Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies.
We previously reported that high-titered neutralizing antibodies directed against the human immunodeficiency virus type 1 (HIV-1) envelope can block the establishment of a simian immunodeficiency virus (SIV)/HIV chimeric virus (SHIV) infection in two monkeys following passive transfer (R. Shibata et al., Nat. Med. 5:204-210, 1999). In the present study, increasing amounts of neutralizing immunoglobulin G (IgG) were administered to 15 pig-tailed macaques in order to obtain a statistically valid protective neutralization endpoint titer in plasma. Using an in vitro assay which measures complete neutralization of the challenge SHIV, we correlated the titers of neutralizing antibodies in plasma at the time of virus inoculation (which ranged from 1:3 to 1:123) with the establishment of infection in virus-challenged animals. Ten of 15 monkeys in the present experiment were virus free as a result of neutralizing IgG administration as monitored by DNA PCR (peripheral blood mononuclear cells and lymph node cells), RNA PCR (plasma), virus isolation, and the transfer of lymph node cell suspensions (10(8) cells) plus 8 ml of whole blood from protected animals to naïve macaques. The titer of neutralizing antibodies in the plasma calculated to protect 99% of virus-challenged monkeys was 1:38.


T cell-mediated acute localized exanthematous pustulosis caused by finasteride.
A 21-year-old man presented with multiple erythematous nonfollicular papules partially confluent to plaques on his breast and lower abdomen that had been present for 1 month. Grouped pustules were present under the right breast. The patient had been taking finasteride over the past 3 months for androgenetic alopecia. His medical history was negative for psoriasis. Our initial differential diagnosis included dyskeratosis follicularis Darier, allergic contact dermatitis, infectious folliculitis, varicella zoster virus infection, fixed drug eruption, and IgA pemphigus. The white blood cell count and differential were within the normal limits. Results of viral cultures and PCR, as well as bacterial and fungal cultures of skin lesions proved negative. A lesional biopsy specimen showed a slight psoriasiform acanthosis in association with spongiosis and infiltration of both the epidermis and dermis by neutrophils and eosinophils, resulting in formation of subcorneal, intraepidermal, and subepidermal pustules. The results of direct immunofluorescence were negative, excluding an IgA pemphigus. The result of a lymphocyte transformation test was positive for finasteride. On the basis of the time relationship between the administration of finasteride and the development of the skin disease in combination with symptoms resolution on cessation of the drug, the histologic findings, and the positive lymphocyte transformation test result, we consider this to be an unusual type of acute generalized exanthematous pustulosis defined as acute localized exanthematous pustulosis caused by finasteride. Within 4 weeks after withdrawal of finasteride, the rash resolved without any specific therapy. Transient discrete residual hyperpigmentation and scaling were present. The patient refused an oral provocation challenge.


Implementation science and stigma reduction interventions in low- and middle-income countries: a systematic review.
Interventions to alleviate stigma are demonstrating effectiveness across a range of conditions, though few move beyond the pilot phase, especially in low- and middle-income countries (LMICs). Implementation science offers tools to study complex interventions, understand barriers to implementation, and generate evidence of affordability, scalability, and sustainability. Such evidence could be used to convince policy-makers and donors to invest in implementation. However, the utility of implementation research depends on its rigor and replicability. Our objectives were to systematically review implementation studies of health-related stigma reduction interventions in LMICs and critically assess the reporting of implementation outcomes and intervention descriptions. PubMed, CINAHL, PsycINFO, and EMBASE were searched for evaluations of stigma reduction interventions in LMICs reporting at least one implementation outcome. Study- and intervention-level characteristics were abstracted. The quality of reporting of implementation outcomes was assessed using a five-item rubric, and the comprehensiveness of intervention description and specification was assessed using the 12-item Template for Intervention Description and Replication (TIDieR). A total of 35 eligible studies published between 2003 and 2017 were identified; of these, 20 (57%) used qualitative methods, 32 (91%) were type 1 hybrid effectiveness-implementation studies, and 29 (83%) were evaluations of once-off or pilot implementations. No studies adopted a formal theoretical framework for implementation research. Acceptability (20, 57%) and feasibility (14, 40%) were the most frequently reported implementation outcomes. The quality of reporting of implementation outcomes was low. The 35 studies evaluated 29 different interventions, of which 18 (62%) were implemented across sub-Saharan Africa, 20 (69%) focused on stigma related to HIV/AIDS, and 28 (97%) used information or education to reduce stigma. Intervention specification and description was uneven. Implementation science could support the dissemination of stigma reduction interventions in LMICs, though usage to date has been limited. Theoretical frameworks and validated measures have not been used, key implementation outcomes like cost and sustainability have rarely been assessed, and intervention processes have not been presented in detail. Adapted frameworks, new measures, and increased LMIC-based implementation research capacity could promote the rigor of future stigma implementation research, helping the field deliver on the promise of stigma reduction interventions worldwide.


Sadism and psychopathy in violent and sexually violent offenders.
A nonrandom sample (N = 41) of inmates from a maximum security prison were classified as either psychopathic or nonpsychopathic (using the Psychopathy Checklist-Revised (PCL-R)) and violent or sexually violent. Sadism was measured using the Millon Clinical Multiaxial Inventory-II (MCMI-II) Scale 6B, the Personality Disorder Examination (PDE) items for sadistic personality disorder, and the sexual sadism criteria of DSM-IV. Psychopaths were found to be significantly more sadistic than nonpsychopaths (MCMI-II and PDE). Overall power was relatively high. Sadism did not differentiate the violent and sexually violent groups. A diagnosis of sexual sadism was too infrequent (n = 3) for meaningful statistical analysis. The trait measures of sadism and psychopathy measures (PCL-R, Factor 1 and Factor 2) significantly and positively correlated. Results provide further empirical validity for the theoretically proposed and clinically observed relationship between sadistic traits and psychopathic personality.


Cuffed endotracheal tubes for neonates and young infants: a comprehensive review.
Traditionally, uncuffed endotracheal tubes (ETTs) have been used for artificial ventilation of infants and children. More recently, newer designed high-volume low-pressure (HVLP) cuffed ETTs are being used with increasing frequency in infants from birth. Considering that many paediatric anaesthetists and intensivists are already using cuffed ETTs in infants >3 kg from birth, should neonatologists be doing the same? This review examines the reasons behind the traditional use of uncuffed ETTs and the problems associated with their use; newer HVLP cuffed ETTs and what they can potentially offer neonates; and reviews evidence from studies comparing the use of cuffed and uncuffed ETTs in neonates and small infants.


Parenting behaviour and paranoia: a network analysis and results from the National Comorbidity Survey-Adolescents (NCS-A).
Parenting behaviours-including the extent to which parents are protective, hostile, or caring-likely impacts whether a child develops a sense of vulnerability that carries forward into adulthood. Ideas of vulnerability are a contributory factor to the occurrence of paranoia. Our aim was to assess whether there is an association between specific parenting behaviours and paranoia. We examined cross-sectional associations of parenting and paranoia in an epidemiologically representative cohort of 10,148 adolescents (National Comorbidity Survey-Adolescents; NCS-A) and a second dataset of 1286 adults in Oxfordshire. Further, a network analysis was conducted with paranoia, parenting behaviours, and cognitive-affective variables (compassion, self-esteem, anxiety, and depression). Overprotectiveness, verbal abuse, physical abuse, and amount of care were assessed in mothers and fathers separately. Nearly all parenting variables were significantly associated with paranoia, with parental verbal and physical abuse showing the largest associations. For example, the odds of reporting paranoia was over four times higher for those in the adult sample reporting a lot of paternal verbal abuse, compared to those reporting none (OR = 4.12, p < 0.001, CI 2.47-6.85). Network analyses revealed high interconnectivity between paranoia, parenting behaviours, and cognitive-affective variables. Of the parenting variables, paranoia most strongly interacted with paternal abuse and maternal lack of care. There are associations between participants' self-reported experiences of parental behaviours and paranoia. Despite being associated with paranoia, cognitive-affective variables did not appear to mediate the relationship between parenting and paranoia, which is surprising. What might explain the link therefore remains to be determined.


Ortho versus Meta Chlorophenyl-2,3-Benzodiazepine Analogues: Synthesis, Molecular Modeling, and Biological Activity as AMPAR Antagonists.
2,3-Benzodiazepine compounds are an important family of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists that act in a noncompetitive manner. Due to the critical role of AMPARs in the synapse and various neurological diseases, significant scientific interest in elucidating the molecular basis of the function of the receptors has spiked. The analogues were synthesized to assess the functional consequence of removing the amine group of the phenyl ring, the potency and efficacy of inhibition by substituting a halogen group at the meta vs ortho position of the phenyl ring, and layout the prediction of potential drug candidates for AMPAR hyperactivation. Using the whole-cell patch-clamp technique, we assessed the effect of the derivative on the amplitude of various AMPA-type glutamate receptors and calculated the desensitization and deactivation rates before and after treatment of HEK293 cells. We noticed that the amino group is not necessary for inhibition as long as an electron-withdrawing group is placed on the meta position of the phenyl ring of BDZ. Furthermore, compound 4a significantly inhibited and affected the desensitization rate of the tested AMPARs but showed no effect on the deactivation rate. The current study paves the way to a better understanding of AMPARs and provides possible drug candidates of 2,3-BDZ different from the conventional derivatives.


[Secondary level nursing schools: agreements and disagreements regarding the actions for their creation and implementation].
This historical-documental study, interpreted under the light of Pierre Bourdieu's theory, was performed with the following objectives: to identify and describe the agreements and disagreements between movements that promote the creation and implementation of secondary-level nursing schools/courses in seven private model-reference hospitals located in São Paulo, from 1945 to 1989; and to explain the intentions of the studied institutions in creating and implementing these schools/courses. The results provided evidence of the agreements and disagreements synthetized in the items: opening and closing of courses, maintenance and direction by religious institutions, sources of funding, objectives and purposes, number of graduates and impact on the workforce. It was concluded that the hospitals created their schools at different times, but their objectives were in agreement, which included: preparing their workforce, use of student services, obtaining tax exemption and support and aggregating cultural, social and economical assets, and, consequently, symbolic power in the battle for reputation.


Interprofessional education: The magical mystery tour now less of a mystery.
Interprofessional education (IPE) is on today's agenda in medical education as a response to advances in medicine, the changes that have taken place in healthcare delivery, and pressures from the public and the profession. Although attention has focused on IPE in the later stages of the education program, there are benefits to be gained from the introduction of IPE in the early years. Curriculum developments supporting this include the adoption of outcome-based education and vertical integration. There is also a recognition that students' attitudes and biases are formed early in their education and the appropriate learning environment in the early years is important. Interprofessional education in the early years can also be seen as a part of a more general trend to greater collaboration in the delivery of an education program in the healthcare professions. Anatomy by incorporating IPE can help shape the future of medical education as well as being shaped by it. The possibility of success or failure with IPE can be captured with the equation IPE = (V × I)/N, where V = the IPE vision, I = the implementation strategy and N = negative perceptions of the approach. Success is more likely where there is a well thought out and shared vision for what is to be achieved, an appropriate implementation strategy and a plan to counteract a negative mind-set.


Effects of oxygenation on the intercalation of 1,10-phenanthroline-5,6/4,7-dione between DNA base pairs: a computational study.
The effects of oxygen in positions 4,7 and 5,6 of phenanthroline when this ligand intercalates between guanine-cytosine and adenine-thymine DNA base pairs (GC/CG and AT/TA) have been studied at the M06-2X/6-31+G(d,p) level of calculation. We focused on the changes in the structure, stabilization and energy contributions in the analysis of the interaction. The obtained trends in stabilization are explained by a model including repulsive Pauli (ΔEPauli) contributions, and attractive dispersion (ΔEdisp), orbital (ΔEorb) and electrostatic (ΔEelstat) contributions to energy. When no solvation is considered, the intrinsic ΔEelstat contribution results are crucial for the stabilization of the system. However, the inclusion of the solvation energy ΔEsolv can reverse the final stability trend of the systems becoming, thus, the driving force of the process. Therefore, the solvent will have a relevant influence in the potential cytotoxicity of the intercalation drugs.


Pharmacokinetics of the Antiviral Lectin Griffithsin Administered by Different Routes Indicates Multiple Potential Uses.
Griffithsin (GRFT) is a red alga-derived lectin with demonstrated broad spectrum antiviral activity against enveloped viruses, including severe acute respiratory syndrome-Coronavirus (SARS-CoV), Japanese encephalitis virus (JEV), hepatitis C virus (HCV), and herpes simplex virus-2 (HSV-2). However, its pharmacokinetic profile remains largely undefined. Here, Sprague Dawley rats were administered a single dose of GRFT at 10 or 20 mg/kg by intravenous, oral, and subcutaneous routes, respectively, and serum GRFT levels were measured at select time points. In addition, the potential for systemic accumulation after oral dosing was assessed in rats after 10 daily treatments with GRFT (20 or 40 mg/kg). We found that parenterally-administered GRFT in rats displayed a complex elimination profile, which varied according to administration routes. However, GRFT was not orally bioavailable, even after chronic treatment. Nonetheless, active GRFT capable of neutralizing HIV-Env pseudoviruses was detected in rat fecal extracts after chronic oral dosing. These findings support further evaluation of GRFT for pre-exposure prophylaxis against emerging epidemics for which specific therapeutics are not available, including systemic and enteric infections caused by susceptible enveloped viruses. In addition, GRFT should be considered for antiviral therapy and the prevention of rectal transmission of HIV-1 and other susceptible viruses.


Risk of Transmission of Antimicrobial Resistant Escherichia coli from Commercial Broiler and Free-Range Retail Chicken in India.
Multidrug-resistant Escherichia coli infections are a growing public health concern. This study analyzed the possibility of contamination of commercial poultry meat (broiler and free-range) with pathogenic and or multi-resistant E. coli in retail chain poultry meat markets in India. We analyzed 168 E. coli isolates from broiler and free-range retail poultry (meat/ceca) sampled over a wide geographical area, for their antimicrobial sensitivity, phylogenetic groupings, virulence determinants, extended-spectrum-β-lactamase (ESBL) genotypes, fingerprinting by Enterobacterial Repetitive Intergenic Consensus (ERIC) PCR and genetic relatedness to human pathogenic E. coli using whole genome sequencing (WGS). The prevalence rates of ESBL producing E. coli among broiler chicken were: meat 46%; ceca 40%. Whereas, those for free range chicken were: meat 15%; ceca 30%. E. coli from broiler and free-range chicken exhibited varied prevalence rates for multi-drug resistance (meat 68%; ceca 64% and meat 8%; ceca 26%, respectively) and extraintestinal pathogenic E. coli (ExPEC) contamination (5 and 0%, respectively). WGS analysis confirmed two globally emergent human pathogenic lineages of E. coli, namely the ST131 (H30-Rx subclone) and ST117 among our poultry E. coli isolates. These results suggest that commercial poultry meat is not only an indirect public health risk by being a possible carrier of non-pathogenic multi-drug resistant (MDR)-E. coli, but could as well be the carrier of human E. coli pathotypes. Further, the free-range chicken appears to carry low risk of contamination with antimicrobial resistant and extraintestinal pathogenic E. coli (ExPEC). Overall, these observations reinforce the understanding that poultry meat in the retail chain could possibly be contaminated by MDR and/or pathogenic E. coli.


Postpartum hemorrhage prevention in Nepal: a program assessment.
In 2009, the Nepal Ministry of Health and Population launched a national program for prevention of postpartum hemorrhage (PPH) during home births that features advance distribution of misoprostol to pregnant women. In the years since, the government has scaled-up the program throughout much of the country. This paper presents findings from the first large-scale assessment of the effectiveness of the advance distribution program. Data collection was carried out in nine districts and all three ecological zones. To assess knowledge, receipt and use of misoprostol, household interviews were conducted with 2070 women who had given birth within the past 12 months. To assess supply and provision of misoprostol, interviews were conducted with 270 Female Community Health Volunteers (FCHVs) and staff at 99 health facilities. Among recently delivered women, only 15% received information about misoprostol and 13% received misoprostol tablets in advance of delivery. Yet 87% who received advance misoprostol and delivered at home used it for PPH prevention. Among FCHVs, 96% were providing advance misoprostol for PPH prevention; however 81% had experienced at least one misoprostol stock out within the past year. About one-half of FCHVs were providing incomplete information about the use of misoprostol; in addition, many did not discuss side effects, how to recognize PPH or where to go if PPH occurs. Among health facilities, just one-half had sufficient misoprostol stock, while 95% had sufficient oxytocin stock, at the time of this assessment. In Nepal, women who receive advance misoprostol are both willing and able to use the medication for PPH prevention during home births. However the supply and personnel challenges identified raise questions about scalability and impact of the program over the long-term. Further assessment is needed.


Effects of the work limitations on the career path of a cohort of health workers.
The median age of the workforce, and of healthcare workers in particular, is increasing, resulting in a reduced work capacity. This may prompt the occupational physician to issue fitness for work limitations. To examine the health surveillance data collected over 20 years on the employees of a large healthcare institution to identify the effects of the limitations imposed on their career paths. The database of health surveillance records gathered over the years was analysed using the same dedicated software. Fourteen types of limitations were classified via a "text mining" treatment. 3,653 subjects were selected, divided in two groups (A: with a limitation and B: without limitation) comprised of 655 and 2,998 subjects, respectively. The subjects were then ranked on the basis of departments and tasks involved. We also evaluated the number of departmental changes for each worker and the corresponding rate of change for the three groups A, B and B post-limitation. Limitations have been increasing in parallel with the aging of workers, in particular those relating to Manual Load Handling/Posture (MLH/P). The limitations due to Allergy/Latex lasted longer, and in a greater proportion than MLH/P, particularly when compared to the limitation for Shift Work and those for "Other Limitations" that were shrinking faster. There is a clear relationship between certain types of limitations/prescriptions and workers' ages. It is necessary to carry out an assessment of the association with the work performed in order to implement age management strategies aimed at maintaining work capacity in aging workers.


Serum ion levels after ceramic-on-ceramic and metal-on-metal total hip arthroplasty: 8-year minimum follow-up.
Alternative bearing surfaces for total hip arthroplasty, such as metal-on-metal and ceramic-on-ceramic, offer the potential to reduce mechanical wear and osteolysis. In the short and medium term, the second generation of metal-on-metal bearings demonstrated high systemic metal ion levels, whereas ceramic-on-ceramic bearings showed the lowest ones. We aimed to verify whether the long-term ion release in metal-on-metal subjects was still relevant at a median 10-year follow-up, and whether a fretting process at the modular junctions occurred in ceramic-on-ceramic patients and induced an ion dissemination. Serum levels were measured in 32 patients with alumina-on-alumina implants (group A), in 16 subjects with metal-on-metal implants (group B), and in 47 healthy subjects (group C). Group B results were compared with medium-term findings. Cobalt and chromium levels were significantly higher in metal-on-metal implants than in ceramic-on-ceramic ones and controls. Nevertheless, ion levels showed a tendency to decrease in comparison with medium-term content. In ceramic-on-ceramic implants, ion values were not significantly different from controls. Both in groups A and B, aluminum and titanium release were not significantly different from controls. In conclusion, negligible serum metal ion content was revealed in ceramic-on-ceramic patients. On the contrary, due to the higher ion release, metal-on-metal coupling must be prudently considered, especially in young patients, in order to obtain definitive conclusions.


A data citation roadmap for scientific publishers.
This article presents a practical roadmap for scholarly publishers to implement data citation in accordance with the Joint Declaration of Data Citation Principles (JDDCP), a synopsis and harmonization of the recommendations of major science policy bodies. It was developed by the Publishers Early Adopters Expert Group as part of the Data Citation Implementation Pilot (DCIP) project, an initiative of FORCE11.org and the NIH BioCADDIE program. The structure of the roadmap presented here follows the "life of a paper" workflow and includes the categories Pre-submission, Submission, Production, and Publication. The roadmap is intended to be publisher-agnostic so that all publishers can use this as a starting point when implementing JDDCP-compliant data citation. Authors reading this roadmap will also better know what to expect from publishers and how to enable their own data citations to gain maximum impact, as well as complying with what will become increasingly common funder mandates on data transparency.


Influence of short-term unweighing and reloading on running kinetics and muscle activity.
In running, body weight reduction is reported to result in decreased lower limb muscle activity with no change in the global activation pattern (Liebenberg et al. in J Sports Sci 29:207-214). Our study examined the acute effects on running mechanics and lower limb muscle activity of short-term unweighing and reloading conditions while running on a treadmill with a lower body positive pressure (LBPP) device. Eleven healthy males performed two randomized running series of 9 min at preferred speed. Each series included three successive running conditions of 3 min [at 100 % body weight (BW), 60 or 80 % BW, and 100 % BW]. Vertical ground reaction force and center of mass accelerations were analyzed together with surface EMG activity recorded from six major muscles of the left lower limb for the first and last 30 s of each running condition. Effort sensation and mean heart rate were also recorded. In both running series, the unloaded running pattern was characterized by a lower step frequency (due to increased flight time with no change in contact time), lower impact and active force peaks, and also by reduced loading rate and push-off impulse. Amplitude of muscle activity overall decreased, but pre-contact and braking phase extensor muscle activity did not change, whereas it was reduced during the subsequent push-off phase. The combined neuro-mechanical changes suggest that LBPP technology provides runners with an efficient support during the stride. The after-effects recorded after reloading highlight the fact that 3 min of unweighing may be sufficient for updating the running pattern.


Biomonitoring acidification using marine gastropods.
Ocean acidification is mainly being monitored using data loggers which currently offer limited coverage of marine ecosystems. Here, we trial the use of gastropod shells to monitor acidification on rocky shores. Animals living in areas with highly variable pH (8.6-5.9) were compared with those from sites with more stable pH (8.6-7.9). Differences in site pH were reflected in size, shape and erosion patterns in Nerita chamaeleon and Planaxis sulcatus. Shells from acidified sites were shorter, more globular and more eroded, with both of these species proving to be good biomonitors. After an assessment of baseline weathering, shell erosion can be used to indicate the level of exposure of organisms to corrosive water, providing a tool for biomonitoring acidification in heterogeneous intertidal systems. A shell erosion ranking system was found to clearly discriminate between acidified and reference sites. Being spatially-extensive, this approach can identify coastal areas of greater or lesser acidification. Cost-effective and simple shell erosion ranking is amenable to citizen science projects and could serve as an early-warning-signal for natural or anthropogenic acidification of coastal waters.


Predictors of student success in an entry-level baccalaureate dental hygiene program.
The purpose of this study was to measure the utility of various predictors used by the Old Dominion University Gene W. Hirschfeld School of Dental Hygiene baccalaureate degree dental hygiene program in selecting dental hygiene students who are most likely to graduate and be successful in passing the National Board Dental Hygiene Examination (NBDHE). The following factors were examined: grade point average (GPA); science GPA; final grade in various prerequisite courses; final grade in first-year dental hygiene courses; academic setting where prerequisite courses were completed; multiple attempts to achieve a passing course grade; and admissions criteria points (ACP). The sample selected for study consisted of the academic records of dental hygiene students admitted to the program from 1998 to 2002 (n = 235), who would have been eligible to take the NBDHE from 2000 to 2004. Data were analyzed using multiple logistic regression to determine success as measured by graduation (n = 146). With NBDHE as the criterion variable, data were analyzed using the multiple linear regression to determine successful entry into the profession (n = 130); significance was predetermined at the 0.05 level. Data analysis revealed that final course grade in oral pathology was a significant predictor of successful graduation (P = 0.0008). Variables that predicted NBDHE success were final course grade in oral pathology, final course grade in oral anatomy and histology, and the ACP rating (P < .0001, P < .0001, and P = .0245, respectively). There was no statistically significant relationship for other variables. Final grades in oral pathology and oral anatomy and histology can significantly predict graduation and NBDHE success at this institution, suggesting that educators look to improving student performance after admission to the program to improve the likelihood of success. Additionally, when this institution's admission variables were combined into a cluster of variables (ACP), they proved significant at predicting success.


Controllable one-step double emulsion formation via phase inversion.
Double emulsions, the simplest form of multiple emulsion, have been intensively utilized in various industries as well as in fundamental research. A variety of strategies to effectively form double emulsions have been developed, but no simple yet controlled and scalable technique has been achieved yet. Herein, we examine the mechanism of the entire process of double emulsion formation by phase inversion, and we propose a universal one-step strategy for the formation of an oil/water/oil double emulsion using oil soluble polymers and hydrophobic silica nanoparticles. We demonstrate that this new approach enables control of both the fraction and the number of inner small droplets; even high internal phase double emulsions could be achieved.


Serotonin receptors and animal models of aggressive behavior.
Various models of rodent agonistic behavior are described, which differentiate between offensive and defensive/flight models. Particular attention is given to one male and one female paradigm for offensive aggression, i.e. resident/intruder or territorial aggression (RI) and maternal aggression (MA). After an overview of the serotonin (5-HT) system in the CNS, a description is given of the ligands available. Subsequently, the effects of various drugs affecting serotonergic transmission in the RI- and MA-paradigms are described. The 5-HT1A receptor agonists busipirone, ipsapirone, and 8-OH-DPAT decreased aggression in RI and MA, but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific antiaggressive profile. Nonselective 5-HT1 receptor agonists, such as RU24969, eltoprazine, and TFMPP reduced aggression quite specifically, did not decrease social interest or exploration, and sometimes even increased these behaviors. In RI and MA, the behavioral effects of these drugs were roughly similar. In contrast, MA was more sensitive to treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression nonspecifically at the highest dose only. DOI, a 5-HT2A/2C# receptor agonist, decreased aggressive behavior and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by "wet dog shaking" characteristic of 5-HT2 receptor stimulation. The nonspecific 5-HT receptor agonist (and 5-HT2 receptor antagonist) quipazine also induced "wet dog shaking" at doses which suppressed aggression, social interest, and exploration but increased inactive behaviors (sitting and lying). The discussion delineates a specific role for 5-HT1B receptor-subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs, and this fact underlines the consistent role of 5-HT in different forms of aggression.


1,3-propanediol binds deep inside the channel to inhibit water permeation through aquaporins.
Aquaporins and aquaglyceroporins (AQPs) are membrane channel proteins responsible for transport of water and for transport of glycerol in addition to water across the cell membrane, respectively. They are expressed throughout the human body and also in other forms of life. Inhibitors of human AQPs have been sought for therapeutic treatment for various medical conditions including hypertension, refractory edema, neurotoxic brain edema, and so forth. Conducting all-atom molecular dynamics simulations, we computed the binding affinity of acetazolamide to human AQP4 that agrees closely with in vitro experiments. Using this validated computational method, we found that 1,3-propanediol (PDO) binds deep inside the AQP4 channel to inhibit that particular aquaporin efficaciously. Furthermore, we used the same method to compute the affinities of PDO binding to four other AQPs and one aquaglyceroporin whose atomic coordinates are available from the protein data bank (PDB). For bovine AQP1, human AQP2, AQP4, AQP5, and Plasmodium falciparum PfAQP whose structures were resolved with high resolution, we obtained definitive predictions on the PDO dissociation constant. For human AQP1 whose PDB coordinates are less accurate, we estimated the dissociation constant with a rather large error bar. Taking into account the fact that PDO is generally recognized as safe by the US FDA, we predict that PDO can be an effective diuretic which directly modulates water flow through the protein channels. It should be free from the serious side effects associated with other diuretics that change the hydro-homeostasis indirectly by altering the osmotic gradients.


Past visual experiences weigh in on body size estimation.
Body size is a salient marker of physical health, with extremes implicated in various mental and physical health issues. It is therefore important to understand the mechanisms of perception of body size of self and others. We report a novel technique we term the bodyline, based on the numberline technique in numerosity studies. One hundred and three young women judged the size of sequentially presented female body images by positioning a marker on a line, delineated with images of extreme sizes. Participants performed this task easily and well, with average standard deviations less than 6% of the total scale. Critically, judgments of size were biased towards the previously viewed body, demonstrating that serial dependencies occur in the judgment of body size. The magnitude of serial dependence was well predicted by a simple Kalman-filter ideal-observer model, suggesting that serial dependence occurs in an optimal, adaptive way to improve performance in size judgments.


The Effects of a Park Awareness Campaign on Rural Park Use and Physical Activity.
To examine the effects of a park awareness campaign on park use in 6 community parks. One-group pretest-posttest design. Six community parks located in a South Carolina county. Children, adolescents, and adults observed in community parks. A 1-month awareness campaign that culminated in single 1.5-hour events at 6 parks in April 2011 and May 2011. The System for Observing Play and Recreation in Communities was used to objectively measure park use in May 2010 (baseline) and May 2011 (postcampaign). Zero-inflated Poisson models tested whether the number of total park users and the number of park users engaged in sedentary, walking, and vigorous activities differed by observation date. Park use was significantly greater at baseline than postcampaign (97 vs 84 users, respectively; χ = 4.69, P = .03). There were no significant differences in the number of park users engaged in sedentary (χ = 2.45, P = .12), walking (χ = 0.29, P = .59), and vigorous (χ = 0.20, P = .65) activities between baseline and postcampaign. Although only 97 and 84 people were observed across all parks at baseline and postcampaign, a total of 629 people were observed during the 6 separate 1.5-hour campaign park events. This suggests that there is potential for greater park utilization in these communities, and important questions remain on how to conduct effective awareness campaigns and how to harness interest in park events for the purpose of contributing to future community-wide physical activity and health promotion efforts.


Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group.
The relations between 24 hour urinary electrolyte excretion and blood pressure were studied in 10,079 men and women aged 20-59 sampled from 52 centres around the world based on a highly standardised protocol with central training of observers, a central laboratory, and extensive quality control. Relations between electrolyte excretion and blood pressure were studied in individual subjects within each centre and the results of these regression analyses pooled for all 52 centres. Relations between population median electrolyte values and population blood pressure values were also analysed across the 52 centres. Sodium excretion ranged from 0.2 mmol/24 h (Yanomamo Indians, Brazil) to 242 mmol/24 h (north China). In individual subjects (within centres) it was significantly related to blood pressure. Four centres found very low sodium excretion, low blood pressure, and little or no upward slope of blood pressure with age. Across the other 48 centres sodium was significantly related to the slope of blood pressure with age but not to median blood pressure or prevalence of high blood pressure. Potassium excretion was negatively correlated with blood pressure in individual subjects after adjustment for confounding variables. Across centres there was no consistent association. The relation of sodium to potassium ratio to blood pressure followed a pattern similar to that of sodium. Body mass index and heavy alcohol intake had strong, significant independent relations with blood pressure in individual subjects.


Electrons dynamics control by shaping femtosecond laser pulses in micro/nanofabrication: modeling, method, measurement and application.
During femtosecond laser fabrication, photons are mainly absorbed by electrons, and the subsequent energy transfer from electrons to ions is of picosecond order. Hence, lattice motion is negligible within the femtosecond pulse duration, whereas femtosecond photon-electron interactions dominate the entire fabrication process. Therefore, femtosecond laser fabrication must be improved by controlling localized transient electron dynamics, which poses a challenge for measuring and controlling at the electron level during fabrication processes. Pump-probe spectroscopy presents a viable solution, which can be used to observe electron dynamics during a chemical reaction. In fact, femtosecond pulse durations are shorter than many physical/chemical characteristic times, which permits manipulating, adjusting, or interfering with electron dynamics. Hence, we proposed to control localized transient electron dynamics by temporally or spatially shaping femtosecond pulses, and further to modify localized transient materials properties, and then to adjust material phase change, and eventually to implement a novel fabrication method. This review covers our progresses over the past decade regarding electrons dynamics control (EDC) by shaping femtosecond laser pulses in micro/nanomanufacturing: (1) Theoretical models were developed to prove EDC feasibility and reveal its mechanisms; (2) on the basis of the theoretical predictions, many experiments are conducted to validate our EDC-based femtosecond laser fabrication method. Seven examples are reported, which proves that the proposed method can significantly improve fabrication precision, quality, throughput and repeatability and effectively control micro/nanoscale structures; (3) a multiscale measurement system was proposed and developed to study the fundamentals of EDC from the femtosecond scale to the nanosecond scale and to the millisecond scale; and (4) As an example of practical applications, our method was employed to fabricate some key structures in one of the 16 Chinese National S&T Major Projects, for which electron dynamics were measured using our multiscale measurement system.


Positive zeta potential of nanodiamonds.
In this paper, the origin of positive zeta potential exhibited by nanodiamond particles is explained. Positive zeta potentials in nano-structured carbons can be explained by the presence of graphitic planes at the surface, which leave oxygen-free Lewis sites and so promotes the suppression of acidic functional groups. Electron Microscopy and Raman Spectroscopy have been used to show that positive zeta potential of nanodiamond is only exhibited in the presence of sp2 carbon at the surface.


Increased plasma sVCAM-1 is associated with severity in IgA nephropathy.
A considerable proportion of IgAN patients present with histological vasculitic/crescentic lesions in glomeruli, indicating activation of vascular inflammation. Using sVCAM-1, a well-proven marker for endothelial injury under inflammatory processes, we investigated vascular injury and its association with clinical and pathological manifestations in IgAN patients. In this study, 327 biopsy-proven IgAN patients and 55 healthy controls were enrolled. The Oxford classification and two variables, Active Crescentic Lesion Percentage (ACLP) and Chronic Glomerular Lesion Percentage (CGLP), were used for evaluating pathological lesions. Human Umbilical Vein Endothelial Cells were treated with 25-400 ug/ml IgA1. sVCAM-1 in plasma and culture supernatant were measured by ELISA. Plasma sVCAM-1 in IgAN patients was significantly higher than healthy controls. In patients with IgAN, plasma sVCAM-1 was significantly correlated with eGFR, 24h urine protein excretion, tubular atrophy/interstitial fibrosis lesion and ACLP, but not CGLP. Meanwhile, compared to healthy volunteers, IgA1 from IgAN patients showed a tendency to increase the HUVECs supernatant sVCAM-1 expression. And IgA1 induced the sVCAM-1 increasing from HUVECs in time- and dose-dependent manner. We found increased plasma sVCAM-1 in IgAN patients and its association with severe clinical and pathological manifestations, which might be partly resulted from effect of IgA1 to endothelial cells.


Confrontation of scabrous expressing and non-expressing cells is essential for normal ommatidial spacing in the Drosophila eye.
The establishment of neural precursor cells in Drosophila depends on cell-cell interactions and lateral inhibition. Scabrous (sca) is involved in this process by preventing an excess of cells from adopting a neural precursor fate. Specifically in eye development, Sca protein function has been implicated in the spacing pattern that is essential for the ordered appearance of the ommatidial array. During this process sca expression is restricted to neurogenic groups of cells and later to the neural precursors. We report that ectopic sca expression in the morphogenetic furrow results in a rough eye phenotype with oversized and fused ommatidia. These defects in adult eyes are due to the generation of too many ommatidial preclusters in the morphogenetic furrow. Strikingly, sca loss-of-function mutants have an almost identical phenotype. Our results suggest that Sca plays a positive role in establishing the spacing pattern within the furrow and that the quantitative difference in sca expression between neighboring groups of cells is a determining factor in this process. Ectopic expression of Sca also represses endogenous sca expression in the furrow, suggesting that Sca is involved in a feedback loop affecting its own transcription. Interestingly, sca shares homology to a group of extracellular matrix proteins that have been implicated in neuronal differentiation. We present a model for sca function based on its phenotypic and molecular features.


Cell-cycle-dependent phosphorylation of the nuclear pore Nup107-160 subcomplex.
The nuclear pore complex (NPC) mediates macromolecular transport between the nucleus and the cytoplasm. Many NPC proteins (nucleoporins, Nups) are modified by phosphorylation. It is believed that phosphorylation regulates the breakdown of the nuclear envelope at mitosis and the disassembly of the NPC into different subcomplexes. In this study, we examined the cell-cycle-dependent phosphorylation of the Nup107-160 subcomplex, a core building block of the NPC. Using in vivo (32)P labeling in HeLa cells, we found that Nup107, Nup96, and Nup133 are phosphorylated during mitosis. To precisely map the phosphorylation sites within the complex, we used a comprehensive multiple-stage MS approach (MS, MS(2), and MS(3)), establishing that Nup160, Nup133, Nup96, and Nup107 are all targets of phosphorylation. We determined that the phosphorylation sites are clustered mainly at the N-terminal regions of these proteins, which are predicted to be natively disordered. In addition, we determined the cell-cycle dependence of the phosphorylation of these sites by using stable isotope labeling and MS(2) analysis. Measurement of the site-specific phosphorylation ratios between mitotic and G(1) cells led us to conclude that several phosphorylation events of the subcomplex are mainly mitotic. Based on these results and our finding that the entire Nup107-160 subcomplex is stable throughout the cell cycle, we propose that phosphorylation does not affect interactions within the Nup107-160 subcomplex, but regulates the association of the subcomplex with the NPC and other proteins.


Necessary and sufficient role for T helper cells to prevent fungal dissemination in allergic lung disease.
Mucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections with Curvularia lunata and Aspergillus fumigatus were typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia of Aspergillus fumigatus administered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient μMT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination.


Focal Suppression of Distractor Sounds by Selective Attention in Auditory Cortex.
Auditory selective attention is required for parsing crowded acoustic environments, but cortical systems mediating the influence of behavioral state on auditory perception are not well characterized. Previous neurophysiological studies suggest that attention produces a general enhancement of neural responses to important target sounds versus irrelevant distractors. However, behavioral studies suggest that in the presence of masking noise, attention provides a focal suppression of distractors that compete with targets. Here, we compared effects of attention on cortical responses to masking versus non-masking distractors, controlling for effects of listening effort and general task engagement. We recorded single-unit activity from primary auditory cortex (A1) of ferrets during behavior and found that selective attention decreased responses to distractors masking targets in the same spectral band, compared with spectrally distinct distractors. This suppression enhanced neural target detection thresholds, suggesting that limited attention resources serve to focally suppress responses to distractors that interfere with target detection. Changing effort by manipulating target salience consistently modulated spontaneous but not evoked activity. Task engagement and changing effort tended to affect the same neurons, while attention affected an independent population, suggesting that distinct feedback circuits mediate effects of attention and effort in A1.


Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity.
Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC(50) values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.


Bisphenol A: an emerging threat to female fertility.
Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.


Factors Associated with HIV/AIDS Sexual Risk Among Young Women Aged 15-24 Years in Nigeria.
The growing rate of sexual risk-taking among young people contributes significantly to the spread of the HIV/AIDS epidemic in Nigeria. This study, explores the influence of socio-demographic, HIV/AIDS awareness and female empowerment on the sexual risk behaviors of unmarried Nigerian women aged 15-24. The data presented in this paper was drawn from the 2003 Nigeria National Demographic and Health Survey. The sample consisted of unmarried women aged 15-24 in the dataset. Data was collected through a structured and interviewer administered questionnaire. Multivariate logistic regression models were used to identify the most important predictors of sexual risk behaviors. Sexual risk-taking is relatively high among unmarried young women. Among those who are sexually active, 80% indicated that they did not use a condom during their first sexual encounter. Regression analysis revealed that younger age, lower HIV/AIDS prevention and transmission knowledge, lower knowledge of where to obtain condoms, lower material standard of living and greater intimate partner violence were significantly associated with sexual risk-taking in this population. Findings revealed that the sexual behavior of unmarried Nigerian women aged 15-24 is influenced by a complex matrix of factors. Identifying specific processes and contexts that promote the concentration of risk among sub-sections of young unmarried women aged 15-24 years in Nigeria should be a research and intervention priority.


Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.


Applications of aminolevulinic Acid-based photodynamic therapy in cosmetic facial plastic practices.
Photodynamic therapy (PDT) using aminolevulinic acid (ALA) is a promising new technique that is being studied extensively and used in a variety of cosmetic facial plastic arenas. These applications include U.S. Food and Drug Administration-approved treatment of premalignant and malignant skin conditions, as well as off-label uses for photorejuvenation, and the treatment of acne vulgaris, sebaceous gland hyperplasia, rosacea, and hirsutism. This article reviews the interplay of factors that contribute to the appearance of actinically damaged or photoaged skin, also known as dermatoheliosis. This is followed by a brief review of the mechanisms of action of ALA-based PDT and some of its cosmetic facial plastic uses.


Identification of radiologic healing phenomena in patients with rheumatoid arthritis.
Conventional radiographic scoring methods in rheumatoid arthritis (RA) are designed to quantify progression and disregard any improvement. Reparative changes observed during longterm followup of RA have rarely been described as healing phenomena. Healing may become increasingly important with the availability of more potent antirheumatic drugs. We investigated whether radiologic healing phenomena can be identified by different observers in a blinded fashion. Healing phenomena were defined as (1) reappearance (and sclerosis) of the cortical plate, (2) partial or complete filling in of an erosion, or (3) subchondral bone sclerosis with osteophyte formation (secondary osteoarthritis). Pairs of radiographs of hands, wrists, and forefeet [taken 2 to 8 (mean 4.8) yrs apart] of 34 patients were selected from longterm studies: 24 sets with healing phenomena and 10 with progressive disease without healing. The radiographs were blinded and read in pairs in random order by 3 observers unaware of the patients selected for the study. One observer read the set a second time after 8 weeks, resulting in a total of 4 observations. Thirty-eight joints were rated 0 to 5 depending on the amount of surface destruction. In addition an attempt was made to identify joints with healing phenomena. The data were analyzed with help of descriptive statistics such as means, standard deviations, and frequency tables. Out of 1292 joints scored at the second time point, 74 had healing phenomena. These joints were identified in a mean of 89% (95/89/88/82%, respectively) in the 4 observations performed by the 3 readers. Patients without healing phenomena were correctly identified by all observers. In 54 joints less typical healing phenomena were seen in all observations. Sixty-two joints with healing in addition to the 74 joints were seen in 3 observations, 76 in 2, and 127 in one observation. All observers agreed that 1090 joints had no healing phenomenon. The 24 patients with healing had a slight reduction in the Ratingen score, while the 10 patients without healing showed a moderate progression. In the group with healing an increase and decrease in the score occurred in the same patients at different joints. In patients with RA followed for several years healing or reparative changes of erosions can be observed. These phenomena can be identified by different observers with high sensitivity even when the observers are blinded to chronological sequence of the films.


Relationship between alanine aminotransferase levels and metabolic syndrome in nonalcoholic fatty liver disease.
To investigate the relationship between alanine aminotransferase (ALT) levels and metabolic syndrome (MS) in nonalcoholic fatty liver disease (NAFLD). A total of 26527 subjects who received medical health checkup in our hospital from January 2005 to July 2007 were enrolled in the study. The diagnosis of fatty liver was based on ultrasound imaging. MS was defined according to the criteria of the Adult Treatment Panel III. ALT, triglyceride (TG), high density lipoprotein cholesterol (HDL-c), fasting plasma glucose (FPG), height, weight, waist circumference (WC), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in each subject to analyze the relationship between MS and ALT activity. (1) The prevalence of NAFLD in men (30.94%) was significantly higher than that in women (15.65%); (2) The incidence of MS in NAFLD (33.83%) was significantly greater than that in non-NAFLD (10.62%); (3) Of the 6470 subjects with NAFLD, in the age-adjusted partial correlation analysis, there were statistically significant correlations between the ALT levels and most metabolic risk factors in each sex (P<0.01), except that ALT levels had no correlation with HDL-c in women. Moreover, in the multiple stepwise regression analysis, SBP lost its significance, and WC, body mass index (BMI), age, DBP, TG and FPG were independently associated with ALT levels in both sexes (P<0.05). HDL-c remained significant and was independently related to ALT levels in men; (4) ALT levels were significantly higher in subjects with MS compared to those without MS (P<0.001). Mean ALT levels increased with the number of MS components in each sex (P<0.05 for trend). We found a strong relationship between ALT levels and MS in NAFLD and revealed that the cluster of MS components might be the predictor for ALT elevations.


Mechanisms of saccadic decision making while encoding naturalistic scenes.
Saccadic eye movements are the primary vehicle by which human gaze is brought in alignment with vital visual information present in naturalistic scenes. Although numerous studies using the double-step paradigm have demonstrated that saccade preparation is subject to modification under certain conditions, this has yet to be studied directly within a naturalistic scene-viewing context. To reveal characteristic properties of saccade programming during naturalistic scene viewing, we contrasted behavior across three conditions. In the Static condition of the main experiment, double-step targets were presented following a period of stable fixation on a central cross. In a Scene condition, targets were presented while participants actively explored a naturalistic scene. During a Noise condition, targets were presented during active exploration of a 1/f noise-filtered scene. In Experiment 2, we measure saccadic responses in three Static conditions (Uniform, Scene, and Noise) in which the backgrounds are the same as Experiment 1 but scene exploration is no longer permitted. We find that the mechanisms underlying saccade modification generalize to both dynamic conditions. However, we show that a property of saccade programming known as the saccadic dead time (SDT), the interval prior to saccade onset during which a saccade may not be canceled or modified, is lower in the Static task than it is in the dynamic tasks. We also find a trend toward longer SDT in the Scene as compared with Noise conditions. We discuss the implication of these results for computational models of scene viewing, reading, and visual search tasks.


Unique effects of energy versus estrogen deficiency on multiple components of bone strength in exercising women.
Many female athletes are energy and/or estrogen deficient, but the independent effects on bone health have not been isolated. Energy deficiency was detrimental at the tibia while estrogen deficiency was detrimental at the radius. Nutrition must be considered alongside menstrual recovery when addressing compromised bone health in female athletes. The purpose of this study was to describe volumetric bone mineral density (vBMD), bone geometry, and estimated bone strength in exercising women (n = 60) grouped according to energy status (energy replete (EnR: n = 30) vs. energy deficient (EnD: n = 30)) and estrogen status (estrogen replete (E2R: n = 33) vs. estrogen deficient (E2D: n = 27)), resulting in four distinct groups: EnR + E2R (n = 17), EnR + E2D (n = 13), EnD + E2R (n = 16), EnD + E2D (n = 14). Energy status was determined using the ratio of measured to predicted resting energy expenditure (mREE/pREE). Estrogen status was based on self-reported menstrual status confirmed by daily evaluation of urinary estrone-1-glucoronide (E1G), pregnanediol glucuronide (PdG), and luteinizing hormone (LH). Eumenorrheic women were considered E2R, amenorrheic women were E2D, and oligomenorrheic women were categorized based on history of menses in the past year. Bone was assessed using peripheral quantitative computed tomography (pQCT). EnD women exhibited lower total vBMD, trabecular vBMD, cortical area, and BSI at the distal tibia and lower total vBMD, smaller cortical area and cortical thickness, and larger endosteal circumference at the proximal tibia compared to EnR women (p < 0.042). E2D women had lower total and cortical vBMD, larger total and trabecular area, and lower BSI at the distal radius and lower cortical vBMD at the proximal radius compared to E2R women (p < 0.023). Energy and estrogen interacted to affect total and trabecular area at the distal tibia (p < 0.021). Efforts to correct energy deficiency, which in turn may promote reproductive health, are warranted in order to address the unique contributions of energy status versus estrogen status to bone health.


Ambulance use for 'primary care' problems: an ethnographic study of seeking and providing help in a UK ambulance service.
To explore what factors shape a service user's decision to call an emergency ambulance for a 'primary care sensitive' condition (PCSC), including contextual factors. Additionally, to understand the function and purpose of ambulance care from the perspective of service users, and the role health professionals may play in influencing demand for ambulances in PCSCs. An ethnographic study set in one UK ambulance service. Patient cases were recruited upon receipt of ambulance treatment for a situation potentially manageable in primary care, as determined by a primary care clinician accompanying emergency medical services (EMS) crews. Methods used included: structured observations of treatment episodes; in-depth interviews with patients, relatives and carers and their GPs; purposeful conversations with ambulance clinicians; analysis of routine healthcare records; analysis of the original EMS 'emergency' telephone call recording. We analysed 170 qualitative data items across 50 cases. Three cross-cutting concepts emerged as central to EMS use for a PCSC: (1) There exists a typology of nine 'triggers', which we categorise as either 'internal' or 'external', depending on how much control the caller feels they have of the situation; (2) Calling an ambulance on behalf of someone else creates a specific anxiety about urgency; (3) Healthcare professionals experience conflict around fuelling demand for ambulances. Previous work suggests a range of sociodemographic factors that may be associated with choosing ambulance care in preference to alternatives. Building on established sociological models, this work helps understand how candidacy is displayed during the negotiation of eligibility for ambulance care. Seeking urgent assistance on behalf of another often requires specific support and different strategies. Use of EMS for such problems-although inefficient-is often conceptualised as 'rational' by service users. Public health strategies that seek to advise the public about appropriate use of EMS need to consider how individuals conceptualise an 'emergency' situation.


Developing energy efficient lignin biomass processing - towards understanding mediator behaviour in ionic liquids.
Environmental concerns have brought attention to the requirement for more efficient and renewable processes for chemicals production. Lignin is the second most abundant natural polymer, and might serve as a sustainable resource for manufacturing fuels and aromatic derivatives for the chemicals industry after being depolymerised. In this work, the mediator 2,2'-azino-bis(3-ethylbenthiazoline-6-sulfonic acid) diammonium salt (ABTS), commonly used with enzyme degradation systems, has been evaluated by means of cyclic voltammetry (CV) for enhancing the oxidation of the non-phenolic lignin model compound veratryl alcohol and three types of lignin (organosolv, Kraft and lignosulfonate) in the ionic liquid 1-ethyl-3-methylimidazolium ethyl sulfate, ([C2mim][C2SO4]). The presence of either veratryl alcohol or organosolv lignin increased the second oxidation peak of ABTS under select conditions, indicating the ABTS-mediated oxidation of these molecules at high potentials in [C2mim][C2SO4]. Furthermore, CV was applied as a quick and efficient way to explore the impact of water in the ABTS-mediated oxidation of both organosolv and lignosulfonate lignin. Higher catalytic efficiencies of ABTS were observed for lignosulfonate solutions either in sodium acetate buffer or when [C2mim][C2SO4] (15 v/v%) was present in the buffer solution, whilst there was no change found in the catalytic efficiency of ABTS in [C2mim][C2SO4]-lignosulfonate mixtures relative to ABTS alone. In contrast, organosolv showed an initial increase in oxidation, followed by a significant decrease on increasing the water content of a [C2mim][C2SO4] solution.


Dimerization opens new avenues into Ras signaling research.
Several reports using recently developed physicochemical and imaging techniques have provided experimental evidence for the existence of dimers of Ras proteins, which was first postulated more than 25 years ago. These data have sparked renewed interest in the potential physiological and pathological importance of homo- or heterodimerization of Ras proteins. Understanding the structural and functional properties of Ras dimers should provide mechanistic explanations for unanswered questions regarding the involvement of Ras proteins in signaling pathways that contribute to both normal physiology and oncogenic processes. Furthermore, this knowledge should enable the development of new drugs targeting Ras proteins.


Crystal Structure of the Metallo-β-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site.
Metallo-beta-lactamases (MBLs) are broad-spectrum, Zn(II)-dependent lactamases able to confer resistance to virtually every β-lactam antibiotic currently available. The large diversity of active-site structures and metal content among MBLs from different sources has limited the design of a pan-MBL inhibitor. GOB-18 is a divergent MBL from subclass B3 that is expressed by the opportunistic Gram-negative pathogen Elizabethkingia meningoseptica This MBL is atypical, since several residues conserved in B3 enzymes (such as a metal ligand His) are substituted in GOB enzymes. Here, we report the crystal structure of the periplasmic di-Zn(II) form of GOB-18. This enzyme displays a unique active-site structure, with residue Gln116 coordinating the Zn1 ion through its terminal amide moiety, replacing a ubiquitous His residue. This situation contrasts with that of B2 MBLs, where an equivalent His116Asn substitution leads to a di-Zn(II) inactive species. Instead, both the mono- and di-Zn(II) forms of GOB-18 are active against penicillins, cephalosporins, and carbapenems. In silico docking and molecular dynamics simulations indicate that residue Met221 is not involved in substrate binding, in contrast to Ser221, which otherwise is conserved in most B3 enzymes. These distinctive features are conserved in recently reported GOB orthologues in environmental bacteria. These findings provide valuable information for inhibitor design and also posit that GOB enzymes have alternative functions.


Life for patients with myelofibrosis: the physical, emotional and financial impact, collected using narrative medicine-Results from the Italian 'Back to Life' project.
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterised by an aggressive clinical course, with disabling symptoms and reduced survival. Patients experience a severely impaired quality of life and their families face the upheaval of daily routines and high disease-related financial costs. The aim of this study was to investigate the perceptions of Italian patients and their caregivers about living with MF and the burden of illness associated with MF. A quali-quantitative questionnaire and a prompted written narrative survey were administered to patients affected by primary or post-essential thrombocythemia/post-polycythaemia vera MF and their primary caregiver in 35 Italian haematological centres. In total, 287 questionnaires were returned by patients and 98 by caregivers, with 215 and 62, respectively, including the narrative. At the time of diagnosis, the most commonly expressed emotional states of patients were fear, distress and anger, confirming the difficulty of this phase. A high level of emotional distress was also reported by caregivers. Along the pathway of care, the ability to cope with the disease differed according to the quality of care received. The mean cost to each patient attributable to MF was estimated as €12,466 per year, with an estimated average annual cost of loss of income of €7774 per patient and €4692 per caregiver. Better understanding of the personal life of MF patients and their families could improve the relationships between health workers and patients, resulting in better focused healthcare pathways and more effective financial support to maintain patients in their social roles.


Informed cytology for triaging HPV-positive women: substudy nested in the NTCC randomized controlled trial.
Human papillomavirus (HPV)-based screening needs triage. In most randomized controlled trials (RCTs) on HPV testing with cytological triage, cytology interpretation has been blind to HPV status. Women age 25 to 60 years enrolled in the New Technology in Cervical Cancer (NTCC) RCT comparing HPV testing with cytology were referred to colposcopy if HPV positive and, if no cervical intraepithelial neoplasia (CIN) was detected, followed up until HPV negativity. Cytological slides taken at the first colposcopy were retrieved and independently interpreted by an external laboratory, which was only aware of patients' HPV positivity. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were computed for histologically proven CIN2+ with HPV status-informed cytology for women with a determination of atypical squamous cells of undetermined significance (ASCUS) or more severe. All statistical tests were two-sided. Among HPV-positive women, informed cytology had cross-sectional sensitivity, specificity, PPV and 1-NPV for CIN2+ of 85.6% (95% confidence interval [CI] = 76.6 to 92.1), 65.9% (95% CI = 63.1 to 68.6), 16.2% (95% CI = 13.0 to 19.8), and 1.7 (95% CI = 0.9 to 2.8), respectively. Cytology was also associated with subsequent risk of newly diagnosed CIN2+ and CIN3+. The cross-sectional relative sensitivity for CIN2+ vs blind cytology obtained by referring to colposcopy and following up only HPV positive women who had HPV status-informed cytology greater than or equal to ASCUS was 1.58 (95% CI = 1.22 to 2.01), while the corresponding relative referral to colposcopy was 0.95 (95% CI = 0.86 to 1.04). Cytology informed of HPV positivity is more sensitive than blind cytology and could allow longer intervals before retesting HPV-positive, cytology-negative women.


The CYP2C19*2 and CYP2C19*17 Polymorphisms play a Vital Role in Clopidogrel Responsiveness after Percutaneous Coronary Intervention: A Pharmacogenomics Study.
Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. A total of 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study. Platelet reactivity (PRU) and % inhibition were measured with VerifyNow P2Y12 assay in blood samples collected from patients who took a standard dose of clopidogrel (75 mg/day) for at least 7 days. The variants in the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes were genotyped using the Sequenom MassARRAY system. When grouped, the patients with PRU values >208 as non-responsiveness to clopidogrel therapy; 104 (30%) patients were non-responders and 243 (70%) patients were responders. A significant association was found between the CYP2C19*2 (G636A) polymorphism and non-responsiveness to clopidogrel therapy (p < 0.001). An allele frequency of this single nucleotide polymorphism was high in non-responders; its odds ratio was 2.92 compared with G allele (p < 0.001). PRU values of CT genotypes were lower (p = 0.029) and % inhibition values of CT genotypes were higher (p = 0.008) compared with CC genotypes for the CYP2C19*17 (C806T) polymorphism. None of the other genetic variants were found to be statistically associated with non-responsiveness to clopidogrel and antiplatelet activity. Our findings suggest that the CYP2C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2C19*17 polymorphism enhances antiplatelet activity of clopidogrel. Depending on haplotypes of these two polymorphisms, clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events.


Application of statistical machine translation to public health information: a feasibility study.
Accurate, understandable public health information is important for ensuring the health of the nation. The large portion of the US population with Limited English Proficiency is best served by translations of public-health information into other languages. However, a large number of health departments and primary care clinics face significant barriers to fulfilling federal mandates to provide multilingual materials to Limited English Proficiency individuals. This article presents a pilot study on the feasibility of using freely available statistical machine translation technology to translate health promotion materials. The authors gathered health-promotion materials in English from local and national public-health websites. Spanish versions were created by translating the documents using a freely available machine-translation website. Translations were rated for adequacy and fluency, analyzed for errors, manually corrected by a human posteditor, and compared with exclusively manual translations. Machine translation plus postediting took 15-53 min per document, compared to the reported days or even weeks for the standard translation process. A blind comparison of machine-assisted and human translations of six documents revealed overall equivalency between machine-translated and manually translated materials. The analysis of translation errors indicated that the most important errors were word-sense errors. The results indicate that machine translation plus postediting may be an effective method of producing multilingual health materials with equivalent quality but lower cost compared to manual translations.


"Straight from the heavens into your bucket": domestic rainwater harvesting as a measure to improve water security in a subarctic indigenous community.
Black Tickle-Domino is an extremely water-insecure remote Inuit community in the Canadian subarctic that lacks piped-water. Drinking water consumption in the community is less than a third of the Canadian national average. Water insecurity in the community contributes to adverse health, economic, and social effects and requires urgent action. To test the ability of domestic rainwater harvesting (DRWH) for the first time in the subarctic with the goal of improving water access and use in the community. This project utilised quantitative weekly reporting of water collection and use, as well as focus group discussions. DRWH units were installed at seven water-insecure households chosen by the local government. Results were measured over a 6-week period in 2016. Participants harvested 19.07 gallons of rainwater per week. General purpose water consumption increased by 17% and water retrieval efforts declined by 40.92%. Households saved $12.70 CDN per week. Participants reported perceived improvements to psychological health. Because no potable water was collected, drinking water consumption did not increase. The study identified additional water-insecurity impacts. DRWH cannot supply drinking water without proper treatment and filtration; however, it can be a partial remedy to water insecurity in the subarctic. DRWH is appropriately scaled, inexpensive, and participants identified several significant benefits.


Surface deterioration of monolithic CAD/CAM restorative materials after artificial abrasive toothbrushing.
The purpose of this in vitro study was to evaluate the effect of abrasive toothbrushing on the surface properties of monolithic computer-assisted design and computer-assisted manufacturing (CAD/CAM) materials stored in food-simulating liquids (FSLs). Fourty-eight disk-shaped test specimens of each material (Paradigm MZ100/PMZ, Lava Ultimate/LU, Vita Enamic/VE, and Vita Mark II/VMII) with a diameter of 10.0 mm and a thickness of 3.0 ± 0.05 mm were prepared. Specimens were divided into 4 subgroups (n=12) and stored in air, distilled water, 0.02 M citric acid, or 75% ethanol/water solution for 7 days at 36.5℃. Then, the specimens were brushed in a multi-station brushing machine under a vertical load of 2.0 N for 3 hours. Surface gloss (GU), roughness (Ra), and hardness (Vickers [VHN]) were measured after storage and brushing simulation. The data sets were statistically analyzed with 2 and 3-way ANOVAs followed by the Tukey's post-hoc comparisons (α=.05). Statistically significant difference was found among the materials concerning the results of surface properties. VMII showed the highest VHN, while PMZ produced the lowest. Storage in FSLs significantly affected the VHN of PMZ and LU. VMII showed the lowest Ra and highest GU irrespective of FSLs and of abrasive toothbrushing. VE, LU, and PMZ produced significant decrease in GU and increase in Ra after toothbrushing. Surface properties of monolithic CAD/CAM restorative materials were differently affected by the storage media and abrasive toothbrushing.


Studying intergenerational transmission of eating attitudes and behaviors: methodological and conceptual questions.
Associations between parent and child attitudes and behaviors related to eating and weight were examined among college-age men and women and their mothers and fathers (ns = 44, 47, 87, and 66, respectively). Parent attitudes and behaviors were assessed from the perspective of the parent and the student, and 2 pathways of influence were examined: modeling and direct criticism. In general, students' attitudes and behaviors were more strongly related to perceptions of their parents rather than to parents' own self-reports. There was more support for perceived direct criticism as a pathway of influence, particularly for daughters. Perceived criticism about eating and appearance had large associations with student attitudes and behaviors. Weight loss behavior was related to perceived criticism among daughters and to perceived paternal eating attitudes among sons. Results highlight important methodological and conceptual questions for intergenerational research.


FeCl3-catalyzed dimerization/elimination of 1,1-diarylalkenes: efficient synthesis of functionalized 4H-chromenes.
An efficient synthesis of valuable poly-substituted 4H-chromenes was developed via a [4 + 2] cycloaddition followed by the elimination of 1,1-diarylalkenes. The inexpensive FeCl3 salt has proven to be an efficient catalyst for this transformation. The commercial availability of the catalyst and reagents, together with a convenient procedure, makes this an attractive method for 4H-chromene synthesis.


Trends in the mortality burden associated with diabetes mellitus: a population-based study in Rochester, Minn, 1970-1994.
The prevalence of diabetes mellitus (DM) has increased markedly in recent decades, but trends in the mortality burden associated with DM are unclear. Therefore, we analyzed population-based longitudinal data to address this issue. The community-based medical records of all Rochester residents 45 years and older who died between January 1, 1970, and December 31, 1994, were reviewed to identify those who met the standardized criteria for DM before death. Trends over successive quinquenniums were assessed for the proportion of all deaths in the community of persons with prevalent DM, for mortality rates for persons with and without DM, and for the distribution of causes of death among decedents with and without DM. Of 10 152 total deaths in 1970-1994, 1384 (13.6%) met the criteria for prevalent DM. Between 1970-1974 and 1990-1994, the proportion of decedents with DM increased by 48.2%. Mortality rates for persons with and without DM declined by 13.8% and 21.4%, respectively. This disparity in mortality trends was most apparent for older women and younger men. There were temporal declines in the proportion of all persons dying of cardiovascular disease, but temporal declines in persons dying of cerebrovascular disease were found only in decedents without DM. The mortality burden associated with DM increased significantly between 1970 and 1994, probably due to increases in DM incidence and smaller declines in mortality for persons with DM relative to those without DM. In the absence of improved DM prevention and treatment, the steady declines in mortality observed for the general population since the 1960s will likely begin to slow or even reverse.


Neurological deficit and canal compromise in thoracolumbar and lumbar burst fractures.
To assess whether canal compromise determines neurological deficit in thoracolumbar and lumbar burst fractures. 105 patients aged 17 to 60 (mean, 34) years who had burst fractures in the thoracolumbar (n=82) and lumbar (n=23) regions were included. Fractures were classified according to the Denis classification. The extent of spinal canal compromise was assessed by computed tomography, and the neurological status according to the modified Frankel grading for traumatic paraplegia. 19 (18%) of the patients had no neurological deficit. Of the remaining 86 (82%) with a deficit, 26 had complete paraplegia. The correlation between the type of the burst fracture and the severity of neurological deficit was not significant (Chi squared=10.57, p=0.835). The mean extent of spinal canal compromise in patients with deficits was 50%, whereas in patients with no deficit it was 36%. The difference between the extent of canal compromise and the severity of neurological deficit at the thoracolumbar and lumbar spine was not significant (p=0.08). Further subanalysis revealed a significant correlation at T11 and T12 (p=0.007) but not at the L1 (p=0.42) level. When studying neurological deficit, T11 and T12 injuries should be analysed separately from L1 injuries.


A history of lameness and low body condition score is associated with reduced digital cushion volume, measured by magnetic resonance imaging, in dairy cattle.
Claw horn lesions (CHL) are the result of a failing of the functional anatomy of the hoof in dairy cows. The digital cushion is understood to be a vital structure in the prevention of CHL. Claw horn lesions have previously been shown to lead to pathological change to the pedal bone; however, their effects on the digital cushion are unknown. The primary aim of this study was to examine associations between the history of CHL through an animal's life and the structure of the digital cushion at slaughter using magnetic resonance imaging. The retrospective cohort study resulted in the scanning of 102 pairs of hindfeet, collected from adult Holstein dairy cows culled from a research herd, using a 3-Tesla research-grade magnetic resonance imaging scanner. Volume and fat measurements were calculated for each digital cushion within each claw from a modified Dixon Quant sequence. Animal-level variables were constructed around the animals' lactating lifetime, with lameness scores and body condition score collected at least every 2 wk. The combined volume of digital cushion in the lateral claws was used as the outcome variable in multivariable linear models. The volume of the digital cushion was negatively associated with the number of lameness events or CHL recorded. Furthermore, animals with body condition score >3, culled later in lactation, or of a greater body weight were more likely to have a higher volume of digital cushion in the lateral claws. We propose that the observations made in the current study are the effects of a range of factors broadly associated with genetic, developmental, and disease-related inputs. Our understanding of how we can select for genetically more robust animals and how we can precondition the hoof before first calving needs to be improved to reduce the risk of future CHL in adult dairy cattle. Furthermore, understanding optimal treatment regimens and their effect on hoof anatomy may reduce the recurrence of CHL in the current lactation and future lactations.


HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.
Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.


Uncoiling CNLs: Structure/Function Approaches to Understanding CC Domain Function in Plant NLRs.
Plant nucleotide-binding leucine-rich repeat receptors (NLRs) are intracellular pathogen receptors whose N-terminal domains are integral to signal transduction after perception of a pathogen-derived effector protein. The two major plant NLR classes are defined by the presence of either a Toll/interleukin-1 receptor (TIR) or a coiled-coil (CC) domain at their N-terminus (TNLs and CNLs). Our knowledge of how CC domains function in plant CNLs lags behind that of how TIR domains function in plant TNLs. CNLs are the most abundant class of NLRs in monocotyledonous plants, and further research is required to understand the molecular mechanisms of how these domains contribute to disease resistance in cereal crops. Previous studies of CC domains have revealed functional diversity, making categorization difficult, which in turn makes experimental design for assaying function challenging. In this review, we summarize the current understanding of CC domain function in plant CNLs, highlighting the differences in modes of action and structure. To aid experimental design in exploring CC domain function, we present a 'best-practice' guide to designing constructs through use of sequence and secondary structure comparisons and discuss the relevant assays for investigating CC domain function. Finally, we discuss whether using homology modeling is useful to describe putative CC domain function in CNLs through parallels with the functions of previously characterized helical adaptor proteins.


Detecting linkage between a trait and a marker in a random mating population without pedigree record.
Modern linkage-based approaches employing extended pedigrees are becoming powerful tools for localizing complex quantitative trait loci. For these linkage mapping methods, it is necessary to reconstruct extended pedigrees which include living individuals, using extensive pedigree records. Unfortunately, such records are not always easy to obtain and application of the linkage-based approaches has been restricted. Within a finite population under random mating, latent inbreeding rather than non-random inbreeding by consanguineous marriages is expected to occur and is attributable to coalescence in a finite population. Interestingly, it has been revealed that significant random inbreeding exists even in general human populations. Random inbreeding should be used to detect the hidden coancestry between individuals for a particular chromosomal position and it could also have application in linkage mapping methods. Here we present a novel method, named finite population based linkage mapping (FPL) method, to detect linkage between a quantitative trait and a marker via random inbreeding in a finite population without pedigree records. We show how to estimate coancestry for a chromosomal position between individuals by using multipoint Bayesian estimation. Subsequently, we describe the FPL method for detecting linkage via interval mapping method using a nonparametric test. We show that the FPL method does work via simulated data. For a random sample from a finite population, the FPL method is more powerful than a standard pedigree-based linkage mapping method with using genotypes of all parents of the sample. In addition, the FPL method was demonstrated by actual microsatellite genotype data of 750 Japanese individuals that are unrelated according to pedigree records to map a known Psoriasis susceptible locus. For samples without pedigree records, it was suggested that the FPL method require limited number of individuals, therefore would be better than other methods using thousands of individuals.


Impact of network structure and cellular response on spike time correlations.
Novel experimental techniques reveal the simultaneous activity of larger and larger numbers of neurons. As a result there is increasing interest in the structure of cooperative--or correlated--activity in neural populations, and in the possible impact of such correlations on the neural code. A fundamental theoretical challenge is to understand how the architecture of network connectivity along with the dynamical properties of single cells shape the magnitude and timescale of correlations. We provide a general approach to this problem by extending prior techniques based on linear response theory. We consider networks of general integrate-and-fire cells with arbitrary architecture, and provide explicit expressions for the approximate cross-correlation between constituent cells. These correlations depend strongly on the operating point (input mean and variance) of the neurons, even when connectivity is fixed. Moreover, the approximations admit an expansion in powers of the matrices that describe the network architecture. This expansion can be readily interpreted in terms of paths between different cells. We apply our results to large excitatory-inhibitory networks, and demonstrate first how precise balance--or lack thereof--between the strengths and timescales of excitatory and inhibitory synapses is reflected in the overall correlation structure of the network. We then derive explicit expressions for the average correlation structure in randomly connected networks. These expressions help to identify the important factors that shape coordinated neural activity in such networks.


Two ancient bacterial endosymbionts have coevolved with the planthoppers (Insecta: Hemiptera: Fulgoroidea).
Members of the hemipteran suborder Auchenorrhyncha (commonly known as planthoppers, tree- and leafhoppers, spittlebugs, and cicadas) are unusual among insects known to harbor endosymbiotic bacteria in that they are associated with diverse assemblages of bacterial endosymbionts. Early light microscopic surveys of species representing the two major lineages of Auchenorrhyncha (the planthopper superfamily Fulgoroidea; and Cicadomorpha, comprising Membracoidea [tree- and leafhoppers], Cercopoidea [spittlebugs], and Cicadoidea [cicadas]), found that most examined species harbored at least two morphologically distinct bacterial endosymbionts, and some harbored as many as six. Recent investigations using molecular techniques have identified multiple obligate bacterial endosymbionts in Cicadomorpha; however, much less is known about endosymbionts of Fulgoroidea. In this study, we present the initial findings of an ongoing PCR-based survey (sequencing 16S rDNA) of planthopper-associated bacteria to document endosymbionts with a long-term history of codiversification with their fulgoroid hosts. Results of PCR surveys and phylogenetic analyses of 16S rDNA recovered a monophyletic clade of Betaproteobacteria associated with planthoppers; this clade included Vidania fulgoroideae, a recently described bacterium identified in exemplars of the planthopper family Cixiidae. We surveyed 77 planthopper species representing 18 fulgoroid families, and detected Vidania in 40 species (representing 13 families). Further, we detected the Sulcia endosymbiont (identified as an obligate endosymbiont of Auchenorrhyncha in previous studies) in 30 of the 40 species harboring Vidania. Concordance of the Vidania phylogeny with the phylogeny of the planthopper hosts (reconstructed based on sequence data from five genes generated from the same insect specimens from which the bacterial sequences were obtained) was supported by statistical tests of codiversification. Codiversification tests also supported concordance of the Sulcia phylogeny with the phylogeny of the planthopper hosts, as well as concordance of planthopper-associated Vidania and Sulcia phylogenies. Our results indicate that the Betaproteobacterium Vidania is an ancient endosymbiont that infected the common ancestor of Fulgoroidea at least 130 million years ago. Comparison of our findings with the early light-microscopic surveys conducted by Müller suggests that Vidania is Müller's x-symbiont, which he hypothesized to have codiversified with most lineages of planthoppers and with the Sulcia endosymbiont.