[Cardiorespiratory fitness among adults in Germany: results of the German Health Interview and Examination Survey for Adults (DEGS1)].
A high level of fitness is an indicator for a good health state. Therefore, cardiorespiratory fitness was examined in the cross-sectional German Health Interview Survey for Adults (DEGS1). Data from 3030 test-qualified adults between 18 and 64 years old were assessed by means of a standardized submaximal cycle ergometer test. Test-qualified participants were significantly younger, more often men, less often obese and showed a better health state than those who were not test-qualified. The calculated physical work capacity at 75 % of the age-predicted maximum heart rate (PWC75%) in watts per kg bodyweight was among men 1.52 and among women 1.15. PWC75% declines by 4.2 % per age decade for men and 4.8 % for women. A higher socioeconomic status (SES) is associated with better fitness among women. No significant association was observed between SES and fitness among men. These findings can be used to develop target-group specific health-promotion interventions in order to enhance cardiorespiratory fitness. It is planned to calculate updated PWC reference values based on the DEGS1 data. An English full-text version of this article is available at SpringerLink as supplemental.


Switchable conductance in functionalized carbon nanotubes via reversible sidewall bond cleavage.
We propose several covalent functionalizations for carbon nanotubes that display switchable on/off conductance in metallic tubes. The switching action is achieved by reversible control of bond-cleavage chemistry in [1 + 2] cycloadditions via the sp(3) ⇌ sp(2) rehybridization that it induces; this leads to remarkable changes of conductance even at very low degrees of functionalization. Reversible bond-cleavage chemistry is achieved by identifying addends that provide optimal compensation between the bond-preserving through-space π orbital interactions with the tube against the bond-breaking strain energy of the cyclopropane moiety. Several strategies for real-time control, based on redox or hydrolysis reactions, cis-trans isomerization or excited-state proton transfer are proposed. Such designer functional groups would allow for the first time direct control of the electrical properties of metallic carbon nanotubes, with extensive applications in nanoscale devices.


Genetic and environmental responses to temperature of Drosophila melanogaster from a latitudinal cline.
Field-collected Drosophila melanogaster from 19 populations in Eastern Australia were measured for body size traits, and the measurements were compared with similar ones on flies from the same populations reared under standard laboratory conditions. Wild caught flies were smaller, and latitudinal trends in size were greater. Reduced size was caused by fewer cells in the wing, and the steeper cline by greater variation in cell area. The reduction in size in field-collected flies may therefore have been caused by reduced nutrition, and the steeper cline may have been caused by an environmental response to latitudinal variation in temperature. No evidence was found for evolution of size traits in response to laboratory culture. The magnitude of phenotypic plasticity in response to temperature of development time, body size, cell size and cell number was examined for six of the populations, to test for latitudinal variation in plasticity. All characters were plastic in response to temperature. Total development time showed no significant latitudinal variation in plasticity, although larval development time showed a marginally significant effect, with most latitudinal variation at intermediate rearing temperatures. Neither thorax length nor wing size and its cellular components showed significant latitudinal variation in plasticity.


Reactive Protection? Fear, Victimization, and Fighting Among U.S. High School Students.
Youth violence in high schools is a pervasive and persistent problem in the United States. Students engage in physical fights, experience bullying and teen dating violence (TDV), are threatened with weapons, and miss school due to safety concerns. However, despite theoretical support, research has not sufficiently addressed the relationship between students' fear and fighting at school. This secondary analysis used data from the 2013 Youth Risk Behavior Survey (n = 13,583) to examine the relationship between fear at school, victimization, and engagement in fighting at school among high school students. We created a 3-item composite fear variable, conducted logistic regression to examine likelihood of fighting, and multinomial regression to examine risk for multiple fights, and stratified all models by gender. Findings indicate that both male and female students who experienced fear were more likely to engage in fights at school than peers who did not experience fear, even when controlling for other factors. Likewise, the more fear incidents a student experienced, the more at risk they were for engaging in multiple fights. Findings on victimization indicate that the relationship with fighting is more straightforward for male students than for female students. For males, being bullied and experiencing multiple incidents of physical and sexual TDV were all associated with fighting at school. For females, however, only one type of victimization was associated with fighting at school: experiencing multiple incidents of physical TDV. Overall, findings suggest that fear may be more than merely a by-product of fighting, but rather-as the extant research supports-fear also can be generalized across situations and displayed through patterns of aggression. Findings support the need for interventions aimed at skill-building in areas of communication, emotion regulation, conflict resolution, and healthy relationships to help youth-particularly those in younger grades-negotiate interpersonal relationships without the use of violence.


Targeted delivery of paromomycin in murine infectious diseases through association to nano lipid systems.
Treatment of intracellular infections such as those caused by Mycobacterium spp. and Leishmania spp. is often hampered by limited access of drugs to infected cells. This is the case of paromomycin (PRM), an antibiotic with broad spectrum in vitro activity against protozoa and mycobacteria. Association of chemotherapeutics to liposomes is a worthy strategy to circumvent poor drug accessibility. Six different PRM liposomal formulations were produced, physicochemically characterized and biologically evaluated in a macrophagic cell line confirming their adequacy for in vivo studies. Biodistribution profiles of PRM liposomes revealed preferential targeting of the antibiotic to the liver, spleen and lungs, relative to free PRM, which translated into an enhanced therapeutic effect in murine models infected with Mycobacterium avium and Leishmania infantum and an absence of toxic effects. Our findings demonstrate the advantages of associating PRM to liposomes indicating their potential as an alternative therapeutic strategy for mycobacterial and parasite infections. Infections caused by intracellular organisms such as Mycobacterium and Leishmania remain a significant problem worldwide. Although effective drugs are available, their actions are limited by access into the intracellular compartment. In this article, the authors developed different liposomal formulations as drug carriers of paromomycin and investigated their efficacy in a mouse model. The positive should provide another treatment option for these organisms in the near future.


Control of Angiogenesis via a VHL/miR-212/132 Axis.
A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl-/- mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.


Long-term restriction by APOBEC3F selects human immunodeficiency virus type 1 variants with restored Vif function.
Tandem stop mutations K26X and H27X in human immunodeficiency virus type 1 (HIV-1) vif compromise virus replication in human T-cell lines that stably express APOBEC3F (A3F) or APOBEC3G (A3G). We previously reported that partial resistance to A3G could develop in these Vif-deficient viruses through a nucleotide A200-to-T/C transversion and a vpr null mutation, but these isolates were still susceptible to restriction by A3F. Here, long-term selection experiments were done to determine how these A3G-selected isolates might evolve to spread in the presence of A3F. We found that A3F, like A3G, is capable of potent, long-term restriction that eventually selects for heritable resistance. In all 7 instances, the selected isolates had restored Vif function to cope with A3F activity. In two isolates, Vif Q26-Q27 and Y26-Q27, the resistance phenotype recapitulated in molecular clones, but when the selected vif alleles were analyzed in the context of an otherwise wild-type viral background, a different outcome emerged. Although HIV-1 clones with Vif Q26-Q27 or Y26-Q27 were fully capable of overcoming A3F, they were now susceptible to restriction by A3G. Concordant with prior studies, a lysine at position 26 proved essential for A3G neutralization. These data combine to indicate that A3F and A3G exert at least partly distinct selective pressures and that Vif function may be essential for the virus to replicate in the presence of A3F.


Transmural versus nontransmural in situ electrical impedance spectrum for healthy, ischemic, and healed myocardium.
Electrical properties of myocardial tissue are anisotropic due to the complex structure of the myocardial fiber orientation and the distribution of gap junctions. For this reason, measured myocardial impedance may differ depending on the current distribution and direction with respect to myocardial fiber orientation and, consequently, according to the measurement method. The objective of this study is to compare the specific impedance spectra of the myocardium measured using two different methods. One method consisted of transmural measurements using an intracavitary catheter and the other method consisted of nontransmural measurements using a four-needle probe inserted into the epicardium. Using both methods, we provide the in situ specific impedance spectrum (magnitude and phase angle) of normal, ischemic, and infarcted pig myocardium tissue from 1 kHz to 1 MHz. Magnitude spectra showed no significant differences between the measurement techniques. However, the phase angle spectra showed significant differences for normal and ischemic tissues according to the measurement technique. The main difference is encountered after 60 min of acute ischeimia in the phase angle spectrum. Healed myocardial tissue showed a small and flat phase angle spectrum in both methods due tothe low content of cells in the transmural infarct scar. In conclusion, both transmural and nontransmural measurements of phase angle spectrum allow the differentiation among normal, ischemic, and infarcted tissue.


Analysis of Evaporative and Exhaust-Related On-Board Diagnostic (OBD) Readiness Monitors and DTCs Using I/M and Roadside Data.
Under contract to the EPA, Eastern Research Group analyzed light-duty vehicle OBD monitor readiness and diagnostic trouble codes (DTCs) using inspection and maintenance (I/M) data from four states. Results from roadside pullover emissions and OBD tests were also compared with same-vehicle I/M OBD results from one of the states. Analysis focused on the evaporative emissions control (evap) system, the catalytic converter (catalyst), the exhaust gas recirculation (EGR) system and the oxygen sensor and oxygen sensor heater (O2 system). Evap and catalyst monitors had similar overall readiness rates (90% to 95%), while the EGR and O2 systems had higher readiness rates (95% to 98%). Approximately 0.7% to 2.5% of inspection cycles with a "ready" evap monitor had at least one stored evap DTC, but DTC rates were under 1% for the catalyst and EGR systems, and under 1.1% for the O2 system, in the states with enforced OBD programs. Monitor readiness decreased, and DTC rates increased, as vehicles aged. DTCs were typically limited to a small subset of all possible DTCs for any particular system. For the on-road versus I/M analysis, lower overall readiness rates and higher overall DTC rates occurred during the roadside test than during the I/M test, and the prevalence of roadside DTCs was shown to decrease around the time of the vehicle's I/M test, possibly indicating some positive I/M influence of reducing on-road DTCs. Roadside Acceleration Simulation Mode (ASM) fail rates also decreased around the time of the I/M test, suggesting a positive influence of I/M programs on reducing vehicle emissions.


Factor D is a selective single-stranded oligodeoxythymidine binding protein.
Factor D, a protein purified from rabbit liver that selectively enhances traversal of template oligodeoxythymidine tracts by diverse DNA polymerases, was examined for the sequence specificity of its binding to DNA. Terminally [32P]-labeled oligomers with the sequence 5'-d[AATTC(N)16G]-3', N being dT, dA, dG, or dC, were interacted with purified factor D and examined for the formation of protein-DNA complexes that exhibit retarded electrophoretic mobility under nondenaturing conditions. Whereas significant binding of factor D to 5'-d[AATTC(T)16G]-3' is detected, there is no discernable association between this protein and oligomers that contain 16 contiguous moieties of dG, dA, or dC. Furthermore, factor D does not form detectable complexes with the duplexes oligo(dA).oligo(dT) or poly(dA).poly(dT). The preferential interaction of factor D with single-stranded poly(dT) is confirmed by experiments in which the polymerase-enhancing activity of this protein is protected by poly(dT) against heat inactivation two- and four-fold more efficiently than by poly(dA) or poly(dA).poly(dT), respectively.


Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information.
The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.


Concomitant gene mutations of MBL and CYBB in chronic granulomatous disease: implications for host defense.
Chronic granulomatous disease (CGD) is associated with defective function of the NADPH-oxidase system in conjunction with phagocytic defects which leads to granuloma formation and serious infectious complications. This is often associated with significant morbidity and mortality. The association of defective phagocyte function with other coincidental immune defects is unknown. Defects in innate pathways seen with CGD, including complement systems, and toll-like and dectin receptor pathways, have not been described before. We present the case of a 2-year old male patient hospitalized with recurrent pneumonia, a non-healing skin ulcer, necrotizing lung granulomas, and epididymo-orchitis. Defective neutrophil chemiluminescence was detected by dihydrorhodamine (DHR) testing. Further evaluation demonstrated characteristic molecular mutations of CYBB consistent with CGD. Immune evaluation demonstrated polyclonal hyperglobulinemia, but a greatly reduced mannose binding lectin (MBL) level. Six biallelic polymorphisms in MBL gene and its promoter were analyzed using Light CyclerTM Real-time PCR assay. The LXPA/LYPB haplotype of MBL was detected in our patient; the latter is the defective haplotype associated with low MBL levels. Due to the implications for innate immunity and the protection against bacterial, viral, and fungal infections provided by MBL, a deficiency of this protein may have disastrous consequences on the long term outcomes of CGD. MBL deficiency can also complicate other disorders affecting the immune system, significantly increasing the risk of infection in such patients. Further studies looking at the frequency and implications of MBL deficiency in CGD are needed.


Tip-oriented adherence of Treponema denticola to fibronectin.
The adherence of Treponema denticola to ligands on cell surfaces or in basement membranes of periodontal tissues might play an important role in its pathogenicity. A direct microscopic assay was used to examine the binding of T. denticola to fibronectin and other protein substrates adsorbed on plastic cover slips. All strains of T. denticola that were tested adhered to fibronectin but to different degrees. The strains which bound in high numbers frequently bound by their tips. Type strain ATCC 33520 bound to fibronectin in high numbers (149 +/- 11.3 bacteria per microscopic field), with 60% bound by the tips. Strain e' bound in high numbers (140 +/- 10.2) and had the highest percentage of tip binding (98%); strain e bound in lowest numbers (39 +/- 8.2) and had the lowest percentage of tip binding (15%). Laminin supported binding at a level similar to that of fibronectin, as did fibronectin fragments which contained the cell binding domain peptides, RGDS. Type IV collagen and non-RGDS peptides did not support binding. Binding to fibronectin and laminin was inhibited by the addition of antifibronectin and antilaminin antibodies. By lowering the incubation temperature from 37 to 4 degrees C, the number of cells that attached decreased by 60% and tip binding was reduced by 50%. Pretreatment of the cells with collagen did not affect binding, whereas fibronectin pretreatment enhanced binding by 50% and laminin pretreatment resulted in a decrease of 60%. T. denticola adheres by its tips to fibronectin-coated surfaces, which suggests that fibronectin-specific adhesins cluster at the tips.


Fast diffusion mechanism in Li4P2S6 via a concerted process of interstitial Li ions.
The synthesis of Li superionic conductor Li7P3S11 may be accompanied by the formation of a detrimental Li4P2S6 phase due to a high mixing sensitivity of precursor materials. This phase exhibits a poor ionic conductivity whose origins are not fully understood. Recently Dietrich et al. investigated the energetics of Li ion migration in Li4P2S6 with nudged elastic band (NEB) calculations. The observed large migration barrier of 0.51 eV for purely interstitial diffusion leads to an interpretation of the low ionic conductivity by kinetic limitations. Based on ab initio molecular dynamics simulations (AIMD) we propose a new and energetically much more favorable diffusion path available to interstitial Li ion charge carriers that has not been considered so far. It consists of a concerted process in which a second lithium atom is pushed out from its equilibrium lattice position by the diffusing lithium ion. A detailed analysis with NEB calculations shows that the energy barrier for this concerted diffusion is only 0.08 eV, i.e. an order of magnitude lower than the previously reported value for purely interstitial diffusion. Therefore, the observed low ionic conductivity of Li4P2S6 is likely not originating from kinetic limitations due to high diffusion barriers but rather from thermodynamic reasons associated with a low concentration of free charge carriers. We therefore expect that increasing the charge carrier concentration by doping is a viable design route to optimize the ionic conductivity of this material.


Prevalence and phase variable expression status of two autotransporters, NalP and MspA, in carriage and disease isolates of Neisseria meningitidis.
Neisseria meningitidis is a human nasopharyngeal commensal capable of causing life-threatening septicemia and meningitis. Many meningococcal surface structures, including the autotransporter proteins NalP and MspA, are subject to phase variation (PV) due to the presence of homopolymeric tracts within their coding sequences. The functions of MspA are unknown. NalP proteolytically cleaves several surface-located virulence factors including the 4CMenB antigen NhbA. Therefore, NalP is a phase-variable regulator of the meningococcal outer membrane and secretome whose expression may reduce isolate susceptibility to 4CMenB-induced immune responses. To improve our understanding of the contributions of MspA and NalP to meningococcal-host interactions, their distribution and phase-variable expression status was studied in epidemiologically relevant samples, including 127 carriage and 514 invasive isolates representative of multiple clonal complexes and serogroups. Prevalence estimates of >98% and >88% were obtained for mspA and nalP, respectively, with no significant differences in their frequencies in disease versus carriage isolates. 16% of serogroup B (MenB) invasive isolates, predominately from clonal complexes ST-269 and ST-461, lacked nalP. Deletion of nalP often resulted from recombination events between flanking repetitive elements. PolyC tract lengths ranged from 6-15 bp in nalP and 6-14 bp in mspA. In an examination of PV status, 58.8% of carriage, and 40.1% of invasive nalP-positive MenB isolates were nalP phase ON. The frequency of this phenotype was not significantly different in serogroup Y (MenY) carriage strains, but was significantly higher in invasive MenY strains (86.3%; p<0.0001). Approximately 90% of MenB carriage and invasive isolates were mspA phase ON; significantly more than MenY carriage (32.7%) or invasive (13.7%) isolates. This differential expression resulted from different mode mspA tract lengths between the serogroups. Our data indicates a differential requirement for NalP and MspA expression in MenB and MenY strains and is a step towards understanding the contributions of phase-variable loci to meningococcal biology.


Correlation from undiluted vitreous cytokines of untreated central retinal vein occlusion with spectral domain optical coherence tomography.
To correlate inflammatory and proangiogenic key cytokines from undiluted vitreous of treatment-naïve central retinal vein occlusion (CRVO) patients with SD-OCT parameters. Thirty-five patients (age 71.1 years, 24 phakic, 30 nonischemic) underwent intravitreal combination therapy, including a single-site 23-gauge core vitrectomy. Twenty-eight samples from patients with idiopathic, non-uveitis floaterectomy served as controls. Interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF-A) levels were correlated with the visual acuity (logMar), category of CRVO (ischemic or nonischemic) and morphologic parameters, such as central macular thickness-CMT, thickness of neurosensory retina-TNeuro, extent of serous retinal detachment-SRT and disintegrity of the IS/OS and others. The mean IL-6 was 64.7pg/ml (SD ± 115.8), MCP-1 1015.7 ( ± 970.1), and VEGF-A 278.4 ( ± 512.8), which was significantly higher than the control IL-6 6.2 ± 3.4pg/ml (P=0.06), MCP-1 253.2 ± 73.5 (P<0.0000001) and VEGF-A 7.0 ± 4.9 (P<0.0006). All cytokines correlated highly with one another (correlation coefficient r=0.82 for IL-6 and MCP-1; r=0.68 for Il-6 and VEGF-A; r=0.64 for MCP-1 and VEGF-A). IL-6 correlated significantly with CMT, TRT, SRT, dIS/OS, and dELM. MCP-1 correlated significantly with SRT, dIS/OS, and dELM. VEGF-A correlated not with changes in SD-OCT, while it had a trend to be higher in the ischemic versus the nonischemic CRVO group (P=0.09). The inflammatory cytokines were more often correlated with morphologic changes assessed by SD-OCT, whereas VEGF-A did not correlate with CRVO-associated changes in SD-OCT. VEGF inhibition alone may not be sufficient in decreasing the inflammatory response in CRVO therapy.


Development and application of a suite of 4-D virtual breast phantoms for optimization and evaluation of breast imaging systems.
Mammography is currently the most widely utilized tool for detection and diagnosis of breast cancer. However, in women with dense breast tissue, tissue overlap may obscure lesions. Digital breast tomosynthesis can reduce tissue overlap. Furthermore, imaging with contrast enhancement can provide additional functional information about lesions, such as morphology and kinetics, which in turn may improve lesion identification and characterization. The performance of these imaging techniques is strongly dependent on the structural composition of the breast, which varies significantly among patients. Therefore, imaging system and imaging technique optimization should take patient variability into consideration. Furthermore, optimization of imaging techniques that employ contrast agents should include the temporally varying breast composition with respect to the contrast agent uptake kinetics. To these ends, we have developed a suite of 4-D virtual breast phantoms, which are incorporated with the kinetics of contrast agent propagation in different tissues and can realistically model normal breast parenchyma as well as benign and malignant lesions. This development presents a new approach in performing simulation studies using truly anthropomorphic models. To demonstrate the utility of the proposed 4-D phantoms, we present a simplified example study to compare the performance of 14 imaging paradigms qualitatively and quantitatively.


The Diagnostic Interview for Social and Communication Disorders: algorithms for ICD-10 childhood autism and Wing and Gould autistic spectrum disorder.
The Diagnostic Interview for Social and Communication Disorders (DISCO) is an interviewer-based schedule for use with parents and carers. In addition to its primary clinical purpose of helping the clinician to obtain a developmental history and description of the child or adult concerned, it can also be used to assist in providing a formal diagnostic category. In this study we compared two algorithms based on the ninth revision of the schedule (DISCO 9). The algorithm for ICD-10 childhood autism comprised 91 individual, operationally defined items covering the behaviour outlined in the ICD-10 research criteria. The algorithm for the autistic spectrum disorder, as defined by Wing and Gould (1979), was based on 5 DISCO items that represented overarching categories of behaviour crucial for the diagnosis of autistic disorders. The aim of the study was to examine the implications for clinical diagnosis of these two different approaches. Parents of 36 children with clinical diagnoses of autistic disorder, 17 children with learning disability and 14 children with language disorders were interviewed by two interviewers. Algorithm diagnoses were applied to interview items in order to analyse the relationship between clinical and algorithm diagnoses and the inter-rater reliability between interviewers. Clinical diagnosis was significantly related to the diagnostic outputs for both algorithms. Inter-rater reliability was also high for both algorithms. The ICD childhood disorder algorithm produced more discrepant diagnoses than the Wing and Gould autistic spectrum algorithm. Analysis of the ICD-10 algorithm items and combination of items helped to explain the reason for these discrepancies. The results indicate that the DISCO is a reliable instrument for diagnosis when sources of information are used from the whole interview. It is particularly effective for diagnosing disorders of the broader autistic spectrum.


Muscle and liver glycogen utilization during prolonged lift and carry exercise: male and female responses.
This study examined the use of carbohydrates by men and women during lift/carry exercise. Effects of menstrual cycle variation were examined in women. Twenty-five subjects (15 M, 10 F) were studied; age 25 ± 2y M, 26 ± 3y F, weight 85 ± 3 kg* M, 63 ± 3 kg F, and height 181 ± 2 cm* M, 161 ± 2 cm F (* P < 0.0001). During exercise subjects squatted to floor level and lifted a 30 kg box, carried it 3 m, and placed it on a shelf 132 cm high 3X/min over a 3-hour period (540 lifts) or until they could not continue. Males were studied in a single session, females were studied on separate occasions (during the luteal (L) and follicular (F) menstrual phases). The protocol was identical for both sexes and on both occasions in the female group. Glycogen utilization was tracked with natural abundance C-13 NMR of quadriceps femoris and biceps brachialis muscles, and in the liver at rest and throughout the exercise period. Males completed more of the 180 min protocol than females [166 ± 9 min M, 112 ± 16 min* F (L), 88 ± 16 min** F (F) (*P = 0.0036, **P < 0.0001)]. Quadriceps glycogen depletion was similar between sexes and within females in L/F phases [4.7 ± 0.8 mmol/L-h M, 4.5 ± 2.4 mmol/L-h F (L), 10.3 ± 3.5 mmol/L-h F (F)]. Biceps glycogen depletion was greater in females [2.7 ± 0.9 mmol/L-h M, 10.3 ± 1.3 mmol/L-h* F (L), 16.8 ± 4.8 mmol/L-h** F (F) (* P = 0.0004, ** P = 0.0122)]. Resting glycogen levels were higher in females during the follicular phase (P = 0.0077). Liver glycogen depletion increased during exercise, but was not significant. We conclude that with non-normalized lift/carry exercise: (1) Based on their smaller size, women are less capable of completing and work their upper body harder than men. (2) Women and men work their lower body at similar levels. (3) Women store more quadriceps carbohydrate during the follicular phase. (4) The liver is not significantly challenged by this protocol.


Self-Ascribed Paranormal Ability: Reflexive Thematic Analysis.
This study investigated personal perceptions (involvements) and comprehensions (interpretations) of self-ascribed paranormal abilities. Twelve participants with supposed supernatural powers took part in semi-structured interviews exploring the origin, phenomenology, and nature of their powers. Interview transcripts were analysed using reflexive thematic analysis (RTA), a qualitative method that identifies patterns within data. Four major themes expressed meanings and representations held by participants: Formative Influences (sub-themes: Gifted Family Members and Anomalous Occurrence), (Inter) Subjective Paranormal Experience (sub-themes: Transcendental/Mystic and Extra-Sensory Perception), Embodied Processes (sub-theme: Control), and Perception of Reality (two sub-themes: Self-Awareness and Fantastic/Surreal Perceptions). Consideration of themes identified an inextricable link between perception, interpretation, and belief in ability. Within narratives, interviewees outlined, contextualised, and established the validity of their powers. They drew upon supporting autobiographical evidence from their life histories and obfuscated and/or discounted conventional explanations. Generally, accounts reflected individual attempts to comprehend and justify the nature and experience of professed abilities. The authors discuss these processes and suggest ways to extend and develop ensuing research.


Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905.
Although azacitidine (AZA) improves survival in patients with high-risk myelodysplastic syndrome, the overall response remains approximately 50%. Entinostat is a histone deacetylase inhibitor that has been combined with AZA with significant clinical activity in a previous phase I dose finding study. Open label phase II randomized trial comparing AZA 50 mg/m(2)/d given for 10 days ± entinostat 4 mg/m(2)/d day 3 and day 10. All subtypes of myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes were eligible for the study. The primary objective was the rate of hematologic normalization (HN; complete remission + partial remission + trilineage hematological improvement). One hundred forty-nine patients were analyzed, including 97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia. In the AZA group, 32% (95% CI, 22% to 44%) experienced HN and 27% (95% CI, 17% to 39%) in the AZA + entinostat group. Both arms exceeded the HN rate of historical control (Cancer and Leukemia Group B 9221 trial), but only the AZA group fulfilled the primary objective of the study. Rates of overall hematologic response were 46% and 44%, respectively. Median overall survivals were 18 months for the AZA group and 13 months for the AZA + entinostat group. The combination arm led to less demethylation compared with the monotherapy arm, suggesting pharmacodynamic antagonism. Addition of entinostat to AZA did not increase clinical response as defined by the protocol and was associated with pharmacodynamic antagonism. However, the prolonged administration of AZA by itself seems to increase HN rate compared with standard dosing and warrants additional investigation.


UK doctors' views on the implementation of the European Working Time Directive as applied to medical practice: a quantitative analysis.
To report on doctors' views, from all specialty backgrounds, about the European Working Time Directive (EWTD) and its impact on the National Health Service (NHS), senior doctors and junior doctors. All medical school graduates from 1999 to 2000 were surveyed by post and email in 2012. The UK. Among other questions, in a multipurpose survey on medical careers and career intentions, doctors were asked to respond to three statements about the EWTD on a five-point scale (from strongly agree to strongly disagree): 'The implementation of the EWTD has benefited the NHS', 'The implementation of the EWTD has benefited senior doctors' and 'The implementation of the EWTD has benefited junior doctors'. The response rate was 54.4% overall (4486/8252), 55.8% (2256/4042) of the 1999 cohort and 53% (2230/4210) of the 2000 cohort. 54.1% (2427) of all respondents were women. Only 12% (498/4136 doctors) agreed that the EWTD has benefited the NHS, 9% (377) that it has benefited senior doctors and 31% (1289) that it has benefited junior doctors. Doctors' views on EWTD differed significantly by specialty groups: 'craft' specialties such as surgery, requiring extensive experience in performing operations, were particularly critical. These cohorts have experience of working in the NHS before and after the implementation of EWTD. Their lack of support for the EWTD 4 years after its implementation should be a concern. However, it is unclear whether problems rest with the current ceiling on hours worked or with the ways in which EWTD has been implemented.


Identification of the Novel TMEM16A Inhibitor Dehydroandrographolide and Its Anticancer Activity on SW620 Cells.
TMEM16A, a calcium-activated chloride channel (CaCC), is highly amplified and expressed in human cancers and is involved in the growth and metastasis of some malignancies. Inhibition of TMEM16A represents a novel pharmaceutical approach for the treatment of cancers and metastases. The purpose of this study is to identify a new TMEM16A inhibitor, investigate the effects of this inhibitor on the proliferation and metastasis of TMEM16A-amplified SW620 cells, and to elucidate the underlying molecular mechanism in vitro. We identified a novel small-molecule TMEM16A inhibitor dehydroandrographolide (DP). By using patch clamp electrophysiology, we showed that DP inhibited TMEM16A chloride currents in Fisher rat thyroid (FRT) cells that were transfected stably with human TMEM16A and in TMEM16A-overexpressed SW620 cells but did not alter cystic fibrosis transmembrane conductance regulator (CFTR) chloride currents. Further functional studies showed that DP suppressed the proliferation of SW620 cells in a dose- and time-dependent manner using MTT assays. Moreover, DP significantly inhibited migration and invasion of SW620 cells as detected by wound-healing and transwell assays. Further mechanistic study demonstrated that knockdown of human TMEM16A decreased the inhibitory effect of DP on the proliferation of SW620 cells and that TMEM16A-dependent cells (SW620 and HCT116) were more sensitive to DP than TMEM16A-independent cells (SW480 and HCT8). In addition, we found that treatment of SW620 cells with DP led to a decrease in TMEM16A protein levels but had no effect on TMEM16A mRNA levels. The current work reveals that DP, a novel TMEM16A inhibitor, exerts its anticancer activity on SW620 cells partly through a TMEM16A-dependent mechanism, which may introduce a new targeting approach for an antitumour therapy in TMEM16A-amplified cancers.


Yeast flocculation and its biotechnological relevance.
Adhesion properties of microorganisms are crucial for many essential biological processes such as sexual reproduction, tissue or substrate invasion, biofilm formation and others. Most, if not all microbial adhesion phenotypes are controlled by factors such as nutrient availability or the presence of pheromones. One particular form of controlled cellular adhesion that occurs in liquid environments is a process of asexual aggregation of cells which is also referred to as flocculation. This process has been the subject of significant scientific and biotechnological interest because of its relevance for many industrial fermentation processes. Specifically adjusted flocculation properties of industrial microorganisms could indeed lead to significant improvements in the processing of biotechnological fermentation products such as foods, biofuels and industrially produced peptides. This review briefly summarises our current scientific knowledge on the regulation of flocculation-related phenotypes, their importance for different biotechnological industries, and possible future applications for microorganisms with improved flocculation properties.


Natural history of the slave making ant, Polyergus lucidus, sensu lato in northern Florida and its three Formica pallidefulva group hosts.
Slave making ants of the Polyergus lucidus Mayr (Hymenoptera: Formicidae) complex enslave 3 different Formica species, Formica archboldi, F. dolosa, and F. pallidefalva, in northern Florida. This is the first record of presumed P. lucidus subspecies co-occurring with and enslaving multiple Formica hosts in the southern end of their range. The behavior, colony sizes, body sizes, nest architecture, and other natural history observations of Polyergus colonies and their Formica hosts are reported. The taxonomic and conservation implications of these observations are discussed.


TMEM16A/anoctamin 1 protein mediates calcium-activated chloride currents in pulmonary arterial smooth muscle cells.
Calcium-activated chloride channels (CaCCs) play important roles in several physiological processes. In vascular smooth muscle, activation of these ion channels by agonist-induced Ca(2+) release results in membrane depolarization and vasoconstriction. The molecular identity of vascular CaCCs is not fully defined. Here we present evidence that TMEM16A (or anoctamin 1), a member of the transmembrane 16 (TMEM16) protein family, forms CaCCs in pulmonary artery smooth muscle cells (PASMCs). Patch-clamp analysis in freshly isolated PASMCs revealed strongly outward-rectifying, slowly activating Ca(2+)-activated Cl(-) currents sharing a high degree of similarity with heterologous TMEM16A currents. TMEM16A mRNA was identified in rat and human pulmonary arteries and various other vascular smooth muscle cell types. Further analyses revealed that several TMEM16A splice variants were detected in rat PASMCs and that TMEM16F and TMEM16K were also expressed in these cells, while TMEM16B, TMEM16D and TMEM16E were all at least 50 times less abundantly expressed and the remaining TMEM16 family members were absent. Downregulation of TMEM16A gene expression in primary cultures of rat PASMCs, with small interfering RNAs, was accompanied by almost total loss of whole-cell CaCC currents. Based on these results, we propose that TMEM16A is the major constituent of the vascular calcium-activated chloride channel in rat pulmonary artery smooth muscle.


The anxiety disorders and suicidal ideation: accounting for co-morbidity via underlying personality traits.
The anxiety disorders are robust correlates/predictors of suicidal ideation, but it is unclear whether (a) the anxiety disorders are specifically associated with suicidal ideation or (b) the association is due to co-morbidity with depression and other disorders. One means of modeling co-morbidity is through the personality traits neuroticism/negative emotionality (N/NE) and extraversion/positive emotionality (E/PE), which account for substantial shared variance among the internalizing disorders. The current study examines the association between the internalizing disorders and suicidal ideation, after controlling for co-morbidity via N/NE and E/PE. The sample consisted of 327 psychiatric out-patients. Multiple self-report and interview measures were collected for internalizing disorders [depression, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), social anxiety, panic and specific phobia] and suicidal ideation, as well as self-report measures for N/NE and E/PE. A model was hypothesized in which each disorder and suicidal ideation was regressed on N/NE, and depression and social anxiety were regressed on E/PE. Structural equation modeling (SEM) was used to examine the unique association of suicidality with each disorder, beyond shared variance with N/NE and E/PE. The hypothesized model was an acceptable fit to the data. Although zero-order analyses indicated that suicidal ideation was moderately to strongly correlated with all of the disorders, only depression and PTSD remained significantly associated with suicidal ideation in the SEM analyses. In a latent variable model that accounts for measurement error and a broad source of co-morbidity, only depression and PTSD were uniquely associated with suicidal ideation; panic, GAD, social anxiety and specific phobia were not.


A urine-dependent human urothelial organoid offers a potential alternative to rodent models of infection.
Murine models describe a defined host/pathogen interaction for urinary tract infection, but human cell studies are scant. Although recent human urothelial organoid models are promising, none demonstrate long-term tolerance to urine, the natural substrate of the tissue and of the uropathogens that live there. We developed a novel human organoid from progenitor cells which demonstrates key structural hallmarks and biomarkers of the urothelium. After three weeks of transwell culture with 100% urine at the apical interface, the organoid stratified into multiple layers. The apical surface differentiated into enlarged and flattened umbrella-like cells bearing characteristic tight junctions, structures resembling asymmetric unit membrane plaques, and a glycosaminoglycan layer. The apical cells also expressed cytokeratin-20, a spatial feature of the mammalian urothelium. Urine itself was necessary for full development, and undifferentiated cells were urine-tolerant despite the lack of membrane plaques and a glycosaminoglycan layer. Infection with Enterococcus faecalis revealed the expected invasive outcome, including urothelial sloughing and the formation of intracellular colonies similar to those previously observed in patient cells. This new biomimetic model could help illuminate invasive behaviours of uropathogens, and serve as a reproducible test bed for disease formation, treatment and resolution in patients.


Enhanced xenobiotic transporter expression in normal teleost hepatocytes: response to environmental and chemotherapeutic toxins.
Many aquatic organisms are resistant to environmental pollutants, probably because their inherent multi-drug-resistant protein extrusion pump (pgp) can be co-opted to handle man-made pollutants. This mechanism of multixenobiotic resistance is similar to the mechanism of multidrug resistance exhibited in chemotherapy-resistant human tumor cells. In the present study, a variety of techniques were used to characterize this toxin defense system in killifish (Fundulus heteroclitus) hepatocytes. The cellular localization and activity of the putative drug efflux system were evaluated. In addition, in vitro and in vivo studies were used to examine the range of expression of this putative drug transporter in the presence of environmental and chemotherapeutic toxins. The broad range of pgp expression generally observed in transformed mammalian cells was found in normal cells of our teleost model. Our findings suggest that the expression of the pgp gene in the killifish could be an excellent indicator of toxin levels or stressors in the environment.


Carbohydrate Mouth Rinse Improves Cycling Time-Trial Performance without Altering Plasma Insulin Concentration.
Rinsing the mouth with a carbohydrate solution has been shown to improve exercise performance in a manner similar to carbohydrate ingestion. However, the underlying mechanisms behind these ergogenic benefits remain unclear. This study evaluated whether rinsing the mouth with a carbohydrate solution alters plasma insulin and glucose concentration during the initial stages of a 40 km cycling time-trial. Eight trained, competitive cyclists [age (mean ± SEM) = 24 ± 2 y; V̇O2max = 64.5 ± 2.2 ml·kg-1·min-1] completed three simulated 40 km time-trials comprised of a familiarization trial, a carbohydrate condition (CHO) and a placebo mouth rinse condition (PLA). In the two mouth rinse conditions, rinsing was administered prior to onset of exercise and every 5 km throughout exercise. Plasma insulin was collected at 5 km intervals throughout the first 25 km, and glucose samples were collected at 5 km intervals throughout the exercise bout. No change in plasma insulin was detected between conditions (p = 0.638, ES < 0.03) for the first 25 km of the time-trial. Likewise, plasma glucose concentration did not differ between CHO and PLA (p = 0.801, ES < 0.01) and remained relatively stable throughout exercise. Time to complete the 40 km time-trial was significantly faster for CHO (67.1 ± 1.1 min) compared to PLA [67.9 ± 1.0 min; (P = 0.028, ES 0.27)]. Performance time was faster by an average of 1.1% (95% confidence interval range 0.2-2.0%) in the CHO condition. Exercise intensity (% V̇O2max) throughout the trial was similar between conditions (p = 0.846). Respiratory exchange ratio was not significantly different between conditions (0.88 ± 0.01 for PLA, and 0.91 ± 0.01 for GLC; p = 0.081). Performance gains elicited by a carbohydrate mouth rinse occurred independently of changes in plasma insulin concentration.


Advances in 3-Dimensional Printing in Otolaryngology: A Review.
Three-dimensional (3-D) printing is an exponentially growing technology that enables the use of a patient's image data to create patient-specific models, devices, and implants. Three-dimensional printing, developed in the 1980s, has emerged in the past decade with the potential to create new paradigms in personalized medicine. The field of otolaryngology has advanced many current and evolving future medical applications of 3-D printing. The predominant uses of 3-D printing have rapidly progressed from patient-specific models and simulators to intraoperative guides. Continued advancements now include 3-D-printed implants and future tissue-engineered constructs, which bring new regulatory challenges. This review summarizes the literature and provides a comprehensive guide to the background, applications, and current limitations of 3-D printing across the head and neck. Three-dimensional printing enables the rapid production of patient-specific devices for personalized medicine. The field of otolaryngology has pioneered many of the underlying advancements in medical 3-D printing and will continue to remain at the forefront of 3-D printing technology.


A single molecule scaffold for the maize genome.
About 85% of the maize genome consists of highly repetitive sequences that are interspersed by low-copy, gene-coding sequences. The maize community has dealt with this genomic complexity by the construction of an integrated genetic and physical map (iMap), but this resource alone was not sufficient for ensuring the quality of the current sequence build. For this purpose, we constructed a genome-wide, high-resolution optical map of the maize inbred line B73 genome containing >91,000 restriction sites (averaging 1 site/ approximately 23 kb) accrued from mapping genomic DNA molecules. Our optical map comprises 66 contigs, averaging 31.88 Mb in size and spanning 91.5% (2,103.93 Mb/ approximately 2,300 Mb) of the maize genome. A new algorithm was created that considered both optical map and unfinished BAC sequence data for placing 60/66 (2,032.42 Mb) optical map contigs onto the maize iMap. The alignment of optical maps against numerous data sources yielded comprehensive results that proved revealing and productive. For example, gaps were uncovered and characterized within the iMap, the FPC (fingerprinted contigs) map, and the chromosome-wide pseudomolecules. Such alignments also suggested amended placements of FPC contigs on the maize genetic map and proactively guided the assembly of chromosome-wide pseudomolecules, especially within complex genomic regions. Lastly, we think that the full integration of B73 optical maps with the maize iMap would greatly facilitate maize sequence finishing efforts that would make it a valuable reference for comparative studies among cereals, or other maize inbred lines and cultivars.


Prolyl hydroxylase domain enzyme 2 is the major player in regulating hypoxic responses in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by hypoxia and the expression of hypoxia-inducible transcription factors (HIFs), which coordinate cellular responses to hypoxia. The objective of this study was to analyze the expression and regulation of prolyl hydroxylase domain (PHD) enzymes and factor-inhibiting HIF-1α (FIH-1), which regulate cellular HIF levels, and to study the roles of these enzymes in RA fibroblast-like synoviocytes (RA FLS). The expression of PHD and FIH and downstream target genes was assessed by quantitative polymerase chain reaction and Western blotting. A small interfering RNA (siRNA) approach and an in vitro endothelial cell angiogenesis assay were used to analyze the roles of HIF hydroxylases. In human RA FLS, knockdown of PHD-2, but not knockdown of PHD-1 or FIH-1, dramatically augmented HIF-1α expression, modestly increased HIF-2α protein expression under normoxic conditions, and up-regulated HIF-dependent gene expression. In contrast, silencing of PHD-3 up-regulated HIF-2α but reduced HIF-1α, thereby decreasing the expression of HIF-regulated genes. A similar effect of PHD-2 knockdown was observed in osteoarthritis FLS (OA FLS) but not in nondiseased primary human dermal fibroblasts. These findings correlated with the induction of in vitro angiogenesis by supernatants from RA FLS and OA FLS transfected with siPHD-2 but not by supernatants from nondiseased fibroblasts or from siPHD-3-transfected cells. Our data suggest that PHD-2 is the major hydroxylase regulating HIF levels and the expression of angiogenic genes in arthritic cells. PHD-2 appears to regulate responses relevant to arthritis via HIF-α, highlighting the major importance of this enzyme in hypoxia- and angiogenesis-dependent inflammatory diseases such as RA.


Cause of death in patients attending multiple sclerosis clinics.
Between 1972 and 1988, 145 deaths occurred among 3,126 patients attending the Multiple Sclerosis (MS) Clinics in Vancouver, British Columbia (N = 1,583), and London, Ontario (N = 1,543). We could determine the exact cause of death in 82.1% of cases (119 of 145). Of the 119 patients for whom the cause of death was known, 56 deaths (47.1%) were directly attributed to complications of MS. Of the remaining 63 deaths, 18 (28.6%) were suicides, 19 (30.2%) were due to malignancy, 13 (20.6%) to an acute myocardial infarction, seven (11.1%) to stroke, and the remainder (9.5%) to miscellaneous causes, of which two may have been suicides. The proportion of suicides among MS deaths was 7.5 times that for the age-matched general population, and the proportion of MS deaths from malignancy was 0.67 times that for the age-matched general population. The proportion of deaths due to malignancy and stroke was the same for the MS patients and the age-matched general population.


Antioxidant pre-treatment prevents omeprazole-induced toxicity in an in vitro model of infectious gastritis.
Omeprazole is a mainstay of therapy for gastroesophageal reflux disease (GERD) and gastritis, and is increasingly used as an over-the-counter remedy for dyspepsia. Omeprazole acts by selectively oxidizing thiol targets in the gastric proton pump, but it also appears to be toxic to the gastric mucosa. We hypothesized that omeprazole toxicity is due to non-specific oxidation of cell structures other than the proton pump, and tested the efficacy of antioxidants to prevent omeprazole-induced toxicity in isolated rabbit gastric glands. Toxicity was measured by uptake and converstion of calcein-AM, following three hours of exposure to omeprazole and a non-selective thiol-oxidant, monochloramine. Intracellular concentration of Zn(2+) and the capacity to maintain luminal acidity were monitored using the fluorescent reporters fluozin-3 and Lysosensor DND-160, respectively. Both omeprazole and monochloramine caused marked reduction in cell viability. The toxicity of omeprazole was independent of monochloramine toxicity. The thiol reducing agent dithiothreitol protected gastric glands from injury. The oxidant scavenger Vitamin C also protected, and did not impair the anti-secretory effects of omeprazole. Thus, omeprazole toxicity appears to be oxidative and preventable with antioxidant therapy, including Vitamin C. Vitamin C may be a safe and efficacious addition to treatments requiring the use of PPIs.


Parents' Experience and Psychoeducation Needs When Supporting a Young Person Who Self-Harms.
Self-harm in young people can have a substantial negative impact on the well-being and functioning of parents and other carers. The "Coping with Self-Harm" booklet was originally developed in the UK as a resource for parents and carers of young people who self-harm, and an adaptation study of this resource was conducted in Australia. This paper presents qualitative analysis of interviews with parents about their experiences and psychoeducational needs when supporting a young person who engages in self harm. The qualitative study drew on semi-structured individual and group interviews with parents (n = 19 participants) of young people who self-harm. Data were analysed using Thematic Analysis. The analysis identified six themes: (1) the discovery of self-harm, (2) challenges in the parent-young person relationship, (3) parents' need to understand self-harm, (4) parents' emotional reactions to self-harm, (5) the importance of self-care and help-seeking among parents, and (6) the need for psychoeducational resources. The study highlights the need for support for parents and carers of young people who engage in self-harm, including development and adaptation of resources, such as the "Coping with Self-Harm" booklet, of which an Australian version has now been developed.


Sustaining our rivers in crisis: setting the international agenda for action.
The history of streams and rivers is as much a social and technological history as it is a scientific one. Rivers are the lifeblood of nations and the control of their waters has been fundamental to the building of human civilisations. The control or regulation of rivers embodied the advancement of institutions, administration and co-ordination; it was a manifestation of military and economic power. Yet the history of human development is also characterised by the degradation of the basic resource--polluted water, increased flooding, and the loss of biological diversity. Many early civilisations collapsed in the face of environmental degradation, manifest by flood, drought, famine and plague. The Industrial Revolution upon which modern societies are founded was based upon a short-term vision that has left rivers in crisis, marked by a legacy of pollution, slums, a loss of confidence in civic life, and a loss of ownership of places and spaces--once seen to be at the heart of civilized society. Within this global or international context of water management, this paper examines the impacts and future of rivers and water within the United Kingdom, establishing some principles for such management in other settings.


Synthetic nerve guide implants in humans: a comprehensive survey.
Lesions of the peripheral nervous system result in the loss of sensory and motor function and may in addition be accompanied by severe neuropathic syndromes originating from aberrant axonal regrowth. The transplantation of autologous nerve grafts represents the current "gold standard" during reconstructive surgery, despite obvious side effects. Depending on the demands of the lesion site, various donor nerves may be used for grafting (e.g., the sural, saphenous), sacrificing native functions in their target areas. Recently, several synthetic nerve guide implants have been introduced and approved for clinical use to replace autologous transplants. This alternative therapy is based on pioneering studies with experimental nerve guides. We present a comprehensive review of all published human studies involving synthetic nerve guides. Data from some 300 patients suggest that for short nerve defects of a few centimeters, resorbable implants provide promising results, whereas a number of late compression syndromes have been documented for nonresorbable implants. To treat longer defects, further implant development is needed, a goal that could be achieved, for example, by more closely imitating the intact nerve architecture and regulatory cell-cell interactions.


Bisphenol A in oocytes leads to growth suppression and altered stress performance in juvenile rainbow trout.
Bisphenol A (BPA), used in the manufacture of plastics, is ubiquitously distributed in the aquatic environment. However, the effect of maternal transfer of these xenobiotics on embryonic development and growth is poorly understood in fish. We tested the hypothesis that BPA in eggs, mimicking maternal transfer, impact development, growth and stress performance in juveniles of rainbow trout (Oncorhynchus mykiss). Trout oocytes were exposed to 0, 30 and 100 microg.mL(-1) BPA for 3 h in ovarian fluid, followed by fertilization. The embryos were maintained in clean water and sampled temporally over 156-days post-fertilization (dpf), and juveniles were sampled at 400-dpf. The egg BPA levels declined steadily after exposure and were undetectable after 21- dpf. Oocyte exposure to BPA led to a delay in hatching and yolk absorption and a consistently lower body mass over 152-dpf. The growth impairment, especially in the high BPA group, correlated with higher growth hormone (GH) content and lower GH receptors gene expression. Also, mRNA abundances of insulin-like growth factors (IGF-1 and IGF-2) and their receptors were suppressed in the BPA treated groups. The juvenile fish grown from the BPA-enriched eggs had lower body mass and showed perturbations in plasma cortisol and glucose response to an acute stressor. BPA accumulation in eggs, prior to fertilization, leads to hatching delays, growth suppression and altered stress response in juvenile trout. The somatotropic axis appears to be a key target for BPA impact during early embryogenesis, leading to long term growth and stress performance defects in fish.


Monoclonal antibodies specific for novel murine cell surface markers define subpopulations of germinal center cells.
A panel of mAbs has been generated which selectively, but not exclusively, recognizes populations of cells within germinal centers of immunized mice. All four mAbs stain B cell populations as defined by flow cytometry. The mAbs FH9.5 and C3.5 also stain T cell subsets (CD4+ and CD8+, respectively). Following density gradient centrifugation of spleen cells from immunized mice the majority of FH9.5+ and C3.5+ B cells are found in the low density, activated fractions. The cells bearing the epitope(s) recognized by the C6C3 and the A6A2 mAbs are less frequent, and from flow cytometric analysis the cells stained with these mAbs are B cells and myeloid cells. The surface markers defined by the four mAbs are not induced following mitogen stimulation of small resting B cells suggesting that these molecules are not general activation markers. Cell lines from a variety of hematopoietic lineages expressing the four markers have been identified. The cell surface molecule immunoprecipitated by the FH9.5 mAb is a polypeptide of 23-28 kDa. The C3.5 antigen is an 85- to 95-kDa protein. These mAbs will be useful in elucidating the complex events involved in B cell differentiation and maturation which occur within germinal centers.


Neural modulation of salt secretion in teleostopercular epithelium by 2-adrenergic receptors and inositol 1,4,5-trisphosphate
Opercular epithelia from seawater-adapted killifish (Fundulus heteroclitus) were dissected with the nerve intact, mounted in Ussing-style membrane chambers and bathed in symmetrical saline solutions. Nerve stimulation rapidly inhibited transepithelial current (a measure of Cl- secretion rate) by 27.3+/-3.3 % (N=22), and the effect could be sustained for more than 10 min using intermittent pulse trains at 10 Hz. The effect was blocked in a dose-dependent manner by yohimbine, but not by propranolol, atropine or tubocurarine, indicating mediation by 2-adrenergic receptors. The effect was also present, but significantly diminished, in opercular membranes from animals that had been transferred to sea water for 48 h (18+/-8.6 % inhibition, N=14). The resting current and the effect were absent in membranes from freshwater-adapted animals. The addition of clonidine (1.0 micromol l-1 serosal side) started to inhibit Cl- current after 40-60 s; immediately before this, at 30 s, there was a significant rise (P<0.05, N=14) in tissue inositol 1,4,5, -trisphosphate (InsP3) level, but no change at later times, compared with LiCl-treated control membranes and measured by radiolabeled receptor assay. The results indicate that seawater-adapted killifish can decrease their Cl- secretion rate through the action of the sympathetic nervous system, a response appropriate for the entry of estuarine fish to fresh water, and that the effect is mediated by 2-adrenoceptors via InsP3. The results imply that euryhaline fish entering fresh water can undergo an autonomic reflex reduction in salt secretion that does not require a stress response.


The Diversity and Molecular Evolution of B-Cell Receptors during Infection.
B-cell receptors (BCRs) are membrane-bound immunoglobulins that recognize and bind foreign proteins (antigens). BCRs are formed through random somatic changes of germline DNA, creating a vast repertoire of unique sequences that enable individuals to recognize a diverse range of antigens. After encountering antigen for the first time, BCRs undergo a process of affinity maturation, whereby cycles of rapid somatic mutation and selection lead to improved antigen binding. This constitutes an accelerated evolutionary process that takes place over days or weeks. Next-generation sequencing of the gene regions that determine BCR binding has begun to reveal the diversity and dynamics of BCR repertoires in unprecedented detail. Although this new type of sequence data has the potential to revolutionize our understanding of infection dynamics, quantitative analysis is complicated by the unique biology and high diversity of BCR sequences. Models and concepts from molecular evolution and phylogenetics that have been applied successfully to rapidly evolving pathogen populations are increasingly being adopted to study BCR diversity and divergence within individuals. However, BCR dynamics may violate key assumptions of many standard evolutionary methods, as they do not descend from a single ancestor, and experience biased mutation. Here, we review the application of evolutionary models to BCR repertoires and discuss the issues we believe need be addressed for this interdisciplinary field to flourish.


Colder environments did not select for a faster metabolism during experimental evolution of Drosophila melanogaster.
The effect of temperature on the evolution of metabolism has been the subject of debate for a century; however, no consistent patterns have emerged from comparisons of metabolic rate within and among species living at different temperatures. We used experimental evolution to determine how metabolism evolves in populations of Drosophila melanogaster exposed to one of three selective treatments: a constant 16°C, a constant 25°C, or temporal fluctuations between 16 and 25°C. We tested August Krogh's controversial hypothesis that colder environments select for a faster metabolism. Given that colder environments also experience greater seasonality, we also tested the hypothesis that temporal variation in temperature may be the factor that selects for a faster metabolism. We measured the metabolic rate of flies from each selective treatment at 16, 20.5, and 25°C. Although metabolism was faster at higher temperatures, flies from the selective treatments had similar metabolic rates at each measurement temperature. Based on variation among genotypes within populations, heritable variation in metabolism was likely sufficient for adaptation to occur. We conclude that colder or seasonal environments do not necessarily select for a faster metabolism. Rather, other factors besides temperature likely contribute to patterns of metabolic rate over thermal clines in nature.


Urokinase plasminogen activator receptor promotes macrophage infiltration into the vascular wall of ApoE deficient mice.
The urokinase plasminogen activator receptor (uPAR) regulates macrophage adhesion and migration by binding directly to matrix proteins and signaling through integrin complexes. In this study, we examined the role of uPAR on macrophage infiltration into the vascular wall. Stable murine macrophage (Raw264.7) cell lines expressing high levels of human uPAR, human urokinase plasminogen activator (uPA), or both were established using expression vectors driven by the human CD68 promoter. Stimulation with human uPA specifically induced phosphorylation of early response regulated kinase (ERK) in cells expressing human uPAR but not in sham transfected cells. The human uPAR expressing Raw264.7 cells showed increased adhesion to both human uPA and vitronectin (Vn). Raw264.7 cells expressing human uPAR or both human uPAR and uPA, but not uPA alone, were detected in the aortic wall of ApoE(-/-) mice, and no cells were detected in that of age-matched C57BL/6J mice after intravenous infusion of the cells. Blocking of Mac-1/ICAM-1 interaction by anti-alphaM antibody (M1/70) significantly reduced the infiltration of huPAR-expressing Raw264.1 cells into aorta of ApoE(-/-) mice. Treatment of C57BL/6J mice with angiotensin II resulted in infiltration of Raw264.7 cells expressing human uPAR. These data demonstrate that uPAR plays a key role in promoting macrophage infiltration into the arterial wall of ApoE(-/-) mice.


Patterns and covariates of benefit finding in young Black breast cancer survivors: A longitudinal, observational study.
To examine the patterns and covariates of benefit finding over time among young Black breast cancer (BC) survivors. Black women (N = 305) with invasive BC diagnosed ≤50 years were recruited an average of 1.9 years post-BC diagnosis. Participants completed self-report questionnaires of benefit finding, social support, and illness intrusions at three time points (M time since BC diagnosis: T2 = 3.1 years, T3 = 4.0 years). Relationships between posttraumatic growth constructs (social support, illness intrusions) and benefit finding over time were examined using mixed models. Models controlled for cultural variables (religiosity, time orientation, and collectivism), receipt of chemotherapy, general health status, and partner status. Participants reported high levels of benefit finding (M = 2.99, SE = 0.04 on a 0-4 scale). When accounting for covariates, benefit finding did not change over time since BC diagnosis (P = .21). Benefit finding scores at BC diagnosis were associated with more illness intrusions, greater religiosity, and having received chemotherapy (all Ps < .04). Social support was associated with change in benefit finding scores over time, such that a 1-point increase in social support was associated with a 0.05 increase in benefit finding per year (P = .02). This study addresses key gaps in knowledge regarding benefit finding among Black cancer survivors. Consistent with findings from majority White samples, social support and illness intrusions appear to play a key role in benefit finding in Black BC survivors. Cultural constructs-including religiosity-must also be considered in future studies of benefit finding among minority populations.


Impact of study design on recruitment of patients to a primary care trial: an observational time series analysis of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study.
recruitment targets to randomized controlled trials (RCTs) are often not met. Many interventions are used to improve recruitment but there is little empirical evidence on whether these approaches work. to examine whether changes to the design and conduct of a primary care-based RCT were associated with changes in patient recruitment. an observational time series analysis of recruitment to a primary care-based multi-centre RCT of aspirin versus warfarin for stroke prevention, which involved 330 practices. Several changes to the trial protocol and procedures were made over the 4 years of patient recruitment. For each quarter throughout the recruitment period, the recruitment rate per 1000 total population in active practices was calculated. the recruitment target of 930 patients was exceeded. Fluctuations in recruitment rate occurred during the recruitment period. Following protocol changes aimed to reduce clinical workload, there was a significant increase in recruitment during the final 6 months of the study, during a period when there was not a similarly large increase in the total population available. these findings suggest that the conduct of a trial is an important consideration if studies are to recruit successfully. Expanding the number of centres may not be the most effective way to improve recruitment.


Thienylpiperidine Donor NIR Xanthene-Based Dye for Photoacoustic Imaging.
Few xanthene-based near-infrared (NIR) photoacoustic (PA) dyes with absorbance >800 nm exist. As accessibility to these dyes requires long and tedious synthetic steps, we designed a NIR dye (XanthCR-880) with thienylpiperidine donors and a xanthene acceptor that is accessible in 3-4 synthetic steps. The dye boasts a strong PA signal at 880 nm with good biological compatibility and photostability, yields multiplexed imaging with an aza-BODIPY reference dye, and is detected at a depth of 4 cm.


Phytophotodermatitis from celery among grocery store workers.
We detected 19 cases of phytophotodermatitis during a cross-sectional epidemiological investigation of two Oregon grocery stores that were part of the same supermarket chain. Outdoor sunlight exposure during the workshift and tanning salon use were identified as risk factors; the most severe cutaneous reactions tended to occur among tanning salon users. Although both stores carried the same brands and varieties of produce, all 19 cases occurred among employees of one store, which had held a celery sale coincident with the outbreak, resulting in a quadrupling of the usual volume of celery sold. We found elevated psoralen levels in two of three celery samples obtained from the affected store; cutaneous provocation tests with trimmed surfaces of these celery samples produced phototoxic reactions. Preliminary experiments with one brand of celery have demonstrated psoralen levels as high as 25 micrograms/cm2 of trimmed surface. These observations suggest that clinical phytophotodermatitis among grocery store workers may be caused by healthy celery and results from a complex interaction of exposure variables, including ultraviolet radiation from tanning salon use, frequency of handling celery, celery brand, and sporadic elevation of psoralen content from environmental stresses.


The role of transient receptor potential channels in joint diseases.
Transient receptor potential channels (TRP channels) are cation selective transmembrane receptors with diverse structures, activation mechanisms and physiological functions. TRP channels act as cellular sensors for a plethora of stimuli, including temperature, membrane voltage, oxidative stress, mechanical stimuli, pH and endogenous, as well as, exogenous ligands, thereby illustrating their versatility. As such, TRP channels regulate various functions in both excitable and non-excitable cells, mainly by mediating Ca2+ homeostasis. Dysregulation of TRP channels is implicated in many pathologies, including cardiovascular diseases, muscular dystrophies and hyperalgesia. However, the importance of TRP channel expression, physiological function and regulation in chondrocytes and intervertebral disc (IVD) cells is largely unexplored. Osteoarthritis (OA) and degenerative disc disease (DDD) are chronic age-related disorders that significantly affect the quality of life by causing pain, activity limitation and disability. Furthermore, currently available therapies cannot effectively slow-down or stop progression of these diseases. Both OA and DDD are characterised by reduced tissue cellularity, enhanced inflammatory responses and molecular, structural and mechanical alterations of the extracellular matrix, hence affecting load distribution and reducing joint flexibility. However, knowledge on how chondrocytes and IVD cells sense their microenvironment and respond to its changes is still limited. In this review, we introduced six families of mammalian TRP channels, their mechanisms of activation, as well as, activation-driven cellular consequences. We summarised the current knowledge on TRP channel expression and activity in chondrocytes and IVD cells, as well as, the significance of TRP channels as therapeutic targets for the treatment of OA and DDD.


Characterizing substance abuse programs that treat adolescents.
Few systematic studies have examined the characteristics of substance abuse treatment programs serving adolescents. An expert panel recently identified nine key elements of effective adolescent substance abuse treatment. We measured the percentage of treatment programs in the United States with at least 10 adolescent clients on a given day that reported these elements using data from the 2003 National Survey of Substance Abuse Treatment Services. This first look into the characteristics of facilities serving significant numbers of adolescents indicates that many facilities may be lacking in components considered important. The most significant measured potential areas for improvement occurred in the areas of including mental health as well as medical issues in comprehensive assessments and developing curricula to meet the developmental and cultural needs of clients. On a more encouraging note, many facilities were conducting discharge planning and providing aftercare, although the specifics of these services were not determined.


The reliability and reproducibility of sagittal spinal curvature measurement using the Microsoft Kinect V2.
Abnormal sagittal spinal curvature is associated with pain, decreased mobility, respiratory problems and increased mortality. Time-of-flight technology of the Microsoft Kinect sensor can reconstruct a three-dimensional image of the back quickly and inexpensively. To estimate the extent of the reproducibility of sagittal spine curvature measurement using the Microsoft Kinect sensor. Simultaneous measurement of thoracic and lumbar spine using the Microsoft Kinect sensor in 37 participants. Two investigators gave standardised instructions and each captured 3 images. Thoracic kyphosis and lumbar lordosis angle indexes were calculated using maximum height divided by the length. Adult participants (mean age in years (SD) = 51.7 (20.6); 57% female; BMI in kg/m2 (SD) = 24.9 (3.3)) kyphosis and lordosis indexes showed high intra-rater and inter-rater ICC values (0.960-0.973). The means of the first images from both raters had significantly larger kyphosis indexes compared to the second and third images, yet no difference between means in lordosis data. The results indicate that the Microsoft Kinect sensor has a reproducible method with high intra-rater and inter-rater reliability. The difference between the means over repeated measures suggest the second image capture is more consistent. It is a reproducible and quick method in clinical and research settings.


A sexual ornament in chickens is affected by pleiotropic alleles at HAO1 and BMP2, selected during domestication.
Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.


Expression of recombinant human interleukin-8 and its purification using a single buffer system.
Chemokines, a class of small secreted proteins, direct immune cells to their target sites and play an important role in chronic inflammations and allergies. To study their interactions with their cellular receptors or potential inhibitors large quantities of chemokines are required. Here we present a fast and efficient strategy to purify the human chemokine interleukin-8 (IL-8, CXCL8). The chemokine is expressed with a pelB-leader peptide that is cleaved off its N-terminus by an endogenous bacterial peptidase. This yields wild-type 72aa IL-8 with a serine at its N-terminus. IL-8 is recovered in the soluble fraction after lysis while pelB-IL8 fusion protein remains in the pellet. Interleukin-8 is purified via cation exchange chromatography and heparin affinity chromatography using a single inexpensive buffer system. No dialysis or membrane filtration steps are required and the final protein fractions may be used without any desalting steps. The use of 0.5% Triton X-114 in the lysis buffer leads to low endotoxin levels in the resulting protein. The protein can be eluted from the gel filtration column with a variety of buffers and is ready to be used in binding assays and activity assays.


Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.


Layer-by-layer assembly of graphene oxide nanosheets on polyamide membranes for durable reverse-osmosis applications.
Improving membrane durability associated with fouling and chlorine resistance remains one of the major challenges in desalination membrane technology. Here, we demonstrate that attractive features of graphene oxide (GO) nanosheets such as high hydrophilicity, chemical robustness, and ultrafast water permeation can be harnessed for a dual-action barrier coating layer that enhances resistance to both fouling and chlorine-induced degradation of polyamide (PA) thin-film composite (TFC) membranes while preserving their separation performance. GO multilayers were coated on the PA-TFC membrane surfaces via layer-by-layer (LbL) deposition of oppositely charged GO nanosheets. Consequently, it was shown that the conformal GO coating layer can increase the surface hydrophilicity and reduce the surface roughness, leading to the significantly improved antifouling performance against a protein foulant. It was also demonstrated that the chemically inert nature of GO nanosheets enables the GO coating layer to act as a chlorine barrier for the underlying PA membrane, resulting in a profound suppression of the membrane degradation in salt rejection upon chlorine exposure.


Cyclin dependent kinase 5, cdk5, is a positive regulator of myogenesis in mouse C2 cells.
We have examined the expression, activity and localization of cyclin dependent kinase 5 (cdk5), during myogenesis. Cdk5 protein was found expressed in adult mouse muscle. In murine C2 cells, both the protein level and kinase activity of cdk5 showed a marked increase during early myogenesis with a peak between 36 and 48 hours of differentiation, decreasing as myotubes fuse after 60 to 72 hours. This increase in cdk5 protein level was specific for differentiation and not simply related to cell cycle arrest since it was not observed in fibroblasts grown for 48 hours in low serum medium. Indirect immunofluorescence using monospecific purified anti-cdk5 antibodies showed a low level cytoplasmic staining in proliferative myoblasts, a rapid increase in nuclear staining during the initial 12 hours of differentiation and a predominant nuclear staining in myotubes. Microinjection of plasmids encoding wild-type cdk5 into C2 myoblasts enhanced differentiation as assessed by both myogenin and troponin T expression after 48 hours of differentiation. In contrast, microinjection of plasmids encoding a dominant negative mutant of cdk5 inhibited the onset of differentiation. These data imply a previously unsuspected role for cdk5 protein kinase as a positive modulator of early myogenesis.


Analysis of childhood brain tumour data in New York City using frailty models.
This paper uses frailty models to analyse overall survival and progression-free survival times for children with a brain tumour. We are interested in how surgery resection affects survival times. We are also interested in how strong a child's progression-free survival correlates with his/her overall survival and if the association differs with age. Traditionally the frailty is modelled parametrically and a maximum likelihood approach is used to estimate the parameters of interest. However, the result is sensitive to the misspecification of the frailty distribution and the currently developed algorithms for the maximum likelihood approach do not allow the association parameter to depend on covariates. Xue formulates a Poisson regression model and applies an estimating equation approach to obtain a consistent estimate of the covariate effect on survival. This paper extends that approach to obtain consistent and efficient estimates of the association parameter as well as the covariate effect and to allow the association parameter to depend on the covariates. The approach does not require the specification of the frailty distribution. The performance of the method is evaluated through simulation studies. We apply this method to a childhood brain tumour data set in New York City.


Single-Cell Based Quantitative Assay of Chromosome Transmission Fidelity.
Errors in mitosis are a primary cause of chromosome instability (CIN), generating aneuploid progeny cells. Whereas a variety of factors can influence CIN, under most conditions mitotic errors are rare events that have been difficult to measure accurately. Here we report a green fluorescent protein-based quantitative chromosome transmission fidelity (qCTF) assay in budding yeast that allows sensitive and quantitative detection of CIN and can be easily adapted to high-throughput analysis. Using the qCTF assay, we performed genome-wide quantitative profiling of genes that affect CIN in a dosage-dependent manner and identified genes that elevate CIN when either increased (icCIN) or decreased in copy number (dcCIN). Unexpectedly, qCTF screening also revealed genes whose change in copy number quantitatively suppress CIN, suggesting that the basal error rate of the wild-type genome is not minimized, but rather, may have evolved toward an optimal level that balances both stability and low-level karyotype variation for evolutionary adaptation.


Detection in fixed and random noise in foveal and parafoveal vision explained by template learning.
Foveal and parafoveal contrast detection thresholds for Gabor and checkerboard targets were measured in white noise by means of a two-interval forced-choice paradigm. Two white-noise conditions were used: fixed and twin. In the fixed noise condition a single noise sample was presented in both intervals of all the trials. In the twin noise condition the same noise sample was used in the two intervals of a trial, but a new sample was generated for each trial. Fixed noise conditions usually resulted in lower thresholds than twin noise. Template learning models are presented that attribute this advantage of fixed over twin noise either to fixed memory templates' reducing uncertainty by incorporation of the noise or to the introduction, by the learning process itself, of more variability in the twin noise condition. Quantitative predictions of the template learning process show that it contributes to the accelerating nonlinear increase in performance with signal amplitude at low signal-to-noise ratios.


Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol.
Enterolignans (enterodiol and enterolactone) can potentially reduce the risk of certain cancers and cardiovascular diseases. Enterolignans are formed by the intestinal microflora after the consumption of plant lignans. Until recently, only secoisolariciresinol and matairesinol were considered enterolignan precursors, but now several new precursors have been identified, of which lariciresinol and pinoresinol have a high degree of conversion. Quantitative data on the contents in foods of these new enterolignan precursors are not available. Thus, the aim of this study was to compile a lignan database including all four major enterolignan precursors. Liquid chromatography-tandem mass spectrometry was used to quantify lariciresinol, pinoresinol, secoisolariciresinol and matairesinol in eighty-three solid foods and twenty-six beverages commonly consumed in The Netherlands. The richest source of lignans was flaxseed (301,129 microg/100 g), which contained mainly secoisolariciresinol. Also, lignan concentrations in sesame seeds (29,331 microg/100 g, mainly pinoresinol and lariciresinol) were relatively high. For grain products, which are known to be important sources of lignan, lignan concentrations ranged from 7 to 764 microg/100 g. However, many vegetables and fruits had similar concentrations, because of the contribution of lariciresinol and pinoresinol. Brassica vegetables contained unexpectedly high levels of lignans (185-2321 microg/100 g), mainly pinoresinol and lariciresinol. Lignan levels in beverages varied from 0 (cola) to 91 microg/100 ml (red wine). Only four of the 109 foods did not contain a measurable amount of lignans, and in most cases the amount of lariciresinol and pinoresinol was larger than that of secoisolariciresinol and matairesinol. Thus, available databases largely underestimate the amount of enterolignan precursors in foods.


Alzheimer's disease risk factors as mediators of subjective memory impairment and objective memory decline: protocol for a construct-level replication analysis.
Subjective memory impairment (SMI), or the perception of memory problems in the absence of objective memory deficits, is associated with negative outcomes of individual and societal significance, including a substantially increased risk of Alzheimer's disease (AD). However, little is known regarding the mediators that link SMI and memory decline in some individuals, or which older adults with SMI are at greatest risk for memory decline. In this study, we will examine modifiable AD risk factors (specifically affective symptoms and activity participation) as mediators underlying linkages among SMI and memory decline over time; furthermore, we will characterize SMI subgroups at highest risk for memory decline via this pathway. This study utilizes a series of construct-level replication analyses across four large longitudinal datasets to maximize the unique aspects of each dataset as well as test the reproducibility of findings across multiple populations to establish generalizability. The current study's sample (n > 40,000) is drawn from the Einstein Aging Study, Health and Retirement Study, Minority Aging Research Study, and National Health and Aging Trends Study. Participants must meet the following basic criteria for inclusion: age 55 or older and no evidence of cognitive impairment at baseline. We will use multilevel modeling to determine whether higher levels of SMI are related to increased affective symptoms and decreased activity participation, as well as whether this relationship is moderated by neuroticism, family history of AD, and race/ethnicity. Finally, we will test our full conceptual model that examines whether changes in affective symptoms and activity participation mediate the relationship between SMI and objective memory decline. Specifically, we will test moderated mediation as we hypothesize these relationships to hold among subgroups of older adults. Discovery of modifiable AD risk factors that mediate the association between SMI and memory decline (the earliest and most central deficit in AD) will provide explicit, and potentially novel, targets for intervention. Additionally, identifying individuals at highest risk for negative reactions to SMI will serve to enrich samples for future research as well as to help guide the development of SMI assessment tools to identify older adults at greatest risk for debilitating outcomes.


Debating DSM-5: diagnosis and the sociology of critique.
The development of the fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders-the DSM-5-has reenergised and driven further forward critical discourse about the place and role of diagnosis in mental health. The DSM-5 has attracted considerable criticism, not least about its role in processes of medicalisation. This paper suggests the need for a sociology of psychiatric critique. Sociological analysis can help map fields of contention, and cast fresh light on the assumptions and nuances of debate around the DSM-5; it underscores the importance of diagnosis to the governance of social and clinical life, as well as the wider discourses critical commentaries connect with and are activated by. More normatively, a sociology of critique can indicate which interests and values are structuring the dialogues being articulated, and just how diverse clinical opinion regarding the DSM can actually be. This has implications for the considerations of health services and policy decision-makers who might look to such debates for guidance.


Optical transitions of symmetrical mixed-valence systems in the Class II-III transition regime.
In the Robin and Day classification, mixed-valence systems are characterized as Class I, II or III depending on the strength of the electronic interaction between the oxidized and reduced sites, ranging from essentially zero (Class I), to moderate (Class II), to very strong electronic coupling (Class III). The properties of Class I systems are essentially those of the separate sites. Class II systems possess new optical and electronic properties in addition to those of the separate sites. However, the interaction between the sites is sufficiently weak that Class II systems are valence trapped or charge localized and can the be described by a double-well potential. In Class III systems the interaction of the donor and acceptor sites is so great that two separate minima are no longer discernible and the energy surface features a single minimum. The electron is delocalized and the system has its own unique properties. The Robin and Day classification has enjoyed considerable success and most of the redox systems studied to date are readily assigned to Class II. However the situation becomes much more complicated when the system shows borderline Class II/III behavior. Such "almost delocalized" mixed-valence systems are difficult to characterize. In this article spectral band shapes and intensities are calculated utilizing increasingly complex models including two to four states. Free-energy surfaces are constructed for harmonic diabetic surfaces and characterized as a function of increasing electronic coupling to simulate the Class II to III transition. The properties of the charge-transfer absorption bands predicted for borderline mixed-valence systems are compared with experimental data. The treatment is restricted to symmetrical (delta G0 = 0) systems.


XX > XY?: The changing female advantage in life expectancy.
Females live a lot longer than males in most parts of the world today. But that was not always the case. We ask when and why the female advantage emerged. We show that reductions in maternal mortality and fertility are only partial reasons. Rather, the sharp reduction in infectious disease in the early twentieth century played a role. Those who survive most infectious diseases carry a health burden that affects organs and impacts general well-being. We use newly collected data from Massachusetts containing information on cause of death since 1887 to show that females between the ages of 5 and 25 were disproportionately affected by infectious diseases. Both males and females lived longer as the burden of infectious disease fell, but women were more greatly impacted. Our explanation does not tell us precisely why women live longer than men, but it does help understand the timing of their relative increase.