EuPathDomains: the divergent domain database for eukaryotic pathogens.
Eukaryotic pathogens (e.g. Plasmodium, Leishmania, Trypanosomes, etc.) are a major source of morbidity and mortality worldwide. In Africa, one of the most impacted continents, they cause millions of deaths and constitute an immense economic burden. While the genome sequence of several of these organisms is now available, the biological functions of more than half of their proteins are still unknown. This is a serious issue for bringing to the foreground the expected new therapeutic targets. In this context, the identification of protein domains is a key step to improve the functional annotation of the proteins. However, several domains are missed in eukaryotic pathogens because of the high phylogenetic distance of these organisms from the classical eukaryote models. We recently proposed a method, co-occurrence domain detection (CODD), that improves the sensitivity of Pfam domain detection by exploiting the tendency of domains to appear preferentially with a few other favorite domains in a protein. In this paper, we present EuPathDomains (http://www.atgc-montpellier.fr/EuPathDomains/), an extended database of protein domains belonging to ten major eukaryotic human pathogens. EuPathDomains gathers known and new domains detected by CODD, along with the associated confidence measurements and the GO annotations that can be deduced from the new domains. This database significantly extends the Pfam domain coverage of all selected genomes, by proposing new occurrences of domains as well as new domain families that have never been reported before. For example, with a false discovery rate lower than 20%, EuPathDomains increases the number of detected domains by 13% in Toxoplasma gondii genome and up to 28% in Cryptospordium parvum, and the total number of domain families by 10% in Plasmodium falciparum and up to 16% in C. parvum genome. The database can be queried by protein names, domain identifiers, Pfam or Interpro identifiers, or organisms, and should become a valuable resource to decipher the protein functions of eukaryotic pathogens.


Asthma management in British South Asian children: an application of the candidacy framework to a qualitative understanding of barriers to effective and accessible asthma care.
In the UK, people of South Asian origin with asthma experience excess morbidity, with hospitalisation rates three times those of the majority White population and evidence suggests that South Asian children with asthma are more likely to suffer uncontrolled symptoms and hospital admissions with acute asthma compared to White British children. This paper draws on data from The Management and Interventions for Asthma (MIA) study to identify the operation of barriers to optimal care and good asthma control for South Asian children. The MIA study followed a multi-phase, iterative, participatory design, underpinned by the socio-ecological model. Findings presented here are from face-to face, semi-structured interviews with South Asian (Indian, Pakistani and Bangladeshi origin) parents and carers of a child with asthma (n = 49). Interviews were conducted in English or relevant South Asian languages using specially trained community facilitators. Data were transcribed verbatim and analysed according to the principles of interpretive thematic analysis, facilitated by the use of NVivo. Seven dimensions of candidacy are identified: identification of candidacy; navigation; the permeability of asthma services; appearances at health services; adjudications; offers and resistance and operating conditions in the local production of candidacy. The analysis demonstrates several ways in which a potential lack of alignment between the priorities and competencies of British South Asian families and the organization of health services combine to create vulnerabilities and difficulties in effectively managing childhood asthma. Healthcare systems have a responsibility to develop services that are sensitive and appropriate to the needs of their communities. In South Asian communities, further efforts are required to raise awareness of symptoms and effectively communicate how, when and where to seek help for children. There is a need for improved diagnosis and consistent, effectively communicated information, especially regarding medication. Parents made several suggestions for improving services: presentations about asthma at easily accessible community venues; an advice centre or telephone helpline to answer queries; opportunities for sharing experiences with other families; having information provided in South Asian languages; longer GP appointments; extended use of asthma nurses; and better education for healthcare professionals to ensure consistency of care and advice.


Does level of motivation for change impact post-treatment outcomes in the eating disorders? Protocol for a systematic review with quantitative analysis.
Eating Disorders are highly prevalent and widespread mental health problems, with marked risk of chronicity and refractoriness to treatment. Affected individuals are hesitant to change their behaviours and therefore struggle to maintain motivation for therapy. This review aims to produce the first high-quality meta-analysis of the literature on the impact of level of motivation for change on post-treatment outcomes in anorexia nervosa, bulimia nervosa, binge-eating disorder, and other specified feeding or eating disorder (OSFED). A systematic review will be conducted using Cochrane library, Embase, MEDLINE, and PsychINFO. Research registrars and bibliographies of included articles will be screened, and experts will be contacted. The search strategy consists of terms related to eating disorders, motivation, and outcome. Randomized controlled trials, clinical controlled trials, time series, and before-after studies will be included. Participants will be adolescents and adults who are diagnosed with anorexia nervosa, bulimia nervosa, binge-eating disorder or OSFED and who are entering psychotherapy treatment. The predictor studied is defined as motivation for change at the beginning of treatment. The primary outcome will be an overall change in eating-disorder symptomatology at the end of treatment and at less than, and over 6-month follow-up. Other outcomes of interest include change in restricting, binging, and compensatory behaviours, change in shape, weight and eating concerns, change in psychiatric comorbidities, weight restoration, and dropout rates. Articles will be selected, data will be extracted, and the risk of bias will be assessed by independent reviewers using forms pre-created on Eppi-Reviewer 4 software. Results will be combined using a random-effects model. Studies of all sizes and qualities will be included in the analyses. Heterogeneity will be examined by funnel plot, Cochran's Q, and I2 statistic. Sensitivity analyses will be performed to account for clinical and methodological differences across studies. This systematic review will help determine the predictive value of motivation for change on treatment outcomes in eating disorders. Our systematic review protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42016035285). All modifications will be available on the PROSPERO website, along with the dates, a description, and a justification.


Total synthesis and biochemical characterization of mirror image barnase.
In this study we synthesized and characterized mirror image barnase (B. amyloliquefaciens ribonuclease). d-Barnase was identical to l-barnase, when analyzed by liquid chromatography and mass-spectrometry. Proteolysis of the mirror image enzyme revealed that in contrast to its native counterpart, d-barnase was completely stable to digestive proteases. In enzymatic assays, d-barnase had the reciprocal chiral specificity and was fully active towards mirror image substrates. Interestingly, d-barnase also hydrolyzed the substrate of the native chirality, albeit 4000 times less efficiently. This effect was further confirmed by digesting a native 112-mer RNA with the enzyme. Additional studies revealed that barnase accommodates a range of substrates with various chiralities, but the prime requirement for guanosine remains. These studies point toward using mirror image enzymes as modern agents in biotechnology.


Characteristics of human fingertips in the shearing direction.
The shearing strain of the human fingertip plays an important role in the determination of the optimal grasping force and in the perception of texture. Most research concerned with the mechanical impedance of the human fingertips has treated the orthogonal direction to the tip surface, and little attention has been paid to the tangential direction. This paper describes impedance characteristics of the human fingertips in the tangential directions to the tip surface. In the experiment, step and ramp shearing forces were individually applied to the tips of the thumb, middle finger, and little finger. Dynamics of the fingertips were represented by the Kelvin model. Experimental results show that each fingertip had different properties with respect to the shearing strain versus the applied force, and that the thumb had the strongest shearing stiffness among these three digits. Moreover, the shearing stiffness depended on the direction of the applied force, and the stiffness in the pointing direction was stronger than that in the perpendicular direction. As the contact force in the orthogonal direction to the fingertip surface was increased, the shearing stiffness and viscosity increased without regard to the load speed of the shearing force. Furthermore, it is shown that the average strain rate of the fingertip in the tangential direction to the fingertip surface became slower and converged to a constant value with higher contact forces.


The G protein regulators EGL-10 and EAT-16, the Giα GOA-1 and the G(q)α EGL-30 modulate the response of the C. elegans ASH polymodal nociceptive sensory neurons to repellents.
Polymodal, nociceptive sensory neurons are key cellular elements of the way animals sense aversive and painful stimuli. In Caenorhabditis elegans, the polymodal nociceptive ASH sensory neurons detect aversive stimuli and release glutamate to generate avoidance responses. They are thus useful models for the nociceptive neurons of mammals. While several molecules affecting signal generation and transduction in ASH have been identified, less is known about transmission of the signal from ASH to downstream neurons and about the molecules involved in its modulation. We discovered that the regulator of G protein signalling (RGS) protein, EGL-10, is required for appropriate avoidance responses to noxious stimuli sensed by ASH. As it does for other behaviours in which it is also involved, egl-10 interacts genetically with the G(o)/(i)α protein GOA-1, the G(q)α protein EGL-30 and the RGS EAT-16. Genetic, behavioural and Ca²(+) imaging analyses of ASH neurons in live animals demonstrate that, within ASH, EGL-10 and GOA-1 act downstream of stimulus-evoked signal transduction and of the main transduction channel OSM-9. EGL-30 instead appears to act upstream by regulating Ca²(+) transients in response to aversive stimuli. Analysis of the delay in the avoidance response, of the frequency of spontaneous inversions and of the genetic interaction with the diacylglycerol kinase gene, dgk-1, indicate that EGL-10 and GOA-1 do not affect signal transduction and neuronal depolarization in response to aversive stimuli but act in ASH to modulate downstream transmission of the signal. The ASH polymodal nociceptive sensory neurons can be modulated not only in their capacity to detect stimuli but also in the efficiency with which they respond to them. The Gα and RGS molecules studied in this work are conserved in evolution and, for each of them, mammalian orthologs can be identified. The discovery of their role in the modulation of signal transduction and signal transmission of nociceptors may help us to understand how pain is generated and how its control can go astray (such as chronic pain) and may suggest new pain control therapies.


Long-term evaluation of a trauma center-based juvenile driving intervention program.
Motor vehicle-related trauma remains the leading cause of adolescent injury and death in the United States. We previously reported results from the Drive Alive (DA) program-a comprehensive juvenile prevention program that highlights risky driving behavior and consequences-and demonstrated a reduction in recidivism 6 months after its completion. We further evaluated the results of the original and subsequent participants on a long-term basis. Bureau of Motor Vehicle records of all individuals who had completed the DA program were prospectively reviewed. This 4-week, Level I trauma center-based program provides 10 contact hours of exposure to mock trauma sessions, drug and alcohol education, former trauma patients and their families, state troopers and other pertinent driving safety, educational, and prevention topics. The County Juvenile Court ordered participation after driving-related convictions. The driving records were compared with a control group consisting of adolescents convicted of similar driving offenses in the same period, not referred to the DA program. Comparisons were made at 6 monthly intervals up to 60 months using Fischer's exact test. A total of 488 teens (346 male and 142 female) completed the DA program between May 2003 and October 2008. Mean participant age was 17.4 years. Speeding and driving under the influence of alcohol were the most frequent reasons for referral. Consistent with our prior results, this interactive intervention for juvenile driving offenders resulted in a statistically significant reduction in driving-related offenses for the 6-month periods after its completion. This effect is lost in the long term. The role of booster interventions at 6 months and beyond, as adjuncts to initial interventional prevention initiatives, needs to be explored to aid sustained positive effects in this population of drivers.


Freezing of living cells: mechanisms and implications.
Cells can endure storage at low temperatures such as--196 degrees C for centuries. The challenge is to determine how they can survive both the cooling to such temperatures and the subsequent return to physiological conditions. A major factor is whether they freeze intracellularly. They do so if cooling is too rapid, because with rapid cooling insufficient cell water is removed osmotically to eliminate supercooling. Equations have been developed that describe the kinetics of this water loss and permit one to predict the likelihood of intracellular freezing as a function of cooling rate. Such predictions agree well with observations. Although the avoidance of intracellular freezing is usually necessary for survival, it is not sufficient. Slow freezing itself can be injurious. As ice forms outside the cell, the residual unfrozen medium forms channels of decreasing size and increasing solute concentration. The cells lie in the channels and shrink in osmotic response to the rising solute concentration. Prior theories have ascribed slow freezing injury to the concentration of solutes or the cell shrinkage. Recent experiments, however, indicate that the damage is due more to the decrease in the size of the unfrozen channels. This new view of the mechanism of slow freezing injury ought to facilitate the development of procedures for the preservation of complex assemblages of cells of biological, medical, and agricultural significance.


Nuclear factor kappa-B and histopathology of chronic gastritis.
Studies suggest that nuclear factor kappa-B (NFkappaB) activation may be a critical event in the production of proinflammatory molecules in Helicobacter pylori-associated gastritis. This study examines the expression and activity of NFkappaB in situ in antral biopsies of 42 consecutive patients with immunohistochemical techniques. NFkappaB was highly expressed in the gastric epithelial cells. The number of cells showing activated NFkappaB correlated with the activity of gastritis (P < 0.05), a measure of neutrophil influx, whereas no correlation was found with the chronicity of inflammation, a measure of the presence of mononuclear inflammatory cells. There was also a strong inverse association with the presence and grade of atrophy. This correlation is direct evidence of the importance of NFkappaB dependent signal transduction for neutrophil influx in gastritis. The role of NFkappaB appears to be only in the initial stages of gastritis, there is no role for the molecule in the development of chronic inflammation or atrophy.


Superficial Siderosis With Verrucous Vegetation Around a Dural Defect Confirmed by Intraoperative Ultrasonography.
Superficial siderosis (SS) of the central nervous system (CNS) is a rare disease caused by repeated hemorrhages in the subarachnoid space. We describe surgical treatment of an SS case in which a dural defect with verrucous vegetation in the spinal canal was detected by intraoperative ultrasonography (US). After laminectomy, intraoperative US imaging confirmed verrucous vegetation and epidural fluid collection around the ventral dural defect before incision of the posterior dura mater. As intraoperative US also showed a dural defect at the ventral and right sides of the spinal cord, the posterior dural incision was made in a manner that was slightly more right lateral than standard midline. The ventral dural defect was repaired by direct sutures. After repair, intraoperative US imaging confirmed dural hole closure, removal of vegetation and resolution of the collected fluid. Dural closure was successful and symptoms partially improved despite the patient's long history of SS. Intraoperative US can help surgeons make decisions about precise dural incision before repair. Intraoperative US is useful for detecting the level of dural defect and verrucous vegetation before repair and confirming closure of the dural defect, successful removal of vegetation and resolution of fluid collection after repair.


Genome Sequencing of Sulfolobus sp. A20 from Costa Rica and Comparative Analyses of the Putative Pathways of Carbon, Nitrogen, and Sulfur Metabolism in Various Sulfolobus Strains.
The genome of Sulfolobus sp. A20 isolated from a hot spring in Costa Rica was sequenced. This circular genome of the strain is 2,688,317 bp in size and 34.8% in G+C content, and contains 2591 open reading frames (ORFs). Strain A20 shares ~95.6% identity at the 16S rRNA gene sequence level and <30% DNA-DNA hybridization (DDH) values with the most closely related known Sulfolobus species (i.e., Sulfolobus islandicus and Sulfolobus solfataricus), suggesting that it represents a novel Sulfolobus species. Comparison of the genome of strain A20 with those of the type strains of S. solfataricus, Sulfolobus acidocaldarius, S. islandicus, and Sulfolobus tokodaii, which were isolated from geographically separated areas, identified 1801 genes conserved among all Sulfolobus species analyzed (core genes). Comparative genome analyses show that central carbon metabolism in Sulfolobus is highly conserved, and enzymes involved in the Entner-Doudoroff pathway, the tricarboxylic acid cycle and the CO2 fixation pathways are predominantly encoded by the core genes. All Sulfolobus species encode genes required for the conversion of ammonium into glutamate/glutamine. Some Sulfolobus strains have gained the ability to utilize additional nitrogen source such as nitrate (i.e., S. islandicus strain REY15A, LAL14/1, M14.25, and M16.27) or urea (i.e., S. islandicus HEV10/4, S. tokodaii strain7, and S. metallicus DSM 6482). The strategies for sulfur metabolism are most diverse and least understood. S. tokodaii encodes sulfur oxygenase/reductase (SOR), whereas both S. islandicus and S. solfataricus contain genes for sulfur reductase (SRE). However, neither SOR nor SRE genes exist in the genome of strain A20, raising the possibility that an unknown pathway for the utilization of elemental sulfur may be present in the strain. The ability of Sulfolobus to utilize nitrate or sulfur is encoded by a gene cluster flanked by IS elements or their remnants. These clusters appear to have become fixed at a specific genomic site in some strains and lost in other strains during the course of evolution. The versatility in nitrogen and sulfur metabolism may represent adaptation of Sulfolobus to thriving in different habitats.


A prospective, randomized comparison of traditional and laparoscopic inguinal exploration in children.
The indications for routine exploration of the asymptomatic contralateral groin during pediatric herniorrhaphy remain controversial. Laparoscopy through the open hernia sac has been described as an alternative to this traditional approach and appears to offer some advantages. In deciding whether this technique should be introduced into our clinical practice, we sought to discover whether there was a significant time difference between these two methods and if there were unique complications associated with this approach. We elected to answer this question in a prospective, randomized study. A total of 18 patients completed the study. There were no significant complications in either group. The average total surgical procedure time in the laparoscopy group was 47.5 minutes versus 41 minutes in the traditional group, which is not a statistically significant difference. We conclude from this prospective, randomized pilot study that laparoscopic exploration can be introduced into a pediatric surgical practice without a significant time penalty, and we currently offer it as a reasonable and safe alternative to our patients.


Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation.
SOX10 is a member of the SOX gene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the RET promoter; and Sox10 binding sites identified in the P0 promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the SOX10 mutants appeared to correlate with the intestinal and/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET transcription may lead to intestinal aganglionosis, overexpression of genes coding for structural myelin proteins such as P0 due to mutant SOX10 may explain the dysmyelination phenotype observed in the patients with an additional neurological disorder.


Levels of cytokines in the aqueous humor of eyes with primary open angle glaucoma, pseudoexfoliation glaucoma and cataract.
The focus of this study aimed at measuring multiple inflammatory cytokines levels in the aqueous humor of patients with primary open angle glaucoma (POAG), pseudoexfoliation glaucoma (PEXG) and senile cataract. This case control study was conducted at the Research Institute of Ophthalmology, Giza, Egypt in 2016. Aqueous humor (AH) samples were withdrawn from 50 patients (30 POAG, and 20 PEXG) and from 15 patients with senile cataract serving as controls. The levels of IL6, IL8, transforming growth factor β1 (TGFβ1), tumor necrosis growth factor α (TNFα) and serum amyloid A (SAA) were analyzed by ELISA immune-assay. Data were analyzed by SPSS 10, using Pearson Product-Moment Correlation and independent-samples t-test. The levels of IL8, TGFβ1, TNFα and SAA were significantly higher in POAG and PEXG patients, compared to senile cataract patients. While the levels of IL6, were significantly decreased in both groups of glaucoma patients compared to cataract patients. Significant positive correlations were detected between IL6, IL 8 & TGF β1, IL 8; SAA, IL8 & TGFβ1, SAA in the aqueous humor of different groups. Thus the assayed cytokines including TGFβ1, TNFα, IL8 and SAA in aqueous humor, play a vital role in IOP elevations in patients with POAG and PEXG.


In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2-infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug's safety profile. Hydroxychloroquine (EC50 = 0.72 μM) was found to be more potent than chloroquine (EC50 = 5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.


Kinetic simulations of the self-focusing and dissipation of finite-width electron plasma waves.
Two-dimensional simulations, both Vlasov and particle-in-cell, are presented that show the evolution of the field and electron distribution of finite-width, nonlinear electron plasma waves. The intrinsically intertwined effects of self-focusing and dissipation of field energy caused by electron trapping are studied in simulated systems that are hundreds of wavelengths long in the transverse direction but only one wavelength long and periodic in the propagation direction. From various initial wave states, both the width at focus Δm relative to the initial width Δ0 and the maximum field amplitude at focus are shown to be a function of the growth rate of the transverse modulational instability γTPMI divided by the loss rate of field energy νE to electrons escaping the trapping region. With dissipation included, an amplitude threshold for self-focusing γTPMI/νE∼1 is found that supports the analysis of Rose [Phys. Plasmas 12, 012318 (2005)].


The orphan nuclear receptor NGFIB regulates transcription of 3beta-hydroxysteroid dehydrogenase. implications for the control of adrenal functional zonation.
3beta-Hydroxysteroid dehydrogenase type 2 (HSD3B2) is a steroid-metabolizing enzyme that is essential for adrenal production of mineralocorticoids and glucocorticoids. Thus, HSD3B2 is expressed at high levels in the glomerulosa and fasciculata, where these steroids are produced. In contrast, the production of dehydroepiandrosterone (DHEA) and DHEA sulfate in the adrenal reticularis is inversely correlated with the expression of HSD3B2. The reasons for the zonal expression of HSD3B2 are not known but represent an important aspect in the biochemical zonation of the adrenal. Using microarray, real time reverse transcriptase-PCR, immunohistochemistry, and HSD3B2 promoter analysis, we demonstrate that the NGFIB family of nuclear hormone receptors plays a critical part in the regulation of HSD3B2 transcription and may play an important role in the functional zonation of the adrenal gland. Microarray analysis of cortisol- versus DHEA sulfate-producing adrenal tissue demonstrated that NGIFB paralleled expression of HSD3B2 with expression much higher in cortisol-producing adrenal tissue; this observation was also demonstrated using real time reverse transcriptase-PCR analysis. In addition, immunohistochemistry confirmed that within adult and fetal adrenal gland NGFIB expression paralleled expression of HSD3B2. Transient transfections into H295R adrenal cells demonstrated that NGFIB family members enhanced HSD3B2 reporter activity but had no effect on a 17alpha-hydroxylase (CYP17) promoter construct. Deletion and mutational analyses of the 5'-flanking region of the HSD3B2 gene identified a consensus NGFIB response element that bound NGFIB in mobility shift assays. Infection of cultured human adrenal cells with adenovirus-containing NGFIB increased cortisol production by 8-fold and increased expression of HSD3B2 mRNA 26-fold over that observed in mock-infected cells. In primary cultures of adrenal cells, ACTH, an activator of HSD3B2, rapidly induced expression of NGFIB. These results suggest that NGFIB plays a crucial role in adrenal zonation by regulating HSD3B2 gene transcription.


Prediction of partitioning between complex organic mixtures and water: application of polyparameter linear free energy relationships.
Equilibrium partitioning between nonaqueous phase liquids (NAPLs) and water is a governing process for contaminants leaching from NAPLs. Conventional prediction methods, such as Raoult's law and single-parameter linear free energy relationship (SP-LFER), are inaccurate for compounds with polar functional groups. Therefore, this study introduces a polyparameter linear free energy relationship (PP-LFER) approach as a more general tool to predict NAPL-water partitioning coefficients. Our approach was evaluated using 441 experimental partitioning data from 30 references. Experimental fuel-water partitioning coefficients were generally well reproduced by existing PP-LFERs for pure solvents using either a volume-fraction weighted sum of partitioning coefficients K (linear model, R2 = 0.983, root-mean-squared error [rmse] = 0.23) or a volume-fraction weighted sum of log K (log linear model, R2 = 0.976, rmse = 0.28). Using the linear model, estimations were, in most cases, within a factor of 2 from the experimental values, regardless of the type of compounds and the presence of a fuel additive. In contrast, the log linear model considerably underestimated partitioning coefficients in the presence of strong solute-solvent hydrogen bonding. For coal tar-water partitioning coefficients (Kcoal tar/w), new PP-LFER equations were calculated based on experimental log Kcoal tar/w values of 35 compounds. The resulting regression equation was log Kcoal tar/w = 0.40(+/-0.33) + 0.34(+/-0.32)E+ 0.61(+/-0.57)S-0.55-(+/-0.61)A-5.07(+/-0.61)B + 3.22(+/-0.35)V with the rmse equal to 0.21, where E, S, A, B, and Vare Abraham's solute descriptors. Partitioning coefficients for phenol and alcohols, calculated by the above equation, were much closer to the experimental values than to those estimated by the SP-LFER approach with octanol-water partitioning coefficients. The values of the coefficients also provide insight into the properties of coal tar in terms of molecular interactions with solutes. Consequently, using the approaches presented in this study, complex organic mixture-water partitioning coefficients of a wide range of organic compounds with varying polarity can be reasonably estimated.


Intragenic CpG islands play important roles in bivalent chromatin assembly of developmental genes.
CpG, 5'-C-phosphate-G-3', islands (CGIs) have long been known for their association with enhancers, silencers, and promoters, and for their epigenetic signatures. They are maintained in embryonic stem cells (ESCs) in a poised but inactive state via the formation of bivalent chromatin containing both active and repressive marks. CGIs also occur within coding sequences, where their functional role has remained obscure. Intragenic CGIs (iCGIs) are largely absent from housekeeping genes, but they are found in all genes associated with organ development and cell lineage control. In this paper, we investigated the epigenetic status of iCGIs and found that they too reside in bivalent chromatin in ESCs. Cell type-specific DNA methylation of iCGIs in differentiated cells was linked to the loss of both the H3K4me3 and H3K27me3 marks, and disruption of physical interaction with promoter regions, resulting in transcriptional activation of key regulators of differentiation such as PAXs, HOXs, and WNTs. The differential epigenetic modification of iCGIs appears to be mediated by cell type-specific transcription factors distinct from those bound by promoter, and these transcription factors may be involved in the hypermethylation of iCGIs upon cell differentiation. iCGIs thus play a key role in the cell type-specific regulation of transcription.


Non-contrast enhanced MR angiography: physical principles.
Noncontrast-enhanced magnetic resonance angiography (NCE-MRA) methods have been demonstrated in anatomies throughout the body. Previously established NCE-MRA techniques suffered from long scan times or low sensitivity. Advances in hardware and software have made NCE-MRA scan times clinically feasible. Recent concerns over the safety of gadolinium-based contrast material combined with the expense of the material and its administration have generated a demand for NCE-MRA. In response, several new NCE-MRA methods have been developed. The physical mechanisms underlying five general classes of NCE-MRA methods (inflow effect, flow-dependency on cardiac phase, flow-encoding, spin labeling, and relaxation) are explained. The original techniques of time-of-flight (TOF) and phase contrast MRA (PC-MRA) are briefly introduced. New developments in NCE-MRA, including hybrid of opposite-contrast (HOP-MRA), four dimensional PC-MRA (4D Flow), cardiac-gated 3D fast-spin-echo, flow-sensitive dephasing (FSD), arterial spin labeling (ASL), and balanced steady-state free-precession (bSSFP) are highlighted. The primary applications, advantages, and limitations of established and emerging NCE-MRA techniques are discussed.


Stimulus rivalry and binocular rivalry share a common neural substrate.
When two incompatible images are shown separately to each eye, a perceptual process known as binocular rivalry occurs by which the two images compete for awareness. The site of competition for binocular rivalry has been a topic of debate, and recent theories are that it may occur either at low levels of the visual system where the inputs from the two eyes are combined or at high levels of the visual system where the two images are processed. One of the major pieces of evidence for a high-level image account of rivalry is a phenomenon known as stimulus rivalry, in which two competing stimuli are swapped between the eyes at 3 Hz. However, there is little available neurophysiological evidence for a neural substrate for this high-level competition. Here, we used frequency tagging of two competing stimuli in binocular rivalry and stimulus rivalry in humans to evaluate whether the steady-state visually evoked potentials (SSVEPs) show similar signatures of neural competition for both conditions. We found that flickering the stimuli generates spectral power at the tagged frequencies in both types of rivalry in the early visual cortex. We then quantified dynamic signatures of competition by tracking amplitude changes in the frequency tags, which showed that both types of rivalry colocalized in occipital regions of the cortex. Thus, contrary to our hypothesis that stimulus rivalry was being mediated by high-level competition between the images, we find that neural competition measured by the SSVEP instead suggests that the sites of competition for stimulus rivalry and binocular rivalry may similarly include the occipital pole and middle temporal gyrus (hMT+/V5) of the visual system, consistent with a low-level, binocular interpretation.


The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development.
The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.


Specific growth inhibitors of Ralstonia solanacearum, Xanthomonas oryzae pv. oryzae, X. campestris pv. campestris, and Clavibacter michiganensis subsp. michiganensis.
Plant pathogenic bacteria cause huge yield losses in crops globally. Therefore, finding effective bactericides to these pathogens is an immediate challenge. In this study, we sought compounds that specifically inhibit the growth of Ralstonia solanacearum. As a result, we identified one promising compound, 1-(4-bromophenyl)-6-methoxy-2,3,4,9-tetrahydro-1H-β-carboline, which inhibited the growth of R. solanacearum (Rs1002) from a pilot library of 376 chemicals provided from RIKEN. We further obtained its structural analogues and assessed their ability to inhibit Rs1002 growth. Then we identified five compounds, named ralhibitins A to E, that specifically inhibit growth of Rs1002 at >5 μg/ml final concentration. The most effective compounds, ralhibitins A, C, and E completely inhibited the growth of Rs1002 at 1.25 μg/ml. In addition, ralhibitins A to E inhibited growth of Xanthomonas oryzae pv. oryzae but not the other bacteria tested at a final concentration of 10 μg/ml. Whereas, ralhibitin E, besides inhibiting R. solanacearum and X. oryzae pv. oryzae, completely inhibited the growth of X. campestris pv. campestris and the Gram-positive bacterium Clavibacter michiganensis subsp. michiganensis at 10 μg/ml. Growth inhibition by these compounds was stable at pH 6-9 and after autoclaving. Because Rs1002 grew in the culture medium in which ralhibitins were incubated with the ralhibitin-insensitive bacteria, the unaffected bacteria may be able to inactivate the inhibitory effect of ralhibitins. These results suggest that ralhibitins might be potential lead compounds for the specific control of phytopathogenic bacteria.


Cold-field switching in PVDF-TrFE ferroelectric polymer nanomesas.
Polarization reversal in ferroelectric nanomesas of polyvinylidene fluoride with trifluoroethylene has been probed by ultrahigh vacuum piezoresponse force microscopy in a wide temperature range from 89 to 326 K. In dramatic contrast to the macroscopic data, the piezoresponse force microscopy local switching was nonthermally activated and, at the same time, occurring at electric fields significantly lower than the intrinsic switching threshold. A "cold-field" defect-mediated extrinsic switching is shown to be an adequate scenario describing this peculiar switching behavior. The extrinsic character of the observed polarization reversal suggests that there is no fundamental bar for lowering the coercive field in ferroelectric polymer nanostructures, which is of importance for their applications in functional electronics.


Calcium-dependent stimulation of renal medullary prostaglandin synthesis by furosemide.
The present study examined the actions of furosemide and other "loop" diuretics on immunoreactive prostaglandin E (iPGE) and [14C]arachidonate (AA) release in vitro in incubates of slices from rat and dog outer or inner medulla. The loop diuretics furosemide, ethacrynic acid, bumetanide and 3-benzylamino-4-phenylthio-5-sulfamoylbenzoic acid all significantly increased [14C]AA and iPGE release (1.5- to 4-fold) into the media of rat outer and inner medulla and dog outer medullary slice incubates. By contrast, equimolar concentrations of chlorothiazide and hydrochlorothiazide were without effects on these parameters. Stimulation of [14C]AA or iPGE by furosemide was abolished by exclusion of Ca++ from the incubation media or by addition of verapamil to complete media, but was not altered by exclusion of Na+. Ca++-free media or verapamil also abolished the increases in [14C]AA and iPGE induced by ionophore A23187. By contrast, these incubation conditions did not influence the iPGE responses to hypertonic mannitol or exogenous AA. The presence of Ca++-responsive acyl hydrolase activity was demonstrated in the microsomal fraction from rat outer medulla. However, this activity was not altered by addition of furosemide to the subcellular fraction in the presence or absence of Ca++. Thus, furosemide and other loop diuretics stimulate renal medullary iPGE synthesis in vitro, and may do so through Ca++-mediated or dependent enhancement of the release of AA.


Histologic and immunohistochemical characteristics of neoplastic and nonneoplastic subgroups of atypical squamous lesions of the uterine cervix.
Atypical squamous lesion (ASL), a histologic diagnosis of unclear significance in the uterine cervix, can be divided into neoplastic and nonneoplastic groups. We aimed to determine the morphologic characteristics of these 2 groups. Histologic and immunohistochemical features were evaluated on the original biopsy specimen from 37 ASL cases, and the results were compared between neoplastic (19 cases) and nonneoplastic (18 cases) groups, which were determined based on the follow-up histopathologic findings. Mitosis, vertical nuclear growth pattern, no perinuclear halo, indistinct cytoplasmic border, primitive cells in the upper third of the squamous layer, p16+ cells in the upper two thirds of the squamous layer, and Ki-67+ cells in the upper two thirds of the squamous layer were significant indicators for neoplastic ASLs. Of the 19 neoplastic ASLs, 16 (84%) had 5 or more of these 7 indicators. The majority (16/18 [89%]) of the nonneoplastic ASLs had 2 or fewer indicators. Determination of the histologic and immunohistochemical characteristics is useful for distinguishing neoplastic and nonneoplastic ASLs.


Carnivore hotspots in Peninsular Malaysia and their landscape attributes.
Mammalian carnivores play a vital role in ecosystem functioning. However, they are prone to extinction because of low population densities and growth rates, and high levels of persecution or exploitation. In tropical biodiversity hotspots such as Peninsular Malaysia, rapid conversion of natural habitats threatens the persistence of this vulnerable group of animals. Here, we carried out the first comprehensive literature review on 31 carnivore species reported to occur in Peninsular Malaysia and updated their probable distribution. We georeferenced 375 observations of 28 species of carnivore from 89 unique geographic locations using records spanning 1948 to 2014. Using the Getis-Ord Gi*statistic and weighted survey records by IUCN Red List status, we identified hotspots of species that were of conservation concern and built regression models to identify environmental and anthropogenic landscape factors associated with Getis-Ord Gi* z scores. Our analyses identified two carnivore hotspots that were spatially concordant with two of the peninsula's largest and most contiguous forest complexes, associated with Taman Negara National Park and Royal Belum State Park. A cold spot overlapped with the southwestern region of the Peninsula, reflecting the disappearance of carnivores with higher conservation rankings from increasingly fragmented natural habitats. Getis-Ord Gi* z scores were negatively associated with elevation, and positively associated with the proportion of natural land cover and distance from the capital city. Malaysia contains some of the world's most diverse carnivore assemblages, but recent rates of forest loss are some of the highest in the world. Reducing poaching and maintaining large, contiguous tracts of lowland forests will be crucial, not only for the persistence of threatened carnivores, but for many mammalian species in general.


Patient satisfaction and efficacy of accent radiofrequency for facial skin wrinkle reduction.
Radiofrequency (RF) is a new technique to treat facial wrinkles. This study was designed to assess the efficacy of Accent RF in wrinkle reduction of different areas of the face. Patients with mild to severe facial wrinkles were treated with Accent using RF energies of 35-145 W. The average energy used in this study was 83.11 W. Patients received four subsequent weekly RF sessions. Wrinkle improvement was rated by two physicians comparing 6-month post treatment photographs with pretreatment photos. Moreover, patient satisfaction was assessed at 1 and 6 months after the last session of the treatment. A total of 45 women participated in this study. In terms of patient satisfaction one month after the last treatment, 8.9% of the patients declared their dissatisfaction, 53.3% were somehow satisfied, 33.3% were satisfied, and 4.4% were very satisfied. At 6 months, patient satisfaction was as follows: 4.4% dissatisfied, 31.1% somehow satisfied, 46.7% satisfied, and 17.8% very satisfied. Patient satisfaction 6 months after the last treatment was significantly higher than 1 month post treatment (P = 0.006). At 6 months, patient satisfaction was not more than 75% in any treatment areas of the face. The results of this study suggest that Accent RF may be considered as a possible effective option for facial skin rejuvenation although its efficacy and safety needs to be evaluated further in randomized controlled trials.


The language of violence in mental health: shifting the paradigm to the language of peace.
Language used in health care, particularly with vulnerable populations such as those with mental illness, is often violent, rising from historical prejudices and politics of power over others. This creates disharmony and distrust between health care providers and patients and families. Peace involves relationships that nurture ongoing harmony, trust, and constructive solutions. In this descriptive philosophical article, we discuss connections between and among the concepts of peace, health, relational ethics, in relation to nurses' responsibilities, current health care realities, and the language of nursing. We propose a shift in discourse within nurse-patient relationships from oppressive and stigmatizing language to the discourse of peace.


World Trade Center-related physical and mental health burden among New York City Fire Department emergency medical service workers.
To describe the health burden among Fire Department of the City of New York (FDNY) emergency medical service (EMS) workers and examine its association with work at the World Trade Center (WTC) disaster site. In this observational cohort study, we used FDNY physician diagnoses to estimate the cumulative incidence of physical health conditions including rhinosinusitis, gastroesophageal reflux disease (GERD), obstructive airways disease (OAD) and cancer among EMS workers and demographically similar firefighters who were active on 11 September 2001 (9/11). Validated screening instruments were used to estimate the prevalence of probable post-traumatic stress disorder (PTSD), probable depression and probable harmful alcohol use. We also analysed the association between health conditions and WTC-exposure. Among 2281 EMS workers, the 12-year post-9/11 cumulative incidence (11 September 2001 to 31 December 2013) of rhinosinusitis was 10.6%; GERD 12.1%; OAD 11.8%; cancer 3.1%. The prevalence of probable PTSD up to 12 years after exposure was 7%; probable depression 16.7%; and probable harmful alcohol use 3%. Compared with unexposed, EMS workers who arrived earliest at the site had higher adjusted relative risks (aRR) for most conditions, including rhinosinusitis (aRR=3.7; 95% CI 2.2 to 6.0); GERD (aRR=3.8; 95% CI 2.4 to 6.1); OAD (aRR=2.4: 95% CI 1.7 to 3.6); probable PTSD (aRR=7.0; 95% CI 3.6 to 13.5); and, probable depression (aRR=2.3; 95% CI 1.6 to 3.1). In this 12-year study, we documented a high burden of health conditions associated with WTC-exposure among FDNY EMS workers. These findings underscore the importance of continued monitoring and treatment of this workforce.


Methylational urinalysis: a prospective study of bladder cancer patients and age stratified benign controls.
Tumour suppressor gene (TSG) methylation has been proposed as a diagnostic marker for urothelial cancer (UC). Here, we compare the frequency of urinary TSG methylation in young and elderly patients, with and without UC. Urine samples were obtained prospectively from 35 UC patients, 35 benign controls over the age of 70 years and 34 healthy volunteers under the age of 40 years. Methylation analysis was performed for eight gene promoters using quantitative methylation-specific PCR. Methylation was detected in urine DNA from all three patient groups. The highest frequencies were seen in UC patients. Significantly less methylation was present in control samples than UC cases for RASSF1a and APC (P < 0.034). The 'methylation index' and level of methylation was highest in the UC group and lowest in the young control group. A marker panel of RASSF1a, E-cad and APC generated a sensitivity of 69%, a specificity of 60% and a diagnostic accuracy of 86%. TSG methylation is detectable in urine DNA from patients with and without bladder cancer. The frequency and extent of methylation appears to increase with age and malignancy. The lack of tumour specificity suggests that further investigation is required before this test is introduced into clinical practice.


Analysis of Haemophilus parasuis by multilocus enzyme electrophoresis.
The diversity among 40 Australian isolates and eight reference strains of Haemophilus parasuis was examined using multilocus enzyme electrophoresis. Thirty-four electrophoretic types (ETs) were recognized with a mean diversity per locus of 0.405. One Australian isolate was located in an ET separated by a considerable distance (> 0.8) from the rest of the isolates, suggesting that it may represent a different species or subspecies. The remaining 33 ETs formed two distinct divisions (A and B), separated from each other by a distance of 0.506. All 12 Australian isolates of serovar 5 plus the two reference strains for this serovar were included in Division A. The only other isolates present in this Division were Australian isolates of serovars 4 and 13 and two nontypeable isolates. Division B contained a diverse range of serovars-Australian isolates of serovars 1, 2, 7/10, 9 and 13 as well as the reference strains for serovars 1, 2, 3, 4, 8 and 9. These results supported other studies which demonstrated considerable diversity, and indicate that the population of H. parasuis may contain more than a single species or subspecies. There was considerable diversity even amongst isolates of the same serovar, indicating that serotyping is not a particularly suitable technique for strain typing in epidemiological studies.


Collectin CL-LK Is a Novel Soluble Pattern Recognition Receptor for Mycobacterium tuberculosis.
Understanding the molecular components of immune recognition of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, can help designing novel strategies to combat TB. Here, we identify collectin CL-LK as a novel soluble C-type lectin able to bind M. tuberculosis, and characterize mycobacterial mannose-capped lipoarabinomannan as a primary ligand for CL-LK. Mice deficient in CL-K1, one of the CL-LK subunits, do not display altered susceptibility to M. tuberculosis. However, we found that the amount of CL-LK in the serum of patients with active TB is reduced, compared to that in controls, and correlates inversely to the magnitude of the immune response to the pathogen. These findings indicate that CL-LK might be of interest for future diagnostic and treatment monitoring purposes.


Herbicide resistance evolution can be tamed by diversity in irrigated Australian cotton: a multi-species, multi-herbicide modelling approach.
Because herbicide resistance evolves in very large populations over periods of many years, modelling is an important tool for investigating the dynamics of the problem. The Diversity model tracks the simultaneous evolution of resistance to multiple herbicides, using multiple genetic pathways, in several weed species at once. Tracking multiple species and simultaneous resistances is an important development in resistance modelling. We used the Diversity model to test weed management strategies for new cropping cotton varieties with multiple herbicide tolerances ('triple-stacked' varieties), in an Australian context. The diversity required for long-term control of three key weeds in Australian cotton goes beyond using three herbicides, especially where there is already a substantial background of existing resistance to one or more of these herbicides. Assuming some glyphosate resistance is already present, simulations showed that glyphosate-resistant summer grass populations reach 20 000 seeds m-2 within 12 years using the triple-stack herbicides (glyphosate, glufosinate and dicamba) and a minimum of other tactics. Adding three pre-emergent modes of action plus cultivation to the system effectively controls glyphosate-resistant grasses for over 30 years. In conditions where resistance genes are as frequent as 1 in 100, however, highly fecund weeds such as Conyza bonariensis are hard to control beyond 15 years even with very highly diverse management. Stacked herbicide tolerances in new crop varieties offers potential for increased herbicide diversity, but existing glyphosate-resistant weed populations need substantial extra management beyond what a glyphosate/glufosinate/dicamba resistance stack provides. More diverse systems can provide robust management over 30 years in the absence of very high levels of background resistance to other herbicides. © 2018 Society of Chemical Industry.


Stimulus Load and Oscillatory Activity in Higher Cortex.
Exploring and exploiting a rich visual environment requires perceiving, attending, and remembering multiple objects simultaneously. Recent studies have suggested that this mental "juggling" of multiple objects may depend on oscillatory neural dynamics. We recorded local field potentials from the lateral intraparietal area, frontal eye fields, and lateral prefrontal cortex while monkeys maintained variable numbers of visual stimuli in working memory. Behavior suggested independent processing of stimuli in each hemifield. During stimulus presentation, higher-frequency power (50-100 Hz) increased with the number of stimuli (load) in the contralateral hemifield, whereas lower-frequency power (8-50 Hz) decreased with the total number of stimuli in both hemifields. During the memory delay, lower-frequency power increased with contralateral load. Load effects on higher frequencies during stimulus encoding and lower frequencies during the memory delay were stronger when neural activity also signaled the location of the stimuli. Like power, higher-frequency synchrony increased with load, but beta synchrony (16-30 Hz) showed the opposite effect, increasing when power decreased (stimulus presentation) and decreasing when power increased (memory delay). Our results suggest roles for lower-frequency oscillations in top-down processing and higher-frequency oscillations in bottom-up processing.


Adherence to Artesunate-Amodiaquine Therapy for Uncomplicated Malaria in Rural Ghana: A Randomised Trial of Supervised versus Unsupervised Drug Administration.
Introduction. To enhance effective treatment, african nations including Ghana changed its malaria treatment policy from monotherapy to combination treatment with artesunate-amodiaquine (AS+AQ). The major challenge to its use in loose form is adherence. Objective. The objectives of this study were to investigate adherence and treatment outcome among patients treated with AS+AQ combination therapy for acute uncomplicated malaria. Methodology. The study was conducted in two rural districts located in the middle belt of Ghana using quantitative methods. Patients diagnosed with acute uncomplicated malaria as per the Ghana Ministry of Health malaria case definitions were randomly allocated to one of two groups. All patients in both groups were educated about the dose regimen of AS+AQ therapy and the need for adherence. Treatment with AS+AQ was supervised in one group while the other group was not supervised. Adherence was assessed by direct observation of the blister package of AS+AQ left on day 2. Results. 401 participants were randomized into the supervised (211) and unsupervised (190) groups. Compliance in both supervised (95.7%) and unsupervised (92.6%) groups were similar (P = .18). The commonest side-effects reported on day 2 among both groups were headaches, and body weakness. Parasite clearance by day 28 was >95% in both groups. Discussion/Conclusions. Administration of AS-AQ in both groups resulted in high levels of adherence to treatment regimen among adolescent and adult population in central Ghana. It appears that high level of adherence to AS-AQ is achievable through a rigorous education programme during routine clinic visits.


Variation in the MC4R gene is associated with bone phenotypes in elderly Swedish women.
Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p≤0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.


Spectral modulation for full linear polarimetry.
Linear (spectro) polarimetry is usually performed using separate photon flux measurements after spatial or temporal polarization modulation. Such classical polarimeters are limited in sensitivity and accuracy by systematic effects and noise. We describe a spectral modulation principle that is based on encoding the full linear polarization properties of light in its spectrum. Such spectral modulation is obtained with an optical train of an achromatic quarter-wave retarder, an athermal multiple-order retarder, and a polarizer. The emergent spectral modulation is sinusoidal with its amplitude scaling with the degree of linear polarization and its phase scaling with the angle of linear polarization. The large advantage of this passive setup is that all polarization information is, in principle, contained in a single spectral measurement, thereby eliminating all differential effects that potentially create spurious polarization signals. Since the polarization properties are obtained through curve fitting, the susceptibility to noise is relatively low. We provide general design options for a spectral modulator and describe the design of a prototype modulator. Currently, the setup in combination with a dedicated retrieval algorithm can be used to measure linear polarization signals with a relative accuracy of 5%.


Neurodegeneration in Type 2 Diabetes: Evidence From Spectral-Domain Optical Coherence Tomography.
The purpose of this study was to assess changes in the neural retina in eyes with different stages of diabetic retinopathy (DR) in comparison to age-matched healthy subjects. Retrospective analysis of spectral-domain optical coherence tomography (SD-OCT) scans of 76 naïve eyes of 62 subjects with diabetes was performed. Key exclusion criteria included presence of diabetic macular edema, any other retinal disease, history of any treatment for DR, or incorrect segmentation of the retinal layers on SD-OCT scans. Eyes from diabetic patients were divided into three groups, including no DR, nonproliferative DR (NPDR), and proliferative DR (PDR). A control group of 67 eyes of 66 age-matched healthy volunteers was included for comparison. Average, minimum, and sectoral thicknesses for the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) were collected from both groups and compared using an ANOVA test. Among the 76 included eyes, 43 had NPDR, 13 had PDR, and 20 had no signs of DR. Average and minimum GCIPL showed significant thinning in diabetic subjects compared with controls in all stages of DR (P < 0.05), especially involving the papillo-macula bundle. However, GCIPL thickness was similar between diabetic groups. There was no significant difference in average or sectoral RNFL thicknesses among groups; however, the minimum RNFL thickness was lower in diabetics compared with controls (P < 0.05). No relationship between GCIPL and RNFL thicknesses and duration of diabetes was present. Early thinning on the inner retina happens in type 2 diabetes, even before visible vascular signs of DR. This supports the presence of a neurodegenerative process in eyes of patients with diabetes and warrants neuroprotective intervention to prevent chronic neurodegeneration. The SD-OCT may represent an indispensable tool for identifying early signs of neurodegeneration in diabetic patients.


Sex-biased gene expression is repeatedly masculinized in asexual females.
Males and females feature strikingly different phenotypes, despite sharing most of their genome. A resolution of this apparent paradox is through differential gene expression, whereby genes are expressed at different levels in each sex. This resolution, however, is likely to be incomplete, leading to conflict between males and females over the optimal expression of genes. Here we test the hypothesis that gene expression in females is constrained from evolving to its optimum level due to sexually antagonistic selection on males, by examining changes in sex-biased gene expression in five obligate asexual species of stick insect, which do not produce males. We predicted that the transcriptome of asexual females would be feminized as asexual females do not experience any sexual conflict. Contrary to our prediction we find that asexual females feature masculinized gene expression, and hypothesise that this is due to shifts in female optimal gene expression levels following the suppression of sex.


A high density genetic map of tobacco (Nicotiana tabacum L.) obtained from large scale microsatellite marker development.
Tobacco (Nicotiana tabacum L.) is a species in the large family of the Solanaceae and is important as an agronomic crop and as a model system in plant biotechnology. Despite its importance, only limited molecular marker resources are available that can be used for genome analysis, genetic mapping and breeding. We report here on the development and characterization of 5,119 new and functional microsatellite markers and on the generation of a high-resolution genetic map for the tetraploid tobacco genome. The genetic map was generated using an F2 mapping population derived from the intervarietal cross of Hicks Broadleaf × Red Russian and merges the polymorphic markers from this new set with those from a smaller set previously used to produce a lower density map. The genetic map described here contains 2,317 microsatellite markers and 2,363 loci, resulting in an average distance between mapped microsatellite markers which is less than 2 million base pairs or 1.5 cM. With this new and expanded marker resource, a sufficient number of markers are now available for multiple applications ranging from tobacco breeding to comparative genome analysis. The genetic map of tobacco is now comparable in marker density and resolution with the best characterized genomes of the Solanaceae: tomato and potato.


Calcium-dependent phosphorylation alters class XIVa myosin function in the protozoan parasite Toxoplasma gondii.
Class XIVa myosins comprise a unique group of myosin motor proteins found in apicomplexan parasites, including those that cause malaria and toxoplasmosis. The founding member of the class XIVa family, Toxoplasma gondii myosin A (TgMyoA), is a monomeric unconventional myosin that functions at the parasite periphery to control gliding motility, host cell invasion, and host cell egress. How the motor activity of TgMyoA is regulated during these critical steps in the parasite's lytic cycle is unknown. We show here that a small-molecule enhancer of T. gondii motility and invasion (compound 130038) causes an increase in parasite intracellular calcium levels, leading to a calcium-dependent increase in TgMyoA phosphorylation. Mutation of the major sites of phosphorylation altered parasite motile behavior upon compound 130038 treatment, and parasites expressing a nonphosphorylatable mutant myosin egressed from host cells more slowly in response to treatment with calcium ionophore. These data demonstrate that TgMyoA undergoes calcium-dependent phosphorylation, which modulates myosin-driven processes in this important human pathogen.


Conducting systematic evidence reviews: core concepts and lessons learned.
A systematic review (SR) is an essential component of evidence-based practice, because it synthesizes information on a particular topic that is necessary to inform health-related decision making. The purpose of this article is to document the process of producing a high-quality SR within the field of rehabilitation in contrast to other fields (eg, pharmaceutic research). We describe the notable methodologic challenges to producing high-quality SRs for rehabilitation researchers. Broadly, we outline how the quality of SRs is evaluated and suggest mechanisms for researchers to address potential pitfalls. Because meaningful SRs can and should be conducted in this field, we provide practical guidance regarding how to conduct such an SR. We outline a series of 8 important steps in the production of an SR: forming a committee, creating a development plan, conducting a literature review, selecting articles for inclusion, extracting data, preparing tables of evidence, facilitating external review and publication, and forming conclusions and recommendations. For each step of the SR process, we provide detailed description about the methodologic decisions involved and recommended strategies that researchers can implement to produce a high-quality SR. Using these preestablished steps and procedures as a guideline will not only help to increase the efficiency of the SR process, but also to improve the quality. The availability of high-quality SRs with plain language summaries promotes access to the best quality information for all involved in decision making.


Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.
Sertraline is one among several selective serotonin reuptake inhibitors (SSRIs) that exhibited improvement of language development in Autism Spectrum Disorder (ASD); however, the molecular mechanism has not been elucidated. A double blind, randomized, 6-month, placebo-controlled, clinical trial of low-dose sertraline in children ages (3-6 years) with ASD was conducted at the UC Davis MIND Institute. It aimed at evaluating the efficacy and benefit with respect to early expressive language development and global clinical improvement. This study aimed to identify molecular biomarkers that might be key players in the serotonin pathway and might be predictive of a clinical response to sertraline. Fifty eight subjects with the diagnosis of ASD were randomized to sertraline or placebo. Eight subjects from the sertraline arm and five from the placebo arm discontinued from the study. Furthermore, four subjects did not have a successful blood draw. Hence, genotypes for 41 subjects (20 on placebo and 21 on sertraline) were determined for several genes involved in the serotonin pathway including the serotonin transporter-linked polymorphic region (5-HTTLPR), the tryptophan hydroxylase 2 (TPH2), and the Brain-Derived Neurotrophic Factor (BDNF). In addition, plasma levels of BDNF, Matrix metallopeptidase 9 (MMP-9) and a selected panel of cytokines were determined at baseline and post-treatment. Intent-to-treat analysis revealed several primary significant correlations between molecular changes and the Mullen Scales of Early Learning (MSEL) and Clinical Global Impression Scale - Improvement (CGI-I) of treatment and control groups but they were not significant after adjustment for multiple testing. Thus, sertraline showed no benefit for treatment of young children with ASD in language development or changes in molecular markers in this study. These results indicate that sertraline may not be beneficial for the treatment of children with ASD; however, further investigation of larger groups as well as longer term follow-up studies are warranted.


Depolymerization of Hydroxylated Polymers via Light-Driven C-C Bond Cleavage.
The accumulation of persistent plastic waste in the environment is widely recognized as an ecological crisis. New chemical technologies are necessary both to recycle existing plastic waste streams into high-value chemical feedstocks and to develop next-generation materials that are degradable by design. Here, we report a catalytic methodology for the depolymerization of a commercial phenoxy resin and high molecular weight hydroxylated polyolefin derivatives upon visible light irradiation near ambient temperature. Proton-coupled electron transfer (PCET) activation of hydroxyl groups periodically spaced along the polymer backbone furnishes reactive alkoxy radicals that promote chain fragmentation through C-C bond β-scission. The depolymerization produces well-defined and isolable product mixtures that are readily diversified to polycondensation monomers. In addition to controlling depolymerization, the hydroxyl group modulates the thermomechanical properties of these polyolefin derivatives, yielding materials with diverse properties. These results demonstrate a new approach to polymer recycling based on light-driven C-C bond cleavage that has the potential to establish new links within a circular polymer economy and influence the development of new degradable-by-design polyolefin materials.


In vivo Molecular Signatures of Cervical Spinal Cord Pathology in Degenerative Compression.
Degenerative cervical myelopathy (DCM) is a severe consequence of degenerative cervical spinal cord (CSC) compression. The non-myelopathic stage of compression (NMDC) is highly prevalent and often progresses to disabling DCM. This study aims to disclose markers of progressive neurochemical alterations in NMDC and DCM by utilizing an approach based on state-of-the-art proton magnetic resonance spectroscopy (1H-MRS). Proton-MRS data were prospectively acquired from 73 participants with CSC compression and 47 healthy controls (HCs). The MRS voxel was centered at the C2 level. Compression-affected participants were clinically categorized as NMDC and DCM, radiologically as mild (MC) or severe (SC) compression. CSC volumes and neurochemical concentrations were compared between cohorts (HC vs. NMDC vs. DCM and HC vs. MC vs. SC) with general linear models adjusted for age and height (pFWE < 0.05) and correlated to stenosis severity, electrophysiology, and myelopathy symptoms (p < 0.05). Whereas the ratio of total creatine (tCr) to total N-acetylaspartate (tNAA) increased in NMDC (+11%) and in DCM (+26%) and SC (+21%), myo-inositol/tNAA, glutamate + glutamine/tNAA, and volumes changed only in DCM (+20%, +73%, and -14%) and SC (+12%, +46%, and -8%, respectively) relative to HCs. Both tCr/tNAA and myo-inositol/tNAA correlated with compression severity and volume (-0.376 < r < -0.259). Myo-inositol/tNAA correlated with myelopathy symptoms (r = -0.670), whereas CSC volume did not. Short-echo 1H-MRS provided neurochemical signatures of CSC impairment that reflected compression severity and clinical significance. Whereas volumetry only reflected clinically manifest myelopathy (DCM), MRS detected neurochemical changes already before the onset of myelopathy symptoms.


Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the use of a quadrivalent human papillomavirus (HPV) vaccine licensed by the U.S. Food and Drug Administration on June 8, 2006. This report summarizes the epidemiology of HPV and associated diseases, describes the licensed HPV vaccine, and provides recommendations for its use for vaccination among females aged 9-26 years in the United States. Genital HPV is the most common sexually transmitted infection in the United States; an estimated 6.2 million persons are newly infected every year. Although the majority of infections cause no clinical symptoms and are self-limited, persistent infection with oncogenic types can cause cervical cancer in women. HPV infection also is the cause of genital warts and is associated with other anogenital cancers. Cervical cancer rates have decreased in the United States because of widespread use of Papanicolaou testing, which can detect precancerous lesions of the cervix before they develop into cancer; nevertheless, during 2007, an estimated 11,100 new cases will be diagnosed and approximately 3,700 women will die from cervical cancer. In certain countries where cervical cancer screening is not routine, cervical cancer is a common cancer in women. The licensed HPV vaccine is composed of the HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein in yeast using recombinant DNA technology produces noninfectious virus-like particles (VLP) that resemble HPV virions. The quadrivalent HPV vaccine is a mixture of four HPV type-specific VLPs prepared from the L1 proteins of HPV 6, 11, 16, and 18 combined with an aluminum adjuvant. Clinical trials indicate that the vaccine has high efficacy in preventing persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts caused by HPV types 6, 11, 16, or 18 among females who have not already been infected with the respective HPV type. No evidence exists of protection against disease caused by HPV types with which females are infected at the time of vaccination. However, females infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types. The vaccine is administered by intramuscular injection, and the recommended schedule is a 3-dose series with the second and third doses administered 2 and 6 months after the first dose. The recommended age for vaccination of females is 11-12 years. Vaccine can be administered as young as age 9 years. Catch-up vaccination is recommended for females aged 13--26 years who have not been previously vaccinated. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.


Alien plant invasions and native plant extinctions: a six-threshold framework.
Biological invasions are widely acknowledged as a major threat to global biodiversity. Species from all major taxonomic groups have become invasive. The range of impacts of invasive taxa and the overall magnitude of the threat is increasing. Plants comprise the biggest and best-studied group of invasive species. There is a growing debate; however, regarding the nature of the alien plant threat-in particular whether the outcome is likely to be the widespread extinction of native plant species. The debate has raised questions on whether the threat posed by invasive plants to native plants has been overstated. We provide a conceptual framework to guide discussion on this topic, in which the threat posed by invasive plants is considered in the context of a progression from no impact through to extinction. We define six thresholds along the 'extinction trajectory', global extinction being the final threshold. Although there are no documented examples of either 'in the wild' (Threshold 5) or global extinctions (Threshold 6) of native plants that are attributable solely to plant invasions, there is evidence that native plants have crossed or breached other thresholds along the extinction trajectory due to the impacts associated with plant invasions. Several factors may be masking where native species are on the trajectory; these include a lack of appropriate data to accurately map the position of species on the trajectory, the timeframe required to definitively state that extinctions have occurred and management interventions. Such interventions, focussing mainly on Thresholds 1-3 (a declining population through to the local extinction of a population), are likely to alter the extinction trajectory of some species. The critical issue for conservation managers is the trend, because interventions must be implemented before extinctions occur. Thus the lack of evidence for extinctions attributable to plant invasions does not mean we should disregard the broader threat.


Efficient gene silencing mediated by tobacco rattle virus in an emerging model plant physalis.
The fruit of Physalis has a berry and a novelty called inflated calyx syndrome (ICS, also named the 'Chinese lantern'). Elucidation of the underlying developmental mechanisms of fruit diversity demands an efficient gene functional inference platform. Here, we tested the application of the tobacco rattle virus (TRV)-mediated gene-silencing system in Physalis floridana. First, we characterized the putative gene of a phytoene desaturase in P. floridana (PfPDS). Infecting the leaves of the Physalis seedlings with the PfPDS-TRV vector resulted in a bleached plant, including the developing leaves, floral organs, ICS, berry, and seed. These results indicated that a local VIGS treatment can efficiently induce a systemic mutated phenotype. qRT-PCR analyses revealed that the bleaching extent correlated to the mRNA reduction of the endogenous PfPDS. Detailed comparisons of multiple infiltration and growth protocols allowed us to determine the optimal methodologies for VIGS manipulation in Physalis. We subsequently utilized this optimized VIGS methodology to downregulate the expression of two MADS-box genes, MPF2 and MPF3, and compared the resulting effects with gene-downregulation mediated by RNA interference (RNAi) methods. The VIGS-mediated gene knockdown plants were found to resemble the mutated phenotypes of floral calyx, fruiting calyx and pollen maturation of the RNAi transgenic plants for both MPF2 and MPF3. Moreover, the two MADS-box genes were appeared to have a novel role in the pedicel development in P. floridana. The major advantage of VIGS-based gene knockdown lies in practical aspects of saving time and easy manipulation as compared to the RNAi. Despite the lack of heritability and mosaic mutation phenotypes observed in some organs, the TRV-mediated gene silencing system provides an alternative efficient way to infer gene function in various developmental processes in Physalis, thus facilitating understanding of the genetic basis of the evolution and development of the morphological diversities within the Solanaceae.


Gender difference in DNA adduct levels among nonsmoking lung cancer patients.
Lung cancer is the leading cause of cancer mortality in Taiwanese women. Cigarette smoking cannot explain the high lung cancer mortality in this population because less than 10% of women in Taiwan are smokers. Therefore, environmental factors other than smoking may play an important role in lung cancer development in female nonsmokers. The purpose of this study was to elucidate the role of environmental carcinogen exposure in lung cancer development in Taiwanese female nonsmokers, based on DNA adduct formation. We collected nontumorous lung tissues resected from 62 nonsmoking lung cancer patients and 20 noncancer controls to investigate whether differences in susceptibility to DNA adduct formation exist between men and women. (32)P-postlabeling and ELISA (enzyme-linked immunosorbent assay) with polyclonal antibody against BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene)-DNA adduct were used to evaluate DNA adduct levels in lung tissues of study subjects. Our data showed that the DNA adduct levels of lung cancer patients determined by both assays were significantly higher than those of noncancer controls (P = 0.0001 for (32)P-postlabeling; P = 0.01 for ELISA). Moreover, DNA adduct levels in females were markedly greater than those in males (P = 0.014 for (32)P-postlabeling; P = 0.001 for ELISA). The difference in DNA adduct levels could not be explained by genetic polymorphisms of cytochrome P-4501A1 (CYP1A1) or glutathione S-transferase (GSTM1), as determined by polymerase chain reaction and restriction fragment length polymorphism. These results demonstrate that lung cancer patients have a higher susceptibility to DNA damage than that of noncancer controls. In addition, differences in susceptibility to DNA damage derived from environmental carcinogen exposure were observed between male and female nonsmokers. In conclusion, high susceptibility to DNA damage in females may partially explain the high mortality rate of lung cancer in nonsmoking Taiwanese women.


Patterns of sensitization to food and aeroallergens in the first 3 years of life.
There is a paucity of longitudinal studies of allergen sensitization in childhood. To investigate the pattern of sensitization in early childhood. A nested cohort of children (n = 543) were followed up from birth and given a skin prick test (SPT) at 1, 2, and 3 years of age. A detailed clinical history was obtained. The prevalences of sensitization to aeroallergens were 1.3%, 6.4%, and 10.7% at 1, 2, and 3 years of age. The figures for food allergens were 2.8%, 3.9%, and 3.7%. There was a statistically significant increase in the prevalence of sensitization to >or=1 allergen between years 1 and 2 (P < .001) and years 2 and 3 (P = .032). Among those with a positive SPT at 1 year, 29% tested positive to additional allergens at 2 years (P = .0054). Sensitization to milk or egg at 1 year was a predictor for increased sensitization to peanut at 3 years (odds ratio, 34.8; P < .0001). Sensitization to egg at 1 year was associated with increased sensitization to aeroallergens at 3 years (odds ratios, house dust mite, 27.1, P < .001; cat, 8.9, P < .01; grass, 11.8, P = .005). For peanut and cat allergens, wheal size increases with the age of the child (P = .009 and P = .017, respectively). Sensitization to allergens as demonstrated by positive SPT tends to increase with age, and this change can be detected in the first 3 years of life. The high predictive value for early sensitization and a linear increase in SPT reactivity provide an opportunity for early intervention.


Coalescent-based genome analyses resolve the early branches of the euarchontoglires.
Despite numerous large-scale phylogenomic studies, certain parts of the mammalian tree are extraordinarily difficult to resolve. We used the coding regions from 19 completely sequenced genomes to study the relationships within the super-clade Euarchontoglires (Primates, Rodentia, Lagomorpha, Dermoptera and Scandentia) because the placement of Scandentia within this clade is controversial. The difficulty in resolving this issue is due to the short time spans between the early divergences of Euarchontoglires, which may cause incongruent gene trees. The conflict in the data can be depicted by network analyses and the contentious relationships are best reconstructed by coalescent-based analyses. This method is expected to be superior to analyses of concatenated data in reconstructing a species tree from numerous gene trees. The total concatenated dataset used to study the relationships in this group comprises 5,875 protein-coding genes (9,799,170 nucleotides) from all orders except Dermoptera (flying lemurs). Reconstruction of the species tree from 1,006 gene trees using coalescent models placed Scandentia as sister group to the primates, which is in agreement with maximum likelihood analyses of concatenated nucleotide sequence data. Additionally, both analytical approaches favoured the Tarsier to be sister taxon to Anthropoidea, thus belonging to the Haplorrhine clade. When divergence times are short such as in radiations over periods of a few million years, even genome scale analyses struggle to resolve phylogenetic relationships. On these short branches processes such as incomplete lineage sorting and possibly hybridization occur and make it preferable to base phylogenomic analyses on coalescent methods.


The role of tooth-grinding in the maintenance of myofascial face pain: a test of alternate models.
While mechanisms of myofascial face pain are poorly understood, bruxism has been implicated in the maintenance of this painful disorder. This study evaluates whether evidence of one aspect of bruxism, tooth-grinding, is positively associated with pain severity, as predicted by a psychophysiological model, or negatively associated, as predicted by an adaptation model of face pain. Participants were 51 women who met Research Diagnostic Criteria for the myofascial subtype of temporomandibular disorder. Tooth-grinding was quantified by changes in microwear features of the molar teeth over 2 weeks. Palpated pain severity was quantified on an 11-point scale in response to palpation of the skin overlying the masseter and temporalis muscles bilaterally. Other measures included validated scales of spontaneous pain severity, stress, distress, and psychological symptoms. Association was quantified as Pearson correlation coefficients. Data showed an inverse correlation (r = -0.37, P < 0.05) between palpated pain severity and the index of tooth wear, supporting the adaptation model. This correlation provided a weighted average of a strong effect (r = -0.80, P < 0.01) seen in those women reporting pain only the right side of their face with an effect that approximated zero in those reporting bilateral pain. Tooth wear measures were negatively associated with ratings of pain severity only over the right masseter. While these data do not address the role of clenching, they cast serious doubt on the theory that myofascial face pain is maintained by tooth-grinding.


Multicohort analysis of the maternal age effect on recombination.
Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination.


Peer Contextual Influences on the Growth of Authority-Acceptance Problems in Early Elementary School.
This study investigated the effects of the peer social context and child characteristics on the growth of authority-acceptance behavior problems across first, second, and third grades, using data from the normative sample of the Fast Track Project. Three hundred sixty-eight European American and African American boys and girls (51% male; 46% African American) and their classmates were assessed in each grade by teacher ratings on the Teacher Observation of Child Adaptation-Revised. Children's growth in authority-acceptance behavior problems across time was partially attributable to the level of disruptive behavior in the class-room peer context into which they were placed. Peer-context influence, however, were strongest among same-gender peers. Findings held for both boys and girls, both European Americans and African Americans, and nondeviant, marginally deviant, and highly deviant children. Findings suggest that children learn and follow behavioral norms from their same-gender peers within the classroom.


Expression of Connexin 43 in Synovial Tissue of Patients With Rheumatoid Arthritis.
This study aims to identify the distribution and expression level of connexin 43 (Cx43) in synovial tissue in patients with rheumatoid arthritis (RA). The expression of Cx43 in synovial tissue from eight patients with RA (2 males, 6 females; mean age 59.5±2.7 years; range 52 to 71 years), five patients with osteoarthritis (2 males, 3 females; mean age 68.4±2.7 years; range 61 to 81 years), and one normal female subject (mean age 61 year) was analyzed by quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry of tissue sections. Induction of Cx43 following stimulation of human RA synovial fibroblasts with tumor necrosis factor-alpha (TNF-a) cultures was examined by quantitative reverse transcriptase polymerase chain reaction. The effect of small interfering ribonucleic acid targeting Cx43 (siCx43) on the expression of TNF-a and interleukin-6 was examined using quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assays. Connexin 43 was highly expressed in RA synovial tissue, which also expressed TNF-a, but was expressed lower in osteoarthritis and normal synovial tissue. Expression of Cx43 was markedly up-regulated in RA synovial fibroblasts after stimulation with TNF-a. The over-expression of pro- inflammatory cytokines was suppressed by transfection of siCx43. This study shows that Cx43 is expressed in RA synovial tissue and that its expression is induced by stimulation with TNF-a. The expression of the pro-inflammatory cytokines was inhibited by transfection of siCx43. Cx43 may be a novel marker of inflammation in RA synovial tissue.


Stereoelectronic effects on molecular geometries and state-energy splittings of ligated monocopper dioxygen complexes.
The relative energies of side-on versus end-on binding of molecular oxygen to a supported Cu(I) species, and the singlet versus triplet nature of the ground electronic state, are sensitive to the nature of the supporting ligands and, in particular, depend upon their geometric arrangement relative to the O2 binding site. Highly correlated ab initio and density functional theory electronic structure calculations demonstrate that optimal overlap (and oxidative charge transfer) occurs for the side-on geometry, and this is promoted by ligands that raise the energy, thereby enhancing resonance, of the filled Cu dxz orbital that hybridizes with the in-plane pi* orbital of O2. Conversely, ligands that raise the energy of the filled Cu dz2 orbital foster a preference for end-on binding as this is the only mode that permits good overlap with the in-plane O2 pi*. Because the overlap of Cu dz2 with O2 pi* is reduced as compared to the overlap of Cu dxz with the same O2 orbital, the resonance is also reduced, leading to generally more stable triplet states relative to singlets in the end-on geometry as compared to the side-on geometry, where singlet ground states become more easily accessible once ligands are stronger donors. Biradical Cu(II)-O2 superoxide character in the electronic structure of the supported complexes leads to significant challenges for accurate quantum chemical calculations that are best addressed by exploiting the spin-purified M06L local density functional, single-reference completely renormalized coupled-cluster theory, or multireference second-order perturbation theory, all of which provide predictions that are qualitatively and quantitatively consistent with one another.


Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons.
Glutamate-induced changes in intracellular free Ca2+ concentration ([Ca2+]i) were recorded in single rat hippocampal neurons grown in primary culture by employing the Ca2+ indicator indo-1 and a dual-emission microfluorimeter. The [Ca2+]i was monitored in neurons exposed to 100 microM glutamate for 5 min and for an ensuing 3 hr period. Ninety-two percent (n = 64) of these neurons buffered the glutamate-induced Ca2+ load back to basal levels after removal of the agonist; thus, the majority of cells had not lost the ability to regulate [Ca2+]i at this time. However, following a variable delay, in 44% (n = 26) of the neurons that buffered glutamate-induced Ca2+ loads to basal levels, [Ca2+]i rose again to a sustained plateau and failed to recover. The changes in [Ca2+]i that occur during glutamate-induced delayed neuronal death can be divided into three phases: (1) a triggering phase during which the neuron is exposed to glutamate and the [Ca2+]i increases to micromolar levels, followed by (2) a latent phase during which the [Ca2+]i recovers to a basal level, and (3) a final phase that begins with a gradual rise in the [Ca2+]i that reaches a sustained plateau from which the neuron does not recover. This delayed Ca2+ overload phase correlated significantly with cell death. The same sequence of events was also observed in recordings from neuronal processes. The delayed Ca2+ increase and subsequent death were dependent upon the presence of extracellular Ca2+ during glutamate exposure. Calcium influx during the triggering phase resulted from the activation of both NMDA and non-NMDA receptors as indicated by studies using receptor antagonists and ion substitution. Treatment with TTX (1 microM) or removal of extracellular Ca2+ for a 30 min window following agonist exposure failed to prevent the delayed Ca2+ overload. The delayed [Ca2+]i increase could be reversed by removing extracellular Ca2+, indicating that it resulted from Ca2+ influx. The three phases defined by changes in the [Ca2+]i during glutamate-induced neuronal toxicity suggest three distinct targets to which neuroprotective agents may be directed.


Red, Amber, or Green? Athlete Monitoring in Team Sport: The Need for Decision-Support Systems.
Decision-support systems are used in team sport for a variety of purposes including evaluating individual performance and informing athlete selection. A particularly common form of decision support is the traffic-light system, where color coding is used to indicate a given status of an athlete with respect to performance or training availability. However, despite relatively widespread use, there remains a lack of standardization with respect to how traffic-light systems are operationalized. This paper addresses a range of pertinent issues for practitioners relating to the practice of traffic-light monitoring in team sports. Specifically, the types and formats of data incorporated in such systems are discussed, along with the various analysis approaches available. Considerations relating to the visualization and communication of results to key stakeholders in the team-sport environment are also presented. In order for the efficacy of traffic-light systems to be improved, future iterations should look to incorporate the recommendations made here.