The role of the endocannabinoid system in eating disorders: neurochemical and behavioural preclinical evidence.
The endocannabinoid system has long been known as a modulator of several physiological functions, among which the homeostatic and hedonic aspects of eating. CB1 receptors are widely expressed in brain regions that control food intake, reward and energy balance. Animal and human studies indicate that CB1 receptor agonists possess orexigenic effects enhancing appetite and increasing the rewarding value of food. Conversely, CB1 antagonists have been shown to inhibit the intake of food. Eating disorders include a range of chronic and disabling related pathological illnesses that are characterized by aberrant patterns of feeding behaviour and weight regulation, and by abnormal attitudes and perceptions toward body shape image. The psychological and biological factors underlying eating disorders are complex and not yet completely understood. However in the last decades, converging evidence have led to hypothesise a link between defects in the endocannabinoid system and eating disorders, including obesity. Here we review the neurochemical and behavioural preclinical evidence supporting the role of the endocannabinoid system in eating disorders to offer the reader an update regarding the state of the art. Despite the recent withdrawal from the market of rimonabant for treating obesity and overweight individuals with metabolic complications due to its psychiatric side effects, preclinical findings support the rationale for the clinical development of drug which modulate the endocannabinoid system in the treatment of eating disorders.


DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells.
Dysregulation of the G(1)/S transition in the cell cycle contributes to tumor development. The oncogenic transcription factors c-Jun and c-Myc are indispensable regulators at this transition, and their aberrant expression is associated with many malignancies. Degradation of c-Jun/c-Myc is a critical process for the G(1)/S transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 β (GSK3β). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this GSK3β modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 functions as a priming kinase of c-Jun and c-Myc. Knockdown of DYRK2 in human cancer cells shortened the G(1) phase and accelerated cell proliferation due to escape of c-Jun and c-Myc from ubiquitination-mediated degradation. In concert with these results, silencing DYRK2 increased cell proliferation in human cancer cells, and this promotion was completely impeded by codeprivation of c-Jun or c-Myc in vivo. We also found marked attenuation of DYRK2 expression in multiple human tumor samples. Downregulation of DYRK2 correlated with high levels of unphosphorylated c-Jun and c-Myc and, importantly, with invasiveness of human breast cancers. These results reveal that DYRK2 regulates tumor progression through modulation of c-Jun and c-Myc.


Damage to ventromedial prefrontal cortex impairs judgment of harmful intent.
Moral judgments, whether delivered in ordinary experience or in the courtroom, depend on our ability to infer intentions. We forgive unintentional or accidental harms and condemn failed attempts to harm. Prior work demonstrates that patients with damage to the ventromedial prefrontal cortex (VMPC) deliver abnormal judgments in response to moral dilemmas and that these patients are especially impaired in triggering emotional responses to inferred or abstract events (e.g., intentions), as opposed to real or actual outcomes. We therefore predicted that VMPC patients would deliver abnormal moral judgments of harmful intentions in the absence of harmful outcomes, as in failed attempts to harm. This prediction was confirmed in the current study: VMPC patients judged attempted harms, including attempted murder, as more morally permissible relative to controls. These results highlight the critical role of the VMPC in processing harmful intent for moral judgment.


Risk factors for complicated grief in older adults.
Older adults grieving the death of a spouse have been found to have a higher risk of complicated grief compared with younger adults. The study objective was to find out whether personal characteristics of the patient and the bereaved partner, or characteristics of the patient's illness, end-of-life care, and the nature of death are risk factors for complicated grief in older adults. We performed a nested case-control study within the Rotterdam Study. We selected 100 couples of which one person had deceased and the other person experienced "complicated grief," and 100 control couples of which one person had deceased and the other person experienced "normal grief." Complicated grief was assessed with a 17-item Inventory of Complicated Grief (ICG). Determinants were assessed using several sources of information that were available for all participants of the Rotterdam Study. Additionally, medical files of the deceased were manually screened. Logistic regression analysis was performed. Only depression at baseline was significantly associated with complicated grief. Bereaved partners with depression at baseline had a higher risk of complicated grief compared to bereaved partners without depression (OR=3.48; 95% CI=1.40-8.68). Our results suggest that complicated grief in older adults is not clearly related to the circumstances of dying of the deceased partner. Preexisting conditions such as depression seem to be more important in explaining the occurrence of complicated grief.


Optimization-based calculation of optical nonlinear processes in a micro-resonator.
We present a new method of calculating the performance of nonlinear processes in a resonator. An optimization-based approach, conceptually similar to techniques used in nonlinear circuit analysis, is formulated and used to find the wave magnitudes that satisfy all of the boundary conditions and account for nonlinear optical effects. Unlike previous solution methods, this technique is applicable to any nonlinear process (second-order, third-order, etc.) and multiple coupled resonators, maintains the phase relations between the waves, and is exact. Examples are given for second-order nonlinear processes in a one-dimensional resonator.


Complementary and alternative therapies: the nurse's role.
One objective of Healthy People 2010 is to increase both quality and years of healthy life. Complementary and alternative medicine (CAM) encompasses strategies that can help individuals meet this goal. CAM includes therapies such as acupuncture, dietary supplements, reflexology, yoga, massage, chiropractic services, Reiki, and aromatherapy. Many CAM therapies focus on the concept of energy. The literature describes the use of CAM in individuals with neurological diseases such as dementias, multiple sclerosis, neuropathies, spinal cord injury, and epilepsy. Nurses have a unique opportunity to provide services that facilitate wholeness. They need to understand all aspects of CAM, including costs, patient knowledge, and drug interactions, if they are to promote holistic strategies for patients seeking to achieve a higher quality of life.


Real-time halo correction in phase contrast imaging.
As a label-free, nondestructive method, phase contrast is by far the most popular microscopy technique for routine inspection of cell cultures. However, features of interest such as extensions near cell bodies are often obscured by a glow, which came to be known as the halo. Advances in modeling image formation have shown that this artifact is due to the limited spatial coherence of the illumination. Nevertheless, the same incoherent illumination is responsible for superior sensitivity to fine details in the phase contrast geometry. Thus, there exists a trade-off between high-detail (incoherent) and low-detail (coherent) imaging systems. In this work, we propose a method to break this dichotomy, by carefully mixing corrected low-frequency and high-frequency data in a way that eliminates the edge effect. Specifically, our technique is able to remove halo artifacts at video rates, requiring no manual interaction or a priori point spread function measurements. To validate our approach, we imaged standard spherical beads, sperm cells, tissue slices, and red blood cells. We demonstrate real-time operation with a time evolution study of adherent neuron cultures whose neurites are revealed by our halo correction. We show that with our novel technique, we can quantify cell growth in large populations, without the need for thresholds and system variant calibration.


Quantitative and qualitative analysis of breakfast nutritional composition in French schoolchildren aged 9-11 years.
The present study aimed to analyse the nutritional quality of childrens' breakfasts using data collected during a cross-sectional observational study on the prevalence of urinary osmolality in 529 French children aged 9-11 years. Total nutrient intake, mean adequacy ratio (MAR), energy density and solid energy density were calculated from breakfast food and fluid nutritional composition. To identify the main qualitative breakfast patterns, each breakfast item was categorised into 15 solid and liquid food categories and a principal component analysis followed by a cluster analysis was performed. Only 9.8% included skipped breakfast. Breakfast provided, on average, 22.9% of the recommended daily energy intake and 24.7% of the mean adequacy ratio of 23 key nutrients. Four breakfast patterns were identified: 'Sweets breakfast' (40.0% of children), 'Traditional French breakfast' (27.2%), 'Ready-to-eat cereal (RTEC) + milk' (18.1%) and 'Dairy and juice breakfast' (9.5%). Nutritionally, the 'RTEC + milk' pattern was the most advantageous. Flavoured milk was the most frequently consumed food (50.5%) and the major component of the 'Traditional French breakfast'. Although breakfast provided a substantial contribution to a range of nutrients, opportunity for improvement, particularly to less nutrient breakfast patterns, should not be overlooked.


Similar neuronal alterations induced by axonal injury and learning in Aplysia.
Learning in the marine mollusk Aplysia has been associated with enhanced sensory function, expressed in mechanosensory neurons as (i) decreases in action potential threshold, accommodation, and afterhyperpolarization, and (ii) increases in action potential duration, afterdischarge, and synaptic transmission. These alterations also occur, with a delay, after sensory axons are injured under conditions in which synaptic transmission is severely reduced. The latency and specificity of injury-induced alterations indicate that induction signals are generated at the site of injury and conveyed centrally by axonal transport. Similarities in neuronal modifications support the hypothesis that some memory mechanisms evolved from mechanisms of injury-induced sensory compensation and repair.


Movement control tests for the lumbopelvic complex. Are these tests reliable and valid?
This study evaluated inter- and intra-observer reliability and discriminative validity of three movement control tests: 1) standing knee-lift test; 2) static lunge test; and 3) dynamic lunge test. Thirty-eight subjects, 21 with low-back pain and 17 healthy, were video-recorded while performing the tests. Four physical therapists scored the tests according to a standardized protocol and calculated a composite score for each test based on the number of incorrect test components. Inter-observer reliability for the composite scores ranged between 0.68 and 0.80 (ICC 2,k) and intra-observer reliability between 0.54 and0.82 (ICC 2,1). The separate test components ranged between 0.32 and 0.91 (κfree) for inter-observer reliability and 0.42 and1.00 for intra-observer reliability. Test components showing the highest values were: back extension; arm lowering; and shoulders moving backwards. Components hip hitch, trunk lateral flexion, knee not lifted straight up and hips moving backwards did not reach accepted thresholds. Discriminative validity ranged between 0.47 and 0.56 (AUC). As our results showed an overall good agreement for the composite, scores and for the majority of the included test components the tests can be considered reliable enough. As the tests' discriminative ability was close to "none", they should, however, not be used for diagnostic purposes but should be further evaluated toward predicted validity.


Resuming Normal Life as a Family Caregiver During Drip-Like Recovery of Older Persons With Cognitive Impairment Recovering From Hip Surgery: A Grounded Theory.
This study was undertaken to develop a theoretical framework explaining family caregiving processes for older persons with cognitive impairment recovering from hip fracture surgery. In this grounded theory study, data were collected in audio-recorded face-to-face interviews with 21 family caregivers. Among these caregivers, 14 cared for hip-fractured persons with cognitive impairment, and seven cared for those without cognitive impairment. Caregivers were interviewed five times after patients' discharge: at 1 week and at 1, 3, 6, and 12 months. Data were analyzed by constant comparative analysis. The core category explaining the family caregiving process for hip-fractured persons with cognitive impairment was "resuming normal life during drip-like recovery." This category captures the slowness of the recovery process, as slow as dripping water. During the early postoperative period, caregivers attempted to gain control of the postoperative situation, using various maintenance and improvement strategies to deal with the chaos in individuals and the family and to protect hip-fractured persons with cognitive impairment from further harm. The goal of recovery was to get back to their original life. Family caregivers of hip-fractured older persons with cognitive impairment needed to deal with more complex chaotic situations, exerted more efforts to administer safety measures, and required more time to achieve a stable life pattern. Since postoperative recovery was perceived as extremely slow, family caregivers of hip-fractured older persons with cognitive impairment should be patient regarding recovery and be informed before hospital discharge of different strategies to resume normal life during postoperative recovery.


Impact of alterations near the [NiFe] active site on the function of the H(2) sensor from Ralstonia eutropha.
In proteobacteria capable of H(2) oxidation under (micro)aerobic conditions, hydrogenase gene expression is often controlled in response to the availability of H(2). The H(2)-sensing signal transduction pathway consists of a heterodimeric regulatory [NiFe]-hydrogenase (RH), a histidine protein kinase and a response regulator. To gain insights into the signal transmission from the Ni-Fe active site in the RH to the histidine protein kinase, conserved amino acid residues in the L0 motif near the active site of the RH large subunit of Ralstonia eutropha H16 were exchanged. Replacement of the strictly conserved Glu13 (E13N, E13L) resulted in loss of the regulatory, H(2)-oxidizing and D(2)/H(+) exchange activities of the RH. According to EPR and FTIR analysis, these RH derivatives contained fully assembled [NiFe] active sites, and para-/ortho-H(2) conversion activity showed that these centres were still able to bind H(2). This indicates that H(2) binding at the active site is not sufficient for the regulatory function of H(2) sensors. Replacement of His15, a residue unique in RHs, by Asp restored the consensus of energy-linked [NiFe]-hydrogenases. The respective RH mutant protein showed only traces of H(2)-oxidizing activity, whereas its D(2)/H(+)-exchange activity and H(2)-sensing function were almost unaffected. H(2)-dependent signal transduction in this mutant was less sensitive to oxygen than in the wild-type strain. These results suggest that H(2) turnover is not crucial for H(2) sensing. It may even be detrimental for the function of the H(2) sensor under high O(2) concentrations.


Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk.
In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose-response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.


Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris.
Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.


Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids.
An approach to 1,3-disubstitued bicyclo[2.1.0]pentane (housane) derivatives was developed. The method relied on lithium bis(trimethylsilyl)amide-mediated intramolecular cyclization of trisubstitued cyclopentane carboxylates bearing a leaving group (at the C-4 position) and an additional substituent (at the C-3 atom), in turn synthesized from cyclopent-3-ene carboxylate. The synthetic sequence allowed for the preparation of both cis- and trans-1,3-disubstituted housane-1-carboxylic acids in diastereoselective manner on up to 80 g scale. In particular, bicyclic γ-amino acids-γ-aminobutyric acid analogues-were synthesized. It was shown that the bicyclo[2.1.0]pentane did not significantly affect pKa of the corresponding derivatives and slightly increased their hydrophilicity (by 0.07-0.25 Log P units) as compared to cyclopentane. X-ray diffraction studies showed that cis- and trans-1,3-disubstituted housanes can be considered as flattened analogues of the corresponding cyclopentane derivatives with fixed envelope conformation of the five-membered ring.


Two-particle problem in comblike structures.
Encounters between walkers performing a random motion on an appropriate structure can describe a wide variety of natural phenomena ranging from pharmacokinetics to foraging. On homogeneous structures the asymptotic encounter probability between two walkers is (qualitatively) independent of whether both walkers are moving or one is kept fixed. On infinite comblike structures this is no longer the case and here we deepen the mechanisms underlying the emergence of a finite probability that two random walkers will never meet, while one single random walker is certain to visit any site. In particular, we introduce an analytical approach to address this problem and even more general problems such as the case of two walkers with different diffusivity, particles walking on a finite comb and on arbitrary bundled structures, possibly in the presence of loops. Our investigations are both analytical and numerical and highlight that, in general, the outcome of a reaction involving two reactants on a comblike architecture can strongly differ according to whether both reactants are moving (no matter their relative diffusivities) or only one is moving and according to the density of shortcuts among the branches.


Metabolism and hemoglobin adduct formation of acrylamide in humans.
Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objectives of this study were to evaluate the metabolism of AM in humans following oral administration, to compare hemoglobin adduct formation on oral and dermal administration, and to measure hormone levels. The health of the people exposed under controlled conditions was continually monitored. Prior to conducting exposures in humans, a low-dose study was conducted in rats administered 3 mg/kg (1,2,3-13C3) AM by gavage. The study protocol was reviewed and approved by Institute Review Boards both at RTI, which performed the sample analysis, and the clinical research center conducting the study. (1,2,3-13C3) AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples (3 mg/kg oral dose) were analyzed for AM metabolites using 13C NMR spectroscopy. Approximately 86% of the urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide, and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine were detected in urine. On oral administration, a linear dose response was observed for N-(2-carbamoylethyl)valine (AAVal) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal) in hemoglobin. Dermal administration resulted in lower levels of AAVal and GAVal. This study indicated that humans metabolize AM via glycidamide to a lesser extent than rodents, and dermal uptake was approximately 6.6% of that observed with oral uptake.


Shifting the limits in wheat research and breeding using a fully annotated reference genome.
An annotated reference sequence representing the hexaploid bread wheat genome in 21 pseudomolecules has been analyzed to identify the distribution and genomic context of coding and noncoding elements across the A, B, and D subgenomes. With an estimated coverage of 94% of the genome and containing 107,891 high-confidence gene models, this assembly enabled the discovery of tissue- and developmental stage-related coexpression networks by providing a transcriptome atlas representing major stages of wheat development. Dynamics of complex gene families involved in environmental adaptation and end-use quality were revealed at subgenome resolution and contextualized to known agronomic single-gene or quantitative trait loci. This community resource establishes the foundation for accelerating wheat research and application through improved understanding of wheat biology and genomics-assisted breeding.


The Ars Moriendi Model for Spiritual Assessment: A Mixed-Methods Evaluation.
To explore nurses' and physicians' experiences with the ars moriendi model (AMM) for spiritual assessment. Convergent, parallel, mixed-methods. Palliative home care in Belgium. 17 nurses and 4 family physicians (FPs) in the quantitative phase, and 19 nurses and 5 FPs in the later qualitative phase. A survey was used to investigate first impressions after a spiritual assessment. Descriptive statistics were applied for the analysis of the survey. In a semistructured interview a few weeks later, nurses and physicians were asked to describe their experiences with using the AMM. Interviews were audio recorded, transcribed, and qualitatively analyzed. Quantitative and qualitative results were compared to see whether the findings were confirmative. The survey assessed the feasibility of the AMM for use in palliative home care, whereas the semistructured interviews collected in-depth descriptions of healthcare providers' (HCPs') experiences with the AMM. The AMM was perceived as valuable. Many patients shared their wishes and expectations about the end of life. Most HCPs said they felt that the patient-provider relationship had been strengthened as a result of the spiritual assessment. Almost all assessments raised new issues; however, many dyads had informally discussed spiritual issues before. The current study suggests that HCPs believe that the AMM is a useful spiritual assessment tool. Guided by the model, HCPs can gather information about the context, life story, and meaningful connections of patients, which enables them to facilitate person-centered care. The AMM appears to be an important tool for spiritual assessment that can offer more insight into patients' spirituality and help nurses to establish person-centered end-of-life care.


Diagnosis of Breakthrough Fungal Infections in the Clinical Mycology Laboratory: An ECMM Consensus Statement.
Breakthrough invasive fungal infections (bIFI) cause significant morbidity and mortality. Their diagnosis can be challenging due to reduced sensitivity to conventional culture techniques, serologic tests, and PCR-based assays in patients undergoing antifungal therapy, and their diagnosis can be delayed contributing to poor patient outcomes. In this review, we provide consensus recommendations on behalf of the European Confederation for Medical Mycology (ECMM) for the diagnosis of bIFI caused by invasive yeasts, molds, and endemic mycoses, to guide diagnostic efforts in patients receiving antifungals and support the design of future clinical trials in the field of clinical mycology. The cornerstone of lab-based diagnosis of breakthrough infections for yeast and endemic mycoses remain conventional culture, to accurately identify the causative pathogen and allow for antifungal susceptibility testing. The impact of non-culture-based methods are not well-studied for the definite diagnosis of breakthrough invasive yeast infections. Non-culture-based methods have an important role for the diagnosis of breakthrough invasive mold infections, in particular invasive aspergillosis, and a combination of testing involving conventional culture, antigen-based assays, and PCR-based assays should be considered. Multiple diagnostic modalities, including histopathology, culture, antibody, and/or antigen tests and occasionally PCR-based assays may be required to diagnose breakthrough endemic mycoses. A need exists for diagnostic tests that are effective, simple, cheap, and rapid to enable the diagnosis of bIFI in patients taking antifungals.


Cystic renal tumors: new entities and novel concepts.
Cystic renal neoplasms and renal epithelial stromal tumors are diagnostically challenging and represent some novel tumor entities. In this article, clinical and pathologic features of established and novel entities are discussed. Predominantly cystic renal tumors include cystic nephroma/mixed epithelial and stromal tumor, synovial sarcoma, and multilocular cystic renal cell carcinoma. These entities are own tumor entities of the 2004 WHO classification of renal tumors. Tubulocystic carcinoma and acquired cystic disease-associated renal cell carcinoma are neoplasms with an intrinsically cystic growth pattern. Both tumor types should be included in a future WHO classification as novel entities owing to their characteristic features. Cysts and clear cell renal cell carcinoma frequently coexist within the kidneys of patients with von Hippel-Lindau disease. Sporadic clear cell renal cell carcinomas often contain cysts, usually as a minor component. Some clear cell renal cell carcinomas have prominent cysts, and multilocular cystic renal cell carcinoma is composed almost exclusively of cysts. Recent molecular findings suggest that clear cell renal cancer may develop through cyst-dependent and cyst-independent molecular pathways.


Intraflagellar Transport Complex B Proteins Regulate the Hippo Effector Yap1 during Cardiogenesis.
Cilia and the intraflagellar transport (IFT) proteins involved in ciliogenesis are associated with congenital heart diseases (CHDs). However, the molecular links between cilia, IFT proteins, and cardiogenesis are yet to be established. Using a combination of biochemistry, genetics, and live-imaging methods, we show that IFT complex B proteins (Ift88, Ift54, and Ift20) modulate the Hippo pathway effector YAP1 in zebrafish and mouse. We demonstrate that this interaction is key to restrict the formation of the proepicardium and the myocardium. In cellulo experiments suggest that IFT88 and IFT20 interact with YAP1 in the cytoplasm and functionally modulate its activity, identifying a molecular link between cilia-related proteins and the Hippo pathway. Taken together, our results highlight a noncanonical role for IFT complex B proteins during cardiogenesis and shed light on a mechanism of action for ciliary proteins in YAP1 regulation.


Atmospheric atomic mercury monitoring using differential absorption lidar techniques.
Three-dimensional mapping of atmospheric atomic mercury has been performed with lidar techniques, to our knowledge, for the first time. Industrial pollution monitoring, as well as measurements of background concentrations, is reported. High-efficiency frequency doubling of narrowband pulsed dye laser radiation was employed to generate intense radiation at the mercury UV resonance line. Field measurements were supplemented with extensive laboratory investigations of absorption cross sections and interfering lines of molecular oxygen.


Pedagogical Merit Review of Animal Use for Education in Canada.
There are two components to the review of animal based protocols in Canada: review for the merit of the study itself, and review of the ethical acceptability of the work. Despite the perceived importance for the quality assurance these reviews provide; there are few studies of the peer-based merit review system for animal-based protocols for research and education. Institutional animal care committees (ACC)s generally rely on the external peer review of scientific merit for animal-based research. In contrast, peer review for animal based teaching/training is dependent on the review of pedagogical merit carried out by the ACC itself or another committee within the institution. The objective of this study was to evaluate the views of ACC members about current practices and policies as well as alternate policies for the review of animal based teaching/training. We conducted a national web-based survey of ACC members with both quantitative and qualitative response options. Responses from 167 ACC members indicated broad concerns about administrative burden despite strong support for both the current and alternate policies. Participants' comments focused mostly on the merit review process (54%) relative to the efficiency (21%), impact (13%), and other (12%) aspects of evaluation. Approximately half (49%) of the comments were classified into emergent themes that focused on some type of burden: burden from additional pedagogical merit review (16%), a limited need for the review (12%), and a lack of resources (expertise 11%; people/money 10%). Participants indicated that the current system for pedagogical merit review is effective (60%); but most also indicated that there was at least some challenge (86%) with the current peer review process. There was broad support for additional guidance on the justification, criteria, types of animal use, and objectives of pedagogical merit review. Participants also supported the ethical review and application of the Three Rs in the review process. A clear priority from participants in the survey was updating guidance to better facilitate the merit review process of animal-based protocols for education. Balancing the need for improved guidance with the reality of limited resources at local institutions will be essential to do this successfully; a familiar dilemma to both scientists and policy makers alike.


Determination of Clinical Parameters Sensitive to Functional Voice Disorders Applying Boosted Decision Stumps.
Various voice assessment tools, such as questionnaires and aerodynamic voice characteristics, can be used to assess vocal function of individuals. However, not much is known about the best combinations of these parameters in identification of functional dysphonia in clinical settings. This study investigated six scores from clinically commonly used questionnaires and seven acoustic parameters. 514 females and 277 males were analyzed. The subjects were divided into three groups: one healthy group (N01) (49 females, 50 males) and two disordered groups with perceptually hoarse (FD23) (220 females, 96 males) and perceptually not hoarse (FD01) (245 females, 131 males) sounding voices. A tree stumps Adaboost approach was applied to find the subset of parameters that best separates the groups. Subsequently, it was determined if this parameter subset reflects treatment outcome for 120 female and 51 male patients by pairwise pre- and post-treatment comparisons of parameters. The questionnaire "Voice-related-quality-of-Life" and three objective parameters ("maximum fundamental frequency", "maximum Intensity" and "Jitter Percent") were sufficient to separate the groups (accuracy ranging from 0.690 (FD01 vs. FD23, females) to 0.961 (N01 vs. FD23, females)). Our study suggests that a reduced parameter subset (4 out of 13) is sufficient to separate these three groups. All parameters reflected treatment outcome for patients with hoarse voices, Voice-related-quality-of-Life showed improvement for the not hoarse group (FD01). Results show that single parameters are insufficient to separate voice disorders but a set of several well-chosen parameters is. These findings will help to optimize and reduce clinical assessment time.


Change-point models to estimate the limit of detection.
In many biological and environmental studies, measured data is subject to a limit of detection. The limit of detection is generally defined as the lowest concentration of analyte that can be differentiated from a blank sample with some certainty. Data falling below the limit of detection is left censored, falling below a level that is easily quantified by a measuring device. A great deal of interest lies in estimating the limit of detection for a particular measurement device. In this paper, we propose a change-point model to estimate the limit of detection by using data from an experiment with known analyte concentrations. Estimation of the limit of detection proceeds by a two-stage maximum likelihood method. Extensions are considered that allow for censored measurements and data from multiple experiments. A simulation study is conducted demonstrating that in some settings the change-point model provides less biased estimates of the limit of detection than conventional methods. The proposed method is then applied to data from an HIV pilot study.


Radioembolization Is a Safe and Effective Treatment for Hepatocellular Carcinoma with Portal Vein Thrombosis: A Propensity Score Analysis.
Limited treatment options are available for patients with hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). Transarterial radioembolization using Yttrium-90 microspheres is a new treatment modality for HCC with PVT. For this analysis, we compared responses to treatment with radioembolization and with sorafenib. We evaluated 32 patients who were part of a multicenter retrospective cohort. All patients had PVT without extrahepatic metastasis and were treated with radioembolization in one of six tertiary referral hospitals in Korea. We retrospectively enrolled another 31 consecutive PVT patients without extrahepatic metastasis from a single center who received sorafenib treatment to serve as the control group. We used inverse probability weighting (IPW) using propensity scores to adjust for the between-group differences in baseline characteristics. At 3 months, the response rate and disease control rate were 32.1% (9/32) and 57.1% (16/32), respectively, in the radioembolization group and 3.2% (1/31) and 41.9% (13/31) in the sorafenib group. Median overall survival (OS) and time to progression (TTP) were not significantly different between the radioembolization group and the sorafenib group (13.8 months and 10.0 months, P = 0.22; and 6.0 months and 6.0 months, P = 0.08; respectively). No differences in OS (P = 0.97) or TTP (P = 0.34) were observed after IPW was applied to balance the population characteristics. The sorafenib group showed significantly more grade 3/4 adverse effects than the radioembolization group (P < 0.01). HCC patients with PVT who underwent radioembolization achieved comparable survival to patients who received sorafenib, even after application of IPW. The radioembolization group also experienced fewer severe adverse effects. Radioembolization can be considered a new treatment option for patients with HCC with PVT.


Brief report: Reduced anxiety following Pivotal Response Treatment in young children with Autism Spectrum Disorder.
Up to 40% of children with Autism Spectrum Disorder (ASD) exhibit co-occurring anxiety symptoms. Despite recent success in mitigating anxiety symptoms in school-aged children with ASD (mean age >9 years) using adapted versions of Cognitive Behavioural Therapy, little is known about potential treatment outcomes for younger children. To address the gap in the literature, this open-label study evaluated change in anxiety following a 16-week open-label trial of Pivotal Response Treatment (PRT) in children with ASD aged 4-8 years. PRT is a behavioural treatment based on the principles of Applied Behaviour Analysis and has a primary aim of increasing social communication skills in children with ASD through natural reinforcements. To minimise conflation of anxiety and other co-occurring symptoms such as disruptive behaviour and attention-deficit hyperactivity disorder, we measured anxiety using the autism anxiety subscale of the Child and Adolescent Symptom Inventory (CASI) devised by Sukhodolsky et al. (2008). We observed significant anxiety reduction over 16-weeks of PRT. Furthermore, anxiety reduction was independent of changes in autism symptom severity. This study shows promising results for PRT as an intervention for reducing anxiety in young children with ASD.


Early-stage squamous cell carcinoma of the glottic larynx managed with radiation therapy.
Between January 1975 and December 1985, 45 patients with carcinoma in situ or invasive squamous cell carcinoma of the glottic larynx received radiation therapy at the Mayo Clinic. Local control in the entire group of 45 patients was 84% (in 6 of 6 with carcinoma in situ and in 32 of 39 with invasive cancers). Three of seven patients (43%) with local recurrences underwent successful larynx-preserving surgical procedures; thus, the rate of laryngeal preservation was 91%. In our study of several treatment factors, including the duration of treatment, type of treatment (continuous course versus split course), photon energy (60Co versus 4-MV photons versus 6-MV photons), total dose, and dose per fraction, we found that only total dose of 6,300 cGy or more was associated with significantly improved local control (in 35 of 38 patients [92%]). Two patients (4%) died of uncontrolled delayed nodal metastases, one of which was preceded by a local recurrence. Severe laryngeal edema developed in two patients, associated with recurrent glottic carcinoma in one of them. No larynx was lost because of complications. In our current treatment recommendations, patients receive a total dose of 6,300 cGy in 28 fractions of 225 cGy each, administered in a continuous course with use of 6-MV photons.


Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.
The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.


Relativistic signatures in laser-assisted scattering at high field intensities.
The complete Dirac-Volkov relativistic treatment of the first Born limit of laser-assisted potential scattering of electrons within a circularly polarized laser field has been compared to the nonrelativistic Bunkin-Fedorov approach. The dependence of the quiver energy on the electron four-momentum in an ultrastrong laser field leads to different energy transfer cross sections depending on the scattering geometry with respect to the laser propagation direction. Visible differences between the relativistic and non-relativistic differential cross sections for small-angle scattering occur already for 10(16) W/cm(2)} intensity of near infrared wavelength and moderate electron initial energies.


Information processing, specificity of practice, and the transfer of learning: considerations for reconsidering fidelity.
Much has been made in the recent medical education literature of the incorrect characterization of simulation along a continuum of low to high fidelity (Cook et al. JAMA 306(9): 978-988, 2011; Norman et al. Med Educ 46(7): 636-647, 2012; Teteris et al. Adv Health Sci Educ 17(1): 137-144, 2012). For the most part, the common definition within the medical education community has been that simulations that present highly realistic performance characteristics, contexts, and scenarios are referred to as high-fidelity, while simulations that reduce to-be-learned skills to simpler constructs or constituent parts are referred to as low-fidelity. The issue with this is that highly-realistic has tended to mean the degree to which the simulation looks like the criterion context with little regard for what features of the simulation are in fact relevant to the skill that the educator hopes to teach. The inherent assumption that high fidelity simulations lead to better learning-an assumption for which there is a lack of supporting evidence (Norman et al. Med Educ 46(7): 636-647, 2012)-only exacerbates the problem. So much so that some have suggested that the term be abandoned all together (Hamstra et al. Acad Med J Assoc Am Med Coll 2014). While, it is true that fidelity and its importance are misconstrued in the medical education literature, the construct, defined classically as the degree of faithfulness that exists between two entities, is still fundamental to understanding the effectiveness that any one simulation might have in preparing learners for clinical performance. However, the concept of simulation fidelity must be recast in terms of the fundamental information processing events that underpin human performance.


Social information and economic decision-making in the ultimatum game.
The present study tested how social information about the proposer biases responders' choices of accepting or rejecting real monetary offers in a classic ultimatum game (UG) and whether this impact is heightened by the uncertainty of the context. Participants in our study conducted a one-shot UG in which their responses had direct consequences on how much money they earned. We used trait-valenced words to provide information about the proposers' personal characteristics. The results show higher acceptance rates for offers preceded by positive words than for those preceded by negative words. In addition, the impact of this information was higher in the uncertain than in the certain context. This suggests that when deciding whether or not to take money from someone, people take into account what they know about the person they are interacting with. Such non-rational bias is stronger in an uncertain context.


Attachment of an oligopeptide epitope to the C-terminus of recombinant SIV gp160 facilitates the construction of SMAA complexes while preserving CD4 binding.
A small 14 amino acid oligopeptide tag (termed SV5-Pk) was fused onto the carboxy-terminus of simian immunodeficiency virus gp160 expressed from a recombinant baculovirus. The presence of the Pk tag had no obvious effect on the expression and glycosylation of gp160 and did not interfere either with CD4 binding or with cleavage at its maturation site by the protease furin. The presence of the Pk tag did, however, facilitate the simplified purification of full-length gp160 and its incorporation into immunogenic solid matrix-antibody-antigen (SMAA) complexes.


Cancer-associated thrombosis.
Thrombosis is a common complication in patients with cancer and it is estimated that about 20% of patients with cancer experience venous thromboembolism (VTE). This complication is associated with high rate of morbidity and mortality and is sometimes the first manifestation of an occult cancer. The risk profiles and markers involved in cancerassociated thrombosis share similarities with inflammation-induced atherosclerosis and thrombosis. The type of cancer, chemotherapy, surgery, central venous catheters, pre-chemotherapy platelet and leukocyte count are associated with high risk of VTE in cancer patients. Landmark studies demonstrated that effective prophylaxis and treatment of VTE reduced morbidity and increased survival. Low-molecular-weight heparin (LMWH) is preferred as an effective and safe means for prophylaxis and treatment of VTE. It has largely replaced unfractionated heparin and vitamin K antagonists. The advantages of LMWH include increased survival and quality of life, decreased rate of VTE, low incidence of thrombocytopenia. New guidelines for prophylaxis and treatment are now available and prophylaxis is recommended in hospitalized cancer patients and patients undergoing major surgery. Treatment with LMWH should be considered as the first line of therapy for established VTE and to prevent recurrent thrombosis in patients with cancer.


An algorithm for the preoperative diagnosis and treatment of ocular surface disorders.
Any ocular surface disease (OSD), but most commonly, dry-eye disease (DED), can reduce visual quality and quantity and adversely affect refractive measurements before keratorefractive and phacorefractive surgeries. In addition, ocular surgery can exacerbate or induce OSD, leading to worsened vision, increased symptoms, and overall dissatisfaction postoperatively. Although most respondents of the recent annual American Society of Cataract and Refractive Surgery (ASCRS) Clinical Survey recognized the importance of DED on surgical outcomes, many were unaware of the current guidelines and most were not using modern diagnostic tests and advanced treatments. To address these educational gaps, the ASCRS Cornea Clinical Committee developed a new consensus-based practical diagnostic OSD algorithm to aid surgeons in efficiently diagnosing and treating visually significant OSD before any form of refractive surgery is performed. By treating OSD preoperatively, postoperative visual outcomes and patient satisfaction can be significantly improved.


Effect-based nationwide surface water quality assessment to identify ecotoxicological risks.
A large portion of the toxic effects observed in surface waters cannot be attributed to compounds regularly measured by water authorities. Hence, there is an urgent need for an effect-based monitoring strategy that employs bioassays to identify environmental risks. The aim of the present study was to perform an effect-based nationwide water quality assessment to identify ecotoxicological risks in a wide variety of surface waters. At 45 locations silicone rubbers and polar organic chemical integrative samplers were exposed to surface water for 6 weeks. Alongside the passive samplers an in-situ daphnid test was performed. Subsequent to field exposure, accumulated compounds were extracted from the passive samplers after which a battery of in vivo and in vitro bioassays was exposed to the extracts. The bioassay battery was selected such that it could identify the risks posed by a wide range of chemical pollutants and their transformation products, while simultaneously allowing for targeted identification of groups of compounds that cause specific effects. Bioassay responses were compared to effect-based trigger values to identify potential ecotoxicological risks at the investigated locations. Responses were observed in all bioassays, and trigger values were exceeded in 9 out of the 21 applied assays, allowing for ranking of the investigated locations based on ecotoxicological risks. No relationship between land use and the identification of ecotoxicological risks was observed. Based on the results, considerations regarding future improvements of effect-based monitoring are given. It is concluded that effect-based water quality assessment allowed prioritization of sites based on ecotoxicological risks, identified the presence of hazardous compounds regardless of being listed as priority substances, and meanwhile could prevent costly chemical analysis at sites with low ecotoxicological risks.


ORF73 of herpesvirus Saimiri strain C488 tethers the viral genome to metaphase chromosomes and binds to cis-acting DNA sequences in the terminal repeats.
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), a human oncogenic gamma-2-herpesvirus, transforms human endothelial cells and establishes latent infection at a low efficiency in vitro. During latent infection, only a limited number of genes are expressed, and the circularized viral genome is maintained as a multicopy episome. Latency-associated nuclear antigen (LANA), exclusively expressed during latency, has been shown to have a multifunctional role in KS pathogenesis. LANA tethers the viral episome to the host chromosome, thus ensuring efficient persistence of the viral genome during successive rounds of cell division. Besides episome maintenance, LANA modulates the expression of genes of various cellular and viral pathways, including those of retinoblastoma protein and p53. Herpesvirus saimiri (HVS), another gamma-2-herpesvirus, primarily infects New World primates. Orf73, encoding the nuclear antigen of HVS, is the positional homolog of the LANA gene, and the ORF73 protein has some sequence homology to KSHV LANA. However, the function of ORF73 of HVS has not been thoroughly investigated. In this report, we show that HVS ORF73 may be important for episome persistence and colocalizes with the HVS genomic DNA on metaphase chromosomes. Furthermore, HVS terminal repeats (TRs) contain a cis-acting sequence similar to that in KSHV TRs, suggesting that the LANA binding sequence is conserved between these two viruses. This cis-acting element is sufficient to bind HVS ORF73 from strains C488 and A11, and plasmids containing the HVS C488 TR element are maintained and replicate in HVS C488 ORF73-expressing cells.


Implementation of evidence-based practice across medical, nursing, pharmacological and allied healthcare professionals: a questionnaire survey in nationwide hospital settings.
Implementation of evidence-based practice (EBP) is regarded as core competence to improve healthcare quality. In the current study, we investigated the EBP of six groups of professionals: physicians, nurses, pharmacists, physical therapists, technicians, and other allied healthcare personnel. A structured questionnaire survey of regional hospitals throughout Taiwan was conducted by post in 2011. Questionnaires were mailed to all healthcare workers of 11 randomly selected hospitals. Linear and logistic regression models were used to examine predictors for implementing EBP. In total, 6,160 returned questionnaires, including 645 from physicians, 4,206 from nurses, 430 from pharmacists, 179 from physical therapists, 537 from technicians, and 163 from other allied healthcare professionals, were valid for the analysis. Physicians and pharmacists were more aware of EBP than were the other professional groups (p < 0.001). Positive attitudes toward and beliefs in EBP were significantly lower among nurses than in the other groups (p < 0.001). Physicians had more sufficient knowledge and skills of EBP than did the other professionals (p < 0.001); in addition, they implemented EBP for clinical decision-making more often and perceived fewer personal barriers to EBP (p < 0.001). Multivariate logistic regression analyses showed that EBP implementation was associated with the following characteristics of participants: EBP training, having a faculty position, academic degree, one's profession, and perceptions (beliefs, attitudes, knowledge, skills and barriers). This study depicts various levels of EBP implementation among medical, nursing, pharmacological, and allied healthcare personnel. There were significant differences in their implementation of EBP. We observed that certain factors were associated with EBP implementation, including personal backgrounds and perceptions toward EBP. The data suggest that strategies for enhancing EBP implementation should differ for various groups of professionals.


Carnosic acid protects against lipopolysaccharide-induced acute lung injury in mice.
Acute respiratory distress syndrome is a well-known inflammatory disease associated with high rates of morbidity and mortality due to a lack of effective treatment methods. Carnosic acid (CA) is a phenolic diterpene compound that serves a central role in cytoprotective responses to inflammation. In the present study, the protective mechanism of CA on acute lung injury (ALI) induced by lipopolysaccharide (LPS) was investigated. Mice were randomly assigned to the following five groups: Control group, LPS group, and LPS plus CA groups (at 10, 20 and 40 mg/kg doses). Following pre-treatment with vehicle or CA, ALI was induced by the administration of LPS. At 6 h after LPS treatment, mice were sacrificed and lung tissues were harvested for histologic analysis and the determination of wet-to-dry ratio, myeloperoxidase activity and toll-like receptor 4 (TLR4) and NF-κB expression. Additionally, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) were determined in bronchoalveolar lavage fluid (BALF) and lung tissues, as well as the rate of apoptosis of the isolated neutrophils from BALF. The alleviation of LPS-induced ALI by CA was confirmed by histologic results and a reduction in the wet-to-dry ratio of lung tissues. Additionally, CA was revealed to significantly suppress the inhibitory effect of LPS on neutrophil apoptosis and the promoting effects of LPS on IL-1β, IL-6, TNF-α, TLR4 and NF-κB expression, and NF-κB phosphorylation. The current results indicated that CA protects against LPS-induced ALI via a mechanism that inhibits inflammation.


Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC.
Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl-]i. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl-]i.


Ultra-wideband Ge-rich silicon germanium mid-infrared polarization rotator with mode hybridization flattening.
In this work we investigate the implementation of ultra-wideband polarization rotator in the mid-infrared spectral region. A new design method of the rotation section is proposed, yielding a polarization rotator with an extinction ratio of at least 15 dB in a wavelength range of 2 µm. For a spectral range wider than 3.8 µm, an extinction ratio of at least 10 dB is achieved for this design. The device is 1660 µm long and the associated insertion loss is below 1.2 dB on the full operational wavelength range. The influence of geometrical parameters with respect to the design method to obtain such a broadband behavior is discussed. Finally, to increase the tolerance to fabrication errors, a tapered rotator design is proposed. Such a device can support up to ± 100 nm fabrication errors and still guarantees remarkable broadband behavior. To the best of our knowledge, this is the first time an integrated polarization rotator is designed to operate for the wavelength range of 4 to 9 µm with a bandwidth exceeding 2 µm.


PRODUCTION OF FATAL BLACKHEAD IN TURKEYS BY FEEDING EMBRYONATED EGGS OF HETERAKIS PAPILLOSA.
In four experiments, three with young incubator turkeys and one with young incubator chickens, in which the feces of old turkeys from an infectious flock, kept at room temperature up to 5, 8, and 10 days, were fed, no infection resulted. In an experiment in which two of four young incubator turkeys used in one of the above experiments were fed embryonated eggs of Heterakis papillosa and feces of turkeys from an infectious flock both contracted blackhead. Two controls remained well. Later they were fed embryonated eggs of Heterakis papillosa and both contracted blackhead. In another experiment three incubator turkeys received embryonated eggs plus turkey feces from an infectious flock. All contracted blackhead. Three received embryonated eggs alone; all contracted blackhead. Three received turkey feces only; none contracted blackhead. Three controls received nothing; one showed blackhead lesions at the autopsy. In a final experiment three turkeys were fed cultures of feces from the ceca of diseased turkeys, three were fed cultures of feces of old turkeys from an infected flock, and three controls were fed nothing. None contracted blackhead. The cultures of feces were prepared precisely as were the earlier ones containing Heterakis eggs but without the latter. From these experiments it becomes evident that blackhead may be produced in healthy incubator-raised turkeys, reared in the open in an environment where blackhead occurs, but out of direct contact with old turkeys and other poultry, by feeding cultures of embryonated eggs of Heterakis papillosa, prepared by cutting up the worms in isotonic salt solution and incubating the suspension at room temperature. These very definite and clear-cut results outweigh any objections which may be raised against the use of turkeys which had been in earlier experiments and which came through such experiments without any signs of disease, or which came from control flocks in which spontaneous cases had occurred. The short time elapsing between feeding embryonated eggs and the first signs of disease made these experiments unusually impressive. It should be stated, furthermore, that from a precise individual record of all turkeys it was possible to select birds from control flocks in which the infection had either not appeared or was very low. All but two turkeys in flocks serving as sources of this material were killed at the close of the year. None at any time had shown symptoms of disease, and no scars or other abnormalities of ceca and liver were found. Furthermore, all other control birds and those in field experiments, with the exception of two reserved for breeding, were likewise killed. As a result of these autopsies, it was determined that of all birds in which symptoms of disease had not been recorded during life, none showed abnormalities or scars at autopsy. The protozoan factor in blackhead was probably disseminated when the first spontaneous cases occurred in the stock, unless it was present and made invasive by incubation in the cultures fed. This latter theory seems at present not acceptable because of the wholly negative outcome of Experiment 8. The production of acute blackhead by feeding embryonated eggs to turkeys in whose ceca adults of Heterakis papillosa are already present seems incomprehensible at first thought. A tentative explanation to be offered is that the worms when invading the ceca in large numbers break down the resistance of the bird which is able to protect itself against a few. This may account for the very irregular occurrence of cases in contact with older recovered birds on infected grounds. The rôle of Heterakis as a preliminary agent may also account for the continuing high mortality in turkeys in which the disease has been operating for so many generations to eliminate the most susceptible. It now seems highly probable that the turkey has become relatively resistant to the invasion of the protozoan parasite acting alone and that such invasion may require other agencies. Whether Heterakis papillosa is the only, or at any rate, the chief accessory agent or whether there are others, living or inert, which when ingested by the turkey assist in preparing the way for the destructive invasion of the walls of the ceca and the liver by Amoeba meleagridis is a question now open to solution by experimentation. The relation of common poultry to outbreaks of blackhead may be accounted for, at least in part, by the fact that they are hosts of Heterakis papillosa. How frequently they also carry Amoeba meleagridis remains to be determined. Since earlier communications have contained certain practical suggestions on the rearing of turkeys and the prevention of blackhead, it is not out of place here to point out that the additional information presented in this article simply emphasizes the suggestions already made. Turkeys should be raised in the incubator and brooder and kept away from older turkeys and poultry. The shelters should be moved from time to time to prevent a too concentrated infection of the soil with Heterakis ova. Inasmuch as the factors producing blackhead may be deposited by certain still undetermined birds on the wing, disease may be looked for at any time during the warm season. It is not, however, very readily transmitted, and in the experiments described elsewhere the mortality from spontaneous blackhead was low. The flock should be looked over as frequently as possible, and whenever a turkey begins to droop, it should be isolated and killed if the drooping continues over several days. If such turkeys are allowed to recover, they should not be returned to the young flock but kept with older, presumably infected birds. Such birds are entirely satisfactory as a source of eggs, since there is no evidence that the latter transmit the infection.


Effects of youth football on selected clinical measures of neurologic function: a pilot study.
We assessed 10 youth football players (13.4 ± 0.7 y) immediately before and after their season to explore the effects of football participation on selected clinical measures of neurologic function. Postseason postural stability in a closed-eye condition was improved compared to preseason (P = .017). Neurocognitive testing with the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery revealed that reaction time was significantly faster at postseason (P = .015). There were no significant preseason versus postseason differences in verbal memory (P = .507), visual memory (P = .750), or visual motor speed (P = .087). Oculomotor performance assessed by the King-Devick test was moderately to significantly improved (P = .047-.115). A 12-week season of youth football did not impair the postural stability, neurocognitive function, or oculomotor performance measures of the players evaluated. Though encouraging, continued and more comprehensive investigations of this at-risk population are warranted.


Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury.
Adiponectin (APN) has traditionally been viewed as an adipocyte-specific endocrine molecule with cardioprotective effects. Recent studies suggest that APN is also expressed in cardiomyocytes. However, biological significances of this locally produced APN remain completely unknown. The aim of this study was to investigate the pathological and pharmacological significance of cardiac-derived APN in cardiomyocyte pathology. Adult cardiomyocytes from wild-type littermates (WT) or gene-deficient mice were pretreated with vehicle (V) or rosiglitazone (RSG) for 6 h followed by simulated ischemia-reperfusion (SI/R, 3 h/12 h). Compared with WT cardiomyocytes, myocytes from APN knockout (APN-KO) mice sustained greater SI/R injury, evidenced by greater oxidative/nitrative stress, caspase-3 activity, and lactate dehydrogenase (LDH) release (P < 0.05). Myocytes from adiponectin receptor 1 knockdown (AdipoR1-KD) or AdipoR1-KD/AdipoR2-KO mice had slightly increased SI/R injury, but the difference was not statistically significant. RSG significantly (P < 0.01) increased APN mRNA and protein expression, upregulated AdipoR1/AdipoR2 expression, reduced SI/R-induced apoptosis, and decreased LDH release in WT cardiomyocytes. However, the anti-oxidative/anti-nitrative and cell protective effects of RSG were completely lost in APN-KO cardiomyocytes (P > 0.05 vs. vehicle group), although a comparable degree of AdipoR1/AdipoR2 upregulation was observed. The upregulatory effect of RSG on APN mRNA and protein expression was significantly potentiated in AdipoR1-KD/AdipoR2-KO cardiomyocytes. However, the cellular protective effects of RSG were significantly blunted, although not completely lost, in these cells. These results demonstrated that cardiomyocyte APN is biologically active in protecting cells against SI/R injury. Moreover, this locally produced APN achieves its protective effect primarily through paracrine/autocrine activation of APN receptors.


Identification of the Mycobacterium ulcerans protein MUL_3720 as a promising target for the development of a diagnostic test for Buruli ulcer.
Buruli ulcer (BU) caused by Mycobacterium ulcerans is a devastating skin disease, occurring mainly in remote West African communities with poor access to health care. Early case detection and subsequent antibiotic treatment are essential to counteract the progression of the characteristic chronic ulcerative lesions. Since the accuracy of clinical BU diagnosis is limited, laboratory reconfirmation is crucial. However, currently available diagnostic techniques with sufficient sensitivity and specificity require infrastructure and resources only accessible at a few reference centres in the African endemic countries. Hence, the development of a simple, rapid, sensitive and specific point-of-care diagnostic tool is one of the major research priorities for BU. In this study, we have identified a previously unknown M. ulcerans protein, MUL_3720, as a promising target for antigen capture-based detection assays. We show that MUL_3720 is highly expressed by M. ulcerans and has no orthologs in other prevalent pathogenic mycobacteria. We generated a panel of anti-MUL_3720 antibodies and used them to confirm a cell wall location for MUL_3720. These antibodies could also specifically detect M. ulcerans in infected human tissue samples as well as in lysates of infected mouse footpads. A bacterial 2-hybrid screen suggested a potential role for MUL_3720 in cell wall biosynthesis pathways. Finally, we demonstrate that a combination of MUL_3720 specific antibody reagents in a sandwich-ELISA format has sufficient sensitivity to make them suitable for the development of antigen capture-based diagnostic tests for BU.


Electrically tunable white-color electroluminescence from Si-implanted silicon nitride thin film.
Visible electroluminescence (EL) with two composite bands, i.e., a violet band and a green-yellow band has been observed from Si-implanted silicon nitride thin films. By varying the intensity ratio of the two composite EL bands in terms of the injection current, strong white-color EL can be achieved at certain injection currents (e.g., ~265 mA/cm(2)). The observed transition in EL color from violet to white under different injection conditions is studied based on the understanding that the violet band is originated from silicon nitride matrix while the green-yellow band is related to the implanted Si. The Si-implanted silicon nitride thin film offers the possibility of electrically tunable white-light Si-based light emitters.


IL-15 promotes IL-12 production by human monocytes via T cell-dependent contact and may contribute to IL-12-mediated IFN-gamma secretion by CD4+ T cells in the absence of TCR ligation.
At inflammatory sites, the number of activated bystander T cells exceeds that of Ag-activated T cells. We investigated whether IL-15, a monocyte-derived cytokine that shares several biologic activities with IL-2, may contribute to bystander T cell activation in the absence of IL-2 and triggering Ag. The addition of IL-15 to cocultures of monocytes and T cells stimulates CD4+ but not CD8+ T cells to produce IFN-gamma. IFN-gamma production requires endogenous IL-12, the production of which in turn is dependent upon CD40/CD154 interactions between CD4+ T cells and monocytes. Indeed, non-TCR-activated CD4+ but not CD8+ T cells express significant levels of CD154. IL-15 may enhance IFN-gamma in this system by up-regulating CD40 expression on monocytes and IL-12Rbeta1 expression on CD4+ T cells. Conversely, using neutralizing anti-IL-15 mAb, we show that the ability of IL-12 to augment IFN-gamma secretion is partly mediated by endogenous IL-15. Finally, in the absence of monocytes, a synergistic effect between exogenous IL-12 and IL-15 is necessary to induce IFN-gamma production by purified CD4+ T cells, while IL-15 alone induces T cell proliferation. It is proposed that this codependence between IL-12 and IL-15 for the activation of inflammatory T cells may be involved in chronic inflammatory disorders that are dominated by a Th1 response. In such a response, a self-perpetuating cycle of inflammation is set forth, because IL-15-stimulated CD4+ T cells may activate monocytes to release IL-12 that synergizes with IL-15 to induce IL-12 response and IFN-gamma production.


Bayesian Estimation of Species Divergence Times Using Correlated Quantitative Characters.
Discrete morphological data have been widely used to study species evolution, but the use of quantitative (or continuous) morphological characters is less common. Here, we implement a Bayesian method to estimate species divergence times using quantitative characters. Quantitative character evolution is modeled using Brownian diffusion with character correlation and character variation within populations. Through simulations, we demonstrate that ignoring the population variation (or population "noise") and the correlation among characters leads to biased estimates of divergence times and rate, especially if the correlation and population noise are high. We apply our new method to the analysis of quantitative characters (cranium landmarks) and molecular data from carnivoran mammals. Our results show that time estimates are affected by whether the correlations and population noise are accounted for or ignored in the analysis. The estimates are also affected by the type of data analyzed, with analyses of morphological characters only, molecular data only, or a combination of both; showing noticeable differences among the time estimates. Rate variation of morphological characters among the carnivoran species appears to be very high, with Bayesian model selection indicating that the independent-rates model fits the morphological data better than the autocorrelated-rates model. We suggest that using morphological continuous characters, together with molecular data, can bring a new perspective to the study of species evolution. Our new model is implemented in the MCMCtree computer program for Bayesian inference of divergence times.


Gpr83 expression is not required for the maintenance of intestinal immune homeostasis and regulation of T-cell-dependent colitis.
Regulatory T (T(R)) cells are integral to the maintenance of intestinal homeostasis, where an intricate balance between tolerance and immunity must be maintained. Recently, studies have focused on the identification of molecules involved in the function and/or development of T(R) cells. One such molecule, the G-protein coupled receptor Gpr83, has been identified through gene expression analysis as being overexpressed within thymic and peripheral naturally arising regulatory T (nT(R)) cell populations. The aim of this study was to further define the characteristics of Gpr83 expression and to investigate the role of Gpr83 in T(R)-cell development and function through the generation and analysis of Gpr83-deficient mice. Following activation, naïve CD4(+) T cells induce Gpr83 expression in a transforming growth factor (TGF)-beta dependent manner. Rather than being a general marker of activation, Gpr83 expression could only be detected in cells also expressing forkhead/winged helix transcription factor (Foxp3), further supporting the association of Gpr83 with the regulatory cell phenotype. Mice deficient in Gpr83 expression developed normally and did not display signs of inflammatory disease. Thymic nT(R)-cell development was unaffected by a lack of Gpr83 expression and peripheral nT(R)-cell homeostasis was normal when compared with that of wild-type mice. Gpr83 expression was dispensable for the regulatory activity of nT(R) cells as Gpr83-deficient nT(R) cells could suppress the development of disease in a T-cell transfer model of colitis. These results suggest a redundant role for Gpr83 in the function of T(R) cells in this model of disease. Further studies are required to determine the role of Gpr83 in T(R)-cell biology.


Mechanisms of granulin deficiency: lessons from cellular and animal models.
The identification of causative mutations in the (pro)granulin gene (GRN) has been a major breakthrough in the research on frontotemporal dementia (FTD). So far, all FTD-associated GRN mutations are leading to neurodegeneration through a "loss-of-function" mechanism, encouraging researchers to develop a growing number of cellular and animal models for GRN deficiency. GRN is a multifunctional secreted growth factor, and loss of its function can affect different cellular processes. Besides loss-of-function (i.e., mostly premature termination codons) mutations, which cause GRN haploinsufficiency through reduction of GRN expression, FTD-associated GRN missense mutations have also been identified. Several of these missense mutations are predicted to increase the risk of developing neurodegenerative diseases through altering various key biological properties of GRN-like protein secretion, proteolytic processing, and neurite outgrowth. With the use of cellular and animal models for GRN deficiency, the portfolio of GRN functions has recently been extended to include functions in important biological processes like energy and protein homeostasis, inflammation as well as neuronal survival, neurite outgrowth, and branching. Furthermore, GRN-deficient animal models have been established and they are believed to be promising disease models as they show accelerated aging and recapitulate at least some neuropathological features of FTD. In this review, we summarize the current knowledge on the molecular mechanisms leading to GRN deficiency and the lessons we learned from the established cellular and animal models. Furthermore, we discuss how these insights might help in developing therapeutic strategies for GRN-associated FTD.


Static linear and nonlinear elastic properties of normal and arterialized venous tissue in dog and man.
Ten normal and four transplanted canine jugular vein segments and four human saphenous vein segments were studied to determine the in vitro static elastic properties of venous tissue and their modification by transplantation into the arterial system. Both the intraluminal pressure and the longitudinal force were varied, and the resulting dimensions were recorded photographically. Venous segments manifested a hysteresis response but showed minimum tendency to creep. The pressure-strain relationships were curvilinear with an initial, highly compliant phase over the physiological venous pressure range followed by a relatively noncompliant phase. This transition occurred at lower pressures for jugular segments than it did for saphenous segments. In contrast, comparable-sized canine carotide artery segments did not show this essentially noncompliant phase over the pressure range studied (0 to 200 cm H2O). At comparable pressures and strains, the jugular vein segments were stiffer than the saphenous vein segments in both the circumferential and the longitudinal directions. At comparable strains, the saphenous vein moduli were similar to those in the carotid artery segments. Jugular segments transplanted into arterial circuits became virtually noncompliant and markedly inhomogeneous, with wall thickening and a histologic picture of intimal proliferation. They showed no tendency to "arterialize," that is, they failed to assume either the elastic or the histologic characteristics of arterial tissue.


TKTL1 expression in human malign and benign cell lines.
Overexpression of transketolase-like 1 protein TKTL1 in cancer cells has been reported to correlate with enhanced glycolysis and lactic acid production. Furthermore, enhanced TKTL1 expression was put into context with resistance to chemotherapy and ionizing radiation. Here, a panel of human malign and benign cells, which cover a broad range of chemotherapy and radiation resistance as well as reliance on glucose metabolism, was analyzed in vitro for TKTL1 expression. 17 malign and three benign cell lines were characterized according to their expression of TKTL1 on the protein level with three commercially available anti-TKTL1 antibodies utilizing immunohistochemistry and Western blot, as well as on mRNA level with three published primer pairs for RT-qPCR. Furthermore, sensitivities to paclitaxel, cisplatin and ionizing radiation were assessed in cell survival assays. Glucose consumption and lactate production were quantified as surrogates for the "Warburg effect". Considerable amounts of tktl1 mRNA and TKTL1 protein were detected only upon stable transfection of the human embryonic kidney cell line HEK293 with an expression plasmid for human TKTL1. Beyond that, weak expression of endogenous tktl1 mRNA was measured in the cell lines JAR and U251. Western blot analysis of JAR and U251 cells did not detect TKTL1 at the expected size of 65 kDa with all three antibodies specific for TKTL1 protein and immunohistochemical staining was observed with antibody JFC12T10 only. All other cell lines tested here revealed expression of tktl1 mRNA below detection limits and were negative for TKTL1 protein. However, in all cell lines including TKTL1-negative HEK293-control cells, antibody JFC12T10 detected multiple proteins with different molecular weights. Importantly, JAR and U251 did neither demonstrate an outstanding production of lactic acid nor increased resistance against chemotherapeutics or to ionizing radiation, respectively. Using RT-qPCR and three different antibodies we observed only exceptional occurrence of TKTL1 in a panel of malignant human cell lines in vitro. The presence of TKTL1 was unrelated to either the rate of glucose consumption/lactic acid production or resistance against chemo- and radiotherapy.


How patients can improve the accuracy of their medical records.
Assess (1) if patients can improve their medical records' accuracy if effectively engaged using a networked Personal Health Record; (2) workflow efficiency and reliability for receiving and processing patient feedback; and (3) patient feedback's impact on medical record accuracy. Improving medical record' accuracy and associated challenges have been documented extensively. Providing patients with useful access to their records through information technology gives them new opportunities to improve their records' accuracy and completeness. A new approach supporting online contributions to their medication lists by patients of Geisinger Health Systems, an online patient-engagement advocate, revealed this can be done successfully. In late 2011, Geisinger launched an online process for patients to provide electronic feedback on their medication lists' accuracy before a doctor visit. Patient feedback was routed to a Geisinger pharmacist, who reviewed it and followed up with the patient before changing the medication list shared by the patient and the clinicians. The evaluation employed mixed methods and consisted of patient focus groups (users, nonusers, and partial users of the feedback form), semi structured interviews with providers and pharmacists, user observations with patients, and quantitative analysis of patient feedback data and pharmacists' medication reconciliation logs. (1) Patients were eager to provide feedback on their medications and saw numerous advantages. Thirty percent of patient feedback forms (457 of 1,500) were completed and submitted to Geisinger. Patients requested changes to the shared medication lists in 89 percent of cases (369 of 414 forms). These included frequency-or dosage changes to existing prescriptions and requests for new medications (prescriptions and over-the counter). (2) Patients provided useful and accurate online feedback. In a subsample of 107 forms, pharmacists responded positively to 68 percent of patient requests for medication list changes. (3) Processing patient feedback will requires both software algorithms and human interpretation. For the 107 forms subsample, pharmacists accepted patient input in 51 percent of cases where they could not contact the patient. Where the patient was contacted, they accepted feedback from 68 percent. This suggests there may be opportunities to automate feedback filtering and processing for more efficient (and larger scale) medication-list optimization. (4) A supportive overall e-health environment makes acceptance of an online patient feedback system more likely. Review of Geisinger usage data showed patients who completed the medication feedback form had previously accessed MyGeisinger 2.3 times as often as the average patient and initiated secure messages with a clinician 1.35 times as often as patients not involved in the pilot. Patient feedback, placed in a useful workflow, can improve medical record accuracy. Electronic health record (EHR) vendors and developers need to build appropriate capabilities into applications. Continued research and development is needed for enabling health care organizations to elicit and process patient information most effectively.


Methods for monitoring patient dose in dental radiology.
Different types of X-ray equipment are used in dental radiology, such as intra-oral, panoramic, cephalometric, cone-beam computed tomography (CBCT) and multi-slice computed tomography (MSCT) units. Digital receptors have replaced film and screen-film systems and other technical developments have been made. The radiation doses arising from different types of examination are sparsely documented and often expressed in different radiation quantities. In order to allow the comparison of radiation doses using conventional techniques, i.e. intra-oral, panoramic and cephalometric units, with those obtained using, CBCT or MSCT techniques, the same quantities and units of dose must be used. Dose determination should be straightforward and reproducible, and data should be stored for each image and clinical examination. It is shown here that air kerma-area product (P(KA)) values can be used to monitor the radiation doses used in all types of dental examinations including CBCT and MSCT. However, for the CBCT and MSCT techniques, the methods for the estimation of dose must be more thoroughly investigated. The values recorded can be used to determine the diagnostic standard doses and to set diagnostic reference levels for each type of clinical examination and equipment used. It should also be possible to use these values for the estimation and documentation of organ or effective doses.


Nature and nurture: A step towards investigating their interactions in the wild.
The debate about the relative importance of nature versus nurture has been around for decades, but despite this, there has been very little evidence about how these might in fact interact to drive evolution in the wild. Recently, the identification of a comparable methodology for analyzing both genetic and social effects of phenotypic variation revealed that fitness variation in a free-living population of dolphin was driven by a strong social and genetic interaction. This study not only provides evidence that nature and nurture do interact to drive phenotypic evolution but also represents a step towards partitioning the effects of genetic, social, environmental factors and their multiway interactions to better understand phenotypic evolution in the wild.


A novel regulatory factor affecting the transcription of methionine biosynthesis genes in Escherichia coli experiencing sustained nitrogen starvation.
The initial adaptive transcriptional response to nitrogen (N) starvation in Escherichia coli involves large-scale alterations to the transcriptome mediated by the transcriptional activator, NtrC. One of these NtrC-activated genes is yeaG, which encodes a conserved bacterial kinase. Although it is known that YeaG is required for optimal survival under sustained N starvation, the molecular basis by which YeaG benefits N starved E. coli remains elusive. By combining transcriptomics with targeted metabolomics analyses, we demonstrate that the methionine biosynthesis pathway becomes transcriptionally dysregulated in ΔyeaG bacteria experiencing sustained N starvation. It appears the ability of MetJ, the master transcriptional repressor of methionine biosynthesis genes, to effectively repress transcription of genes under its control is compromised in ΔyeaG bacteria under sustained N starvation, resulting in transcriptional derepression of MetJ-regulated genes. Although the aberrant biosynthesis does not appear to be a contributing factor for the compromised viability of ΔyeaG bacteria experiencing sustained N starvation, this study identifies YeaG as a novel regulatory factor in E. coli affecting the transcription of methionine biosynthesis genes under sustained N starvation.


NrCAM-regulating neural systems and addiction-related behaviors.
We have previously shown that a haplotype associated with decreased NrCAM expression in brain is protective against addiction vulnerability for polysubstance abuse in humans and that Nrcam knockout mice do not develop conditioned place preferences for morphine, cocaine or amphetamine. In order to gain insight into NrCAM involvement in addiction vulnerability, which may involve specific neural circuits underlying behavioral characteristics relevant to addiction, we evaluated several behavioral phenotypes in Nrcam knockout mice. Consistent with a potential general reduction in motivational function, Nrcam knockout mice demonstrated less curiosity for novel objects and for an unfamiliar conspecific, showed also less anxiety in the zero maze. Nrcam heterozygote knockout mice reduced alcohol preference and buried fewer marbles in home cage. These observations provide further support for a role of NrCAM in substance abuse including alcoholism vulnerability, possibly through its effects on behavioral traits that may affect addiction vulnerability, including novelty seeking, obsessive compulsion and responses to aversive or anxiety-provoking stimuli. Additionally, in order to prove glutamate homeostasis hypothesis of addiction, we analyzed glutamatergic molecules regulated by NRCAM expression. Glutaminase appears to be involved in NrCAM-related molecular pathway in two different tissues from human and mouse. An inhibitor of the enzyme, prolyl-leucyl-glycinamide, treatment produced, at least, some of the phenotypes of mice shown in alcohol preference and in anxiety-like behavior. Thus, NrCAM could affect addiction-related behaviors via at least partially modulation of some glutamatergic pathways and neural function in brain.


DroughtDB: an expert-curated compilation of plant drought stress genes and their homologs in nine species.
Plants are sessile and therefore exposed to a number of biotic and abiotic stresses. Drought is the major abiotic stress restricting plant growth worldwide. A number of genes involved in drought stress response have already been characterized, mainly in the model species Arabidopsis thaliana and Oryza sativa. However, with the aim to produce drought tolerant crop varieties, it is of importance to identify the respective orthologs for each species. We have developed DroughtDB, a manually curated compilation of molecularly characterized genes that are involved in drought stress response. DroughtDB includes information about the originally identified gene, its physiological and/or molecular function and mutant phenotypes and provides detailed information about computed orthologous genes in nine model and crop plant species including maize and barley. All identified orthologs are interlinked with the respective reference entry in MIPS/PGSB PlantsDB, which allows retrieval of additional information like genome context and sequence information. Thus, DroughtDB is a valuable resource and information tool for researchers working on drought stress and will facilitate the identification, analysis and characterization of genes involved in drought stress tolerance in agriculturally important crop plants. Database URL: http://pgsb.helmholtz-muenchen.de/droughtdb/


Altered tricarboxylic acid cycle flux in primary myotubes from severely obese humans.
The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m2, n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m2, n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [-4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[14C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux.


Discrimination between intracellular uptake and surface adhesion of bacterial pathogens.
Most bacterial pathogens initiate infectious diseases by adhering to host cells. Bacterial adherence to nonphagocytic cells usually leads to extracellular colonization; however, many invasive microorganisms enter host cells after binding to the host cell surface. It is unclear why bacterial adherence can result in these two different fates for the microorganism. Analyses of model systems, such as the uptake of enteropathogenic Yersinia into cultured cells, indicate that the particular mammalian cell receptors bound and the nature of the binding event dictate whether the bacterium remains extracellular or enters host cells.


UGT2B gene expression analysis in multiple tobacco carcinogen-targeted tissues.
The UDP-glucuronosyltransferase (UGT) 2B subfamily of enzymes plays an important role in the metabolism of numerous endogenous and exogenous compounds, including various carcinogens present in tobacco smoke. The goal of the present study was to examine the levels of expression of individual UGT2B genes in various tissues that are targets for tobacco carcinogenesis. Using MT-ATP6 as the experimentally validated housekeeping gene, the highest extrahepatic expression of UGT2B genes was observed in human tonsil, with UGT2B expression levels similar to that observed in human liver. UGT2B17 exhibited high relative expression in most tissues examined, including lung, most tissues of the aerodigestive tract, and pancreas. UGT2B7 expression was highest in pancreas but low or undetectable in most other tissues examined. UGT2B10 expression was high in both tonsil and tongue. There was wide variability between individuals in the magnitude of expression in each tissue site, and there were strong correlations between UGT2B expression levels in different individuals within many of the tissue sites, suggesting coordinated regulation of UGT2B gene expression in extrahepatic tissues. In the liver, UGTs 2B4, 2B7, 2B10, and 2B15 were significantly correlated with each other (all r(2) > 0.70, P < 0.0001). In all examined tissues of the aerodigestive tract, UGTs 2B10, 2B11, and 2B17 exhibited a strong correlation with each other (all r(2) > 0.75, P < 0.05). UGTs 2B7 and 2B10 exhibited a strong inverse correlation in the pancreas (r(2) = -0.95, P < 0.01). These data suggest that specific UGT2B enzymes important in tobacco carcinogen metabolism are expressed and coordinately regulated in various target sites for tobacco-related cancers.


Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training.
The purpose of this study was to examine the effect of creatine supplementation in conjunction with resistance training on physiological adaptations including muscle fiber hypertrophy and muscle creatine accumulation. Nineteen healthy resistance-trained men were matched and then randomly assigned in a double-blind fashion to either a creatine (N = 10) or placebo (N = 9) group. Periodized heavy resistance training was performed for 12 wk. Creatine or placebo capsules were consumed (25 g x d(-1)) for 1 wk followed by a maintenance dose (5 g x d(-1)) for the remainder of the training. After 12 wk, significant (P < or = 0.05) increases in body mass and fat-free mass were greater in creatine (6.3% and 6.3%, respectively) than placebo (3.6% and 3.1%, respectively) subjects. After 12 wk, increases in bench press and squat were greater in creatine (24% and 32%, respectively) than placebo (16% and 24%, respectively) subjects. Compared with placebo subjects, creatine subjects demonstrated significantly greater increases in Type I (35% vs 11%), IIA (36% vs 15%), and IIAB (35% vs 6%) muscle fiber cross-sectional areas. Muscle total creatine concentrations were unchanged in placebo subjects. Muscle creatine was significantly elevated after 1 wk in creatine subjects (22%), and values remained significantly greater than placebo subjects after 12 wk. Average volume lifted in the bench press during training was significantly greater in creatine subjects during weeks 5-8. No negative side effects to the supplementation were reported. Creatine supplementation enhanced fat-free mass, physical performance, and muscle morphology in response to heavy resistance training, presumably mediated via higher quality training sessions.