Detection of a large-scale structure of intracluster globular clusters in the Virgo cluster.
Globular clusters are usually found in galaxies, and they are excellent tracers of dark matter. Long ago it was suggested that intracluster globular clusters (IGCs) may exist that are bound to a galaxy cluster rather than to any single galaxy. Here we present a map showing the large-scale distribution of globular clusters over the entire Virgo cluster. It shows that IGCs are found out to 5 million light years from the Virgo center and that they are concentrated in several substructures that are much larger than galaxies. These objects might have been mostly stripped off from low-mass dwarf galaxies.


Spectral tuning of adaptation supports coding of sensory context in auditory cortex.
Perception of vocalizations and other behaviorally relevant sounds requires integrating acoustic information over hundreds of milliseconds. Sound-evoked activity in auditory cortex typically has much shorter latency, but the acoustic context, i.e., sound history, can modulate sound evoked activity over longer periods. Contextual effects are attributed to modulatory phenomena, such as stimulus-specific adaption and contrast gain control. However, an encoding model that links context to natural sound processing has yet to be established. We tested whether a model in which spectrally tuned inputs undergo adaptation mimicking short-term synaptic plasticity (STP) can account for contextual effects during natural sound processing. Single-unit activity was recorded from primary auditory cortex of awake ferrets during presentation of noise with natural temporal dynamics and fully natural sounds. Encoding properties were characterized by a standard linear-nonlinear spectro-temporal receptive field (LN) model and variants that incorporated STP-like adaptation. In the adapting models, STP was applied either globally across all input spectral channels or locally to subsets of channels. For most neurons, models incorporating local STP predicted neural activity as well or better than LN and global STP models. The strength of nonlinear adaptation varied across neurons. Within neurons, adaptation was generally stronger for spectral channels with excitatory than inhibitory gain. Neurons showing improved STP model performance also tended to undergo stimulus-specific adaptation, suggesting a common mechanism for these phenomena. When STP models were compared between passive and active behavior conditions, response gain often changed, but average STP parameters were stable. Thus, spectrally and temporally heterogeneous adaptation, subserved by a mechanism with STP-like dynamics, may support representation of the complex spectro-temporal patterns that comprise natural sounds across wide-ranging sensory contexts.


The yeast SR-like protein Npl3 links chromatin modification to mRNA processing.
Eukaryotic gene expression involves tight coordination between transcription and pre-mRNA splicing; however, factors responsible for this coordination remain incompletely defined. Here, we explored the genetic, functional, and biochemical interactions of a likely coordinator, Npl3, an SR-like protein in Saccharomyces cerevisiae that we recently showed is required for efficient co-transcriptional recruitment of the splicing machinery. We surveyed the NPL3 genetic interaction space and observed a significant enrichment for genes involved in histone modification and chromatin remodeling. Specifically, we found that Npl3 genetically interacts with both Bre1, which mono-ubiquitinates histone H2B as part of the RAD6 Complex, and Ubp8, the de-ubiquitinase of the SAGA Complex. In support of these genetic data, we show that Bre1 physically interacts with Npl3 in an RNA-independent manner. Furthermore, using a genome-wide splicing microarray, we found that the known splicing defect of a strain lacking Npl3 is exacerbated by deletion of BRE1 or UBP8, a phenomenon phenocopied by a point mutation in H2B that abrogates ubiquitination. Intriguingly, even in the presence of wild-type NPL3, deletion of BRE1 exhibits a mild splicing defect and elicits a growth defect in combination with deletions of early and late splicing factors. Taken together, our data reveal a connection between Npl3 and an extensive array of chromatin factors and describe an unanticipated functional link between histone H2B ubiquitination and pre-mRNA splicing.


Functional consequences of neuropeptide Y Y 2 receptor knockout and Y2 antagonism in mouse and human colonic tissues.
1 Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) differentially activate three Y receptors (Y(1), Y(2) and Y(4)) in mouse and human isolated colon. 2 The aim of this study was to characterise Y(2) receptor-mediated responses in colon mucosa and longitudinal smooth muscle preparations from wild type (Y(2)+/+) and knockout (Y(2)-/-) mice and to compare the former with human mucosal Y agonist responses. Inhibition of mucosal short-circuit current and increases in muscle tone were monitored in colonic tissues from Y(2)+/+ and Y(2)-/- mice+/-Y(1) ((R)-N-[[4-(aminocarbonylaminomethyl)phenyl)methyl]-N(2)-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304) or Y(2) (S)-N(2)-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide (BIIE0246) antagonists. 3 Predictably, Y(2)-/- tissues were insensitive to Y(2)-preferred agonist PYY(3-36) (</=100 nM), but unexpectedly Y(4)-preferred PP responses were right-shifted probably as a consequence of elevated circulating PP levels, particularly in male Y(2)-/- mice (Sainsbury et al., 2002). 4 BIBO3304 and BIIE0246 elevated mucosal ion transport, indicating blockade of inhibitory mucosal tone in Y(2)+/+ tissue. While BIBO3304 effects were unchanged, those to BIIE0246 were absent in Y(2)-/- mucosae. Neither antagonist altered muscle tone; however, BIIE0246 blocked NPY and PYY(3-36) increases in Y(2)+/+ basal tone. BIBO3304 abolished residual Y(1)-mediated NPY responses in Y(2)-/- smooth muscle. 5 Tetrodotoxin significantly reduced BIIE0246 and PYY(3-36) effects in Y(2)+/+ mouse and human mucosae, but had no effect upon Y-agonist contractile responses, indicating that Y(2) receptors are located on submucosal, but not myenteric neurones. 6 Tonic activation of submucosal Y(2) receptors by endogenous NPY, PYY or PYY(3-36) could indirectly reduce mucosal ion transport in murine and human colon, while direct activation of Y(2) receptors on longitudinal muscle results in contraction.


Synthesis and characterization of ruthenium polypyridyl complexes with hydroxypyridine derivatives: effect of protonation and ethylation at the pyridyl nitrogen.
A new series of ruthenium polypyridyl complexes with a hydroxypyridine ligand were prepared, and their properties were investigated spectroscopically and electrochemically. Particular focus is paid to the effects of protonation-deprotonation and ethylation of the hydroxypyridine ligand, which affects the NMR, electronic spectroscopy, and electrochemistry of the complex. The changes to the UV-vis spectrum were used to determine a pka of 10.5 for the hydroxypyridine nitrogen. In the NMR, protonation of the hydroxypyridine ligand of the complex causes changes in the chemical shifts of the protons on both the hydroxypyridine and bipyridine rings, indicating some degree of electronic communication between these ligands. In addition, it is found that deprotonation of the hydroxypyridine ligand strongly affects the redox potential of the ruthenium metal center, shifting it more negative by 0.4 V. While the electrochemistry of the protonated complex contains irreversible electrochemical events, both deprotonation and subsequent ethylation of the hydroxypyridine ligand result in reversible electrochemistry for all events within the solvent window. For the ethylated complex, we search for a ligand to ligand charge transfer band, corresponding to electron transfer between bipyridine ligands in the mixed valence state. Despite the potential for electronic coupling between ligands through the metal center, we were unable to find any spectroscopic evidence of such electronic coupling.


Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles for two-photon photodynamic therapy or photoacoustic imaging.
Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles (BSPOR and BSPHT) were prepared. Their endocytosis in MCF-7 cancer cells was shown with two-photon excited fluorescence (TPEF) imaging. With two-photon excited photodynamic therapy (TPE-PDT), BSPOR was more phototoxic than BSPHT, which in contrast displayed a very high signal for photoacoustic imaging in mice.


In vitro culture of previously uncultured oral bacterial phylotypes.
Around a third of oral bacteria cannot be grown using conventional bacteriological culture media. Community profiling targeting 16S rRNA and shotgun metagenomics methods have proved valuable in revealing the complexity of the oral bacterial community. Studies investigating the role of oral bacteria in health and disease require phenotypic characterizations that are possible only with live cultures. The aim of this study was to develop novel culture media and use an in vitro biofilm model to culture previously uncultured oral bacteria. Subgingival plaque samples collected from subjects with periodontitis were cultured on complex mucin-containing agar plates supplemented with proteose peptone (PPA), beef extract (BEA), or Gelysate (GA) as well as on fastidious anaerobe agar plus 5% horse blood (FAA). In vitro biofilms inoculated with the subgingival plaque samples and proteose peptone broth (PPB) as the growth medium were established using the Calgary biofilm device. Specific PCR primers were designed and validated for the previously uncultivated oral taxa Bacteroidetes bacteria HOT 365 and HOT 281, Lachnospiraceae bacteria HOT 100 and HOT 500, and Clostridiales bacterium HOT 093. All agar media were able to support the growth of 10 reference strains of oral bacteria. One previously uncultivated phylotype, Actinomyces sp. HOT 525, was cultivated on FAA. Of 93 previously uncultivated phylotypes found in the inocula, 26 were detected in in vitro-cultivated biofilms. Lachnospiraceae bacterium HOT 500 was successfully cultured from biofilm material harvested from PPA plates in coculture with Parvimonas micra or Veillonella dispar/parvula after colony hybridization-directed enrichment. The establishment of in vitro biofilms from oral inocula enables the cultivation of previously uncultured oral bacteria and provides source material for isolation in coculture.


Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (Zonotrichia leucophrys).
There is a general trend that parasitism risk declines as latitude increases. Host populations breeding at high latitudes should therefore invest less in costly immune defenses than populations breeding in temperate or tropical zones, although it is unknown if such an effect is mediated by environmental (photoperiodic) or genetic factors or both. Acquired immune function (humoral, cell-mediated) and behavioral sickness responses to lipopolysaccharide (LPS; mimics bacterial infection) were assessed in two subspecies of white-crowned sparrow (Zonotrichia leucophrys) that breed at different latitudes in western North America. Zonotrichia l. gambelii (GWCS) is a high-latitude breeder (47-68 degrees N) while Z. l. pugetensis (PWCS) breeds at temperate latitudes (40-49 degrees N). Captive males of each subspecies were acclimated to (1) a short day (non-breeding) photoperiod (8L:16D), (2) the breeding photoperiod of PWCS (16L:8D), or (3) the breeding photoperiod of GWCS (20L:4D). Photoperiod was manipulated because shorter day lengths may enhance immune function. In support of a genetic effect, humoral responses to diphtheria-tetanus vaccination were significantly higher in PWCS compared to GWCS, regardless of photoperiod. There were no differences in cell-mediated responses to phytohemagglutinin (PHA) between subspecies or among photoperiods. For sickness responses to LPS, a significant interaction between photoperiod and subspecies was found, with long day GWCS producing stronger sickness responses (losing more weight, eating less) than short day GWCS and PWCS on all day lengths. However, these effects were influenced by photoperiodic changes in body condition. In conclusion, we find evidence for genetic control of immune responses across latitude, but no support for environmental (photoperiodic) regulation.


Epidemiology of gastric cancer.
The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socio-economic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socio-economic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori (H pylori) infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.


Newly acquired arthroscopic skills: Are they transferable during simulator training of other joints?
This randomized study investigates whether novices learning simulation-based arthroscopic skills in one anatomical joint environment can immediately transfer their learnt skills to another joint. Medical students were randomized to a simulated diagnostic knee or shoulder arthroscopic task on benchtop training models. After nine task repetitions over 3 weeks on one model, each participant undertook the simulation task of the other anatomical joint. Performance was objectively measured using a validated electromagnetic motion analysis system and a validated global rating scale (GRS). Eighteen students participated; eight started the knee task and ten the shoulder task. All participants demonstrated a learning curve in all parameters during task repetition (time taken, hand path length, number of hand movements and GRS scores; p < 0.001) with learning effects >1 SD from initial performance (range 1.1-2.2 SD). When the groups swapped models, there was no immediate evidence of skill transfer, with a significant drop in performance between the final training episode and the transfer task (all parameters p < 0.003). In particular, the transfer task performance was no better than the first episode performance on that model by these novices. This study showed basic arthroscopic skills did not immediately transfer to an unfamiliar anatomical environment within a simulated setting. These findings have important clinical implications with regard to surgical training as they potentially challenge the assumption that arthroscopic skills acquired in one joint are universally transferrable to other joints. Future orthopaedic simulation training should aim to deliver exposure to a greater variety of arthroscopic procedures and joint environments. This would allow trainees to become familiar with the different arthroscopic setting before undertaking real surgery and consequently improve patient safety. Therapeutic, Level II.


CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation.
Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.


Assessing the influence of treatment nonadherence on noninferiority trials using the tipping point approach.
In noninferiority (NI) trials, an ongoing methodological challenge is how to handle in the analysis the subjects who are nonadherent to their assigned treatment. Some investigators perform the intent-to-treat (ITT) as the primary analysis and the per-protocol (PP) analysis as sensitivity analysis, whereas others do the reverse since ITT results may be anticonservative in the NI setting. But even when there is agreement between the ITT and PP approaches, NI of the experimental therapy to the comparator is not guaranteed. We propose that a tipping point method be used to further assess the impact of nonadherence on the results of a NI trial. In this approach, data from the nonadherers obtained after treatment discontinuation is not used, and their outcomes under the counterfactual situation of complete adherence are considered missing. The tipping point analysis indicates how sensitive the NI trial results are to the values of these missing counterfactual outcomes. The advantages of this approach are that a model or mechanism for the missing outcomes does not have to be assumed, and all subjects who were randomized are included in the analysis. We consider both binary and continuous outcomes and propose extensions to accommodate different types of nonadherence. The methods are illustrated with examples from two NI trials, one to evaluate different doses of radiation therapy to treat painful bone metastases and the other to compare treatments for reducing depression in adolescents.


Protective Effects of Licochalcone A Ameliorates Obesity and Non-Alcoholic Fatty Liver Disease Via Promotion of the Sirt-1/AMPK Pathway in Mice Fed a High-Fat Diet.
Licochalcone A is a chalcone isolated from Glycyrrhiza uralensis. It showed anti-tumor and anti-inflammatory properties in mice with acute lung injuries and regulated lipid metabolism through the activation of AMP-activated protein kinase (AMPK) in hepatocytes. However, the effects of licochalcone A on reducing weight gain and improving nonalcoholic fatty liver disease (NAFLD) are unclear. Thus, the present study investigated whether licochalcone A ameliorated weight loss and lipid metabolism in the liver of high-fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed an HFD to induce obesity and NAFLD, and then were injected intraperitoneally with licochalcone A. In another experiment, a fatty liver cell model was established by incubating HepG2 hepatocytes with oleic acid and treating the cells with licochalcone A to evaluate lipid metabolism. Our results demonstrated that HFD-induced obese mice treated with licochalcone A had decreased body weight as well as inguinal and epididymal adipose tissue weights compared with HFD-treated mice. Licochalcone A also ameliorated hepatocyte steatosis and decreased liver tissue weight and lipid droplet accumulation in liver tissue. We also found that licochalcone A significantly regulated serum triglycerides, low-density lipoprotein, and free fatty acids, and decreased the fasting blood glucose value. Furthermore, in vivo and in vitro, licochalcone A significantly decreased expression of the transcription factor of lipogenesis and fatty acid synthase. Licochalcone A activated the sirt-1/AMPK pathway to reduce fatty acid chain synthesis and increased lipolysis and β-oxidation in hepatocytes. Licochalcone A can potentially ameliorate obesity and NAFLD in mice via activation of the sirt1/AMPK pathway.


School effectiveness and students' future orientation: A multilevel analysis of upper secondary schools in Stockholm, Sweden.
Future orientation (FO) refers to individuals' beliefs and feelings about their future. Earlier research has primarily investigated correlates of FO at the individual and family level, but it seems likely that FO is also shaped by other central agents or institutions, such as the school. Earlier studies have found positive associations between "school effectiveness" and student performance, and negative associations in relation to e.g., bullying, delinquency, and health risk behaviors. The current study investigated three teacher-reported features of school effectiveness - school leadership, teacher cooperation and consensus, and school ethos - and their links with student-reported FO. Survey data were collected in 2016 among 5131 students (aged 17-18 years) and 1061 teachers in 46 upper secondary schools in Stockholm, Sweden, and merged with school-level register data. Two-level binary logistic regression analyses were performed. The analyses showed that higher teacher ratings of school leadership and school ethos were associated with a greater likelihood of reporting an optimistic FO among students. Teacher cooperation and consensus was however not associated with students' FO. The findings indicate that the school environment contributes to shaping students' beliefs about their future. Thus, enhancing features of school effectiveness may be a way of promoting a positive development and brighter objective future prospects for the young, via pathways such as good student-teacher relations and academic motivation and achievement.


Prophylactic Administration of a Bacteriophage Cocktail Is Safe and Effective in Reducing Salmonella enterica Serovar Typhimurium Burden in Vivo.
Nontyphoidal Salmonella bacteria are the causative agent of salmonellosis, which accounts for the majority of foodborne illness of bacterial etiology in humans. Here, we demonstrate the safety and efficacy of the prophylactic administration of a bacteriophage preparation termed FOP (foodborne outbreak pill), which contains lytic phages targeting Salmonella (SalmoFresh phage cocktail), Shiga toxin-producing Escherichia coli (STEC), and Listeria monocytogenes, for lowering Salmonella burdens in OMM12 gnotobiotic mice. Prophylactic administration of FOP significantly reduced the levels of Salmonella in feces and in intestinal sections compared to the levels in controls. Moreover, the overall symptoms of the disease were also considerably lessened. Dose-dependent administration of FOP showed that phage amplification reached similarly high levels in less than 48 h independent of dose. In addition, 16S rRNA gene analysis showed that FOP did not alter the intestinal microbiota of healthy OMM12 mice and reduced microbiota perturbations induced by Salmonella. FOP maintained its full potency against Salmonella in comparison to that of SalmoFresh, its Salmonella-targeting component phages alone. Altogether, the data support that preventive administration of FOP may offer a safe and effective approach for reducing the risk of foodborne infections caused by Salmonella and, potentially, other foodborne bacteria (namely, STEC and L. monocytogenes) targeted by the FOP preparation. IMPORTANCE Foodborne bacterial infections cause worldwide economic loss. During an epidemic, the use of antibiotics to slow down the spread of the disease is not recommended because of their side effects on the resident microbiota and the selection of antibiotic-resistant bacteria. Here, we investigated the potential for the prophylactic administration of bacteriophages (viruses infecting bacteria) to reduce the burden of Salmonella in vivo using mice colonized by a synthetic microbiota. We found that the repeated administration of bacteriophages was safe and efficient in lowering the Salmonella burden. Perturbations of the microbiota by the Salmonella infection were also reduced when mice received bacteriophages. Altogether, these data support the use of bacteriophages as a prophylactic intervention to lower the spread of foodborne epidemics.


Non-exercise activity thermogenesis: the crouching tiger hidden dragon of societal weight gain.
Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique, and independent beings such as working, playing, and dancing. Because people of the same weight have markedly variable activity levels, it is not surprising that NEAT varies substantially between people by up to 2000 kcal per day. Evidence suggests that low NEAT may occur in obesity but in a very specific fashion. Obese individuals appear to exhibit an innate tendency to be seated for 2.5 hours per day more than sedentary lean counterparts. If obese individuals were to adopt the lean "NEAT-o-type," they could potentially expend an additional 350 kcal per day. Obesity was rare a century ago and the human genotype has not changed over that time. Thus, the obesity epidemic may reflect the emergence of a chair-enticing environment to which those with an innate tendency to sit, did so, and became obese. To reverse obesity, we need to develop individual strategies to promote standing and ambulating time by 2.5 hours per day and also re-engineer our work, school, and home environments to render active living the option of choice.


Identification of subunits of the anaphase-promoting complex of Saccharomyces cerevisiae.
Entry into anaphase and proteolysis of B-type cyclins depend on a complex containing the tetratricopeptide repeat proteins Cdc16p, Cdc23p, and Cdc27p. This particle, called the anaphase-promoting complex (APC) or cyclosome, functions as a cell cycle-regulated ubiquitin-protein ligase. Two additional subunits of the budding yeast APC were identified: The largest subunit, encoded by the APC1 gene, is conserved between fungi and vertebrates and shows similarity to BIMEp from Aspergillus nidulans. A small heat-inducible subunit is encoded by the CDC26 gene. The yeast APC is a 36S particle that contains at least seven different proteins.


Revisiting the heterogeneous global genomic population structure of Leishmania infantum.
Leishmania infantum is the main causative agent responsible for visceral leishmaniasis (VL), a disease with global distribution. The genomic structure and genetic variation of this species have been widely studied in different parts of the world. However, in some countries, this information is still yet unknown, as is the genomic behaviour of the main antigens used in VL diagnosis (rK39 and rK28), which have demonstrated variable sensitivity and specificity in a manner dependent on the geographic region analysed. The objective of this study was to explore the genomic architecture and diversity of four Colombian L. infantum isolates obtained in this study and to compare these results with the genetic analysis of 183 L. infantum isolates from across the world (obtained from public databases), as well as to analyse the whole rK39 and rK28 antigen sequences in our dataset. The results showed that, at the global level, L. infantum has high genetic homogeneity and extensive aneuploidy. Furthermore, we demonstrated that there are distinct populations of L. infantum circulating in various countries throughout the globe and that populations of distant countries have close genomic relationships. Additionally, this study demonstrated the high genetic variability of the rK28 antigen worldwide. In conclusion, our study allowed us to (i) expand our knowledge of the genomic structure of global L. infantum; (ii) describe the intra-specific genomic variability of this species; and (iii) understand the genomic characteristics of the main antigens used in the diagnosis of VL. Additionally, this is the first study to report whole-genome sequences of Colombian L. infantum isolates.


Stereo matching using epipolar distance transform.
In this paper, we propose a simple but effective image transform, called the epipolar distance transform, for matching low-texture regions. It converts image intensity values to a relative location inside a planar segment along the epipolar line, such that pixels in the low-texture regions become distinguishable. We theoretically prove that the transform is affine invariant, thus the transformed images can be directly used for stereo matching. Any existing stereo algorithms can be directly used with the transformed images to improve reconstruction accuracy for low-texture regions. Results on real indoor and outdoor images demonstrate the effectiveness of the proposed transform for matching low-texture regions, keypoint detection, and description for low-texture scenes. Our experimental results on Middlebury images also demonstrate the robustness of our transform for highly textured scenes. The proposed transform has a great advantage, its low computational complexity. It was tested on a MacBook Air laptop computer with a 1.8 GHz Core i7 processor, with a speed of about 9 frames per second for a video graphics array-sized image.


Triatoma maculata, the Vector of Trypanosoma cruzi, in Venezuela. Phenotypic and Genotypic Variability as Potential Indicator of Vector Displacement into the Domestic Habitat.
Triatoma maculata is a wild vector of Trypanosoma cruzi, the causative agent of Chagas disease; its incursion in the domestic habitat is scant. In order to establish the possible domestic habitat of T. maculata, we evaluated wing variability and polymorphism of genotypic markers in subpopulations of T. maculata that live in different habitats in Venezuela. As markers, we used the mtCyt b gene, previously apply to evaluate population genetic structure in triatomine species, and the β-tubulin gene region, a marker employed to study genetic variability in Leishmania subgenera. Adults of T. maculata were captured in the period 2012-2013 at domestic, peridomestic (PD), and wild areas of towns in the Venezuelan states of Anzoátegui, Bolívar, Portuguesa, Monagas, Nueva Esparta, and Sucre. The phenotypic analysis was conducted through the determination of the isometric size and conformation of the left wing of each insect (492 individuals), using the MorphoJ program. Results reveal that insects of the domestic habitat showed significant reductions in wing size and variations in anatomical characteristics associated with flying, in relation to the PD and wild habitats. The largest variability was found in Anzoátegui and Monagas. The genotypic variability was assessed by in silico sequence comparison of the molecular markers and PCR-RFLP assays, demonstrating a marked polymorphism for the markers in insects of the domestic habitat in comparison with the other habitats. The highest polymorphism was found for the β-tubulin marker with enzymes BamHI and KpnI. Additionally, the infection rate by T. cruzi was higher in Monagas and Sucre (26.8 and 37.0%, respectively), while in domestic habitats the infestation rate was highest in Anzoátegui (22.3%). Results suggest domestic habitat colonization by T. maculata that in epidemiological terms, coupled with the presence in this habitat of nymphs of the vector, represents a high risk of transmission of Chagas disease.


Comparison of the Ways in Which Nitidine Chloride and Bufalin Induce Programmed Cell Death in Hematological Tumor Cells.
The objective of this work to study the programmed cell death (PCD) in hematological tumor cells induced by nitidine chloride (NC) and bufalin (BF). Hematological tumor cells were exposed to various doses of NC and BF to measure the level of growth inhibition. While inverted microscope is used to observe cell morphology, western blot technique is used to detect apoptosis-related protein expression levels. The effects of NC and BF on hematological tumor cells were different. Although abnormal cell morphology could be seen under the inverted microscope, the western blot results showed that the two medicines induced PCD through different pathways. Drug resistance varied in intensity across distinct cells. THP-1, Jurkat, and RPMI-8226 each had half maximum inhibitory concentrations (IC50) of 36.23 nM, 26.71 nM, and 40.46 nM in BF, and 9.24 µM, 4.33 µM, and 28.18 µM in NC, respectively. Different hematopoietic malignancy cells exhibit varying degrees of drug resistance, and the mechanisms by which apoptosis of hematologic tumor cells is triggered by NC and BF are also distinct.


Factors influencing reproductive performance of cows from different Nguni ecotypes in southern Mozambique.
The objective of this study was to assess the reproductive performance of two Nguni ecotypes (Nguni and Landim) raised in a subtropical environment to enhance strategies for livestock development and restocking programmes within the southern African region. Reproduction data collected between 1996 and 2009 from 365 cows of the Landim and Nguni ecotypes were analysed. From the results, ecotype, place of birth, year and season of birth/calving had significant effects on age at first calving (AFC) and calving interval (CI). Overall means for AFC and CI were 1,071 ± 166 days and 432 ± 85 days, respectively, while average calving rate was 88.0 ± 4.7%. Heifers born in the dry season had lower AFC than heifers born in the wet season. Heifers born at Impaputo Breeding Center were the youngest at first calving, followed by the South African born ones. Heifers of the Landim ecotype also calved younger than heifers of the Nguni ecotype. CI was shorter in wet seasons (main breeding seasons) than in dry seasons. Interaction between ecotype and year-season (p < 0.005) showed that, in wet and dry seasons, Nguni cows had shorter CI than the Landim. This study demonstrates for the first time a possible genotype-by-environment interaction between Nguni ecotypes. This might aid future cattle development and restocking programmes in southern Africa taking into consideration the adaptation of indigenous genotypes and climate change.


The association between the ratio of monocytes:lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life.
Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV. We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious. Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%). Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.


One-year survey of enteroviruses, adenoviruses, and reoviruses isolated from effluent at an activated-sludge purification plant.
Samples of raw sewage, primary effluent, and secondary effluent from a large activated-sludge purification plant near Melbourne (Victoria, Australia) were collected every second week for 1 year. Viruses were detected in all secondary effluent samples and in six of seven samples obtained after final chlorination. Adenoviruses (85% reduction) and reoviruses (28% reduction) were removed less efficiently by this treatment process than were enteroviruses (93% reduction). In addition, 57 of 171 samples of effluent tested were positive for either adenoviruses or reoviruses, or both, when enteroviruses were not isolated. This clearly shows that the use of enteroviruses as sole indicators of viruses in water may miss up to one-third of instances of viral contamination. Enteroviruses and adenoviruses were isolated most frequently in HeLa-R cell cultures, whereas reoviruses were most often isolated in primary monkey kidney cells.


Current treatment approaches for chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder that progresses through distinct phases characterized by progressive loss of the differentiation of the malignant clone. Over the past 4 decades, it has been established that the Bcr-Abl protein, created as a consequence of a (9:22) chromosomal translocation, is the cause of the disease. Bcr-Abl functions as a constitutively activated tyrosine kinase, and this kinase activity is absolutely required for the transforming function of the Bcr-Abl protein. Thus, a specific inhibitor of the Bcr-Abl tyrosine kinase would be predicted to be an effective and selective therapeutic agent for CML. STI571, an Abl-specific tyrosine kinase inhibitor, has shown remarkable activity in all phases of CML. The clinical features, molecular pathogenesis, and current treatment options of CML are reviewed along with the development of STI571, the phase I clinical results, and the application of this paradigm to other malignancies.


Aging in individuals with lifelong disabilities.
The major research data and findings related to aging among persons with developmental disabilities are discussed. Differences between the aging processes noted in the general population and individuals who have developmental disabilities are highlighted. Topics addressed include prevalence of developmental disabilities and mortality rates for individuals with developmental disabilities. The effects of aging on the senses, the neuromusculoskeletal system, and the cardiopulmonary system are presented along with the clinical implications of these changes in individuals with developmental disabilities who are aging.


Plasma Membrane Abundance of Human Aquaporin 5 Is Dynamically Regulated by Multiple Pathways.
Aquaporin membrane protein channels mediate cellular water flow. Human aquaporin 5 (AQP5) is highly expressed in the respiratory system and secretory glands where it facilitates the osmotically-driven generation of pulmonary secretions, saliva, sweat and tears. Dysfunctional trafficking of AQP5 has been implicated in several human disease states, including Sjögren's syndrome, bronchitis and cystic fibrosis. In order to investigate how the plasma membrane expression levels of AQP5 are regulated, we studied real-time translocation of GFP-tagged AQP5 in HEK293 cells. We show that AQP5 plasma membrane abundance in transfected HEK293 cells is rapidly and reversibly regulated by at least three independent mechanisms involving phosphorylation at Ser156, protein kinase A activity and extracellular tonicity. The crystal structure of a Ser156 phosphomimetic mutant indicates that its involvement in regulating AQP5 membrane abundance is not mediated by a conformational change of the carboxy-terminus. We suggest that together these pathways regulate cellular water flow.


Differential induction of Toll-like receptors & type 1 interferons by Sabin attenuated & wild type 1 polioviruses in human neuronal cells.
Polioviruses are the causative agent of paralytic poliomyelitis. Attenuated polioviruses (Sabin oral poliovirus vaccine strains) do not replicate efficiently in neurons as compared to the wild type polioviruses and therefore do not cause disease. This study was aimed to investigate the differential host immune response to wild type 1 poliovirus (wild PV) and Sabin attenuated type 1 poliovirus (Sabin PV) in cultured human neuronal cells. By using flow cytometry and real time PCR methods we examined host innate immune responses and compared the role of toll like receptors (TLRs) and cytoplasmic RNA helicases in cultured human neuronal cells (SK-N-SH) infected with Sabin PV and wild PV. Human neuronal cells expressed very low levels of TLRs constitutively. Sabin PV infection induced significantly higher expression of TLR3, TLR7 and melanoma differentiation-associated protein-5 (MDA-5) m-RNA in neuronal cells at the beginning of infection (up to 4 h) as compared to wild PV. Further, Sabin PV also induced the expression of interferon α/β at early time point of infection. The induced expression of IFN α/β gene by Sabin PV in neuronal cells could be suppressed by inhibiting TLR7. Neuronal cell innate immune response to Sabin and wild polioviruses differ significantly for TLR3, TLR7, MDA5 and type 1 interferons. Effects of TLR7 activation and interferon production and Sabin virus replication in neuronal cells need to be actively investigated in future studies.


ADP-glucose drives starch synthesis in isolated maize endosperm amyloplasts: characterization of starch synthesis and transport properties across the amyloplast envelope.
We recently developed a method of purifying amyloplasts from developing maize (Zea mays L.) endosperm tissue [Neuhaus, Thom, Batz and Scheibe (1993) Biochem. J. 296, 395-401]. In the present paper we analyse how glucose 6-phosphate (Glc6P) and other phosphorylated compounds enter the plastid compartment. Using a proteoliposome system in which the plastid envelope membrane proteins are functionally reconstituted, we demonstrate that this type of plastid is able to transport [14C]Glc6P or [32P]Pi in counter exchange with Pi, Glc6P, dihydroxyacetone phosphate and phosphoenolpyruvate. Glucose 1-phosphate, fructose 6-phosphate and ribose 5-phosphate do not act as substrates for counter exchange. Besides hexose phosphates, ADP-glucose (ADPGlc) also acts as a substrate for starch synthesis in isolated maize endosperm amyloplasts. This process exhibits saturation kinetics with increasing concentrations of exogenously supplied [14C]ADPGlc, reaching a maximum at 2mM. Ultrasonication of isolated amyloplasts greatly reduces the rate of ADPGlc-dependent starch synthesis, indicating that the process is dependent on the intactness of the organelles. The plastid ATP/ADP transporter is not responsible for ADPGlc uptake. Data are presented that indicate that ADPGlc is transported by another translocator in counter exchange with AMP. To analyse the physiology of starch synthesis in more detail, we examined how Glc6P- and ADPGlc-dependent starch synthesis in isolated maize endosperm amyloplasts interact. Glc6P-dependent starch synthesis is not inhibited by increasing concentrations of ADPGlc. In contrast, the rate of ADPGlc-dependent starch synthesis is reduced by increasing concentrations of ATP necessary for Glc6P-dependent starch synthesis. The possible modes of inhibition of ADPGlc-dependent starch synthesis by ATP are discussed with respect to the stromal generation of AMP required for ADPGlc uptake.


A wake up call for urinary schistosomiasis: reconciling research effort with public health importance.
This review considers the current status of urinary schistosomiasis, caused by infection with Schistosoma haematobium, and argues that greater research effort and focus are needed to improve understanding of this neglected tropical disease (NTD). The inappropriateness of relying solely on data concerning the much more extensively studied intestinal form of schistosomiasis caused by S. mansoni is highlighted. The current lack of genome and transcriptome information for S. haematobium is directly hindering further targeted research and must be quickly rectified. Recent molecular phylogenies caution the expectation of similarities between schistosome species and highlight the close relationships of species within the S. haematobium group. Treatment, current and prospective drugs and vaccines, together with diagnosis are considered, highlighting the differences associated with urinary schistosomiasis. This infection has a significant and specific impact on the urino-genital system and has a strong association with bladder cancer, leading to severe and chronic morbidity. There is a clear need for new clinical initiatives in this area to better quantify the disease burden. Furthermore, emerging associations with HIV and other pathogens need to be closely monitored. Research is urgently needed to improve current knowledge in order to develop the next generation of control tools.


The dynamic ups and downs of genome size evolution in Brassicaceae.
Crucifers (Brassicaceae, Cruciferae) are a large family comprising some 338 genera and c. 3,700 species. The family includes important crops as well as several model species in various fields of plant research. This paper reports new genome size (GS) data for more than 100 cruciferous species in addition to previously published C-values (the DNA amount in the unreplicated gametic nuclei) to give a data set comprising 185 Brassicaceae taxa, including all but 1 of the 25 tribes currently recognized. Evolution of GS was analyzed within a phylogenetic framework based on gene trees built from five data sets (matK, chs, adh, trnLF, and ITS). Despite the 16.2-fold variation across the family, most Brassicaceae species are characterized by very small genomes with a mean 1C-value of 0.63 pg. The ancestral genome size (ancGS) for Brassicaceae was reconstructed as (anc)1C=0.50 pg. Approximately 50% of crucifer taxa analyzed showed a decrease in GS compared with the ancGS. The remaining species showed an increase in GS although this was generally moderate, with significant increases in C-value found only in the tribes Anchonieae and Physarieae. Using statistical approaches to analyze GS, evolutionary gains or losses in GS were seen to have accumulated disproportionately faster within longer branches. However, we also found that GS has not changed substantially through time and most likely evolves passively (i.e., a tempo that cannot be distinguished between neutral evolution and weak forms of selection). The data reveal an apparent paradox between the narrow range of small GSs over long evolutionary time periods despite evidence of dynamic genomic processes that have the potential to lead to genome obesity (e.g., transposable element amplification and polyploidy). To resolve this, it is suggested that mechanisms to suppress amplification and to eliminate amplified DNA must be active in Brassicaceae although their control and mode of operation are still poorly understood.


Carotenoids affect proliferation of human prostate cancer cells.
We investigated whether various carotenoids present in foodstuffs were potentially involved in cancer-preventing action on human prostate cancer. The effects of 15 kinds of carotenoids on the viability of three lines of human prostate cancer cells, PC-3, DU 145 and LNCaP, were evaluated. When the prostate cancer cells were cultured in a carotenoid-supplemented medium for 72 h at 20 micromol/L, 5,6-monoepoxy carotenoids, namely, neoxanthin from spinach and fucoxanthin from brown algae, significantly reduced cell viability to 10.9 and 14.9% for PC-3, 15.0 and 5.0% for DU 145, and nearly zero and 9.8% for LNCaP, respectively. Acyclic carotenoids such as phytofluene, zeta-carotene and lycopene, all of which are present in tomato, also significantly reduced cell viability. On the other hand, phytoene, canthaxanthin, beta-cryptoxanthin and zeaxanthin did not affect the growth of the prostate cancer cells. DNA fragmentation of nuclei in neoxanthin- and fucoxanthin-treated cells was detected by in situ TdT-mediated dUTP nick end labeling (TUNEL) assay. Neoxanthin and fucoxanthin were found to reduce cell viability through apoptosis induction in the human prostate cancer cells. These results suggest that ingestion of leafy green vegetables and edible brown algae rich in neoxanthin and fucoxanthin might have the potential to reduce the risk of prostate cancer.


Cell-mediated and antibody responses to Bordetella pertussis antigens in children vaccinated with acellular or whole-cell pertussis vaccines. The Progetto Pertosse-CMI Working Group.
To examine induction and persistence of cell-mediated immunity (CMI) and antibody responses to Bordetella pertussis antigens in infants receiving antipertussis vaccines. A randomized, blinded study of 142 children receiving acellular pertussis vaccines combined with diphtheria-tetanus toxoids (DTaP) (DTaP manufactured by SmithKline Beecham [DTaP-SB], Rixensart, Belgium, and DTaP manufactured by Chiron Biocin [DTaP-CB], Siena, Italy), or a whole-cell pertussis vaccine (DTwP) (Connaught Laboratories Inc, Swiftwater, Pa), or a diphtheria-tetanus (DT) (Chiron Biocine) only vaccine. Three doses of each vaccine were given at 2, 4, and 6 months of age, and CMI and antibody responses were evaluated before and at 1 and 14 months after vaccination. Cell-mediated immunity was assessed by proliferation of peripheral blood mononuclear cells stimulated in vitro by B pertussis antigens (pertussis toxin, filamentous hemagglutinin, and pertactin). Antibody titers against pertussis toxin, filamentous hemagglutinin, and pertactin were determined by a standardized enzyme-linked immunosorbent assay. A CMI-positive response to at least 1 B pertussis antigen at 1 or both postvaccination assays was detected in 46%, 55%, and 83% of DTwP, DTaP-SB, and DTaP-CB vaccine recipients, respectively. Frequency of CMI response to individual antigens ranged from less than 4.9% against pertussis toxin in DTwP recipients to 52% against pertactin in DTaP-CB recipients. The postvaccination responses measured at 14 months equalled, or had increased frequency or intensity, that of the 1-month postvaccination responses. Elevated antibody titers against the 3 antigens were present in all DTaP recipients 1 month after vaccination and were higher in CMI-positive children than in CMI-negative children. They fell, however, to low, if not negligible, levels 14 months after vaccination. Acellular pertussis vaccines were better inducers of CMI response than the whole-cell vaccine, particularly against pertussis toxin. Once acquired, CMI persisted, in contrast with the rapid antibody decline. Thus, CMI responses could be a useful adjunct to serology in the evaluation of pertussis vaccine immunogenicity and a better correlate of long-term immunity to B pertussis than antibody titers.


Standard versus trans-epithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking.
Evaluating the clinical results of trans-epithelial collagen cross-linking (CXL) and standard CXL in patients with progressive keratoconus. This prospective study comprised 20 eyes of 20 patients with progressive keratoconus. Ten eyes were treated by standard CXL and ten by trans-epithelial cross-linking (TE-CXL, epithelium on) with 1 year of follow-up. All patients underwent complete ophthalmologic testing that included pre- and postoperative uncorrected visual acuity, corrected visual acuity, spherical error, spherical equivalent, corneal astigmatism, simulated maximum, minimum, and average keratometry, coma and spherical aberration, optical pachymetry, and endothelial cell density. Intra-and postoperative complications were recorded. The solution used for standard CXL comprised riboflavin 0.1% and dextran 20.0% (Ricrolin), while the solution for TE-CXL (Ricrolin, TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with UV-X System at 3 mW/cm(2). In both the standard CXL group (ten patients, ten eyes; mean age, 30.4±7.3 years) and the TE-CXL group (ten patients, ten eyes; mean age, 28±3.8 years), uncorrected visual acuity and corrected visual acuity improved significantly after treatment. Furthermore, a significant improvement in topographic outcomes, spherical error, and spherical equivalent was observed in both groups at month 12 posttreatment. No significant variations were recorded in other parameters. No complications were noted. A 1-year follow-up showed stability of clinical and refractive outcomes after standard CXL and TE-CXL.


A large-scale, higher-level, molecular phylogenetic study of the insect order Lepidoptera (moths and butterflies).
Higher-level relationships within the Lepidoptera, and particularly within the species-rich subclade Ditrysia, are generally not well understood, although recent studies have yielded progress. We present the most comprehensive molecular analysis of lepidopteran phylogeny to date, focusing on relationships among superfamilies. 483 taxa spanning 115 of 124 families were sampled for 19 protein-coding nuclear genes, from which maximum likelihood tree estimates and bootstrap percentages were obtained using GARLI. Assessment of heuristic search effectiveness showed that better trees and higher bootstrap percentages probably remain to be discovered even after 1000 or more search replicates, but further search proved impractical even with grid computing. Other analyses explored the effects of sampling nonsynonymous change only versus partitioned and unpartitioned total nucleotide change; deletion of rogue taxa; and compositional heterogeneity. Relationships among the non-ditrysian lineages previously inferred from morphology were largely confirmed, plus some new ones, with strong support. Robust support was also found for divergences among non-apoditrysian lineages of Ditrysia, but only rarely so within Apoditrysia. Paraphyly for Tineoidea is strongly supported by analysis of nonsynonymous-only signal; conflicting, strong support for tineoid monophyly when synonymous signal was added back is shown to result from compositional heterogeneity. Support for among-superfamily relationships outside the Apoditrysia is now generally strong. Comparable support is mostly lacking within Apoditrysia, but dramatically increased bootstrap percentages for some nodes after rogue taxon removal, and concordance with other evidence, strongly suggest that our picture of apoditrysian phylogeny is approximately correct. This study highlights the challenge of finding optimal topologies when analyzing hundreds of taxa. It also shows that some nodes get strong support only when analysis is restricted to nonsynonymous change, while total change is necessary for strong support of others. Thus, multiple types of analyses will be necessary to fully resolve lepidopteran phylogeny.


The Value Proposition for Pathologists: A Population Health Approach.
The transition to a value-based payment system offers pathologists the opportunity to play an increased role in population health by improving outcomes and safety as well as reducing costs. Although laboratory testing itself accounts for a small portion of health-care spending, laboratory data have significant downstream effects in patient management as well as diagnosis. Pathologists currently are heavily engaged in precision medicine, use of laboratory and pathology test results (including autopsy data) to reduce diagnostic errors, and play leading roles in diagnostic management teams. Additionally, pathologists can use aggregate laboratory data to monitor the health of populations and improve health-care outcomes for both individual patients and populations. For the profession to thrive, pathologists will need to focus on extending their roles outside the laboratory beyond the traditional role in the analytic phase of testing. This should include leadership in ensuring correct ordering and interpretation of laboratory testing and leadership in population health programs. Pathologists in training will need to learn key concepts in informatics and data analytics, health-care economics, public health, implementation science, and health systems science. While these changes may reduce reimbursement for the traditional activities of pathologists, new opportunities arise for value creation and new compensation models. This report reviews these opportunities for pathologist leadership in utilization management, precision medicine, reducing diagnostic errors, and improving health-care outcomes.


XRCC3 ATPase activity is required for normal XRCC3-Rad51C complex dynamics and homologous recombination.
Homologous recombinational repair preserves chromosomal integrity by removing double-strand breaks, cross-links, and other DNA damage. In eukaryotic cells, the Rad51 paralogs (XRCC2/3, Rad51B/C/D) are involved in this process, although their exact functions are largely undetermined. All five paralogs contain ATPase motifs, and XRCC3 exists in a single complex with Rad51C. To examine the function of this Rad51C-XRCC3 complex, we generated mammalian expression vectors that produce human wild-type XRCC3 or mutant XRCC3 with either a nonconservative mutation (K113A) or a conservative mutation (K113R) in the GKT Walker A box of the ATPase motif. The three vectors were independently transfected into Xrcc3-deficient irs1SF Chinese hamster ovary cells. Wild-type XRCC3 complemented irs1SF cells, albeit to varying degrees, whereas ATPase mutants had no complementing activity, even when the mutant protein was expressed at comparable levels to that in wild-type-complemented clones. Because of dysfunction of the mutants, we propose that ATP binding and hydrolyzing activities of XRCC3 are essential. We tested in vitro complex formation by wild-type and mutant XRCC3 with His6-tagged Rad51C upon co-expression in bacteria, nickel-affinity purification, and Western blotting. Wild-type and K113A mutant XRCC3 formed stable complexes with Rad51C and co-purified with Rad51C, whereas the K113R mutant did not and was predominantly insoluble. The addition of 5 mm ATP but not ADP also abolished complex formation by the wild-type proteins. These results suggest that XRCC3 probably regulates the dissociation and formation of Rad51C-XRCC3 complex through ATP binding and hydrolysis with both processes being essential for the ability of the complex to participate in homologous recombinational repair.


Peer relationship antecedents of delinquent behavior in late adolescence: is there evidence of demographic group differences in developmental processes?
A longitudinal prospective design was used to test the generalizability of low levels of social preference and high levels of antisocial peer involvement as risk factors for delinquent behavior problems to African American (AA) and European American (EA) boys and girls (N = 384). Social preference scores were computed from peer reports in middle childhood (ages 6-9). Parents and adolescents reported antisocial peer involvement in early adolescence (ages 13-16) and adolescents reported on their own delinquent behavior in late adolescence (ages 17 and 18). Analyses tested for differences across four groups (AA boys, EA boys, AA girls, EA girls) in construct measurement, mean levels, and associations among variables. Few measurement differences were found. Mean-level differences were found for social preference and delinquent behavior. AA boys were least accepted by peers and reported the highest level of delinquent behavior. EA girls were most accepted by peers and reported the lowest level of delinquent behavior. Associations among peer experiences and delinquent behavior were equivalent across groups, with lower levels of social preference and higher levels of antisocial peer involvement associated with more delinquent behavior. Person-centered analyses showed the risk associated with low social preference and high antisocial peer involvement to be similar across groups, providing further evidence of the generalizability of the peer relationship experiences as risk factors for subsequent delinquent behavior problems.


Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men.
Studies on the relation between thrombin activatable fibrinolysis inhibitor (TAFI) and arterial thrombosis have produced conflicting results. TAFI regulates fibrinolysis, but other roles of this inhibitor, including anti-inflammatory properties, have also been demonstrated. We investigated the association between TAFI activity and the risk of myocardial infarction. Additionally, we studied the association of common single nucleotide polymorphisms in the TAFI gene with levels of the TAFI protein and risk of myocardial infarction.We included 554 men under 70 years old with a first myocardial infarction and 643 controls participating in the Study of Myocardial Infarctions Leiden (SMILE), a case-control study. We found odds ratios (95% confidence intervals) of a first myocardial infarction of 2.4 (1.6-3.6), 3.2 (2.1-4.7) and 3.4 (2.3-5.1) for subjects whose TAFI levels were in the third, second and first quartiles (lowest TAFI levels), respectively, compared with the fourth quartile, after adjusting for arterial disease risk factors. The rare -438A and 1040T alleles were associated with lower, and the rare 505G allele with higher TAFI levels than the common alleles. Carriers of the -438A allele had an increased risk of myocardial infarction (odds ratio 1.6 (1.0-2.5) for AA; odds ratio 1.2 (0.9-1.5) for AG compared with GG). The other single nucleotide polymorphisms were not associated with myocardial infarction. Low TAFI activity levels are associated with increased risk of a first myocardial infarction in men. The results on the association between TAFI single nucleotide polymorphisms and myocardial infarction were inconsistent.


Analysis of Margin Classification Systems for Assessing the Risk of Local Recurrence After Soft Tissue Sarcoma Resection.
Purpose To compare the ability of margin classification systems to determine local recurrence (LR) risk after soft tissue sarcoma (STS) resection. Methods Two thousand two hundred seventeen patients with nonmetastatic extremity and truncal STS treated with surgical resection and multidisciplinary consideration of perioperative radiotherapy were retrospectively reviewed. Margins were coded by residual tumor (R) classification (in which microscopic tumor at inked margin defines R1), the R+1mm classification (in which microscopic tumor within 1 mm of ink defines R1), and the Toronto Margin Context Classification (TMCC; in which positive margins are separated into planned close but positive at critical structures, positive after whoops re-excision, and inadvertent positive margins). Multivariate competing risk regression models were created. Results By R classification, LR rates at 10-year follow-up were 8%, 21%, and 44% in R0, R1, and R2, respectively. R+1mm classification resulted in increased R1 margins (726 v 278, P < .001), but led to decreased LR for R1 margins without changing R0 LR; for R0, the 10-year LR rate was 8% (range, 7% to 10%); for R1, the 10-year LR rate was 12% (10% to 15%) . The TMCC also showed various LR rates among its tiers ( P < .001). LR rates for positive margins on critical structures were not different from R0 at 10 years (11% v 8%, P = .18), whereas inadvertent positive margins had high LR (5-year, 28% [95% CI, 19% to 37%]; 10-year, 35% [95% CI, 25% to 46%]; P < .001). Conclusion The R classification identified three distinct risk levels for LR in STS. An R+1mm classification reduced LR differences between R1 and R0, suggesting that a negative but < 1-mm margin may be adequate with multidisciplinary treatment. The TMCC provides additional stratification of positive margins that may aid in surgical planning and patient education.


A systematic review and meta-analysis of digital application use in clinical research in pain medicine.
Pain is a silent global epidemic impacting approximately a third of the population. Pharmacological and surgical interventions are primary modes of treatment. Cognitive/behavioural management approaches and interventional pain management strategies are approaches that have been used to assist with the management of chronic pain. Accurate data collection and reporting treatment outcomes are vital to addressing the challenges faced. In light of this, we conducted a systematic evaluation of the current digital application landscape within chronic pain medicine. The primary objective was to consider the prevalence of digital application usage for chronic pain management. These digital applications included mobile apps, web apps, and chatbots. We conducted searches on PubMed and ScienceDirect for studies that were published between 1st January 1990 and 1st January 2021. Our review included studies that involved the use of digital applications for chronic pain conditions. There were no restrictions on the country in which the study was conducted. Only studies that were peer-reviewed and published in English were included. Four reviewers had assessed the eligibility of each study against the inclusion/exclusion criteria. Out of the 84 studies that were initially identified, 38 were included in the systematic review. The AMSTAR guidelines were used to assess data quality. This assessment was carried out by 3 reviewers. The data were pooled using a random-effects model. Before data collection began, the primary outcome was to report on the standard mean difference of digital application usage for chronic pain conditions. We also recorded the type of digital application studied (e.g., mobile application, web application) and, where the data was available, the standard mean difference of pain intensity, pain inferences, depression, anxiety, and fatigue. 38 studies were included in the systematic review and 22 studies were included in the meta-analysis. The digital interventions were categorised to web and mobile applications and chatbots, with pooled standard mean difference of 0.22 (95% CI: -0.16, 0.60), 0.30 (95% CI: 0.00, 0.60) and -0.02 (95% CI: -0.47, 0.42) respectively. Pooled standard mean differences for symptomatologies of pain intensity, depression, and anxiety symptoms were 0.25 (95% CI: 0.03, 0.46), 0.30 (95% CI: 0.17, 0.43) and 0.37 (95% CI: 0.05, 0.69), respectively. A sub-group analysis was conducted on pain intensity due to the heterogeneity of the results (I 2 = 82.86%; p = 0.02). After stratifying by country, we found that digital applications were more likely to be effective in some countries (e.g., United States, China) than others (e.g., Ireland, Norway). The use of digital applications in improving pain-related symptoms shows promise, but further clinical studies would be needed to develop more robust applications. https://www.crd.york.ac.uk/prospero/, identifier: CRD42021228343.


Can self-reported strokes be used to study stroke incidence and risk factors?: evidence from the health and retirement study.
Most stroke incidence studies use geographically localized (community) samples with few national data sources available. Such samples preclude research on contextual risk factors, but national samples frequently collect only self-reported stroke. We examine whether incidence estimates from clinically verified studies are consistent with estimates from a nationally representative US sample assessing self-reported stroke. Health and Retirement Study (HRS) participants (n=17 056) age 50+ years were followed for self- or proxy-reported first stroke (1293 events) from 1998 to 2006 (average, 6.8 years). We compared incidence rates by race, sex, and age strata with those previously documented in leading geographically localized studies with medically verified stroke. We also examined whether cardiovascular risk factor effect estimates in HRS are comparable to those reported in studies with clinically verified strokes. The weighted first-stroke incidence rate was 10.0 events/1000 person-years. Total age-stratified incidence rates in whites were mostly comparable with those reported elsewhere and were not systematically higher or lower. However, among blacks in HRS, incidence rates generally appeared higher than those previously reported. HRS estimates were most comparable with those reported in the Cardiovascular Health Study. Incidence rates approximately doubled per decade of age and were higher in men and blacks. After demographic adjustment, all risk factors predicted stroke incidence in whites. Smoking, hypertension, diabetes, and heart disease predicted incident stroke in blacks. Associations between known risk factors and stroke incidence were verified in HRS, suggesting that misreporting is nonsystematic. HRS may provide valuable data for stroke surveillance and examination of classical and contextual risk factors.


Genetically modulated educational attainment and coronary disease risk.
Genetic disposition and lifestyle factors are understood as independent components underlying the risk of multiple diseases. In this study, we aim to investigate the interplay between genetics, educational attainment-an important denominator of lifestyle-and coronary artery disease (CAD) risk. Based on the effect sizes of 74 genetic variants associated with educational attainment, we calculated a 'genetic education score' in 13 080 cases and 14 471 controls and observed an inverse correlation between the score and risk of CAD [P = 1.52 × 10-8; odds ratio (OR) 0.79, 95% confidence interval (CI) 0.73-0.85 for the higher compared with the lowest score quintile]. We replicated in 146 514 individuals from UK Biobank (P = 1.85 × 10-6) and also found strong associations between the 'genetic education score' with 'modifiable' risk factors including smoking (P = 5.36 × 10-23), body mass index (BMI) (P = 1.66 × 10-30), and hypertension (P = 3.86 × 10-8). Interestingly, these associations were only modestly attenuated by adjustment for years spent in school. In contrast, a model adjusting for BMI and smoking abolished the association signal between the 'genetic education score' and CAD risk suggesting an intermediary role of these two risk factors. Mendelian randomization analyses performed with summary statistics from large genome-wide meta-analyses and sensitivity analysis using 1271 variants affecting educational attainment (OR 0.68 for the higher compared with the lowest score quintile; 95% CI 0.63-0.74; P = 3.99 × 10-21) further strengthened these findings. Genetic variants known to affect educational attainment may have implications for a health-conscious lifestyle later in life and subsequently affect the risk of CAD.


The importance of physician knowledge of autism spectrum disorder: results of a parent survey.
Early diagnosis and referral to treatment prior to age 3-5 years improves the prognosis of children with Autism Spectrum Disorder (ASD). However, ASD is often not diagnosed until age 3-4 years, and medical providers may lack training to offer caregivers evidence-based treatment recommendations. This study tested hypotheses that 1) children with ASD would be diagnosed between ages 3-4 years (replicating prior work), 2) caregivers would receive little information beyond the diagnosis from their medical providers, and 3) caregivers would turn to other sources, outside of their local health care professionals, to learn more about ASD. 146 ASD caregivers responded to an online survey that consisted of questions about demographics, the diagnostic process, sources of information/support, and the need and availability of local services for ASDs. Hypotheses were tested using descriptives, regression analyses, analyses of variance, and chi-squared. The average age of diagnosis was 4 years, 10 months and the mode was 3 years. While approximately 40% of professionals gave additional information about ASD after diagnosis and 15-34% gave advice on medical/educational programs, only 6% referred to an autism specialist and 18% gave no further information. The diagnosis of Autism was made at earlier ages than Asperger's Disorder or PDD-NOS. Developmental pediatricians (relative to psychiatrists/primary care physicians, neurologists, and psychologists) were associated with the lowest age of diagnosis and were most likely to distribute additional information. Caregivers most often reported turning to the media (i.e., internet, books, videos), conferences, and other parents to learn more about ASD. The average age of ASD diagnosis (4 years, 10 months) was later than optimal if children are to receive the most benefit from early intervention. Most professionals gave caregivers further information about ASDs, especially developmental pediatricians, but a sizeable minority did not. This may reflect a lack of training in the wide range of behaviors that occur across the autism spectrum. Parents turned to outside sources to learn more about ASD. We recommend that all physicians receive specialized training about ASDs to improve upon early screening and diagnosis, and then advise caregivers about empirically-supported services.


Hostile attribution of intent and aggressive behavior: a meta-analysis.
A meta-analytic review was conducted to explain divergent findings on the relation between children's aggressive behavior and hostile attribution of intent to peers. Forty-one studies with 6,017 participants were included in the analysis. Ten studies concerned representative samples from the general population, 24 studies compared nonaggressive to extremely aggressive nonreferred samples, and 7 studies compared nonreferred samples with children referred for aggressive behavior problems. A robust significant association between hostile attribution of intent and aggressive behavior was found. Effect sizes differed considerably between studies. Larger effects were associated with more severe aggressive behavior, rejection by peers as one of the selection criteria, inclusion of 8- to-12-year-old participants, and absence of control for intelligence. Video and picture presentation of stimuli were associated with smaller effect sizes than was audio presentation. Staging of actual social interactions was associated with the largest effects. The importance of understanding moderators of effect size for theory development is stressed.


Evaluation of two enzyme-linked immunosorbent assays for diagnosis of bluetongue virus in wild ruminants.
Bluetongue (BT) is a reportable re-emerging vector-borne disease of animal health concern. Enzyme-linked immunosorbent assays (ELISA) are frequently used in BT surveillance programs in domestic ruminants, but their diagnostic accuracy has not been evaluated for wild ruminants, which can play an important role as natural reservoirs of bluetongue virus (BTV). The aim of this study was to assess two commercial ELISAs for BT diagnosis in wild ruminants using control sera of known BTV infection status and field samples. When control sera were tested, the double recognition ELISA (DR-ELISA) showed 100 % sensitivity (Se) and specificity (Sp), while the competitive ELISA (C-ELISA) had 86.4 % Se and 97.1 % Sp. Using field samples, the selected latent-class analysis model showed 95.7 % Se and 85.9 % Sp for DR-ELISA, 58.2 % Se and 95.8 % Sp for C-ELISA and 84.2 % Se for the serum neutralization test (SNT). Our results indicate that the DR-ELISA may be a useful diagnostic method to assess BTV circulation in endemic areas, while the C-ELISA should be selected when free-areas are surveyed. The discrepancy between control and field samples point out that the inclusion of field samples is required to assess the accuracy of commercial ELISAs for the serological diagnosis of BTV in wild ruminants.


Urinary functional outcomes in female neobladder patients.
The ratio between orthotopic and non-orthotopic diversions in women is far lower than in male patients. Data on urinary function in female patients with neobladders are therefore sparse. We investigated the urinary function of female neobladder patients utilizing the Bladder Cancer Index, a validated and reliable health-related quality-of-life (HRQOL) questionnaire. Furthermore, we tried to identify preoperative factors that may influence functional results. All living female patients with an orthotopic neobladder (N = 82) from the University of Southern California Bladder Cancer Database were sent a questionnaire including the University of Michigan Bladder Cancer Index. Univariate analyses were performed using the Kruskal-Wallis test followed by a multivariate stepwise regression model. Fifty-six patients (68.3%) responded and were included in the analysis. Thirty-five (62.5%) of these patients had to catheterize their neobladder to a certain amount, while 25 patients (44.6%) depend on catheterization to empty their neobladder. Univariate analyses showed that patient age (>65 years) was the only variable associated with a statistically significant lower rate of neobladder catheterization. Better urinary bother scores were associated with organ-confined disease (p = 0.038) and education level (p = 0.01). However, these variables were not significant in a multivariate stepwise linear regression model. Considerably more women require urinary catheterization to void than previously reported. In this study, representing the largest investigated cohort in this topic, we were unable to identify any predictors of this outcome or any other urinary HRQOL in this cohort.


Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model.
Allogeneic hematopoietic cell transplantation (HCT) is widely used to treat patients with life-threatening malignant and nonmalignant hematological diseases. However, allogeneic HCT often is accompanied by severe and lethal complications from graft-versus-host disease (GVHD), in which activated donor T cells recognize histocompatibility antigenic mismatches and cause significant toxicity in the recipient. In the current study, we tested the hypothesis that activation of cannabinoid receptors on donor-derived T cells may prevent GVHD. We tested the effect of Δ(9)-tetrahydrocannabinol (THC) in an acute model of GVHD that was induced by transferring parental C57BL/6 (B6) spleen cells into (C57BL/6 × DBA/2) F(1)(BDF1) mice. Transfer of B6 cells into BDF1 mice produced severe acute GVHD in the recipient, characterized by lymphoid hyperplasia, weight loss, T helper l cytokine production and mortality. THC administration led to early recovery from body weight loss, reduced tissue injury in the liver and intestine, as well as complete survival. THC treatment reduced the expansion of donor-derived effector T cells and blocked the killing of host-derived immune cells while promoting Foxp3(+) regulatory T cells. Impaired hematopoiesis seen during GVHD was rescued by treatment with THC. The ability of THC to reduce the clinical GVHD was reversed, at least in part, by administration of cannabinoid receptor (CB) 1 and CB2 antagonists, thereby demonstrating that THC-mediated amelioration of GVHD was cannabinoid receptor-dependent. Our results demonstrate for the first time that targeting cannabinoid receptors may constitute a novel treatment modality against acute GVHD.


Coma in fatal adult human malaria is not caused by cerebral oedema.
The role of brain oedema in the pathophysiology of cerebral malaria is controversial. Coma associated with severe Plasmodium falciparum malaria is multifactorial, but associated with histological evidence of parasitized erythrocyte sequestration and resultant microvascular congestion in cerebral vessels. To determine whether these changes cause breakdown of the blood-brain barrier and resultant perivascular or parenchymal cerebral oedema, histology, immunohistochemistry and image analysis were used to define the prevalence of histological patterns of oedema and the expression of specific molecular pathways involved in water balance in the brain in adults with fatal falciparum malaria. The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection. The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02). Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.


Effects of subthalamic deep brain stimulation on noun/verb generation and selection from competing alternatives in Parkinson's disease.
Impaired generation of verbs relative to nouns has been reported in Parkinson's disease (PD) and has been associated with the frontal pathophysiology of PD. The aim of the present study was to measure noun/verb generation abilities in PD and to determine whether noun/verb generation is affected by stimulation of the subthalamic nucleus (STN). 8 participants who had been diagnosed with PD and had received surgery for deep brain stimulation (DBS) of the STN as well as 15 control participants completed a noun/verb generation task with four probe-response conditions-namely, noun-noun, verb-noun, noun-verb and verb-verb conditions. Patients with PD were assessed while receiving STN stimulation and without stimulation. During the off stimulation condition, patients with PD presented with a selective deficit in verb generation compared with control participants. However, when receiving STN stimulation, patients with PD produced significantly more errors than controls during the noun-noun and verb-verb conditions, supporting evidence from previous studies that STN stimulation modulates a frontotemporal network associated with word generation. Finally, errors during verb generation were significantly correlated with item selection constraint (ie, the degree to which a response competes with other response alternatives) in the on stimulation condition, but not the off stimulation condition. Our results suggest that STN stimulation affects the ability to select from many competing lexical alternatives during verb generation.


Unique morphology of the human eye and its adaptive meaning: comparative studies on external morphology of the primate eye.
In order to clarify the morphological uniqueness of the human eye and to obtain cues to understanding its adaptive significance, we compared the external morphology of the primate eye by measuring nearly half of all extant primate species. The results clearly showed exceptional features of the human eye: (1) the exposed white sclera is void of any pigmentation, (2) humans possess the largest ratio of exposed sclera in the eye outline, and (3) the eye outline is extraordinarily elongated in the horizontal direction. The close correlation of the parameters reflecting (2) and (3) with habitat type or body size of the species examined suggested that these two features are adaptations for extending the visual field by eyeball movement, especially in the horizontal direction. Comparison of eye coloration and facial coloration around the eye suggested that the dark coloration of exposed sclera of nonhuman primates is an adaptation to camouflage the gaze direction against other individuals and/or predators, and that the white sclera of the human eye is an adaptation to enhance the gaze signal. The uniqueness of human eye morphology among primates illustrates the remarkable difference between human and other primates in the ability to communicate using gaze signals.


Efficacy of calcium formate as a technological feed additive (preservative) for all animal species.
In 2015, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) issued an opinion on the safety and efficacy of ammonium formate, calcium formate and sodium formate when used as a technological additive (preservative) for all animal species. Calcium formate was considered safe for all animal species at a maximum concentration of 10,000 mg formic acid equivalents/kg complete feed (with the exception of pigs, for which a maximum concentration of 12,000 mg formic acid equivalents/kg complete feed was considered safe). Calcium formate was also considered safe for the consumer and the environment. The Panel also concluded that calcium formate is non-irritant to the skin, but mildly irritant to the eyes, and is a respiratory irritant with a potential for sensitisation. The Panel also concluded that 'Calcium formate or solid sodium formate had no discernible effects on microbial numbers in the feed materials examined. The preservative effect of the three formate salts in water for drinking was not demonstrated'. In the current opinion, additional data to demonstrate the efficacy of calcium formate as a preservative in feed for all animal species were assessed. The Panel concluded that calcium formate has the potential to be efficacious as a preservative in feedingstuffs for all animal species at the proposed use level. In the absence of data, the Panel cannot conclude on the efficacy of the use of the additive in water for drinking.


Deciphering moral intuition: How agents, deeds, and consequences influence moral judgment.
Moral evaluations occur quickly following heuristic-like intuitive processes without effortful deliberation. There are several competing explanations for this. The ADC-model predicts that moral judgment consists in concurrent evaluations of three different intuitive components: the character of a person (Agent-component, A); their actions (Deed-component, D); and the consequences brought about in the situation (Consequences-component, C). Thereby, it explains the intuitive appeal of precepts from three dominant moral theories (virtue ethics, deontology, and consequentialism), and flexible yet stable nature of moral judgment. Insistence on single-component explanations has led to many centuries of debate as to which moral precepts and theories best describe (or should guide) moral evaluation. This study consists of two large-scale experiments and provides a first empirical investigation of predictions yielded by the ADC model. We use vignettes describing different moral situations in which all components of the model are varied simultaneously. Experiment 1 (within-subject design) shows that positive descriptions of the A-, D-, and C-components of moral intuition lead to more positive moral judgments in a situation with low-stakes. Also, interaction effects between the components were discovered. Experiment 2 further investigates these results in a between-subject design. We found that the effects of the A-, D-, and C-components vary in strength in a high-stakes situation. Moreover, sex, age, education, and social status had no effects. However, preferences for precepts in certain moral theories (PPIMT) partially moderated the effects of the A- and C-component. Future research on moral intuitions should consider the simultaneous three-component constitution of moral judgment.


Comparison of devices used for stent-assisted coiling of intracranial aneurysms.
Two self-expandable stents, the Neuroform and the Enterprise stent, are widely used for stent-assisted coiling (SAC) of complex shaped intracranial aneurysms. However, comparative knowledge about technical feasibility, peri- and post-procedural morbidity and mortality, packing densities as well as follow-up data is limited. We conducted a retrospective study to investigate differences in aneurysms stented with the Enterprise or Neuroform stents. Angiographic follow-up (mean 19.42 months) was available in 72.6% (61/84) of aneurysms treated with stent-assisted coiling. We further sought to compare stent-assisted coiling to a matched patient population with aneurysms treated by conventional coil embolization. The stenting success rate of the Enterprise was higher compared to the Neuroform stent (46/48 and 42/51, respectively). In 5 of 9 cases in which the Neuroform stent was not navigable to the landing zone, we successfully deployed an Enterprise stent instead. Eventually, 42 aneurysms were coiled after stenting in each group. We observed no significant differences in peri-procedural complication rate, post-procedural hospital stay, packing density, recurrence rate or number of in-stent stenosis. Strikingly, 36.1% of followed aneurysms in the SAC group showed progressive occlusion on angiographic follow-up imaging. The packing density was significantly higher in aneurysms treated by SAC as compared to conventionally coiled aneurysms, while recanalization rate was significantly lower in the SAC group. The procedural success rate is higher using the Enterprise, but otherwise both stents exhibited similar characteristics. Lower recurrence frequency and complication rates comparable to conventional coil embolization emphasize the importance of stent-assisted coiling in the treatment of complex aneurysms. Progressive occlusion on angiographic follow-up was a distinct and frequent observation in the SAC group and may in part be due to flow diversion.


Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development.
The polarising region expresses the signalling molecule sonic hedgehog (Shh), and is an embryonic signalling centre essential for outgrowth and patterning of the vertebrate limb. Previous work has suggested that there is a buffering mechanism that regulates polarising activity. Little is known about how the number of Shh-expressing cells is controlled but, paradoxically, the polarising region appears to overlap with the posterior necrotic zone, a region of programmed cell death. We have investigated how Shh expression and cell death respond when levels of polarising activity are altered, and show an autoregulatory effect of Shh on Shh expression and that Shh affects cell death in the posterior necrotic zone. When we increased Shh signalling, by grafting polarising region cells or applying Shh protein beads, this led to a reduction in the endogenous Shh domain and an increase in posterior cell death. In contrast, cells in other necrotic regions of the limb bud, including the interdigital areas, were rescued from death by Shh protein. Application of Shh protein to late limb buds also caused alterations in digit morphogenesis. When we reduced the number of Shh-expressing cells in the polarising region by surgery or drug-induced killing, this led to an expansion of the Shh domain and a decrease in the number of dead cells. Furthermore, direct prevention of cell death using a retroviral vector expressing Bcl2 led to an increase in Shh expression. Finally, we provide evidence that the fate of some of the Shh-expressing cells in the polarising region is to undergo apoptosis and contribute to the posterior necrotic zone during normal limb development. Taken together, these results show that there is a buffering system that regulates the number of Shh-expressing cells and thus polarising activity during limb development. They also suggest that cell death induced by Shh could be the cellular mechanism involved. Such an autoregulatory process based on cell death could represent a general way for regulating patterning signals in embryos.


Reproducibility and relative validity of food group intake in a food frequency questionnaire developed for the Tehran Lipid and Glucose Study.
To examine the validity and reproducibility of food groups in the semi-quantitative food frequency questionnaire (FFQ) developed for the Tehran Lipid and Glucose Study (TLGS). To evaluate the reproducibility of food groups included in the FFQ, 132 subjects (61 men and 71 women) aged 20 years or older twice completed a 168-item FFQ (FFQ1, FFQ2), with a 14-month interval between FFQ1 and FFQ2. Over the 1-year interval, 12 dietary recalls (DRs) were collected (1 each month) to assess the validity of the FFQ. Seventeen food groups were derived from the FFQ based on methods described in previous studies. Age-adjusted and deattenuated Spearman correlation coefficients were used to assess the validity of the FFQ. The mean (SD) age and body mass index of subjects were 35.5 (16.8) years and 25.5 (5.2) kg/m(2), respectively. Validity correlation coefficients ranged from 0.03 (liquid oil) to 0.77 (simple sugars) in men (median, 0.44), and from 0.12 (snacks) to 0.79 (simple sugars) in women (median, 0.37). The energy-adjusted intraclass correlation coefficient, which reflects the reproducibility of the FFQ, was 0.51 in men and was highest for tea and coffee (0.91); in women it was 0.59 and was highest for simple sugars (0.74). The highest percentage of complete agreement and disagreement was observed for snacks and desserts (60.6%) and potatoes and dairy products (12.8%), respectively, in men, and tea and coffee (62.9%) and legumes (15.7%) in women. The FFQ that was designed for the TLGS was found to be reliable and valid for assessing the intake of several food groups.


Temporally Dissociable Contributions of Human Medial Prefrontal Subregions to Reward-Guided Learning.
In decision making, dorsal and ventral medial prefrontal cortex show a sensitivity to key decision variables, such as reward prediction errors. It is unclear whether these signals reflect parallel processing of a common synchronous input to both regions, for example from mesocortical dopamine, or separate and consecutive stages in reward processing. These two perspectives make distinct predictions about the relative timing of feedback-related activity in each of these regions, a question we address here. To reconstruct the unique temporal contribution of dorsomedial (dmPFC) and ventromedial prefrontal cortex (vmPFC) to simultaneously measured EEG activity in human subjects, we developed a novel trialwise fMRI-informed EEG analysis that allows dissociating correlated and overlapping sources. We show that vmPFC uniquely contributes a sustained activation profile shortly after outcome presentation, whereas dmPFC contributes a later and more peaked activation pattern. This temporal dissociation is expressed mainly in the alpha band for a vmPFC signal, which contrasts with a theta based dmPFC signal. Thus, our data show reward-related vmPFC and dmPFC responses have distinct time courses and unique spectral profiles, findings that support distinct functional roles in a reward-processing network. Multiple subregions of the medial prefrontal cortex are known to be involved in decision making and learning, and expose similar response patterns in fMRI. Here, we used a novel approach to analyzing simultaneous EEG-fMRI that allows to dissociate the individual time courses of brain regions. We find that vmPFC and dmPFC have distinguishable time courses and time-frequency patterns.


Validation of an a priori, index model of successful aging in a population-based cohort study: the successful aging index.
Many definitions of successful aging (SA) exist in the absence of an established consensus definition. There are few examples of a priori application of SA models in real world contexts using external validation procedures. The current study aims to establish the predictive validity of an a priori, continuous model of SA with respect to service utilization. Individuals (n = 740; 64.2% female) aged 65 years and over (mean 75.9; SD 6.2), randomly selected from general practitioner registries in five sites across the United Kingdom included in the second and third combined screen and assessment waves of the Medical Research Council Cognitive Function and Aging Study (MRC CFAS; a longitudinal population-based cohort study) comprised the baseline and two-year follow-up in the current study. A Successful Aging Index (SAI) was created using items identified by systematic reviews of operational definitions and lay perspectives of SA, capturing physiological and psychosocial components. Demographic data and SAI components were collected at baseline. Outcome measures, i.e. health service use, informal care use, and functional service, were captured at two years follow-up. Logistic regression revealed significant relationships between the SAI and six of eight service use outcomes in models adjusted for age, sex, education, and socio-economic status. Analysis of the area under the receiver operating characteristic (ROC) curve demonstrated sufficient predictive capabilities for all models, (range 0.65-0.86). The SAI demonstrated a strong association, and predictive accuracy, with respect to service use, providing preliminary support for the practical utility and usefulness of this measure.