Using Publicly Available Data to Quantify Plant-Pollinator Interactions and Evaluate Conservation Seeding Mixes in the Northern Great Plains.
Concern over declining pollinators has led to multiple conservation initiatives for improving forage for bees in agroecosystems. Using data available through the Pollinator Library (npwrc.usgs.gov/pollinator/), we summarize plant-pollinator interaction data collected from 2012-2015 on lands managed by the U.S. Fish and Wildlife Service and private lands enrolled in U.S. Department of Agriculture conservation programs in eastern North Dakota (ND). Furthermore, we demonstrate how plant-pollinator interaction data from the Pollinator Library and seed cost information can be used to evaluate hypothetical seeding mixes for pollinator habitat enhancements. We summarize records of 314 wild bee and 849 honey bee (Apis mellifera L.) interactions detected on 63 different plant species. The wild bee observations consisted of 46 species, 15 genera, and 5 families. Over 54% of all wild bee observations were represented by three genera-Bombus, Lassioglossum, and Melissodes. The most commonly visited forbs by wild bees were Monarda fistulosa, Sonchus arvensis, and Zizia aurea. The most commonly visited forbs by A. mellifera were Cirsium arvense, Melilotus officinalis, and Medicago sativa. Among all interactions, 13% of A. mellifera and 77% of wild bee observations were made on plants native to ND. Our seed mix evaluation shows that mixes may often need to be tailored to meet the unique needs of wild bees and managed honey bees in agricultural landscapes. Our evaluation also demonstrates the importance of incorporating both biologic and economic information when attempting to design cost-effective seeding mixes for supporting pollinators in a critically important part of the United States.


Sexually transmitted infections: challenges ahead.
WHO estimated that nearly 1 million people become infected every day with any of four curable sexually transmitted infections (STIs): chlamydia, gonorrhoea, syphilis, and trichomoniasis. Despite their high global incidence, STIs remain a neglected area of research. In this Commission, we have prioritised five areas that represent particular challenges in STI treatment and control. Chlamydia remains the most commonly diagnosed bacterial STI in high-income countries despite widespread testing recommendations, sensitive and specific non-invasive testing techniques, and cheap effective therapy. We discuss the challenges for chlamydia control and evidence to support a shift from the current focus on infection-based screening to improved management of diagnosed cases and of chlamydial morbidity, such as pelvic inflammatory disease. The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is globally recognised. We review current and potential future control and treatment strategies, with a focus on novel antimicrobials. Bacterial vaginosis is the most common vaginal disorder in women, but current treatments are associated with frequent recurrence. Recurrence after treatment might relate to evidence that suggests sexual transmission is integral to the pathogenesis of bacterial vaginosis, which has substantial implications for the development of effective management approaches. STIs disproportionately affect low-income and middle-income countries. We review strategies for case management, focusing on point-of-care tests that hold considerable potential for improving STI control. Lastly, STIs in men who have sex with men have increased since the late 1990s. We discuss the contribution of new biomedical HIV prevention strategies and risk compensation. Overall, this Commission aims to enhance the understanding of some of the key challenges facing the field of STIs, and outlines new approaches to improve the clinical management of STIs and public health.


Transmission of 20-Gb/s OFDM signals occupying 7-GHz license-free band at 60 GHz using a RoF system employing frequency sextupling optical up-conversion.
This work describes a proposed 60-GHz radio-over-fiber (RoF) system employing a frequency sextupling optical up-conversion scheme. Based on the modified single sideband modulation scheme, spectrally efficient vector signals were transmitted with no performance degradation due to dispersion-induced fading. Wavelength-division- multiplexed optical up-conversion can be realized using the proposed system. Since the required transmitter bandwidth is significantly reduced, radio-frequency components with lower bandwidth and higher reliability can be utilized. Both 13.75-Gb/s QPSK-OFDM and 20.625-Gb/s 8QAM-OFDM signals were experimentally demonstrated. After transmission over 25-km of standard single mode fiber, no significant received power penalty was observed.


Polycystic Ovarian Syndrome-Related Depression in Adolescent Girls: A Review.
Polycystic ovarian syndrome (PCOS), a common endocrinal disorder of reproductive age characterized by heterogeneous complications, is nowadays prevailing among females at adolescent stage. Infrequent or prolonged menstrual periods, excess hair growth, acne, and obesity can occur in women with PCOS. In adolescents, infrequent or absence of menstruation may raise chances for this condition. The increased prevalence of PCOS among general population throughout the world is found to be 5%-10% in the women of reproductive age, and about 40% women with PCOS experience depression, particularly young girls. The exact cause of PCOS is unknown. Early diagnosis and treatment along with weight loss may reduce the risk of long-term complications. Depression and anxiety are common in women with PCOS but are often overlooked and therefore left untreated. Along with the physical disturbances, many mental problems are also associated with PCOS. Therefore, PCOS not only has problems associated with reproduction but also has associated crucial metabolic and psychological health risks with increasing age of the patients. Because of the increased number of cases with PCOS around the world in present times, with prominent symptom of, specifically, depression at the adolescent stage, it is important to highlight the disease.


In-Home Telerehabilitation Compared with Face-to-Face Rehabilitation After Total Knee Arthroplasty: A Noninferiority Randomized Controlled Trial.
The availability of less resource-intensive alternatives to home visits for rehabilitation following orthopaedic surgeries is important, given the increasing need for home care services and the shortage of health resources. The goal of this trial was to determine whether an in-home telerehabilitation program is not clinically inferior to a face-to-face home visit approach (standard care) after hospital discharge of patients following a total knee arthroplasty. Two hundred and five patients who had a total knee arthroplasty were randomized before hospital discharge to the telerehabilitation group or the face-to-face home visit group. Both groups received the same rehabilitation intervention for two months after hospital discharge. Patients were evaluated at baseline (before total knee arthroplasty), immediately after the rehabilitation intervention (two months after discharge), and two months later (four months after discharge). The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the last follow-up evaluation. Secondary outcome measures included the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, functional and strength tests, and knee range of motion. The noninferiority margin was set at 9% for the WOMAC. The demographic and clinical characteristics of the two groups of patients were similar at baseline. At the last follow-up evaluation, the mean differences between the groups with regard to the WOMAC gains, adjusted for baseline values, were near zero (for 182 patients in the per-protocol analysis): -1.6% (95% confidence interval [CI]: -5.6%, 2.3%) for the total score, -1.6% (95% CI: -5.9%, 2.8%) for pain, -0.7% (95% CI: -6.8%, 5.4%) for stiffness, and -1.8% (95% CI: -5.9%, 2.3%) for function. The confidence intervals were all within the predetermined zone of noninferiority. The secondary outcomes had similar results, as did the intention-to-treat analysis, which was conducted afterward for 198 patients. Our results demonstrated the noninferiority of in-home telerehabilitation and support its use as an effective alternative to face-to-face service delivery after hospital discharge of patients following a total knee arthroplasty. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


Amorphous molybdenum sulfides as hydrogen evolution catalysts.
Providing energy for a population projected to reach 9 billion people within the middle of this century is one of the most pressing societal issues. Burning fossil fuels at a rate and scale that satisfy our near-term demand will irreversibly damage the living environment. Among the various sources of alternative and CO2-emission-free energies, the sun is the only source that is capable of providing enough energy for the whole world. Sunlight energy, however, is intermittent and requires an efficient storage mechanism. Sunlight-driven water splitting to make hydrogen is widely considered as one of the most attractive methods for solar energy storage. Water splitting needs a hydrogen evolution catalyst to accelerate the rate of hydrogen production and to lower the energy loss in this process. Precious metals such as Pt are superior catalysts, but they are too expensive and scarce for large-scale applications. In this Account, we summarize our recent research on the preparation, characterization, and application of amorphous molybdenum sulfide catalysts for the hydrogen evolution reaction. The catalysts can be synthesized by electrochemical deposition under ambient conditions from readily available and inexpensive precursors. The catalytic activity is among the highest for nonprecious catalysts. For example, at a loading of 0.2 mg/cm(2), the optimal catalyst delivers a current density of 10 mA/cm(2) at an overpotential of 160 mV. The growth mechanism of the electrochemically deposited film catalysts was revealed by an electrochemical quartz microcrystal balance study. While different electrochemical deposition methods produce films with different initial compositions, the active catalysts are the same and are identified as a "MoS(2+x)" species. The activity of the film catalysts can be further promoted by divalent Fe, Co, and Ni ions, and the origins of the promotional effects have been probed. Highly active amorphous molybdenum sulfide particles can also be prepared from simple wet-chemical routes. Electron transport is sometimes slow in the particle catalysts, and an impedance model has been established to identify this slow electron transport. Finally, the amorphous molybdenum sulfide film catalyst has been integrated onto a copper(I) oxide photocathode for photoelectrochemical hydrogen evolution. The conformal catalyst efficiently extracts the excited electrons to give an impressive photocurrent density of -5.7 mA/cm(2) at 0 V vs RHE. The catalyst also confers good stability.


Association of body surface area and body composition with heart structural characteristics of female swimmers.
In healthy nonathletic populations, some left ventricle (LV) parameters such as LV mass (LVM) and LV end diastolic dimension (LVEDD) can be predicted by some of body size parameters such as body surface area (BSA), fat-free mass (FFM), and height (H). These body size parameters use to remove covariate influence of body size from cardiac dimension variables and allow comparisons to be made between individuals and groups of different body size. Endurance exercise has been associated with changes in LV size and body composition of athletes. The aim of this study was to evaluate in 30 trained female swimmers (12-17 y) possible correlations between BSA, FFM, fat mass (FM) determined by bioelectrical impedance analyzer(BIA); and a range of cardiac dimensions derived by echocardiography. Univariate correlations were studied between left ventricular and body size variables. Stepwise multiple linear regression was performed to determine the best determinants of LV variables. LVM and LVEDD had a significant relation with FFM (P<0.001) and BSA (p<0.05). Left ventricle posterior wall thickness (PWT) had a significant relation with BSA (p<0.001) and FFM (p<0.005). No relation was found between heart's structural variable (LVM, LVEDD, LVESD and PWT) and FM. Using a multivariate regression analysis, FFM was the only independent predictor of both LVM (R2=0.541, P<0.001) and LVEDD (R2=0.189, P<0.05). These results suggest that Correction of LVM and LVEDD by FFM in athletes may be more appropriate than other measures of body size for indexing absolute amounts of LV dimension. Yet further researches in other athletes are required to confirm these findings.


Economic development, flow of funds, and the equilibrium interaction of financial frictions.
We use a variety of different datasets from Thailand to study not only the extremes of micro and macro variables but also within-country flow of funds and labor migration. We develop a general equilibrium model that encompasses regional variation in the type of financial friction and calibrate it to measured variation in regional aggregates. The model predicts substantial capital and labor flows from rural to urban areas even though these differ only in the underlying financial regime. Predictions for micro variables not used directly provide a model validation. Finally, we estimate the impact of a policy of counterfactual, regional isolationism.


Bayesian population decoding of spiking neurons.
The timing of action potentials in spiking neurons depends on the temporal dynamics of their inputs and contains information about temporal fluctuations in the stimulus. Leaky integrate-and-fire neurons constitute a popular class of encoding models, in which spike times depend directly on the temporal structure of the inputs. However, optimal decoding rules for these models have only been studied explicitly in the noiseless case. Here, we study decoding rules for probabilistic inference of a continuous stimulus from the spike times of a population of leaky integrate-and-fire neurons with threshold noise. We derive three algorithms for approximating the posterior distribution over stimuli as a function of the observed spike trains. In addition to a reconstruction of the stimulus we thus obtain an estimate of the uncertainty as well. Furthermore, we derive a 'spike-by-spike' online decoding scheme that recursively updates the posterior with the arrival of each new spike. We use these decoding rules to reconstruct time-varying stimuli represented by a Gaussian process from spike trains of single neurons as well as neural populations.


Momentum space analysis of multiphoton double ionization of helium by intense attosecond xuv pulses.
We investigate the momentum and energy distributions of the two electrons in multiphoton double ionization of He by intense attosecond xuv pulses, based on a two-dimensional model. Two different patterns of the momentum distributions are identified, corresponding to the uncorrelated and correlated channels, respectively. Our analysis of the electron correlations focuses on two-photon and three-photon double ionization processes for different pulse durations and for different time delays after the pulses. For both two-photon and three-photon cases, a clear correlation valley in energy distributions is found when both electrons are ejected in opposite directions. This is mostly attributed to the electron correlations during the ionization of the first electron. We also find that when two electrons are ejected in the same direction, their Coulomb repulsion has an significant influence on the electron energy distributions during the postionization stage. Finally, in the case of three photon double ionization, we observe that the effects of the Coulomb repulsion become much more complicated, and a new catch-up collision phenomena is observed in the energy distributions.


Danish children born with glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies at birth had an increased risk to develop type 1 diabetes.
A large, population-based case-control cohort was used to test the hypothesis that glutamic acid decarboxylase-65 (GAD65) and islet antigen-2 autoantibodies (IA-2A) at birth predict type 1 diabetes. The design was an individually matched case-control study of all Danish type 1 diabetes patients born between 1981 and 2002 and diagnosed before May 1 2004 (median age at diagnosis was 8.8 years). Dried blood spot samples collected 5 days after birth in the 1981-2002 birth cohorts and stored at -25 °C were identified from 2023 patients and from two matched controls (n = 4042). Birth data and information on parental age and diabetes were obtained from Danish registers. GAD65A and IA-2A were determined in a radiobinding assay. HLA-DQB1 alleles were analyzed by PCR using time-resolved fluorescence. GAD65A and IA-2A were found in 70/2023 (3.5%) patients compared to 21/4042 (0.5%) controls resulting in a hazard ratio (HR) of 7.49 (P < 0.0001). The HR decreased to 4.55 but remained significant (P < 0.0003) after controlling for parental diabetes and HLA-DQB1 alleles. Conditional logistic regression analysis showed a HR of 2.55 (P < 0.0001) for every tenfold increase in the levels of GAD65A and IA-2A. This HR decreased to 1.93 but remained significant (P < 0.001) after controlling for parental diabetes and HLA-DQB1 alleles. These data suggest that GAD65A and IA-2A positivity at birth are associated with an increased risk of developing type 1 diabetes in Danish children diagnosed between 1981 and 2004.


Graphene growth by molecular beam epitaxy: an interplay between desorption, diffusion and intercalation of elemental C species on islands.
The growth of graphene by molecular beam epitaxy from an elemental carbon precursor is a very promising technique to overcome some of the main limitations of the chemical vapour deposition approach, such as the possibility to synthesize graphene directly on a wide variety of surfaces including semiconductors and insulators. However, while the individual steps of the chemical vapour deposition growth process have been extensively studied for several surfaces, such knowledge is still missing for the case of molecular beam epitaxy, even though it is a key ingredient to optimise its performance and effectiveness. In this work, we have performed a combined experimental and theoretical study comparing the growth rate of the molecular beam epitaxy and chemical vapour deposition processes on the prototypical Ir (111) surface. In particular, by employing high-resolution fast X-ray photoelectron spectroscopy, we were able to follow the growth of both single- and multi-layer graphene in real time, and to identify the spectroscopic fingerprints of the different C layers. Our experiments, supported by density functional theory calculations, highlight the role of the interaction between different C precursor species and the growing graphene flakes on the growth rate of graphene. These results provide an overview of the main differences between chemical vapour deposition and molecular beam epitaxy growth and thus on the main parameters which can be tuned to optimise growth conditions.


Regulation of breast cancer cell cycle progression by growth factors, steroids and steroid antagonists.
The control of human breast cancer cell proliferation in vitro is known to involve complex interactions between steroid hormones, peptide hormones and growth factors. Little is known, however, of the mechanisms by which these factors, alone or in combination, control cell cycle progression and the expression of specific genes involved in cell cycle control. A pre-requisite for such studies is a cellular system in which non-proliferating or slowly proliferating cells can be maintained in a defined environment and stimulated to progress through the cell cycle by addition of hormones and growth factors. Such a system has been developed for T-47D human breast cancer cells: quiescent or slowly proliferating cells maintained in a serum-free medium can be stimulated to increase their rate of cell cycle progression upon a single addition of insulin, IGF-I, EGF, TGF alpha or bFGF. Oestradiol alone was ineffective but caused a significant increase in % S phase cells when added in the presence of insulin. Progestins, in the presence of absence of insulin, had a biphasic effect with an initial increase in cell cycle progression followed by cell cycle arrest. Both antioestrogens and the antiprogestin, RU 486, in the absence of oestrogen or progestin, were potent inhibitors of insulin-induced proliferation. Increases in cell cycle progression were invariably accompanied by acute increases in c-fos and c-myc mRNA levels. Induction of c-myc by oestrogen and progestin was inhibited by antioestrogens and RU 486, respectively. These data illustrate that the culture of breast cancer cells in a serum-free, chemically defined environment provides an excellent model in which to define the role of individual factors involved in breast cancer growth control. The biological data derived from this system provide a basis for identifying and characterizing genes involved in the control of cell cycle progression in human breast cancer.


Enhanced Chromatographic Determination of Nicotine in Human Plasma: Applied to Human Volunteers.
Development of enhanced UPLC-UV method for determination of nicotine in human plasma was achieved on a Symmetry(®) C18 column (100 mm × 2.1 mm, 2.2 μm) applying isocratic elution based on Methanol: Acetonitrile: Phosphate Buffer (pH: 2.7) with the ratio (20:30:50, v/v/v) as a mobile phase. The ultraviolet detector was operated at 260 nm. The mobile phase was pumped through the column at a flow rate of 0.2 mL min(-1). The column temperature was adjusted to 50ºC and the injection volume was 2 μL. Quinine was selected as an internal standard (IS) due to its structure similarity to nicotine having basic pyridine ring to optimize the liquid liquid extraction procedure using diethyl ether coupled with vacuum evaporation at 40°C. Validation parameters for nicotine were found to be acceptable over the concentration range of 2.5-50 ng ml(-1). The application of the proposed method on four healthy human volunteers was approved by the ethical committee. The study was carried out under fasting conditions and the concerned subjects were informed about the objectives and possible risks involved in the study. The proposed method proved to be simple and fast which is a major advantage to analyze large number of samples per day using the accelerated vacuum evaporation technique. The method showed satisfactory data for all the parameters tested within the limits for bioanalytical assays. The lower limit of quantification (LLOQ) permits the application of the method for further pharmacological and clinical studies.


Does coffee enriched with chlorogenic acids improve mood and cognition after acute administration in healthy elderly? A pilot study.
Caffeine exerts positive effects on cognitive and behavioral processes, especially in sub-optimal conditions when arousal is low. Apart from caffeine, coffee contains other compounds including the phenolic compounds ferulic acid, caffeic acid, and the chlorogenic acids, which have purported antioxidant properties. The chlorogenic acids are the most abundant family of compounds found in coffee, yet their effects on cognition and mood have not been investigated. This study aims to ascertain whether a coffee rich in chlorogenic acid modulates brain function. The present pilot study examined the acute effects of decaffeinated coffee with regular chlorogenic acid content and decaffeinated coffee with high chlorogenic acid content on mood and cognitive processes, as measured by behavioral tasks and event-related potentials (ERPs). Performance and ERP responses to a battery of cognitive tasks were recorded at baseline and following the equivalent of three cups of coffee in a randomized, double-blind, crossover study of 39 healthy older participants. Compared with the decaffeinated coffee with regular chlorogenic acid and placebo, caffeinated coffee showed a robust positive effect on higher-level mood and attention processes. To a lesser extent, the decaffeinated coffee high in chlorogenic acid also improved some mood and behavioral measures, relative to regular decaffeinated coffee. Our pilot results suggest that non-caffeine compounds in coffee such as the chlorogenic acids may be capable of exerting some acute behavioral effects, thus warranting further investigation.


Structural Effects in Visible-Light-Responsive Metal-Organic Frameworks Incorporating ortho-Fluoroazobenzenes.
The ability to control the interplay of materials with low-energy photons is important as visible light offers several appealing features compared to ultraviolet radiation (less damaging, more selective, predominant in the solar spectrum, possibility to increase the penetration depth). Two different metal-organic frameworks (MOFs) were synthesized from the same linker bearing all-visible ortho-fluoroazobenzene photoswitches as pendant groups. The MOFs exhibit different architectures that strongly influence the ability of the azobenzenes to isomerize inside the voids. The framework built with Al-based nodes has congested 1D channels that preclude efficient isomerization. As a result, local light-heat conversion can be used to alter the CO2 adsorption capacity of the material on exposure to green light. The second framework, built with Zr nodes, provides enough room for the photoswitches to isomerize, which leads to a unique bistable photochromic MOF that readily responds to blue and green light. The superiority of green over UV irradiation was additionally demonstrated by reflectance spectroscopy and analysis of digested samples. This material offers promising perspectives for liquid-phase applications such as light-controlled catalysis and adsorptive separation.


PFN2 and NAA80 cooperate to efficiently acetylate the N-terminus of actin.
The actin cytoskeleton is of profound importance to cell shape, division, and intracellular force generation. Profilins bind to globular (G-)actin and regulate actin filament formation. Although profilins are well-established actin regulators, the distinct roles of the dominant profilin, profilin 1 (PFN1), versus the less abundant profilin 2 (PFN2) remain enigmatic. In this study, we use interaction proteomics to discover that PFN2 is an interaction partner of the actin N-terminal acetyltransferase NAA80, and further confirm this by analytical ultracentrifugation. Enzyme assays with NAA80 and different profilins demonstrate that PFN2 binding specifically increases the intrinsic catalytic activity of NAA80. NAA80 binds PFN2 through a proline-rich loop, deletion of which abrogates PFN2 binding. Small-angle X-ray scattering shows that NAA80, actin, and PFN2 form a ternary complex and that NAA80 has partly disordered regions in the N-terminus and the proline-rich loop, the latter of which is partly ordered upon PFN2 binding. Furthermore, binding of PFN2 to NAA80 via the proline-rich loop promotes binding between the globular domains of actin and NAA80, and thus acetylation of actin. However, the majority of cellular NAA80 is stably bound to PFN2 and not to actin, and we propose that this complex acetylates G-actin before it is incorporated into filaments. In conclusion, we reveal a functionally specific role of PFN2 as a stable interactor and regulator of the actin N-terminal acetyltransferase NAA80, and establish the modus operandi for NAA80-mediated actin N-terminal acetylation, a modification with a major impact on cytoskeletal dynamics.


Validity and Reliability of A-Mode Ultrasound for Body Composition Assessment of NCAA Division I Athletes.
This study evaluated the validity and reliability of the BodyMetrix™ BX2000 A-mode ultrasound for estimating percent body fat (%BF) in athletes by comparing it to skinfolds and the BOD POD. Forty-five (22 males, 23 females) National Collegiate Athletic Association (NCAA) Division-I athletes volunteered for this study. Subjects were measured once in the BOD POD then twice by two technicians for skinfolds and ultrasound. A one-way repeated-measures ANOVA revealed significant differences between body composition methods (F = 13.24, p < 0.01, η² = 0.24). This difference was further explained by a sex-specific effect such that the mean difference between ultrasound and BOD POD was large for females (~ 5% BF) but small for males (~ 1.5% BF). Linear regression using the %BF estimate from ultrasound to predict %BF from BOD POD resulted in an R2 = 0.849, SEE = 2.6% BF and a TE = 4.4% BF. The inter-rater intraclass correlation (ICC) for skinfold was 0.966 with a large 95% confidence interval (CI) of 0.328 to 0.991. The inter-rater ICC for ultrasound was 0.987 with a much smaller 95% CI of 0.976 to 0.993. Both skinfolds and ultrasound had test-retest ICCs ≥ 0.996. The BX2000 ultrasound device had excellent test-retest reliability, and its inter-rater reliability was superior to the skinfold method. The validity of this method is questionable, particularly for female athletes. However, due to its excellent reliability, coaches and trainers should consider this portable and easy to use A-mode ultrasound to assess body composition changes in athletes.


A low-cost instrumented spatial linkage accurately determines ASIS position during cycle ergometry.
The purpose of this study was to develop and evaluate an alternative method for determining the position of the anterior superior iliac spine (ASIS) during cycling. The approach used in this study employed an instrumented spatial linkage (ISL) system to determine the position of the ASIS in the parasagittal plane. A two-segment ISL constructed using aluminum segments, bearings, and digital encoders was tested statically against a calibration plate and dynamically against a video-based motion capture system. Four well-trained cyclists provided data at three pedaling rates. Statically, the ISL had a mean horizontal error of 0.03 +/- 0.21 mm and a mean vertical error of -0.13 +/- 0.59 mm. Compared with the video-based motion capture system, the agreement of the location of the ASIS had a mean error of 0.30 +/- 0.55 mm for the horizontal dimension and -0.27 +/- 0.60 mm for the vertical dimension. The ISL system is a cost-effective, accurate, and valid measure for two-dimensional kinematic data within a range of motion typical for cycling.


Newly identified patterns of Pax2 expression in the developing mouse forebrain.
The availability of specific markers expressed in different regions of the developing nervous system provides a useful tool for the study of mouse mutants. One such marker, the transcription factor Pax2, is expressed at the midbrain-hindbrain boundary and in the cerebellum, spinal cord, retina, optic stalk, and optic chiasm. We recently described a group of diencephalic cells that express Pax2 as early as embryonic day (E) 10.5, and become part of the eminentia thalami by E11.5. The discovery of this previously undescribed cell population prompted us to examine Pax2 protein expression in the developing mouse forebrain in more detail. We determined the expression pattern of Pax2 in the forebrain of wild type mouse embryos between E10.5 and postnatal day (P) 15. Pax2 expression was detected in the septum of the basal forebrain, hypothalamus, eminentia thalami and in the subfornical organ. To evaluate Pax2 as a marker for septal cells, we examined Pax2 expression in Pax6Sey/Sey mutants, which have an enlarged septum. We found that Pax2 clearly marks a population of septal cells equivalent to that seen in wild types, indicating its utility as a marker of septal identity. These cells did not express the GABAergic marker calbindin nor the cholinergic marker choline acetyltransferase and were not detectable after P15. Pax2 is expressed in populations of cells within the developing septum, hypothalamus, and eminentia thalami. It seems especially useful as a marker of the telencephalic septum, because of its early, strong and characteristic expression in this structure. Further, its expression is maintained in the enlarged septum of Pax6Sey/Sey mutants.


Signature wood modifications reveal decomposer community history.
Correlating plant litter decay rates with initial tissue traits (e.g. C, N contents) is common practice, but in woody litter, predictive relationships are often weak. Variability in predicting wood decomposition is partially due to territorial competition among fungal decomposers that, in turn, have a range of nutritional strategies (rot types) and consequences on residues. Given this biotic influence, researchers are increasingly using culture-independent tools in an attempt to link variability more directly to decomposer groups. Our goal was to complement these tools by using certain wood modifications as 'signatures' that provide more functional information about decomposer dominance than density loss. Specifically, we used dilute alkali solubility (DAS; higher for brown rot) and lignin:density loss (L:D; higher for white rot) to infer rot type (binary) and fungal nutritional mode (gradient), respectively. We first determined strength of pattern among 29 fungi of known rot type by correlating DAS and L:D with mass loss in birch and pine. Having shown robust relationships for both techniques above a density loss threshold, we then demonstrated and resolved two issues relevant to species consortia and field trials, 1) spatial patchiness creating gravimetric bias (density bias), and 2) brown rot imprints prior or subsequent to white rot replacement (legacy effects). Finally, we field-tested our methods in a New Zealand Pinus radiata plantation in a paired-plot comparison. Overall, results validate these low-cost techniques that measure the collective histories of decomposer dominance in wood. The L:D measure also showed clear potential in classifying 'rot type' along a spectrum rather than as a traditional binary type (brown versus white rot), as it places the nutritional strategies of wood-degrading fungi on a scale (L:D=0-5, in this case). These information-rich measures of consequence can provide insight into their biological causes, strengthening the links between traits, structure, and function during wood decomposition.


Updates in Rhea: SPARQLing biochemical reaction data.
Rhea (http://www.rhea-db.org) is a comprehensive and non-redundant resource of over 11 000 expert-curated biochemical reactions that uses chemical entities from the ChEBI ontology to represent reaction participants. Originally designed as an annotation vocabulary for the UniProt Knowledgebase (UniProtKB), Rhea also provides reaction data for a range of other core knowledgebases and data repositories including ChEBI and MetaboLights. Here we describe recent developments in Rhea, focusing on a new resource description framework representation of Rhea reaction data and an SPARQL endpoint (https://sparql.rhea-db.org/sparql) that provides access to it. We demonstrate how federated queries that combine the Rhea SPARQL endpoint and other SPARQL endpoints such as that of UniProt can provide improved metabolite annotation and support integrative analyses that link the metabolome through the proteome to the transcriptome and genome. These developments will significantly boost the utility of Rhea as a means to link chemistry and biology for a more holistic understanding of biological systems and their function in health and disease.


Concurrent validity studies of blood pressure instrumentation. The Philadelphia Blood Pressure Project.
There is increasing evidence that blood pressure (BP) screening during adolescence may detect early evidence of hypertensive disease. Choice of instrumentation becomes important to maximize the accuracy and interpretive value of several serial readings. We therefore conducted two studies of adolescents, comparing auscultatory (Baumanometer and Random-zero), ultrasonic (Arteriosonde 1216), and infrasonic (Physiometrics SR-2) devices. These instruments were compared serially (Study 1) for older adolescents (n = 48). The Baumanometer, Arteriosonde 1216, and Physiometrics SR-2 were compared both serially and simultaneously (Study 2) for younger and older adolescents (n = 24). In both studies, the order of device presentation was completely counterbalanced. In Study 1, reliability estimates were high (r greater than 0.65), with the exception of the Arteriosonde 1216 diastolic readings, and the Physiometrics SR-2 yielded significantly lower mean diastolic BP readings than the other devices. Diastolic Phase V readings taken with the Random-zero were significantly higher when the Random-zero was presented at the end of the sequence of instrument presentation. This order of presentation effect is probably attributable to the need for overinflation when using the Random-zero device and may cause an overestimation of diastolic BP in the young. In Study 2, again the Arteriosonde 1216 did not perform reliably in recording diastolic BP. Further, the Physiometrics SR-2 device, although reliable, yielded diastolic readings significantly lower (p less than 0.001) than diastolic Phase IV readings taken both serially and simultaneously.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of Retinoblastoma Protein Family (Rb/p105 and Rb2/p130) Expression in the Histopathological Classification of Borderline Ovarian Tumors.
Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. The identification of valuable markers for the diagnosis and classification of these tumors is in need. Among the molecular candidates, the Retinoblastoma (Rb) family members Rb/p105 and Rb2/p130 seem to play a pivotal role in ovarian cancer. In particular, Rb/p105, when in the unphosphorylated form, acts as a growth suppressor controlling cell cycle and tumor progression; whereas, the phosphorylated form activates gene transcription and cellular proliferation. While Rb/p105 is ubiquitously confined to the nuclei of cycling and quiescent cells, Rb2/p130 activity is also regulated by intracellular localization. According to this, Rb family members could represent a novel marker in diagnosis and classification risk for patients with BOT. In this study, we evaluated the expression and subcellular localization of proteins of the retinoblastoma (Rb) gene family in 65 ovarian borderline tumors. Statistically significant differences were found in nuclear and cytoplasmic expressions of Rb/p105 and Rb2/p130 according to different examined histotypes. In detail, the nuclear expression of Rb/p105 and Rb2/p130 was more frequently detected in serous (84.6%) than sero-mucinous (42.1%) and mucinous (50%) types. Conversely, the cytoplasmic expression of Rb2/p130 was not detected in serous tumors and frequently observed in mucinous subtypes (80%). Our findings suggest that Rb proteins do not play a key role in the tumor progression of serous borderline tumors since any cases showed cytoplasmic localization. By contrast, the observed higher cytoplasmic expression of Rb2/p130 in intestinal mucinous BOTs is indicative of Rb protein family involvement in the cancerogenesis pathway of mucinous ovarian tumors. Also, mucinous BOTs of intestinal-type, exhibiting low nuclear and high cytoplasmic levels of Rb2/p130 might potentially be considered a high-risk category of malignant evolution. Further studies on larger series are needed to clarify how BOTs could be stratified in different prognostic groups according to their Rb proteins immunohistochemical profile.


Co-enzyme Q10 supplementation for the primary prevention of cardiovascular disease.
Cardiovascular disease (CVD) remains the number one cause of death and disability worldwide and public health interventions focus on modifiable risk factors, such as diet. Coenzyme Q10 (CoQ10) is an antioxidant that is naturally synthesised by the body and can also be taken as a dietary supplement. Studies have shown that a CoQ10 deficiency is associated with cardiovascular disease. To determine the effects of coenzyme Q10 supplementation as a single ingredient for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 11); MEDLINE (Ovid, 1946 to November week 3 2013); EMBASE (Ovid, 1947 to 27 November 2013) and other relevant resources on 2 December 2013. We applied no language restrictions. Randomised controlled trials (RCTs) lasting at least three months involving healthy adults or those at high risk of CVD but without a diagnosis of CVD. Trials investigated the supplementation of CoQ10 alone as a single supplement. The comparison group was no intervention or placebo. The outcomes of interest were CVD clinical events and major CVD risk factors, adverse effects and costs. We excluded any trials involving multifactorial lifestyle interventions to avoid confounding. Two authors independently selected trials for inclusion, abstracted data and assessed the risk of bias.We contacted authors for additional information where necessary. We identified six RCTs with a total of 218 participants randomised, one trial awaiting classification and five ongoing trials. All trials were conducted in participants at high risk of CVD, two trials examined CoQ10 supplementation alone and four examined CoQ10 supplementation in patients on statin therapy; we analysed these separately. All six trials were small-scale, recruiting between 20 and 52 participants; one trial was at high risk of bias for incomplete outcome data and one for selective reporting; all studies were unclear in the method of allocation and therefore for selection bias. The dose of CoQ10 varied between 100 mg/day and 200 mg/day and the duration of the interventions was similar at around three months.No studies reported mortality or non-fatal cardiovascular events. None of the included studies provided data on adverse events.Two trials examined the effect of CoQ10 on blood pressure. For systolic blood pressure we did not perform a meta-analysis due to significant heterogeneity. In one trial CoQ10 supplementation had no effect on systolic blood pressure (mean difference (MD) -1.90 mmHg, 95% confidence interval (CI) -13.17 to 9.37, 51 patients randomised). In the other trial there was a statistically significant reduction in systolic blood pressure (MD -15.00 mmHg, 95% CI -19.06 to -10.94, 20 patients randomised). For diastolic blood pressure we performed a random-effects meta-analysis, which showed no evidence of effect of CoQ10 supplementation when these two small trials were pooled (MD -1.62 mmHg, 95% CI -5.2 to 1.96).One trial (51 patients randomised) looked at the effect of CoQ10 on lipid levels. The trial showed no evidence of effect of CoQ10 supplementation on total cholesterol (MD 0.30 mmol/L, 95% CI -0.10 to 0.70), high-density lipoprotein (HDL)-cholesterol (MD 0.02 mmol/L, 95% CI -0.13 to 0.17) or triglycerides (MD 0.05 mmol/L, 95% CI -0.42 to 0.52).Of the four trials that investigated CoQ10 supplementation in patients on statin therapy, three of them showed that simultaneous administration of CoQ10 did not significantly influence lipid levels or systolic blood pressure levels between the two groups. The fourth trial showed a significant increase in the change in total and low-density lipoprotein (LDL)-cholesterol at three months across the four arms of the trial (α-tocopherol, CoQ10, CoQ10 + α-tocopherol and placebo), however the way in which the data were presented meant that we were unable to determine if there was any significant difference between the CoQ10 only and placebo arms. In contrast, there was no significant difference in the change in HDL-cholesterol and triglycerides after three months between the four arms of the trial. There are very few studies to date examining CoQ10 for the primary prevention of CVD. The results from the ongoing studies will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution and further high quality trials with longer-term follow-up are needed to determine the effects on cardiovascular events.


The global trace graph, a novel paradigm for searching protein sequence databases.
Propagating functional annotations to sequence-similar, presumably homologous proteins lies at the heart of the bioinformatics industry. Correct propagation is crucially dependent on the accurate identification of subtle sequence motifs that are conserved in evolution. The evolutionary signal can be difficult to detect because functional sites may consist of non-contiguous residues while segments in-between may be mutated without affecting fold or function. Here, we report a novel graph clustering algorithm in which all known protein sequences simultaneously self-organize into hypothetical multiple sequence alignments. This eliminates noise so that non-contiguous sequence motifs can be tracked down between extremely distant homologues. The novel data structure enables fast sequence database searching methods which are superior to profile-profile comparison at recognizing distant homologues. This study will boost the leverage of structural and functional genomics and opens up new avenues for data mining a complete set of functional signature motifs. http://www.bioinfo.biocenter.helsinki.fi/gtg. Supplementary data are available at Bioinformatics online.


Quantitative differentiation between healthy and disordered brain matter in patients with neurofibromatosis type I using diffusion tensor imaging.
Hyperintensities on T2-weighted images are seen in the brains of most patients with neurofibromatosis type I (NF-1), but the origin of these unidentified bright objects (UBOs) remains obscure. In the current study, we examined the diffusion characteristics of brain tissue in children with NF-1 to test the hypothesis that a microstructural abnormality is present in NF-1. Diffusion tensor imaging (DTI) was performed in 50 children with NF-1 and 8 controls. Circular regions of interest were manually placed in 7 standardized locations in both hemispheres, including UBO sites. Apparent diffusion coefficients (ADC), fractional anisotropy (FA), and axial anisotropy (A(m)) were used to differentiate quantitatively between healthy and disordered brain matter. Differences in eigenvalues (lambda(1), lambda(2), lambda(3)) were determined to examine parenchymal integrity. We found higher ADC values for UBOs than for normal-appearing sites (P < .01) and higher ADC values for normal-appearing sites than for controls (P < .04 in 5 of 7 regions). In most regions, we found no differences in FA or A(m). Eigenvalues lambda(2) and lambda(3) were higher at UBO sites than in normal-appearing sites (P < .04). With ADC, it was possible to differentiate quantitatively between normal- and abnormal-appearing brain matter in NF-1 and also between normal-appearing brain matter in NF-1 and healthy brain matter in controls, indicating subtle pathologic damage disrupting the tissue microstructure in the NF-1 brain. Higher diffusivity for lambda(1), lambda(2), and lambda(3) indicates that this disturbance of microstructure is caused by accumulation of fluid or vacuolation.


Structural hierarchy governs fibrin gel mechanics.
Fibrin gels are responsible for the mechanical strength of blood clots, which are among the most resilient protein materials in nature. Here we investigate the physical origin of this mechanical behavior by performing rheology measurements on reconstituted fibrin gels. We find that increasing levels of shear strain induce a succession of distinct elastic responses that reflect stretching processes on different length scales. We present a theoretical model that explains these observations in terms of the unique hierarchical architecture of the fibers. The fibers are bundles of semiflexible protofibrils that are loosely connected by flexible linker chains. This architecture makes the fibers 100-fold more flexible to bending than anticipated based on their large diameter. Moreover, in contrast with other biopolymers, fibrin fibers intrinsically stiffen when stretched. The resulting hierarchy of elastic regimes explains the incredible resilience of fibrin clots against large deformations.


Establishing nurse-led active surveillance for men with localised prostate cancer: development and formative evaluation of a model of care in the ProtecT trial.
To develop a nurse-led, urologist-supported model of care for men managed by active surveillance or active monitoring (AS/AM) for localised prostate cancer and provide a formative evaluation of its acceptability to patients, clinicians and nurses. Nurse-led care, comprising an explicit nurse-led protocol with support from urologists, was developed as part of the AM arm of the Prostate testing for cancer and Treatment (ProtecT) trial. Interviews and questionnaire surveys of clinicians, nurses and patients assessed acceptability. Nurse-led clinics were established in 9 centres in the ProtecT trial and compared with 3 non-ProtecT urology centres elsewhere in UK. Within ProtecT, 22 men receiving AM nurse-led care were interviewed about experiences of care; 11 urologists and 23 research nurses delivering ProtecT trial care completed a questionnaire about its acceptability; 20 men managed in urology clinics elsewhere in the UK were interviewed about models of AS/AM care; 12 urologists and three specialist nurses working in these clinics were also interviewed about management of AS/AM. Nurse-led care was commended by ProtecT trial participants, who valued the flexibility, accessibility and continuity of the service and felt confident about the quality of care. ProtecT consultant urologists and nurses also rated it highly, identifying continuity of care and resource savings as key attributes. Clinicians and patients outside the ProtecT trial believed that nurse-led care could relieve pressure on urology clinics without compromising patient care. The ProtecT AM nurse-led model of care was acceptable to men with localised prostate cancer and clinical specialists in urology. The protocol is available for implementation; we aim to evaluate its impact on routine clinical practice. NCT02044172; ISRCTN20141297.


Cross-trimester repeated measures testing for Down's syndrome screening: an assessment.
To provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein A (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution.


Long-term exposure to sensory feed additives during the gestational and postnatal periods affects sows' colostrum and milk sensory profiles, piglets' growth, and feed intake.
This study investigated the effect of feed supplementation in sows and/or their progeny with 2 sensory feed additives (FA1: limonene and cinnamaldehyde; FA2: menthol, carvone, and anethole) on sows' feed intake, body weight, fat deposition, and colostrum/milk composition, as well as piglets' feed intake growth and feed efficiency from birth to slaughter at postnatal day 160 (PND160). During the last third of gestation and the whole of lactation, sows were subjected to a control diet (C) or the same diet containing FA1 or FA2 at 0.1% of complete feed content. Colostrum/milk samples were taken at days 1, 14, and 28 of lactation for gas chromatography-mass spectrometry analyses. After weaning, the progeny was subjected to a control diet (C) or experimental diets with a sweetener (0.015%) but no other additive (S), or to diets with a sweetener and the additive FA1 (FA1S) or FA2 (FA2S). There was no effect of dietary treatment on sows' feed intake, body weight, or adiposity (P > 0.15 for all), but the sensory characteristics of their colostrum/milk were modified by the diet and diet*time interaction. Limonene concentrations were higher in FA1 samples from PND1 to PND28, whereas carvone and anethole concentrations were higher in FA2 samples from PND1 to PND28. The concentration of these 3 compounds increased with time in the respective groups where they were mostly detected. Menthol concentrations were higher in FA2 samples at PND14 and PND28, but there was no time effect. Overall, cinnamaldehyde was always below the detection range. Piglets born from FA1 and FA2 sows had higher body weight (P = 0.034 at PND160), average daily gain (ADG; P = 0.036 for PND0-160), and average daily feed intake (ADFI; P = 0.006 for PND28-160) than piglets born from C sows. Overall, piglets that were never exposed to FA or only after weaning had lower ADG (P = 0.030 for PND0-160) and ADFI (P = 0.016 for PND28-160) than piglets that were exposed to FA only via the maternal diet, the condition combining both pre- and post-natal exposure being intermediary. In conclusion, FA1 and FA2 provided to gestating and lactating sows increased the progeny's feed intake and growth, suggesting nutritional programming and/or sensory conditioning during the perinatal period. Addition of FA only in the progeny's diet was not beneficial.


Plasma levels of IL-6 in patients with untreated major depressive disorder: comparison with catecholamine metabolites.
IL-6 and catecholamines play roles in the pathophysiology of major depressive disorder (MDD). The present study investigated associations between plasma IL-6 and plasma catecholamine metabolites in patients with MDD. A total of 148 patients (male/female 65/83, age 49.5±12.1 years) who met the criteria for MDD based on the Diagnostic and Statistical Manual of Mental Disorders IV and 40 participants as healthy controls (HC; male/female 23/17, age 44.0±10.5 years) were enrolled in the present study. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were analyzed using high-performance liquid chromatography, and plasma IL-6 levels were measured using ELISA. No correlations were observed among plasma IL-6 levels, MHPG levels, and HVA levels in patients with MDD. Plasma IL-6 levels in patients with MDD were significantly higher than in the HC. A positive correlation was found between plasma IL-6 levels and Hamilton Rating Scale for Depression-17 scores. No correlations existed between plasma IL-6 levels and plasma catecholamine metabolite levels in patients with MDD, and the severity of depressive state was related to plasma IL-6 levels in MDD.


Evaluation of apolipoproteins A-I and B as markers of angiographically assessed coronary artery disease.
The aim of this study was to evaluate the ability of plasma levels of apo A-I and apo B to discriminate between male patients with and without angiographically determined coronary artery disease (CAD) in comparison to the levels of cholesterol, HDL-cholesterol and triglycerides. The plasma apo A-I and B levels were measured by a radial immunodiffusion assay that made use of well characterized monoclonal antibodies. Univariate statistical analysis showed that the mean values for HDL-cholesterol and apo A-I were significantly lower in patients with single-, double- and triple-vessel disease than in the control subjects. The mean values for plasma cholesterol and apo B were significantly higher in the group with double- and triple-, but not single-vessel disease, than in the group without CAD. No statistically significant difference among groups was found for plasma triglyceride values. Since the considered variables failed to assess the severity of the disease, as determined by the number of vessels involved, the 3 groups of patients with CAD were combined into one group. A multiple logistic analysis, performed in order to assess the independent role of the variables and to estimate the corresponding odds ratio, indicated an independent association of HDL-cholesterol, apo A-I and apo B with CAD. When the multiple logistic analysis was repeated with a stepwise procedure, only apo A-I and B entered into the model. The results of our study indicate that plasma levels of apo A-I and B are more useful than plasma lipid in detecting the presence or absence of coronary artery disease in a group of male patients undergoing coronary angiography.


Transfer of radionuclides in aquatic ecosystems--default concentration ratios for aquatic biota in the Erica Tool.
The process of assessing risk to the environment following a given release of radioactivity requires the quantification of activity concentrations in environmental media and reference organisms. The methodology adopted by the ERICA Integrated Approach involves the application of concentration ratios (CR values) and distribution coefficients (K(d) values) for aquatic systems. Within this paper the methodologies applied to derive default transfer parameters, collated within the ERICA Tool databases, are described to provide transparency and traceability in the documentation process. Detailed information is provided for the CR values used for marine and freshwater systems. Of the total 372 CR values derived for the marine ecosystem, 195 were identified by literature review. For the freshwater system, the number of values based on review was less, but still constituted 129 from a total of 372 values. In both types of aquatic systems, 70-80% of the data gaps have been filled by employing "preferable" approaches such as those based on substituting values from taxonomically similar organisms or biogeochemically similar elements.


HOG on the promoter: regulation of the osmotic stress response.
Members of the mitogen-activated protein (MAP) kinase family regulate transcription through phosphorylation of specific transcription factors. New studies indicate that this process may be more complex than previously anticipated. The yeast Hog1 protein kinase (a homolog of the mammalian p38 MAP kinase) interacts with transcription factors and perhaps with the general transcription machinery at target promoters. Chellappan discusses the recent results and their implications for understanding control of transcription by stress-activated MAP kinases.


Failed awake craniotomy: a retrospective analysis in 424 patients undergoing craniotomy for brain tumor.
Awake craniotomy for removal of intraaxial tumors within or adjacent to eloquent brain regions is a well-established procedure. However, awake craniotomy failures have not been well characterized. In the present study, the authors aimed to analyze and assess the incidence and causes for failed awake craniotomy. The database of awake craniotomies performed at Tel Aviv Medical Center between 2003 and 2010 was reviewed. Awake craniotomy was considered a failure if conversion to general anesthesia was required, or if adequate mapping or monitoring could not have been achieved. Of 488 patients undergoing awake craniotomy, 424 were identified as having complete medical, operative, and anesthesiology records. The awake craniotomies performed in 27 (6.4%) of these 424 patients were considered failures. The main causes of failure were lack of intraoperative communication with the patient (n = 18 [4.2%]) and/or intraoperative seizures (n = 9 [2.1%]). Preoperative mixed dysphasia (p < 0.001) and treatment with phenytoin (p = 0.0019) were related to failure due to lack of communication. History of seizures (p = 0.03) and treatment with multiple antiepileptic drugs (p = 0.0012) were found to be related to failure due to intraoperative seizures. Compared with the successful awake craniotomy group, a significantly lower rate of gross-total resection was achieved (83% vs 54%, p = 0.008), there was a higher incidence of short-term speech deterioration postoperatively (6.1% vs 23.5%, p = 0.0017) as well as at 3 months postoperatively (2.3% vs 15.4%, p = 0.0002), and the hospitalization period was longer (4.9 ± 6.2 days vs 8.0 ± 10.1 days, p < 0.001). Significantly more major complications occurred in the failure group (4 [14.8%] of 27) than in the successful group (16 [4%] of 397) (p = 0.037). Failures of awake craniotomy were associated with a lower incidence of gross-total resection and increased postoperative morbidity. The majority of awake craniotomy failures were preventable by adequate patient selection and avoiding side effects of drugs administered during surgery.


Regulation of Lysosomal Function by the DAF-16 Forkhead Transcription Factor Couples Reproduction to Aging in Caenorhabditis elegans.
Aging in eukaryotes is accompanied by widespread deterioration of the somatic tissue. Yet, abolishing germ cells delays the age-dependent somatic decline in Caenorhabditis elegans In adult worms lacking germ cells, the activation of the DAF-9/DAF-12 steroid signaling pathway in the gonad recruits DAF-16 activity in the intestine to promote longevity-associated phenotypes. However, the impact of this pathway on the fitness of normally reproducing animals is less clear. Here, we explore the link between progeny production and somatic aging and identify the loss of lysosomal acidity-a critical regulator of the proteolytic output of these organelles-as a novel biomarker of aging in C. elegans The increase in lysosomal pH in older worms is not a passive consequence of aging, but instead is timed with the cessation of reproduction, and correlates with the reduction in proteostasis in early adult life. Our results further implicate the steroid signaling pathway and DAF-16 in dynamically regulating lysosomal pH in the intestine of wild-type worms in response to the reproductive cycle. In the intestine of reproducing worms, DAF-16 promotes acidic lysosomes by upregulating the expression of v-ATPase genes. These findings support a model in which protein clearance in the soma is linked to reproduction in the gonad via the active regulation of lysosomal acidification.


Does body mass index impact the early outcome of surgical revascularization? A comparison between off-pump and on-pump coronary artery bypass grafting.
To investigate the effects of body mass index (BMI) on early outcomes after revascularization using either on-pump or off-pump surgery. Data for 3714 of 4314 patients who underwent surgical revascularization at our institution between 1999 and 2008 were analysed. Patients were divided into two groups [off-pump coronary artery bypass (OPCAB); n = 1958 and on-pump coronary artery bypass (ONCAB); n = 1756] and further assigned into five classes according to their BMI (underweight <20 kg/m(2), normal 20-24.99 kg/m(2), overweight 25-29.99 kg/m(2), obese 30-34.99 kg/m(2) and morbidly obese ≥35 kg/m(2)). Thirty-day mortality, occurrence of major adverse cardiac events (MACEs), occurrence of major non-cardiac adverse events (MNCAEs) and length of in-hospital stay were analysed in relation to BMI only (whole cohort analysis), to BMI and chosen surgical method (ONCAB versus OPCAB) as well as confounding factors. In the whole cohort analysis (n = 3714), no significant differences between BMI classes could be identified with regard to 30-day mortality (P = 0.78), MACEs (P = 0.72), MNCAEs (P = 0.45) or length of in-hospital stay (P = 0.94). With increasing BMI values, 30-day mortality tended to steadily increase (1.8% in BMI class 'underweight' vs 2.6% in BMI class 'morbidly obese'; P = 0.78), whereas MNCAEs tended to decrease with an increasing BMI (17.5% in BMI class 'underweight' vs 12.2% in BMI class 'morbidly obese'; P = 0.45). Compared with ONCAB, in patients with higher BMI values, OPCAB appeared to reduce slightly the frequency of 30-day mortality, MACEs and MNCAEs, while slightly increasing the length of in-hospital stay. Adjustment for other risk factors by covariate analysis in multiple regression models did not change the inferences drawn. Our study did not detect significant differences between BMI classes with regard to mortality and morbidity. However, a slight trend towards a steadily increasing short-term mortality was detectable for patients with higher BMI values. When comparing ONCAB versus OPCAB, patients with higher BMI values appeared to have a weak tendency towards a reduced short-term morbidity and mortality in favour of OPCAB.


Visuo-tactile links in covert exogenous spatial attention remap across changes in unseen hand posture.
We investigated the effect of unseen hand posture on cross-modal, visuo-tactile links in covert spatial attention. In Experiment 1, a spatially nonpredictive visual cue was presented to the left or right hemifield shortly before a tactile target on either hand. To examine the spatial coordinates of any cross-modal cuing, the unseen hands were either uncrossed or crossed so that the left hand lay to the right and vice versa. Tactile up/down (i.e., index finger/thumb) judgments were better on the same side of external space as the visual cue, for both crossed and uncrossed postures. Thus, which hand was advantaged by a visual cue in a particular hemifield reversed across the different unseen postures. In Experiment 2, nonpredictive tactile cues now preceded visual targets. Up/down judgments for the latter were better on the same side of external space as the tactile cue, again for both postures. These results demonstrate cross-modal links between vision and touch in exogenous covert spatial attention that remap across changes in unseen hand posture, suggesting a modulatory role for proprioception.


Oxide nanoelectronics on demand.
Electronic confinement at nanoscale dimensions remains a central means of science and technology. We demonstrate nanoscale lateral confinement of a quasi-two-dimensional electron gas at a lanthanum aluminate-strontium titanate interface. Control of this confinement using an atomic force microscope lithography technique enabled us to create tunnel junctions and field-effect transistors with characteristic dimensions as small as 2 nanometers. These electronic devices can be modified or erased without the need for complex lithographic procedures. Our on-demand nanoelectronics fabrication platform has the potential for widespread technological application.


Neurostimulation for Treatment of Migraine and Cluster Headache.
The objective of this narrative review is to summarize the current state of neurostimulation therapies for the treatment of migraine and/or cluster. For this narrative review, publications were identified by searching PubMed using the search terms "migraine" or "cluster" combined with "vagal nerve stimulation," "transcranial magnetic stimulation," "supraorbital nerve stimulation," "sphenopalatine ganglion stimulation," "occipital nerve stimulation," "deep brain stimulation," "neurostimulation," or "neuromodulation." Publications were chosen based on the quality of data that were provided and their relevance to the chosen topics of interest for this review. Reference lists of chosen articles and the authors' own files were used to identify additional publications. Current clinical trials were identified by searching clinicaltrials.org. Neurostimulation of the vagal nerve, supraorbital nerve, occipital nerve and sphenopalatine ganglion, transcranial magnetic stimulation (TMS), and deep brain stimulation have been investigated for the treatment of migraine and/or cluster. Whereas invasive methods of neurostimulation would be reserved for patients with very severe and treatment refractory migraine or cluster, noninvasive methods of stimulation might serve as useful adjuncts to more conventional therapies. Currently, transcutaneous supraorbital nerve stimulation is FDA approved and commercially available for migraine prevention and TMS is FDA approved for the treatment of migraine with aura. The potential utility of each type of neurostimulation has yet to be completely defined.


Regulation of TLR3 Activation by S100A9.
Recognition of viral dsRNA by endosomal TLR3 activates innate immune response during virus infection. Trafficking of TLR3 to the endolysosomal compartment arising from fusion of late endosome (LE) with lysosome is required for recognition and detection of pathogen associated molecular patterns, which results in activation of the TLR3-dependent signaling cascade. Existing knowledge about the mechanism(s) and cellular factor(s) governing TLR3 trafficking is limited. In the current study, we identified intracellular S100A9 protein as a critical regulator of TLR3 trafficking. S100A9 was required for maturation of TLR3 containing early endosome (EE) into LE, the compartment that fuses with lysosome to form the endolysosomal compartment. A drastic reduction in cytokine production was observed in S100A9-knockout (KO) primary macrophages following RNA virus infection and treatment of cells with polyinosinic-polycytidylic acid (polyIC; a dsRNA mimetic that acts as a TLR3 agonist). Mechanistic studies revealed colocalization and interaction of S100A9 with TLR3 following polyIC treatment. S100A9-TLR3 interaction was critical for maturation of TLR3 containing EE into LE because TLR3 could not be detected in the LE of polyIC-treated S100A9-KO macrophages. Subsequently, TLR3 failed to colocalize with its agonist (i.e., biotin-labeled polyIC) in S100A9-deficient macrophages. The in vivo physiological role of S100A9 was evident from loss of cytokine production in polyIC-treated S100A9-KO mice. Thus, we identified intracellular S100A9 as a regulator of TLR3 signaling and demonstrated that S100A9 functions during pre-TLR3 activation stages by facilitating maturation of TLR3 containing EE into LE.


Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis.
Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-β) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.


Pregnancy and interferon-tau induce conjugation of bovine ubiquitin cross-reactive protein to cytosolic uterine proteins.
Conceptus-derived interferon-tau (IFN-tau) induces bovine endometrial ubiquitin cross-reactive protein (UCRP) mRNA and protein on Days 15-21 of pregnancy. Bovine UCRP retains the Leu-Arg-Gly-Gly C-terminal sequence of ubiquitin that ligates to and directs degradation of cytosolic proteins. The objectives of the present experiments were to determine whether UCRP became conjugated to endometrial cytosolic proteins during early pregnancy and in response to recombinant bovine (rbo) IFN-tau. Ubiquitin (8 kDa), UCRP (17 kDa), and conjugates thereof (> or = 30 kDa) were quantitated using Western blotting and densitometry. Endometrial ubiquitin and its conjugates did not differ between Day 18 pregnant and nonpregnant cows, or between control and rboIFN-tau-treated (25 nM) explant cultures (Day 14; nonpregnant). Bovine UCRP was induced in endometrium from pregnant as compared with nonpregnant cows. Conjugation of endometrial proteins to UCRP was induced in pregnant as compared to nonpregnant cows. Recombinant boIFN-tau induced UCRP and its conjugates in cultured endometrial explants from nonpregnant cows. It is concluded that UCRP, in response to rboIFN-tau, becomes conjugated to endometrial cytosolic proteins during early pregnancy. The regulation of uterine proteins by UCRP may be integral to the maintenance of early pregnancy in ruminants.


AIDS in Africa: an epidemiologic paradigm.
Cases of the acquired immune deficiency syndrome (AIDS) have been reported in countries throughout the world. Initial surveillance studies in Central Africa suggest an annual incidence of AIDS of 550 to 1000 cases per million adults. The male to female ratio of cases is 1:1, with age- and sex-specific rates greater in females less than 30 years of age and greater in males over age 40. Clinically, AIDS in Africans is often characterized by a diarrhea-wasting syndrome, opportunistic infections, such as tuberculosis, cryptococcosis, and cryptosporidiosis, or disseminated Kaposi's sarcoma. From 1 to 18% of healthy blood donors and pregnant women and as many as 27 to 88% of female prostitutes have antibodies to human immunodeficiency virus (HIV). The present annual incidence of infection is approximately 0.75% among the general population of Central and East Africa. The disease is transmitted predominantly by heterosexual activity, parenteral exposure to blood transfusions and unsterilized needles, and perinatally from infected mothers to their newborns, and will continue to spread rapidly where economic and cultural factors favor these modes of transmission. Prevention and control of HIV infection through educational programs and blood bank screening should be an immediate public health priority for all African countries.


Effectiveness of curcuminoids in the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomized clinical trials.
To critically appraise and evaluate the evidence for effectiveness of curcuminoids in the treatment of osteoarthritis (OA) in adults. We conducted electronic searches in Medline, Embase, AMED, Cinahl and the Cochrane library. We included randomized controlled trials (RCTs) that investigated the effectiveness of orally-administered curcuminoids in OA in adults, and assessed risk of bias using the Cochrane risk of bias criteria. We used a random-effect model for meta-analysis. We included seven studies with a total of 797 participants with primarily knee OA. All studies were conducted in Asia. The overall risk of bias was moderate. Compared with placebo, curcuminoids significantly reduced knee pain (visual analogue scale): (standardized mean difference: -3.45; 95% CI: -5.52 to -1.38; I2 = 95% P = 0.001), and improved quality of life (Lequesne pain-function index): (mean difference: -2.69; 95% CI: -3.48 to -1.90; I2 = 0% P < 0.00001). There were significantly fewer effects on pain relief, knee stiffness and physical function with curcuminoids compared with ibuprofen. Significant improvements in Western Ontario and McMaster Universities Arthritis Index total scores, with significant reductions in the use of rescue medication were also observed with curcuminoids. No serious adverse events were reported. Curcuminoids may have some beneficial effects on knee pain and quality of life in patients with knee OA. However, they are less effective at relieving pain compared with ibuprofen. Curcuminoids appear safe on the short-term, and may reduce the need for rescue medication. Published RCTs vary in reporting quality, are characterized by small sample sizes, and have all been conducted in Asia. Further clinical trials are therefore warranted.


Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study.
A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Forty-four patients with stage IIIB/IV NSCLC were treated with a combination of tirapazamine and cisplatin. Patients received tirapazamine 260 mg/m2 administered intravenously over 2 hours, followed 1 hour later by cisplatin 75 mg/m2 administered over an additional hour, repeated every 21 days. The duration of therapy was meant to be limited to four cycles for nonresponders and eight cycles for responders. Ten of 44 patients (23%) showed a partial response. The estimated median survival for all patients was 37 weeks. Toxicities were treatable and included grade 3 nausea or vomiting (25%), fatigue (27.3%), and muscle cramps (4.5%). No dose reductions were necessary. The results show that tirapazamine can safely be added to cisplatin. Both the median survival and response rate observed strongly suggest that tirapazamine with cisplatin is more active than cisplatin alone.


Effect of antibiotic treatment on fat absorption in mice with cystic fibrosis.
Improving fat absorption remains a challenge in cystic fibrosis (CF). Antibiotics (AB) treatment has been shown to improve body weight in CF mice. The mechanism may include improvement in fat absorption. We aimed to determine the effect of AB on fat absorption in two CF mouse models. AB did not improve total fat absorption. Interestingly, AB accelerated the absorption of isotope-labeled fats, in both Δ/Δ and WT mice. The changes observed were not related to the solubilization capacity of bile or to changes in the bacteria in the small intestine. AB reduced the fecal excretion of cholate by ~50% (P < 0.05) in both CF mouse models, indicating improved intestinal bile salt absorption. In conclusion, AB treatment does not improve total fat absorption in CF mice but does decrease fecal loss of bile salts and accelerate long-chain fatty acid (LCFA) absorption. For 3 weeks, we administered oral AB (ciprofloxacin/metronidazole) or control treatment to homozygous ΔF508 (Δ/Δ), cystic fibrosis transmembrane conductance regulator (CFTR) knockout (-/-), and wild-type (WT) mice and quantified fat absorption using a 72-h fat balance test. In Δ/Δ mice, we assessed fat absorption kinetics by administering tri-1-(13)C-palmitin and 1-(13)C-stearate intragastrically and determining the appearance of stable isotope-labeled fats in plasma. We quantified biliary and fecal bile salts (gas chromatography) and small intestinal bacteria (quantitative-PCR).


Binding immunoglobulin protein resolves rheumatoid synovitis: a xenogeneic study using rheumatoid arthritis synovial membrane transplants in SCID mice.
Binding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies. Rheumatoid arthritis synovial membrane (RASM) was engrafted into SCID mice. Following successful engraftment, mice were intravenously injected with BiP or human serum albumin in the presence or absence of anti-IL-10 mAb. Twelve days later the grafts were removed for analysis and human cytokines in the sera were quantified by ELISA. The extent of residual inflammatory cellular infiltrate in the synovial explants was determined by weight of the explants. The RASM transplants from mice treated with BiP showed visual reduction in cellular infiltrate and downregulation of all quantifiable features of inflammation as assessed by the Koizumi or Rooney histological criteria. Also downregulated were HLA-DR, CD86, IL-6 and TNFα expression as assessed by immunohistology. ELISA detected significantly less human IL-6 circulating in the BiP-treated mouse serum. After removal of transplanted tissue 12 days post administration of BiP, the RASM explants from the BiP-treated SCID mice weighed significantly less, indicating a suppression of tissue inflammation. Mice given concomitant neutralising anti-IL-10 antibody and BiP showed no such suppression. BiP has anti-inflammatory properties partially dependent on the downregulation of HLA-DR and co-stimulatory molecules and the predominant production of IL-10.


The SH3 domain of Tec kinase is essential for its targeting to activated CD28 costimulatory molecule.
The Tec family of protein tyrosine kinases plays an important role in T cell signaling. Tec, the prototypical member of this kinase family, can interact with CD28, which is a costimulatory molecule. However, the regulation of Tec upon CD28 stimulation remains poorly understood. Here we show that CD28-B7-mediated interactions are likely involved in the relocalization of Tec at the contact zone between T cells and APC. Upon CD28 ligation with specific antibodies or natural ligands, Tec translocates to the plasma membrane where it colocalizes with the CD28 molecule. The Src-homology 3(SH3) domain of Tec and the two proline-rich motifs of CD28 are involved in this process. Furthermore, we show that CD28 signaling requires the SH3 domain of Tec as well as proline residues present in the intracytoplasmic tail of CD28. These results should provide new insights into the complex regulation of Tec kinases in T cells.


The hypothalamic-pituitary-adrenal axis in childhood cancer survivors.
Endocrine abnormalities are common among childhood cancer survivors. Abnormalities of the hypothalamic-pituitary-adrenal axis (HPAA) are relatively less common, but the consequences are severe if missed. Patients with tumours located and/or had surgery performed near the hypothalamic-pituitary region and those treated with an accumulative cranial radiotherapy dose of over 30 Gy are most at risk of adrenocorticotrophic hormone (ACTH) deficiency. Primary adrenal insufficiency may occur in patients with tumours located in or involving one or both adrenals. The effects of adjunct therapies also need to be considered, particularly, new immunotherapies. High-dose and/or prolonged courses of glucocorticoid treatment can result in secondary adrenal insufficiency, which may take months to resolve and hence reassessment is important to ensure patients are not left on long-term replacement steroids inappropriately. The prevalence and cumulative incidences of HPAA dysfunction are difficult to quantify because of its non-specific presentation and lack of consensus regarding its investigations. The insulin tolerance test remains the gold standard for the diagnosis of central cortisol deficiency, but due to its risks, alternative methods with reduced diagnostic sensitivities are often used and must be interpreted with caution. ACTH deficiency may develop many years after the completion of oncological treatment alongside other pituitary hormone deficiencies. It is essential that health professionals involved in the long-term follow-up of childhood cancer survivors are aware of individuals at risk of developing HPAA dysfunction and implement appropriate monitoring and treatment.


Dietary fat, fatty acids, and risk of prostate cancer in the NIH-AARP diet and health study.
Observational studies report inconsistent associations of fat and fatty acids with prostate cancer. We investigated associations between dietary fats and fatty acids and risk of prostate cancer in the NIH-American Association of Retired Persons (AARP) Diet and Health Study. Diet was assessed at baseline with self-administered food-frequency questionnaires. Cases were determined by linkage with state cancer registries. HR and 95% confidence intervals (CI) were estimated with Cox proportional hazards models. Among 288,268 men with average follow-up of nine years, 23,281 prostate cancer cases (18,934 nonadvanced and 2,930 advanced including 725 fatal cases) were identified. Total fat and mono- and polyunsaturated fat intakes were not associated with incidence of prostate cancer. Saturated fat intake was related to increased risk of advanced prostate cancer (HRQuintile 5 vs. Qunitile 1 (Q1 vs. Q5), 1.21; 95% CI, 1.00-1.46; Ptrend = 0.03) and fatal prostate cancer (HRQ5 vs. Q1, 1.47; 95% CI, 1.01-2.15; Ptrend = 0.04). α-Linolenic acid (ALA) intake was related to increased risk of advanced prostate cancer (HRQ5 vs. Q1, 1.17; 95% CI, 1.04-1.31; Ptrend = 0.01). Eicosapentanoic acid (EPA) intake was related to decreased risk of fatal prostate cancer (HRQ5 vs. Q1, 0.82; 95% CI, 0.64-1.04; Ptrend = 0.02). Our study suggests that the associations of fat and fatty acids differ by prostate cancer severity. Saturated fat, ALA, and EPA intakes were related to the risk of advanced or fatal prostate cancer but not to nonadvanced prostate cancer. Identifying factors associated with advanced prostate cancer could reduce morbidity and mortality.


Effects of stochasticity on the length and behaviour of ecological transients.
There is a growing recognition that ecological systems can spend extended periods of time far away from an asymptotic state, and that ecological understanding will therefore require a deeper appreciation for how long ecological transients arise. Recent work has defined classes of deterministic mechanisms that can lead to long transients. Given the ubiquity of stochasticity in ecological systems, a similar systematic treatment of transients that includes the influence of stochasticity is important. Stochasticity can of course promote the appearance of transient dynamics by preventing systems from settling permanently near their asymptotic state, but stochasticity also interacts with deterministic features to create qualitatively new dynamics. As such, stochasticity may shorten, extend or fundamentally change a system's transient dynamics. Here, we describe a general framework that is developing for understanding the range of possible outcomes when random processes impact the dynamics of ecological systems over realistic time scales. We emphasize that we can understand the ways in which stochasticity can either extend or reduce the lifetime of transients by studying the interactions between the stochastic and deterministic processes present, and we summarize both the current state of knowledge and avenues for future advances.


Health care of youth aging out of foster care.
Youth transitioning out of foster care face significant medical and mental health care needs. Unfortunately, these youth rarely receive the services they need because of lack of health insurance. Through many policies and programs, the federal government has taken steps to support older youth in foster care and those aging out. The Fostering Connections to Success and Increasing Adoptions Act of 2008 (Pub L No. 110-354) requires states to work with youth to develop a transition plan that addresses issues such as health insurance. In addition, beginning in 2014, the Patient Protection and Affordable Care Act of 2010 (Pub L No. 111-148) makes youth aging out of foster care eligible for Medicaid coverage until age 26 years, regardless of income. Pediatricians can support youth aging out of foster care by working collaboratively with the child welfare agency in their state to ensure that the ongoing health needs of transitioning youth are met.


Evolution of plant-made pharmaceuticals.
The science and policy of pharmaceuticals produced and/or delivered by plants has evolved over the past twenty-one years from a backyard remedy to regulated, purified products. After seemingly frozen at Phase I human clinical trials with six orally delivered plant-made vaccines not progressing past this stage over seven years, plant-made pharmaceuticals have made a breakthrough with several purified plant-based products advancing to Phase II trials and beyond. Though fraught with the usual difficulties of pharmaceutical development, pharmaceuticals made by plants have achieved pertinent milestones albeit slowly compared to other pharmaceutical production systems and are now at the cusp of reaching the consumer. Though the current economic climate begs for cautious investment as opposed to trail blazing, it is perhaps a good time to look to the future of plant-made pharmaceutical technology to assist in planning for future developments in order not to slow this technology's momentum. To encourage continued progress, we highlight the advances made so far by this technology, particularly the change in paradigms, comparing developmental timelines, and summarizing the current status and future possibilities of plant-made pharmaceuticals.


Does treatment fidelity predict client outcomes in 12-Step Facilitation for stimulant abuse?
This study examined the relationships between treatment fidelity and treatment outcomes in a community-based trial of a 12-Step Facilitation (TSF) intervention. In a prior multi-site randomized clinical trial, 234 participants in 10 outpatient drug treatment clinics were assigned to receive the Stimulant Abuser Groups to Engage in 12-Step (STAGE-12) intervention. A secondary analysis reviewed and coded all STAGE-12 sessions for fidelity to the protocol, using the Twelve Step Facilitation Adherence Competence Empathy Scale (TSF ACES). Linear mixed-effects models tested the relationship between three fidelity measures (adherence, competence, empathy) and six treatment outcomes (number of days of drug use and five Addiction Severity Index (ASI) composite scores) measured at 3 months post-baseline. Adherence, competence and empathy were robustly associated with improved employment status at follow up. Empathy was inversely associated with drug use, as was competence in a non-significant trend (p=.06). Testing individual ASI drug composite score items suggested that greater competence was associated with fewer days of drug use and, at the same time, with an increased sense of being troubled or bothered by drug use. Greater competence and empathy in the delivery of a TSF intervention were associated with better drug use and employment outcomes, while adherence was associated with employment outcomes only. Higher therapist competence was associated with lower self-report drug use, and also associated with greater self-report concern about drug use. The nature of TSF intervention may promote high levels of concern about drug use even when actual use is low.


DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability.
"Replicative stress" is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n=206; United Kingdom, n=117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.


Widespread detection of Candidatus Accumulibacter phosphatis, a polyphosphate-accumulating organism, in sediments of the Columbia River estuary.
Enhanced biological phosphorus removal (EBPR) exploits the metabolism of polyphosphate-accumulating organisms (PAOs) to remove excess phosphorus (P) from wastewater treatment. Candidatus Accumulibacter phosphatis (Accumulibacter) is the most abundant and well-studied PAO in EBPR systems. In a previous study, we detected polyphosphates throughout peripheral bay sediments, and hypothesized that an estuary is an ideal setting to evaluate PAOs in a natural system, given that estuaries are characterized by dynamic dissolved oxygen fluctuations that potentially favour PAO metabolism. We detected nucleotide sequences attributable to Accumulibacter (16S rRNA, ppk1) in sediments within three peripheral bays of the Columbia River estuary at abundances rivalling those observed in conventional wastewater treatment plants (0.01%-2.6%). Most of the sequences attributable to Accumulibacter were Type I rather than Type II, despite the fact that the estuary does not have particularly high nutrient concentrations. The highest diversity of Accumulibacter was observed in oligohaline peripheral bays, while the greatest abundances were observed at the mouth of the estuary in mesohaline sediments in the spring and summer. In addition, an approximately 70% increase in polyphosphate concentrations observed at one of the sites between dawn and dusk suggests that PAOs may play an important role in P cycling in estuary sediments.


The role of left ventrolateral prefrontal cortex during episodic decisions: semantic elaboration or resolution of episodic interference?
Context memory retrieval tasks often implicate the left ventrolateral pFC (LVPFC) during functional imaging. Although this region has been linked to controlled semantic processing of materials, it may also play a more general role in selecting among competing episodic representations during demanding retrieval tasks. Thus, the LVPFC response during context memory retrieval may reflect either semantic processing of memoranda or adjudication of interfering episodic memories evoked by memoranda. To distinguish between these hypotheses, we contrasted context and item memory retrieval tasks for meaningful and nonmeaningful memoranda using fMRI. Increased LVPFC activation during context compared with item memory only occurred for meaningful memory probes. In contrast, even demanding context retrieval for nonmeaningful materials failed to engage LVPFC. These data demonstrate that the activation previously seen during episodic tasks likely reflects semantic processing of the probes during episodic retrieval attempt, not the selection among competing elicited episodic representations. Posterior middle temporal gyrus and the body/head of the caudate demonstrated the same selective response as LVPFC, although resting state functional connectivity analyses suggested that these two regions likely shared separate functional relationships with the LVPFC.