles of cued breaths, has been developed to cause transient hypocapnia, and consequently a strong, short-lived BOLD signal decrease. Data from CDB hypocapnia paradigms and traditional breath-holding hypercapnia paradigms were analyzed on a voxel-wise basis to map regional heterogeneity in magnitude and timing parameters. The tasks caused comparable absolute BOLD percent signal changes (approximately 0.5-3.0% in gray matter) and both datasets suggested consistent regional heterogeneity in the response timing: parts of the basal ganglia, particularly the putamen, and bilateral areas of medial cortex reached their maximum signal change several seconds earlier than remaining cortical gray matter voxels. This phenomenon and a slightly delayed response in posterior cortical regions were present in group-maps of ten healthy subjects. An auxiliary experiment in different subjects measured end-tidal CO2 changes associated with the new CDB task and quantitatively compared the resulting reactivity maps with those acquired using a traditional hypercapnia challenge of 4% CO2 gas inspiration. The CDB task caused average end-tidal CO2 decreases between 6.0+/-1.1 and 10.5+/-2.6 mm Hg, with levels returning to baseline after approximately three breaths, giving evidence that the task indeed causes transient mild hypocapnia. Similarity between resulting reactivity maps suggest CDB offers an alternative method for mapping cerebrovascular reactivity.


A synchronized quorum of genetic clocks.
The engineering of genetic circuits with predictive functionality in living cells represents a defining focus of the expanding field of synthetic biology. This focus was elegantly set in motion a decade ago with the design and construction of a genetic toggle switch and an oscillator, with subsequent highlights that have included circuits capable of pattern generation, noise shaping, edge detection and event counting. Here we describe an engineered gene network with global intercellular coupling that is capable of generating synchronized oscillations in a growing population of cells. Using microfluidic devices tailored for cellular populations at differing length scales, we investigate the collective synchronization properties along with spatiotemporal waves occurring at millimetre scales. We use computational modelling to describe quantitatively the observed dependence of the period and amplitude of the bulk oscillations on the flow rate. The synchronized genetic clock sets the stage for the use of microbes in the creation of a macroscopic biosensor with an oscillatory output. Furthermore, it provides a specific model system for the generation of a mechanistic description of emergent coordinated behaviour at the colony level.


Nut Production in Bertholletia excelsa across a Logged Forest Mosaic: Implications for Multiple Forest Use.
Although many examples of multiple-use forest management may be found in tropical smallholder systems, few studies provide empirical support for the integration of selective timber harvesting with non-timber forest product (NTFP) extraction. Brazil nut (Bertholletia excelsa, Lecythidaceae) is one of the world's most economically-important NTFP species extracted almost entirely from natural forests across the Amazon Basin. An obligate out-crosser, Brazil nut flowers are pollinated by large-bodied bees, a process resulting in a hard round fruit that takes up to 14 months to mature. As many smallholders turn to the financial security provided by timber, Brazil nut fruits are increasingly being harvested in logged forests. We tested the influence of tree and stand-level covariates (distance to nearest cut stump and local logging intensity) on total nut production at the individual tree level in five recently logged Brazil nut concessions covering about 4000 ha of forest in Madre de Dios, Peru. Our field team accompanied Brazil nut harvesters during the traditional harvest period (January-April 2012 and January-April 2013) in order to collect data on fruit production. Three hundred and ninety-nine (approximately 80%) of the 499 trees included in this study were at least 100 m from the nearest cut stump, suggesting that concessionaires avoid logging near adult Brazil nut trees. Yet even for those trees on the edge of logging gaps, distance to nearest cut stump and local logging intensity did not have a statistically significant influence on Brazil nut production at the applied logging intensities (typically 1-2 timber trees removed per ha). In one concession where at least 4 trees ha-1 were removed, however, the logging intensity covariate resulted in a marginally significant (0.09) P value, highlighting a potential risk for a drop in nut production at higher intensities. While we do not suggest that logging activities should be completely avoided in Brazil nut rich forests, when a buffer zone cannot be observed, low logging intensities should be implemented. The sustainability of this integrated management system will ultimately depend on a complex series of socioeconomic and ecological interactions. Yet we submit that our study provides an important initial step in understanding the compatibility of timber harvesting with a high value NTFP, potentially allowing for diversification of forest use strategies in Amazonian Perù.


Feasibility of MR-Based Body Composition Analysis in Large Scale Population Studies.
Quantitative and accurate measurements of fat and muscle in the body are important for prevention and diagnosis of diseases related to obesity and muscle degeneration. Manually segmenting muscle and fat compartments in MR body-images is laborious and time-consuming, hindering implementation in large cohorts. In the present study, the feasibility and success-rate of a Dixon-based MR scan followed by an intensity-normalised, non-rigid, multi-atlas based segmentation was investigated in a cohort of 3,000 subjects. 3,000 participants in the in-depth phenotyping arm of the UK Biobank imaging study underwent a comprehensive MR examination. All subjects were scanned using a 1.5 T MR-scanner with the dual-echo Dixon Vibe protocol, covering neck to knees. Subjects were scanned with six slabs in supine position, without localizer. Automated body composition analysis was performed using the AMRA Profiler™ system, to segment and quantify visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT) and thigh muscles. Technical quality assurance was performed and a standard set of acceptance/rejection criteria was established. Descriptive statistics were calculated for all volume measurements and quality assurance metrics. Of the 3,000 subjects, 2,995 (99.83%) were analysable for body fat, 2,828 (94.27%) were analysable when body fat and one thigh was included, and 2,775 (92.50%) were fully analysable for body fat and both thigh muscles. Reasons for not being able to analyse datasets were mainly due to missing slabs in the acquisition, or patient positioned so that large parts of the volume was outside of the field-of-view. In conclusion, this study showed that the rapid UK Biobank MR-protocol was well tolerated by most subjects and sufficiently robust to achieve very high success-rate for body composition analysis. This research has been conducted using the UK Biobank Resource.


The imprinted retrotransposon-like gene PEG11 (RTL1) is expressed as a full-length protein in skeletal muscle from Callipyge sheep.
Members of the Ty3-Gypsy retrotransposon family are rare in mammalian genomes despite their abundance in invertebrates and some vertebrates. These elements contain a gag-pol-like structure characteristic of retroviruses but have lost their ability to retrotranspose into the mammalian genome and are thought to be inactive relics of ancient retrotransposition events. One of these retrotransposon-like elements, PEG11 (also called RTL1) is located at the distal end of ovine chromosome 18 within an imprinted gene cluster that is highly conserved in placental mammals. The region contains several conserved imprinted genes including BEGAIN, DLK1, DAT, GTL2 (MEG3), PEG11 (RTL1), PEG11as, MEG8, MIRG and DIO3. An intergenic point mutation between DLK1 and GTL2 causes muscle hypertrophy in callipyge sheep and is associated with large changes in expression of the genes linked in cis between DLK1 and MEG8. It has been suggested that over-expression of DLK1 is the effector of the callipyge phenotype; however, PEG11 gene expression is also strongly correlated with the emergence of the muscling phenotype as a function of genotype, muscle type and developmental stage. To date, there has been no direct evidence that PEG11 encodes a protein, especially as its anti-sense transcript (PEG11as) contains six miRNA that cause cleavage of the PEG11 transcript. Using immunological and mass spectrometry approaches we have directly identified the full-length PEG11 protein from postnatal nuclear preparations of callipyge skeletal muscle and conclude that its over-expression may be involved in inducing muscle hypertrophy. The developmental expression pattern of the PEG11 gene is consistent with the callipyge mutation causing recapitulation of the normal fetal-like gene expression program during postnatal development. Analysis of the PEG11 sequence indicates strong conservation of the regions encoding the antisense microRNA and in at least two cases these correspond with structural or functional domains of the protein suggesting co-evolution of the sense and antisense genes.


Refractory absence seizures: An Italian multicenter retrospective study.
To evaluate evidence and prognosis of refractory cases of absence seizures. Subjects with refractory absence seizures were identified retrospectively in 17 Italian epilepsy pediatrics Centers. We analyzed age at onset, family history, presence of myoclonic components, seizure frequency, treatment with antiepileptic drugs (AEDs), interictal electroencephalography (EEG) and neuropsychological assessment. Two subgroups were identified: one with patients with current absence seizures and another with patients that had become seizure free with or without AED treatment. The chi-square test was applied. A total of 92 subjects with drug-resistant absence seizures were analyzed. 45 subjects still show absence seizures (49%) and the other 47 became seizure free (51%) after a period of drug-resistance. The statistical analysis between these two groups showed no correlation between age of onset, family history and abnormalities at interictal EEG. Statistically significant differences were observed with regard to the number of AEDs used and intellectual disability. Typical absence epilepsy classifiable as Childhood Absence Epilepsy could not be considered so "benign", as suggested in literature. A longer duration of disease and a higher frequency of seizure seem to be correlated with a higher presence of cognitive impairment. No significant risk factor was observed to allow the faster and better recognition of patients with worse prognosis.


[Effectiveness of physical exercise on cardiovascular endurance and functional capacity in hemodialysis patients: a systematic review and meta-analysis].
Background. Physical exercise is a health intervention in the treatment of numerous chronic diseases. In patients on hemodialysis, physical exercise has been introduced during hemodialysis for different outcomes. Several meta-analyses show uncertainty about the effects. Objective. Our systematic review and meta-analysis aim at summarizing and evaluating the evidence of the effects of physical exercise on cardiovascular endurance and functional capacity of hemodialysis patients. Results. Five studies were included in the review (462 patients). Physical exercise brought an improvement in cardiovascular endurance and functional capacity (MD, 95%CI:62.24 [18.71, 105.77], p=0.005), compared to the control group. Most trials were at high risk of bias due to lack of blinding between the patients and the personnel, and between the patients and the outcome assessor. Conclusions. Physical exercise may have beneficial effect on cardiovascular endurance and functional capacity in hemodialysis patients. The quality of evidence is low and the strength of recommendations is weak for cardiovascular endurance. Future studies should consider a power analysis for an adequate sample size and minimize the risk of sample bias. Further research should provide the additional results required for an acceptable estimate of the effects of physical exercises in hemodialysis patients.


Fast-Running Tools for Personalized Monitoring of Blast Exposure in Military Training and Operations.
During training and combat operations, military personnel may be exposed to repetitive low-level blast while using explosives to gain entry or by firing heavy weapon systems such as recoilless weapons and high-caliber sniper rifles. This repeated exposure, even within allowable limits, has been associated with cognitive deficits similar to that of accidental and sports concussion such as delayed verbal memory, visual-spatial memory, and executive function. This article presents a novel framework for accurate calculation of the human body blast exposure in military heavy weapon training scenarios using data from the free-field and warfighter wearable pressure sensors. The CoBi human body model generator tools were used to reconstruct multiple training scenes with different weapon systems. The CoBi Blast tools were used to develop the weapon signature and estimate blast overpressure exposure. The authors have used data from the free-field and wearable pressure sensors to evaluate the framework. Carl-Gustav and 0.50 caliber sniper training scenarios were used to demonstrate and validate the developed framework. These simulations can calculate spatially and temporally resolved blast loads on the whole human body and on specific organs vulnerable to blast loads, such as head, face, and lungs. This framework has numerous advantages including easier model setup and shorter simulation times. The framework is an important step towards developing an advanced field-applicable technology to monitor low-level blast exposure during heavy weapon military training and combat scenarios.


vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1.
vHNF1 and HNF1 are two nuclear proteins that bind to an essential element in the promoter proximal sequences of albumin and of many other liver-specific genes. HNF1 predominates in hepatocytes but is absent in dedifferentiated hepatoma cells. These cells contain vHNF1 but fail to express most of the liver traits. In the present work we have isolated cDNA clones for vHNF1 and found that it is a homeoprotein homologous to HNF1 in regions important for DNA binding. Unexpectedly, vHNF1 transactivated the albumin promoter in transfection experiments. Like the HNF1 mRNA, the vHNF1 message was found in kidney, liver and intestine although in different proportions. The fact that vHNF1 and HNF1 readily form heterodimers in vitro and the biochemical characterization of vHNF1/HNF1 heterodimers in nuclear extracts of kidney, liver and several cell lines, strongly argue that such heterodimers exist in vivo. Our results raise the possibility that heterodimerization between homeoproteins could be a common phenomenon in higher eukaryotes, which may have implications in the regulatory network sustained between these factors.


Peroxisome Proliferator-Activated Receptor α Protects Renal Tubular Cells from Gentamicin-Induced Apoptosis via Upregulating Na+/H+ Exchanger NHE1.
Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor that has been reported to inhibit gentamicin-induced apoptosis in renal tubular cells. However, the antiapoptotic mechanism of PPARα is still unknown. In this study, we found that PPARα overexpression induced Na+/H+ exchanger-1 (NHE1) expression in the rat renal tubular cells NRK-52E. Beraprost, a PPARα ligand, also increased NHE1 expression in the renal tubules in normal mice, but not in PPARα knockout mice. Chromatin immunoprecipitation assays revealed that two PPARα binding elements were located in the rat NHE1 promoter region. Na+/H+ exchanger activity also increased in the PPARα-overexpressed cells. Flow cytometry showed that the PPARα-overexpressed cells were resistant to apoptosis-induced shrinkage. Cariporide, a selective NHE1 inhibitor, inhibited the antiapoptotic effect of PPARα in the gentamicin-treated cells. The interaction between NHE1 and ezrin/radixin/moesin (ERM) and between ERM and phosphatidylinositol 4,5-bisphosphate in the PPARα-overexpressed cells was more than in the control cells. ERM short interfering RNA (siRNA) transfection inhibited the PPARα-induced antiapoptotic effect. PPARα overexpression also increased the phosphoinositide 3-kinase (PI3K) expression, which is dependent on NHE1 activity. Increased PI3K further increased the phosphorylation of the prosurvival kinase Akt in the PPARα-overexpressed cells. Wortmannin, a PI3K inhibitor, inhibited PPARα-induced Akt activity and the antiapoptotic effect. We conclude that PPARα induces NHE1 expression and then recruits ERM to promote PI3K/Akt-mediated cell survival in renal tubular cells. The application of PPARα activation reduces the nephrotoxicity of gentamicin and may expand the clinical use of gentamicin.


Performance, carcass characteristics and meat quality of Nellore cattle supplemented with supranutritional doses of sodium selenite or selenium-enriched yeast.
The enrichment of meat with selenium is important to improve the intake of selenium by humans. The effects of supranutritional doses of sodium selenite or selenium-enriched yeast on performance, carcass characteristics and meat quality were evaluated using 63 Nellore cattle in a completely randomized design with two sources (sodium selenite and selenium-enriched yeast), three levels (0.3, 0.9 and 2.7 mg Se/kg DM) and control treatment (without addition of selenium). Final body weight (BW), average daily gain, dry matter intake and gain to feed ratio (G : F) at the end of 84 days of supplementation were not influenced by treatments (P>0.05). Values of pH, ribeye area, back fat thickness and marbling score were also not influenced by treatments ( P>0.05). Dressing percentage was greater (P=0.02) in Nellore cattle supplemented with organic Se (58.70%) compared to animals supplemented with inorganic Se (57.94%). Hot carcass weight increased ( P=0.05) with the increasing of Se levels in the diet. Colour, shear force (SF), cooking and drip loss remained unchanged ( P>0.05); however thiobarbituric acid reactive substances was 15.51% higher with inorganic Se compared with organic Se. The selenium concentration in the meat of animals receiving organic selenium was higher ( P<0.001) than that of animals receiving sodium selenite, at all levels (0.3; 0.9 and 2.7 mg/kg DM). The meat of animals receiving 2.7 mg of organic Se/kg of DM presented concentration of 372.7 μg Se/kg in the L.dorsi muscle, and the intake of 150 g of this meat by humans provides approximately 100% of the recommended Se intake (55 μg Se/day for adults). Therefore, the use of supranutritional doses of 2.7 mg Se/kg of DM, regardless of source, is a way of naturally producing selenium-enriched meat without compromising performance, carcass characteristics and quality of Nellore bovine meat.


Experimental characterization of the human non-sequence-specific nucleic acid interactome.
The interactions between proteins and nucleic acids have a fundamental function in many biological processes, including gene transcription, RNA homeostasis, protein translation and pathogen sensing for innate immunity. While our knowledge of the ensemble of proteins that bind individual mRNAs in mammalian cells has been greatly augmented by recent surveys, no systematic study on the non-sequence-specific engagement of native human proteins with various types of nucleic acids has been reported. We designed an experimental approach to achieve broad coverage of the non-sequence-specific RNA and DNA binding space, including methylated cytosine, and tested for interaction potential with the human proteome. We used 25 rationally designed nucleic acid probes in an affinity purification mass spectrometry and bioinformatics workflow to identify proteins from whole cell extracts of three different human cell lines. The proteins were profiled for their binding preferences to the different general types of nucleic acids. The study identified 746 high-confidence direct binders, 139 of which were novel and 237 devoid of previous experimental evidence. We could assign specific affinities for sub-types of nucleic acid probes to 219 distinct proteins and individual domains. The evolutionarily conserved protein YB-1, previously associated with cancer and drug resistance, was shown to bind methylated cytosine preferentially, potentially conferring upon YB-1 an epigenetics-related function. The dataset described here represents a rich resource of experimentally determined nucleic acid-binding proteins, and our methodology has great potential for further exploration of the interface between the protein and nucleic acid realms.


Neuropsychiatric symptoms following metal-on-metal implant failure with cobalt and chromium toxicity.
There were at least 31,171 metal-on-metal (MoM) hip implants in the UK between 2003 and 2011. Some of these were subject to failure and widescale recalls and revisions followed. This is a presentation of ten cases (mean age 60 years) where we evaluated neuropsychiatric morbidity following metal-on-metal hip implant failure and revision. Implants were ASR total hip replacement (acetabular implant, taper sleeve adaptor and unipolar femoral implants) performed between 2005 and 2009. This case series describes, for the first time, neuropsychiatric complications after revision where there has been cobalt and chromium toxicity. Pre-revision surgery, nine patients had toxic levels of chromium and cobalt (mean level chromium 338 nmol/l, mean cobalt 669.4 nmol/l). Depression assessment showed 9 of 9 respondents fulfilled the BDI criteria for depression and 3 of these were being treated. 7 of 9 patients showing short term memory deficit with mean mini mental state examination score of 24.2. The normal population mean MMSE for this group would be expected to be 28 with <25 indicating possible dementia. We found neurocognitive and depressive deficits after cobalt and chromium metallosis following MoM implant failure. Larger studies of neurocognitive effects are indicated in this group. There may be implications for public health.


The Eating and Appraisal Due to Emotions and Stress (EADES) Questionnaire: development and validation.
To develop and validate the Eating and Appraisal Due to Emotions and Stress (EADES) Questionnaire that was created to measure how one uses food to cope with stress and emotions. Data were collected from a cross-sectional study using the EADES Questionnaire. Convenience sample (response rate 22%) from a southeastern public university, including staff and faculty (n=854) with ages ranging from 18 to 83 years and a mean body mass index of 27.3+/-6.4. Exploratory factor analysis was completed on 54 items that were originally meant to describe constructs from the Transactional Model of Stress and Coping. Reliability of scales was estimated using Cronbach's alpha. Total sum scores were given to each factor. Pearson correlation coefficients assessed linear associations between factors. Three factors accounting for 43.5% of the variance were retained with a total Cronbach's alpha=.949. The factors did not represent the theoretical constructs from the Transactional Model of Stress and Coping as anticipated. A new model was created, including Emotion- and Stress-Related Eating, Appraisal of Resources and Ability to Cope, Appraisal of Outside Stressors and Influences with Cronbach's alpha being .949, .869, and .652, respectively. These factors were significantly correlated with one another. The EADES model provides a viable conceptual model to help explain variables that may contribute to overeating, whereas the EADES Questionnaire provides a measurement tool for evaluating these variables that have not traditionally been explored in weight management efforts.


Associations between family presence and neonatal intubation outcomes: a report from the National Emergency Airway Registry for Neonates: NEAR4NEOS.
Describe the current practice of family presence during neonatal tracheal intubations (TIs) across neonatal intensive care units (NICUs) and examine the association with outcomes. Retrospective analysis of TIs performed in NICUs participating in the National Emergency Airway Registry for Neonates (NEAR4NEOS). Thirteen academic NICUs. Infants undergoing TI between October 2014 and December 2017. Association of family presence with TI processes and outcomes including first attempt success (primary outcome), success within two attempts, adverse TI-associated events (TIAEs) and severe oxygen desaturation ≥20% from baseline. Of the 2570 TIs, 242 (9.4%) had family presence, which varied by site (median 3.6%, range 0%-33%; p<0.01). Family member was more often present for older infants and those with chronic respiratory failure. Fewer TIs were performed by residents when family was present (FP 10% vs no FP 18%, p=0.041). Among TIs with family presence versus without family presence, the first attempt success rate was 55% vs 49% (p=0.062), success within two attempts was 74% vs 66% (p=0.014), adverse TIAEs were 18% vs 20% (p=0.62) and severe oxygen desaturation was 49% vs 52%, (p=0.40). In multivariate analyses, there was no independent association between family presence and intubation success, adverse TIAEs or severe oxygen desaturation. Family are present in less than 10% of TIs, with variation across NICUs. Even after controlling for important patient, provider and site factors, there were no significant associations between family presence and intubation success, adverse TIAEs or severe oxygen desaturation.


Endocrinological evaluations of brief hand massages in palliative care.
Some patients with advanced cancer make use of complementary therapies for the reduction of anxiety and stress. These patients can suffer distressing end-of-life symptoms, which conventional treatments might not relieve satisfactorily. Although previous studies have suggested that complementary therapies could be useful for reducing distress in patients with cancer, it has remained unclear whether these benefits are applicable at the end-of-life stage. The current study examined to validate salivary chromogranin A (CgA) as a biomarker for relieving stress by hand massage in terminally ill patients. The study group comprised 34 inpatients in palliative care units. Each of these patients received a 5-minute massage to the upper extremity. Before and after the massage, saliva samples were collected in order to measure the CgA levels. The brief hand massage appears to reduce levels of stress according to the salivary CgA (p < 0.05). In addition, we found statistically significant changes in patient satisfaction with hand massage. Salivary CgA could potentially be used as a biomarker to measure relieving stress by hand massage in a palliative-care setting.


Procyanidin effects on oesophageal adenocarcinoma cells strongly depend on flavan-3-ol degree of polymerization.
Epidemiological studies have shown that the risk of developing oesophageal adenocarcinoma (OA) is inversely correlated to consumption of fruits and vegetables. Flavan-3-ols are the most abundant subclass of flavonoids in these types of foods. Three apple-derived procyanidin fractions with different average degrees of polymerization (aDP) were characterized and the effects of these fractions and of pure flavan-3-ol monomers ((-)-epicatechin and (+)-catechin) and dimers (B1, B2) on two OA cell lines were investigated. Flavan-3-ol monomers and dimers had no effect on the two cell lines, while apple-derived flavan-3-ol oligomers and polymers induced a time-dependent reduction of cell viability. The reduction in the cell viability was due to the induction of caspase-mediated apoptosis and an arrest of the cell cycle in G0/G1. The magnitude of the reduction in cell viability and induction of apoptosis after exposure to flavan-3-ol oligomeric/polymeric fractions positively correlated with their aDP. These results indicate that only flavan-3-ol oligomers and polymers, but not monomers and dimers, have an effect on the proliferation of OA cells in vitro. As tested flavan-3-ol concentrations are achievable through diet, this study suggests that apple-derived PA may possess chemotherapeutic effects against OA.


Diagnosis and management of benign fibro-osseous lesions of the jaws: a current review for the dental clinician.
Benign fibro-osseous lesions of the maxillofacial skeleton constitute a heterogeneous group of disorders that includes developmental, reactive (dysplastic) and neoplastic lesions. Although their classification has been reviewed multiple times in the past, the most common benign fibro-osseous lesions are fibrous dysplasia, osseous dysplasia and ossifying fibroma. For the dental clinician, the challenges involve diagnosis and treatment (or lack thereof). A careful correlation of all clinical, radiologic and microscopic features is essential to establish a proper diagnosis and a clear treatment plan. This article aimed to review the clinical, radiologic and histopathologic characteristics of benign fibro-osseous lesions of the jaws, with emphasis on their differential diagnoses. With a deeper understanding of benign fibro-osseous lesions, clinicians will be better prepared to manage these lesions in their practice.


Spatial resolution and noise in organic light-emitting diode displays for medical imaging applications.
We report on the resolution and noise characteristics of handheld and workstation organic light-emitting diode (OLED) displays in comparison with liquid crystal displays (LCDs). The results demonstrate advantages, in terms of sharpness, of handheld OLED displays with modulation transfer function (MTF) values exceeding 0.60 at the Nyquist frequencies. The OLED workstation included in this study exhibits significant signal contamination among adjacent pixels resulting in degraded resolution performance indicated by horizontal and vertical MTF values of 0.13 and 0.24 at the Nyquist frequency. On the other hand, its noise characteristics are superior to the LCD workstation tested. While the noise power spectral (NPS) values of the OLED workstation are 8.0×10(-6) mm2 at 1 mm(-1), the LCD workstation has NPS values of 2.6×10(-5) mm2. Although phone-size OLED displays have superior resolution and noise per pixel, the perceived resolution characteristics at appropriate viewing distances are inferior to tablet-size and workstation LCDs. In addition, our results show some degree of dependency of the resolution and noise on luminance level and viewing orientation. We also found a slightly degraded resolution and increased low-frequency noise at off-normal orientations in the handheld displays.


Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells.
Autologous dendritic cells transfected with total renal tumor RNA have been shown to be potent stimulators of CTLs and antitumor immunity in vitro. A Phase I trial was conducted to evaluate this strategy for feasibility, safety, and efficacy to induce tumor-specific T-cell responses in subjects with metastatic renal cell carcinoma. Renal tumor RNA-transfected dendritic cells were administered to 10 evaluable study patients with no evidence of dose-limiting toxicity or vaccine-related adverse effects including autoimmunity. In six of seven evaluable subjects, expansion of tumor-specific T cells was detected after immunization. The vaccine-induced T-cell reactivities were directed against a broad set of renal tumor-associated antigens, including telomerase reverse transcriptase, G250, and oncofetal antigen, but not against self-antigens expressed by normal renal tissues. Although most patients underwent secondary therapies after vaccination, tumor-related mortality of the study subjects was unexpectedly low with only 3 of 10 patients dying from disease after a mean follow-up of 19.8 months. These data provide a scientific rationale for continued clinical investigation of this polyvalent vaccine strategy in the treatment of metastatic renal cell carcinoma and, potentially, other cancers.


Activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV-infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1-mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1-mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1-mediated lipogenesis promotes tumor cell growth and is involved in EBV-driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


A theory of the evolutionary origins of psychosis.
The incidence and typical symptoms of schizophrenia are similar in diverse human populations; it is likely that the same is true for manic-depressive illnesses. Relative constancy of incidence over time and place (referred to as the 'anthropo-parity principle') and absence of evidence for environmental causation suggest that these disorders are genetic in origin and in some way characteristic of the human condition. Continued high prevalence in the face of a fertility disadvantage requires explanation--why do the genes persist and what is their function? It is proposed that the origins of psychosis are closely linked to the evolution of the human brain. The capacity for language evolved by the process of hemispheric specialisation, a gene for asymmetry (the 'right shift factor' or cerebral dominance gene) playing a critical role. This gene, it is suggested, is represented in homologous form on the X and Y chromosomes and has been subject to sexual selection. Such a locus could explain sex differences in cerebral asymmetry, and in age of onset and outcome of psychosis.


Mind over metabolism: the cephalic phase in relation to non-insulin-dependent diabetes and obesity.
The notion that a defect in hypothalamic function may be a critical factor in the aetiology of obesity and diabetes stems from observations of the important role that this brain region plays in both the behavioural and metabolic events related to feeding and energy balance. Sensory events associated with the beginning of a meal trigger a series of metabolic changes, the function of which is to prepare an organism to receive, and properly dispose of, the incoming nutrients. Insulin release and nervous control of hepatic glucose output are important components of these neural, or cephalic-phase, sensory-driven metabolic events. The present review firstly summarizes evidence for direct autonomic nervous system links between the hypothalamus and the pancreas and liver, that is, the physical basis for cephalic-phase reflexes. Secondly, an assessment is made of both the normal function of the cephalic phase and how derangements might be central to the aetiology of important disease states such as obesity and non-insulin-dependent diabetes mellitus. A central hypothesis in this article is that a primary failure of normal cephalic-phase responses, over time, leads to increased post-meal hyperglycaemia and decreased thermogenesis. The persistent hyperglycaemia (among other metabolic abnormalities) leads to insulin resistance (insulin not being effective in disposing of glucose). The reduced post-meal thermogenesis leads to weight gain through reduced energy expenditure rather than through increased intake. The obesity in turn leads to further insulin resistance and, in genetically predisposed individuals, on to frank diabetes.


Whole Genome-Sequencing and Phylogenetic Analysis of a Historical Collection of Bacillus anthracis Strains from Danish Cattle.
Bacillus anthracis, the causative agent of anthrax, is known as one of the most genetically monomorphic species. Canonical single-nucleotide polymorphism (SNP) typing and whole-genome sequencing were used to investigate the molecular diversity of eleven B. anthracis strains isolated from cattle in Denmark between 1935 and 1988. Danish strains were assigned into five canSNP groups or lineages, i.e. A.Br.001/002 (n = 4), A.Br.Ames (n = 2), A.Br.008/011 (n = 2), A.Br.005/006 (n = 2) and A.Br.Aust94 (n = 1). The match with the A.Br.Ames lineage is of particular interest as the occurrence of such lineage in Europe is demonstrated for the first time, filling an historical gap within the phylogeography of the lineage. Comparative genome analyses of these strains with 41 isolates from other parts of the world revealed that the two Danish A.Br.008/011 strains were related to the heroin-associated strains responsible for outbreaks of injection anthrax in drug users in Europe. Eight novel diagnostic SNPs that specifically discriminate the different sub-groups of Danish strains were identified and developed into PCR-based genotyping assays.


Application of magnetic field hyperthermia and superparamagnetic iron oxide nanoparticles to HIV-1-specific T-cell cytotoxicity.
The latent HIV-1 reservoir remains the major barrier to HIV-1 eradication. Although successful at limiting HIV replication, highly active antiretroviral therapy is unable to cure HIV infection, thus novel therapeutic strategies are needed to eliminate the virus. Magnetic field hyperthermia (MFH) generates thermoablative cytotoxic temperatures in target-cell populations, and has delivered promising outcomes in animal models, as well as in several cancer clinical trials. MFH has been proposed as a strategy to improve the killing of HIV-infected cells and for targeting the HIV latent reservoirs. We wished to determine whether MFH could be used to enhance cytotoxic T-lymphocyte (CTL) targeting of HIV-infected cells in a proof-of-concept study. Here, for the first time, we apply MFH to an infectious disease (HIV-1) using the superparamagnetic iron oxide nanoparticle FeraSpin R. We attempt to improve the cytotoxic potential of T-cell receptor-transfected HIV-specific CTLs using thermotherapy, and assess superparamagnetic iron oxide nanoparticle toxicity, uptake, and effect on cell function using more sensitive methods than previously described. FeraSpin R exhibited only limited toxicity, demonstrated efficient uptake and cell-surface attachment, and only modestly impacted T-cell function. In contrast to the cancer models, insufficient MFH was generated to enhance CTL killing of HIV-infected cells. MFH remains an exciting new technology in the field of cancer therapeutics, which, as technology improves, may have significant potential to enhance CTL function and act as an adjunctive therapy in the eradication of latently infected HIV-positive cells.


Effectiveness of chest physiotherapy and pulmonary rehabilitation in patients with non-cystic fibrosis bronchiectasis: a narrative review.
Respiratory physiotherapy and rehabilitation are important therapeutic options in non-cystic fibrosis bronchiectasis (NCFB). The aims of this review of clinical trials were to evaluate the safety and the effects on physiologic and clinical outcomes of airway clearance techniques (ACTs) and rehabilitation in NCFB patients, in comparison to usual care. The search was performed on March 2018 by using PubMed and PeDro databases. 33 studies were selected. The use of ACTs for NCFB were effective in increasing sputum volume although no benefit in quality of life (QoL) or pulmonary exacerbations were observed. There were no differences in effectiveness between the several techniques used. Humidification and saline inhalation were able to aid airway clearance. Hypertonic solution (HS) was more effective than isotonic solutions (IS) in improving expectoration and sputum viscosity. Pulmonary rehabilitation (PR) was found to be associated with short term benefits in exercise capacity, dyspnea and fatigue. Exercise training seems to improve quality of life and lower exacerbation rate, but long-term data are not available. Further studies are necessary to identify the most feasible long-term outcomes such as QoL and exacerbation rate.


Global genetic variations predict brain response to faces.
Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼ 500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40-50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R(2) = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R(2) = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.


Repealing Federal Health Reform: Economic and Employment Consequences for States.
Issue: The incoming Trump administration and Republicans in Congress are seeking to repeal the Affordable Care Act (ACA), likely beginning with the law's insurance premium tax credits and expansion of Medicaid eligibility. Research shows that the loss of these two provisions would lead to a doubling of the number of uninsured, higher uncompensated care costs for providers, and higher taxes for low-income Americans. Goal: To determine the state-by-state effect of repeal on employment and economic activity. Methods: A multistate economic forecasting model (PI+ from Regional Economic Models, Inc.) was used to quantify for each state the effects of the federal spending cuts. Findings and Conclusions: Repeal results in a $140 billion loss in federal funding for health care in 2019, leading to the loss of 2.6 million jobs (mostly in the private sector) that year across all states. A third of lost jobs are in health care, with the majority in other industries. If replacement policies are not in place, there will be a cumulative $1.5 trillion loss in gross state products and a $2.6 trillion reduction in business output from 2019 to 2023. States and health care providers will be particularly hard hit by the funding cuts.


Arabidopsis halleri shows hyperbioindicator behaviour for Pb and leaf Pb accumulation spatially separated from Zn.
Lead (Pb) ranks among the most problematic environmental pollutants. Background contamination of soils is nearly ubiquitous, yet plant Pb accumulation is barely understood. In a survey covering 165 European populations of the metallophyte Arabidopsis halleri, several field samples had indicated Pb hyperaccumulation, offering a chance to dissect plant Pb accumulation. Accumulation of Pb was analysed in A. halleri individuals from contrasting habitats under controlled conditions to rule out aerial deposition as a source of apparent Pb accumulation. Several elemental imaging techniques were employed to study the spatial distribution and ligand environment of Pb. Regardless of genetic background, A. halleri individuals showed higher shoot Pb accumulation than A. thaliana. However, dose-response curves revealed indicator rather than hyperaccumulator behaviour. Xylem sap data and elemental imaging unequivocally demonstrated the in planta mobility of Pb. Highest Pb concentrations were found in epidermal and vascular tissues. Distribution of Pb was distinct from that of the hyperaccumulated metal zinc. Most Pb was bound by oxygen ligands in bidentate coordination. A. halleri accumulates Pb whenever soil conditions render Pb phytoavailable. Considerable Pb accumulation under such circumstances, even in leaves of A. thaliana, strongly suggests that Pb can enter food webs and may pose a food safety risk.


Salt and public health: contested science and the challenge of evidence-based decision making.
For more than four decades, starting in the late 1960s, a sometimes furious battle has raged among scientists over the extent to which elevated salt consumption has adverse implications for population health and contributes to deaths from stroke and cardiovascular disease. Various studies and trials have produced conflicting results. Despite this scientific controversy over the quality of the evidence implicating dietary salt in disease, public health leaders at local, national, and international levels have pressed the case for salt reduction at the population level. This article explores the development of this controversy. It concludes that the concealment of scientific uncertainty in this case has been a mistake that has served neither the ends of science nor good policy. The article poses questions that arise from this debate and frames the challenges of formulating evidence-based public health practice and policy, particularly when the evidence is contested.


Improved Species-Specific Lysine Acetylation Site Prediction Based on a Large Variety of Features Set.
Lysine acetylation is a major post-translational modification. It plays a vital role in numerous essential biological processes, such as gene expression and metabolism, and is related to some human diseases. To fully understand the regulatory mechanism of acetylation, identification of acetylation sites is first and most important. However, experimental identification of protein acetylation sites is often time consuming and expensive. Therefore, the alternative computational methods are necessary. Here, we developed a novel tool, KA-predictor, to predict species-specific lysine acetylation sites based on support vector machine (SVM) classifier. We incorporated different types of features and employed an efficient feature selection on each type to form the final optimal feature set for model learning. And our predictor was highly competitive for the majority of species when compared with other methods. Feature contribution analysis indicated that HSE features, which were firstly introduced for lysine acetylation prediction, significantly improved the predictive performance. Particularly, we constructed a high-accurate structure dataset of H.sapiens from PDB to analyze the structural properties around lysine acetylation sites. Our datasets and a user-friendly local tool of KA-predictor can be freely available at http://sourceforge.net/p/ka-predictor.


Glutathione: a review on biotechnological production.
This Mini-Review summarizes the historic developments and technological achievements in the biotechnological production of glutathione in the past 30 years. Glutathione is the most abundant non-protein thiol compound present in living organisms. It is used as a pharmaceutical compound and can be used in food additives and the cosmetic industries. Glutathione can be produced using enzymatic methods in the presence of ATP and its three precursor amino acids (L-glutamic acid, L-cysteine, glycine). Alternatively, glutathione can be produced by direct fermentative methods using sugar as a starting material. In the latter method, Saccharomyces cerevisiae and Candida utilis are currently used to produce glutathione on an industrial scale. At the molecular level, the genes gshA and gshB, which encode the enzymes gamma-glutamylcysteine synthetase and glutathione synthetase, respectively, have been cloned from Escherichia coli and over-expressed in E. coli, S. cerevisiae, and Lactococcus lactis. It is anticipated that, with the design and/or discovery of novel producers, the biotechnological production of glutathione will be further improved to expand the application range of this physiologically and medically important tripeptide.


The crystal structure of coxsackievirus A9: new insights into the uncoating mechanisms of enteroviruses.
Coxsackievirus A9 (CAV9), a human pathogen causing symptoms ranging from common colds to fatal infections of the central nervous system, is an icosahedral single-stranded RNA virus that belongs to the genus Enterovirus of the family Picornaviridae. One of the four capsid proteins, VP1, includes the arginine-glycine-aspartate (RGD) motif within its C-terminal extension. This region binds to integrin alpha v beta 3, the only receptor for CAV9 to be conclusively identified to date. The crystal structure of CAV9 in complex with the antiviral compound WIN 51711 has been solved to 2.9 A resolution. The structures of the four capsid proteins, VP1 to VP4, resemble those of other picornaviruses. The antiviral compound is bound in the VP1 hydrophobic pocket, and it is possible that the pocket entrance contains a second WIN 51711 molecule. Continuous electron density for the VP1 N terminus provides a complete picture of the structure close to the fivefold axis. The VP1 C-terminal portion is on the outer surface of the virus and becomes disordered five-residues N-terminal to the RGD motif. The RGD motif is exposed and flexible in common with other known integrin ligands. Although CAV9 resembles coxsackie B viruses (CBVs), several substitutions in the areas implicated in CBV receptor attachment suggest it may recognise a different receptor. The structure along the fivefold axis provides new information on the uncoating mechanism of enteroviruses. CAV9 might bind a larger natural pocket factor than other picornaviruses, an observation of particular relevance to the design of new antiviral compounds.


Flexible control of mutual inhibition: a neural model of two-interval discrimination.
Networks adapt to environmental demands by switching between distinct dynamical behaviors. The activity of frontal-lobe neurons during two-interval discrimination tasks is an example of these adaptable dynamics. Subjects first perceive a stimulus, then hold it in working memory, and finally make a decision by comparing it with a second stimulus. We present a simple mutual-inhibition network model that captures all three task phases within a single framework. The model integrates both working memory and decision making because its dynamical properties are easily controlled without changing its connectivity. Mutual inhibition between nonlinear units is a useful design motif for networks that must display multiple behaviors.


A Multistage Process Model of How a Person Who Currently Injects Drugs Comes to Assist Persons Who Do not Inject with Their First Injections.
Injecting drugs for the first time almost always requires assistance from an experienced person who injects drugs (PWID). While there has been moderate amount of research on PWID who assist with first injections, most of this research has focused on identifying characteristics of PWID who assist with first injections. We do not have a formal model that describes how the minority of PWID come to assist do so, while the majority never assist. Through comparison of persons who did or did not recently assist with first injections using data from PWID in Tallinn, Estonia (N = 286) and Staten Island, New York City (N = 101), we developed a formal multi-stage model of how PWID come to assist with first injections. The model had a primary pathway 1) of engaging in "injection promoting" behaviors, 2) being asked to assist, and 3) assisting. Statistical testing using odds ratios showed participation in each stage was strongly associated with participation in the next stage (all odds ratios >3.0) and the probabilities of assisting significantly increased with participation in the successive stages. We then used the model to compare engagement in the stages pre-vs. post participation in an intervention, and to compare persons who recently assisted to persons who had assisted in the past but had not recently assisted and to persons who had never assisted. Advantages of a formal model for how current PWID come to assist with first injections include: facilitating comparisons across different PWID populations and assessing strengths and limitations of interventions to reduce assisting with first injections.


A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity.
Premature infants, especially those with birth weights of <1500 g, often suffer from anemia of prematurity and associated problems. Erythropoietin therapy is a safe effective way to prevent and to treat anemia of prematurity. We hypothesized that combined administration of vitamin B12 and folate with erythropoietin and iron would enhance erythropoietin-induced erythropoiesis. In a randomized, controlled trial, 64 premature infants (birth weight: 801-1300 g) receiving erythropoietin and iron supplementation were assigned randomly to receive either vitamin B12 (3 microg/kg per day) and folate (100 microg/kg per day) (treatment group) or a lower dose of folate (60 microg/kg per day) (control group). During the 4-week observation period, vitamin B12 and folate enhanced erythropoietin-induced erythropoiesis significantly, as indicated by a 10% increase in red blood cell counts, compared with folate alone. Hemoglobin and hematocrit levels remained stable in the treatment group, whereas they decreased in the control group. Vitamin B12 levels in the treatment group increased over baseline and control values, whereas red blood cell folate levels were comparable between the groups. Subsequent analysis showed slight nonsignificant differences in baseline red blood cell count, hemoglobin level, hematocrit level, and mean corpuscular volume values, which must be addressed as a limitation. With the limitation of a slight imbalance in baseline data between the study groups, combined therapy with vitamin B12, folate, erythropoietin, and orally and intravenously administered iron seemed more effective in stimulating erythropoiesis among premature infants, compared with erythropoietin, iron, and low-dose folate alone. Additional trials are necessary to confirm these data.