Washing away your sins in the brain: physical cleaning and priming of cleaning recruit different brain networks after moral threat.
The association between moral purity and physical cleanliness has been widely discussed recently. Studies found that moral threat initiates the need of physical cleanliness, but actual physical cleaning and priming of cleaning have inconsistent effects on subsequent attitudes and behaviors. Here, we used resting-state functional magnetic resonance imaging to explore the underlying neural mechanism of actual physical cleaning and priming of cleaning. After recalling moral transgression with strong feelings of guilt and shame, participants either actually cleaned their faces with a wipe or were primed with cleanliness through viewing its pictures. Results showed that actual physical cleaning reduced the spontaneous brain activities in the right insula and MPFC, regions that involved in embodied moral emotion processing, while priming of cleaning decreased activities in the right superior frontal gyrus and middle frontal gyrus, regions that participated in executive control processing. Additionally, actual physical cleaning also changed functional connectivity between insula/MPFC and emotion related regions, whereas priming of cleaning modified connectivity within both moral and sensorimotor areas. These findings revealed that actual physical cleaning and priming of cleaning led to changes in different brain regions and networks, providing neural evidence for the inconsistent effects of cleanliness on subsequent attitudes and behaviors.


Evaluation of the expression of the oncogen C-ERBB-2/HER2 in advanced gastric cancer cases from Costa Rica.
The prevalence of gastric cancer (GC) with increased expression of the HER2 oncoprotein shows important variations worldwide. Incidence and mortality rates of GC in Costa Rica are among the highest in Latin America and the world; however, the prevalence of HER2-positive cases in this country is unknown. Evaluation of this parameter is important to decide the therapeutic approach for GC patients. The aim of this study was to provide an estimation of the prevalence of GC patients overexpressing the HER2 oncogene in Costa Rica. The investigation was carried out in two phases. The first one consisted of a retrospective review of 331 clinical records of patients diagnosed with advanced or metastatic GC from January 2010 to January 2012 in four hospitals in Costa Rica. In the second phase, immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) analyses were performed in formalin-fixed and paraffin-embedded (FFPE) surgical samples from 50 patients diagnosed with GC between 2012 and 2015. Of the 331 clinical files reviewed, the assessment of HER2 status was carried out in 62 patients (18.7%), of which only five (8%) were HER2-positive. In the 50 surgical specimens in which IHC and FISH analyses were performed, two of them (4%) presented overexpression and amplification of the HER2 oncogene. This study suggests that the prevalence of GC cases overexpressing the HER2 oncogene in Costa Rica is less than 8%. This is the first attempt ever undertaken to estimate the prevalence of HER2-positivity in GC in Costa Rica.


Brains at necropsy: to fix or not to fix?
To investigate whether routine formalin fixation of all brains coming to necropsy increases the rate of detection of brain abnormalities relative to either selective formalin fixation of brain tissue or fresh dissection of all brain tissue at the time of post mortem examination. A retrospective study of 300 medicolegal necropsies was performed. One hundred cases were examined by doctors with little or no formal training in necropsy pathology. One hundred cases were examined by forensic pathologists, who used their discretion as to whether to fix the brain in formalin. A further 100 cases were examined by neuropathologists; all the brains had already been fixed at the time of necropsy. When examined by doctors with little or no formal necropsy pathology training, only 15% of brains were found to be abnormal. In the case of selective fixation, 33% were found to be abnormal. When there was obligatory fixation of all brains, 51% of all brains were found to be abnormal. It is concluded that formalin fixation of the whole brain at the time of necropsy, followed by detailed examination of the brain by a neuropathologist, significantly increases the detection rate of brain pathology at necropsy.


The gut microbiota and lipid metabolism: implications for human health and coronary heart disease.
Coronary heart disease (CHD) is the leading cause of mortality in Western societies, affecting about one third of the population before their seventieth year. Over the past decades modifiable risk factors of CHD have been identified, including smoking and diet. These factors when altered can have a significant impact on an individuals' risk of developing CHD, their overall health and quality of life. There is strong evidence suggesting that dietary intake of plant foods rich in fibre and polyphenolic compounds, effectively lowers the risk of developing CHD. However, the efficacy of these foods often appears to be greater than the sum of their recognised biologically active parts. Here we discuss the hypothesis that beneficial metabolic and vascular effects of dietary fibre and plant polyphenols are due to an up regulation of the colon-systemic metabolic axis by these compounds. Fibres and many polyphenols are converted into biologically active compounds by the colonic microbiota. This microbiota imparts great metabolic versatility and dynamism, with many of their reductive or hydrolytic activities appearing complementary to oxidative or conjugative human metabolism. Understanding these microbial activities is central to determining the role of different dietary components in preventing or beneficially impacting on the impaired lipid metabolism and vascular dysfunction that typifies CHD and type II diabetes. This approach lays the foundation for rational selection of health promoting foods, rational target driven design of functional foods, and provides an essential thus-far, overlooked, dynamic to our understanding of how foods recognised as "healthy" impact on the human metabonome.


Sparse Epistatic Patterns in the Evolution of Terpene Synthases.
We explore sequence determinants of enzyme activity and specificity in a major enzyme family of terpene synthases. Most enzymes in this family catalyze reactions that produce cyclic terpenes-complex hydrocarbons widely used by plants and insects in diverse biological processes such as defense, communication, and symbiosis. To analyze the molecular mechanisms of emergence of terpene cyclization, we have carried out in-depth examination of mutational space around (E)-β-farnesene synthase, an Artemisia annua enzyme which catalyzes production of a linear hydrocarbon chain. Each mutant enzyme in our synthetic libraries was characterized biochemically, and the resulting reaction rate data were used as input to the Michaelis-Menten model of enzyme kinetics, in which free energies were represented as sums of one-amino-acid contributions and two-amino-acid couplings. Our model predicts measured reaction rates with high accuracy and yields free energy landscapes characterized by relatively few coupling terms. As a result, the Michaelis-Menten free energy landscapes have simple, interpretable structure and exhibit little epistasis. We have also developed biophysical fitness models based on the assumption that highly fit enzymes have evolved to maximize the output of correct products, such as cyclic products or a specific product of interest, while minimizing the output of byproducts. This approach results in nonlinear fitness landscapes that are considerably more epistatic. Overall, our experimental and computational framework provides focused characterization of evolutionary emergence of novel enzymatic functions in the context of microevolutionary exploration of sequence space around naturally occurring enzymes.


Soft-tissue sarcomas in the head and neck: 25 years of experience.
Sarcomas are infrequent and heterogeneous tumours. They represent 1-2% of all malignant neoplasms in adults and between 4% and 10% of head and neck cancers. The research was retrospective, descriptive, and cross-sectional. A study population of 62 patients with a mean age of 44 years was obtained; the most frequent location was the soft tissues of the neck (25.3%) and the mean tumour size was 7.1 cm; the most frequent diagnosis was undifferentiated pleomorphic sarcoma (25.5%) and the majority were stage III (41.4%). The lowest survival rates were associated with T2a and T2b tumours (p = 0.014), the presence of lymph node metastasis (p = 0.001), advanced stages (p = 0.003), and invasion of bone, blood vessels and/or nerves (p = 0.008). Late diagnosis is the main factor associated with decreased survival in patients with head and neck sarcomas.


NASA multipurpose airborne DIAL system and measurements of ozone and aerosol profiles.
An airborne differential absorption lidar (DIAL) system has been developed for the remote measurement of gas and aerosol profiles in the troposphere and lower stratosphere. The multipurpose DIAL system can operate from 280 to 1064 nm for measurements of ozone, sulfur dioxide, nitrogen dioxide, water vapor, temperature,pressure, and aerosol backscattering. The laser transmitter consists of two narrow linewidth Nd: YAG pumped dye lasers with automatic wavelength control. The DIAL wavelengths are transmitted with a 00-,usec temporal separation to reduce receiver system complexity. A coaxial receiver system is used to collect and optically separate the DIAL and aerosol lidar returns. Photomultiplier tubes detect the backscattered laser returns after optical filtering, and the analog signals from three tubes are digitized and stored on high-speed magnetic tape. Real-time gas concentration profiles or aerosol backscatter distributions are calculated and displayed for experiment control. Operational parameters for the airborne DIAL system are presented for measurements of ozone, water vapor, and aerosols in the 290-, 720-, and 600-nm wavelength regions, respectively. The first ozone profile measurements from an aircraft using the DIAL technique are discussed in this paper. Comparisons between DIAL and in situ ozone measurements show agreement to within +/-5 ppbv in the lower troposphere. Lidar aerosol data obtained simultaneously with DIAL ozone measurements are presented for a flight over Virginia and the Chesapeake Bay. DIAL system performance for profiling ozone in a tropopause folding experiment is evaluated, and the applications of the DIAL system to regional and global-scale tropospheric investigations are discussed.


Mito-nuclear discord in six congeneric lineages of Holarctic ducks (genus Anas).
Many species have Holarctic distributions that extend across Europe, Asia and North America. Most genetics research on these species has examined only mitochondrial (mt) DNA, which has revealed wide variance in divergence between Old World (OW) and New World (NW) populations, ranging from shallow, unstructured genealogies to deeply divergent lineages. In this study, we sequenced 20 nuclear introns to test for concordant patterns of OW-NW differentiation between mtDNA and nuclear (nu) DNA for six lineages of Holarctic ducks (genus Anas). Genetic differentiation for both marker types varied widely among these lineages (idiosyncratic population histories), but mtDNA and nuDNA divergence within lineages was not significantly correlated. Moreover, compared with the association between mtDNA and nuDNA divergence observed among different species, OW-NW nuDNA differentiation was generally lower than mtDNA divergence, at least for lineages with deeply divergent mtDNA. Furthermore, coalescent estimates indicated significantly higher rates of gene flow for nuDNA than mtDNA for four of the six lineages. Thus, Holarctic ducks show prominent mito-nuclear discord between OW and NW populations, and we reject differences in sorting rates as the sole cause of the within-species discord. Male-mediated intercontinental gene flow is likely a leading contributor to this discord, although selection could also cause increased mtDNA divergence relative to weak nuDNA differentiation. The population genetics of these ducks contribute to growing evidence that mtDNA can be an unreliable indicator of stage of speciation and that more holistic approaches are needed for species delimitation.


A high density physical map of chromosome 1BL supports evolutionary studies, map-based cloning and sequencing in wheat.
As for other major crops, achieving a complete wheat genome sequence is essential for the application of genomics to breeding new and improved varieties. To overcome the complexities of the large, highly repetitive and hexaploid wheat genome, the International Wheat Genome Sequencing Consortium established a chromosome-based strategy that was validated by the construction of the physical map of chromosome 3B. Here, we present improved strategies for the construction of highly integrated and ordered wheat physical maps, using chromosome 1BL as a template, and illustrate their potential for evolutionary studies and map-based cloning. Using a combination of novel high throughput marker assays and an assembly program, we developed a high quality physical map representing 93% of wheat chromosome 1BL, anchored and ordered with 5,489 markers including 1,161 genes. Analysis of the gene space organization and evolution revealed that gene distribution and conservation along the chromosome results from the superimposition of the ancestral grass and recent wheat evolutionary patterns, leading to a peak of synteny in the central part of the chromosome arm and an increased density of non-collinear genes towards the telomere. With a density of about 11 markers per Mb, the 1BL physical map provides 916 markers, including 193 genes, for fine mapping the 40 QTLs mapped on this chromosome. Here, we demonstrate that high marker density physical maps can be developed in complex genomes such as wheat to accelerate map-based cloning, gain new insights into genome evolution, and provide a foundation for reference sequencing.


Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy.
See Lenck-Santini (doi:10.1093/awx205) for a scientific commentary on this article. Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast-spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy.


Influence of plants on the reduction of hexavalent chromium in wetland sediments.
This work addresses the effect that plants (Typha latifolia and Carex lurida) have on the reduction of Cr(VI) in wetland sediments. Experiments were carried out using tubular microcosms, where chemical species were monitored along the longitudinal flow axis. Cr(VI) removal was enhanced by the presence of plants. This is explained by a decrease in the redox potential promoted by organic root exudates released by plants. Under these conditions sulfate reduction is enhanced, increasing the concentration of sulfide species in the sediment pore water, which reduce Cr(VI). Evapotranspiration induced by plants also contributed to enhance the reduction of Cr(VI) by concentrating all chemical species in the sediment pore water. Both exudates release and evapotranspiration have a diurnal component that affects Cr(VI) reduction. Concentration profiles were fitted to a kinetic model linking sulfide and Cr(VI) concentrations corrected for evapotranspiration. This expression captures both the longitudinal as well as the diurnal Cr(VI) concentration profiles.


Composition profiling of seized ecstasy tablets by Raman spectroscopy.
Raman spectroscopy with far-red excitation has been investigated as a simple and rapid technique for composition profiling of seized ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine) tablets. The spectra obtained are rich in vibrational bands and allow the active drug and excipient used to bulk the tablets to be identified. Relative band heights can be used to determine drug/excipient ratios and the degree of hydration of the drug while the fact that 50 tablets per hour can be analysed allows large numbers of spectra to be recorded. The ability of Raman spectroscopy to distinguish between ecstasy tablets on the basis of their chemical composition is illustrated here by a sample set of 400 tablets taken from a large seizure of > 50,000 tablets that were found in eight large bags. The tablets are all similar in appearance and carry the same logo. Conventional analysis by GC-MS showed they contained MDMA. Initial Raman studies of samples from each of the eight bags showed that despite some tablet-to-tablet variation within each bag the contents could be classified on the basis of the excipients used. The tablets in five of the bags were sorbitol-based, two were cellulose-based and one bag contained tablets with a glucose excipient. More extensive analysis of 50 tablets from each of a representative series of sample bags have distribution profiles that showed the contents of each bag were approximately normally distributed about a mean value, rather than being mixtures of several discrete types. Two of the sorbitol-containing sample sets were indistinguishable while a third was similar but not identical to these, in that it contained the same excipient and MDMA with the same degree of hydration but had a slightly different MDMA/sorbitol ratio. The cellulose-based samples were badly manufactured and showed considerable tablet-to-tablet variation in their drug/excipient ratio while the glucose-based tablets had a tight distribution in their drug/excipient ratios. The degree of hydration in the MDMA feedstocks used to manufacture the cellulose-, glucose- and sorbitol-based tablets were all different from each other. This study, because it centres on a single seizure of physically similar tablets with the same active drug, highlights the fact that simple physical descriptions coupled with active drug content do not in themselves fully characterize the nature of the seized materials. There is considerable variation in the composition of the tablets within this single seizure and the fact that this variation can be detected from Raman spectra demonstrates that the potential benefits of obtaining highly detailed spectra can indeed translate into information that is not readily available from other methods but would be useful for tracing of drug distribution networks.


Molecular and epidemiological characterization of carbapenemase-producing Enterobacteriaceae in Norway, 2007 to 2014.
The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) is increasing worldwide. Here we present associated patient data and molecular, epidemiological and phenotypic characteristics of all CPE isolates in Norway from 2007 to 2014 confirmed at the Norwegian National Advisory Unit on Detection of Antimicrobial Resistance. All confirmed CPE isolates were characterized pheno- and genotypically, including by whole genome sequencing (WGS). Patient data were reviewed retrospectively. In total 59 CPE isolates were identified from 53 patients. Urine was the dominant clinical sample source (37%) and only 15% of the isolates were obtained from faecal screening. The majority of cases (62%) were directly associated with travel or hospitalization abroad, but both intra-hospital transmission and one inter-hospital outbreak were observed. The number of CPE cases/year was low (2-14 cases/year), but an increasing trend was observed. Klebsiella spp. (n = 38) and E. coli (n = 14) were the dominant species and blaKPC (n = 20), blaNDM (n = 19), blaOXA-48-like (n = 12) and blaVIM (n = 7) were the dominant carbapenemase gene families. The CPE isolates were genetically diverse except for K. pneumoniae where clonal group 258 associated with blaKPC dominated. All isolates were multidrug-resistant and a significant proportion (21%) were resistant to colistin. Interestingly, all blaOXA-48-like, and a large proportion of blaNDM-positive Klebsiella spp. (89%) and E. coli (83%) isolates were susceptible in vitro to mecillinam. Thus, mecillinam could have a role in the treatment of uncomplicated urinary tract infections caused by OXA-48- or NDM-producing E. coli or K. pneumoniae. In conclusion, the impact of CPE in Norway is still limited and mainly associated with travel abroad, reflected in the diversity of clones and carbapenemase genes.


Properties of mouse and human IgG receptors and their contribution to disease models.
Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcγRIII and FcγRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcγRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock.


Intense pulsed light.
In addition to lasers, intense pulsed light (IPL) sources are widely used in medicine to treat various indications, such as vascular lesions, irregular pigmentation and hypertrichosis. In contrast to lasers, IPL systems are broadband flash lamps that emit polychromatic incoherent light ranging from visible to infrared (500-1,300 nm). Optical filters are used to tailor the polychromatic light to specific needs. As a broad range of wavelengths are delivered, treatment of multiple chromophores--including melanin, hemoglobin, water and collagen--within the same exposure is possible.


An enhancer-titration effect induces digit-specific regulatory alleles of the HoxD cluster.
Mice carrying transgenes targeted upstream the HoxD cluster display abnormal digits, with alterations resembling those obtained with loss of functions of Hoxd genes. Because the HoxD cluster remained entirely untouched by the insertional events, we investigated whether these phenotypes were induced by regulatory modifications at a distance. We report here that these targeted relocations behaved as hypomorphic alleles of the distantly located gene Hoxd13 and showed that posterior Hoxd genes located in cis with the integration site were down-regulated. Genetic analyses suggested that this down-regulation resulted from the titration of the activity of a remote located enhancer sequence. These results indicate that the transcriptional efficiency of Hoxd genes in digits could be modulated by the presence of other, unrelated, promoters, within the regulatory landscape of this enhancer. Modifications in these latter transcription units may thus impact upon digit morphology, through misregulation of Hoxd genes, thus illustrating the "buffering effect" that such a global regulatory element can exert upon a short genomic interval.


A comparative study of different machine learning methods on microarray gene expression data.
Several classification and feature selection methods have been studied for the identification of differentially expressed genes in microarray data. Classification methods such as SVM, RBF Neural Nets, MLP Neural Nets, Bayesian, Decision Tree and Random Forrest methods have been used in recent studies. The accuracy of these methods has been calculated with validation methods such as v-fold validation. However there is lack of comparison between these methods to find a better framework for classification, clustering and analysis of microarray gene expression results. In this study, we compared the efficiency of the classification methods including; SVM, RBF Neural Nets, MLP Neural Nets, Bayesian, Decision Tree and Random Forrest methods. The v-fold cross validation was used to calculate the accuracy of the classifiers. Some of the common clustering methods including K-means, DBC, and EM clustering were applied to the datasets and the efficiency of these methods have been analysed. Further the efficiency of the feature selection methods including support vector machine recursive feature elimination (SVM-RFE), Chi Squared, and CSF were compared. In each case these methods were applied to eight different binary (two class) microarray datasets. We evaluated the class prediction efficiency of each gene list in training and test cross-validation using supervised classifiers. We presented a study in which we compared some of the common used classification, clustering, and feature selection methods. We applied these methods to eight publicly available datasets, and compared how these methods performed in class prediction of test datasets. We reported that the choice of feature selection methods, the number of genes in the gene list, the number of cases (samples) substantially influence classification success. Based on features chosen by these methods, error rates and accuracy of several classification algorithms were obtained. Results revealed the importance of feature selection in accurately classifying new samples and how an integrated feature selection and classification algorithm is performing and is capable of identifying significant genes.


Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia.
Amiodarone (AMD) and nifekalant (NIF) are used in the treatment of ventricular fibrillation or tachycardia; however, only few studies have been conducted on their efficacies. Therefore, a meta-analysis was conducted. Relevant sources were identified from PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi. The outcomes were short-term and long-term survival in patients with shock-resistant ventricular fibrillation /pulseless ventricular tachycardia. Thirty-three studies were analysed. The results showed that, compared to the control treatment, AMD did not improve short-term survival (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.91-1.71) or long-term survival (OR: 1.00, 95% CI: 0.63-1.57). However, compared to the control treatment, NIF significantly improved short-term survival (OR: 3.23, 95% CI: 2.21-4.72) and long-term survival (OR: 1.88, 95% CI: 1.36-2.59). No significant difference was observed in short-term survival (OR: 0.85, 95% CI: 0.63-1.15) or long-term survival (OR: 1.25, 95% CI: 0.67-2.31) between AMD- and NIF-treated patients. The results suggest that NIF is beneficial for short-term and long-term survival in shock-resistant ventricular fibrillation/pulseless ventricular tachycardia; however, the efficacy of AMD in either outcome is not clear.


Assessment of the intraocular pressure-lowering activity of bicyclic derivatives of 1-substituted benzyloctahydroisoquinoline.
In our study of IOP-lowering agents, we have synthesized several bicyclic analogs of 1-benzyloctahydroisoquinoline. The target molecules were synthesized in an eleven-step process. Structures were proved through spectrometry, elemental analysis and, in selected cases, high resolution mass spectrometry. The final products were secondary or tertiary amines containing a 1-benzyl moiety substituted at the p-position with a methoxy, methyl or chloro group. All target molecules were analyzed in 1% solution in distilled water in normotensive rabbits. After topical administration, IOP was monitored in both eyes for up to seven hours. The 1-p-methoxybenzyl molecule 2 was the most active, and caused a maximal IOP drop of 8.8 +/- 1.9 (n = 7) mm Hg in the ipsilateral eye at 4 hours post-administration, with only partial recovery at seven hours. All other compounds tested either showed very weak activity (3-6) or were inactive (1). All compounds produced a contralateral effect, and 5 induced rebound ocular hypertension. We conclude that selected tertiary bicyclic 1-p-methoxybenzyl-octahydroisoquinolines, particularly N-methylated structures, exhibit a significant IOP-lowering effect in normotensive rabbits.


Psychophysical evidence for auditory motion parallax.
Distance is important: From an ecological perspective, knowledge about the distance to either prey or predator is vital. However, the distance of an unknown sound source is particularly difficult to assess, especially in anechoic environments. In vision, changes in perspective resulting from observer motion produce a reliable, consistent, and unambiguous impression of depth known as motion parallax. Here we demonstrate with formal psychophysics that humans can exploit auditory motion parallax, i.e., the change in the dynamic binaural cues elicited by self-motion, to assess the relative depths of two sound sources. Our data show that sensitivity to relative depth is best when subjects move actively; performance deteriorates when subjects are moved by a motion platform or when the sound sources themselves move. This is true even though the dynamic binaural cues elicited by these three types of motion are identical. Our data demonstrate a perceptual strategy to segregate intermittent sound sources in depth and highlight the tight interaction between self-motion and binaural processing that allows assessment of the spatial layout of complex acoustic scenes.


Imaging seizure-induced inflammation using an antibody targeted iron oxide contrast agent.
Early inflammation following status epilepticus has been implicated in the development of epilepsy and the evolution of brain injury, yet its precise role remains unclear. The development of non-invasive imaging markers of inflammation would enable researchers to test this hypothesis in vivo and study its temporal progression in relation to epileptogenic insults. In this study we have investigated the potential of a targeted magnetic resonance imaging contrast agent--vascular cell adhesion molecule 1 antibody labelled iron oxide--to image the inflammatory process following status epilepticus in the rat lithium-pilocarpine model. Intravascular administration of the targeted contrast agent was performed at approximately 1 day following status epilepticus. The control group received diazepam prior to pilocarpine to prevent status epilepticus. Magnetic resonance imaging of rats was performed before and after contrast administration. Comparison with quantitative T₂ measurements was also performed. At the end of the study, brains were removed for ex vivo magnetic resonance imaging and histology. Marked focal hypointensities caused by contrast agent binding were observed on in vivo magnetic resonance images in the post status epilepticus group. In particular these occurred in the periventricular organs, the hippocampus and the cerebral cortex. Relatively little contrast agent binding was observed in the control group. T₂ relaxation times were not significantly increased for the hippocampus or the cerebral cortex in post status epilepticus animals. These results demonstrate the feasibility of in vivo imaging of seizure-induced inflammation in an animal model of epilepsy. The antibody targeted MRI contrast agent identified regions of acute inflammation following status epilepticus and may provide an early marker of brain injury. This technique could be used to determine the role of inflammation in models of epileptogenesis and to study the potential for anti-inflammatory therapeutic interventions.


Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours.
The poor blood supply to solid tumours introduces many factors that affect the outcome of chemotherapy, one of which is the problem of drug delivery to poorly vascularized regions of tumours. Whereas poor drug penetration has been recognized as a contributing factor to the poor response of many solid tumours, the question of drug penetration through multicell layers has not been thoroughly addressed, largely because of restrictions imposed upon these studies by the requirement for either radiolabelled or naturally fluorescent compounds. The aim of this study is to describe modifications made to a recently published assay that broadens the scope for assessing drug penetration during the early stages of drug development and to characterize the ability of various drugs to penetrate multicell layers. DLD-1 human colon carcinoma cells were cultured on Transwell-COL plastic inserts placed into 24-well culture plates so that a top and bottom chamber were established, the two chambers being separated by a microporous membrane. Drugs were added to the top chamber at doses equivalent to peak plasma concentrations in vivo and the rate of appearance of drugs in the bottom chamber determined by high-performance liquid chromatography (HPLC). Both 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) and 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (NITP) rapidly penetrated DLD-1 multicell layers (50.9 +/- 12.1 microm thick) with t(1/2) values of 1.36 and 2.38 h respectively, whereas the rate of penetration of 5-aziridino-3-hydroxymethyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol (EO9) and doxorubicin through multicell layers was significantly slower (t(1/2) = 4.62 and 13.1 h respectively). Inclusion of dicoumarol increases the rate of EO9 penetration, whereas reducing the oxygen tension to 5% causes a reduction in tirapazamine penetration through multicell layers, suggesting that the extent of drug metabolism is one factor that determines the rate at which drugs penetrate multicell layers. The fact that EO9 does not readily penetrate a multicell layer, in conjunction with its rapid elimination in vivo (t(1/2) < 10 min), suggests that EO9 is unlikely to penetrate more than a few microm from a blood vessel within its pharmacokinetic lifespan. These results suggest that the failure of EO9 in the clinic is due to a combination of poor drug penetration and rapid elimination in vivo.


Distribution of GABAergic synapses and their targets in the dentate gyrus of rat: a quantitative immunoelectron microscopic analysis.
The dentate gyrus has been shown to receive a laminated and target selective GABAergic input (Han et al., 1993; Halasy and Somogyi, 1993), but the numerical parameters of this innervation are not known. In order to establish the relative weight of GABAergic inputs to the dendritic versus somatic regions of granule cells the numerical density and proportion of GABA-immunopositive and immunonegative synaptic boutons and their postsynaptic targets were determined in the molecular and granule cell layers of the dentate gyrus using the postembedding immunogold method. The granule cell layer contained 9% of all synapses with the remaining 91% being in the molecular layer. Altogether 17% of all synaptic boutons were GABA-immunoreactive, and they formed either type 1 or type 2 synaptic junctions. About 88% of synaptic boutons in the granule cell layer and 7-8% in the molecular layer were GABA-positive. However, the numerical density (number of synapses per unit volume) of GABA-immunoreactive type 2 synapses was calculated to be only slightly less in the molecular layer than in the granule cell layer (100 x 10(6)/mm3 tissue in the granule cell layer and about 86 x 10(6)/mm3 in the molecular layer). In addition, GABA-positive type 1 synapses were found in lower number at the border region of the two layers. The mean volume of the molecular layer of the dentate gyrus in the Wistar rat was calculated to be nearly 4 times larger than the volume of the granule cell layer (West and Andersen, 1980). This means that 25-26% of all GABAergic type 2 synapses are located in the granule cell layer, and 74-75% in the molecular layer. The mean postsynaptic targets of the GABA-immunoreactive boutons in the granule cell layer were granule cell somata (46-60%), followed by dendritic shafts (26-29%), spines (up to 14%), and axon initial segments (7-9%). In the molecular layer the dominant postsynaptic targets of GABAergic synapses were dendritic shafts (63-72%), followed by dendritic spines (26-37%). About 2-3% of the targets of all GABA-immunoreactive synapses were GABA-immunoreactive dendritic shafts or somata. Up to 98% of all GABA-immunonegative synaptic boutons were found in the molecular layer, most of them terminating on dendritic spines. These results show that the dendritic region of the granule cells provides sites for GABAergic inhibition which in quantitative terms highly outnumber the somatic region in the dentate gyrus.


Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network.
Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.


From morphology to neural information: the electric sense of the skate.
Morphology typically enhances the fidelity of sensory systems. Sharks, skates, and rays have a well-developed electrosense that presents strikingly unique morphologies. Here, we model the dynamics of the peripheral electrosensory system of the skate, a dorsally flattened batoid, moving near an electric dipole source (e.g., a prey organism). We compute the coincident electric signals that develop across an array of the skate's electrosensors, using electrodynamics married to precise morphological measurements of sensor location, infrastructure, and vector projection. Our results demonstrate that skate morphology enhances electrosensory information. Not only could the skate locate prey using a simple population vector algorithm, but its morphology also specifically leads to quick shifts in firing rates that are well-suited to the demonstrated bandwidth of the electrosensory system. Finally, we propose electrophysiology trials to test the modeling scheme.


EEG Microstates Indicate Heightened Somatic Awareness in Insomnia: Toward Objective Assessment of Subjective Mental Content.
People with Insomnia Disorder (ID) not only experience abundant nocturnal mentation, but also report altered spontaneous mental content during daytime wakefulness, such as an increase in bodily experiences (heightened somatic awareness). Previous studies have shown that resting-state EEG can be temporally partitioned into quasi-stable microstates, and that these microstates form a small number of canonical classes that are consistent across people. Furthermore, the microstate classes have been associated with individual differences in resting mental content including somatic awareness. To address the hypothesis that altered resting mental content in ID would be reflected in an altered representation of the corresponding EEG microstates, we analyzed resting-state high-density EEG of 32 people with ID and 32 age- and sex-matched controls assessed during 5-min eyes-closed wakefulness. Using data-driven topographical k-means clustering, we found that 5 microstate classes optimally explained the EEG scalp voltage map sequences across participants. For each microstate class, 3 dynamic features were obtained: mean duration, frequency of occurrence, and proportional coverage time. People with ID had a shorter mean duration of class C microstates, and more frequent occurrence of class D microstates. The finding is consistent with previously established associations of these microstate properties with somatic awareness, and increased somatic awareness in ID. EEG microstate assessment could provide objective markers of subjective experience dimensions in studies on consciousness during the transition between wake and sleep, when self-report is not possible because it would interfere with the very process under study. Addressing somatic awareness may benefit psychotherapeutic treatment of insomnia.


Acquisition of myogenic specificity by replacement of three amino acid residues from MyoD into E12.
The basic helix-loop-helix (bHLH) protein MyoD is a transcription factor that is important for the induction of the myogenic phenotype. The DNA binding basic region (13 amino acids) is necessary for recognition of the consensus MyoD binding site, for transcriptional activation, and for conversion of fibroblasts to muscle. In contrast, the non-tissue-specific bHLH protein E12 can bind to the MyoD binding site but does not induce myogenesis. Here, it is shown that only two amino acids in the MyoD basic region and a single amino acid from the junction, which separates the basic region and helix 1, are sufficient for myogenic specificity when substituted into the corresponding region of E12. These findings suggest that the recognition of particular determinants in the basic region is required for conversion of fibroblasts to muscle.


Recommended patient information sheet on the impact of haematopoietic cell transplantation on sexual functioning and sexuality.
Sexual concerns are common after haematopoietic cell transplantation (HCT). Exposure to total body irradiation (TBI), alkylating agent and graft versus host disease (GvHD) can all affect sexual function, leading to problems in sexual desire, arousal and the orgasm phase of the sexual response cycle. In high-risk haematological malignancies, such as acute leukaemia and myelodysplastic syndromes, HCT often offers the highest chance for long-term survival. In addition, these haematological diseases and HCT can have an impact on body image, self-esteem, (sexual) relationship and psychosocial factors, all of which are able to affect sexuality and sexual function. Five years post HCT, 80% of the female survivors and 46% of the male survivors report sexual dysfunction. It has been shown that these patients cope better after having discussed sexual health. While healthcare providers (HCPs) have the responsibility to address sexual issues, it has been demonstrated that 48%-82% HCT recipients reported not having discussed sexual issues with their HCPs and that only one-third of the HCPs routinely discussed sexual issues with their patients. HCPs describe a lack of knowledge and being uncomfortable with the topic as the most important reasons for not addressing sexual functioning. Even so, it would help >90% HCPs if the patient initiated discussing sexual issues. However, to empower patients addressing sexual issues, adequate comprehensive patient information is needed. In an effort to better meet the patients' need, a patient information sheet: 'Information for patients undergoing Hematopoietic Cell Transplantation: the impact of the disease and treatment on sexual function and sexuality', has been created. In this review, we describe what is known about the impact of HCT on sexual function and briefly the management of sexual problems.


Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus.
The global population at risk from mosquito-borne diseases-including dengue, yellow fever, chikungunya and Zika-is expanding in concert with changes in the distribution of two key vectors: Aedes aegypti and Aedes albopictus. The distribution of these species is largely driven by both human movement and the presence of suitable climate. Using statistical mapping techniques, we show that human movement patterns explain the spread of both species in Europe and the United States following their introduction. We find that the spread of Ae. aegypti is characterized by long distance importations, while Ae. albopictus has expanded more along the fringes of its distribution. We describe these processes and predict the future distributions of both species in response to accelerating urbanization, connectivity and climate change. Global surveillance and control efforts that aim to mitigate the spread of chikungunya, dengue, yellow fever and Zika viruses must consider the so far unabated spread of these mosquitos. Our maps and predictions offer an opportunity to strategically target surveillance and control programmes and thereby augment efforts to reduce arbovirus burden in human populations globally.


Motivational interviewing versus brief advice for cigarette smokers in residential alcohol treatment.
Residential treatment for substance use disorders (SUD) provides opportunity for smoking intervention. A randomized controlled trial compared: (1) motivational interviewing (MI) to brief advice (BA), (2) in one session or with two booster sessions, for 165 alcoholics in SUD treatment. All received nicotine replacement (NRT). MI and BA produced equivalent confirmed abstinence, averaging 10% at 1 month, and 2% at 3, 6 and 12 months. However, patients with more drug use pretreatment (>22 days in 6 months) given BA had more abstinence at 12 months (7%) than patients in MI or with less drug use (all 0%). Boosters produced 16-31% fewer cigarettes per day after BA than MI. Substance use was unaffected by treatment condition or smoking cessation. Motivation to quit was higher after BA than MI. Thus, BA plus NRT may be a cost-effective way to reduce smoking for alcoholics with comorbid substance use who are not seeking smoking cessation.


Dissecting the complexity of the nervous system by enhancer detection.
Enhancer detectors are DNA constructs which, when introduced into a eukaryotic genome, respond to nearby genomic transcriptional regulatory elements by means of a reporter gene, revealing the expression pattern of genes in their vicinity. Recent experiments in Drosophila suggest that enhancer detection is a powerful method to identify genes that are expressed in the nervous system. Since enhancer detectors allow a rapid molecular and genetic characterization of genes in their vicinity, the method will greatly facilitate the study of neural development and behavior.


Preischemic hyperglycemia leads to delayed postischemic hyperthermia.
Temperature alterations are known to influence the outcome of transient ischemia, even when instituted in the postischemic period. Since preischemic hyperglycemia aggravates ischemic brain damage, the question of whether hyperglycemic animals become hyperthermic arose. To explore this possibility, we measured body temperature telemetrically in normoglycemic and hyperglycemic rats subjected to 10 minutes of forebrain ischemia at a body (and brain) temperature of 37 degrees C. Isoflurane-anesthetized animals were subjected to 10 minutes of forebrain ischemia under normoglycemic or hyperglycemic conditions. Temperature changes after ischemia were measured by means of a telemetric temperature coil. In normoglycemic animals, temperature decreased to 35.6 +/- 1.1 degrees C (mean +/- SD) during the first 4 hours of recovery, after which it gradually increased to normal values (38 degrees C). Hyperglycemic animals behaved differently in that they remained normothermic for approximately 10 hours during recovery and later became hyperthermic, with core temperatures rising above 39 degrees C. The rise in temperature was not due to the osmotic load of the glucose administered because infusion of mannitol, which gave a comparable increase in plasma osmolality, failed to cause delayed postischemic hyperthermia. Excessive hypercapnia during ischemia in normoglycemic animals, which produces cerebral acidosis of a magnitude similar to that of hyperglycemia and is known to aggravate ischemic lesions, likewise failed to induce hyperthermia. When post-ischemic seizures ensued in hyperglycemic subjects, temperature was 39.8 +/- 0.6 degrees C. Animals with seizures invariably died. To evaluate the influence of postischemic hyperthermia on the outcome, an additional series of experiments was performed in which delayed hyperthermia was avoided by gentle cooling (n = 6) or by acetaminophen administration (n = 5). Although these procedures prevented delayed hyperthermia, they neither blocked seizure induction nor affected the fatal outcome. Postischemic seizures developed when the core temperatures of animals were 37.9 +/- 0.1 degrees C and 37.8 +/- 0.2 degrees C in the cooled and acetaminophen-treated groups, respectively. The results suggest that both delayed hyperthermia and delayed seizures in hyperglycemic animals are caused by the aggravated damage incurred by these animals during or immediately after the ischemic insult.


Myricetin treatment induces apoptosis in canine osteosarcoma cells by inducing DNA fragmentation, disrupting redox homeostasis, and mediating loss of mitochondrial membrane potential.
Canine osteosarcoma is an aggressive primary bone tumor that shows metastasis to distal regions and is associated with a high mortality rate. However, the pathophysiological mechanisms of canine osteosarcoma are not well characterized. In addition, development of prognostic factors and novel therapeutic agents is necessary to efficiently treat osteosarcoma. Therefore, we studied the effects of myricetin, an antioxidant found in berries, nuts, teas, wine, and vegetables, on apoptosis and signal transduction in the canine osteosarcoma cell lines, D-17 and DSN. Results of the present study demonstrated that treatment with myricetin decreased cell proliferation and DNA replication, while it increased apoptotic DNA fragmentation in D-17 and DSN cells. In addition, it increased generation of ROS, lipid peroxidation, and depolarization of MMP in both D-17 and DSN cells. Myricetin treatment activated phosphorylation of AKT, p70S6K, ERK1/2, JNK, and p90RSK in canine osteosarcoma cells. Moreover, inhibition of PI3K and MAPK using LY294002, U0126, or SP600125, in addition to myricetin treatment, effectively suppressed cell proliferation compared to treatment with myricetin or each inhibitor alone. Therefore, we concluded that myricetin may be a potentially effective and less toxic therapeutic agent to prevent and control progression of canine osteosarcoma.


Deep stromal opacity after corneal cross-linking.
To describe 3 cases with deep corneal stromal opacity that occurred several months after corneal cross-linking. A 36-year-old man, a 19-year-old man, and a 14-year-old girl underwent corneal cross-linking for their progressive keratoconus. Corneal cross-linking was performed according to the Dresden protocol. The corneal epithelium was ablated using an excimer laser in 2 cases and manually in 1 case. After 30 minutes of riboflavin presoaking, hypotonic riboflavin solution was applied until the corneal stroma swelled, after which the eyes were exposed to ultraviolet irradiation. Slit-lamp microscopy findings, uncorrected visual acuity, best-corrected visual acuity, manifest refraction, intraocular pressure, and corneal endothelial cell counts were evaluated, and corneal topography with Scheimpflug imaging was performed. In all cases, the epithelium healed without delay. All eyes showed mild stromal infiltration a few days after the procedure; however, the inflammation was resolved within 1 week. The corneal stroma revealed no opacity up to 1 month after the procedure. A deep stromal opacity that extended to the inferior paracentral area developed after a few months and remained for 6 months to 1 year. Because the opacity was not on the visual axis, the visual acuity was not involved. Deep stromal opacity developed several months after uneventful corneal cross-linking. Postoperative inflammation may play a crucial role in its pathogenesis.


Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma.
The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70-75 mg/m(2)) and cisplatin (70-75 mg/m(2)) on day 1, and continuous infusion of fluorouracil (750 mg/m(2)/day) on days 1-5. Antibiotic prophylaxis on days 5-15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty-two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty-one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment-related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2-year progression-free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).


On the psychology of poverty.
Poverty remains one of the most pressing problems facing the world; the mechanisms through which poverty arises and perpetuates itself, however, are not well understood. Here, we examine the evidence for the hypothesis that poverty may have particular psychological consequences that can lead to economic behaviors that make it difficult to escape poverty. The evidence indicates that poverty causes stress and negative affective states which in turn may lead to short-sighted and risk-averse decision-making, possibly by limiting attention and favoring habitual behaviors at the expense of goal-directed ones. Together, these relationships may constitute a feedback loop that contributes to the perpetuation of poverty. We conclude by pointing toward specific gaps in our knowledge and outlining poverty alleviation programs that this mechanism suggests.


Blood cell redistribution in the lung after administration of recombinant human granulocyte-macrophage colony-stimulating factor.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a haematopoietic growth factor, has been shown to stimulate in vitro the production of interleukins 1, 6 and 8 (IL-1, IL-6 and IL-8), tumour necrosis factor-alpha (TNF-alpha) and GM-CSF by polymorphonuclear cells (PMNs), alveolar macrophages (AMs), fibroblasts and endothelial cells of the lung, and the growth and differentiation of resident alveolar macrophages. The aim of this study was to establish whether recombinant GM-CSF (rhGM-CSF), administered subcutaneously at a dose of 5 micrograms.kg-1 for 3 days in five patients with unresectable non-small cell lung cancer before starting chemotherapy, induces an increase in the alveolar cell count, and whether these cellular lung variations may be related to increases in the above-mentioned cytokines. In the bronchoalveolar lavage fluid (BALF) total cell count, polymorphonuclear cells, neutrophils, and alveolar macrophages increased significantly in comparison with the baseline, and the extent of variation of the BAL cell count was considerably greater than that of the circulating leucocytes. The mean levels of all the cytokines increased, but a significant difference with respect to the basal condition was observed only for IL-6 and IL-8. After rhGM-CSF treatment, significant correlations were found between neutrophil counts and the levels of IL-6 and IL-8. In conclusion, rhGM-CSF administration induces a cellular expansion in the lung, and the neutrophil increase appears to be related to increased levels of IL-8.


A smart deoxyribozyme-based fluorescent sensor for in vitro detection of androgen receptor mRNA.
Nowadays a variety of biosensors are widely used in different fields, including biomedical diagnostics and self-testing. Nucleic acid-based biosensors are typically applied to detect another nucleic acid, proteins, ions, and several other types of compounds. It is most promising to develop simple and effective biosensors for the use in situations where traditional methods are not available due to their complexity and laboriousness. In this project, a novel smart deoxyribozyme-based fluorescent sensor for the detection of androgen receptor mRNA was developed. It consists of several functional modules including two deoxyribozymes 10-23, an RNA-dependent split malachite green aptamer, and an oligonucleotide platform. Deoxyribozymes specifically release a 27-nucleotide RNA fragment that is readily available for the interaction with the aptamer module. This solves a problem of secondary structure in hybridization with the target sequence of full-length mRNA. It was shown that within 24 hours the proposed sensor specifically recognized both a synthetic 60-nucleotide RNA fragment (LOD is 1.4 nM of RNA fragment at 37 °C) and a full-sized mRNA molecule of the androgen receptor. The constructed sensor is easy to use, has high efficiency and selectivity for the RNA target, and can be reconstructed for the detection of various nucleic acid sequences due to its modular structure. Thus, similar biosensors may be useful for the differential diagnosis.


Nanostructures boost the thermoelectric performance of PbS.
In situ nanostructuring in bulk thermoelectric materials through thermo-dynamic phase segregation has established itself as an effective paradigm for optimizing the performance of thermoelectric materials. In bulk PbTe small compositional variations create coherent and semicoherent nanometer sized precipitates embedded in a PbTe matrix, where they can impede phonon propagation at little or no expense to the electronic properties. In this paper the nanostructuring paradigm is for the first time extended to a bulk PbS based system, which despite obvious advantages of price and abundancy, so far has been largely disregarded in thermoelectric research due to inferior room temperature thermoelectric properties relative to the pristine fellow chalcogenides, PbSe and PbTe. Herein we report on the synthesis, microstructural morphology and thermoelectric properties of two phase (PbS)(1-x)(PbTe)(x)x = 0-0.16 samples. We have found that the addition of only a few percent PbTe to PbS results in a highly nanostructured material, where PbTe precipitates are coherently and semicoherently embedded in a PbS matrix. The present (PbS)(1-x)(PbTe)(x) nanostructured samples show substantial decreases in lattice thermal conductivity relative to pristine PbS, while the electronic properties are left largely unaltered. This in turn leads to a marked increase in the thermoelectric figure of merit. This study underlines the efficiency of the nanostructuring approach and strongly supports its generality and applicability to other material systems. We demonstrate that these PbS-based materials, which are made primarily from abundant Pb and S, outperform optimally n-type doped pristine PbTe above 770 K.


Osmotically driven drug delivery through remote-controlled magnetic nanocomposite membranes.
Implantable drug delivery systems can provide long-term reliability, controllability, and biocompatibility, and have been used in many applications, including cancer pain and non-malignant pain treatment. However, many of the available systems are limited to zero-order, inconsistent, or single burst event drug release. To address these limitations, we demonstrate prototypes of a remotely operated drug delivery device that offers controllability of drug release profiles, using osmotic pumping as a pressure source and magnetically triggered membranes as switchable on-demand valves. The membranes are made of either ethyl cellulose, or the proposed stronger cellulose acetate polymer, mixed with thermosensitive poly(N-isopropylacrylamide) hydrogel and superparamagnetic iron oxide particles. The prototype devices' drug diffusion rates are on the order of 0.5-2 μg/h for higher release rate designs, and 12-40 ng/h for lower release rates, with maximum release ratios of 4.2 and 3.2, respectively. The devices exhibit increased drug delivery rates with higher osmotic pumping rates or with magnetically increased membrane porosity. Furthermore, by vapor deposition of a cyanoacrylate layer, a drastic reduction of the drug delivery rate from micrograms down to tens of nanograms per hour is achieved. By utilizing magnetic membranes as the valve-control mechanism, triggered remotely by means of induction heating, the demonstrated drug delivery devices benefit from having the power source external to the system, eliminating the need for a battery. These designs multiply the potential approaches towards increasing the on-demand controllability and customizability of drug delivery profiles in the expanding field of implantable drug delivery systems, with the future possibility of remotely controlling the pressure source.


Select Skeletal Muscle mRNAs Related to Exercise Adaptation Are Minimally Affected by Different Pre-exercise Meals that Differ in Macronutrient Profile.
Background: Substantial research has been done on the impact of carbohydrate and fat availability on endurance exercise adaptation, though its role in the acute adaptive response to resistance exercise has yet to be fully characterized. Purpose: We aimed to assess the effects of a pre-resistance exercise isocaloric mixed meal containing different amounts of carbohydrates and fat, on post-resistance exercise gene expression associated with muscle adaptation. Methods: Thirteen young (age 21.2 ± 1.6 year), recreationally trained (VO2max 51.3 ± 4.8 ml/kg/min) men undertook an aerobic exercise session of 90-min continuous cycling (70% VO2max) in the morning with pre- and post-exercise protein ingestion (10 and 15 g casein in a 500 ml beverage pre- and post-exercise, respectively). Subjects then rested for 2 h and were provided with a meal consisting of either 3207 kJ; 52 g protein; 51 g fat; and 23 g carbohydrate (FAT) or 3124 kJ; 53 g protein; 9 g fat; and 109 g carbohydrate (CHO). Two hours after the meal, subjects completed 5 × 8 repetitions (80% 1-RM) for both bilateral leg press and leg extension directly followed by 25 g of whey protein (500 ml beverage). Muscle biopsies were obtained from the vastus lateralis at baseline (morning) and 1 and 3 h post-resistance exercise (afternoon) to determine intramuscular mRNA response. Results: Muscle glycogen levels were significantly decreased post-resistance exercise, without any differences between conditions. Plasma free fatty acids increased significantly after the mixed meal in the FAT condition, while glucose and insulin were higher in the CHO condition. However, PDK4 mRNA quantity was significantly higher in the FAT condition at 3 h post-resistance exercise compared to CHO. HBEGF, INSIG1, MAFbx, MURF1, SIRT1, and myostatin responded solely as a result of exercise without any differences between the CHO and FAT group. FOXO3A, IGF-1, PGC-1α, and VCP expression levels remained unchanged over the course of the day. Conclusion: We conclude that mRNA quantity associated with muscle adaptation after resistance exercise is not affected by a difference in pre-exercise nutrient availability. PDK4 was differentially expressed between CHO and FAT groups, suggesting a potential shift toward fat oxidation and reduced glucose oxidation in the FAT group.


Food retailer practices, attitudes and beliefs about the supply of healthy foods.
Non-supermarket food retailers can be a promising channel for increasing the availability of healthy foods in underserved communities. The present paper reports on retailer practices, attitudes and beliefs about the supply of healthy foods before and after the introduction of new subsidies for healthy foods by the US Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in October 2009. We designed and conducted in-person standardized interviews with store owners and managers to assess perceptions of demand and profits for different foods, supply networks, barriers to stocking healthy foods and their changes following implementation of the new WIC packages. Non-supermarket retailers in five towns of Connecticut, USA (n 68 in 2009 and n 58 in 2010). Owners and managers of WIC-authorized and non-WIC convenience stores and non-chain grocery stores. Retailers identified customer demand as the primary factor in stocking decisions. They reported observing a significantly weaker demand for healthy foods compared with unhealthy foods, although it improved for certain foods with the new WIC subsidies. Less healthy foods were also perceived as more profitable. Supplier networks varied by product from convenient manufacturer delivery for salty snacks to self-supply for produce. WIC retailers were able to quickly adapt and supply healthy foods required under the new WIC programme guidelines. Retailers other than supermarkets currently perceive little demand for healthy foods, but new WIC subsidies have the power to change these perceptions. Supply barriers seem secondary in the limited offerings of healthy foods by stores and could be overcome when policy changes generate new demand for healthy foods.


Mitochondrial replacement techniques: egg donation, genealogy and eugenics.
Several objections against the morality of researching or employing mitochondrial replacement techniques have been advanced recently. In this paper, I examine three of these objections and show that they are found wanting. First I examine whether mitochondrial replacement techniques, research and clinical practice, should not be carried out because of possible harms to egg donors. Next I assess whether mitochondrial replacement techniques should be banned because they could affect the study of genealogical ancestry. Finally, I examine the claim that mitochondrial replacement techniques are not transferring mitochondrial DNA but nuclear DNA, and that this should be prohibited on ethical grounds.


The pVHL-hIF-1 system. A key mediator of oxygen homeostasis.
Matching oxygen consumption and supply represents a fundamental challenge to multicellular organisms. HIF-1 is a transcription complex which is emerging as a key mediator of oxygen homeostasis. HIF-1 controls the expression of many genes, including erythropoietin, angiogenic growth factors, glucose transporters and glycolytic enzymes. The HIF-1 complex, which contains an alpha and beta subunit (both basic helix-loop-helix proteins of the PAS family) is formed in hypoxia and modulates gene expression through hypoxia response elements. Regulation involves ubiquitin-mediated oxygen-dependent destruction of the alpha subunit. Oxygen-regulated destruction of HIF-alpha requires the von Hippel Lindau tumour suppressor protein (pVHL). pVHL acts as the recognition component of a ubiquitin E3 ligase complex which binds HIF-alpha. Loss of pVHL function, which results in constitutive activation of the hypoxic response, is important in the development of clear cell renal cancer, where both copies of the gene are usually inactivated. The importance of the VHL-HIF system in multicellular organisms is supported by conservation in the nematode C. elegans. Understanding the events resulting in HIF activation should provide novel therapeutic targets. This would be useful in preventing angiogenesis in cancers and promoting adaptive changes in hypoxic/ischaemic tissue.


INAPPROPRIATE CONFIDENCE AND RETIREMENT PLANNING: FOUR STUDIES WITH A NATIONAL SAMPLE.
Financial decisions about investing and saving for retirement are increasingly complex, requiring financial knowledge and confidence in that knowledge. Few studies have examined whether direct assessments of individuals' confidence are related to the outcomes of their financial decisions. Here, we analyzed data from a national sample recruited through RAND's American Life Panel (ALP), an internet panel of U.S. adults aged 18 to 88. We examined the relationship of confidence with self-reported and actual financial decisions, using four different tasks, each performed by overlapping samples of ALP participants. The four tasks were designed by different researchers for different purposes, using different methods to assess confidence. Yet, measures of confidence were correlated across tasks, and results were consistent across methodologies. Confidence and knowledge showed only modest positive correlations. However, even after controlling for actual knowledge, individuals with greater confidence were more likely to report financial planning for retirement and to successfully minimize fees on a hypothetical investment task. Implications for the role of confidence (even if it is unjustified) in investment behavior is discussed.


Information-optimal genome assembly via sparse read-overlap graphs.
In the context of third-generation long-read sequencing technologies, read-overlap-based approaches are expected to play a central role in the assembly step. A fundamental challenge in assembling from a read-overlap graph is that the true sequence corresponds to a Hamiltonian path on the graph, and, under most formulations, the assembly problem becomes NP-hard, restricting practical approaches to heuristics. In this work, we avoid this seemingly fundamental barrier by first setting the computational complexity issue aside, and seeking an algorithm that targets information limits In particular, we consider a basic feasibility question: when does the set of reads contain enough information to allow unambiguous reconstruction of the true sequence? Based on insights from this information feasibility question, we present an algorithm-the Not-So-Greedy algorithm-to construct a sparse read-overlap graph. Unlike most other assembly algorithms, Not-So-Greedy comes with a performance guarantee: whenever information feasibility conditions are satisfied, the algorithm reduces the assembly problem to an Eulerian path problem on the resulting graph, and can thus be solved in linear time. In practice, this theoretical guarantee translates into assemblies of higher quality. Evaluations on both simulated reads from real genomes and a PacBio Escherichia coli K12 dataset demonstrate that Not-So-Greedy compares favorably with standard string graph approaches in terms of accuracy of the resulting read-overlap graph and contig N50. Available at github.com/samhykim/nsg firstname.lastname@example.com or firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


CbiZ, an amidohydrolase enzyme required for salvaging the coenzyme B12 precursor cobinamide in archaea.
The existence of a pathway for salvaging the coenzyme B(12) precursor dicyanocobinamide (Cbi) from the environment was established by genetic and biochemical means. The pathway requires the function of a previously unidentified amidohydrolase enzyme that converts adenosylcobinamide to adenosylcobyric acid, a bona fide intermediate of the de novo coenzyme B(12) biosynthetic route. The cbiZ gene of the methanogenic archaeon Methanosarcina mazei strain Göl was cloned, was overproduced in Escherichia coli, and the recombinant protein was isolated to homogeneity. HPLC, UV-visible spectroscopy, MS, and bioassay data established adenosylcobyric as the corrinoid product of the CbiZ-catalyzed reaction. Inactivation of the cbiZ gene in the extremely halophilic archaeon Halobacterium sp. strain NRC-1 blocked the ability of this archaeon to salvage Cbi. cbiZ function restored Cbi salvaging in a strain of the bacterium Salmonella enterica, whose Cbi-salvaging pathway was blocked. The salvaging of Cbi through the CbiZ enzyme appears to be an archaeal strategy because all of the genomes of B(12)-producing archaea have a cbiZ ortholog. Reasons for the evolution of two distinct pathways for Cbi salvaging in prokaryotes are discussed.


Changes in blood lactate and pyruvate concentrations and the lactate-to-pyruvate ratio during the lactate minimum speed test.
The aim of this study was to assess the responses of blood lactate and pyruvate during the lactate minimum speed test. Ten participants (5 males, 5 females; mean +/- s: age 27.1+/-6.7 years, VO2max 52.0+/-7.9 ml x kg(-1) x min(-1)) completed: (1) the lactate minimum speed test, which involved supramaximal sprint exercise to invoke a metabolic acidosis before the completion of an incremental treadmill test (this results in a 'U-shaped' blood lactate profile with the lactate minimum speed being defined as the minimum point on the curve); (2) a standard incremental exercise test without prior sprint exercise for determination of the lactate threshold; and (3) the sprint exercise followed by a passive recovery. The lactate minimum speed (12.0+/-1.4 km x h(-1)) was significantly slower than running speed at the lactate threshold (12.4+/-1.7 km x h(-1)) (P < 0.05), but there were no significant differences in VO2, heart rate or blood lactate concentration between the lactate minimum speed and running speed at the lactate threshold. During the standard incremental test, blood lactate and the lactate-to-pyruvate ratio increased above baseline values at the same time, with pyruvate increasing above baseline at a higher running speed. The rate of lactate, but not pyruvate, disappearance was increased during exercising recovery (early stages of the lactate minimum speed incremental test) compared with passive recovery. This caused the lactate-to-pyruvate ratio to fall during the early stages of the lactate minimum speed test, to reach a minimum point at a running speed that coincided with the lactate minimum speed and that was similar to the point at which the lactate-to-pyruvate ratio increased above baseline in the standard incremental test. Although these results suggest that the mechanism for blood lactate accumulation at the lactate minimum speed and the lactate threshold may be the same, disruption to normal submaximal exercise metabolism as a result of the preceding sprint exercise, including a three- to five-fold elevation of plasma pyruvate concentration, makes it difficult to interpret the blood lactate response to the lactate minimum speed test. Caution should be exercised in the use of this test for the assessment of endurance capacity.


Prospective surveillance of streptococcal sore throat in a tropical country.
Acute rheumatic fever and rheumatic heart disease cause a high burden of disease in Fiji and surrounding Pacific Island countries, but little is known about the epidemiology of group A streptococcal (GAS) pharyngitis in the region. We designed a study to estimate the prevalence of carriage of beta-hemolytic streptococci (BHS) and the incidence of BHS culture-positive sore throat in school aged children in Fiji. We conducted twice-weekly prospective surveillance of school children aged 5 to 14 years in 4 schools in Fiji during a 9-month period in 2006, after an initial phase of pharyngeal swabbing to determine the prevalence of BHS carriage. We enrolled 685 children. The prevalence of GAS carriage was 6.0%, while the prevalence of group C streptococcal (GCS) and group G streptococcal (GGS) carriage was 6.9% and 12%, respectively. There were 61 episodes of GAS culture-positive sore throat during the study period equating to an incidence of 14.7 cases per 100 child-years (95% CI, 11.2-18.8). The incidence of GCS/GGS culture-positive sore throat was 28.8 cases per 100 child-years (95% CI, 23.9-34.5). The clinical nature of GAS culture-positive sore throat was more severe than culture-negative sore throat, but overall was mild compared with that found in previous studies. Of the 101 GAS isolates that emm sequence typed there were 45 emm types with no dominant types. There were very few emm types commonly encountered in industrialized nations and only 9 of the 45 emm types found in this study are emm types included in the 26-valent GAS vaccine undergoing clinical trials. GAS culture-positive sore throat was more common than expected. Group C and group G streptococci were frequently isolated in throat cultures, although their contribution to pharyngeal infection is not clear. The molecular epidemiology of pharyngeal GAS in our study differed greatly from that in industrialized nations and this has implications for GAS vaccine clinical research in Fiji and other tropical developing countries.


Leaf hydraulic vulnerability is related to conduit dimensions and drought resistance across a diverse range of woody angiosperms.
Hydraulic dysfunction in leaves determines key aspects of whole-plant responses to water stress; however, our understanding of the physiology of hydraulic dysfunction and its relationships to leaf structure and ecological strategy remains incomplete. Here, we studied a morphologically and ecologically diverse sample of angiosperms to test whether the water potential inducing a 50% loss in leaf hydraulic conductance (P50(leaf)) is predicted by properties of leaf xylem relating to water tension-induced conduit collapse. We also assessed the relationships between P50(leaf) and other traits considered to reflect drought resistance and ecological strategy. Across species, P50(leaf) was strongly correlated with a theoretical predictor of vulnerability to cell collapse in minor veins (the cubed ratio of the conduit wall thickness to the conduit lumen breadth). P50(leaf) was also correlated with mesophyll traits known to be related to drought resistance, but unrelated to traits associated with carbon economy. Our data indicate a link between the structural mechanics of leaf xylem and hydraulic function under water stress. Although it is possible that collapse may contribute directly to dysfunction, this relationship may also be a secondary product of vascular economics, suggesting that leaf xylem is dimensioned to avoid wall collapse.


Anti-HIV-1 activity of propolis in CD4(+) lymphocyte and microglial cell cultures.
An urgent need for additional agents to treat human immunodeficiency virus type 1 (HIV-1) infection led us to assess the anti-HIV-1 activity of the natural product propolis in CD4(+) lymphocytes and microglial cell cultures. Propolis inhibited viral expression in a concentration-dependent manner (maximal suppression of 85 and 98% was observed at 66.6 microg/ml propolis in CD4(+) and microglial cell cultures, respectively). Similar anti-HIV-1 activity was observed with propolis samples from several geographic regions. The mechanism of propolis antiviral property in CD4(+) lymphocytes appeared to involve, in part, inhibition of viral entry. While propolis had an additive antiviral effect on the reverse transcriptase inhibitor zidovudine, it had no noticeable effect on the protease inhibitor indinavir. The results of this in vitro study support the need for clinical trials of propolis or one or more of its components in the treatment of HIV-1 infection.


Effects of short-term continuous positive airway pressure withdrawal on cerebral vascular reactivity measured by blood oxygen level-dependent magnetic resonance imaging in obstructive sleep apnoea: a randomised controlled trial.
Impaired cerebral vascular reactivity (CVR) increases long-term stroke risk. Obstructive sleep apnoea (OSA) is associated with peripheral vascular dysfunction and vascular events. The aim of this trial was to evaluate the effect of continuous positive airway pressure (CPAP) withdrawal on CVR.41 OSA patients (88% male, mean age 57±10 years) were randomised to either subtherapeutic or continuation of therapeutic CPAP. At baseline and after 2 weeks, patients underwent a sleep study and magnetic resonance imaging (MRI). CVR was estimated by quantifying the blood oxygen level-dependent (BOLD) MRI response to breathing stimuli.OSA did recur in the subtherapeutic CPAP group (mean treatment effect apnoea-hypopnoea index +38.0 events·h-1, 95% CI 24.2-52.0; p<0.001) but remained controlled in the therapeutic group. Although there was a significant increase in blood pressure upon CPAP withdrawal (mean treatment effect +9.37 mmHg, 95% CI 1.36-17.39; p=0.023), there was no significant effect of CPAP withdrawal on CVR assessed via BOLD MRI under either hyperoxic or hypercapnic conditions.Short-term CPAP withdrawal did not result in statistically significant changes in CVR as assessed by functional MRI, despite the recurrence of OSA. We thus conclude that, unlike peripheral endothelial function, CVR is not affected by short-term CPAP withdrawal.


Tumor-induced hypercalcemia: predictors of early mortality.
To delineate the demographics and predictors of early mortality associated with tumor-induced hypercalcemia (TIH) amongst cancer patients in Pakistan. A tertiary care hospital in Pakistan. Retrospective analysis of patients with cancers, presenting with TIH and admitted to the hospital between January 1988 and December 1997, was carried out. Eighty-four patients (56 males and 28 females) were diagnosed to have TIH. The mean age at the time of presentation was 55 +/- 14 years. Twenty-five percent of the patients each had multiple myeloma and hepatocellular carcinoma whereas 20% of the patients had underlying breast cancer. Other malignancies included lung cancer, gall bladder cancer and colorectal carcinomas. Univariate analysis revealed male sex (p < 0.04), underlying diagnosis other than multiple myeloma (p < 0.025) and a high TLC (p < 0.05) at presentation, as predictors of an early mortality. Multiple myeloma, hepatoma and breast carcinoma were common cancers causing TIH. One-third patients died within first few days. Male sex, a high white cell count and an underlying diagnosis other than multiple myeloma predicted early mortality.


Crystal structure of the sensory domain of Escherichia coli CadC, a member of the ToxR-like protein family.
The membrane-integral transcriptional activator CadC comprises sensory and transcriptional regulatory functions within one polypeptide chain. Its C-terminal periplasmic domain, CadC(pd), is responsible for sensing of environmental pH as well as for binding of the feedback inhibitor cadaverine. Here we describe the crystal structure of CadC(pd) (residues 188-512) solved at a resolution of 1.8 Å via multiple wavelength anomalous dispersion (MAD) using a ReCl(6)(2-) derivative. CadC(pd) reveals a novel fold comprising two subdomains: an N-terminal subdomain dominated by a β-sheet in contact with three α-helices and a C-terminal subdomain formed by an eleven-membered α-helical bundle, which is oriented almost perpendicular to the helices in the first subdomain. Further to the native protein, crystal structures were also solved for its variants D471N and D471E, which show functionally different behavior in pH sensing. Interestingly, in the heavy metal derivative of CadC(pd) used for MAD phasing a ReCl(6)(2-) ion was found in a cavity located between the two subdomains. Amino acid side chains that coordinate this complex ion are conserved in CadC homologues from various bacterial species, suggesting a function of the cavity in the binding of cadaverine, which was supported by docking studies. Notably, CadC(pd) forms a homo-dimer in solution, which can be explained by an extended, albeit rather polar interface between two symmetry-related monomers in the crystal structure. The occurrence of several acidic residues in this region suggests protonation-dependent changes in the mode of dimerization, which could eventually trigger transcriptional activation by CadC in the bacterial cytoplasm.


Clinical Study of An Ayurvedic Compound (Divyadi Yoga) in the Management of Shayyamutrata (enuresis).
Child health has assumed great significance in all over world. Its importance is being realized more and more by pediatricians and general public in developing as well as developed countries. Enuresis is defined as the voluntary or involuntary repeated discharge of urine into clothes or bed after a developmental age when bladder control should be established. The present clinical study was planned to evaluate the effect of Divyadi Yoga along with counseling in the management of Shayyamutra. Total 40 selected cases were divided into two groups, i.e. 20 in each group. One group of children were given the trial drug Divyadi Yoga (D(1)) with counseling and other group of children were given placebo Divyadi Yoga (D(2)) with counseling. Divyadi Yoga was given in the dose of 3-6 gms. twice a day with luke warm water. The result of the study showed that groups provided a highly significant.


Stable eusociality via maternal manipulation when resistance is costless.
In many eusocial species, queens use pheromones to influence offspring to express worker phenotypes. Although evidence suggests that queen pheromones are honest signals of the queen's reproductive health, here I show that queen's honest signalling can result from ancestral maternal manipulation. I develop a mathematical model to study the coevolution of maternal manipulation, offspring resistance to manipulation and maternal resource allocation. I assume that (i) maternal manipulation causes offspring to be workers against offspring's interests; (ii) offspring can resist at no direct cost, as is thought to be the case with pheromonal manipulation; and (iii) the mother chooses how much resource to allocate to fertility and maternal care. In the coevolution of these traits, I find that maternal care decreases, thereby increasing the benefit that offspring obtain from help, which in the long run eliminates selection for resistance. Consequently, ancestral maternal manipulation yields stable eusociality despite costless resistance. Additionally, ancestral manipulation in the long run becomes honest signalling that induces offspring to help. These results indicate that both eusociality and its commonly associated queen honest signalling can be likely to originate from ancestral manipulation.


Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells.
Antiviral mechanisms by which natural killer (NK) cells control murine cytomegalovirus (MCMV) infection in the spleens and livers of C57BL/6 mice were measured, revealing different mechanisms of control in different organs. Three days postinfection, MCMV titers in the spleens of perforin 0/0 mice were higher than in those of perforin +/+ mice, but no elevation of liver titers was found in perforin 0/0 mice. NK cell depletion in MCMV-infected perforin 0/0 mice resulted only in an increase in liver viral titers and not in spleen titers. Depletion of gamma interferon (IFN-gamma) in C57BL/6 mice by injections with monoclonal antibodies to IFN-gamma resulted in an increase of viral titers in the liver but not in the spleen. Analyses using IFN-gamma-receptor-deficient mice, rendered chimeric with C57BL/6 bone marrow cells, indicated that in a recipient environment where IFN-gamma cannot exert its effects, the depletion of NK cells caused an increase in MCMV titers in the spleens but had little effect in the liver. IFN-gamma has the ability to induce a variety of cells to produce nitric oxide, and administrating the nitric oxide synthase inhibitor N(omega)-monomethyl-L-arginine into MCMV-infected C57BL/6 mice resulted in MCMV titer increases in the liver but not in the spleen. Taken together, these data suggest that in C57BL/6 mice, there is a dichotomy in the mechanisms utilized by NK cells in the regulation of MCMV in different organs. In the spleen NK cells exert their effects in a perforin-dependent manner, suggesting a cytotoxic mechanism, while in the liver the production of IFN-gamma by NK cells may be a predominant mechanism in the regulation of MCMV synthesis. These results may explain why the Cmv-lr locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver.


The Associations Between Happiness Motives and Well-Being in China: The Mediating Role of Psychological Need Satisfaction and Frustration.
Happiness can be pursued based on hedonic motives (i.e., seeking pleasure and comfort) and/or eudaimonic motives (i.e., seeking to develop and make the best use of the self). Substantial studies have found that hedonic and eudaimonic motives relate to well-being outcomes in different ways. However, these findings were predominantly based on Western samples, while study about the relationship between happiness motives and well-being outcomes in Eastern cultures is scanty. Furthermore, little is known about the mechanisms that underlie these associations. To address these gaps, we conducted two studies based on Chinese college students. In study 1 (N = 301), structural equation modeling demonstrated that eudaimonic motives were positively associated with life satisfaction and meaning in life, but hedonic motives were not significantly associated with either indicator of well-being. In study 2 (N = 526), structural equation modeling showed that (1) hedonic motives had an indirect effect on life satisfaction through need frustration and (2) eudaimonic motives had indirect effects on life satisfaction and meaning in life through need satisfaction and need frustration. These findings highlight the important roles that the satisfaction and the frustration of basic psychological needs play in translating happiness motives into well-being outcomes.


Passive protection of diabetic rats with antisera specific for the polysaccharide portion of the lipopolysaccharide isolated from Pseudomonas pseudomallei.
Polyclonal and monoclonal antisera raised to tetanus toxoid-conjugated polysaccharide of lipopolysaccharide (lps) and purified lps of Pseudomonas pseudomallei that reacted with a collection of 41 strains of this bacterium from 23 patients are described. The common antigen recognized by these sera was within the polysaccharide component of the lps of the cells. The sera were specific for P pseudomallei in that none of 37 strains of other bacteria, including 20 Gram-negative and three Gram-positive species, were recognized, although cross-reaction occurred using the anticonjugate serum with some strains of Pseudomonas cepacia serotype A, a closely related bacterium. Passive protection studies using a diabetic rat model of P pseudomallei infection showed that partially purified rabbit polyclonal and mouse monoclonal antisera were protective when the median lethal dose was raised by four to five orders of magnitude. The wide distribution of the polysaccharide antigen among isolates of P pseudomallei used in this study and the protective role of antibody to the conjugated polysaccharide antigen suggest potential as a vaccine.


A facile approach toward 1,2-diazabenzo[ghi]perylene derivatives: structures and electronic properties.
A new class of pyridazine fused aromatics, 1,2-diazabenzo[ghi]perylenes, is conveniently synthesized from 2,7-dihydroxynaphthalene via intermolecular oxidative coupling followed by a condensation reaction. These new compounds are fully characterized via X-ray crystallographic analysis, optical spectroscopy and electrochemistry, in addition to DFT calculations. They show a twisted structure and unique P-/P- and M-/M-enantiomer pairs are observed in their single crystals. They exhibit intramolecular charge transfer character and emit at a longer wavelength with a larger Stokes shift compared with their all-carbon analog.


Accuracy of definitive casts using 4 implant-level impression techniques in a scenario of multi-implant system with different implant angulations and subgingival alignment levels.
To evaluate the effect of various implant-level impression techniques on the accuracy of definitive casts for a multiple internal connection implant system with different implant angulations and subgingival depths. Six tapered Screw-Vent implants were placed in a reference model with different angles (0, 15, and 30 degrees) and subgingival positions (0, 1, and 3 mm). Twenty medium-consistency polyether impressions of this model were made with 4 techniques (n = 5 per group): (1) indirect technique, (2) unsplinted direct technique, (3) acrylic resin-splinted direct technique, and (4) metal-splinted direct technique. Impressions were poured with type IV dental stone. The interimplant distances were measured for casts using a coordinate measuring machine and the deviations compared with the reference model were calculated. Data were analyzed using intraclass correlation coefficient, ANOVA and Bonferroni test (α = 0.05). Four impression procedures showed significant differences (P = 0.0001). Only group 4 casts showed no significant differences in comparison with the reference model (P = 0.666) (ANOVA repeated measures). The impression procedure affected the accuracy of definitive casts. The metal-splinted direct technique produced the most accurate casts, followed by acrylic resin-splinted direct, indirect, and unsplinted direct techniques.


Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation.
The bone morphogenetic protein (BMP) signaling pathway, including antagonists, functions in lung development and regeneration of tracheal epithelium from basal stem cells. Here, we explore its role in the alveolar region, where type 2 epithelial cells (AT2s) and Pdgfrα+ type 2-associated stromal cells (TASCs) are components of the stem cell niche. We use organoids and in vivo alveolar regrowth after pneumonectomy (PNX) - a process that requires proliferation of AT2s and differentiation into type 1 cells (AT1s). BMP signaling is active in AT2s and TASCs, transiently declines post-PNX in association with upregulation of antagonists, and is restored during differentiation of AT2s to AT1s. In organoids, BMP4 inhibits AT2 proliferation, whereas antagonists (follistatin, noggin) promote AT2 self-renewal at the expense of differentiation. Gain- and loss-of-function genetic manipulation reveals that reduced BMP signaling in AT2s after PNX allows self-renewal but reduces differentiation; conversely, increased BMP signaling promotes AT1 formation. Constitutive BMP signaling in Pdgfrα+ cells reduces their AT2 support function, both after PNX and in organoid culture. Our data reveal multiple cell-type-specific roles for BMP signaling during alveolar regeneration.