lambda RNA internal standards quantify sensitivity and amplification efficiency of mammalian gene expression profiling.
There is an increasing interest in being able to document simultaneous levels of multiple mRNAs from limited amounts of mammalian tissue. The combination of amplified antisense RNA (aRNA) and reverse Northern blot analysis is one technology that allows the measurement of relative levels of multiple mRNAs. However, potential problems exist with this approach, such as (i) unknown amplification efficiencies and sensitivity of detection, (ii) an inherent 3' bias of amplified products and (iii) cross-hybridization of homologous mRNAs with the gene targets. Each of these potential problems was addressed experimentally by the use of poly(A) RNA internal standards synthesized from lambda phage (lambda) DNA. The results showed detection levels of as few as 10 copies of the poly(A) RNA internal standards. The internal standards aid in the optimization of reaction conditions and also reduce dependence on traditional "housekeeping" genes whose mRNA levels might or might not change. The overall results of these experiments highlight and extend the general usefulness of amplified antisense aRNA and reverse Northern blot analysis to study mRNA expression profiles.


Probing hyperconjugative aromaticity in 2H-pyrrolium and cyclopentadiene containing group 9 transition metal substituents: bridged carbonyl ligands can enhance aromaticity.
Aromaticity and hyperconjugation are two fundamental concepts in organic chemistry. By combination of the two concepts together, the resulting hyperconjugative aromaticity has attracted considerable attention from both theoretical and computational chemists. However, previous studies are mainly focused on the main group chemistry. For the hyperconjugative aromaticity in the transition metal chemistry, the studies are limited to groups 10 and 11. Here, we demonstrate that hyperconjugative aromaticity can be achieved in 2H-pyrrolium and cyclopentadiene containing group 9 transition metal substituents via density functional theory calculations. More importantly, further studies reveal that the metal-metal bonding interaction between two substituents could reduce hyperconjugative aromaticity, whereas the bridged carbonyl ligands will enhance aromaticity due to the significantly elevated HOMO orbital of the CR2 fragment. All these findings not only extend the scope of the concept of hyperconjugative aromaticity but also are helpful to develop the chemistry of metalla-aromatics.


Reformulating and testing the perfectionism model of binge eating among undergraduate women: a short-term, three-wave longitudinal study.
The perfectionism model of binge eating (PMOBE) is an integrative model explaining why perfectionism is related to binge eating. This study reformulates and tests the PMOBE, with a focus on addressing limitations observed in the perfectionism and binge-eating literature. In the reformulated PMOBE, concern over mistakes is seen as a destructive aspect of perfectionism contributing to a cycle of binge eating via 4 binge-eating maintenance variables: interpersonal discrepancies, low interpersonal esteem, depressive affect, and dietary restraint. This test of the reformulated PMOBE involved 200 undergraduate women studied using a 3-wave longitudinal design. As hypothesized, concern over mistakes appears to represent a vulnerability factor for binge eating. Bootstrapped tests of mediation suggested concern over mistakes contributes to binge eating through binge-eating maintenance variables, and results supported the incremental validity of the reformulated PMOBE beyond perfectionistic strivings and neuroticism. The reformulated PMOBE also predicted binge eating, but not binge drinking, supporting the specificity of this model. The reformulated PMOBE offers a framework for understanding how key contributors to binge eating work together to generate and to maintain binge eating.


Network Topology Analysis of Post-Mortem Brain Microarrays Identifies More Alzheimer's Related Genes and MicroRNAs and Points to Novel Routes for Fighting with the Disease.
Network-based approaches are powerful and beneficial tools to study complex systems in their entirety, elucidating the essential factors that turn the multitude of individual elements into a functional system. In this study we used critical network topology descriptors and guilt-by-association rule to explore and understand the significant molecular players, drug targets and underlying biological mechanisms of Alzheimer's disease. Analyzing two post-mortem brain gene microarrays (GSE4757 and GSE28146) with Pathway Studio software package we constructed and analyzed a set of protein-protein interaction, as well as miRNA-target networks. In a 4-step procedure the expression datasets were normalized using Robust Multi-array Average approach, while the modulation of gene expression by the disease was statistically evaluated by the empirical Bayes method from the limma Bioconductor package. Representative set of 214 seed-genes (p<0.01) common for the three brain sections of the two microarrays was thus created. The Pathway Studio analysis of the networks built identified 15 new potential AD-related genes and 17 novel AD-involved microRNAs. Using KEGG pathways relevant in Alzheimer's disease we built an integrated mechanistic network from the interactions between the overlapping genes in these pathways. Routes of possible disease initiation process were thus revealed through the CD4, DCN, and IL8 extracellular ligands. DAVID and IPA enrichment analysis uncovered a number of deregulated biological processes and pathways including neuron projection/differentiation, aging, oxidative stress, chemokine/ neurotrophin signaling, long-term potentiation and others. The findings in this study offer information of interest for subsequent experimental studies.


Inferring causal molecular networks: empirical assessment through a community-based effort.
It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense.


Study of the possible relationships between tramway front-end geometry and pedestrian injury risk.
The aim of this article is to report on the possible relationships between tramway front-end geometry and pedestrian injury risk over a wide range of possible tramway shapes. To study the effect of tramway front-end shape on pedestrian injury metrics, accidents were simulated using a custom parameterized model of tramway front-end and pedestrian models available with the MADYMO multibody solver. The approach was automated, allowing the systematic exploration of tramway shapes in conjunction with 4 pedestrian sizes (e.g., 50th percentile male or M50). A total of 8,840 simulations were run, showing that the injury risk is more important for the head than for other body regions (thorax and lower extremities). The head of the M50 impacted the windshield of the tramway in most of the configurations. Two antagonist mechanisms affecting impact velocity of the head and corresponding head injury criterion (HIC) values were observed. The first is a trunk rotation resulting from an engagement of the lower body that can contribute to an increase in head velocity in the direction of the tram. The second is the loading of the shoulder, which can accelerate the upper trunk and head away from the windshield, resulting in lower impact velocities. Groups of design were defined based on 2 main parameters (windshield height and offset), some of which seem more beneficial than others for tramway design. The pedestrian size and tramway velocity (30 vs. 20 km/h) also affected the results. When considering only the front-end shape, the best strategy to limit the risk of head injury due to contact with the stiff windshield seems to be to promote the mechanism involving shoulder loading. Because body regions engaged vary with the pedestrian size, none of the groups of designs performed equally well for all pedestrian sizes. The best compromise is achieved with a combination of a large windscreen offset and a high windscreen. Conversely, particularly unfavorable configurations are observed for low windshield heights, especially with a large offset. Beyond the front-end shape, considering the stiffness of the current windshields and the high injury risks predicted for 30 km/h, the stiffness of the windshield should be considered in the future for further gains in pedestrian safety.


HIV infection results in clonal expansions containing integrations within pathogenesis-related biological pathways.
The genomic integration of HIV into cells results in long-term persistence of virally infected cell populations. This integration event acts as a heritable mark that can be tracked to monitor infected cells that persist over time. Previous reports have documented clonal expansion in people and have linked them to proto-oncogenes; however, their significance or contribution to the latent reservoir has remained unclear. Here, we demonstrate that a directed pattern of clonal expansion occurs in vivo, specifically in gene pathways important for viral replication and persistence. These biological processes include cellular division, transcriptional regulation, RNA processing, and posttranslational modification pathways. This indicates preferential expansion when integration events occur within genes or biological pathways beneficial for HIV replication and persistence. Additionally, these expansions occur quickly during unsuppressed viral replication in vivo, reinforcing the importance of early intervention for individuals to limit reservoir seeding of clonally expanded HIV-infected cells.


The effect of bilateral isometric forces in different directions on motor cortical function in humans.
The activity in the primary motor cortex (M1) reflects the direction of movements, but little is known about physiological changes in the M1 during generation of bilateral isometric forces in different directions. Here, we used transcranial magnetic stimulation to examine motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and interhemispheric inhibition (IHI) in the left first dorsal interosseous (FDI) during isometric index finger abduction while the right index finger remained at rest or performed isometric forces in different directions (abduction or adduction) and in different postures (prone and supine). Left FDI MEPs were suppressed during bilateral compared with unilateral forces, with a stronger suppression when the right index finger force was exerted in the adduction direction regardless of hand posture. IHI targeting the left FDI increased during bilateral compared with unilateral forces and this increase was stronger during right index finger adduction despite the posture of the right hand. SICI decreased to a similar extent during both bilateral forces in both hand postures. Thus generation of index finger isometric forces away from the body midline (adduction direction), regardless of the muscle engaged in the task, down-regulates corticospinal output in the contralateral active hand to a greater extent than forces exerted toward the body midline (abduction direction). Transcallosal inhibition, but not GABAergic intracortical circuits, was modulated by the direction of the force. These findings suggest that during generation of bimanual isometric forces the M1 is driven by "extrinsic" parameters related to the hand action.


Effects of lupin-enriched foods on body composition and cardiovascular disease risk factors: a 12-month randomized controlled weight loss trial.
Regular consumption of diets with increased protein or fibre intakes may benefit body weight and composition and cardiovascular disease risk factors. Lupin flour is a novel food ingredient high in protein and fibre. To investigate the effects of a lupin-enriched diet, during and following energy restriction, on body weight and composition and cardiovascular disease risk factors in overweight individuals. Participants (n = 131) were recruited to a 12-month parallel-design trial. They were randomly assigned to consume lupin-enriched foods or matching high-carbohydrate control foods. All participants underwent 3 months of weight loss, 1 month of weight stabilization and 8 months of weight maintenance. Body weight and composition and cardiovascular disease risk factors were assessed at baseline, 4 and 12 months. Lupin, relative to control, did not significantly influence (mean difference (95% CI)) weight loss at 4 months (0.1 kg (-1.2, 1.4)) and 12 months (-0.6 kg (-2.0, 0.8)), maintenance of weight loss from 4 to 12 months (-0.7 kg (-1.83, 0.48)) or measures of body fat and fat-free mass. Relative to control, 24-h ambulatory systolic (-1.3 mm Hg (-2.4, -0.3), P = 0.016) and diastolic (-1.0 mm Hg (-1.9, -0.2), P = 0.021) blood pressures were lower at 12 months but not at 4 months; fasting insulin concentrations and homeostasis model assessment (HOMA) scores were significantly lower at 4 months (-1.2 mU l(-1) (-1.3, -1.1), P = 0.004 and -0.6 units (-1.0, -0.19), P = 0.004) and 12 months (-1.3 mU l(-1) (-1.4, -1.1), P < 0.001 and -0.7 units (-1.1, -0.24), P = 0.002). A diet higher in protein and fibre derived from lupin-enriched foods does not enhance weight loss or improve the maintenance of weight loss. However, such a diet may provide cardiovascular health benefits in terms of insulin sensitivity and blood pressure.


Real-life treatment practice for malignant pleural mesothelioma in Belgium.
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, for which treatment is often limited to palliative combination chemotherapy. Multimodality-therapy, including radical surgery, is largely restricted to clinical trials, leaving its benefit currently unclear. This study aimed to get a comprehensive view on real-world MPM treatment at the Belgian population level, to assess survival and to identify prognostic factors. The study period covered the incidence years 2004-2012 (N = 1453). Starting from the Belgian Cancer Registry, additional information regarding patient characteristics, diagnosis and treatment was retrieved from multiple data sources. Adjusted cox proportional-hazard regression models using time-dependent covariates were performed to assess survival in relation to treatment patterns and centre volume. Sixty-nine percent of patients underwent tumour-directed treatment, mostly cisplatin-pemetrexed chemotherapy. Radical surgery was mainly performed in younger patients with epithelioid subtype. Centre volume, surgery and chemotherapy showed a positive relation with survival in univariable analyses, but only chemotherapy remained significantly relevant in multivariable analyses. Younger patients, females, and epithelioid subtypes also independently had a better survival. This large population-based study provides insights in MPM treatment practice in Belgium. Centre volume and surgery being related to survival in univariable analyses, only chemotherapy remained prognostic after adjustment.


Dynamic light scattering from pulsatile flow in the presence of induced motion artifacts.
Continuous health monitoring has become a major theme of our aging society. Portable devices play an important role here. Many optical portable devices are susceptible to motion induced artifacts. We have performed an experimental study for detection of fluid pulsation based on multi-exposure speckle images, in presence of motion induced artifacts. Induced motion of a wide range of frequencies and amplitudes were generated to resemble sensor motion with respect to skin. The data was analyzed using speckle contrast and correlation. We concluded that both techniques have their own advantages, depending on the measurement configuration. A study of angles between illumination and detection revealed that larger angles yields better signal. Shorter exposure time was more successful in extracting the signal. We also performed in-vivo measurements that agree with the in-vitro case. We also show that a minimum collection of two pixels from the speckle image is sufficient to extract relevant results.


The Implementation of Medical Informatics in the National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM).
The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) describes medical skills and attitudes without being ordered by subjects or organs. Thus, the NKLM enables systematic curriculum mapping and supports curricular transparency. In this paper we describe where learning objectives related to Medical Informatics (MI) in Hannover coincide with other subjects and where they are taught exclusively in MI. An instance of the web-based MERLIN-database was used for the mapping process. In total 52 learning objectives overlapping with 38 other subjects could be allocated to MI. No overlap exists for six learning objectives describing explicitly topics of information technology or data management for scientific research. Most of the overlap was found for learning objectives relating to documentation and aspects of data privacy. The identification of numerous shared learning objectives with other subjects does not mean that other subjects teach the same content as MI. Identifying common learning objectives rather opens up the possibility for teaching cooperations which could lead to an important exchange and hopefully an improvement in medical education. Mapping of a whole medical curriculum offers the opportunity to identify common ground between MI and other medical subjects. Furthermore, in regard to MI, the interaction with other medical subjects can strengthen its role in medical education.


Evaluation of the effect of performance monitoring and feedback on care process, utilization, and outcome.
We evaluated a program of performance measurement and monitoring by assessing care process, utilization of services, and outcomes. Information on 63,264 diabetic individuals who were continuously enrolled as members of Kaiser Permanente Southern California from 1 January 1994 to 31 December 1997 was used to evaluate the program. Time trends in testing for glycemic test and control and screening for dyslipidemia, use of lipid-lowering drugs, and microalbuminuria were evaluated as measures of care process. Time trends in hospitalization, outpatient appointments, prescriptions, and laboratory tests were evaluated as measures of utilization. Outcomes were hospitalization for myocardial infarction, ischemic stroke, and lower-limb amputation. Between 1994 and 1997, improvements were evident in the process measures. The mean number of hospitalizations and the mean and median number of outpatients visits did not change. The mean number of laboratory tests increased from 13.2 in 1994 to 23.6 in 1997. The mean number of prescriptions for any medication increased from 19.7 to 24.3. Hospitalization rates for myocardial infarction did not change, but rates increased for ischemic stroke and lower-limb amputation. Our findings suggest that measurement and monitoring of clinical performance can bring about modest improvements in measures of the processes of care in the absence of financial incentives, centrally driven interventions, and specialty care for all patients. In our setting, process improvements were associated with higher utilization of laboratory services and more prescriptions without an immediate return in terms of lower hospital utilization.


An exploration of prospective imagery: the impact of future events scale.
Mental imagery of the future has clear clinical importance, although little is known about intrusive, prospective imagery of personally-relevant events. Currently, no measure is available to assess this. The Impact of Future Events Scale (IFES) was created to assess the impact of intrusive, prospective, personally-relevant imagery. It was examined in relation to predictions about dysphoria. To form the IFES, the IES-R (a measure of the impact of a past traumatic event on posttraumatic stress disorder symptomatology such as intrusive re-experiencing) was adapted item-by-item to assess intrusive "pre-experiencing" and imagery of specific, future events. Participants (N = 75) completed the IFES and assessments of depression, anxiety and general imagery use. As predicted, the IFES significantly and positively correlated with depression scores. Analyses using subgroups of non-dysphoric and mild-dysphoric participants confirmed that the mild-dysphoric group reported significantly higher IFES scores, indicating higher levels of pre-experiencing of the future and related hyperarousal and avoidance. IFES provides a measure of the impact of "pre-experiencing" in the form of intrusive prospective, personally-relevant imagery, with sensitivity to group differences on the basis of depression scores. Further research is required to extend these finding into clinical depression and other psychopathological conditions.


Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation.
Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration.


Embryonic stem cells, derived either after in vitro fertilization or nuclear transfer, prolong survival of semiallogeneic heart transplants.
Tolerance induction toward allogeneic organ grafts represents one of the major aims of transplantation medicine. Stem cells are promising candidates for promoting donor-specific tolerance. In this study, we investigated the immunomodulatory properties of murine embryonic stem cells (ESCs), obtained either by in vitro fertilization (IVF-ESCs) or by nuclear transfer (NT-ESCs), in heart transplant mouse models. IVF-ESCs did not prolong the survival of fully allogeneic cardiac transplants but significantly prolonged the survival of semiallogeneic hearts from the same ESC donor strain for >100 d in 44% of the animals. However, 28% of transplanted animals infused with IVF-ESCs experienced development of a teratoma. NT-ESCs similarly prolonged semiallogeneic heart graft survival (>100 d in 40% of the animals) but were less teratogenic. By in vitro studies, IVF-ESC and NT-ESC immunoregulation was mediated both by cell contact-dependent mechanisms and by the release of soluble factors. By adding specific inhibitors, we identified PGE(2) as a soluble mediator of ESC immunoregulation. Expansion of regulatory T cells was found in lymphoid organs and in the grafts of IVF-ESC- and NT-ESC-tolerized mice. Our study demonstrates that both IVF-ESCs and NT-ESCs modulate recipient immune response toward tolerance to solid organ transplantation, and that NT-ESCs exhibit a lower tendency for teratoma formation. Because NT-ESCs are obtained by NT of a somatic cell from living individuals into an enucleated oocyte, they could represent a source of donor-derived stem cells to induce tolerance to solid organ allograft.


Effect of Repeated Anthelminthic Treatment on Malaria in School Children in Kenya: A Randomized, Open-Label, Equivalence Trial.
School children living in the tropics are often concurrently infected with plasmodium and helminth parasites. It has been hypothesized that immune responses evoked by helminths may modify malaria-specific immune responses and increase the risk of malaria. We performed a randomized, open-label, equivalence trial among 2436 school children in western Kenya. Eligible children were randomized to receive either 4 repeated doses or a single dose of albendazole and were followed up during 13 months to assess the incidence of clinical malaria. Secondary outcomes were Plasmodium prevalence and density, assessed by repeat cross-sectional surveys over 15 months. Analysis was conducted on an intention-to-treat basis with a prespecified equivalence range of 20%. During 13 months of follow-up, the incidence rate of malaria was 0.27 episodes/person-year in the repeated treatment group and 0.26 episodes/person-year in the annual treatment group (incidence difference, 0.01; 95% confidence interval, -.03 to .06). The prevalence and density of malaria parasitemia did not differ by treatment group at any of the cross-sectional surveys. Our findings suggest that repeated deworming does not alter risks of clinical malaria or malaria parasitemia among school children and that school-based deworming in Africa may have no adverse consequences for malaria. NCT01658774.


Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
Partial agonists produce submaximal activation of ligand-gated ion channels. To address the question of partial agonist action at the NR1 subunit of the NMDA receptor, we performed crystallographic and electrophysiological studies with 1-aminocyclopropane-1-carboxylic acid (ACPC), 1-aminocyclobutane-1-carboxylic acid (ACBC), and 1-aminocyclopentane-1-carboxylic acid (cycloleucine), three compounds with incrementally larger carbocyclic rings. Whereas ACPC and ACBC partially activate the NMDA receptor by 80% and 42%, respectively, their cocrystal structures of the NR1 ligand binding core show the same degree of domain closure as found in the complex with glycine, a full agonist, illustrating that the NR1 subunit provides a new paradigm for partial agonist action that is distinct from that of the evolutionarily related GluR2, AMPA-sensitive receptor. Cycloleucine behaves as an antagonist and stabilizes an open-cleft conformation. The NR1-cycloleucine complex forms a dimer that is similar to the GluR2 dimer, thereby suggesting a conserved mode of subunit-subunit interaction in AMPA and NMDA receptors.


Protein and peptide array analysis of autoimmune disease.
Molecular cloning, sequencing of the human genome, and other major advances in biomedical research have contributed substantially to our understanding of autoimmune disease. Nevertheless, to date, such advances have failed to reveal the etiology of or yield curative therapies for autoimmune disease. New approaches are needed. Proteomics, the large-scale study of expression and function of proteins that compose our tissues and mediate disease, represents a powerful and promising strategy. We developed protein and peptide arrays to profile autoantibody responses in autoimmune disease. Protein and peptide array analysis of autoimmune samples is revealing human and pathogen proteins involved in initiation and perpetuation of autoimmunity. Proteomic determination of autoantibody profiles can be utilized for diagnosis, prognostication, and guiding tolerizing therapy for autoimmune disease.


Prevention of travel-related infectious diseases: knowledge, practices and attitudes of Swedish travellers.
More Swedish residents travel to countries where they are at risk for contracting malaria, hepatitis, and other serious travel-related diseases. To safeguard the public's health, it is important to determine if travellers accurately perceive health risks and take appropriate preventative measures before and during their trips. This study examined travel health knowledge, attitudes and practices among Swedish residents traveling to destinations with risk of malaria and hepatitis. Self-administered anonymous questionnaires were distributed to Swedish residents (n=957) waiting to board intercontinental flights at the Stockholm-Arlanda International Airport. A majority of travellers sought general information (74%) and travel health advice (59%) prior to departure. Most perceived vaccination as safe and effective, but only 40% and 3% of travellers reported adequate vaccine coverage against hepatitis A or hepatitis B, respectively. Although most did not know the actual malaria risk at the destination, 97% of persons flying to high-risk areas were carrying malaria medication. The study results were in line with those found in surveys conducted in other countries, and demonstrate need for further health education among travellers to risk destinations. Efforts should focus on reaching more travellers, providing clear information and improving compliance with recommended travel health advice.


Poly(tetrafluoroethylene) separation capillaries for capillary electrophoresis. Properties and applications.
Poly(tetrafluoroethylene) (PTFE) is a material widely known for its inertness and excellent electrical properties. It is also transparent in the UV region and has a reasonable thermal conductivity. These properties make PTFE a suitable material for the separation capillary in capillary electrophoresis. Differences in the chemistry of the capillary wall compared to fused silica (FS) can make PTFE an interesting alternative to FS for some special applications. In this work, properties of a commercial PTFE capillary of approx. 100 microm i.d. were investigated, including the dependence of electroosmotic flow (EOF) on pH for unmodified and dynamically modified PTFE, optical properties, and practical aspects of use. The main problems encountered for the particular PTFE capillary used in this study were that it was mechanically too soft for routine usage and the crystallinity of the PTFE caused light scattering, leading to high background absorbance values in the low UV region. The profile of the EOF versus pH for bare PTFE surprisingly showed significantly negative EOF values at pH < 4.2, with an EOF of -30 x 10(-9) m2 V(-1) s(-1) being observed at pH 2.5. This is likely to be caused by either impurities or additives of basic character in the PTFE, so that after their protonation at acidic pH they establish a positive charge on the capillary wall and create a negative EOF. A stable cationic semi-permanent coating of poly(diallyldimethylammonium chloride) (PDDAC) could be established on the PTFE capillary and led to very similar magnitudes of EOF to those observed with FS. A hexadecanesulfonate coating produced a cathodic EOF of extremely high magnitude ranging between +90 and +110 x 10(-9) m2 s(-1) V(-1), which are values high enough to allow counter-EOF separation of high mobility inorganic anions. In addition, pH-independent micellar electrokinetic capillary chromatography (MEKC) separations could be easily realised due to hydrophobic adsorption of sodium dodecylsulfate (used to form the micelles) on the wall of the PTFE capillary. The use of polymers that would be mechanically more robust and optically transparent in the low-UV region should make such CE capillaries an interesting alternative to fused silica.


Identification of non-Hodgkin's lymphoma prognosis signatures using the CTGDR method.
Although NHL (non-Hodgkin's lymphoma) is the fifth leading cause of cancer incidence and mortality in the USA, it remains poorly understood and is largely incurable. Biomedical studies have shown that genomic variations, measured with SNPs (single nucleotide polymorphisms) in genes, may have independent predictive power for disease-free survival in NHL patients beyond clinical measurements. We apply the CTGDR (clustering threshold gradient directed regularization) method to genetic association studies using SNPs, analyze data from an association study of NHL and identify prognosis signatures to diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common subtypes of NHL. With the CTGDR method, we are able to account for the joint effects of multiple genes/SNPs, whereas most existing studies are single-marker based. In addition, we are able to account for the 'gene and SNP-within-gene' hierarchical structure and identify not only predictive genes but also predictive SNPs within identified genes. In contrast, existing studies are limited to either gene or SNP identification, but not both. We propose using resampling methods to evaluate the predictive power and reproducibility of identified genes and SNPs. Simulation study and data analysis suggest satisfactory performance of the CTGDR method.


Immunosenescence and vaccination in nursing home residents.
The elderly population continues to increase in most countries. Concomitantly, the number of individuals who are institutionalized is also increasing, unfortunately, with more and more individuals being institutionalized at greater ages. These elderly individuals are very different from healthy, community-dwelling elderly individuals, in that many are considered to be frail and have various chronic diseases. It is apparent that the immune response diminishes even in healthy elderly people and that the pathologies that occur in nursing home patients, together with malnutrition, further impair immunity required for an effective vaccine response. Therefore, it is important to take secondary age-related effects, attributable to factors such as chronic diseases, inflammation, frailty, nutrition, functional status, and stress, into account when assessing vaccination strategies. Despite these alterations that can affect immune function and their potential interaction with vaccination, vaccination is still worthwhile and is recommended for elderly nursing home residents. Research efforts should continue attempts to elucidate the immunological basis of impaired immunity in nursing home residents to design improved prevention strategies for this vulnerable group.


A feature selection method for multivariate performance measures.
Feature selection with specific multivariate performance measures is the key to the success of many applications such as image retrieval and text classification. The existing feature selection methods are usually designed for classification error. In this paper, we propose a generalized sparse regularizer. Based on the proposed regularizer, we present a unified feature selection framework for general loss functions. In particular, we study the novel feature selection paradigm by optimizing multivariate performance measures. The resultant formulation is a challenging problem for high-dimensional data. Hence, a two-layer cutting plane algorithm is proposed to solve this problem, and the convergence is presented. In addition, we adapt the proposed method to optimize multivariate measures for multiple-instance learning problems. The analyses by comparing with the state-of-the-art feature selection methods show that the proposed method is superior to others. Extensive experiments on large-scale and high-dimensional real-world datasets show that the proposed method outperforms l₁-SVM and SVM-RFE when choosing a small subset of features, and achieves significantly improved performances over SVM(perf) in terms of F₁-score.


The prevalence of transmitted HIV drug resistance among MSM in Anhui province, China.
To optimize treatment regimens, we assessed human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) among men who have sex with men (MSM) in Anhui province, China. A total of 139 MSM who were newly diagnosed and antiretroviral treatment-naive were enrolled in Anhui in 2011. A partial pol fragment was amplified and sequenced, and HIV subtypes were determined by phylogenetic analyses. Surveillance/transmitted drug resistance mutations (SDRMs) were identified according to the 2009 World Health Organization (WHO) list. A total of 133 (95.7%) samples were successfully amplified and sequenced. Based on phylogenetic analyses of the pol fragment, CRF01_AE accounted for 55.6% (74/133) of the infections, followed by CRF07_BC with 32.3% (43/133), B with 5.3% (7/133), and unique recombinant forms with 6.8% (9/133). A total of 3.0% (4/133) of the subjects were found to harbor HIV variants with SDRMs, including 1.5% with NRTI-related mutations and 1.5% with NNRTI-related mutations. PI-related mutations were absent. The SDRMs included L210W (1.5%), Y181C (0.8%), and G190A (0.8%). In Anhui, CRF01_AE strains contributed to most of the HIV infections among MSM, and the prevalence of TDR was relatively low in this population. Further studies should be performed to evaluate the trend of TDR among MSM in Anhui and to inform first-line antiretroviral treatment.


Herpes simplex encephalitis and management of acyclovir in encephalitis patients in France.
This study reports on the clinical profiles of herpes simplex encephalitis (HSE) case-patients and the management of acyclovir prescriptions. We designed a study on the causes of encephalitis in France in 2007. Case-patients fulfilling the inclusion criteria were enrolled in all the hospitals that volunteered to participate. Fifty-five of 253 enrolled case-patients were diagnosed with HSE. Three (5%) HSE patients died and 48 (89%) were discharged with persistent neurological symptoms. All HSE patients were prescribed acyclovir, 10 of whom had a 2-week course; 42 a 3-week course; two received incomplete courses; and one received two courses of 21 days each due to relapse. The acyclovir dosage was reported for 45 adult HSE patients, 25 (53%) of whom received 10 mg/kg t.i.d. and 22 (47%) received 15 mg/kg t.i.d. The mortality rate was low despite 49% of patients being admitted to intensive-care units. A high dose of acyclovir was not associated with a better outcome in HSE patients. Most patients had persisting symptoms on discharge suggesting neuropsychological rehabilitation is an important issue for survivors.


Dynamic motor practice improves movement accuracy, force control and leads to increased corticospinal excitability compared to isometric motor practice.
The central nervous system has a remarkable ability to plan motor actions, to predict and monitor the sensory consequences during and following motor actions and integrate these into future actions. Numerous studies investigating human motor learning have employed tasks involving either force control during isometric contractions or position control during dynamic tasks. To our knowledge, it remains to be elucidated how motor practice with an emphasis on position control influences force control and vice versa. Furthermore, it remains unexplored whether these distinct types of motor practice are accompanied by differential effects on corticospinal excitability. In this study, we tested motor accuracy and effects of motor practice in a force or position control task allowing wrist flexions of the non-dominant hand in the absence of online visual feedback. For each trial, motor performance was quantified as errors (pixels) between the displayed target and the movement endpoint. In the main experiment, 46 young adults were randomized into three groups: position control motor practice (PC), force control motor practice (FC), and a resting control group (CON). Following assessment of baseline motor performance in the position and force control tasks, intervention groups performed motor practice with, augmented visual feedback on performance. Motor performance in both tasks was assessed following motor practice. In a supplementary experiment, measures of corticospinal excitability were obtained in twenty additional participants by application of transcranial magnetic stimulation to the primary motor cortex hot spot of the flexor carpi radialis muscle before and following either position or force control motor practice. Following motor practice, accuracy in the position task improved significantly more for PC compared to FC and CON. For the force control task, both the PC and FC group improved more compared to CON. The two types of motor practice thus led to distinct effects including positive between-task transfer accompanying dynamic motor practice The results of the supplementary study demonstrated an increase in corticospinal excitability following dynamic motor practice compared to isometric motor practice. In conclusion, dynamic motor practice improves movement accuracy, and force control and leads to increased corticospinal excitability compared to isometric motor practice.


How digital are the Digital Humanities? An analysis of two scholarly blogging platforms.
In this paper we compare two academic networking platforms, HASTAC and Hypotheses, to show the distinct ways in which they serve specific communities in the Digital Humanities (DH) in different national and disciplinary contexts. After providing background information on both platforms, we apply co-word analysis and topic modeling to show thematic similarities and differences between the two sites, focusing particularly on how they frame DH as a new paradigm in humanities research. We encounter a much higher ratio of posts using humanities-related terms compared to their digital counterparts, suggesting a one-way dependency of digital humanities-related terms on the corresponding unprefixed labels. The results also show that the terms digital archive, digital literacy, and digital pedagogy are relatively independent from the respective unprefixed terms, and that digital publishing, digital libraries, and digital media show considerable cross-pollination between the specialization and the general noun. The topic modeling reproduces these findings and reveals further differences between the two platforms. Our findings also indicate local differences in how the emerging field of DH is conceptualized and show dynamic topical shifts inside these respective contexts.


Generation of mucin gel particles with self-degradable and -releasable properties.
Herein, we focused on mucin, which is a large viscous glycoprotein in terms of materials science, and reported preparation of mucin gel particles and incorporation of enzymes to provide the particle with self-degradable and releasable properties. To expose the hydrophobic peptide cores, trimming of sugar moieties was carried out by β-elimination reaction under alkaline conditions (tMucin). Nano-sized tMucin particles were prepared by the assembly of tMucin with the aid of a cationic surfactant. Then, cross-linking of tMucin particles was carried out via heat treatment (annealing) to induce thermal aggregation of the polypeptide chains. The hydrodynamic diameter of tMucin particles reversibly changed in response to calcium ions. Next, in an attempt to render the particle degradable, lysozyme was incorporated into the tMucin particles for the hydrolysis of oligosaccharide chains. These particles were gradually degraded upon enzymatic cleavage of the mucin molecules, facilitating the release of their incorporated substances. Also, the degradation of the mucin particles and the release of lysozyme were tunable by environmental conditions, such as temperature and calcium ions, in addition to the degree of cross-linking of the particles.


Enhanced expression of the neuronal K+/Cl- cotransporter, KCC2, in spontaneously depressed Flinders Sensitive Line rats.
We used Flinder Sensitive Line (FSL) rats, a genetic model of unipolar depression, to examine whether changes in central GABAergic transmission are associated with a depressed phenotype. FSL rats showed an increased behavioral response to low doses of diazepam, as compared to either Sprague Dawley (SD) or Flinder Resistant Line (FRL) rats used as controls. Diazepam at a dose of 0.3 mg/kg, i.p., induced a robust impairment of motor coordination in FSL rats, but was virtually inactive in SD or FRL rats. The increased responsiveness of FSL rats was not due to changes in the brain levels of diazepam or its active metabolites, or to increases in the number or affinity of benzodiazepine recognition sites, as shown by the analysis of [(3)H]-flunitrazepam binding in the hippocampus, cerebral cortex or cerebellum. We therefore examined whether FSL rats differed from control rats for the expression levels of the K(+)/Cl(-) cotransporter, KCC2, which transports Cl(-) ions out of neurons, thus creating the concentration gradient that allows Cl(-) influx through the anion channel associated with GABA(A) receptors. Combined immunoblot and immunohistochemical data showed a widespread increase in KCC2 expression in FSL rats, as compared with control rats. The increase was more prominent in the cerebellum, where KCC2 was largely expressed in the granular layer. These data raise the interesting possibility that a spontaneous depressive state in animals is associated with an amplified GABAergic transmission in the CNS resulting from an enhanced expression of KCC2.


Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers.
Premutation carriers of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease characterized by motor, cognitive, and psychiatric decline as well as cerebellar and cerebral white matter pathology. Several studies have documented preclinical sensorimotor issues in aging premutation carriers, but the extent to which sensorimotor brain systems are affected and may represent early indicators of atypical neurodegeneration has not been determined. Eighteen healthy controls and 16 FMR1 premutation carriers (including five with possible, probable, or definite FXTAS) group-matched on age, sex, and handedness completed a visually guided precision gripping task with their right hand during fMRI. During the test, they used a modified pinch grip to press at 60% of their maximum force against a custom fiber-optic transducer. Participants viewed a horizontal white force bar that moved upward with increased force and downward with decreased force and a static target bar that was red during rest and turned green to cue the participant to begin pressing at the beginning of each trial. Participants were instructed to press so that the white force bar stayed as steady as possible at the level of the green target bar. Trials were 2-sec in duration and alternated with 2-sec rest periods. Five 24-sec blocks consisting of six trials were presented. Participants' reaction time, the accuracy of their force relative to the target force, and the variability of their force accuracy across trials were examined. BOLD signal change and task-based functional connectivity (FC) were examined during force vs. rest. Relative to healthy controls, premutation carriers showed increased trial-to-trial variability of force output, though this was specific to younger premutation carriers in our sample. Relative to healthy controls, premutation carriers also showed reduced extrastriate activation during force relative to rest. FC between ipsilateral cerebellar Crus I and extrastriate cortex was reduced in premutation carriers compared to controls. Reduced Crus I-extrastriate FC was related to increased force accuracy variability in premutation carriers. Increased reaction time was associated with more severe clinically rated neurological abnormalities. Findings of reduced activation in extrastriate cortex and reduced Crus I-extrastriate FC implicate deficient visual feedback processing and reduced cerebellar modulation of corrective motor commands. Our results are consistent with documented cerebellar pathology and visual-spatial processing in FXTAS and pre-symptomatic premutation carriers, and suggest FC alterations of cerebellar-cortical networks during sensorimotor behavior may represent a "prodromal" feature associated with FXTAS degeneration.


On the Brink of Genuinely Collaborative Care: Experience-Based Co-Design in Mental Health.
Inpatient mental health services in the United Kingdom are currently dissatisfactory for service-users and staff. For young people with psychosis, being hospitalized is often distressing, and can lead to disengagement with mental health services. This article describes how we took three qualitative research studies about hospitalization in early psychosis (exploring the perspectives of service-users, parents, and staff) and translated them into service improvements developed in collaboration with a range of stakeholders, including service-users, carers, community and inpatient staff, and management. We used an adapted form of experience-based co-design (EBCD), a participatory action-research method for collaboratively improving health care services. The use of EBCD is still relatively novel in mental health settings, and we discuss how we adapted the methodology, and some of the implications of using EBCD with vulnerable populations in complex services. We reflect on both the disappointments and successes and give some recommendations for future research and methodological development.


Access to immunology through the Gene Ontology.
The Gene Ontology (GO) is widely recognized as the premier tool for the organization and functional annotation of molecular aspects of cellular systems. However, for many immunologists the use of GO is a very foreign concept. Indeed, as a controlled vocabulary, GO can almost be considered a new language, and it can be difficult to appreciate the use and value of this approach for understanding the immune system. This review reflects on the application of GO to the field of immunology and explains the process of GO annotation. Finally, this review hopes to inspire immunologists to invest time and energy in improving both the content of the GO and the quality of GO annotations associated with genes of immunological interest.


Pneumonia in mice produced by Neisseria gonorrhoeae.
Gonococci of colony type 1 were introduced by intranasal inoculation into the lungs of mice in an attempt to produce infection. The organisms were eliminated from the three strains of mice used within 24 hours of challenge. Cyclophosphamide treatment of mice failed to render them susceptible although the organisms disappeared more slowly. The lungs of immunologically normal animals that had received either viable or heat-killed gonococci were acutely inflamed with infiltration of bronchioles and alveoli by polymorphonuclear and mononuclear leucocytes. Most of the changes had resolved after about four days. In cyclophosphamide-treated mice pulmonary infiltration by polymorphonuclear leucocytes was not evident, suggesting that these cells were not primarily responsible for the clearance of the gonococci. Despite the failure to produce a sustained infection, this model may be valuable for studying the local inflammatory effect of gonococcal endotoxin.


Feasibility of a left atrial electrical disconnection procedure for atrial fibrillation using transcatheter radiofrequency ablation.
An effective, catheter-based treatment for persistent atrial fibrillation (AF) remains elusive. This study assessed the feasibility of transcatheter left atrial (LA) electrical disconnection and its effect on AF inducibility. Thirteen anesthetized swine underwent noncontact mapping of the right atrium (RA) during coronary sinus (CS) pacing. Sites of earliest RA activation were identified using isopotential maps. An ablation catheter was navigated to these sites and a cluster of radiofrequency (RF) lesions applied until earliest activation shifted to a new site. The procedure was repeated until the atria were electrically disconnected. AF induction was attempted before and after ablation. Earliest RA activation was the CS os during proximal CS pacing and Bachmann's bundle during distal CS pacing. These two sites were successfully ablated in all 13 animals. Earliest activation then shifted to the fossa ovalis. RF energy was applied at a median of 2.5 sites (range 1 to 5) around the fossa, then at sites in the triangle of Koch, septum, cavotricuspid isthmus, and posterior wall. Atrial electrical disconnection was achieved in 10 of 13 animals (5 LA electrical disconnection, 3 RA electrical disconnection, 2 biatrial electrical disconnection with complete heart block). After atrial electrical disconnection, the LA became electrically silent. Before ablation, AF was inducible in every animal. After atrial electrical disconnection, AF was inducible in 3 of 10 animals. Atrial electrical disconnection is feasible using noncontact mapping and RF ablation. Successful electrical disconnection of the atria reduces AF inducibility. This approach is worthy of further evaluation as a management strategy for persistent AF, combined with device therapies.


Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with substance dependence: a systematic review and meta-analysis.
Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as an intervention for treating substance dependence. We aimed to assess evidence of the anti-craving and consumption-reducing effects of rTMS in patients with alcohol, nicotine and illicit drug dependence. A systematic review and meta-analysis of 26 randomized controlled trials (RCTs) published from January 2000 to October 2018 that investigated the effects of rTMS on craving and substance consumption in patients with nicotine, alcohol and illicit drug dependence (n = 748). Craving, measured using self-reported questionnaires or visual analog scale, and substance consumption, measured using self-report substance intake or number of addiction relapse cases, were considered as primary and secondary outcomes, respectively. Substance type, study design and rTMS parameters were used as the independent factors in the meta-regression. Results showed that excitatory rTMS of the left dorsolateral pre-frontal cortex (DLPFC) significantly reduced craving [Hedges' g = -0.62; 95% confidence interval (CI) = -0.89 to -0.35; P < 0.0001], compared with sham stimulation. Moreover, meta-regression revealed a significant positive association between the total number of stimulation pulses and effect size among studies using excitatory left DLPFC stimulation (P = 0.01). Effects of other rTMS protocols on craving were not significant. However, when examining substance consumption, excitatory rTMS of the left DLPFC and excitatory deep TMS (dTMS) of the bilateral DLPFC and insula revealed significant consumption-reducing effects, compared with sham stimulation. Excitatory repetitive transcranial magnetic stimulation of the dorsolateral pre-frontal cortex appears to have an acute effect on reducing craving and substance consumption in patients with substance dependence. The anti-craving effect may be associated with stimulation dose.


Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone.
Inhaled steroids are frequently used in childhood asthma, but concerns based on limited objective evidence remain, regarding long-term side-effects. In this study the systemic effects of standard doses of inhaled steroids in childhood asthma were assessed, comparing beclomethasone dipropionate (BDP) with fluticasone propionate (FP). The study was prospective, randomized and double-blind. Twenty-three steroid-naive children with moderately severe asthma, aged 5-10 yrs, were allocated either BDP (400 microg x day(-1) or FP (200 microg x day(-1)) using a metered-dose inhaler with a spacer. Asthma control was assessed at regular intervals over 20 months. Fasting morning blood and overnight urine samples were collected for estimation of serum cortisol, serum 1-carboxyterminal telopeptide (ICTP), serum osteocalcin and urine deoxypyridinoline (DPD). Bone mineral density (BMD) was measured at each visit. None of the markers of bone turnover showed any change during the study period. BMD increased at normal rates with age. Serum cortisol significantly decreased on BDP, but not on FP. A significant difference in growth rates was found between the groups, with a slower rate of growth towards the end of the observation period in the BDP group. In conclusion when taken in a relatively modest dose over a period of time, beclomethasone dipropionate had significant effects on the hypothalamic-pituitary-adrenal axis and statural growth in childhood asthma. These systemic effects were not seen with an equipotent dose of fluticasone propionate.


Visual field loss and vision-related quality of life in the Italian Primary Open Angle Glaucoma Study.
The aim of this study was to examine the relationship between visual field (VF) loss, vision-related quality of life (QoL) and glaucoma-related symptoms in a large cohort of primary open angle glaucoma (POAG) patients. POAG patients with or without VF defects or "glaucoma suspect" patients were considered eligible. QoL was assessed using the validated versions of the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and glaucoma-related symptoms were assessed using the Glaucoma Symptom Scale (GSS). Patients were classified as having VF damage in one eye (VFD-1), both eyes (VFD-2), or neither eye (VFD-0). 3227 patients were enrolled and 2940 were eligible for the analysis. 13.4% of patients were classified in the VFD-0, 23.7% in the VFD-1, and 62.9% in the VFD-2 group. GSS visual symptoms domain (Func-4) and GSS non-visual symptoms domain (Symp-6) scores were similar for the VFD-0 and VFD-1 groups (p = 0.133 and p = 0.834 for Func-4 and Symp-6, respectively). VFD-0 group had higher scores than VFD-2 both in Func-4 (p < 0.001) and Symp-6 domains (p = 0.035). Regarding the NEI-VFQ-25, our data demonstrated that bilateral VF defects are associated with vision-related QoL deterioration, irrespective of visual acuity.


Dopamine neuron agenesis in Nurr1-deficient mice.
Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson's disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth. Nurr1 expression continued into adulthood, and brains of heterozygous animals, otherwise apparently healthy, contained reduced dopamine levels. These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry.


Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial.
Herbal supplements are widely used for vasomotor symptoms. To test the efficacy of 3 herbal regimens and hormone therapy for relief of vasomotor symptoms compared with placebo. 1-year randomized, double-blind, placebo-controlled trial conducted from May 2001 to September 2004. Group Health, Washington State. 351 women age 45 to 55 years with 2 or more vasomotor symptoms per day; 52% of the women were in menopausal transition and 48% were postmenopausal. Rate and intensity of vasomotor symptoms (1 = mild to 3 = severe), and Wiklund Vasomotor Symptom Subscale. 1) Black cohosh, 160 mg daily; 2) multibotanical with black cohosh, 200 mg daily, and 9 other ingredients; 3) multibotanical plus dietary soy counseling; 4) conjugated equine estrogen, 0.625 mg daily, with or without medroxyprogesterone acetate, 2.5 mg daily; or 5) placebo. Vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale score did not differ between the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the follow-up time points (P > 0.05 for all comparisons) with 1 exception: At 12 months, symptom intensity was significantly worse with the multibotanical plus soy intervention than with placebo (P = 0.016). The difference in vasomotor symptoms per day between placebo and any of the herbal treatments at any time point was less than 1 symptom per day; for the average over all the follow-up time points, the difference was less than 0.55 symptom per day. The difference for hormone therapy versus placebo was -4.06 vasomotor symptoms per day for the average over all the follow-up time points (95% CI, -5.93 to -2.19 symptoms per day; P < 0.001). The trial did not simulate the whole-person approach used by naturopathic physicians. Differences between treatment groups smaller than 1.5 Vasomotor symptoms per day cannot be ruled out. Black cohosh used in isolation, or as part of a multibotanical regimen, shows little potential as an important therapy for relief of vasomotor symptoms. NCT00169299.


Outcomes of antiretroviral therapy in a northern Indian urban clinic.
Antiretroviral therapy (ART) programmes have been successful in several countries. However, whether they would succeed as part of a national programme in a resource-constrained setting such as India is not clear. The outcomes and specific problems encountered in such a setting have not been adequately studied. We assessed the efficacy and functioning of India's national ART programme in a tertiary care centre in northern India. All ART-naive patients started on ART between May 2005 and October 2006 were included in the study and were followed until 31 April 2008. Periodic clinical and laboratory evaluations were carried out in accordance with national guidelines. Changes in CD4+ lymphocyte count, body weight and body mass index were assessed at follow-up, and the operational problems analysed. The setting was a tertiary care centre in northern India with a mixed population of patients, mostly of low socioeconomic status. The centre is reasonably well resourced but faces constraints in health-care delivery, such as lack of adequate human resources and a high patient load. The response to ART in the cohort studied was comparable to that reported from other countries. However, the programme had a high attrition rate, possibly due to patient-related factors and operational constraints. A high rate of attrition can affect the overall efficacy and functioning of an ART programme. Addressing the issues causing attrition might improve patient outcomes in India and in other resource-constrained countries.


Osseous outgrowth on the buccal maxilla associated with piezosurgery-assisted en-masse retraction: A case series.
Piezoelectric surgery is a novel surgical approach used in orthodontic treatment for rapid tooth movement. This paper presents a case series wherein osseous outgrowths were observed in response to piezosurgery-assisted en-masse retraction. Sixteen patients requiring upper premolar extractions were treated with miniscrew-supported en-masse retraction and received minimally invasive decortication via piezosurgery. Computed tomography (CT) of the maxillary anterior region was performed to investigate the nature of the outgrowths. In 8 of the 16 patients, hemispheric or disc-shaped osseous outgrowths were observed on the sites where piezosurgery was performed during retraction. CT images revealed that these outgrowths were alveolar bone. This case series presents a previously unreported osseous response to piezosurgery-assisted tooth movement during orthodontic treatment. The response is mostly transient and is observed in 50% of the treated patients, suggesting a bone turnover that can be assessed clinically and radiographically.


Approaches to reduce the glycemic response of gluten-free products: in vivo and in vitro studies.
This article aims to discuss the current approaches used to reduce the postprandial glycemic response (GR) of starchy gluten-free products (GFP) and to provide some further prospects. The GR is evaluated through in vivo trials to determine the glycemic index (GI) and the glycemic load (GL) of foods or using the in vitro starch digestibility method to predict the GI. The reviewed studies demonstrated that a reduction in the GR of GFP can be achieved by replacing traditionally used refined flours and starches with nutrient-dense alternative raw materials due to an increase in dietary fiber, resistant starch and protein contents, which can alter the rate of starch digestion, reduce the GI and dilute the amount of available carbohydrate; both the factors contribute to reduce the GL. The addition of viscous dietary fibers could also be a successful way to reduce the GR of GFP. Some studies have demonstrated the potential of germination of GF grains and sourdough fermentation in decreasing the GR of GF bread. Further studies could evaluate alternative GF flours, soluble fibers, resistant starch, and other formulation factors that may affect the GR of different types of GFP. New studies should be performed to test and optimize processing methods by considering the reduction of GR of GFP. Another key aspect for further investigation is the confirmation of the promising results obtained through in vitro assays by in vivo GI evaluation.


Endosonography-guided pancreatic duct drainage for chronic pancreatitis: a case report and review.
A 50-year-old man was admitted to our department, complaining of epigastric pain and high fever. CT revealed a pseudocyst at the pancreatic head with upstream dilatation of the pancreatic duct (PD) and fluid collection surrounding the pancreas. Endosonography-guided PD drainage (ESPD) was performed because of unsuccessful ERCP. With a curved linear array echoendoscope, a 7.2 F catheter was placed in the PD. Laboratory data showed improvement in a few days and revealed disappearance of the fluid collection. Ten days after ESPD, a 7 F stent was placed in the PD via the puncture tract across the papilla of Vater followed by transpapillary replacement with a 10 F stent. CT showed a reduction in diameter of the PD and disappearance of the pseudocyst. ESPD is a feasible and useful procedure in selected patients with chronic pancreatitis showing stenosis of the main PD when transpapillary approach is impossible.


Persistent inflammation and endothelial dysfunction in patients with treated acromegaly.
Acromegaly is characterized by an excess of growth hormone (GH) and insulin-like growth factor 1 (IGF1). Cardiovascular disease (CVD) risk factors are common in acromegaly and often persist after treatment. Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Therefore, we hypothesized that inflammation persists in treated acromegaly and may contribute to CVD risk. In this cross-sectional study, we assessed cardiovascular structure and function, and inflammatory parameters in treated acromegaly patients. Immune cell populations and inflammatory markers were assessed in peripheral blood from 71 treated acromegaly patients (with controlled or uncontrolled disease) and 41 matched controls. Whole blood (WB) was stimulated with Toll-like receptor ligands. In a subgroup of 21 controls and 33 patients with controlled disease, vascular ultrasound measurements were performed. Leukocyte counts were lower in patients with controlled acromegaly compared to patients with uncontrolled acromegaly and controls. Circulating IL18 concentrations were lower in patients; concentrations of other inflammatory mediators were comparable with controls. In stimulated WB, cytokine production was skewed toward inflammation in patients, most pronounced in those with uncontrolled disease. Vascular measurements in controlled patients showed endothelial dysfunction as indicated by a lower flow-mediated dilatation/nitroglycerine-mediated dilatation ratio. Surprisingly, pulse wave analysis and pulse wave velocity, both markers of endothelial dysfunction, were lower in patients, whereas intima-media thickness did not differ. Despite treatment, acromegaly patients display persistent inflammatory changes and endothelial dysfunction, which may contribute to CVD risk and development of CVD.


A surface on the androgen receptor that allosterically regulates coactivator binding.
Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.


Long-Term Nutrient Enrichment of an Oligotroph-Dominated Wetland Increases Bacterial Diversity in Bulk Soils and Plant Rhizospheres.
In nutrient-limited conditions, plants rely on rhizosphere microbial members to facilitate nutrient acquisition, and in return, plants provide carbon resources to these root-associated microorganisms. However, atmospheric nutrient deposition can affect plant-microbe relationships by changing soil bacterial composition and by reducing cooperation between microbial taxa and plants. To examine how long-term nutrient addition shapes rhizosphere community composition, we compared traits associated with bacterial (fast-growing copiotrophs, slow-growing oligotrophs) and plant (C3 forb, C4 grass) communities residing in a nutrient-poor wetland ecosystem. Results revealed that oligotrophic taxa dominated soil bacterial communities and that fertilization increased the presence of oligotrophs in bulk and rhizosphere communities. Additionally, bacterial species diversity was greatest in fertilized soils, particularly in bulk soils. Nutrient enrichment (fertilized versus unfertilized) and plant association (bulk versus rhizosphere) determined bacterial community composition; bacterial community structure associated with plant functional group (grass versus forb) was similar within treatments but differed between fertilization treatments. The core forb microbiome consisted of 602 unique taxa, and the core grass microbiome consisted of 372 unique taxa. Forb rhizospheres were enriched in potentially disease-suppressive bacterial taxa, and grass rhizospheres were enriched in bacterial taxa associated with complex carbon decomposition. Results from this study demonstrate that fertilization serves as a strong environmental filter on the soil microbiome, which leads to distinct rhizosphere communities and can shift plant effects on the rhizosphere microbiome. These taxonomic shifts within plant rhizospheres could have implications for plant health and ecosystem functions associated with carbon and nitrogen cycling.IMPORTANCE Over the last century, humans have substantially altered nitrogen and phosphorus cycling. Use of synthetic fertilizer and burning of fossil fuels and biomass have increased nitrogen and phosphorus deposition, which results in unintended fertilization of historically low-nutrient ecosystems. With increased nutrient availability, plant biodiversity is expected to decline, and the abundance of copiotrophic taxa is anticipated to increase in bacterial communities. Here, we address how bacterial communities associated with different plant functional types (forb, grass) shift due to long-term nutrient enrichment. Unlike other studies, results revealed an increase in bacterial diversity, particularly of oligotrophic bacteria in fertilized plots. We observed that nutrient addition strongly determines forb and grass rhizosphere composition, which could indicate different metabolic preferences in the bacterial communities. This study highlights how long-term fertilization of oligotroph-dominated wetlands could alter diversity and metabolism of rhizosphere bacterial communities in unexpected ways.


Is tryptophan catabolism increased under indoleamine 2,3 dioxygenase activity during chronic lung inflammation in pigs?
In a preliminary study we observed that piglets suffering from chronic lung inflammation induced by an intravenous injection of complete Freund adjuvant showed a marked decrease in plasma tryptophan (Trp) concentration suggesting increased Trp utilisation. During the inflammatory process, a cytokine-induced enzyme called indoleamine 2,3-dioxygenase (IDO) has been shown to catabolise Trp into kynurenine (Kyn). Yet, during inflammation, increased Trp catabolism may decrease Trp availability for other functions such as growth. This metabolic pathway has never been studied in pigs. So, the objectives of this study were to measure IDO activity in pigs and to determine if the decrease in plasma Trp concentrations previously observed in piglets suffering from chronic lung inflammation could be explained by the induction of IDO activity. In order to do so, we compared IDO activity measured in the tracheo-bronchial lymph nodes and in the lungs of 7 piglets, injected with complete Freund adjuvant (CFA), to 7 pair-fed littermate healthy controls. Blood samples were taken at 0, 2, 5, 7 and 10 days following CFA injection in order to measure plasma Trp, Kyn and haptoglobin concentrations. Indoleamine 2,3-dioygenase activity in the tracheo-bronchial lymph nodes (P < 0.05), in the lungs (P < 0.07) and plasma haptoglobin (P < 0.01) were higher in pigs with lung inflammation than in the controls. Plasma Trp and Kyn were not significantly affected by CFA injection. Our data showed that IDO is activated under chronic lung inflammation in pigs. The impact of IDO activation on plasma Trp concentration and its availability is discussed according to the amount of Trp provided by the diet.


Modeling the population dynamics of lemon sharks.
Long-lived marine megavertebrates (e.g. sharks, turtles, mammals, and seabirds) are inherently vulnerable to anthropogenic mortality. Although some mathematical models have been applied successfully to manage these animals, more detailed treatments are often needed to assess potential drivers of population dynamics. In particular, factors such as age-structure, density-dependent feedbacks on reproduction, and demographic stochasticity are important for understanding population trends, but are often difficult to assess. Lemon sharks (Negaprion brevirostris) have a pelagic adult phase that makes them logistically difficult to study. However, juveniles use coastal nursery areas where their densities can be high. We use a stage-structured, Markov-chain stochastic model to describe lemon shark population dynamics from a 17-year longitudinal dataset at a coastal nursery area at Bimini, Bahamas. We found that the interaction between delayed breeding, density-dependence, and demographic stochasticity accounts for 33 to 49% of the variance in population size. Demographic stochasticity contributed all random effects in this model, suggesting that the existence of unmodeled environmental factors may be driving the majority of interannual population fluctuations. In addition, we are able to use our model to estimate the natural mortality rate of older age classes of lemon sharks that are difficult to study. Further, we use our model to examine what effect the length of a time series plays on deciphering ecological patterns. We find that-even with a relatively long time series-our sampling still misses important rare events. Our approach can be used more broadly to infer population dynamics of other large vertebrates in which age structure and demographic stochasticity are important. This article was reviewed by Yang Kuang, Christine Jacob, and Ollivier Hyrien.


New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia.
Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09 ∶ 01 (P = 1.36 × 10(-6); OR= 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02 ∶ 01 (P = 5.22 × 10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02 ∶ 01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55 × 10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.


Extra-axonal restricted diffusion as an in-vivo marker of reactive microglia.
Reactive microgliosis is an important pathological component of neuroinflammation and has been implicated in a wide range of brain diseases including brain tumors, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and schizophrenia. Mapping reactive microglia in-vivo is often performed with PET scanning whose resolution, cost, and availability prevent its widespread use. The advent of diffusion compartment imaging (DCI) to probe tissue microstructure in vivo holds promise to map reactive microglia using MRI scanners. But this potential has never been demonstrated. In this paper, we performed longitudinal DCI in rats that underwent dorsal root axotomy triggering Wallerian degeneration of axons-a pathological process which reliably activates microglia. After the last DCI at 51 days, rats were sacrificed and histology with Iba-1 immunostaining for microglia was performed. The fraction of extra-axonal restricted diffusion from DCI was found to follow the expected temporal dynamics of reactive microgliosis. Furthermore, a strong and significant correlation between this parameter and histological measurement of microglial density was observed. These findings strongly suggest that extra-axonal restricted diffusion is an in-vivo marker of reactive microglia. They pave the way for MRI-based microglial mapping which may be important to characterize the pathogenesis of neurological and psychiatric diseases.


The burden of chronic obstructive pulmonary disease and its attributable risk factors in the Middle East and North Africa region, 1990-2019.
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation. The present study reported the burden of COPD, and its attributable risk factors, in the Middle East and North Africa (MENA) region between 1990 and 2019, by age, sex and socio-demographic index (SDI). Data from the Global Burden of Disease (GBD) 2019 study were used to report the burden of COPD in the MENA countries. The prevalence, deaths, and disability-adjusted life-years (DALYs) were presented as counts and age-standardised rates per 100,000 population, with their associated 95% uncertainty intervals (UIs). In 2019, the regional age-standardised point prevalence and rates of death due to COPD were 2333.9 (2230.1, 2443.6) and 26.1 (22.2, 29.5) per 100,000, which represent a 30.6% (28.2%, 33.0%) increase and an 18.0% (2.8%, 30.9%) decrease, respectively, since 1990. The regional age-standardised DALY rate in 2019 was 649.1 (574.6, 717.7) per 100,000, which had decreased by 11.8% (0.9%, 21.1%) since 1990. Turkey had the highest age-standardised point prevalence in 2019 [3287.1 (3187.4, 3380.3)], while Afghanistan had the highest age-standardised death [40.4 (24.2, 52.6)] and DALY [964.5 (681.8, 1203.2)] rates. The regional age-standardised point prevalence, death and DALY rates in 2019 increased with advancing age and were higher in males in almost all age groups. There was a U-shaped association between SDI and the burden of COPD over the period 1990 to 2019. Moreover, in 2019 smoking (43.7%), ambient particulate matter pollution (22.8%) and occupational particulate matter (11.4%) had the largest proportion of attributable DALYs for both sexes. COPD is one of the leading causes of death and disability in the MENA region, although the age-standardised burden has decreased over the last 30 years. Nevertheless, COPD accounted for a substantial number of deaths and DALYs, especially among the elderly. Programs targeting risk factors, like smoking, should be taken into consideration.


Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor.
The Notch signaling pathway is essential in many cell fate decisions in invertebrates as well as in vertebrates. After ligand binding, a two-step proteolytic cleavage releases the intracellular part of the receptor which translocates to the nucleus and acts as a transcriptional activator. Although Notch-induced transcription of genes has been reported extensively, its endogenous nuclear form has been seldom visualized. We report that the nuclear intracellular domain of Notch1 is stabilized by proteasome inhibitors and is a substrate for polyubiquitination in vitro. SEL-10, an F-box protein of the Cdc4 family, was isolated in a genetic screen for Lin12/Notch-negative regulators in Caenorhabditis elegans. We isolated human and murine counterparts of SEL-10 and investigated the role of a dominant-negative form of this protein, deleted of the F-box, on Notch1 stability and activity. This molecule could stabilize intracellular Notch1 and enhance its transcriptional activity but had no effect on inactive membrane-anchored forms of the receptor. We then demonstrated that SEL-10 specifically interacts with nuclear forms of Notch1 and that this interaction requires a phosphorylation event. Taken together, these data suggest that SEL-10 is involved in shutting off Notch signaling by ubiquitin-proteasome-mediated degradation of the active transcriptional factor after a nuclear phosphorylation event.


Increasing temporal resolution of DSC perfusion MRI using the analytic image concept.
Dynamic susceptibility contrast MRI (DSC-MRI) is increasingly being used to evaluate cerebral microcirculation. In this study, the use of the analytic image reconstruction (AIR), with the aim to increase the temporal resolution, is evaluated for DSC-MRI in small animals. Imaging was performed using a T (2)*- weighted sequence to acquire male Lewis rats raw data. Results show that AIR satisfactory reconstructs DSC-MRI while preserving a good reconstruction quality and the image characteristics compared to the full k-space and keyhole reconstructed images. The combination of the choice of the baseline image and the proposed asymmetric acquisition schema enables an increase in temporal resolution, by a factor of four, thus having more sample points for better estimating perfusion parameters. Computer simulations result in a mean cerebral blood volume of 1.22 that deviates from the full k-space value by -3% and a mean cerebral blood flow of 1.97 deviating from the full k-space value by -3% when the mean transit time did not change. Even if these deviations increase when achieving real acquisitions, AIR still better computes quantitative values than keyhole. AIR allows a good reconstruction of the dynamic stage of the image series thus leading to better dynamic effects analysis.


Self-recovering caddisfly silk: energy dissipating, Ca(2+)-dependent, double dynamic network fibers.
Single fibers of the sticky underwater larval silk of the casemaker caddisfly (H. occidentalis) are viscoelastic, display large strain cycle hysteresis, and self-recover 99% of their initial stiffness and strength within 120 min. Mechanical response to cyclical strains suggested viscoelasticity is due to two independent, self-recovering Ca(2+)-crosslinked networks. The networks display distinct pH dependence. The first network is attributed to Ca(2+)-stabilized phosphoserine motifs in H-fibroin, the second to Ca(2+) complexed carboxylate groups in the N-terminus of H-fibroin and a PEVK-like protein. These assignments were corroborated by IR spectroscopy. The results are consolidated into a multi-network model in which reversible rupture of the Ca(2+)-crosslinked domains at a critical stress results in pseudo-plastic deformation. Slow refolding of the domains results in nearly full recovery of fiber length, stiffness, and strength. The fiber toughening, energy dissipation, and recovery mechanisms, are highly adaptive for the high energy aquatic environment of caddisfly larvae.


Age of Acquiring Causal Human Papillomavirus (HPV) Infections: Leveraging Simulation Models to Explore the Natural History of HPV-induced Cervical Cancer.
Although new human papillomavirus (HPV) infections can occur at all ages, the age at which women acquire their "causal" HPV infection that develops into cervical cancer is poorly understood and practically unobservable. We aimed to estimate the age distribution at which individuals acquired their causal HPV infection in the absence of HPV vaccination or screening to help guide the optimal use of both. Using an empirically calibrated mathematical model that simulates the natural history of cervical cancer, we estimated the cumulative number of causal HPV infections by age, stratified by HPV genotype (HPV16 vs. other HPV genotypes), and the direct age-specific reduction in cancer incidence for alternative vaccination initiation scenarios (i.e., age 9-45 years). Our model projected that among all cervical cancers, 50% and 75% of women acquired their causal HPV infection by ages 20.6 (range: 20.1-21.1) and 30.6 (range: 29.6-31.6) years, respectively. HPV16 infections were acquired at an earlier age. Assuming 95% efficacy against HPV16 and HPV18 infections, the direct reduction in lifetime risk of cervical cancer varied from 55% (53-56%) among women vaccinated at age 9 years to 6% (range: 6-7%) among women vaccinated at age 45 years. Similar patterns were observed for the second-generation vaccine. Although new HPV infections and precancers can occur throughout a woman's lifetime, only a small proportion are acquired in mid-adult women and are vaccine-preventable. Our simulations highlight the potential limitations of using surrogate endpoints for vaccine efficacy studies of mid-adult women to guide policy decisions for implementation.


[Acupuncture reflexotherapy of neurogenic bladder dysfunction in children with enuresis].
The urodynamics of the lower urinary tract was evaluated in 25 children treated for enuresis. The unstable bladder was observed in 16 patients. Twelve children with detrusor hyperreflexia comprised the largest group. Acupuncture was beneficial in 17 cases. The follow-up showed its detrusor-stabilizing effects in patients with neurogenic bladder dysfunctions. The success of the therapy is depended on the patients' mental and emotional status, concurrent abnormalities and accuracy in observing the practitioner's recommendations. The mechanisms of therapeutic effects of acupuncture are also discussed.


Positive transcriptional regulation of an iron-regulated virulence gene in Vibrio cholerae.
We have previously described a virulence gene in Vibrio cholerae (irgA) that is more than 850-fold regulated in response to iron. Negative regulation of irgA by iron occurred at the transcriptional level, and there was a dyad symmetric nucleotide sequence in the vicinity of the irgA promoter homologous to the Fur binding site in Escherichia coli. When irgA was cloned into E. coli, we showed that transcription of irgA required 900 base pairs of DNA upstream of the irgA promoter that contained an open reading frame in inverse orientation to irgA. In the present study, we show that this upstream region of DNA encodes a gene in inverse orientation to irgA (named irgB) that is also negatively regulated by iron. Insertional inactivation of irgB on the V. cholerae chromosome leads to loss of expression of a chromosomal irgA'-'phoA fusion (in which the primes indicate truncated genes), which is restored to normal by provision of irgB on a plasmid in trans. DNA sequencing of irgB shows that the protein product (IrgB) is homologous to the LysR family of positive transcriptional activators, and secondary structure analysis of IrgB predicts a helix-turn-helix DNA binding motif. The promoters of irgB and irgA are divergent but overlap each other and the previously defined Fur-binding site. We propose a model for iron regulation of irgA expression in V. cholerae. In the presence of sufficient iron, transcription of both irgA and irgB is negatively regulated by a Fur-like protein. In low iron conditions, negative regulation of transcription is removed, and production of IrgB leads to positive transcriptional activation of irgA. It seems likely that the high induction ratio of irgA expression under low- and high-iron conditions (850-fold) relates to the fact that its cognate positive transcriptional activator (irgB) is itself negatively regulated by iron.


Efficient synthesis of esters through oxone-catalyzed dehydrogenation of carboxylic acids and alcohols.
Since esters are important organic synthesis intermediates, an environmentally friendly oxone catalyzed-esterification of carboxylic acids with alcohols has been developed. A series of carboxylic acid esters are obtained in high yield. This strategy requires mild reaction conditions, providing an attractive alternative for the construction of valuable carbonyl esters. Electron-rich and electron-deficient groups are compatible with the standard conditions and a variety of substrates are demonstrated. Moreover, the reaction could easily be adapted to typical prodrugs, drugs and gram-scale synthesis.


Functional disability assessment.
The widespread introduction of computers into clinical settings has increased the feasibility of conducting comprehensive functional disability assessment. The Functional Status Questionnaire (FSQ) is a brief, self-administered questionnaire designed to facilitate clinical assessment of functional disability. The FSQ items can be scored by computer using a simple algorithm and summarized into disability index scores. These scales have alpha reliability coefficients of .64 to .82 and substantial convergent validity when used with primary care patients. Disability assessment tools like the FSQ can be adapted easily for clinical use by physical therapists.


The Evolution and Ecology of Bacterial Warfare.
Bacteria have evolved a wide range of mechanisms to harm and kill their competitors, including chemical, mechanical and biological weapons. Here we review the incredible diversity of bacterial weapon systems, which comprise antibiotics, toxic proteins, mechanical weapons that stab and pierce, viruses, and more. The evolution of bacterial weapons is shaped by many factors, including cell density and nutrient abundance, and how strains are arranged in space. Bacteria also employ a diverse range of combat behaviours, including pre-emptive attacks, suicidal attacks, and reciprocation (tit-for-tat). However, why bacteria carry so many weapons, and why they are so often used, remains poorly understood. By comparison with animals, we argue that the way that bacteria live - often in dense and genetically diverse communities - is likely to be key to their aggression as it encourages them to dig in and fight alongside their clonemates. The intensity of bacterial aggression is such that it can strongly affect communities, via complex coevolutionary and eco-evolutionary dynamics, which influence species over space and time. Bacterial warfare is a fascinating topic for ecology and evolution, as well as one of increasing relevance. Understanding how bacteria win wars is important for the goal of manipulating the human microbiome and other important microbial systems.


Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial.
Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24. This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for <3 months (glucocorticoid-initiating) or for ≥3 months (glucocorticoid-continuing) before screening. All patients <50 years old had a history of osteoporotic fracture. Glucocorticoid-continuing patients ≥50 years old had T scores of -2.0 or less (or -1.0 or less with fracture history). Patients were randomized (1:1) to receive denosumab 60 mg subcutaneously Q6M or risedronate 5 mg orally QD for 24 months, with daily calcium and vitamin D. Of 795 patients, 590 (74.2%) completed the study (in the glucocorticoid-initiating group, 109 of 145 patients treated with denosumab and 117 of 145 patients treated with risedronate; in the glucocorticoid-continuing group, 186 of 253 patients treated with denosumab and 178 of 252 patients treated with risedronate). Denosumab was superior to risedronate in increasing lumbar spine and total hip BMD at all time points assessed, among glucocorticoid-initiating patients (24-month lumbar spine: BMD increase of 6.2% versus 1.7%, respectively [P < 0.001]; 24-month total hip: BMD increase of 3.1% versus 0.0% [P < 0.001]) and among glucocorticoid-continuing patients (24-month lumbar spine: BMD increase of 6.4% versus 3.2% [P < 0.001]; 24-month total hip: BMD increase of 2.9% versus 0.5% [P < 0.001]). Adverse events, serious adverse events (including infections), and fractures were similar between treatment groups. Denosumab was superior to risedronate in terms of increases in spine and hip BMD through month 24, and the safety profile was similar between treatment groups. Denosumab may offer a new osteoporosis treatment option for glucocorticoid-treated patients.


Dual inhibitors of β-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates.
Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer's disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multitarget anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.