ALBERT

Description: by Johnatan Aljadeff, Ronen Segev, Michael J. Berry, Tatyana O. Sharpee Many biological systems perform computations on inputs that have very large dimensionality. Determining the relevant input combinations for a particular computation is often key to understanding its function. A common way to find the relevant input dimensions is to examine the difference in variance between the input distribution and the distribution of inputs associated with certain outputs. In systems neuroscience, the corresponding method is known as spike-triggered covariance (STC). This method has been highly successful in characterizing relevant input dimensions for neurons in a variety of sensory systems. So far, most studies used the STC method with weakly correlated Gaussian inputs. However, it is also important to use this method with inputs that have long range correlations typical of the natural sensory environment. In such cases, the stimulus covariance matrix has one (or more) outstanding eigenvalues that cannot be easily equalized because of sampling variability. Such outstanding modes interfere with analyses of statistical significance of candidate input dimensions that modulate neuronal outputs. In many cases, these modes obscure the significant dimensions. We show that the sensitivity of the STC method in the regime of strongly correlated inputs can be improved by an order of magnitude or more. This can be done by evaluating the significance of dimensions in the subspace orthogonal to the outstanding mode(s). Analyzing the responses of retinal ganglion cells probed with Gaussian noise, we find that taking into account outstanding modes is crucial for recovering relevant input dimensions for these neurons.

Description: The predicted effect of effective population size on the distribution of fitness effects and substitution rate is critically dependent on the relationship between sequence and fitness. This highlights the importance of using models that are informed by the molecular biology, biochemistry, and biophysics of the evolving systems. We describe a computational model based on fundamental aspects of biophysics, the requirement for (most) proteins to be thermodynamically stable. Using this model, we find that differences in population size have minimal impact on the distribution of population-scaled fitness effects, as well as on the rate of molecular evolution. This is because larger populations result in selection for more stable proteins that are less affected by mutations. This reduction in the magnitude of the fitness effects almost exactly cancels the greater selective pressure resulting from the larger population size. Conversely, changes in the population size in either direction cause transient increases in the substitution rate. As differences in population size often correspond to changes in population size, this makes comparisons of substitution rates in different lineages difficult to interpret.

Description: by Lydia Nakiyingi, John Mark Bwanika, Bruce Kirenga, Damalie Nakanjako, Catherine Katabira, Gloria Lubega, Joseph Sempa, Barnabas Nyesiga, Heidi Albert, Yukari C. Manabe Introduction The existing diagnostic algorithms for sputum smear-negative tuberculosis (TB) are complicated, time-consuming, and often difficult to implement. The decision to initiate TB treatment in resource-limited countries is often largely based on clinical predictors. We sought to determine the clinical predictors and accuracy of empiric TB treatment initiation in HIV-infected sputum smear-negative TB suspects using sputum culture as a reference standard. Setting Out-patient HIV-TB integrated urban clinic in Kampala, Uganda. Methods HIV-infected TB suspects were screened using sputum smear microscopy, and mycobacterial sputum liquid and solid cultures were performed. Smear results were made available to the clinician who made a clinical decision on empiric TB treatment initiation for sputum smear-negative patients. Clinic records were reviewed for patients whose sputum smears were negative to collect data on socio-demographics, TB symptomatology, chest X-ray findings, CD4 cell counts and TB treatment initiation. Results Of 253 smear-negative TB suspects, 56% (142/253) were females, median age 38 IQR (31–44) years, with a median CD4 cell count of 291 IQR (150–482) cells/mm 3 . Of the 85 (33.6%) smear-negative patients empirically initiated on TB treatment, 35.3% (n = 30) were sputum culture positive compared to only 18 (10.7%) of the 168 untreated patients (p

Description: by Cyril Dégletagne, Damien Roussel, Jean Louis Rouanet, Fanny Baudimont, Elodie-Marie Moureaux, Steve Harvey, Claude Duchamp, Yvon Le Maho, Mireille Raccurt The evolutionary trade-off between tissue growth and mature function restricts the post natal development of polar birds. The present study uses an original integrative approach as it includes gene expression, plus biochemical and physiological analysis to investigate how Adélie penguin chicks achieve a rapid growth despite the energetic constraints linked to the cold and the very short breeding season in Antarctica. In pectoralis muscle, the main thermogenic tissue in birds, our data show that the transition from ectothermy to endothermy on Day 15 post- hatching is associated with substantial and coordinated changes in the transcription of key genes. While the early activation of genes controlling cell growth and differentiation (avGHR, avIGF-1R, T3Rβ) is rapidly down-regulated after hatching, the global increase in the relative expression of genes involved in thermoregulation (avUCP, avANT, avLPL) and transcriptional regulation (avPGC1α, avT3Rβ) underlie the muscular acquisition of oxidative metabolism. Adélie chicks only become real endotherms at 15 days of age with the development of an oxidative muscle phenotype and the ability to shiver efficiently. The persistent muscular expression of IGF-1 throughout growth probably acts as a local mediator to adjust muscle size and its oxidative capacity to anticipate the new physiological demands of future Dives in cold water. The up-regulation of T3Rβ mRNA levels suggests that circulating T3 may play an important role in the late maturation of skeletal muscle by reinforcing, at least in part, the paracrine action of IGF-1. From day 30, the metabolic shift from mixed substrate to lipid metabolism, with the markedly increased mRNA levels of muscle avLPL, avANT and avUCP, suggests the late development of a fatty acid-enhanced muscle non-shivering thermogenesis mechanism. This molecular control is the key to this finely-tuned strategy by which the Adélie penguin chick successfully heads for the sea on schedule.

Description: by Philip Wing-Lok Ho, Zero Ho-Man Tse, Hui-Fang Liu, Song Lu, Jessica Wing-Man Ho, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho Xenoestrogens are either natural or synthetic compounds that mimic the effects of endogenous estrogen. These compounds, such as bisphenol-A (BPA), and phthalates, are commonly found in plastic wares. Exposure to these compounds poses major risk to human health because of the potential to cause endocrine disruption. There is huge demand for a wide range of chemicals to be assessed for such potential for the sake of public health. Classical in vivo assays for endocrine disruption are comprehensive but time-consuming and require sacrifice of experimental animals. Simple preliminary in vitro screening assays can reduce the time and expense involved. We previously demonstrated that catechol-O-methyltransferase (COMT) is transcriptionally regulated by estrogen via estrogen receptor (ER). Therefore, detecting corresponding changes of COMT expression in estrogen-responsive cells may be a useful method to estimate estrogenic effects of various compounds. We developed a novel cell-based ELISA to evaluate cellular response to estrogenicity by reduction of soluble-COMT expression in ER-positive MCF-7 cells exposed to estrogenic compounds. In contrast to various existing methods that only detect bioactivity, this method elucidates direct physiological effect in a living cell in response to a compound. We validated our assay using three well-characterized estrogenic plasticizers - BPA, benzyl butyl phthalate (BBP), and di-n-butyl phthalate (DBP). Cells were exposed to either these plasticizers or 17β-estradiol (E2) in estrogen-depleted medium with or without an ER-antagonist, ICI 182,780, and COMT expression assayed. Exposure to each of these plasticizers (10 -9 -10 -7 M) dose-dependently reduced COMT expression (p

Description: by Luca Laudani, Giuseppe Vannozzi, Zimi Sawacha, Ugo della Croce, Andrea Cereatti, Andrea Macaluso Maintaining adequate levels of physical activity is known to preserve health status and functional independence as individuals grow older. However, the relationship between determinants of physical activity (volume and intensity) and physiological factors underlying mobility (cardio-respiratory fitness, neuromuscular function and functional abilities) is still unclear. The aim of this study was to investigate the association between objectively quantified physical activity and a spectrum of physiological factors underlying mobility in young, middle-aged and older individuals living in a city district. Experiments were carried out on 24 young (28±2 years), 24 middle-aged (48±2 years) and 24 older (70±3 years) gender-matched volunteers. Physical activity was monitored by a wearable activity monitor to quantify volume and intensity of overall physical activity and selected habitual activities over 24 hours. Ventilatory threshold was assessed during an incremental cycling test. Torque, muscle fiber conduction velocity and agonist-antagonist coactivation were measured during maximal voluntary contraction of knee extensors and flexors. Ground reaction forces were measured during sit-to-stand and counter-movement jump. K-means cluster analysis was used to classify the participants’ physical activity levels based on parameters of volume and intensity. Two clusters of physical activity volume (i.e., high and low volume) and three clusters of physical activity intensity (i.e. high, medium and low intensity) were identified in all participants. Cardio-respiratory fitness was associated with volume of overall physical activity as well as lying, sitting, standing, walking and stair climbing. On the other hand, neuromuscular function and functional abilities showed a significant association with intensity of overall physical activity as well as postural transition, walking and stair climbing. As a practical application, the relative role played by volume and intensity of overall physical activity and selected habitual activities should be taken into account in the design of preventative training interventions to preserve mobility as individuals grow older.

Description: by Daniel Garcia de la serrana, Ian A. Johnston Heat shock proteins 90 (Hsp90) have an essential role in sarcomere formation and differentiation in skeletal muscle and also act as molecular chaperones during protein folding impacting a wide range of physiological processes. We characterised and provided a phylogenetically consistent nomenclature for the complete repertoire of six Hsp90 paralogues present in duplicated salmonid fish genomes (Hsp90α1a, Hsp90α1b, Hsp90α2a, Hsp90α2b, Hsp90ß1a and Hsp90ß1b). The expression of paralogues in fast skeletal muscle was investigated using in vivo fasting-feeding experiments and primary myogenic cultures. Fasted juvenile Atlantic salmon ( Salmo salar ) showed a transient 2 to 8-fold increase in the expression of all 4 Hsp90α paralogues within 24h of satiation feeding. H sp90α1a and hsp90α1b also showed a pronounced secondary increase in expression after 10 days, concomitant with muscle differentiation and the expression of myogenin and sarcomeric proteins ( mlc2 , myhc ). Hsp90ß1b was constitutively expressed whereas Hsp90ß1a expression was downregulated 10-fold between fasted and fed individuals. Hsp90α1a and Hsp90α1b were upregulated 10 to 15-fold concomitant with myotube formation and muscle differentiation in vitro whereas other Hsp90 paralogues showed no change in expression. In cells starved of amino acid (AA) and serum for 72h the addition of AA, but not insulin-like growth factor 1, increased phosphorylation of mTor and expression of all 4 hsp90α paralogues and associated co-chaperones including hsp30 , tbcb , pdia4 , pdia6 , stga and fk504bp1 , indicating a general activation of the protein folding response. In contrast, Hsp90ß1a expression in vitro was unresponsive to AA treatment indicating that some other as yet uncharacterised signal(s) regulate its expression in response to altered nutritional state.

Description: by Monika Marejková, Květa Bláhová, Jan Janda, Angelika Fruth, Petr Petráš Background Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea-associated hemolytic uremic syndrome (D+ HUS) worldwide, but no systematic study of EHEC as the causative agents of HUS was performed in the Czech Republic. We analyzed stools of all patients with D+ HUS in the Czech Republic between 1998 and 2012 for evidence of EHEC infection. We determined virulence profiles, phenotypes, antimicrobial susceptibilities and phylogeny of the EHEC isolates. Methodology/Principal Findings Virulence loci were identified using PCR, phenotypes and antimicrobial susceptibilities were determined using standard procedures, and phylogeny was assessed using multilocus sequence typing. During the 15-year period, EHEC were isolated from stools of 39 (69.4%) of 56 patients. The strains belonged to serotypes [ fliC types] O157:H7/NM[ fliC H7 ] (50% of which were sorbitol-fermenting; SF), O26:H11/NM[ fliC H11 ], O55:NM[ fliC H7 ], O111:NM[ fliC H8 ], O145:H28[ fliC H28 ], O172:NM[ fliC H25 ], and Orough:NM[ fliC H25 ]. O26:H11/NM[ fliC H11 ] was the most common serotype associated with HUS (41% isolates). Five stx genotypes were identified, the most frequent being stx 2a (71.1% isolates). Most strains contained EHEC- hlyA encoding EHEC hemolysin, and a subset (all SF O157:NM and one O157:H7) harbored cdt-V encoding cytolethal distending toxin. espP α encoding serine protease EspPα was found in EHEC O157:H7, O26:H11/NM, and O145:H28, whereas O172:NM and Orough:NM strains contained espP γ. All isolates contained eae encoding adhesin intimin, which belonged to subtypes β (O26), γ (O55, O145, O157), γ2/θ (O111), and ε (O172, Orough). Loci encoding other adhesins ( efa1, lpfA O26 , lpfA O157OI-141 , lpfA O157OI-154 , iha ) were usually associated with particular serotypes. Phylogenetic analysis demonstrated nine sequence types (STs) which correlated with serotypes. Of these, two STs (ST660 and ST1595) were not found in HUS-associated EHEC before. Conclusions/Significance EHEC strains, including O157:H7 and non-O157:H7, are frequent causes of D+ HUS in the Czech Republic. Identification of unusual EHEC serotypes/STs causing HUS calls for establishment of an European collection of HUS-associated EHEC, enabling to study properties and evolution of these important pathogens.

Description: by Hanneke K. M. Meeren, Beatrice de Gelder, Seppo P. Ahlfors, Matti S. Hämäläinen, Nouchine Hadjikhani Evidence from functional neuroimaging indicates that visual perception of human faces and bodies is carried out by distributed networks of face and body-sensitive areas in the occipito-temporal cortex. However, the dynamics of activity in these areas, needed to understand their respective functional roles, are still largely unknown. We monitored brain activity with millisecond time resolution by recording magnetoencephalographic (MEG) responses while participants viewed photographs of faces, bodies, and control stimuli. The cortical activity underlying the evoked responses was estimated with anatomically-constrained noise-normalised minimum-norm estimate and statistically analysed with spatiotemporal cluster analysis. Our findings point to distinct spatiotemporal organization of the neural systems for face and body perception. Face-selective cortical currents were found at early latencies (120–200 ms) in a widespread occipito-temporal network including the ventral temporal cortex (VTC). In contrast, early body-related responses were confined to the lateral occipito-temporal cortex (LOTC). These were followed by strong sustained body-selective responses in the orbitofrontal cortex from 200–700 ms, and in the lateral temporal cortex and VTC after 500 ms latency. Our data suggest that the VTC region has a key role in the early processing of faces, but not of bodies. Instead, the LOTC, which includes the extra-striate body area (EBA), appears the dominant area for early body perception, whereas the VTC contributes to late and post-perceptual processing.

Description: by Volkhard Göber, Andreas Hohl, Brigitta Gahl, Florian Dick, Verena Eigenmann, Thierry P. Carrel, Hendrik T. Tevaearai Background Peak levels of troponin T (TnT) reliably predict morbidity and mortality after cardiac surgery. However, the therapeutic window to manage CABG-related in-hospital complications may close before the peak is reached. We investigated whether early TnT levels correlate as well with complications after coronary artery bypass grafting (CABG) surgery. Methods A 12 month consecutive series of patients undergoing elective isolated CABG procedures (mini-extra-corporeal circuit, Cardioplegic arrest) was analyzed. Logistic regression modeling was used to investigate whether TnT levels 6 to 8 hours after surgery were independently associated with in-hospital complications (either post-operative myocardial infarction, stroke, new-onset renal insufficiency, intensive care unit (ICU) readmission, prolonged ICU stay (〉48 hours), prolonged need for vasopressors (〉24 hours), resuscitation or death). Results A total of 290 patients, including 36 patients with complications, was analyzed. Early TnT levels (odds ratio (OR): 6.8, 95% confidence interval (CI): 2.2-21.4, P=.001), logistic EuroSCORE (OR: 1.2, 95%CI: 1.0-1.3, P=.007) and the need for vasopressors during the first 6 postoperative hours (OR: 2.7, 95%CI: 1.0-7.1, P=.05) were independently associated with the risk of complications. With consideration of vasopressor use during the first 6 postoperative hours, the sum of specificity (0.958) and sensitivity (0.417) of TnT for subsequent complications was highest at a TnT cut-off value of 0.8 ng/mL. Conclusion Early TnT levels may be useful to guide ICU management of CABG patients. They predict clinically relevant complications within a potential therapeutic window, particularly in patients requiring vasopressors during the first postoperative hours, although with only moderate sensitivity.

Description: by Valentine S. Moullé, Christelle Le Foll, Erwann Philippe, Nadim Kassis, Claude Rouch, Nicolas Marsollier, Linh-Chi Bui, Christophe Guissard, Julien Dairou, Anne Lorsignol, Luc Pénicaud, Barry E. Levin, Céline Cruciani-Guglielmacci, Christophe Magnan Variations in plasma fatty acid (FA) concentrations are detected by FA sensing neurons in specific brain areas such as the hypothalamus. These neurons play a physiological role in the control of food intake and the regulation of hepatic glucose production. Le Foll et al. previously showed in vitro that at least 50% of the FA sensing in ventromedial hypothalamic (VMH) neurons is attributable to the interaction of long chain FA with FA translocase/CD36 (CD36). The present work assessed whether in vivo effects of hypothalamic FA sensing might be partly mediated by CD36 or intracellular events such as acylCoA synthesis or β-oxidation. To that end, a catheter was implanted in the carotid artery toward the brain in male Wistar rats. After 1 wk recovery, animals were food-deprived for 5 h, then 10 min infusions of triglyceride emulsion, Intralipid +/− heparin (IL, IL H , respectively) or saline/heparin (S H ) were carried out and food intake was assessed over the next 5 h. Experimental groups included: 1) Rats previously injected in ventromedian nucleus (VMN) with shRNA against CD36 or scrambled RNA; 2) Etomoxir (CPT1 inhibitor) or saline co-infused with IL H /S H ; and 3) Triacsin C (acylCoA synthase inhibitor) or saline co-infused with IL H /S H . IL H significantly lowered food intake during refeeding compared to S H (p

Description: by Paul A. Stevenson, Jan Rillich Population density has profound influences on the physiology and behaviour of many animal species. Social isolation is generally reported to lead to increased aggressiveness, while grouping lowers it. We evaluated the effects of varying degrees of isolation and grouping on aggression in a territorial insect, the Mediterranean field cricket, Gryllus bimaculatus . Substantiating early observations, we show that dyadic contests between weight-matched, adult male crickets taken from groups rarely escalate beyond threat displays, whereas interactions between pairs of previously isolated crickets typically escalate to physical fights lasting several seconds. No significant differences were found between 1, 2 and 6-day isolates, or between individuals grouped for a few hours or lifelong. Unexpectedly, crickets grouped in immediate proximity within individual mesh cages that precluded fighting while permitting visual, olfactory and mechanical, antennal contact, were as aggressive as free isolates. This suggests that reduced aggression of grouped animals may be an acquired result of fighting. Supporting this notion, isolated crickets initially engage in vigorous fights when first grouped, but fighting intensity and duration rapidly decline to the level of life-long grouped crickets within only 10 min. Furthermore, grouped crickets become as aggressive as life-long isolates after only 3 hours of isolation, and on the same time course required for crickets to regain their aggressiveness after social defeat. We conclude that the reduced aggressiveness of grouped crickets is a manifestation of the loser effect resulting from social subjugation, while isolation allows recovery to a state of heightened aggressiveness, which in crickets can be considered as the default condition. Given the widespread occurrence of the loser effect in the Animal Kingdom, many effects generally attributed to social isolation are likely to be a consequence of recovery from social subjugation.

Description: by Horst Kierdorf, Uwe Kierdorf, Kai Frölich, Carsten Witzel We studied the structural characteristics and periodicities of regular incremental markings in sheep enamel using fluorochrome injections for vital labeling of forming enamel and backscattered electron imaging in the scanning electron microscope. Microscopic analysis of mandibular first molars revealed the presence of incremental markings with a daily periodicity (laminations) that indicated successive positions of the forming front of interprismatic enamel. In addition to the laminations, incremental markings with a sub-daily periodicity were discernible both in interprismatic enamel and in enamel prisms. Five sub-daily increments were present between two consecutive laminations. Backscattered electron imaging revealed that each sub-daily growth increment consisted of a broader and more highly mineralized band and a narrower and less mineralized band (line). The sub-daily markings in the prisms of sheep enamel morphologically resembled the (daily) prisms cross striations seen in primate enamel. Incremental markings with a supra-daily periodicity were not observed in sheep enamel. Based on the periodicity of the incremental markings, maximum mean daily apposition rates of 17.0 µm in buccal enamel and of 13.4 µm in lingual enamel were recorded. Enamel extension rates were also high, with maximum means of 180 µm/day and 217 µm/day in upper crown areas of buccal and lingual enamel, respectively. Values in more cervical crown portions were markedly lower. Our results are in accordance with previous findings in other ungulate species. Using the incremental markings present in primate enamel as a reference could result in a misinterpretation of the incremental markings in ungulate enamel. Thus, the sub-daily growth increments in the prisms of ungulate enamel might be mistaken as prism cross striations with a daily periodicity, and the laminations misidentified as striae of Retzius with a supra-daily periodicity. This would lead to a considerable overestimation of crown formation times in ungulate teeth.

Description: by Zhu Huang, Xiao-Dong Pan, Ping-Gu Wu, Jian-Long Han, Qing Chen Environmental pollution with toxic heavy metals can lead to the possible contamination of the rice. Selected metals (As, Cd, Hg and Pb) and their accumulation in rice collected from Zhejiang, China were analyzed to evaluate the potential health risk to the local adults and children. The mean levels found in rice were as follows: As, 0.080 mg/kg; Cd, 0.037 mg/kg; Hg, 0.005 mg/kg; Pb, 0.060 mg/kg. The estimated daily intakes (EDIs) were calculated in combination of the rice consumption data. The mean intakes of As, Cd, Hg and Pb through rice were estimated to be 0.49, 0.23, 0.03 and 0.37 µg/kg bw/day for adults, and 0.34, 0.29, 0.04 and 0.47 µg/kg bw/day for children. The 97.5th percentile (P97.5) daily intakes of As, Cd, Hg and Pb were 1.02, 0.64, 0.37 and 1.26 µg/kg bw/day for adults, and 0.63, 0.83, 0.47 and 1.63 µg/kg bw/day for children. The risk assessment in mean levels showed that health risk associated with these elements through consumption of rice was absent. However, estimates in P97.5 level of Cd and Pb for children, and Hg for adults have exceeded the respective safe limits.

Description: O -GlcNAcylation is an inducible, highly dynamic and reversible post-translational modification, mediated by a unique enzyme named O -linked N -acetyl- d -glucosamine ( O -GlcNAc) transferase (OGT). In response to nutrients, O -GlcNAc levels are differentially regulated on many cellular proteins involved in gene expression, translation, immune reactions, protein degradation, protein–protein interaction, apoptosis and signal transduction. In contrast to eukaryotic cells, little is known about the role of O -GlcNAcylation in the viral life cycle. Here, we show that the overexpression of the OGT reduces the replication efficiency of Kaposi's sarcoma-associated herpesvirus (KSHV) in a dose-dependent manner. In order to investigate the global impact of O -GlcNAcylation in the KSHV life cycle, we systematically analyzed the 85 annotated KSHV-encoded open reading frames for O -GlcNAc modification. For this purpose, an immunoprecipitation (IP) strategy with three different approaches was carried out and the O -GlcNAc signal of the identified proteins was properly controlled for specificity. Out of the 85 KSHV-encoded proteins, 18 proteins were found to be direct targets for O -GlcNAcylation. Selected proteins were further confirmed by mass spectrometry for O -GlcNAc modification. Correlation of the functional annotation and the O -GlcNAc status of KSHV proteins showed that the predominant targets were proteins involved in viral DNA synthesis and replication. These results indicate that O -GlcNAcylation plays a major role in the regulation of KSHV propagation.

Description: Galectins are potent adhesion/growth-regulatory effectors with characteristic expression profiles. Understanding the molecular basis of gene regulation in each case requires detailed information on copy number of genes and sequence(s) of their promoter(s). Our report reveals plasticity in this respect between galectins and species. We here describe occurrence of a two-gene constellation for human galectin (Gal)-7 and define current extent of promoter-sequence divergence. Interestingly, cross-species genome analyses also detected single-copy display. Because the regulatory potential will then be different, extrapolations of expression profiles are precluded between respective species pairs. Gal-4 coding in chromosomal vicinity was found to be confined to one gene, whereas copy-number variation also applied to Gal-9. The example of rat Gal-9 teaches the lesson that the presence of multiple bands in Southern blotting despite a single-copy gene constellation is attributable to two pseudogenes. The documented copy-number variability should thus be taken into consideration when studying regulation of galectin genes, in a species and in comparison between species.

Description: In studying the molecular basis for the potent immune activity of previously described gamma and delta inulin particles and to assist in production of inulin adjuvants under Good Manufacturing Practice, we identified five new inulin isoforms, bringing the total to seven plus the amorphous form. These isoforms comprise the step-wise inulin developmental series amorphous -〉 alpha-1 (AI-1) -〉 alpha-2 (AI-2) -〉 gamma (GI) -〉 delta (DI) -〉 zeta (ZI) -〉 epsilon (EI) -〉 omega (OI) in which each higher isoform can be made either by precipitating dissolved inulin or by direct conversion from its precursor, both cases using regularly increasing temperatures. At higher temperatures, the shorter inulin polymer chains are released from the particle and so the key difference between isoforms is that each higher isoform comprises longer polymer chains than its precursor. An increasing trend of degree of polymerization is confirmed by end-group analysis using 1 H nuclear magnetic resonance spectroscopy. Inulin isoforms were characterized by the critical temperatures of abrupt phase-shifts (solubilizations or precipitations) in water suspensions. Such (aqueous) "melting" or "freezing" points are diagnostic and occur in strikingly periodic steps reflecting quantal increases in noncovalent bonding strength and increments in average polymer lengths. The (dry) melting points as measured by modulated differential scanning calorimetry similarly increase in regular steps. We conclude that the isoforms differ in repeated increments of a precisely repeating structural element. Each isoform has a different spectrum of biological activities and we show the higher inulin isoforms to be more potent alternative complement pathway activators.

Description: The methylotrophic yeast, Pichia pastoris , is an important organism used for the production of therapeutic proteins. Previously, we have reported the glycoengineering of this organism to produce human-like N -linked glycans but up to now no one has addressed engineering the O -linked glycosylation pathway. Typically, O -linked glycans produced by wild-type P. pastoris are linear chains of four to five α-linked mannose residues, which may be capped with β- or phospho-mannose. Previous genetic engineering of the N-linked glycosylation pathway of P. pastoris has eliminated both of these two latter modifications, resulting in O -linked glycans which are linear α-linked mannose structures. Here, we describe a method for the co-expression of an α-1,2-mannosidase, which reduces these glycans to primarily a single O -linked mannose residue. In doing so, we have reduced the potential of these glycans to interact with carbohydrate-binding proteins, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin. Furthermore, the introduction of the enzyme protein- O -linked-mannose β-1,2- N -acetylglucosaminyltransferase 1, resulted in the capping of the single O -linked mannose residues with N -acetylglucosamine. Subsequently, this glycoform was extended into human-like sialylated glycans, similar in structure to α-dystroglycan-type glycoforms. As such, this represents the first example of sialylated O -linked glycans being produced in yeast and extends the utility of the P. pastoris production platform beyond N -linked glycosylated biotherapeutics to include molecules possessing O -linked glycans.

Description: Neurons and other cells require intracellular transport of essential components for viability and function. Previous work has shown that while net amyloid precursor protein (APP) transport is generally anterograde, individual vesicles containing APP move bi-directionally. This discrepancy highlights our poor understanding of the in vivo regulation of APP-vesicle transport. Here, we show that reduction of presenilin (PS) or suppression of gamma-secretase activity substantially increases anterograde and retrograde velocities for APP vesicles. Strikingly, PS deficiency has no effect on an unrelated cargo vesicle class containing synaptotagmin, which is powered by a different kinesin motor. Increased velocities caused by PS or gamma-secretase reduction require functional kinesin-1 and dynein motors. Together, our findings suggest that a normal function of PS is to repress kinesin-1 and dynein motor activity during axonal transport of APP vesicles. Furthermore, our data suggest that axonal transport defects induced by loss of PS-mediated regulatory effects on APP-vesicle motility could be a major cause of neuronal and synaptic defects observed in Alzheimer's Disease (AD) pathogenesis. Thus, perturbations of APP/PS transport could contribute to early neuropathology observed in AD, and highlight a potential novel therapeutic pathway for early intervention, prior to neuronal loss and clinical manifestation of disease.

Description: With age, muscle mass and integrity are progressively lost leaving the elderly frail, weak and unable to independently care for themselves. Defined as sarcopenia, this age-related muscle atrophy appears to be multifactorial but its definite cause is still unknown. Mitochondrial dysfunction has been implicated in this process. Using a novel transgenic mouse model of mitochondrial DNA (mtDNA) double-strand breaks (DSBs) that presents a premature aging-like phenotype, we studied the role of mtDNA damage in muscle wasting. We caused DSBs in mtDNA of adult mice using a ubiquitously expressed mitochondrial-targeted endonuclease, mito- Pst I. We found that a short, transient systemic mtDNA damage led to muscle wasting and a decline in locomotor activity later in life. We found a significant decline in muscle satellite cells, which decreases the muscle's capacity to regenerate and repair during aging. This phenotype was associated with impairment in acetylcholinesterase (AChE) activity and assembly at the neuromuscular junction (NMJ), also associated with muscle aging. Our data suggests that systemic mitochondrial dysfunction plays important roles in age-related muscle wasting by preferentially affecting the myosatellite cell pool.

Description: by Simone Picelli, Justo Lorenzo Bermejo, Jenny Chang-Claude, Michael Hoffmeister, Ceres Fernández-Rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellví-Bel, Members of the EPICOLON Consortium (Gastrointestinal Oncology Group of the Spanish Gastroenterological Association): , Alessio Naccarati, Barbara Pardini, Ludmila Vodickova, Heiko Müller, Bente A. Talseth-Palmer, Geoffrey Stibbard, Paolo Peterlongo, Carmela Nici, Silvia Veneroni, Li Li, Graham Casey, Albert Tenesa, Susan M. Farrington, Ian Tomlinson, Victor Moreno, Tom van Wezel, Juul Wijnen, Malcolm Dunlop, Paolo Radice, Rodney J. Scott, Pavel Vodicka, Clara Ruiz-Ponte, Hermann Brenner, Stephan Buch, Henry Völzke, Jochen Hampe, Clemens Schafmayer, Annika Lindblom In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.

Description: by Takashi Ochiai, Yuji Suehiro, Katsuhiro Nishinari, Takeo Kubo, Hideaki Takeuchi Background Coordinated movement in social animal groups via social learning facilitates foraging activity. Few studies have examined the behavioral cause-and-effect between group members that mediates this social learning. Methodology/Principal Findings We first established a behavioral paradigm for visual food learning using medaka fish and demonstrated that a single fish can learn to associate a visual cue with a food reward. Grouped medaka fish (6 fish) learn to respond to the visual cue more rapidly than a single fish, indicating that medaka fish undergo social learning. We then established a data-mining method based on Kullback-Leibler divergence (KLD) to search for candidate behaviors that induce alignment and found that high-speed movement of a focal fish tended to induce alignment of the other members locally and transiently under free-swimming conditions without presentation of a visual cue. The high-speed movement of the informed and trained fish during visual cue presentation appeared to facilitate the alignment of naïve fish in response to some visual cues, thereby mediating social learning. Compared with naïve fish, the informed fish had a higher tendency to induce alignment of other naïve fish under free-swimming conditions without visual cue presentation, suggesting the involvement of individual recognition in social learning. Conclusions/Significance Behavioral cause-and-effect studies of the high-speed movement between fish group members will contribute to our understanding of the dynamics of social behaviors. The data-mining method used in the present study is a powerful method to search for candidates factors associated with inter-individual interactions using a dataset for time-series coordinate data of individuals.

Description: by Anthony Singhal, Simona Monaco, Liam D. Kaufman, Jody C. Culham Behavioral and neuropsychological research suggests that delayed actions rely on different neural substrates than immediate actions; however, the specific brain areas implicated in the two types of actions remain unknown. We used functional magnetic resonance imaging (fMRI) to measure human brain activation during delayed grasping and reaching. Specifically, we examined activation during visual stimulation and action execution separated by a 18-s delay interval in which subjects had to remember an intended action toward the remembered object. The long delay interval enabled us to unambiguously distinguish visual, memory-related, and action responses. Most strikingly, we observed reactivation of the lateral occipital complex (LOC), a ventral-stream area implicated in visual object recognition, and early visual cortex (EVC) at the time of action. Importantly this reactivation was observed even though participants remained in complete darkness with no visual stimulation at the time of the action. Moreover, within EVC, higher activation was observed for grasping than reaching during both vision and action execution. Areas in the dorsal visual stream were activated during action execution as expected and, for some, also during vision. Several areas, including the anterior intraparietal sulcus (aIPS), dorsal premotor cortex (PMd), primary motor cortex (M1) and the supplementary motor area (SMA), showed sustained activation during the delay phase. We propose that during delayed actions, dorsal-stream areas plan and maintain coarse action goals; however, at the time of execution, motor programming requires re-recruitment of detailed visual information about the object through reactivation of (1) ventral-stream areas involved in object perception and (2) early visual areas that contain richly detailed visual representations, particularly for grasping.

Description: by Annabel Meyer, Andreas Focks, Viviane Radl, Daniel Keil, Gerhard Welzl, Ingo Schöning, Steffen Boch, Sven Marhan, Ellen Kandeler, Michael Schloter Understanding factors driving the ecology of N cycling microbial communities is of central importance for sustainable land use. In this study we report changes of abundance of denitrifiers, nitrifiers and nitrogen-fixing microorganisms (based on qPCR data for selected functional genes) in response to different land use intensity levels and the consequences for potential turnover rates. We investigated selected grassland sites being comparable with respect to soil type and climatic conditions, which have been continuously treated for many years as intensely used meadows ( IM ), intensely used mown pastures ( IP ) and extensively used pastures ( EP ), respectively. The obtained data were linked to above ground biodiversity pattern as well as water extractable fractions of nitrogen and carbon in soil. Shifts in land use intensity changed plant community composition from systems dominated by s-strategists in extensive managed grasslands to c-strategist dominated communities in intensive managed grasslands. Along the different types of land use intensity, the availability of inorganic nitrogen regulated the abundance of bacterial and archaeal ammonia oxidizers. In contrast, the amount of dissolved organic nitrogen determined the abundance of denitrifiers ( nirS and nirK ). The high abundance of nifH carrying bacteria at intensive managed sites gave evidence that the amounts of substrates as energy source outcompete the high availability of inorganic nitrogen in these sites. Overall, we revealed that abundance and function of microorganisms involved in key processes of inorganic N cycling (nitrification, denitrification and N fixation) might be independently regulated by different abiotic and biotic factors in response to land use intensity.

Description: by Xiaofeng Wang, Liang Zhang, Zixian Chen, Yushui Ma, Yuan Zhao, Abudouaini Rewuti, Feng Zhang, Da Fu, Yusong Han Background The association between polymorphisms on 5p12 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two wildly studied polymorphisms (rs10941679 and rs4415084) on 5p12. Methods Databases including Pubmed, EMBASE, Web of Science, EBSCO, and Cochrane Library databases were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias. Results A total of 19 articles involving 100,083 cases and 163,894 controls were included. An overall random-effects per-allele OR of 1.09 (95% CI: 1.06–1.12; P =  4.5×10 −8 ) and 1.09 (95% CI: 1.05–1.12; P  = 4.2×10 −7 ) was found for the rs10941679 and rs4415084 polymorphism respectively. Significant results were found in Asians and Caucasians when stratified by ethnicity; whereas no significant associations were found among Africans/African-Americans. Similar results were also observed using dominant or recessive genetic models. In addition, we find both rs4415084 and rs10941679 conferred significantly greater risks of ER-positive breast cancer than of ER-negative tumors. Conclusions Our findings demonstrated that rs10941679-G allele and rs4415084-T allele might be risk-conferring factors for the development of breast cancer, especially in Caucasians and East-Asians.

Description: Populations of widely distributed species encounter and must adapt to local environmental conditions. However, comprehensive characterization of the genetic basis of adaptation is demanding, requiring genome-wide genotype data, multiple sampled populations, and an understanding of population structure and potential selection pressures. Here, we used single-nucleotide polymorphism genotyping and data on numerous environmental variables to describe the genetic basis of local adaptation in 21 populations of teosinte, the wild ancestor of maize. We found complex hierarchical genetic structure created by altitude, dispersal events, and admixture among subspecies, which complicated identification of locally beneficial alleles. Patterns of linkage disequilibrium revealed four large putative inversion polymorphisms showing clinal patterns of frequency. Population differentiation and environmental correlations suggest that both inversions and intergenic polymorphisms are involved in local adaptation.

Description: We present a methodology for infrasonic remote sensing of winds in the stratosphere that does not require discrete ground-truth events. Our method uses measured time delays between arrays of sensors to provide group velocities (referred to here as celerities) and then minimizes the difference between observed and predicted celerities by perturbing an initial atmospheric specification. Because we focus on interarray propagation effects, it is not necessary to simulate the full propagation path from source to receiver. This feature allows us to use a relatively simple forward model that is applicable over short-regional distances. By focusing on stratospheric returns, we show that our non-linear inversion scheme converges much better if the starting model contains a strong stratospheric duct. Using the Horizontal Wind Model (HWM)/Mass Spectrometer Incoherent Scatter (MSISE) empirical climatology as a starting model, we demonstrate that the inversion scheme is robust to large uncertainties in backazimuth, but that uncertainties in the measured trace velocity and celerity require the use of prior constraints to ensure suitable convergence. The inversion of synthetic data, using realistic estimates of measurement error, shows that our scheme will nevertheless improve upon a starting model under most scenarios. The inversion scheme is applied to infrasound data recorded from a large event on 2010 December 25, which is presumed to be a bolide, using data from a nine-element infrasound network in Utah. We show that our recorded data require a stronger zonal wind speed in the stratosphere than is present in the HWM profile, and are more consistent with the Ground-to-Space (G2S) profile.

Description: Coda- Q is a stochastic parameter reflecting the heterogeneities of medium that seismic waves travel through. We confirmed that coda- Q would vary with the stress loaded to an elastic medium using numerical simulations of seismic wave propagation. When the stress is loaded, cracks in the crust could either close or newly open. The closure and opening of the cracks are not random but depending on the magnitude and the direction of the stress and the crack aspect ratio. The cracks in the medium after loading stress could be aligned in a specific orientation, and elastic wave velocity field would become anisotropic due to the alignment of specific crack orientations. Elastic wave velocity is in general faster along the direction corresponding with the crack orientation while slower along the perpendicular direction. In the numerical simulation, the effect of anisotropy in elastic wave velocity field due to the selective closure and opening of the cracks is calculated using a 2-D finite difference method assuming elastic wave velocity to be a function of the magnitude of loaded stress. The coda- Q calculated from seismic waves simulated for a model varies when the averaged normal stress changes. Our simulation indicated that the sensitivity of coda- Q –1 , that is the reciprocal of the coda- Q , would be 1.0 10 –2 (1.0 MPa –1 ) against the magnitude of the confining pressure and 1.0 10 –3 (1.0 deg –1 ) against the direction of principal stress. We would like to conclude that coda- Q , a stochastic parameter reflecting heterogeneities of subsurface medium, could become a quantitative state indicator of the stress field of the medium where seismic waves propagate through. Spatiotemporal variation of coda- Q reflects change in the stress field in the crust.

Description: How do body-wave traveltimes constrain the Earth's radial (1-D) seismic structure? Existing 1-D seismological models underpin 3-D seismic tomography and earthquake location algorithms. It is therefore crucial to assess the quality of such 1-D models, yet quantifying uncertainties in seismological models is challenging and thus often ignored. Ideally, quality assessment should be an integral part of the inverse method. Our aim in this study is twofold: (i) we show how to solve a general Bayesian non-linear inverse problem and quantify model uncertainties, and (ii) we investigate the constraint on spherically symmetric P -wave velocity ( V P ) structure provided by body-wave traveltimes from the EHB bulletin (phases Pn , P , PP and PKP ). Our approach is based on artificial neural networks, which are very common in pattern recognition problems and can be used to approximate an arbitrary function. We use a Mixture Density Network to obtain 1-D marginal posterior probability density functions (pdfs), which provide a quantitative description of our knowledge on the individual Earth parameters. No linearization or model damping is required, which allows us to infer a model which is constrained purely by the data. We present 1-D marginal posterior pdfs for the 22 V P parameters and seven discontinuity depths in our model. P -wave velocities in the inner core, outer core and lower mantle are resolved well, with standard deviations of ~0.2 to 1 per cent with respect to the mean of the posterior pdfs. The maximum likelihoods of V P are in general similar to the corresponding ak135 values, which lie within one or two standard deviations from the posterior means, thus providing an independent validation of ak135 in this part of the radial model. Conversely, the data contain little or no information on P -wave velocity in the D '' layer, the upper mantle and the homogeneous crustal layers. Further, the data do not constrain the depth of the discontinuities in our model. Using additional phases available in the ISC bulletin, such as PcP , PKKP and the converted phases SP and ScP , may enhance the resolvability of these parameters. Finally, we show how the method can be extended to obtain a posterior pdf for a multidimensional model space. This enables us to investigate correlations between model parameters.

Description: We have developed a network optimization method for regional-scale microseismic monitoring networks and applied it to optimize the densification of the existing seismic network in northeastern Switzerland. The new network will build the backbone of a 10-yr study on the neotectonic activity of this area that will help to better constrain the seismic hazard imposed on nuclear power plants and waste repository sites. This task defined the requirements regarding location precision (0.5 km in epicentre and 2 km in source depth) and detection capability [magnitude of completeness M c  = 1.0 ( M L )]. The goal of the optimization was to find the geometry and size of the network that met these requirements. Existing stations in Switzerland, Germany and Austria were considered in the optimization procedure. We based the optimization on the simulated annealing approach proposed by Hardt & Scherbaum, which aims to minimize the volume of the error ellipsoid of the linearized earthquake location problem ( D -criterion). We have extended their algorithm to: calculate traveltimes of seismic body waves using a finite difference ray tracer and the 3-D velocity model of Switzerland, calculate seismic body-wave amplitudes at arbitrary stations assuming the Brune source model and using scaling and attenuation relations recently derived for Switzerland, and estimate the noise level at arbitrary locations within Switzerland using a first-order ambient seismic noise model based on 14 land-use classes defined by the EU-project CORINE and open GIS data. We calculated optimized geometries for networks with 10–35 added stations and tested the stability of the optimization result by repeated runs with changing initial conditions. Further, we estimated the attainable magnitude of completeness ( M c ) for the different sized optimal networks using the Bayesian Magnitude of Completeness (BMC) method introduced by Mignan et al. The algorithm developed in this study is also applicable to smaller optimization problems, for example, small local monitoring networks. Possible applications are volcano monitoring, the surveillance of induced seismicity associated with geotechnical operations and many more. Our algorithm is especially useful to optimize networks in populated areas with heterogeneous noise conditions and if complex velocity structures or existing stations have to be considered.

Description: Fluid injection in and withdrawal from wells are basic procedures in mining activities and deep resources exploitation, such as oil and gas extraction, permeability enhancement for geothermal exploitation and waste fluid disposal. All of these activities have the potential to induce seismicity, as exemplified by the 2006 Basel earthquake ( M L 3.4). Despite several decades of experience, the mechanisms of induced seismicity are not known in detail, which prevents effective risk assessment and/or mitigation. In this study, we provide an interpretation of induced seismicity based on computation of Coulomb stress changes that result from fluid injection/withdrawal at depth, mainly focused on the interpretation of induced seismicity due to stimulation of a geothermal reservoir. Seismicity is, theoretically, more likely where Coulomb stress changes are larger. For modeling purposes, we simulate the thermodynamic evolution of a system after fluid injection/withdrawal. The associated changes in pressure and temperature are subsequently considered as sources of incremental stress changes, which are then converted to Coulomb stress changes on favourably oriented faults, taking into account the background regional stress. Numerical results are applied to the water injection that was performed to create the fractured reservoir at the enhanced-geothermal-system site, Soultz-sous-Forets (France). Our approach describes well the observed seismicity, and provides an explanation for the different behaviors of a system when fluids are injected or withdrawn.

Description: We report on a broad-band high-resolution attenuation model for the North China Craton and surrounding regions based on regional Lg -wave data. Vertical broad-band waveforms recorded at 39 stations from 176 crustal earthquakes are collected to extract the Lg -wave amplitude spectra between 0.05 and 10.0 Hz. We use the dual-station method to generate a preliminary Q Lg model and use it as the initial model. Then, we combine the dual- and single-station data together to jointly invert the Q Lg distribution and Lg source excitation functions. These inversions are conducted independently at individual frequencies without using any a priori assumption about the frequency dependences in Q Lg and source terms. The maximum spatial resolution is approximately 1° x 1° in well-covered areas for frequencies between 0.05 and 2.0 Hz. The Q Lg image is then used to determine the relationship between the attenuation and different geological structures. Results show an average Q 0 (1 Hz Q Lg ) of 374 for the entire North China Craton with an increasing trend from east to west. Average Q 0 values are 337, 361 and 421 for the east, central and west blocks, respectively. For the surrounding regions, the Eastern Tibetan plateau has a very low Q 0 of 188, while the Northeast China Plate and the Tianshan–Xingmeng fold belts are characterized by high Q 0 values of 506 and 424, respectively. We also investigate regional variations of the Lg attenuation in low-frequency band between 0.2 and 1.0 Hz.

Description: We present a systematic study on the influence of pressure (0.1–600 MPa), temperature (750–1200 °C), carbon dioxide fugacity (log f CO 2  = –4.41 to 3.60) and time (2–12 hr) on the chemical and physical properties of carbonate rock. Our experiments aim to reproduce the conditions at the periphery of magma chamber where carbonate host rock is influenced by, but not readily assimilated by, magma. This permits the investigation of the natural conditions at which circulating fluids/gases promote infiltration reactions typical of metasomatic skarns that can involve large volumes of subvolcanic carbonate basements. Results show that, providing that carbon dioxide is retained in the pore space, decarbonation does not proceed at any magmatic pressure and temperature. However, when the carbon dioxide is free to escape, decarbonation can occur rapidly and is not hindered by a low initial porosity or permeability. Together with carbon dioxide and lime, portlandite, a mineral commonly found in voluminous metasomatic skarns, readily forms during carbonate decomposition. Post-experimental analyses highlight that thermal microcracking, a result of the highly anisotropic thermal expansion of calcite, exerts a greater influence on rock physical properties (porosity, ultrasonic wave velocities and elastic moduli) than decarbonation. Our data suggest that this will be especially true at the margins of dykes or magma bodies, where temperatures can reach up to 1200 °C. However, rock compressive strength is significantly reduced by both thermal cracking and decarbonation, explained by the relative weakness of lime + portlandite compared to calcite, and an increase in grain size with increasing temperature. Metasomatic skarns, whose petrogenetic reactions may involve a few tens of cubic kilometres, could therefore represent an important source of volcanic instability.

Description: The scattering of plane SH waves incident on a circular sectorial canyon is considered. An accurate region-matching technique is applied to derive a rigorous series solution. Appropriate wavefunctions are employed to describe antiplane motions. Judicious basis functions, involving Gegenbauer polynomials, are well utilized to correctly capture the singular behaviour in stress fields near the canyon bottom. The enforcement of matching conditions on the auxiliary boundary leads to the determination of unknown coefficients. Plotted results demonstrate the influence of pertinent parameters on surface and subsurface motions. Both steady-state and transient results are included. The solution technique proposed achieves a considerable reduction in the computational effort, facilitating benchmark computations. The derived series solution enriches the limited list of series solutions presently known for canyon problems related to SH -wave scattering.

Description: We present 3-D models of the P- and S -wave velocity distributions in the crust and uppermost mantle beneath Sicily, Calabria (Southern Italy), and surrounding submerged areas, obtained by tomographic inversion of traveltimes of regional body waves phases. Our method combines double-difference tomographic inversion with a post-processing procedure [Weighted Average Model method (WAM)]. This procedure was applied to a set of models consistent with the experimental data. We tested the ability of the WAM procedure to mitigate the uncertainty associated with the arbitrary nature of the many input parameters required for each inversion. The local reliability and resolution of the obtained models have been assessed through: synthetic tests, experimental tests carried out with independent data sets and unconventional tests based on the analysis of the internal consistency of the P - and S -velocity models. The tomographic images provide a detailed sketch of P- and S- wave velocity anomalies. These clearly show the shape of the Sicilian-Maghrebian belt beneath Sicily and Calabrian Arc at different depths. Low V P and Vs bodies are imaged beneath Stromboli and Marsili volcanoes in the southern Tyrrhenian, whereas high and low seismic velocities alternate beneath the Etna giving inferences on the possible depth of the mantle melting feeding the volcano. In the upper crust, the main sedimentary basins and tectonic features are also well imaged. Finally, tomographic cross sections show the trend of the Moho in the study area, where its depth ranges between 35 and 40 km beneath the Sicilian belt and between 15 and 22 km in the southern Tyrrhenian basin and Ionian Sea.

Description: We used two tracks of ALOS PALSAR images to investigate the focal mechanism and slip distribution of the 2011 March 24, M W 6.8 Burma strike-slip earthquake. Three different SAR techniques, namely conventional interferometry, SAR pixel offsets (SPO) and multiple-aperture InSAR (MAI), were employed to obtain the coseismic surface deformation fields along the ~30 km length of the fault rupture. Along-track measurements from SPO and MAI techniques show a high correlation, and were subsequently used to precisely determine the location and extent of the surface fault trace. The best-fitting fault model geometry derived from an iterative inversion technique suggests that the rupture occurred on a near-vertical sinistral strike-slip fault west of the Nam Ma fault with a strike of 70°. A maximum slip of 4.2 m occurs at a depth of 2.5 km, with significant slip constrained only to the upper 10 km of the crust.

Description: Knowledge of the mantle reflectivity structure is highly dependent on our ability to efficiently extract, and properly interpret, small seismic arrivals. Among the various data types and techniques, long-period SS/PP precursors and high-frequency receiver functions are routinely utilized to increase the confidence of the recovered mantle stratifications at distinct spatial scales. However, low resolution and a complex Fresnel zone are glaring weaknesses of SS precursors, while over-reliance on receiver distribution is a formidable challenge for the analysis of converted waves from oceanic regions. A promising high frequency alternative to receiver functions is P ' P ' precursors, which are capable of resolving mantle structures at vertical and lateral resolution of ~5 and ~200 km, respectively, owing to their spectral content, shallow angle of incidence and near-symmetric Fresnel zones. This study presents a novel processing method for both SS (or PP) and P ' P ' precursors based on deconvolution, stacking, Radon transform and depth migration. A suite of synthetic tests is performed to quantify the fidelity and stability of this method under different data conditions. Our multiresolution survey of the mantle at targeted areas near Nazca-South America subduction zone reveal both olivine and garnet related transitions at depths below 400 km. We attribute a depressed 660 to thermal variations, whereas compositional variations atop the upper-mantle transition zone are needed to explain the diminished or highly complex reflected/scattered signals from the 410 km discontinuity. We also observe prominent P ' P ' reflections within the transition zone, and the anomalous amplitudes near the plate boundary zone indicate a sharp (~10 km thick) transition that likely resonates with the frequency content of P ' P ' precursors. The migration of SS precursors in this study shows no evidence of split 660 reflections, but potential majorite–ilmenite (590–640 km) and ilmenite–perovskite transitions (740–750 km) are identified based on similarly processed high-frequency P ' P ' precursors. Additional findings of severely scattered energy in the lithosphere and distinct lower mantle reflections at ~800 km could be potentially important but require further verifications. Overall, our improved imaging methods and the strong sensitivity of P ' P ' precursors to the existence, depth, sharpness and strength of reflective structures offer significant future promise for the understanding of mantle mineralogy and dynamics.

Description: Time-dependent probabilistic seismic hazard assessment requires a stochastic description of earthquake occurrences. While short-term seismicity models are well-constrained by observations, the recurrences of characteristic on-fault earthquakes are only derived from theoretical considerations, uncertain palaeo-events or proxy data. Despite the involved uncertainties and complexity, simple statistical models for a quasi-period recurrence of on-fault events are implemented in seismic hazard assessments. To test the applicability of statistical models, such as the Brownian relaxation oscillator or the stress release model, we perform a systematic comparison with deterministic simulations based on rate- and state-dependent friction, high-resolution representations of fault systems and quasi-dynamic rupture propagation. For the specific fault network of the Lower Rhine Embayment, Germany, we run both stochastic and deterministic model simulations based on the same fault geometries and stress interactions. Our results indicate that the stochastic simulators are able to reproduce the first-order characteristics of the major earthquakes on isolated faults as well as for coupled faults with moderate stress interactions. However, we find that all tested statistical models fail to reproduce the characteristics of strongly coupled faults, because multisegment rupturing resulting from a spatiotemporally correlated stress field is underestimated in the stochastic simulators. Our results suggest that stochastic models have to be extended by multirupture probability distributions to provide more reliable results.

Description: Stress waves, known as acoustic emissions (AEs), are released by localized inelastic deformation events during the progressive failure of brittle rocks. Although several numerical models have been developed to simulate the deformation and damage processes of rocks, such as non-linear stress–strain behaviour and localization of failure, only a limited number have been capable of providing quantitative information regarding the associated seismicity. Moreover, the majority of these studies have adopted a pseudo-static approach based on elastic strain energy dissipation that completely disregards elastodynamic effects. This paper describes a new AE modelling technique based on the combined finite-discrete element method (FEM/DEM), a numerical tool that simulates material failure by explicitly considering fracture nucleation and propagation in the modelling domain. Given the explicit time integration scheme of the solver, stress wave propagation and the effect of radiated seismic energy can be directly captured. Quasi-dynamic seismic information is extracted from a FEM/DEM model with a newly developed algorithm based on the monitoring of internal variables (e.g. relative displacements and kinetic energy) in proximity to propagating cracks. The AE of a wing crack propagation model based on this algorithm are cross-analysed by traveltime inversion and energy estimation from seismic recordings. Results indicate a good correlation of AE initiation times and locations, and scaling of energies, independently calculated with the two methods. Finally, the modelling technique is validated by simulating a laboratory compression test on a granite sample. The micromechanical parameters of the heterogeneous model are first calibrated to reproduce the macroscopic stress–strain response measured during standard laboratory tests. Subsequently, AE frequency–magnitude statistics, spatial clustering of source locations and the evolution of AE rate are investigated. The distribution of event magnitude tends to decay as power law while the spatial distribution of sources exhibits a fractal character, in agreement with experimental observations. Moreover, the model can capture the decrease of seismic b value associated with the macrorupture of the rock sample and the transition of AE spatial distribution from diffuse, in the pre-peak stage, to strongly localized at the peak and post-peak stages, as reported in a number of published laboratory studies. In future studies, the validated FEM/DEM-AE modelling technique will be used to obtain further insights into the micromechanics of rock failure with potential applications ranging from laboratory-scale microcracking to engineering-scale processes (e.g. excavations within mines, tunnels and caverns, petroleum and geothermal reservoirs) to tectonic earthquakes triggering.

Description: We used strong-motion records from the 2012 May 20 and 29 Emilia-Romagna earthquakes ( M w 6.1 and 5.9, respectively) and four aftershocks with magnitudes ranging between 4.9 and 5.5 to analyse the S -wave spectral amplitude decay with distance and estimate acceleration source functions and site effects. The data set consists of six earthquakes, 44 stations and 248 records with hypocentral distances in the range 10 〈 r  〈 100 km. We rotated the accelerograms to calculate transverse and radial components of the acceleration spectrum. We found non-parametric attenuation functions that describe the spectral amplitude decay of SH and SV waves with distance at 60 different frequencies between 0.1 and 40 Hz. These attenuation functions provide an estimate of the quality factor Q at each frequency analysed. Assuming that geometrical spreading is 1/ r for r  ≤ r x and 1/( r x r ) 0.5 for r  〉 r x with r x  = 60 km and normalizing at 15 km (the recording distance where the attenuation functions start to decay), we find that the average Q for SH waves can be approximated by Q SH  = 82 ± 1 f  1.2±0.02 and by Q SV  = 79 ± 1 f  1.24±0.03 for SV waves in the frequency range 0.10 ≤ f  ≤ 10.7 Hz. At higher frequencies, 11.8 ≤ f  ≤ 40 Hz, the frequency dependence of Q weakens and is approximated by Q SH  = 301 ± 1 f   0.36±0.04 and Q SV  = 384 ± 1 f  0.28±0.04 . These results indicate that the S -wave attenuation is radially isotropic at local distances in the epicentral area. Nevertheless, we used these attenuation parameters separately to correct the radial (with Q SV ) and transverse (with Q SH ) components of the acceleration spectra and to separate source and site effects using a non-parametric spectral inversion scheme. We found that the source function of the main event and the bigger aftershocks show enhanced low frequency radiation between 0.4 and 3.0 Hz. We converted the source functions into far-field source acceleration spectra and interpreted the resulting source spectra in terms of Brune's model. The stress drops obtained range between approximately 0.9 and 2.9 MPa. Although all the recording stations used are located in the Po Plain, the site functions obtained from the spectral inversion show important amplification variability between the sites. We compared these site functions with the average horizontal to vertical spectral ratios calculated for each station, and we found consistent results for most stations.

Description: by Dongnhu T. Truong, Ashley Bonet, Amanda R. Rendall, Glenn D. Rosen, Roslyn H. Fitch Disruption of neuronal migration in humans is associated with a wide range of behavioral and cognitive outcomes including severe intellectual disability, language impairment, and social dysfunction. Furthermore, malformations of cortical development have been observed in a number of neurodevelopmental disorders (e.g. autism and dyslexia), where boys are much more commonly diagnosed than girls (estimates around 4 to 1). The use of rodent models provides an excellent means to examine how sex may modulate behavioral outcomes in the presence of comparable abnormal neuroanatomical presentations. Initially characterized by Rosen et al. 2012, the BXD29- Tlr4lps−2J /J mouse mutant exhibits a highly penetrant neuroanatomical phenotype that consists of bilateral midline subcortical nodular heterotopia with partial callosal agenesis. In the current study, we confirm our initial findings of a severe impairment in rapid auditory processing in affected male mice. We also report that BXD29- Tlr4lps−2J /J (mutant) female mice show no sparing of rapid auditory processing, and in fact show deficits similar to mutant males. Interestingly, female BXD29- Tlr4lps−2J /J mice do display superiority in Morris water maze performance as compared to wild type females, an affect not seen in mutant males. Finally, we report new evidence that BXD29- Tlr4lps−2J /J mice, in general, show evidence of hyper-social behaviors. In closing, the use of the BXD29- Tlr4lps−2J /J strain of mice – with its strong behavioral and neuroanatomical phenotype – may be highly useful in characterizing sex independent versus dependent mechanisms that interact with neural reorganization, as well as clinically relevant abnormal behavior resulting from aberrant neuronal migration.

Description: by Peng Zhao, Xue-mei Zhou, Li-yao Zhang, Wei Wang, Li-gang Ma, Li-bo Yang, Xiong-bo Peng, Peter V. Bozhkov, Meng-xiang Sun Plant zygote divides asymmetrically into an apical cell that develops into the embryo proper and a basal cell that generates the suspensor, a vital organ functioning as a conduit of nutrients and growth factors to the embryo proper. After the suspensor has fulfilled its function, it is removed by programmed cell death (PCD) at the late stages of embryogenesis. The molecular trigger of this PCD is unknown. Here we use tobacco ( Nicotiana tabacum ) embryogenesis as a model system to demonstrate that the mechanism triggering suspensor PCD is based on the antagonistic action of two proteins: a protease inhibitor, cystatin NtCYS, and its target, cathepsin H-like protease NtCP14. NtCYS is expressed in the basal cell of the proembryo, where encoded cystatin binds to and inhibits NtCP14, thereby preventing precocious onset of PCD. The anti-cell death effect of NtCYS is transcriptionally regulated and is repressed at the 32-celled embryo stage, leading to increased NtCP14 activity and initiation of PCD. Silencing of NtCYS or overexpression of NtCP14 induces precocious cell death in the basal cell lineage causing embryonic arrest and seed abortion. Conversely, overexpression of NtCYS or silencing of NtCP14 leads to profound delay of suspensor PCD. Our results demonstrate that NtCYS-mediated inhibition of NtCP14 protease acts as a bipartite molecular module to control initiation of PCD in the basal cell lineage of plant embryos.

Description: by William Henry Gilbert

Description: by Kaheina Aizel, Valérie Biou, Jorge Navaza, Lionel V. Duarte, Valérie Campanacci, Jacqueline Cherfils, Mahel Zeghouf The mechanisms whereby guanine nucleotide exchange factors (GEFs) coordinate their subcellular targeting to their activation of small GTPases remain poorly understood. Here we analyzed how membranes control the efficiency of human BRAG2, an ArfGEF involved in receptor endocytosis, Wnt signaling, and tumor invasion. The crystal structure of an Arf1–BRAG2 complex that mimics a membrane-bound intermediate revealed an atypical PH domain that is constitutively anchored to the catalytic Sec7 domain and interacts with Arf. Combined with the quantitative analysis of BRAG2 exchange activity reconstituted on membranes, we find that this PH domain potentiates nucleotide exchange by about 2,000-fold by cumulative conformational and membrane-targeting contributions. Furthermore, it restricts BRAG2 activity to negatively charged membranes without phosphoinositide specificity, using a positively charged surface peripheral to but excluding the canonical lipid-binding pocket. This suggests a model of BRAG2 regulation along the early endosomal pathway that expands the repertoire of GEF regulatory mechanisms. Notably, it departs from the auto-inhibitory and feedback loop paradigm emerging from studies of SOS and cytohesins. It also uncovers a novel mechanism of unspecific lipid-sensing by PH domains that may allow sustained binding to maturating membranes.

Description: by Shuncang Zhang, Pengda Ma, Dongfeng Yang, Wenjing Li, Zongsuo Liang, Yan Liu, Fenghua Liu Salvia miltiorrhiza Bunge is one of the most renowned traditional medicinal plants in China. Phenolic acids that are derived from the rosmarinic acid pathway, such as rosmarinic acid and salvianolic acid B, are important bioactive components in S. miltiorrhiza . Accumulations of these compounds have been reported to be induced by various elicitors, while little is known about transcription factors that function in their biosynthetic pathways. We cloned a subgroup 4 R2R3 MYB transcription factor gene ( SmMYB39 ) from S. miltiorrhiza and characterized its roles through overexpression and RNAi-mediated silencing. As the results showed, the content of 4-coumaric acid, rosmarinic acid, salvianolic acid B, salvianolic acid A and total phenolics was dramatically decreased in SmMYB39 -overexpressing S. miltiorrhiza lines while being enhanced by folds in SmMYB39 -RNAi lines. Quantitative real-time PCR and enzyme activities analyses showed that SmMYB39 negatively regulated transcripts and enzyme activities of 4-hydroxylase (C4H) and tyrosine aminotransferase (TAT). These data suggest that SmMYB39 is involved in regulation of rosmarinic acid pathway and acts as a repressor through suppressing transcripts of key enzyme genes.

Description: by Sang-Eun Yeon, Da Yoon No, Sang-Hoon Lee, Suk Woo Nam, Il-Hoan Oh, Jaehwi Lee, Hyo-Jeong Kuh Intrinsic drug resistance of pancreatic ductal adenocarcinoma (PDAC) warrants studies using models that are more clinically relevant for identifying novel resistance mechanisms as well as for drug development. Tumor spheroids (TS) mimic in vivo tumor conditions associated with multicellular resistance and represent a promising model for efficient drug screening, however, pancreatic cancer cells often fail to form spheroids using conventional methods such as liquid overlay. This study describes the induction of TS of human pancreatic cancer cells (Panc-1, Aspc-1, Capan-2) in concave polydimethylsiloxane (PDMS) microwell plates and evaluation of their usefulness as an anticancer efficacy test model. All three cell lines showed TS formation with varying degree of necrosis inside TS. Among these, Panc-1 spheroid with spherical morphology, a rather rough surface, and unique adhesion structures were successfully produced with no notable necrosis in concave microwell plates. Panc-1 TS contained growth factors or enzymes such as TGF-β1, CTGF, and MT1-MMP, and extracellular matrix proteins such as collagen type I, fibronectin, and laminin. Panc-1 cells grown as TS showed changes in stem cell populations and in expression levels of miRNAs that may play roles in chemoresistance. Visualization of drug penetration and detection of viability indicators, such as Ki-67 and MitoSOX, were optimized for TS for quantitative analysis. Water-soluble tetrazolium (MTS) and acid phosphatase (APH) assays were also successfully optimized. Overall, we demonstrated that concave PDMS microwell plates are a novel platform for preparation of TS of weakly aggregating cells and that Panc-1 spheroids may represent a novel three-dimensional model for anti-pancreatic cancer drug screening.

Description: by Duncan Howie, Hugo Garcia Rueda, Marion H. Brown, Herman Waldmann Most T cell responses to pathogens or self antigens are modulated through the action of regulatory T cells and tissue-specific inhibitory mechanisms. To this end, several receptor-ligand pairs have evolved which either augment or diminish T cell function. Here we describe the tissue ligand SECTM1A (Secreted and transmembrane1A) as an alternative murine CD7 ligand. We show that SECTM1A, like SECTM1B, binds strongly to CD7, and that SECTM1B was able to compete with SECTM1A for CD7 binding. SECTM1A is ubiquitously expressed and has two major alternative transcripts which differ in expression between tissues. Both immobilised soluble forms of SECTM1A and SECTM1B and cell surface anchored forms demonstrated opposing effects on CD4+ T cell activation. Whereas SECTM1A acted as a co-stimulator of T cells, enhancing IL-2 production and proliferation, SECTM1B proved inhibitory to TCR mediated T cell activation. Surprisingly, both functional outcomes proved to be CD7-independent, indicating the existence of alternative receptors for both ligands. We used a SECTM1A-Fc fusion protein to immunoprecipitate potential alternative ligands from detergent lysates of CD7 −/− T cells and, using mass spectrometry, identified GITR as a SECTM1A binder. SECTM1A was found to bind to activated CD4+ and CD8+ T cells as well as to CHO cells expressing cell surface GITR. Binding of SECTM1A to activated primary T cells was inhibited by either GITRL-Fc or anti GITR antibodies. Thus SECTM1A and SECTM1B represent novel reciprocal alternative ligands which may function to modulate the activation of effector and regulatory T cells. The ability of SECTM1A to activate T cells may be explained by its ability to bind to GITR.

Description: by Wei-Jun Zhou, Ren-Ying Wang, Yan Li, Dong-Rui Chen, Er-Zhen Chen, Ding-Liang Zhu, Ping-Jin Gao Objective β-blockers (BBs) with different pharmacological properties may have heterogeneous effects on sympathetic nervous activity (SNA) and central aortic pressure (CAP), which are independent cardiovascular factors for hypertension. Hence, we analyzed the effects of bisoprolol and atenolol on SNA and CAP in hypertensive patients. Methods This was a prospective, randomized, controlled study in 109 never-treated hypertensive subjects randomized to bisoprolol (5 mg) or atenolol (50 mg) for 4–8 weeks. SNA, baroreflex sensitivity (BRS) and heart rate (HR) variability (HRV) were measured using power spectral analysis using a Finometer. CAP and related parameters were determined using the SphygmoCor device (pulse wave analysis). Results Both drugs were similarly effective in reducing brachial BP. However, central systolic BP (−14±10 mm Hg vs −6±9 mm Hg; P

Description: by Catherine J. Mondloch, Nicole L. Nelson, Matthew Horner The accuracy and speed with which emotional facial expressions are identified is influenced by body postures. Two influential models predict that these congruency effects will be largest when the emotion displayed in the face is similar to that displayed in the body: the emotional seed model and the dimensional model. These models differ in whether similarity is based on physical characteristics or underlying dimensions of valence and arousal. Using a 3-alternative forced-choice task in which stimuli were presented briefly (Exp 1a) or for an unlimited time (Exp 1b) we provide evidence that congruency effects are more complex than either model predicts; the effects are asymmetrical and cannot be accounted for by similarity alone. Fearful postures are especially influential when paired with facial expressions, but not when presented in a flanker task (Exp 2). We suggest refinements to each model that may account for our results and suggest that additional studies be conducted prior to drawing strong theoretical conclusions.

Description: by Robert Savit, Maria Riolo, Rick Riolo Co-adaptation (or co-evolution), the parallel feedback process by which agents continuously adapt to the changes induced by the adaptive actions of other agents, is a ubiquitous feature of complex adaptive systems, from eco-systems to economies. We wish to understand which general features of complex systems necessarily follow from the (meta)-dynamics of co-adaptation, and which features depend on the details of particular systems. To begin this project, we present a model of co-adaptation (“The Stigmergy Game”) which is designed to be as a priori featureless as possible, in order to help isolate and understand the naked consequences of co-adaptation. In the model, heterogeneous, co-adapting agents, observe, interact with and change the state of an environment. Agents do not, ab initio , directly interact with each other. Agents adapt by choosing among a set of random “strategies,” particular to each agent. Each strategy is a complete specification of an agent's actions and payoffs. A priori , all environmental states are equally likely and all strategies have payoffs that sum to zero, so without co-adaptation agents would on average have zero “wealth”. Nevertheless, the dynamics of co-adaptation generates a structured environment in which only a subset of environmental states appear with high probability (niches) and in which agents accrue positive wealth. Furthermore, although there are no direct agent-agent interactions, there are induced non-trivial inter-agent interactions mediated by the environment. As a function of the population size and the number of possible environmental states, the system can be in one of three dynamical regions. Implications for a basic understanding of complex adaptive systems are discussed.

Description: by Sandra Laner-Plamberger, Florian Wolff, Alexandra Kaser-Eichberger, Stefan Swierczynski, Cornelia Hauser-Kronberger, Anna-Maria Frischauf, Thomas Eichberger Sustained hedgehog (Hh) signaling mediated by the GLI transcription factors is implicated in many types of cancer. Identification of Hh/GLI target genes modulating the activity of other pathways involved in tumor development promise to open new ways for better understanding of tumor development and maintenance. Here we show that SOCS1 is a direct target of Hh/GLI signaling in human keratinocytes and medulloblastoma cells. SOCS1 is a potent inhibitor of interferon gamma (IFN-y)/STAT1 signaling. IFN-у/STAT1 signaling can induce cell cycle arrest, apoptosis and anti-tumor immunity. The transcription factors GLI1 and GLI2 activate the SOCS1 promoter, which contains five putative GLI binding sites, and GLI2 binding to the promoter was shown by chromatin immunoprecipitation. Consistent with a role of GLI in SOCS1 regulation, STAT1 phosphorylation is reduced in cells with active Hh/GLI signaling and IFN-у/STAT1 target gene activation is decreased. Furthermore, IFN-у signaling is restored by shRNA mediated knock down of SOCS1. Here, we identify SOCS1 as a novel Hh/GLI target gene, indicating a negative role of Hh/GLI pathway in IFN-y/STAT1 signaling.

Description: by Xuting Xu, Yunliang Wang, Lingyan Wang, Qi Liao, Lan Chang, Leiting Xu, Yi Huang, Huadan Ye, Limin Xu, Cheng Chen, Xiaowei Shen, Fuqiang Zhang, Meng Ye, Qinwen Wang, Shiwei Duan Aims The aim of this study was to evaluate the combined contribution of 8 polymorphisms to the risk of Alzheimer's disease (AD). Methods Through a comprehensive literature search for genetic variants involved in the AD association study, we harvested a total of 6 genes (8 polymorphisms) for the current meta-analyses. These genes consisted of A2M (5bp I/D and V1000I), ABCA2 (rs908832), CHAT (1882G 〉A, 2384G 〉A), COMT (Val158Met), HTR6 (267C 〉T) and LPL (Ser447Ter). Results A total of 33 studies among 9,453 cases and 10,833 controls were retrieved for the meta-analyses of 8 genetic variants. It was showed that A2M V1000I (odd ratio (OR) = 1.26, 95% confidence interval (CI) = 1.07–1.49, P = 0.007), rs908832 allele of ABCA2 (OR = 1.55, 95% CI = 1.12–2.16, P = 0.009), 2384G 〉A of CHAT (OR = 1.22, 95% CI = 1.00–1.49, P = 0.05) and Ser447Ter of LPL in the Northern-American population (OR = 0.56, 95% CI = 0.35–0.91, P = 0.02) were significantly associated with the risk of AD. No association was found between the rest of the 5 polymorphisms and the risk of AD. Conclusion Our results showed that A2M V1000I polymorphism in German, Korean, Chinese, Spanish, Italian and Polish populations, rs90883 of ABCA2 gene in French, American, Swiss, Greek and Japanese populations, 2384G 〉A of CHAT gene in British and Korean populations and LPL Ser447Ter in the Northern-American population were associated with the risk of AD.

Description: The tension between the meaning of causality in science and law or public policy is well-known; however, defendants in product liability cases or industries that might be affected by a government regulation may try to convince the factfinder to require evidence of a causal relationship that meets the standards of science. From the perspective of public health, however, people may be exposed unnecessarily to a health risk during the time period between the establishment of reasonably strong evidence of a causal relationship and the overwhelming evidence required for scientific causality. The Bayesian paradigm enables one to update information from epidemiologic studies as they accumulate, providing estimates of the probability that the relative risk of a particular harm from exposure exceeds a threshold value, e.g. 2.0 or 4.0 that is sufficient to meet the preponderance of the evidence standard or to support a health initiative. In order to diminish the role of the initial prior distribution, which may be quite subjective, the first case-control study or an analysis of adverse event and case reports is used to determine two prior distributions. One is the most favourable to the defendant, or industry that might be regulated, which is consistent with the previous data. The other is centred on or near the estimated relative risk from the first study. The method is applied to the studies that linked aspirin use to Reye syndrome and demonstrates that the evidence of a causal association was sufficiently strong in 1982, when the Food and Drug Administration first proposed that the public be warned of the risk, to support the regulation. Thus, lives would have been saved had the warning been given at the end of 1982 rather than in early 1985.

Description: In law, inferences of causation are sometimes made through a structured process in which multiple participants play various roles, and make decisions concerning various logical components of the overall inference (such as legal rules, policy objectives, presumptions, evidence, burdens of proof and findings of fact). This article illustrates such a process using empirical research into compensation decisions in the USA for injuries allegedly caused by vaccinations. Empirical research into actual legal processes is essential, in order to discover how various players approach their sub-tasks of decision-making. It also provides insights for areas outside of law, such as non-monotonic logic, cognitive science, sociology and artificial intelligence.

Description: Situations of causal factual uncertainty are relatively common in law. The problems and difficulties regarding ‘factual causation’ in law point to the need of ‘evidence’ and ‘proof’ models that are adequate and capable to accommodate the tests and methodologies used to explain and demonstrate it in a legal context. Given the configuration of the situations of causal factual uncertainty and the available ‘evidence’ and ‘proof’ models, I argue that it is justified to use an ‘argumentative-narrative’ model for ‘proving causation’ in law. However, considering that each model of ‘evidence’ and ‘proof’ reveals a different kind of ‘rationality’ that can still be viewed in different ways, I also argue that we must try to match the perspective we have on the ‘rationality’ behind the chosen model of ‘evidence’ and ‘proof’ with the ‘rationality’ underlying ‘causation’ in law.

Description: At least in some cases, the values confronted in legal decision-making appear to be incommensurable. Some legal theorists resist incommensurability because they fear that this presents an overwhelming obstacle to rational decision-making. By offering a close analysis of proportionality and, more particularly, measures of proportional value satisfaction, I show that this fear is unfounded. Comparative measures of proportional value satisfaction do not require the values to be commensurable. However, assuming incommensurability presents us with the problem of public significance in the proportional satisfaction of values. When two values are commensurable, this public significance is provided by the mediating effects of the overarching third value that provides the common measure of the values. However, when this common measure is removed, then the public significance of value satisfaction must be otherwise achieved. This is why I propose an equal proportional value satisfaction as the most appropriate proportionality maximand. Under equal proportional value satisfaction, the proportional satisfaction of any one value has significance for each and every other value. This kind of public significance is interpersonal rather than impersonal (or second-personal rather than third-personal). The article then shows that the legal process that is most appropriate to equal proportionality is a process that implements defeasible legal rules.

Description: In order to allocate the risk between parties in legal adjudication, we use evidentiary techniques with the main device among them being the standard of proof (SoP). The traditional view holds the grade of probability to be the parameter that shifts when moving to different standards. However, as soon as we dig slightly deeper, an incoherent picture is being revealed. In this article, I challenge the accepted view and try to show that it faces insurmountable problems concerning the rationality, the grammatical consistency and the impact of the SoP for the acceptability of verdicts. At the end of the article, I shortly discuss the theory of epistemological contextualism and propose a framework that allows rational distinctions to be drawn between different standards of proof. In the second part of this project (forthcoming), I will defend a contextualist view according to which shifting parameter is not the grade of (aleatory) probability, but instead the Set of Epistemic Defeaters in play.

Description: by Katerina Douka, Christopher A. Bergman, Robert E. M. Hedges, Frank P. Wesselingh, Thomas F. G. Higham The Out-of-Africa model holds that anatomically modern humans (AMH) evolved and dispersed from Africa into Asia, and later Europe. Palaeoanthropological evidence from the Near East assumes great importance, but AMH remains from the region are extremely scarce. ‘Egbert’, a now-lost AMH fossil from the key site of Ksar Akil (Lebanon) and ‘Ethelruda’, a recently re-discovered fragmentary maxilla from the same site, are two rare examples where human fossils are directly linked with early Upper Palaeolithic archaeological assemblages. Here we radiocarbon date the contexts from which Egbert and Ethelruda were recovered, as well as the levels above and below the findspots. In the absence of well-preserved organic materials, we primarily used marine shell beads, often regarded as indicative of behavioural modernity. Bayesian modelling allows for the construction of a chronostratigraphic framework for Ksar Akil, which supports several conclusions. The model-generated age estimates place Egbert between 40.8–39.2 ka cal BP (68.2% prob.) and Ethelruda between 42.4–41.7 ka cal BP (68.2% prob.). This indicates that Egbert is of an age comparable to that of the oldest directly-dated European AMH (Peştera cu Oase). Ethelruda is older, but on current estimates not older than the modern human teeth from Cavallo in Italy. The dating of the so-called “transitional” or Initial Upper Palaeolithic layers of the site may indicate that the passage from the Middle to Upper Palaeolithic at Ksar Akil, and possibly in the wider northern Levant, occurred later than previously estimated, casting some doubts on the assumed singular role of the region as a locus for human dispersals into Europe. Finally, tentative interpretations of the fossil's taxonomy, combined with the chronometric dating of Ethelruda's context, provides evidence that the transitional/IUP industries of Europe and the Levant, or at least some of them, may be the result of early modern human migration(s).

Description: by Thomas Lund, Johan Hviid Andersen, Trine Nøhr Winding, Karin Biering, Merete Labriola Background Most previous studies on reliance on social benefits have focused on health, sickness absence, work environment and socioeconomic status in adulthood. Extending the focus to include early life circumstances may improve our understanding of processes leading to educational and occupational marginalisation and exclusion. The aim of this study was to investigate if multiple negative life events in childhood determined future labour market participation, and to identify important negative life events for labour market participation in young adulthood. Methods Of a cohort of 3,681 born in 1989 in the county of Ringkjoebing, Denmark, 3,058 (83%) completed a questionnaire in 2004. They were followed in a register on social benefits for 12 months in 2010-2011. Logistic regression analyses were used to investigate associations between negative life events in childhood and future labour market participation, taking into account effects of socio-economic position, school performance, educational plans, vocational expectations and general health. Results A total of 17.1% (19.9% males, 14.4% females) received social benefits for at least 4 weeks during follow-up. Labour market participation decreased with number of negative life events, especially for females: Females who had experienced their parents’ divorce, had been abused, or had witnessed a violent event, showed decreased labour market participation, when adjusting for SES, school performance, educational plans, vocational expectations and general health at baseline. Attributable fractions ranged from 2.4% (parents’ alcohol/drug abuse) to 16.1% (parents’ divorce) for women. For men, risk estimates were lower and insignificant in the most adjusted models. Attributable fractions ranged from 1.0% (parents’ alcohol/drug abuse) to 4.9% for witnessing a violent event. Conclusions Information on childhood conditions may increase the understanding of determinants of labour market participation for young adults. Knowledge of negative life events in childhood should be taken into account when considering determinants of labour market participation and identifying high-risk groups.

Description: by Britt G. de Jong, Aart Lammers, Leonora A. A. Oberendorf, Mike G. B. Nieuwland, Huub F. J. Savelkoul, Henk K. Parmentier Specificity, antibody isotype distribution and levels of natural antibodies (NAb) may be potential informative parameters for immune mediated natural disease resistance, immune modulation, and maintenance of physiological homeostasis. A large proportion of mammalian NAb have affinity for or are directed against self-antigens; so called natural auto antibodies (N(A)Ab). In the present study we showed the presence and typed levels and isotypes (total immunoglobulins, IgG and IgM) of N(A)Ab in plasma binding the ‘auto-antigen’ complex chicken liver cell lysate (CLL) of one-year old chickens from different genotype and phenotype backgrounds by ELISA and quantitative Western blotting. Higher levels of N(A)Ab binding CLL were found in plasma from chickens genetically selected for high specific antibody responses. In all birds, extensive staining patterns of plasma antibodies binding CLL were found for all isotypes, with IgG binding the highest number of CLL antigens and also showing the highest variation in staining patterns between individuals. Patterns of IgM antibodies binding CLL appeared to be more similar in all lines. Significant differences of binding patterns of N(A)Ab (antigen fragments of CLL and staining intensity) were detected between the different chicken lines, and lines could be clustered on the basis of their auto-antibody profile. In addition, also individual differences within lines were found. The present results indicate that analysis of the levels and the N(A)Ab repertoire of poultry like in mammals could provide a new way of distinguishing differences of immune competence and immune maturation between individuals, and could provide tools to select birds for health traits, or optimize hygiene and husbandry procedures.

Description: by Pei-Yi Chu, Chih-Jen Cheng, Yi-Chang Wu, Yu-Wei Fang, Tom Chau, Shinichi Uchida, Sei Sasaki, Sung-Sen Yang, Shih-Hua Lin Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na + -Cl − cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo . Wnk4 D561A/+ mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP- Osr1 −/− ) and Spak knockout ( Spak −/− ) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 D561A/+ , KSP- Osr1 −/− , and Spak −/− mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 D561A/+ .KSP- Osr1 −/− remained phenotypically PHA II while Wnk4 D561A/+ . Spak −/− mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 D561A/+ and Wnk4 D561A/+ .KSP- Osr1 −/− mice while phosphorylated Ncc normalized in Wnk4 D561A/+ . Spak −/− mice. Furthermore, Wnk4 D561A/+ .KSP- Osr1 −/− mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 D561A/+ . Spak −/− mice exhibited normal responses. Wnk4D561A/+.Spak −/− . KSP-Osr1 −/− triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.

Description: by Magdalena Migocka, Anna Warzybok, Anna Papierniak, Grażyna Kłobus Studies in the last few years have shed light on the process of nitrate accumulation within plant cells, achieving molecular identification and partial characterization of the genes and proteins involved in this process. However, contrary to the plasma membrane-localized nitrate transport activities, the kinetics of active nitrate influx into the vacuole and its adaptation to external nitrate availability remain poorly understood. In this work, we have investigated the activity and regulation of the tonoplast-localized H + /NO 3 − antiport in cucumber roots in response to N starvation and NO 3 − induction. The time course of nitrate availability strongly influenced H + /NO 3 − antiport activity at the tonoplast of root cells. However, under N starvation active nitrate accumulation within the vacuole still occurred. Hence, either a constitutive H + -coupled transport system specific for nitrate operates at the tonoplast, or nitrate uses another transport protein of broader specificity to different anions to enter the vacuole via a proton-dependent process. H + /NO 3 − antiport in cucumber was significantly stimulated in NO 3 − -induced plants that were supplied with nitrate for 24 hours following 6-day-long N starvation. The cytosolic fraction isolated from the roots of NO 3 − -induced plants significantly stimulated H + /NO 3 − antiport in tonoplast membranes isolated from cucumbers growing on nitrate. The stimulatory effect of the cytosolic fraction was completely abolished by EGTA and the protein kinase inhibitor staurosporine and slightly enhanced by the phosphatase inhibitors okadaic acid and cantharidin. Hence, we conclude that stimulation of H + /NO 3 − antiport at the tonoplast of cucumber roots in response to nitrate provision may occur through the phosphorylation of a membrane antiporter involving Ca-dependent, staurosporine-sensitive protein kinase.

Description: by I-Cheng Chen, Hsuan-Yuan Lin, Ya-Chin Hsiao, Chiung-Mei Chen, Yih-Ru Wu, Hsin-Chieh Shiau, Yu-Fang Shen, Kuo-Shiu Huang, Ming-Tsan Su, Hsiu-Mei Hsieh-Li, Guey-Jen Lee-Chen Spinocerebellar ataxia type 8 (SCA8) involves the expansion of CTG/CAG repeats from the overlapping ataxin 8 opposite strand ( ATXN8OS ) and ataxin 8 ( ATXN8 ) genes located on chromosome 13q21. Although being transcribed, spliced and polyadenylated in the CTG orientation, ATXN8OS does not itself appear to be protein coding, as only small open reading frames (ORFs) were noted. In the present study we investigated the translation of a novel 102 amino acids containing-ORF in the ATXN8OS RNA. Expression of chimeric construct with an in-frame ORF-EGFP gene demonstrated that ATXN8OS RNA is translatable. Using antiserum raised against ORF, ATXN8OS ORF expression was detected in various human cells including lymphoblastoid, embryonic kidney 293, neuroblastoma IMR-32, SK-N-SH, SH-SY5Y cells and human muscle tissue. The biological role of the ATXN8OS ORF and its connection to SCA8 remains to be determined.

Description: by Carel P. van Schaik, Laura Damerius, Karin Isler The ability to plan for the future beyond immediate needs would be adaptive to many animal species, but is widely thought to be uniquely human. Although studies in captivity have shown that great apes are capable of planning for future needs, it is unknown whether and how they use this ability in the wild. Flanged male Sumatran orangutans ( Pongo abelii ) emit long calls, which females use to maintain earshot associations with them. We tested whether long calls serve to communicate a male's ever-changing predominant travel direction to facilitate maintaining these associations. We found that the direction in which a flanged male emits his long calls predicts his subsequent travel direction for many hours, and that a new call indicates a change in his main travel direction. Long calls given at or near the night nest indicate travel direction better than random until late afternoon on the next day. These results show that male orangutans make their travel plans well in advance and announce them to conspecifics. We suggest that such a planning ability is likely to be adaptive for great apes, as well as in other taxa.

Description: There is much interest in using high-throughput DNA sequencing methodology to monitor microorganisms, complex plant and animal communities. However, there are experimental and analytical issues to consider before applying a sequencing technology, which was originally developed for genome projects, to ecological projects. Many of these issues have been highlighted by recent microbial studies. Understanding how high-throughput sequencing is best implemented is important for the interpretation of recent results and the success of future applications. Addressing complex biological questions with metagenomics requires the interaction of researchers who bring different skill sets to problem solving. Educators can help by nurturing a collaborative interdisciplinary approach to genome science, which is essential for effective problem solving. Educators are in a position to help students, teachers, the public and policy makers interpret the new knowledge that metagenomics brings. To do this, they need to understand, not only the excitement of the science but also the pitfalls and shortcomings of methodology and research designs. We review these issues and some of the research directions that are helping to move the field forward.

Description: We believe that undergraduate biology students must acquire a foundational background in computing including how to formulate a computational problem; develop an algorithmic solution; implement their solution in software and then test, document and use their code to explore biological phenomena. Moreover, by learning these skills in the first year, students acquire a powerful tool set that they can use and build on throughout their studies. To address this need, we have developed a first-year undergraduate course that teaches students the foundations of computational thinking and programming in the context of problems in biology. This article describes the structure and content of the course and summarizes assessment data on both affective and learning outcomes.

Description: Bioinformatics is an integral part of modern life sciences. It has revolutionized and redefined how research is carried out and has had an enormous impact on biotechnology, medicine, agriculture and related areas. Yet, it is only rarely integrated into high school teaching and learning programs, playing almost no role in preparing the next generation of information-oriented citizens. Here, we describe the design principles of bioinformatics learning environments, including our own, that are aimed at introducing bioinformatics into senior high school curricula through engaging learners in scientifically authentic inquiry activities. We discuss the bioinformatics-related benefits and challenges that high school teachers and students face in the course of the implementation process, in light of previous studies and our own experience. Based on these lessons, we present a new approach for characterizing the questions embedded in bioinformatics teaching and learning units, based on three criteria: the type of domain-specific knowledge required to answer each question (declarative knowledge, procedural knowledge, strategic knowledge, situational knowledge), the scientific approach from which each question stems (biological, bioinformatics, a combination of the two) and the associated cognitive process dimension (remember, understand, apply, analyze, evaluate, create). We demonstrate the feasibility of this approach using a learning environment, which we developed for the high school level, and suggest some of its implications. This review sheds light on unique and critical characteristics related to broader integration of bioinformatics in secondary education, which are also relevant to the undergraduate level, and especially on curriculum design, development of suitable learning environments and teaching and learning processes.

Description: The aim of this paper is to study the relations between the Hausdorff dimensions of k -quasilines and the theory of extremal quasiconformal mappings. We show that there is an open and dense subset (Strebel points) of the universal Teichmüller space T (H) such that, for every [ f ] in the set, the Hausdorff dimension of the k -quasiline determined by [ f ] is strictly less than 1 + k 2 . We also show that there are some points [ f ] != [id] outside the open and dense set in the universal Teichmüller space such that the Hausdorff dimension of the quasiline determined by [ f ] is 1. Moreover, some results on the Hausdorff dimensions of the quasilines varying in the asymptotic Teichmüller space are also obtained.

Description: Next-generation sequencing (NGS) is increasingly being adopted as the backbone of biomedical research. With the commercialization of various affordable desktop sequencers, NGS will be reached by increasing numbers of cellular and molecular biologists, necessitating community consensus on bioinformatics protocols to tackle the exponential increase in quantity of sequence data. The current resources for NGS informatics are extremely fragmented. Finding a centralized synthesis is difficult. A multitude of tools exist for NGS data analysis; however, none of these satisfies all possible uses and needs. This gap in functionality could be filled by integrating different methods in customized pipelines, an approach helped by the open-source nature of many NGS programmes. Drawing from community spirit and with the use of the Wikipedia framework, we have initiated a collaborative NGS resource: The NGS WikiBook. We have collected a sufficient amount of text to incentivize a broader community to contribute to it. Users can search, browse, edit and create new content, so as to facilitate self-learning and feedback to the community. The overall structure and style for this dynamic material is designed for the bench biologists and non-bioinformaticians. The flexibility of online material allows the readers to ignore details in a first read, yet have immediate access to the information they need. Each chapter comes with practical exercises so readers may familiarize themselves with each step. The NGS WikiBook aims to create a collective laboratory book and protocol that explains the key concepts and describes best practices in this fast-evolving field.

Description: A new uniqueness result for a general n th order differential equation is obtained. We show that some previous results follow immediately from our theorem.

Description: Consider a discrete uniformly elliptic divergence form equation on the d ≥3 dimensional lattice Z d with random coefficients. In Conlon and Spencer [ Trans. Amer. Math. Soc. , http://www.math.lsa.umich.edu/~conlon/paper/hom10.pdf ], rate of convergence results in homogenization and estimates on the difference between the averaged Green's function and the homogenized Green's function for random environments which satisfy a Poincaré inequality were obtained. Here, these results are extended to certain environments in which correlations can have arbitrarily small power law decay. These environments are simply related via a convolution to environments which do satisfy a Poincaré inequality.

Description: In this paper, we prove that, for any a , M N with ( a , M ) = 1, there are infinitely many Carmichael numbers m such that m a mod M .

Description: We give a topological analogue for openness of a criterion for flatness that originates with Auslander. Over a normal base of dimension n , failure of openness is detected by a vertical component in the n th fibred power of the morphism.

Description: Investigated are regular maps from real algebraic varieties into real Fermat varieties. It is proved that under some natural assumptions, all such maps are null homotopic.

Description: Let ( M , g ) be a complete non-compact Riemannian manifold. We consider operators of the form g + V , where g is the non-negative Laplacian associated with the metric g , and V a locally integrable function. Let be a Riemannian covering, with Laplacian g and potential . If the operator + V is non-negative on ( M , g ), then the operator is non-negative on . In this note, we show that the converse statement is true provided that is a co-amenable subgroup of 1 ( M ).

Description: Peak interpolation is concerned with a foundational kind of mathematical task: building functions in a fixed algebra A , which have prescribed values or behaviour on a fixed closed subset (or on several disjoint subsets). In this paper, we do the same but now A is an algebra of operators on a Hilbert space. We briefly survey this noncommutative peak interpolation , which we have studied with coauthors in a long series of papers, and whose basic theory now appears to be approaching its culmination. This programme developed from, and is based partly on, theorems of Hay and Read whose proofs were spectacular, but therefore inaccessible to an uncommitted reader. We give short proofs of these results, using recent progress in noncommutative peak interpolation, and conversely give examples of the use of these theorems in peak interpolation. For example, we prove a useful new noncommutative peak interpolation theorem.

Description: We show how a parameterized family of maps of the spine of a manifold can be used to construct a family of homeomorphisms of the ambient manifold which have the inverse limits of the spine maps as global attractors. We describe applications to unimodal families of interval maps, to rotation sets, and to the standard family of circle maps.

Description: For every prime p , we give infinitely many examples of torsors under abelian varieties over Q that are locally trivial but not divisible by p in the Weil–Châtelet group. We also give an example of a locally trivial torsor under an elliptic curve over Q that is not divisible by 4 in the Weil–Châtelet group. This gives a negative answer to a question of Cassels.

Description: We show that at least of the zeros of the Riemann zeta-function are simple, assuming the Riemann hypothesis. This was previously established by Conrey, Ghosh and Gonek [ Proc. London Math. Soc. 76 (1998) 497–522] under the additional assumption of the generalized Lindelöf hypothesis. We are able to remove this hypothesis by careful use of the generalized Vaughan identity.

Description: We construct an infinite family of hyperbolic, homologically thin knots that are not quasi-alternating. To establish the latter, we argue that the branched double-cover of each knot in the family does not bound a negative-definite 4-manifold with trivial first homology and bounded second Betti number. This fact depends in turn on information from the correction terms in Heegaard Floer homology, which we establish by way of a relationship to, and calculation of, the Turaev torsion.

Description: We observe that E -resultant of a very ample rank 2 vector bundle E on a real projective curve (with no real points) is nonnegative when restricted to the space of real sections. Moreover, we show that if E has a section vanishing at exactly two points and the degree d of E satisfies d ( d – 6) ≥ 4( g – 1), then this polynomial cannot be written as a sum of squares.

Description: Let G be one of the Ricci-flat holonomy groups SU( n ), Sp( n ), Spin(7) or G 2 , and M a compact manifold of dimension 2 n , 4 n , 8 or 7, respectively. We prove that the natural map from the moduli space of torsion-free G -structures on M to the moduli space of Ricci-flat metrics is open, and that the image is a smooth manifold. For the exceptional cases G = Spin(7) and G 2 , we extend the result to asymptotically cylindrical manifolds.

Description: We improve the results of Booker and Krishnamurthy ( Compos. Math. 147 (2011) 669–715) by allowing restricted sets of poles among the unramified twists. This allows for a clean statement of the GL(2) converse theorem which includes all cases of Eisenstein series.

Description: Let G be a solvable subgroup of the automorphism group Aut( X ) of a compact Kähler manifold X of complex dimension n , and let N ( G ) be the normal subgroup of G consisting of elements with null entropy. Let us denote by G * the image of G under the natural map from Aut( X ) to GL( V , R ), where V is the Dolbeault cohomology group H 1, 1 ( X , R ). Assume that the Zariski closure of G * in GL( V C ) is connected. The main aim of this paper is to show that, when the rank r ( G ) of the quotient group G / N ( G ) is equal to n – 1 and the identity component of Aut( X ) is trivial, then the normal subgroup N ( G ) of G is finite. This affirmatively answers a question in Invent. Math. posed by D.-Q. Zhang.

Description: by M. H. Eileen Tan, X. Edward Zhou, Fen-Fen Soon, Xiaodan Li, Jun Li, Eu-Leong Yong, Karsten Melcher, H. Eric Xu Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor’s structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.

Description: by Ayako Suzuki, Sachiyo Mimaki, Yuki Yamane, Akikazu Kawase, Koutatsu Matsushima, Makito Suzuki, Koichi Goto, Sumio Sugano, Hiroyasu Esumi, Yutaka Suzuki, Katsuya Tsuchihara We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinoma patients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may be used for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normal tissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available.

Description: by Lin Huang Objective: Ischemic pre-conditioning and post-conditioning are useful manipulations to reduce the undesirable effects of ischemia-reperfusion skin flap each. But the impact of post-conditioning on the pre-conditioning skin flap is not manifested. Here we investigated the influence of ischemic post-conditioning in a preconditioned axial pattern skin flap model.Method: We used the skin flap in 40 rabbits and divided them into 5 groups randomly. At first we induced the ischemic pre-conditioning of the flap which was applied by 2 periods of 15 minutes of ischemia/15 minutes of reperfusion cycle. Next post-conditioning was performed by 6 cycles of 10 seconds of repeated ischemia/reperfusion periods at different times of just after the reperfusion,5 minutes after the reperfusion,10 minutes after the reperfusion. The animals were allocated into 5 groups: group 1 (Ischemia Group); group 2: (Pre-conditioning Group); group 3: (Pre-conditioning+ Post-conditioning Group); group 4 (Pre-conditioning+ Post-conditioning 5 minutes later Group); group5 (Pre-conditioning+ Post-conditioning 10 minutes later). The neutrophil count was assessed with histologic analysis before the dissection of the skin flap. Flap viability was assessed 1 week after the operation, and surviving flap area was recorded as a percentage of the whole flap area. LSD test was used for statistical analysis among different groups to evaluate the effects of ischemic pre-conditioning against ischemia.Result: Among the varying groups, the neutrophil count varied: Group 1 was50.12±5.91; Group 2, 30.00±2.00, and Group 3, 18.87±3; Group 4, 22.50±1.92; Group 5, 30.12±1.88.The mean± SD surviving areas of the flaps for groups 1, 2, 3, 4 and 5 were 31.76±4.59, 51.26±3.24,82.18±5.28,66.85±3.87 and 51.13±2.90 respectively. Spearman correlation analysis shows an increase relation between neutrophil count and flap survival rate in the different groups (P

Description: by Hiroyuki Nishi, Taichi Sakaguchi, Shigeru Miyagawa, Yasushi Yoshikawa, Satsuki Fukushima, Shunsuke Saito, Takayoshi Ueno, Toru Kuratani, Yoshiki Sawa Background Although microRNA (miRNA) regulates initiation and/or progression of atrial fibrillation (AF) in canine AF models, the underlying mechanism in humans remains unclear. We speculated that certain miRNAs in atrial tissue are related to AF, and evaluated the relationship of miRNA expression in human atrial tissue in cardiac surgery patients. Methods Right atrial tissues from 29 patients undergoing cardiovascular surgery were divided into 3 groups [A: chronic AF or unsuccessful maze, n=6; B: successful maze, n=10; C: sinus rhythm (SR) n=13]. miRNA expression was determined using high density microarrays and with Reverse transcriptase-polymerase chain reaction (RT-PCR). Fibrosis was examined using Masson trichrome staining. Results miRNA microarray analysis showed elevated miRNA-21, miRNA-23b, miRNA-199b, and miRNA-208b in AF as compared to SR groups. RT-PCR showed elevated miRNA-21 (1.9-fold) and miRNA-208b (4.2-fold) in AF as compared to the SR groups. miRNA-21 expression increased from Group C to A (A: 2.1-fold, B: 1.8-fold, C: 1.0-fold). Fibrosis increased from C to A (A: 43.0±12.9%, B: 21.3±6.1%, C: 11.9±3.1%). Percent fibrosis and miRNA-21 expression were correlated (r=0.508, p

Description: by Habiba I. Ali, Amjad H. Jarrar, Mohamed El Sadig, Karin B. Yeatts Background Diet therapy is the cornerstone for the management of gestational diabetes mellitus (GDM). Carbohydrate is the primary nutrient affecting postprandial blood glucose levels. Hence, knowledge of food containing carbohydrates can assist women with GDM optimize glycemic control. Despite that, there is a paucity of research on carbohydrate-related knowledge of women with GDM. The United Arab Emirates (UAE) has one of the highest prevalence of diabetes (19.2%) in the world. This study compared diet and knowledge of carbohydrate-containing foods among pregnant women with and without GDM in the UAE. Methods The sample consisted of multi-ethnic women with GDM (n = 94) and a control group of healthy pregnant women (n = 90) attending prenatal clinics in three hospitals in Al Ain, UAE. Data were collected using a questionnaire and a 24-hour recall. Knowledge of food sources of carbohydrate, dietary patterns, and nutrient intakes of the two groups were compared. Results There were no significant differences in the mean knowledge score of food sources of carbohydrate between women with GDM and that of pregnant women without GDM. Similarly, there were no significant differences in energy and nutrient intakes between the two groups with the exception of percent energy from protein. Women with GDM reported significantly lower intake of fruits and fruit juices (P = 0.012) and higher consumption of milk and yogurt (P = 0.004) compared to that of women without GDM. Twenty-two percent of women with GDM indicated they never visited a dietitian for counseling while 65% reported they visited a dietitian only once or twice during the pregnancy. Predictors of carbohydrate knowledge score were perceived knowledge of diet and GDM and parity among women with GDM and parity and educational level among those without GDM. Conclusion The results of the study highlight the urgent need to provide nutrition education for women with GDM in the UAE.

Description: by Soumya Lipsa Rath, Sanjib Senapati Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a conserved catalytic core. This makes the design of inhibitors specific for a particular CDK difficult. There is, however, growing need for CDK5 specific inhibitors to treat various neurodegenerative diseases. Recently, cis-substituted cyclobutyl-4-aminoimidazole inhibitors have been identified as potent CDK5 inhibitors that gave up to 30-fold selectivity over CDK2. Available IC 50 values also indicate a higher potency of this class of inhibitors over commercially available drugs, such as roscovitine. To understand the molecular basis of higher potency and selectivity of these inhibitors, here, we present molecular dynamics simulation results of CDK5/p25 and CDK2/CyclinE complexed with a series of cyclobutyl-substituted imidazole inhibitors and roscovitine. The atomic details of the stereospecificity and selectivity of these inhibitors are obtained from energetics and binding characteristics to the CDK binding pocket. The study not only complements the experimental findings, but also provides a wealth of detailed information that could help the structure-based drug designing processes.

Description: by Valente Aritua, Diann Achor, Frederick G. Gmitter, Gene Albrigo, Nian Wang Huanglongbing (HLB) is the most destructive disease that affects citrus worldwide. The disease has been associated with Candidatus Liberibacter. HLB diseased citrus plants develop a multitude of symptoms including zinc and copper deficiencies, blotchy mottle, corky veins, stunting, and twig dieback. Ca . L. asiaticus infection also seriously affects the roots. Previous study focused on gene expression of leaves and fruit to Ca . L. asiaticus infection. In this study, we compared the gene expression levels of stems and roots of healthy plants with those in Ca . L. asiaticus infected plants using microarrays. Affymetrix microarray analysis showed a total of 988 genes were significantly altered in expression, of which 885 were in the stems, and 111 in the roots. Of these, 551 and 56 were up-regulated, while 334 and 55 were down-regulated in the stem and root samples of HLB diseased trees compared to healthy plants, respectively. Dramatic differences in the transcriptional responses were observed between citrus stems and roots to Ca . L. asiaticus infection, with only 8 genes affected in both the roots and stems. The affected genes are involved in diverse cellular functions, including carbohydrate metabolism, cell wall biogenesis, biotic and abiotic stress responses, signaling and transcriptional factors, transportation, cell organization, protein modification and degradation, development, hormone signaling, metal handling, and redox. Microscopy analysis showed the depletion of starch in the roots of the infected plants but not in healthy plants. Collapse and thickening of cell walls were observed in HLB affected roots, but not as severe as in the stems. This study provides insight into the host response of the stems and roots to Ca . L. asiaticus infection.

Description: by Hong Ding, Xin Sun, Wei-wei Chang, Liu Zhang, Xi-ping Xu Background The government of China promulgated new medical care reform policies in March 2009. After that, provincial-level governments launched new medical care reform which focusing on local comprehensive medical care reform (LCMR). Anhui Province is an example of an area affected by LCMR, in which the LCMR was started in October 2009 and implemented in June 2010. The objective of this study was to compare the job satisfaction (JS) of community health workers (CHWs) before and after the reform in Anhui Province. Methods A baseline survey was carried out among 813 community health workers (CHWs) of 57 community health centers (CHCs) (response rate: 94.1%) and an effect evaluation survey among 536 CHWs of 30 CHCs (response rate: 92.3%) in 2009 and 2012 respectively. A self-completion questionnaire was used to assess the JS of the CHWs (by the job satisfaction scale, JSS). Results The average scores of total JS and satisfaction with pay, contingent rewards, operating procedures and communication in the effect evaluation survey were statistically significantly higher than those of the baseline survey ( P

Description: by Gerda G. Fillenbaum, Sergio L. Blay, Carl F. Pieper, Katherine E. King, Sergio B. Andreoli, Fábio L. Gastal Objectives In high income, developed countries, health status tends to improve as income increases, but primarily through the 50 th -66 th percentile of income. It is unclear whether the same limitation holds in middle income countries, and for both general assessments of health and specific conditions. Methods Data were obtained from Brazil, a middle income country. In-person interviews with a representative sample of community residents age ≥60 (N=6963), in the southern state of Rio Grande do Sul, obtained information on demographic characteristics including household income and number of persons supported, general health status (self-rated health, functional status), depression, and seven physician-diagnosed, self-reported health conditions. Analyses used household income (adjusted for number supported and economies of scale) together with higher order income terms, and controlled for demographics and comorbidities, to ascertain nonlinearity between income and general and specific health measures. Results In fully controlled analyses income was associated with general measures of health (linearly with self-rated health, nonlinearly with functional status). For specific health measures there was a consistent linear association with depression, pulmonary disorders, renal disorders, and sensory impairment. For musculoskeletal, cardiovascular (negative association), and gastrointestinal disorders this association no longer held when comorbidities were controlled. There was no association with diabetes. Conclusion Contrary to findings in high income countries, the association of household-size-adjusted income with health was generally linear, sometimes negative, and sometimes absent when comorbidities were controlled.

Description: by Sudheer Gupta, Pallavi Kapoor, Kumardeep Chaudhary, Ankur Gautam, Rahul Kumar, Open Source Drug Discovery Consortium , Gajendra P. S. Raghava Background Over the past few decades, scientific research has been focused on developing peptide/protein-based therapies to treat various diseases. With the several advantages over small molecules, including high specificity, high penetration, ease of manufacturing, peptides have emerged as promising therapeutic molecules against many diseases. However, one of the bottlenecks in peptide/protein-based therapy is their toxicity. Therefore, in the present study, we developed in silico models for predicting toxicity of peptides and proteins. Description We obtained toxic peptides having 35 or fewer residues from various databases for developing prediction models. Non-toxic or random peptides were obtained from SwissProt and TrEMBL. It was observed that certain residues like Cys, His, Asn, and Pro are abundant as well as preferred at various positions in toxic peptides. We developed models based on machine learning technique and quantitative matrix using various properties of peptides for predicting toxicity of peptides. The performance of dipeptide-based model in terms of accuracy was 94.50% with MCC 0.88. In addition, various motifs were extracted from the toxic peptides and this information was combined with dipeptide-based model for developing a hybrid model. In order to evaluate the over-optimization of the best model based on dipeptide composition, we evaluated its performance on independent datasets and achieved accuracy around 90%. Based on above study, a web server, ToxinPred has been developed, which would be helpful in predicting (i) toxicity or non-toxicity of peptides, (ii) minimum mutations in peptides for increasing or decreasing their toxicity, and (iii) toxic regions in proteins. Conclusion ToxinPred is a unique in silico method of its kind, which will be useful in predicting toxicity of peptides/proteins. In addition, it will be useful in designing least toxic peptides and discovering toxic regions in proteins. We hope that the development of ToxinPred will provide momentum to peptide/protein-based drug discovery (http://crdd.osdd.net/raghava/toxinpred/).

Description: by Peter Walentek, Isabelle Schneider, Axel Schweickert, Martin Blum Breakage of bilateral symmetry in amphibian embryos depends on the development of a ciliated epithelium at the gastrocoel roof during early neurulation. Motile cilia at the gastrocoel roof plate (GRP) give rise to leftward flow of extracellular fluids. Flow is required for asymmetric gene expression and organ morphogenesis. Wnt signaling has previously been involved in two steps, Wnt/ß-catenin mediated induction of Foxj1 , a regulator of motile cilia, and Wnt/planar cell polarity (PCP) dependent cilia polarization to the posterior pole of cells. We have studied Wnt11b in the context of laterality determination, as this ligand was reported to activate canonical and non-canonical Wnt signaling. Wnt11b was found to be expressed in the so-called superficial mesoderm (SM), from which the GRP derives. Surprisingly, Foxj1 was only marginally affected in loss-of-function experiments, indicating that another ligand acts in this early step of laterality specification. Wnt11b was required, however, for polarization of GRP cilia and GRP morphogenesis, in line with the known function of Wnt/PCP in cilia-driven leftward flow. In addition Xnr1 and Coco expression in the lateral-most GRP cells, which sense flow and generate the first asymmetric signal, was attenuated in morphants, involving Wnt signaling in yet another process related to symmetry breakage in Xenopus .

Description: by Heng Zhao, Jiani Liu, Shinong Pan, Yingwei Sun, Qi Li, Fei Li, Li Ma, Qiyong Guo Purpose Although superoxide dismutase (SOD) and malondialdehyde (MDA) affect Delayed Onset Muscle Soreness (DOMS), their effects are unclear in rectus femoris muscles (RFM) of rats with different eccentric exercise programs and time points. The purpose of this study is to investigate the effects of the various eccentric exercise programs at different time points on the SOD mRNA expression and MDA using rat as the animal model. Methods 248 male rats were randomly divided into 4 groups: control group (CTL, n  = 8), once-only exercise group (OEG, n  = 80), continuous exercise group (CEG, n  = 80), and intermittent exercise group (IEG, n =  80). Each exercise group was divided into 10 subgroups that exercised 0.5 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, or 168 h. Rats were sacrificed and their SOD mRNA expression, and MDA concentrations of skeletal muscle tissue were measured. Results The specimen in all eccentric exercise programs showed increased RFM SOD1 mRNA expression levels at 0.5 h ( P 〈 0.05), and decreased RFM SOD3 mRNA expression at 0.5 h ( P 〈 0.05). The continuous eccentric exercise (CE) significantly enhanced muscle SOD2 mRNA level at 0.5 h ( P 〈 0.05). After once-only eccentric exercise (OE), SOD1 , SOD2 , and SOD3 mRNA expression significantly increased at 96 h, whereas MDA concentrations decreased at 96 h. After CE, the correlation coefficients of SOD1 , SOD2 , SOD3 mRNA expression levels and MDA concentrations were −0.814, −0.763, −0.845 (all P 〈 0.05) at 12 h. Conclusion Regular eccentric exercise, especially CE could enhance SOD1 and SOD2 mRNA expression in acute stage and the SOD2 mRNA expression correlates to MDA concentration in vivo , which may improve the oxidative adaption ability of skeletal muscles.

Description: by Qian Fan, Zheng M. Huang, Matthieu Boucher, Xiying Shang, Lin Zuo, Henriette Brinks, Wayne Bond Lau, Jianke Zhang, J. Kurt Chuprun, Erhe Gao Aim As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure. Methods Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed. Results FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R-induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20±3.90% in NLC to 26.83±4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3. Conclusion Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure.

Description: by Shuang Li, Ting Hu, Yile Chen, Hang Zhou, Xiong Li, Xiaodong Cheng, Ru Yang, Shixuan Wang, Xing Xie, Ding Ma Radiotherapy is the standard treatment for cervical cancer, but causes radiotherapy-induced complications. Recently, chemotherapy has been more extensively utilized. Here, we perform a large-scale comparison of chemotherapy and radiotherapy. From 2002 to 2008, 2,268 patients were grouped according to adjuvant radiotherapy or chemotherapy before and/or after surgery, and we compared the 5-year overall survival (OS) and disease-free survival (DFS) rates, recurrence rates, side effects, quality of life (QoL), and sexual activity. There were no significant differences between the treatment groups for the 5-year OS and DFS rates (OS: p =  0.053, DFS: p  = 0.095), although marginally improved outcomes were observed in the chemotherapy group (OS: 86.5% vs. 82.8%; DFS: 84.5% vs. 81.4%). However, patients with early-stage disease, clinical response, and younger age had increased 5-year OS and DFS rates following chemotherapy compared to radiotherapy ( p