ALBERT

Description: We evaluated whether the central nervous system (CNS) chooses muscle activations not only to achieve behavioral goals but also to minimize stresses and strains within joints. We analyzed the coordination between quadriceps muscles during locomotion in rats before and after imposing a lateral force on the patella. Vastus lateralis (VL) and vastus medialis (VM) in the rat produce identical knee torques but opposing mediolateral patellar forces. If the CNS regulates internal joint stresses, we predicted that after imposing a lateral patellar load by attaching a spring between the patella and lateral femur, the CNS would reduce the ratio between VL and VM activation to minimize net mediolateral patellar forces. Our results confirmed this prediction, showing that VL activation was reduced after attaching the spring whereas VM and rectus femoris (RF) activations were not significantly changed. This adaptation was reversed after the spring was detached. These changes were not observed immediately after attaching the spring but only developed after 3–5 days, suggesting that they reflected gradual processes rather than immediate compensatory reflexes. Overall, these results support the hypothesis that the CNS chooses muscle activations to regulate internal joint variables.

Description: Pesticide use is one of the main causes of pollinator declines in agricultural ecosystems. Traditionally, most laboratory studies on bee ecotoxicology test acute exposure to single compounds. However, under field conditions, bees are often chronically exposed to a variety of chemicals, with potential synergistic effects. We studied the effects of field-realistic concentrations of three pesticides measured in pollen and nectar of commercial melon fields on the solitary bee Osmia bicornis L. We orally exposed females of this species throughout their life span to 8 treatments combining two neonicotinoid insecticides (acetamiprid, imidacloprid) and a triazole fungicide (myclobutanil) via pollen and sugar syrup. We measured pollen and syrup consumption, longevity, ovary maturation and thermogenesis. Although bees consumed larger amounts of syrup than pollen, pesticide intake via syrup and pollen were similar. At the tested concentrations, no synergistic effects emerged, and we found no effects on longevity and ovary maturation. However, all treatments containing imidacloprid resulted in suppressed syrup consumption and drastic decreases in thoracic temperature and bee activity. Our results have important implications for pesticide regulation. If we had measured only lethal effects we would have wrongly concluded that the pesticide combinations containing imidacloprid were safe to O. bicornis. The incorporation of tests specifically intended to detect sublethal effects in bee risk assessment schemes should be an urgent priority. In this way, the effects of pesticide exposure on the dynamics of bee populations in agroecosystems will be better assessed.

Description: Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.

Description: Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways. The proteins that aggregate in mRNA surveillance mutants tend to be more highly expressed, more abundant and more stable proteins compared with the wider proteome. There is also a strong correlation with the proteins that aggregate in response to nascent protein misfolding and an enrichment for proteins that are substrates of ribosome-associated Hsp70 chaperones, consistent with susceptibility for aggregation primarily occurring during translation/folding. We also identified a significant overlap between the aggregated proteins in mRNA surveillance mutants and ageing yeast cells suggesting that translation-dependent protein aggregation may be a feature of the loss of proteostasis that occurs in aged cell populations.

Description: Hepes simplex Virus type 1 (HSV-1) is an enveloped DNA virus that can cause lytic and latent infection. miRNAs post-transcriptionally regulate gene expression and our previous work has indicated that HSV-1 infection induces miR-101 expression in HeLa cells. The present study demonstrates that HSV-1-induced miR-101 is mainly derived from its precursor hsa-mir-101-2 and the HSV-1 immediate early gene ICP4 (infected-cell polypeptide 4) directly binds to the hsa-mir-101-2 promoter to activate its expression. RNA-binding protein G-rich sequence factor 1 (GRSF1) was identified as a new target of miR-101; GRSF1 binds to HSV-1 p40 mRNA and enhances its expression, facilitating viral proliferation. Together, ICP4 induces miR-101 expression, which downregulates GRSF1 expression and attenuates the replication of HSV-1. This allows host cells to maintain a permissive environment for viral replication by preventing lytic cell death. These findings indicate that HSV-1 early gene expression modulates host miRNAs to regulate molecular defense mechanisms. This study provides novel insight into host-virus interactions in HSV-1 infection and may contribute to the development of antiviral therapeutics.

Description: Savanna fires produce significant emissions globally, but if managed effectively could provide an important mitigation opportunity, particularly in African least developed countries. Here we show global opportunities for emissions reductions through early dry season burning for 37 countries including: 29 countries in Africa (69.1 MtCO2-e yr−1), six countries in South America (13.3 MtCO2-e yr−1), and Australia and Papua New Guinea (6.9 MtCO2-e yr−1). Emissions reduction estimates are based on the successful approach developed in Australia to reduce emissions from savanna fires using global-scale, remotely sensed estimates of monthly emissions. Importantly, 20 least developed countries in Africa account for 74% of the mitigation potential (60.2 MtCO2-e yr−1). More than 1.02 million km2 of savanna dominated protected areas within these countries could be used as pilot sites to test and advance a regional approach to mitigation efforts for savanna fires in Africa. Potential versus actual abatement opportunities are discussed.

Description: Distributed optical fibre sensors possess the unique capability of measuring the spatial and temporal map of environmental quantities that can be of great interest for several field applications. Although existing methods for performance enhancement have enabled important progresses in the field, they do not take full advantage of all information present in the measured data, still giving room for substantial improvement over the state-of-the-art. Here we propose and experimentally demonstrate an approach for performance enhancement that exploits the high level of similitude and redundancy contained on the multidimensional information measured by distributed fibre sensors. Exploiting conventional image and video processing, an unprecedented boost in signal-to-noise ratio and measurement contrast is experimentally demonstrated. The method can be applied to any white-noise-limited distributed fibre sensor and can remarkably provide a 100-fold improvement in the sensor performance with no hardware modification.

Description: Damage to the corticospinal tract is widely studied following unilateral subcortical stroke, whereas less is known about changes to other sensorimotor pathways. This may be due to the fact that many studies investigated morphological changes in the brain, where the majority of descending and ascending brain pathways are overlapping, and did not investigate the brainstem where they separate. Moreover, these pathways continue passing through separate regions in the spinal cord. Here, using a high-resolution structural MRI of both the brainstem and the cervical spinal cord, we were able to identify a number of microstructurally altered pathways, in addition to the corticospinal tract, post stroke. Moreover, decreases in ipsi-lesional corticospinal tract integrity and increases in contra-lesional medial reticulospinal tract integrity were correlated with motor impairment severity in individuals with stroke.

Description: Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types.

Description: Migratory birds usually respond to climate change by modifying breeding and/or wintering areas, as well as by reproducing earlier. In addition, changes in winter habitat use or breeding phenology could have important carry-over effects on subsequent breeding success. Here, we studied age- and sex-dependent carry-over effects from wintering to the breeding stage of a small aerial insectivorous long-distance migratory bird, the barn swallows (Hirundo rustica) breeding in Denmark during 1984–2013. First, we used stable isotope analyses combined with ringing recoveries to identify wintering areas. Second, we found that environmental conditions as inferred by Normalized Difference Vegetation Index (NDVI) have improved at the wintering grounds. Third, we used confirmatory path analysis to quantify the indirect effect of winter conditions on subsequent breeding success. Males delayed onset of breeding and raised fewer fledglings in the first brood when ecological conditions during the previous winter improved. This response was age dependent, since yearlings did not respond to this environmental cue but the response was increasingly stronger as males aged. Females showed a similar response to winter conditions, although not statistically significant. These results highlight the importance of studying carry-over effects within the context of climate change, especially in relation to age of individuals.

Description: The hot injection synthesis of nanomaterials is a highly diverse and fundamental field of chemical research, which has shown much success in the bottom up approach to nanomaterial design. Here we report a synthetic strategy for the production of anisotropic metal chalcogenide nanomaterials of different compositions and shapes, using an optimised hot injection approach. Its unique advantage compared to other hot injection routes is that it employs one chemical to act as many agents: high boiling point, viscous solvent, reducing agent, and surface coordinating ligand. It has been employed to produce a range of nanomaterials, such as CuS, Bi2S3, Cu2-xSe, FeSe2, and Bi4Se3, among others, with various structures including nanoplates and nanosheets. Overall, this article will highlight the excellent versatility of the method, which can be tuned to produce many different materials and shapes. In addition, due to the nature of the synthesis, 2D nanomaterial products are produced as monolayers without the need for exfoliation; a significant achievement towards future development of these materials.

Description: PIK3CA mutations are seemingly the most common driver mutations in breast cancer with H1047R and E545K being the most common of these, accounting together for around 60% of all PIK3CA mutations and have promising therapeutic implications. Given the low sensitivity and the high cost of current genotyping methods we sought to develop fast, simple and inexpensive assays for PIK3CA H1047R and E545K mutation screening in clinical material. The methods we describe are based on a real-time PCR including a mutation specific primer combined with a non-productive oligonucleotide which inhibits wild-type amplification and a parallel internal control reaction. We demonstrate consistent detection of PIK3CA H1047R mutant DNA in genomic DNA extracted from frozen breast cancer biopsies, FFPE material or cancer cell lines with a detection sensitivity of approximately 5% mutant allele fraction and validate these results using both Sanger sequencing and deep next generation sequencing methods. The detection sensitivity for PIK3CA E545K mutation was approximately 10%. We propose these methods as simple, fast and inexpensive diagnostic tools to determine PIK3CA mutation status.

Description: Adaptive neuro-fuzzy inference system (ANFIS) includes two novel GIS-based ensemble artificial intelligence approaches called imperialistic competitive algorithm (ICA) and firefly algorithm (FA). This combination could result in ANFIS-ICA and ANFIS-FA models, which were applied to flood spatial modelling and its mapping in the Haraz watershed in Northern Province of Mazandaran, Iran. Ten influential factors including slope angle, elevation, stream power index (SPI), curvature, topographic wetness index (TWI), lithology, rainfall, land use, stream density, and the distance to river were selected for flood modelling. The validity of the models was assessed using statistical error-indices (RMSE and MSE), statistical tests (Friedman and Wilcoxon signed-rank tests), and the area under the curve (AUC) of success. The prediction accuracy of the models was compared to some new state-of-the-art sophisticated machine learning techniques that had previously been successfully tested in the study area. The results confirmed the goodness of fit and appropriate prediction accuracy of the two ensemble models. However, the ANFIS-ICA model (AUC = 0.947) had a better performance in comparison to the Bagging-LMT (AUC = 0.940), BLR (AUC = 0.936), LMT (AUC = 0.934), ANFIS-FA (AUC = 0.917), LR (AUC = 0.885) and RF (AUC = 0.806) models. Therefore, the ANFIS-ICA model can be introduced as a promising method for the sustainable management of flood-prone areas.

Description: by Cheng-Jui Lin, Tai-Cherng Liou, Chi-Feng Pan, Pei-Chen Wu, Fang-Ju Sun, Hsuan-Liang Liu, Han-Hsiang Chen, Chih-Jen Wu Evidence has shown that indoxyl sulfate (IS) and p-cresyl sulfate (PCS) may be alternative predictors of clinical outcomes in chronic kidney disease (CKD). Both toxins are derived from the gastrointestinal tract and metabolised in the liver. However, it is unclear whether the liver affects the production of IS and PCS. Here, we explore the association between IS and PCS levels in liver cirrhosis and a CKD-based cohort (N = 115). Liver and kidney function was assessed and classified by a Child-Pugh score (child A–C) and a modified version of the Modification of Diet in Renal Disease (MDRD) equation (Stages 1–4), respectively. An animal model was also used to confirm the two toxin levels in a case of liver fibrosis. In patients with early liver cirrhosis (child A), IS and PCS were significantly associated with CKD stages. In contrast, serum IS and PCS did not significantly change in advanced liver cirrhosis (child C). A stepwise multiple linear regression analysis also showed that T-PCS was significantly associated with stages of liver cirrhosis after adjusting for other confounding factors (B = -2.29, p = 0.012). Moreover, the serum and urine levels of T-PCS and T-IS were significantly lower in rats with liver failure than in those without ( p

Description: by Guangde Zhang, Hongbo Shi, Lin Wang, Meng Zhou, Zhenzhen Wang, Xiaoxia Liu, Liang Cheng, Weimin Li, Xueqi Li Myocardial infarction (MI) is a severe coronary artery disease and a leading cause of mortality and morbidity worldwide. However, the molecular mechanisms of MI have yet to be fully elucidated. In this study, we compiled MI-related genes, MI-related microRNAs (miRNAs) and known human transcription factors (TFs), and we then identified 1,232 feed-forward loops (FFLs) among these miRNAs, TFs and their co-regulated target genes through integrating target prediction. By merging these FFLs, the first miRNA and TF mediated regulatory network for MI was constructed, from which four regulators (SP1, ESR1, miR-21-5p and miR-155-5p) and three regulatory modules that might play crucial roles in MI were then identified. Furthermore, based on the miRNA and TF mediated regulatory network and literature survey, we proposed a pathway model for miR-21-5p, the miR-29 family and SP1 to demonstrate their potential co-regulatory mechanisms in cardiac fibrosis, apoptosis and angiogenesis. The majority of the regulatory relations in the model were confirmed by previous studies, which demonstrated the reliability and validity of this miRNA and TF mediated regulatory network. Our study will aid in deciphering the complex regulatory mechanisms involved in MI and provide putative therapeutic targets for MI.

Description: by Dominik Eichin, Juha P. Laurila, Sirpa Jalkanen, Marko Salmi The ectoenzyme CD73 catalyzes the hydrolysis of AMP, and is one of the most important producers of extracellular adenosine. On regulatory T cells, CD73 is necessary for immunosuppressive functions, and on Th17 cells CD73-generated adenosine exerts anti-inflammatory effects. However, the expression and function of CD73 in pro-inflammatory M1 and in immunosuppressive M2 macrophages is largely unknown. Here we show that CD73 expression and enzyme activity were induced in in vitro polarized pro-inflammatory human M(LPS+TNF) monocytes/macrophages, while CD73 was absent from immunosuppressive M(IL-4+M-CSF)-polarized macrophages. Inhibition of CD73 activity with the inhibitor AMPCP did not affect the polarization of human monocytes. In mice, CD73 was present on resident peritoneal macrophages. In striking contrast, elicited peritoneal macrophages remained CD73 negative regardless of their polarization towards either a pro-inflammatory M(LPS) or anti-inflammatory M(IL-4c) direction. Finally, the ability of peritoneal macrophages to polarize to pro- and anti-inflammatory cells was perfectly normal in CD73-deficient mice in vivo . These data indicate that, in contrast to other major leukocyte subpopulations, CD73 activity on macrophages does not play a major role in their polarization and that in mice host CD73 on any cell type is not required in vivo for peritoneal macrophage polarization towards either a pro- or an anti-inflammatory direction.

Description: by Hui San Ong, Mohd Syafiq Rahim, Mohd Firdaus-Raih, Effirul Ikhwan Ramlan The unique programmability of nucleic acids offers alternative in constructing excitable and functional nanostructures. This work introduces an autonomous protocol to construct DNA Tetris shapes (L-Shape, B-Shape, T-Shape and I-Shape) using modular DNA blocks. The protocol exploits the rich number of sequence combinations available from the nucleic acid alphabets, thus allowing for diversity to be applied in designing various DNA nanostructures. Instead of a deterministic set of sequences corresponding to a particular design, the protocol promotes a large pool of DNA shapes that can assemble to conform to any desired structures. By utilising evolutionary programming in the design stage, DNA blocks are subjected to processes such as sequence insertion, deletion and base shifting in order to enrich the diversity of the resulting shapes based on a set of cascading filters. The optimisation algorithm allows mutation to be exerted indefinitely on the candidate sequences until these sequences complied with all the four fitness criteria. Generated candidates from the protocol are in agreement with the filter cascades and thermodynamic simulation. Further validation using gel electrophoresis indicated the formation of the designed shapes. Thus, supporting the plausibility of constructing DNA nanostructures in a more hierarchical, modular, and interchangeable manner.

Description: by Nima Toosizadeh, Jane Mohler, David G. Armstrong, Talal K. Talal, Bijan Najafi Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m 2 ) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m 2 ) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-control slope = 1.23±1.06×10 -2 cm 2 /sec, P

Description: by Raphael H. Heiberger Today´s connected world allows people to gather information in shorter intervals than ever before, widely monitored by massive online data sources. As a dramatic economic event, recent financial crisis increased public interest for large companies considerably. In this paper, we exploit this change in information gathering behavior by utilizing Google query volumes as a "bad news" indicator for each corporation listed in the Standard and Poor´s 100 index. Our results provide not only an investment strategy that gains particularly in times of financial turmoil and extensive losses by other market participants, but reveal new sectoral patterns between mass online behavior and (bearish) stock market movements. Based on collective attention shifts in search queries for individual companies, hence, these findings can help to identify early warning signs of financial systemic risk. However, our disaggregated data also illustrate the need for further efforts to understand the influence of collective attention shifts on financial behavior in times of regular market activities with less tremendous changes in search volumes.

Description: by Sea H. Kim, Birendra Babu Adhikari, Siobanth Cruz, Michael P. Schramm, Joe A. Vinson, Vasanthy Narayanaswami The objective of this study is to transport and deliver resveratrol to intracellular sites using apolipoprotein E3 (apoE3). Reconstituted high-density lipoprotein (rHDL) bearing resveratrol (rHDL/res) was prepared using phospholipids and the low-density lipoprotein receptor (LDLr)-binding domain of apoE3. Biophysical characterization revealed that resveratrol was partitioned into the phospholipid bilayer of discoidal rHDL/res particles (~19 nm diameter). Co-immunoprecipitation studies indicated that the LDLr-binding ability of apoE3 was retained. Cellular uptake of resveratrol to intracellular sites was evaluated in glioblastoma A-172 cells by direct fluorescence using chemically synthesized NBD-labeled resveratrol (res/NBD) embedded in rHDL/res. Competition and inhibition studies indicate that the uptake is by receptor mediated endocytosis via the LDLr, with co-localization of apoE3 and res/NBD in late endosomes/lysosomes. We propose that rHDL provides an ideal hydrophobic milieu to sequester resveratrol and that rHDL containing apoE3 serves as an effective “nanovehicle” to transport and deliver resveratrol to targeted intracellular sites.

Description: by JunLi Liu, YiHu Wang, ShuJun Song, XiJie Wang, YaYa Qin, ShaoYan Si, YanChuan Guo Purpose Collagen peptides (CPs) and calcium citrate are commonly used as bone health supplements for treating osteoporosis. However, it remains unknown whether the combination of oral bovine CPs with calcium citrate is more effective than administration of either agent alone. Methods Forty 12-week-old Sprague-Dawley rats were randomly divided into five groups ( n = 8) for once-daily intragastric administration of different treatments for 3 months at 3 months after ovariectomy (OVX) as follows: sham + vehicle; OVX + vehicle; OVX + 750 mg/kg CP; OVX + CP-calcium citrate (75 mg/kg); OVX + calcium citrate (75 mg/kg). After euthanasia, the femurs were removed and analyzed by dual energy X-ray absorptiometry and micro-computed tomography, and serum samples were analyzed for bone metabolic markers. Results OVX rats supplemented with CPs or CP-calcium citrate showed osteoprotective effects, with reductions in the OVX-induced decreases in their femoral bone mineral density. Moreover, CP-calcium citrate prevented trabecular bone loss, improved the microarchitecture of the distal femur, and significantly inhibited bone loss with increased bone volume, connectivity density, and trabecular number compared with OVX control rats. CP or CP-calcium citrate administration significantly increased serum procollagen type I N-terminal propeptide levels and reduced serum bone-specific alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen levels. Conclusions Our data indicate that combined oral administration of bovine CPs with calcium citrate inhibits bone loss in OVX rats. The present findings suggest that combined oral administration of bovine CPs with calcium citrate is a promising alternative for reducing bone loss in osteopenic postmenopausal women.

Description: Article How variation in species responses to climate may influence the resilience of ecological communities to environmental change is not fully understood. Here, the authors characterize the thermal niches of insect pollinator communities and show that resilience increases along a gradient of land-use intensity. Nature Communications doi: 10.1038/ncomms8989 Authors: Sara Kühsel, Nico Blüthgen

Description: Article Sepsis, a systemic inflammatory response to bacterial infection, can lead to organ failure and death. Here, Chai et al. investigate the mechanisms behind the septic response and identify the role of oestrogen sulfotransferase in this process in mice. Nature Communications doi: 10.1038/ncomms8979 Authors: Xiaojuan Chai, Yan Guo, Mengxi Jiang, Bingfang Hu, Zhigang Li, Jie Fan, Meihong Deng, Timothy R. Billiar, Heidi R. Kucera, Nilesh W. Gaikwad, Meishu Xu, Peipei Lu, Jiong Yan, Haiyan Fu, Youhua Liu, Lushan Yu, Min Huang, Su Zeng, Wen Xie

Description: Article Antisense oligonucleotides (ASOs) can repress the expression of specific genes. Here, the authors show that a DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from ASOs is more potent in suppressing target gene expression, and causes a less adverse effect in mouse liver. Nature Communications doi: 10.1038/ncomms8969 Authors: Kazutaka Nishina, Wenying Piao, Kie Yoshida-Tanaka, Yumiko Sujino, Tomoko Nishina, Tsuyoshi Yamamoto, Keiko Nitta, Kotaro Yoshioka, Hiroya Kuwahara, Hidenori Yasuhara, Takeshi Baba, Fumiko Ono, Kanjiro Miyata, Koichi Miyake, Punit P. Seth, Audrey Low, Masayuki Yoshida, C. Frank Bennett, Kazunori Kataoka, Hidehiro Mizusawa, Satoshi Obika, Takanori Yokota

Description: Article Mycobacterium tuberculosis feeds on host fatty acids during infection, a process that requires a fructose bisphosphatase (FBPase) enzyme for gluconeogenesis. Here, Ganapathy et al. show that the bacterium has two different FBPases and that this enzymatic activity is required for full virulence. Nature Communications doi: 10.1038/ncomms8912 Authors: Uday Ganapathy, Joeli Marrero, Susannah Calhoun, Hyungjin Eoh, Luiz Pedro Sorio de Carvalho, Kyu Rhee, Sabine Ehrt

Description: Article The regulatory subunits (RI) of protein kinase A (PKA) form a disulfide bond in response to cellular hydrogen peroxide. Here the authors show that disulfide-activation of PKARIa regulates VEGF-induced angiogenesis in mice and may represent a new therapeutic target in diseases with abnormal angiogenesis. Nature Communications doi: 10.1038/ncomms8920 Authors: Joseph R. Burgoyne, Olena Rudyk, Hyun-ju Cho, Oleksandra Prysyazhna, Natasha Hathaway, Amanda Weeks, Rachel Evans, Tony Ng, Katrin Schröder, Ralf P. Brandes, Ajay M. Shah, Philip Eaton

Description: Article It has been conjectured that not only states but also quantum operations can be placed in a superposition of causal order. Here, the authors use a qubit superpose the order in which two photonic gates are applied, which is shown to enable a more efficient detection of their commutation relations. Nature Communications doi: 10.1038/ncomms8913 Authors: Lorenzo M. Procopio, Amir Moqanaki, Mateus Araújo, Fabio Costa, Irati Alonso Calafell, Emma G. Dowd, Deny R. Hamel, Lee A. Rozema, Časlav Brukner, Philip Walther

Description: Article The confined surface plasmon-polariton modes in plasmonic waveguides are a promising platform for single-photon manipulation in small, coplanar architectures. Here, Bermúdez Ureña et al . demonstrate efficient coupling of a single quantum emitter to the supported modes of a V-groove plasmonic waveguide. Nature Communications doi: 10.1038/ncomms8883 Authors: Esteban Bermúdez-Ureña, Carlos Gonzalez-Ballestero, Michael Geiselmann, Renaud Marty, Ilya P. Radko, Tobias Holmgaard, Yury Alaverdyan, Esteban Moreno, Francisco J. García-Vidal, Sergey I. Bozhevolnyi, Romain Quidant

Description: Article Helical nanofilaments—composed of achiral, bent core molecules—have been shown to assemble into left- and right-handed structures. Here, the authors show diastereomeric interactions on the mesocale between chiral liquid crystal guest compounds and helical nanofilament-based pores. Nature Communications doi: 10.1038/ncomms8763 Authors: Dong Chen, Michael R. Tuchband, Balazs Horanyi, Eva Korblova, David M. Walba, Matthew A. Glaser, Joseph E. Maclennan, Noel A. Clark

Description: Article Exploring magnetic excitations and spin textures on the nanoscale may lead to new spintronic technologies and new understanding of condensed matter. Here, the authors demonstrate the potential of single-electron spins in diamond to image such excitations by characterizing spin waves in a ferromagnetic microdisc. Nature Communications doi: 10.1038/ncomms8886 Authors: Toeno van der Sar, Francesco Casola, Ronald Walsworth, Amir Yacoby

Description: Article The impact of drops on surfaces is highly relevant to our daily life and many industrial applications, such as self-cleaning and ink printing. Here, Hao et al . show the transition from superhydrophobic-like drop bouncing, due to a trapped air layer, to substrate-dependent bouncing on a liquid thin film. Nature Communications doi: 10.1038/ncomms8986 Authors: Chonglei Hao, Jing Li, Yuan Liu, Xiaofeng Zhou, Yahua Liu, Rong Liu, Lufeng Che, Wenzhong Zhou, Dong Sun, Lawrence Li, Lei Xu, Zuankai Wang

Description: by Jennifer Choe Bush, Peter Christopher Pantelis, Xavier Morin Duchesne, Sebastian Alexander Kagemann, Daniel Patrick Kennedy We present a novel “Gaze-Replay” paradigm that allows the experimenter to directly test how particular patterns of visual input—generated from people’s actual gaze patterns—influence the interpretation of the visual scene. Although this paradigm can potentially be applied across domains, here we applied it specifically to social comprehension. Participants viewed complex, dynamic scenes through a small window displaying only the foveal gaze pattern of a gaze “donor.” This was intended to simulate the donor’s visual selection, such that a participant could effectively view scenes “through the eyes” of another person. Throughout the presentation of scenes presented in this manner, participants completed a social comprehension task, assessing their abilities to recognize complex emotions. The primary aim of the study was to assess the viability of this novel approach by examining whether these Gaze-Replay windowed stimuli contain sufficient and meaningful social information for the viewer to complete this social perceptual and cognitive task. The results of the study suggested this to be the case; participants performed better in the Gaze-Replay condition compared to a temporally disrupted control condition, and compared to when they were provided with no visual input. This approach has great future potential for the exploration of experimental questions aiming to unpack the relationship between visual selection, perception, and cognition.

Description: by David G. Warnock, Daniel G. Bichet, Myrl Holida, Ozlem Goker-Alpan, Kathy Nicholls, Mark Thomas, Francois Eyskens, Suma Shankar, Mathews Adera, Sheela Sitaraman, Richie Khanna, John J. Flanagan, Brandon A. Wustman, Jay Barth, Carrolee Barlow, Kenneth J. Valenzano, David J. Lockhart, Pol Boudes, Franklin K. Johnson Trial Registration ClinicalTrials.gov NCT01196871

Description: by Clementine Menz, Mahroo K. Parsi, Julian R. J. Adams, Mohamed A. Sideek, Zlatko Kopecki, Allison J. Cowin, Mark A. Gibson Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) belongs to the fibrillin-LTBP superfamily of extracellular matrix proteins. LTBPs and fibrillins are involved in the sequestration and storage of latent growth factors, particularly transforming growth factor β (TGF-β), in tissues. Unlike other LTBPs, LTBP-2 does not covalently bind TGF-β, and its molecular functions remain unclear. We are screening LTBP-2 for binding to other growth factors and have found very strong saturable binding to fibroblast growth factor-2 (FGF-2) (Kd = 1.1 nM). Using a series of recombinant LTBP-2 fragments a single binding site for FGF-2 was identified in a central region of LTBP-2 consisting of six tandem epidermal growth factor-like (EGF-like) motifs (EGFs 9–14). This region was also shown to contain a heparin/heparan sulphate-binding site. FGF-2 stimulation of fibroblast proliferation was completely negated by the addition of 5-fold molar excess of LTBP-2 to the assay. Confocal microscopy showed strong co-localisation of LTBP-2 and FGF-2 in fibrotic keloid tissue suggesting that the two proteins may interact in vivo. Overall the study indicates that LTBP-2 is a potent inhibitor of FGF-2 that may influence FGF-2 bioactivity during wound repair particularly in fibrotic tissues.

Description: by Xinwei Shi, Hao Liu, Jing Cao, Qing Liu, Guiju Tang, Wanlu Liu, Haiyi Liu, Dongrui Deng, Fuyuan Qiao, Yuanyuan Wu Objective Extravillous trophoblast (EVT) cells invade the endometrium and the maternal spiral arterioles during the first trimester. Mammary Serine Protease Inhibitor (Maspin, SERPINB5) plays a putative role in regulating the invasive activity of cytotrophoblasts. The maspin gene is silenced in various cancers by an epigenetic mechanism that involves aberrant cytosine methylation. We investigated the effect of the methylation status of the maspin promoter on the maspin expression and the aggressiveness of EVT cells. Methods Western blotting was used to detect the maspin protein expression in EVT cells upon hypoxia. The proliferative ability, the apoptosis rate and the migration and invasiveness were measured with Cell Counting Kit-8 assay, Flow Cytometry technology and Transwell methods. Subsequently, we treated cells with recombinant maspin protein. The methylation degree of maspin promoter region upon hypoxia/ decitabine was detected by bisulfite sequencing PCR and methylation-specific PCR. Finally, we explored the effects of decitabine on maspin protein expression and the aggressiveness of EVT cells. Results Hypoxia effectively increased maspin protein expression in EVT cells and significantly inhibited their aggressiveness. The addition of recombinant maspin protein inhibited this aggressiveness. Decitabine reduced the methylation in the maspin promoter region and effectively increased the maspin protein expression, which significantly weakened the migration and invasiveness of EVT cells. Discussion The methylation status of the maspin promoter is an important factor that affects the migration and invasion of EVT cells during early pregnancy. A decrease in the methylation status can inhibit the migration and invasion of EVT cells to affect placentation and can result in the ischemia and hypoxia of placenta.

Description: by Jun-Ha Hwang, Mi Ran Byun, A. Rum Kim, Kyung Min Kim, Hang Jun Cho, Yo Han Lee, Juwon Kim, Mi Gyeong Jeong, Eun Sook Hwang, Jeong-Ho Hong Mesenchymal stem cell (MSC) differentiation is regulated by the extracellular matrix (ECM) through activation of intracellular signaling mediators. The stiffness of the ECM was shown to be an important regulatory factor for MSC differentiation, and transcriptional coactivator with PDZ-binding motif (TAZ) was identified as an effector protein for MSC differentiation. However, the detailed underlying mechanism regarding the role of ECM stiffness and TAZ in MSC differentiation is not yet fully understood. In this report, we showed that ECM stiffness regulates MSC fate through ERK or JNK activation. Specifically, a stiff hydrogel matrix stimulates osteogenic differentiation concomitant with increased nuclear localization of TAZ, but inhibits adipogenic differentiation. ERK and JNK activity was significantly increased in cells cultured on a stiff hydrogel. TAZ activation was induced by ERK or JNK activation on a stiff hydrogel because exposure to an ERK or JNK inhibitor significantly decreased the nuclear localization of TAZ, indicating that ECM stiffness-induced ERK or JNK activation is important for TAZ-driven osteogenic differentiation. Taken together, these results suggest that ECM stiffness regulates MSC differentiation through ERK or JNK activation.

Description: by Maria Cecilia P. Moura, Steven J. Smith, David B. Belzer Residential buildings are a key driver of energy consumption and also impact transportation and land-use. Energy consumption in the residential sector accounts for one-fifth of total U.S. energy consumption and energy-related CO 2 emissions, with floor space a major driver of building energy demands. In this work a consistent, vintage-disaggregated, annual long-term series of U.S. housing stock and residential floor space for 1891–2010 is presented. An attempt was made to minimize the effects of the incompleteness and inconsistencies present in the national housing survey data. Over the 1891–2010 period, floor space increased almost tenfold, from approximately 24,700 to 235,150 million square feet, corresponding to a doubling of floor space per capita from approximately 400 to 800 square feet. While population increased five times over the period, a 50% decrease in household size contributed towards a tenfold increase in the number of housing units and floor space, while average floor space per unit remains surprisingly constant, as a result of housing retirement dynamics. In the last 30 years, however, these trends appear to be changing, as household size shows signs of leveling off, or even increasing again, while average floor space per unit has been increasing. GDP and total floor space show a remarkably constant growth trend over the period and total residential sector primary energy consumption and floor space show a similar growth trend over the last 60 years, decoupling only within the last decade.

Description: by Yi-Ling Chen, Shiun Chang, Ting-Ting Chen, Chien-Kuo Lee Dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs) are critical for initiating and controlling the immune response. However, study of DC, particularly pDC, function is hampered by their low frequency in lymphoid organs, and existing methods for in vitro DC generation preferentially favor the production of cDCs over pDCs. Here, we demonstrated that pDCs could be efficiently generated in vitro from common lymphoid progenitors (CLPs) using Flt3 ligand (FL) in three different culture systems, namely feeder-free, BM-feeder and AC-6-feeder. This was in stark contrast to common DC progenitors (CDPs), in which cDCs were prominently generated under the same conditions. Moreover, the efficiency and function of pDCs generated from these three systems varied. While AC-6 system showed the greatest ability to support pDC development from CLPs, BM-feeder system was able to develop pDCs with better functionality. pDCs could also be expanded in vivo using hydrodynamic gene transfer of FL, which was further enhanced by the combined treatment of FL and IFN-α. Interestingly, IFN-α selectively promoted the proliferation of CLPs and not CDPs, which might contribute to enhanced pDC development. Together, we have defined conditions for in vitro and in vivo generation of pDCs, which may be useful for investigating the biology of pDCs.

Description: by Andrew Erwin, Frank C. Sup In this paper, a novel haptic feedback scheme, used for accurately positioning a 1DOF virtual wrist prosthesis through sensory substitution, is presented. The scheme employs a three-node tactor array and discretely and selectively modulates the stimulation frequency of each tactor to relay 11 discrete haptic stimuli to the user. Able-bodied participants were able to move the virtual wrist prosthesis via a surface electromyography based controller. The participants evaluated the feedback scheme without visual or audio feedback and relied solely on the haptic feedback alone to correctly position the hand. The scheme was evaluated through both normal (perpendicular) and shear (lateral) stimulations applied on the forearm. Normal stimulations were applied through a prototype device previously developed by the authors while shear stimulations were generated using an ubiquitous coin motor vibrotactor. Trials with no feedback served as a baseline to compare results within the study and to the literature. The results indicated that using normal and shear stimulations resulted in accurately positioning the virtual wrist, but were not significantly different. Using haptic feedback was substantially better than no feedback. The results found in this study are significant since the feedback scheme allows for using relatively few tactors to relay rich haptic information to the user and can be learned easily despite a relatively short amount of training. Additionally, the results are important for the haptic community since they contradict the common conception in the literature that normal stimulation is inferior to shear. From an ergonomic perspective normal stimulation has the potential to benefit upper limb amputees since it can operate at lower frequencies than shear-based vibrotactors while also generating less noise. Through further tuning of the novel haptic feedback scheme and normal stimulation device, a compact and comfortable sensory substitution device for upper limb amputees might be created.

Description: by Aparajita Chatterjee, Daniel M. Ratner, Christopher M. Ryan, Patricia J. Johnson, Barry R. O’Keefe, W. Evan Secor, Deborah J. Anderson, Phillips W. Robbins, John Samuelson Trichomonas vaginalis causes vaginitis and increases the risk of HIV transmission by heterosexual sex, while Tritrichomonas foetus causes premature abortion in cattle. Our goals were to determine the effects, if any, of anti-retroviral lectins, which are designed to prevent heterosexual transmission of HIV, on adherence of Trichomonas to ectocervical cells and on Tritrichomonas infections in a mouse model. We show that Trichomonas Asn-linked glycans ( N -glycans), like those of HIV, bind the mannose-binding lectin (MBL) that is part of the innate immune system. N -glycans of Trichomonas and Tritrichomonas bind anti-retroviral lectins (cyanovirin-N and griffithsin) and the 2G12 monoclonal antibody, each of which binds HIV N -glycans. Binding of cyanovirin-N appears to be independent of susceptibility to metronidazole, the major drug used to treat Trichomonas . Anti-retroviral lectins, MBL, and galectin-1 cause Trichomonas to self-aggregate and precipitate. The anti-retroviral lectins also increase adherence of ricin-resistant mutants, which are less adherent than parent cells, to ectocervical cell monolayers and to organotypic EpiVaginal tissue cells. Topical application of either anti-retroviral lectins or yeast N -glycans decreases by 40 to 70% the recovery of Tritrichomonas from the mouse vagina. These results, which are explained by a few simple models, suggest that the anti-retroviral lectins have a modest potential for preventing or treating human infections with Trichomonas .

Description: by Suzan J. W. Robroek, Anne Rongen, Coos H. Arts, Ferdy W. H. Otten, Alex Burdorf, Merel Schuring Background Individuals with lower socioeconomic status are at increased risk of involuntary exit from paid employment. To give sound advice for primary prevention in the workforce, insight is needed into the role of mediating factors between socioeconomic status and labour force participation. Therefore, it is aimed to investigate the influence of health status, lifestyle-related factors and work characteristics on educational differences in exit from paid employment. Methods 14,708 Dutch employees participated in a ten-year follow-up study during 1999–2008. At baseline, education, self-perceived health, lifestyle (smoking, alcohol, sports, BMI) and psychosocial (demands, control, rewards) and physical work characteristics were measured by questionnaire. Employment status was ascertained monthly based on tax records. The relation between education, health, lifestyle, work-characteristics and exit from paid employment through disability benefits, unemployment, early retirement and economic inactivity was investigated by competing risks regression analyses. The mediating effects of these factors on educational differences in exit from paid employment were tested using a stepwise approach. Results Lower educated workers were more likely to exit paid employment through disability benefits (SHR:1.84), unemployment (SHR:1.74), and economic inactivity (SHR:1.53) but not due to early retirement (SHR:0.92). Poor or moderate health, an unhealthy lifestyle, and unfavourable work characteristics were associated with disability benefits and unemployment, and an unhealthy lifestyle with economic inactivity. Educational differences in disability benefits were explained for 40% by health, 31% by lifestyle, and 12% by work characteristics. For economic inactivity and unemployment, up to 14% and 21% of the educational differences could be explained, particularly by lifestyle-related factors. Conclusions There are educational differences in exit from paid employment, which are partly mediated by health, lifestyle and work characteristics, particularly for disability benefits. Health promotion and improving working conditions seem important measures to maintain a productive workforce, particularly among workers with a low education.

Description: by SK Hafizul Islam, Muhammad Khurram Khan, Xiong Li Over the past few years, secure and privacy-preserving user authentication scheme has become an integral part of the applications of the healthcare systems. Recently, Wen has designed an improved user authentication system over the Lee et al.’s scheme for integrated electronic patient record (EPR) information system, which has been analyzed in this study. We have found that Wen’s scheme still has the following inefficiencies: (1) the correctness of identity and password are not verified during the login and password change phases; (2) it is vulnerable to impersonation attack and privileged-insider attack; (3) it is designed without the revocation of lost/stolen smart card; (4) the explicit key confirmation and the no key control properties are absent, and (5) user cannot update his/her password without the help of server and secure channel. Then we aimed to propose an enhanced two-factor user authentication system based on the intractable assumption of the quadratic residue problem (QRP) in the multiplicative group. Our scheme bears more securities and functionalities than other schemes found in the literature.

Description: by Sherif H. Elmeligy Abdelhamid, Chris J. Kuhlman, Madhav V. Marathe, Henning S. Mortveit, S. S. Ravi Discrete dynamical systems are used to model various realistic systems in network science, from social unrest in human populations to regulation in biological networks. A common approach is to model the agents of a system as vertices of a graph, and the pairwise interactions between agents as edges. Agents are in one of a finite set of states at each discrete time step and are assigned functions that describe how their states change based on neighborhood relations. Full characterization of state transitions of one system can give insights into fundamental behaviors of other dynamical systems. In this paper, we describe a discrete graph dynamical systems (GDSs) application called GDSCalc for computing and characterizing system dynamics. It is an open access system that is used through a web interface. We provide an overview of GDS theory. This theory is the basis of the web application; i.e., an understanding of GDS provides an understanding of the software features, while abstracting away implementation details. We present a set of illustrative examples to demonstrate its use in education and research. Finally, we compare GDSCalc with other discrete dynamical system software tools. Our perspective is that no single software tool will perform all computations that may be required by all users; tools typically have particular features that are more suitable for some tasks. We situate GDSCalc within this space of software tools.

Description: by Lisa Kellman, Amy Myette, Hugo Beltrami Forest harvesting induces a step change in the climatic variables (temperature and moisture), that control carbon dioxide ( CO 2 ) production arising from soil organic matter decomposition within soils. Efforts to examine these vertically complex relationships in situ within soil profiles are lacking. In this study we examined how the climatic controls on CO 2 production change within vertically distinct layers of the soil profile in intact and clearcut forest soils of a humid temperate forest system of Atlantic Canada. We measured mineral soil temperature (0, 5, 10, 20, 50 and 100 cm depth) and moisture (0–15 cm and 30–60 cm depth), along with CO 2 surface efflux and subsurface concentrations (0, 2.5, 5, 10, 20, 35, 50, 75 and 100 cm depth) in 1 m deep soil pits at 4 sites represented by two forest-clearcut pairs over a complete annual cycle. We examined relationships between surface efflux at each site, and soil heat, moisture, and mineral soil CO 2 production. Following clearcut harvesting we observed increases in temperature through depth (1–2°C annually; often in excess of 4°C in summer and spring), alongside increases in soil moisture (30%). We observed a systematic breakdown in the expected exponential relationship between CO 2 production and heat with mineral soil depth, consistent with an increase in the role moisture plays in constraining CO 2 production. These findings should be considered in efforts to model and characterize mineral soil organic matter decomposition in harvested forest soils.

Description: by Peng Yu, Jing Zhang, Shuchun Yu, Zhenzhong Luo, Fuzhou Hua, Linhui Yuan, Zhidong Zhou, Qin Liu, Xiaohong Du, Sisi Chen, Lieliang Zhang, Guohai Xu Background and Purpose Myocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R) in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC) in myocardial I/R is through restored impaired autophagic flux. Methods Except for the sham control (SHAM) group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by hemodynamics and echocardiography. The activation of autophagy was evaluated by autophagosome accumulation, LC3 conversion and p62 degradation. Potential molecular mechanisms were investigated by immunoblotting, real-time PCR and immunofluorescence staining. Results SPC improved the hemodynamic parameters, cardiac dysfunction, histopathological and ultrastructural damages, and decreased myocardial infarction size after myocardial I/R injury ( P 〈 0.05 vs. I/R group). Compared with the cases in I/R group, myocardial ATP and NAD + content, mitochondrial function related genes and proteins, and the expressions of SOD2 and HO-1 were increased, while the expressions of ROS and Vimentin were decreased in the SPC group ( P 〈 0.05 vs. I/R group). SPC significantly activated Akt/mTOR signaling, and inhibited the formation of Vps34/Beclin1 complex via increasing expression of Bcl2 protein ( P 〈 0.05 vs. I/R group). SPC suppressed elevated expressions of LC3 II/I ratio, Beclin1, Atg5 and Atg7 in I/R rat, which indicated that SPC inhibited over-activation of autophagy, and promoted autophagosome clearance. Meanwhile, SPC significantly suppressed the decline of Opa1 and increases of Drp1 and Parkin induced by I/R injury ( P 〈 0.05 vs. I/R group). Moreover, SPC maintained the contents of ATP by reducing impaired mitochondria. Conclusion SPC protects rat hearts against I/R injury via ameliorating mitochondrial impairment, oxidative stress and rescuing autophagic clearance.

Description: by Lisa Müller, Erich Müller, Carolin Hildebrandt, Elmar Kornexl, Christian Raschner The relative age effect (RAE), which refers to an over-representation of selected athletes born early in the selection year, was proven to be present in alpine ski racing in all age categories at both national and international levels. However, the influential factors on, or the causal mechanisms of, the RAE are still unknown. Therefore, the aim of the present study was to examine three possible influential factors on the relative age effect in alpine skiing: physical performance, anthropometric characteristics and biological maturational status. The study included the investigation of 282 elite Austrian youth ski racers and 413 non-athletes (comparison group) of the same age (10–13 years) and region. Six physical performance tests were performed, body mass and height were assessed, and the age at peak height velocity (APHV) was calculated. A significant RAE was present in the ski racers. No differences were shown in the physical performance characteristics or in the calculated APHV between the relative age quarters. These results suggest that ski racers born in the last quarter can counteract the relative age disadvantages if they already present the same level of physical performance and maturational status as those born at the beginning of the year. The height and weight of ski racers born at the beginning of the year were significantly higher compared to the non-athletes, and ski racers born in relative age quarter 1 were taller and heavier compared to the ski racers of the other quarters. This indicates that the anthropometric characteristics influence the selection process in alpine ski racing, and that relatively older athletes are more likely to be selected if they exhibit advanced anthropometric characteristics.

Description: by Andrea Pelletier-Baldelli, Jessica A. Bernard, Vijay A. Mittal Social processes are key to navigating the world, and investigating their underlying mechanisms and cognitive architecture can aid in understanding disease states such as schizophrenia, where social processes are highly impacted. Evidence suggests that social processes are impaired in individuals at ultra high-risk for the development of psychosis (UHR). Understanding these phenomena in UHR youth may clarify disease etiology and social processes in a period that is characterized by significantly fewer confounds than schizophrenia. Furthermore, understanding social processing deficits in this population will help explain these processes in healthy individuals. The current study examined resting state connectivity of the salience (SN) and default mode networks (DMN) in association with facial emotion recognition (FER), an integral aspect of social processes, as well as broader social functioning (SF) in UHR individuals and healthy controls. Consistent with the existing literature, UHR youth were impaired in FER and SF when compared with controls. In the UHR group, we found increased connectivity between the SN and the medial prefrontal cortex, an area of the DMN relative to controls. In UHR youth, the DMN exhibited both positive and negative correlations with the somatosensory cortex/cerebellum and precuneus, respectively, which was linked with better FER performance. For SF, results showed that sensory processing links with the SN might be important in allowing for better SF for both groups, but especially in controls where sensory processing is likely to be unimpaired. These findings clarify how social processing deficits may manifest in psychosis, and underscore the importance of SN and DMN connectivity for social processing more generally.

Description: Article Individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) can map RNA binding sites of RNA-binding proteins (RBPs). Here, the authors report an analysis tool that improves the binding site assignment for some RBPs that have length-dependent broader distribution for their iCLIP fragments. Nature Communications doi: 10.1038/ncomms8921 Authors: Christian Hauer, Tomaz Curk, Simon Anders, Thomas Schwarzl, Anne-Marie Alleaume, Jana Sieber, Ina Hollerer, Madhuri Bhuvanagiri, Wolfgang Huber, Matthias W. Hentze, Andreas E. Kulozik

Description: Article Pathological neovascularization causes blinding eye disease. Here the authors show that IL10 activates STAT3 signalling in the macrophages in the ageing eye, promoting their polarization towards a pro-angiogenic phenotype; interfering with this pathway reverses the pathology in a mouse model. Nature Communications doi: 10.1038/ncomms8847 Authors: Rei Nakamura, Abdoulaye Sene, Andrea Santeford, Abdelaziz Gdoura, Shunsuke Kubota, Nicole Zapata, Rajendra S. Apte

Description: by Marc O. Nadon, Jerald S. Ault, Ivor D. Williams, Steven G. Smith, Gerard T. DiNardo The coral reef fish community of Hawaii is composed of hundreds of species, supports a multimillion dollar fishing and tourism industry, and is of great cultural importance to the local population. However, a major stock assessment of Hawaiian coral reef fish populations has not yet been conducted. Here we used the robust indicator variable “average length in the exploited phase of the population (L¯)”, estimated from size composition data from commercial fisheries trip reports and fishery-independent diver surveys, to evaluate exploitation rates for 19 Hawaiian reef fishes. By and large, the average lengths obtained from diver surveys agreed well with those from commercial data. We used the estimated exploitation rates coupled with life history parameters synthesized from the literature to parameterize a numerical population model and generate stock sustainability metrics such as spawning potential ratios (SPR). We found good agreement between predicted average lengths in an unfished population (from our population model) and those observed from diver surveys in the largely unexploited Northwestern Hawaiian Islands. Of 19 exploited reef fish species assessed in the main Hawaiian Islands, 9 had SPRs close to or below the 30% overfishing threshold. In general, longer-lived species such as surgeonfishes, the redlip parrotfish ( Scarus rubroviolaceus ), and the gray snapper ( Aprion virescens ) had the lowest SPRs, while short-lived species such as goatfishes and jacks, as well as two invasive species ( Lutjanus kasmira and Cephalopholis argus ), had SPRs above the 30% threshold.

Description: by Leonie J. P. Steenis, Marjolein Verhoeven, Dave J. Hessen, Anneloes L. van Baar Background The Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) are frequently used to assess early child development worldwide. However, the original standardization only included US children, and it is still unclear whether or not these norms are adequate for use in other populations. Recently, norms for the Dutch version of the Bayley-III (The Bayley-III-NL) were made. Scores based on Dutch and US norms were compared to study the need for population-specific norms. Methods Scaled scores based on Dutch and US norms were compared for 1912 children between 14 days and 42 months 14 days. Next, the proportions of children scoring 〈 1-SD and 〈 -2 SD based on the two norms were compared, to identify over- or under-referral for developmental delay resulting from non-population-based norms. Results Scaled scores based on Dutch norms fluctuated around values based on US norms on all subtests. The extent of the deviations differed across ages and subtests. Differences in means were significant across all five subtests (p 〈 .01) with small to large effect sizes ( η p 2 ) ranging from .03 to .26). Using the US instead of Dutch norms resulted in over-referral regarding gross motor skills, and under-referral regarding cognitive, receptive communication, expressive communication, and fine motor skills. Conclusions The Dutch norms differ from the US norms for all subtests and these differences are clinically relevant. Population specific norms are needed to identify children with low scores for referral and intervention, and to facilitate international comparisons of population data.

Description: by Xiao-Dan Wang, Hui Lu, Zhihong Shi, Li Cai, Shuai Liu, Shuling Liu, Tong Han, Ying Wang, Yuying Zhou, Xinping Wang, Shuo Gao, Yong Ji Posterior cortical atrophy (PCA) is a clinicoradiologic neurodegenerative syndrome characterized by predominant impairment of higher visual functions. Neuroimaging and neuropathological studies show that PCA is probably an atypical presentation of Alzheimer’s disease. However, in China PCA has rarely been studied and remains largely unknown. Our study therefore aimed to analyze the clinical manifestations and patterns of cerebral atrophy, amyloid beta deposition and regional glucose metabolism in Chinese PCA patients, comparing them directly with those of typical Alzheimer’s disease (TAD). Seven PCA patients, 6 TAD patients and 5 controls underwent neuropsychological assessment, MRI scan, 11 C-PIB PET scan and 18 F-FDG PET scan. Cerebral atrophy including ventricular enlargement, posterior atrophy and medial temporal lobe atrophy were evaluated with MRI. The uptake of 11 C-PIB was quantified at the voxel level using the standardized uptake value ratio. Comparisons of regional cerebral glucose metabolism were calculated with statistical parametric mapping. PCA patients showed significant impairment on visuospatial function in neuropsychological assessment. And PCA patients showed more severe posterior atrophy and less severe left medial temporal lobe atrophy compared with TAD patients. The data from 11 C-PIB PET scanning showed that amyloid beta deposition in PCA was comparable to TAD. Moreover, in PCA the results from 18 F-FDG PET scanning revealed significant hypometabolism in the temporoparietooccipital region and identified specific hypometabolism in the right occipital lobe, compared with TAD. Our study thus provides a preliminary view of PCA in Chinese patients. A further study with a larger number of subjects would be recommended to confirm these findings.

Description: by Q. Wang, M. Li, Edmond H. M. Lou, M. S. Wong Background Non-ionizing radiation imaging assessment has been advocated for the patients with adolescent idiopathic scoliosis (AIS). As one of the radiation-free methods, ultrasound imaging has gained growing attention in scoliosis assessment over the past decade. The center of laminae (COL) method has been proposed to measure the spinal curvature in the coronal plane of ultrasound image. However, the reliability and validity of this ultrasound method have not been validated in the clinical setting. Objectives To evaluate the reliability and validity of clinical ultrasound imaging on lateral curvature measurements of AIS with their corresponding magnetic resonance imaging (MRI) measurements. Methods Thirty curves (ranged 10.2°–68.2°) from sixteen patients with AIS were eligible for this study. The ultrasound scan was performed using a 3-D ultrasound unit within the same morning of MRI examination. Two researchers were involved in data collection of these two examinations. The COL method was used to measure the coronal curvature in ultrasound image, compared with the Cobb method in MRI. The intra- and inter-rater reliability of the COL method was evaluated by intra-class correlation coefficient (ICC). The validity of this method was analyzed by paired Student’s t -test, Bland–Altman statistics and Pearson correlation coefficient. The level of significance was set as 0.05. Results The COL method showed high intra- and inter-rater reliabilities (both with ICC (2, K) 〉0.9, p

Description: by Yongkang Kim, Taesung Park Genome-wide association studies (GWAS) have successfully discovered hundreds of associations between genetic variants and complex traits. Most GWAS have focused on the identification of single variants. It has been shown that most of the variants that were discovered by GWAS could only partially explain disease heritability. The explanation for this missing heritability is generally believed to be gene-gene (GG) or gene-environment (GE) interactions and other structural variants. Generalized multifactor dimensionality reduction (GMDR) has been proven to be reasonably powerful in detecting GG and GE interactions; however, its performance has been found to decline when outlying quantitative traits are present. This paper proposes a robust GMDR estimation method (based on the L-estimator and M-estimator estimation methods) in an attempt to reduce the effects caused by outlying traits. A comparison of robust GMDR with the original MDR based on simulation studies showed the former method to outperform the latter. The performance of robust GMDR is illustrated through a real GWA example consisting of 8,577 samples from the Korean population using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) level as a phenotype. Robust GMDR identified the KCNH1 gene to have strong interaction effects with other genes on the function of insulin secretion.

Description: by Min Gao, Renli Tian, Junhao Wen, Qingyu Xiong, Bin Ling, Linda Yang In recent years, recommender systems have become an effective method to process information overload. However, recommendation technology still suffers from many problems. One of the problems is shilling attacks-attackers inject spam user profiles to disturb the list of recommendation items. There are two characteristics of all types of shilling attacks: 1) Item abnormality: The rating of target items is always maximum or minimum; and 2) Attack promptness: It takes only a very short period time to inject attack profiles. Some papers have proposed item anomaly detection methods based on these two characteristics, but their detection rate, false alarm rate, and universality need to be further improved. To solve these problems, this paper proposes an item anomaly detection method based on dynamic partitioning for time series. This method first dynamically partitions item-rating time series based on important points. Then, we use chi square distribution (χ 2 ) to detect abnormal intervals. The experimental results on MovieLens 100K and 1M indicate that this approach has a high detection rate and a low false alarm rate and is stable toward different attack models and filler sizes.

Description: by Morgan Kruse, Rebecca Wildner, Gisoo Barnes, Monique Martin, Udo Mueller, Francesco Lo-Coco, Ashutosh Pathak The objective of this study was to estimate the net cost of arsenic trioxide (ATO) added to all- trans retinoic acid (ATRA) compared to ATRA plus chemotherapy when used in first-line acute promyelocytic leukemia (APL) treatment for low to intermediate risk patients from the perspective of the overall Italian healthcare systemA Markov model was developed with 3 health states: stable disease, disease event and death. Each month, patients could move from stable to disease event or die from either state. After a disease event, patients discontinued initial treatment and switched to the other regimen as second-line therapy. Treatment regimens, efficacy and adverse events were derived from published sources and expert opinion; unit costs were collected from standard Italian sources. Clinical outcomes and costs for pre-ATO and post-ATO scenarios were combined with population and product utilization information to calculate the total budgetary impact using a 3-year time horizon; one-way sensitivity analyses were conducted. Three-year cumulative pharmacy costs for ATO+ATRA were €46,700 per-patient versus €6,500 for ATRA+chemotherapy; however, medical costs for ATO+ATRA were €12,300 per-patient versus €30,200 for ATRA+chemotherapy. The total budgetary impact was estimated to be an additional €127,300, €312,500 and €477,800 in the first, second and third years, respectively. The model was most sensitive to changes in the cost of the ATO+ATRA regimen during the consolidation phase. Budgetary impact models are valuable to payers making formulary decisions regarding the access and affordability of new medicines. The cost of treatment analysis showed that pharmacy costs for ATO+ATRA were higher than for ATRA+chemotherapy, while all other evaluated costs were lower for ATO+ATRA treated patients. The average budgetary impact was €305,900 per year overall, representing a 3.5% increase. Further research is needed to determine the cost-effectiveness of ATO+ATRA compared to the current first-line standard of care in APL.

Description: by Antonella Agodi, Martina Barchitta, Annalisa Quattrocchi, Andrea Maugeri, Manlio Vinciguerra Objective The Death-Associated Protein Kinase 1 ( DAPK1 ) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic review and a meta-analysis in order to evaluate DAPK1 promoter methylation as an epigenetic marker for CC risk. Methods A systematic literature search was carried out. The Cochrane software package Review Manager 5.2 was used. The fixed-effects or random-effects models, according to heterogeneity across studies, were used to calculate odds ratios (ORs) and 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by histological type, assays used to evaluate DAPK1 promoter methylation, and control sample source. Results A total of 20 papers, published between 2001 and 2014, on 1929 samples, were included in the meta-analysis. DAPK1 promoter methylation was associated with an increased CC risk based on the random effects model (OR: 21.20; 95%CI = 11.14–40.35). Omitting the most heterogeneous study, the between study heterogeneity decreased and the association increased (OR: 24.13; 95% CI = 15.83–36.78). The association was also confirmed in all the subgroups analyses. Conclusions A significant strong association between DAPK1 promoter methylation and CC was shown and confirmed independently by histological tumor type, method used to evaluate methylation and source of control samples. Methylation markers may have value in early detection of CC precursor lesions, provide added reassurances of safety for women who are candidates for less frequent screens, and predict outcomes of women infected with human papilloma virus.

Description: by Yufeng Huang, Chuchu Wang, Yufeng Yao, Xiaoyu Zuo, Shanshan Chen, Chengqi Xu, Hongfu Zhang, Qiulun Lu, Le Chang, Fan Wang, Pengxia Wang, Rongfeng Zhang, Zhenkun Hu, Qixue Song, Xiaowei Yang, Cong Li, Sisi Li, Yuanyuan Zhao, Qin Yang, Dan Yin, Xiaojing Wang, Wenxia Si, Xiuchun Li, Xin Xiong, Dan Wang, Yuan Huang, Chunyan Luo, Jia Li, Jingjing Wang, Jing Chen, Longfei Wang, Li Wang, Meng Han, Jian Ye, Feifei Chen, Jingqiu Liu, Ying Liu, Gang Wu, Bo Yang, Xiang Cheng, Yuhua Liao, Yanxia Wu, Tie Ke, Qiuyun Chen, Xin Tu, Robert Elston, Shaoqi Rao, Yanzong Yang, Yunlong Xia, Qing K. Wang Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for

Description: by Shu-I Wu, Su-Chiu Chen, Shen-Ing Liu, Fang-Ju Sun, Jimmy J. M. Juang, Hsin-Chien Lee, Kai-Liang Kao, Michael E. Dewey, Martin Prince, Robert Stewart Objective Despite high mortality associated with serious mental illness, risk of acute myocardial infarction (AMI) remains unclear, especially for patients with bipolar disorder. The main objective was to investigate the relative risk of AMI associated with schizophrenia and bipolar disorders in a national sample. Method Using nationwide administrative data, an 11-year historic cohort study was assembled, comprised of cases aged 18 and above who had received a diagnosis of schizophrenia or bipolar disorder, compared to a random sample of all other adults excluding those with diagnoses of serious mental illness. Incident AMI as a primary diagnosis was ascertained. Hazard ratios stratified by age and gender were calculated and Cox regression models were used to adjust for other covariates. Results A total of 70,225 people with schizophrenia or bipolar disorder and 207,592 people without serious mental illness were compared. Hazard ratios in men adjusted for age, income and urbanization were 1.15 (95% CI 1.01~1.32) for schizophrenia and 1.37 (1.08~1.73)for bipolar disorder, and in women, 1.85 (1.58~2.18) and 1.88(1.47~2.41) respectively. Further adjustment for treated hypertension, diabetes and hyperlipidaemia attenuated the hazard ratio for men with schizophrenia but not the other comparison groups. Hazard ratios were significantly stronger in women than men and were stronger in younger compared to older age groups for both disorders; however, gender modification was only significant in people with schizophrenia, and age modification only significant in people with bipolar disorder. Conclusions In this large national sample, schizophrenia and bipolar disorder were associated with raised risk of AMI in women and in the younger age groups although showed differences in potential confounding and modifying factors.

Description: by Kwi Young Kang, In Je Kim, Min A Yoon, Yeon Sik Hong, Sung-Hwan Park, Ji Hyeon Ju Objective To study the relationship between inflammatory and structural lesions in the sacroiliac joints (SIJs) on MRI and spinal progression observed on conventional radiographs in patients with axial spondyloarthritis (axSpA). Methods One hundred and ten patients who fulfilled the ASAS axSpA criteria were enrolled. All underwent SIJ MRI at baseline and lumbar spine radiographs at baseline and after 2 years. Inflammatory and structural lesions on SIJ MRI were scored using the SPondyloArthritis Research Consortium of Canada (SPARCC) method. Spinal radiographs were scored using the Stoke AS Spinal Score (SASSS). Multivariate logistic regression analysis was performed to identify predictors of spinal progression. Results Among the 110 patients, 25 (23%) showed significant radiographic progression (change of SASSS≥2) over 2 years. There was no change in the SASSS over 2 years according to the type of inflammatory lesion. Patients with fat metaplasia or ankyloses on baseline MRI showed a significantly higher SASSS at 2 years than those without (p

Description: Article A hybrid incompatibility between Capsella plant species is due to an interaction between two immune regulators. Here, the authors show that highly divergent haplotypes result from balancing selection in the ancestral lineage and their sorting into derived lineages facilitated the evolution of the incompatibility. Nature Communications doi: 10.1038/ncomms8960 Authors: Adrien Sicard, Christian Kappel, Emily B. Josephs, Young Wha Lee, Cindy Marona, John R. Stinchcombe, Stephen I. Wright, Michael Lenhard

Description: Nature Reviews Microbiology 13, 526 (2015). doi:10.1038/nrmicro3538 Author: Cláudio Nunes-Alves Persisters are dormant bacterial populations that contribute to multidrug tolerance (MDT) because they are able to escape treatment with most antibiotics, which target metabolically active cells. A new study now characterizes the molecular basis for persister generation involving HipA, a kinase that inhibits protein synthesis

Description: Nature Reviews Microbiology 13, 589 (2015). doi:10.1038/nrmicro3504 Authors: Peter Liehl, Vanessa Zuzarte-Luis & Maria M. Mota Many clinically relevant pathogens, including certain bacteria and protozoan parasites, have developed an intracellular lifestyle that enables them to nestle in customized vacuoles. Although these pathogens are protected from extracellular defences, recent findings indicate that host cells have evolved multiple strategies to unmask the pathogen

Description: Article Mapping the distribution of fluorescence molecules, rather than just their emission intensity, can improve super-resolution fluorescence microscopy. Here, the authors present a general solution for rendering the number of fluorescent molecules recorded by confocal or STED microscopy. Nature Communications doi: 10.1038/ncomms8977 Authors: Haisen Ta, Jan Keller, Markus Haltmeier, Sinem K. Saka, Jürgen Schmied, Felipe Opazo, Philip Tinnefeld, Axel Munk, Stefan W. Hell

Description: Article Persistent antigen stimulation can cause exhaustion and unresponsiveness of CD8 cells, impairing the immune response. Here the authors show that increasing the number of CD8 cells, decreasing the antigen load or providing CD4 help can overcome the exhaustion and establish a memory response. Nature Communications doi: 10.1038/ncomms8994 Authors: Juhyun Kim, Su Jeong Ryu, Keunhee Oh, Ji-Min Ju, Ji Yeong Jeon, Giri Nam, Dong-Sup Lee, Hang-Rae Kim, Joo Young Kim, Jun Chang, Thomas Sproule, Kyungho Choi, Derry Roopenian, Eun Young Choi

Description: Article Plasmonic surfaces are used as two-dimensional metamaterials for light manipulation on nanoscale, and their optical properties can be further tuned by coating. Here the authors report a new absorption-induced scattering mode in a silver nanoparticle array coated with semiconducting organic absorbers. Nature Communications doi: 10.1038/ncomms8899 Authors: Christopher E. Petoukhoff, Deirdre M. O’Carroll

Description: Article U-shaped glacial valleys dominate 〉10 ka since the last major glaciation and the transitions from glacier-dominated to fluvial regimes are poorly understood. Here, the authors use digital topographic data to show that glacial topography is rapidly replaced by fluvial topography where rock uplift rates are high. Nature Communications doi: 10.1038/ncomms9028 Authors: Günther Prasicek, Isaac J. Larsen, David R. Montgomery

Description: by Andrew J. Massey High-content imaging is a powerful tool for determining cell phenotypes at the single cell level. Characterising the effect of small molecules on cell cycle distribution is important for understanding their mechanism of action especially in oncology drug discovery but also for understanding potential toxicology liabilities. Here, a high-throughput phenotypic assay utilising the PerkinElmer Operetta high-content imager and Harmony software to determine cell cycle distribution is described. PhenoLOGIC, a machine learning algorithm within Harmony software was employed to robustly separate single cells from cell clumps. DNA content, EdU incorporation and pHH3 (S10) expression levels were subsequently utilised to separate cells into the various phases of the cell cycle. The assay is amenable to multiplexing with an additional pharmacodynamic marker to assess cell cycle changes within a specific cellular sub-population. Using this approach, the cell cycle distribution of γH2AX positive nuclei was determined following treatment with DNA damaging agents. Likewise, the assay can be multiplexed with Ki67 to determine the fraction of quiescent cells and with BrdU dual labelling to determine S-phase duration. This methodology therefore provides a relatively cheap, quick and high-throughput phenotypic method for determining accurate cell cycle distribution for small molecule mechanism of action and drug toxicity studies.

Description: Article G protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins in humans and exhibit diverse activation mechanisms. Here, the authors combine electron microscopy, hydrogen deuterium exchange and Molecular dynamics simulations to gain insight into the activation mechanism of the glucagon receptor. Nature Communications doi: 10.1038/ncomms8859 Authors: Linlin Yang, Dehua Yang, Chris de Graaf, Arne Moeller, Graham M. West, Venkatasubramanian Dharmarajan, Chong Wang, Fai Y. Siu, Gaojie Song, Steffen Reedtz-Runge, Bruce D. Pascal, Beili Wu, Clinton S. Potter, Hu Zhou, Patrick R. Griffin, Bridget Carragher, Huaiyu Yang, Ming-Wei Wang, Raymond C. Stevens, Hualiang Jiang

Description: Article Light atoms are hardly visible through standard microscopy techniques, because of their smaller scattering power and higher knock-on probability. Here, the authors present an approach to probe light atoms by means of electron energy loss spectroscopy, relying on inelastically scattered electrons. Nature Communications doi: 10.1038/ncomms8943 Authors: Ryosuke Senga, Kazu Suenaga

Description: by Stéphane J. Montuelle, Susan H. Williams Cranial kinesis refers to movements of skeletal sub-units relative to one another at mobile sutures within the skull. The presence and functional significance of cranial kinesis has been investigated in various vertebrates, with much of our understanding coming from comparative studies and manipulation of ligamentous specimens. Drawing on these studies, cranial kinesis in lizards has been modeled as a four-bar linkage system involving streptostyly (rotation of the quadrate), hypokinesis (dorsoventral flexion and extension of the palato-maxillary sub-unit), mesokinesis (dorsoventral flexion and extension of the snout at the fronto-parietal suture) and metakinesis (sliding movements between parietal and supraocciptal bones). In vivo studies, although limited, suggest that cranial kinesis serves an important role during routine behaviors such as feeding. Here, we use X-ray Reconstruction Of Moving Morphology to further quantify mesokinesis in vivo in Gekko gecko during three routine behaviors: gape display, biting and post-ingestion feeding. During gape display, the snout rotates dorsally above rest position, with mesokinesis accounting for a 10% increase in maximum gape over that achieved solely by the depression of the lower jaw. During defensive biting, the snout rotates ventrally below rest position to participate in gape closure. Finally, ventroflexion of the snout also occurs during post-ingestion feeding, accounting for 42% of gape closure during intra-oral transport, 86% during puncture-crushing, and 61% during pharyngeal packing. Mesokinesis thus appears to facilitate prey puncturing by allowing the snout to rotate ventrally so that the upper teeth pierce the prey item, thus limiting the need for large movements of the lower jaw. This is suggested to maintain a firm grip on the prey and reduce the possibility of prey escape. More generally, this study demonstrates that mesokinesis is a key component of defensive biting and gape display behaviors, as well as post-ingestion feeding, all of which are linked to organismal fitness.

Description: by Xianqiong Gong, Jiaen Yang, Jinmo Tang, Chong Gu, Lijian Huang, Ying Zheng, Huiqing Liang, Min Wang, Chuncheng Wu, Yue Chen, Manying Zhang, Zhijian Yu, Qianguo Mao To understand the mechanisms underlying the discordance between normal serum alanine aminotransferase (ALT) levels and significant alterations in liver histology of chronic hepatitis B virus (HBV) infection with persistent normal ALT (PNALT) or minimally elevated ALT. A total of 300 treatment-naive chronic HBV-infected patients with PNALT (ALT ≤ upper limit of normal [ULN, 40 U/ml]) or minimally elevated ALT (1-2×ULN) were retrospectively enrolled. All patients underwent liver biopsy and histological changes were analyzed along with biochemical and HBV markers. Among 300 participants, 177 were HBeAg-positive and 123 HBeAg-negative. Significant histologic abnormalities were found in 42.9% (76/177) and 52.8% (65/123) of HBeAg-positive and HBeAg-negative patients, respectively. Significant fibrosis, which is a marker of prior injury, was more frequently detected than significant necroinflammation (suggesting active liver injury) in both HBeAg-positive and -negative groups, suggesting that liver injury occurred intermittently in our cohort. No significant differences were noticed in the percentage of patients with severe fibrosis between HBeAg-positive and negative phases or between ages 30 and 40 and over 40, suggesting that the fibrosis was possibly carried over from an early phase. Finally, lowering ALT ULN (30 U/L for men, 19 U/L for women) alone was not adequate to increase the sensitivity of ALT detection of liver injury. However, the study was limited to a small sample size of 13 HBeAg-positive patients with ALT in the revised normal range. We detected significant liver pathology in almost 50% of chronic HBV infected patients with PNALT (ALT ≤ 40 U/ml) or minimally elevated ALT. We postulated that small-scale intermittent liver injury was possibly responsible for the discordance between normal serum ALT and significant liver changes in our cohort.

Description: Article Unmet need exists for a vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV). Here the authors report the establishment and evaluation, in mice and primates, of a series of MERS-CoV immunogens and show that they can serve as promising leads for vaccine development. Nature Communications doi: 10.1038/ncomms8712 Authors: Lingshu Wang, Wei Shi, M. Gordon Joyce, Kayvon Modjarrad, Yi Zhang, Kwanyee Leung, Christopher R. Lees, Tongqing Zhou, Hadi M. Yassine, Masaru Kanekiyo, Zhi-yong Yang, Xuejun Chen, Michelle M. Becker, Megan Freeman, Leatrice Vogel, Joshua C. Johnson, Gene Olinger, John P. Todd, Ulas Bagci, Jeffrey Solomon, Daniel J. Mollura, Lisa Hensley, Peter Jahrling, Mark R. Denison, Srinivas S. Rao, Kanta Subbarao, Peter D. Kwong, John R. Mascola, Wing-Pui Kong, Barney S. Graham

Description: Article Noble metals typically crystallize with the face-centered cubic structure. Here, the authors report the synthesis of gold nanoribbons in the 4H hexagonal polytype, a previously unreported, metastable phase of gold, and use it to stabilize 4H hexagonal phases of silver, palladium and platinum. Nature Communications doi: 10.1038/ncomms8684 Authors: Zhanxi Fan, Michel Bosman, Xiao Huang, Ding Huang, Yi Yu, Khuong P. Ong, Yuriy A. Akimov, Lin Wu, Bing Li, Jumiati Wu, Ying Huang, Qing Liu, Ching Eng Png, Chee Lip Gan, Peidong Yang, Hua Zhang

Description: Article All quantum systems are connected to their environment, and this reduces their quantumness through decoherence. Here, the authors show that the interaction between a macroscale quantum system—a micromechanical oscillator—and its environment leads to non-Markovian Brownian motion Nature Communications doi: 10.1038/ncomms8606 Authors: S. Gröblacher, A. Trubarov, N. Prigge, G. D. Cole, M. Aspelmeyer, J. Eisert

Description: Article Sensory cortical tuning is shaped by experience to facilitate coding of features that are predictive of behaviourally relevant outcomes. Here the authors demonstrate that rapid behaviourally driven retuning of human visual cortex involves top–down projections as well as local inhibitory interactions. Nature Communications doi: 10.1038/ncomms8823 Authors: Lisa M. McTeague, L. Forest Gruss, Andreas Keil

Description: Article The MCM8-9 complex is required for repair of DNA double-strand breaks (DSBs). Here, the authors show that MCM8-9 is required for the nuclease activity of the MRE11-RAD50-NBS1 complex (MRN) and stabilizes its association with DNA damage sites, promoting resection of DSB ends. Nature Communications doi: 10.1038/ncomms8744 Authors: Kyung Yong Lee, Jun-Sub Im, Etsuko Shibata, Jonghoon Park, Naofumi Handa, Stephen C. Kowalczykowski, Anindya Dutta

Description: Article Homologous repair of DNA double strand breaks in Saccharomyces cerevisiae is dependent on several conserved Rad51 paralogs. Here the authors provide biochemical evidence that Rad55-Rad57 synergistically interacts with the Shu complex to promote Rad51 filament formation and homology directed repair. Nature Communications doi: 10.1038/ncomms8834 Authors: William A. Gaines, Stephen K. Godin, Faiz F. Kabbinavar, Timsi Rao, Andrew P. VanDemark, Patrick Sung, Kara A. Bernstein

Description: Article Phytochromes are red-light photoreceptors in plants that regulate key life cycle processes, yet their evolutionary origins are not well understood. Using transcriptomic and genomic data, Li et al. find that canonical plant phytochromes originated in a common ancestor of land plants and charophyte algae. Nature Communications doi: 10.1038/ncomms8852 Authors: Fay-Wei Li, Michael Melkonian, Carl J. Rothfels, Juan Carlos Villarreal, Dennis W. Stevenson, Sean W. Graham, Gane Ka-Shu Wong, Kathleen M. Pryer, Sarah Mathews

Description: Article Experimental studies of hydrogen at high pressure are challenging, so theory is central to understanding its phase behaviour; however, computed phase diagrams do not agree with previous measurements. Here, the authors use a quantum Monte Carlo method and present results in qualitative agreement with experiment. Nature Communications doi: 10.1038/ncomms8794 Authors: N. D. Drummond, Bartomeu Monserrat, Jonathan H. Lloyd-Williams, P. López Ríos, Chris J. Pickard, R. J. Needs

Description: Article The onset of neurodegenerative disorders is associated at the molecular level with insoluble protein aggregates, named amyloids. Here, the authors characterize by infrared nanospectroscopy and nanomechanical studies, the amyloid aggregation at the individual species scale. Nature Communications doi: 10.1038/ncomms8831 Authors: F. S. Ruggeri, G. Longo, S. Faggiano, E. Lipiec, A. Pastore, G. Dietler

Description: by Seungcheol Kang, Han-Soo Kim, Ilkyu Han Unplanned excision of extremity soft tissue sarcoma (STS) is common and has detrimental effects not only on patients’ oncologic outcomes but also on functional and economic issues. However, no study has analyzed a nationwide population-based database. To estimate the incidence and treatment pattern of unplanned excision in extremity STS in the Korean population, a nationwide epidemiologic study was performed using the Korean Health Insurance Review and Assessment Service database, a centralized nationwide healthcare claims registry of Korea that covers the entire Korean population. Among 1,517 patients with extremity STS in the 4-year study period, 553 (36.5%) underwent unplanned excision (unplanned group). About 80% of unplanned excisions were performed in tertiary or general hospitals. Of the unplanned group, 240 (43.4%) underwent re-excision with or without radiation therapy and/or chemotherapy, and 51 (9.2%) did not undergo re-excision but were treated with radiation therapy and/or chemotherapy; whereas, 262 (47.4%) did not undergo any further treatment following unplanned excision. This study is the first nationwide population-based study on the unplanned excision of extremity STS. The results may have implications in establishing preventive or therapeutic measures to reduce the burden of unplanned excision of extremity STS.

Description: by Dong-He Li, Wei Shi, Thomas A. Munroe, Li Gong, Xiao-Yu Kong Mitogenomes of flatfishes (Pleuronectiformes) exhibit the greatest diversity of gene rear-rangements in teleostean fishes. Duplicate control regions (CRs) have been found in the mito-genomes of two flatfishes, Samariscus latus (Samaridae) and Laeops lanceolata (Bothidae), which is rare in teleosts. It has been reported that duplicate CRs have evolved in a concerted fashion in fishes and other animals, however, whether concerted evo-lution exists in flatfishes remains unknown. In this study, based on five newly sequenced and six previously reported mitogenomes of lefteye flounders in the Bothidae, we explored whether duplicate CRs and concerted evolution exist in these species. Results based on the present study and previous reports show that four out of eleven bothid species examined have duplicate CRs of their mitogenomes. The core regions of the duplicate CRs of mitogenomes in the same species have identical, or nearly identical, sequences when compared to each other. This pattern fits the typical characteristics of concerted evolution. Additionally, phylogenetic and ancestral state reconstruction analysis also provided evidence to support the hypothesis that duplicate CRs evolved concertedly. The core region of concerted evolution is situated at the conserved domains of the CR of the mitogenome from the termination associated sequences (TASs) to the conserved sequence blocks (CSBs). Commonly, this region is con-sidered to regulate mitochondrial replication and transcription. Thus, we hypothesize that the cause of concerted evolution of the duplicate CRs in the mtDNAs of these four bothids may be related to some function of the conserved sequences of the CRs during mitochondrial rep-lication and transcription. We hope our results will provide fresh insight into the molecular mechanisms related to replication and evolution of mitogenomes.

Description: by David Knight, Konstantin G. Iliadi, Natalia Iliadi, Ronit Wilk, Jack Hu, Henry M. Krause, Paul Taylor, Michael F. Moran, Gabrielle L. Boulianne Synaptic transmission is highly plastic and subject to regulation by a wide variety of neuromodulators and neuropeptides. In the present study, we have examined the role of isoforms of the cytochrome b561 homologue called no extended memory ( nemy ) in regulation of synaptic strength and plasticity at the neuromuscular junction (NMJ) of third instar larvae in Drosophila . Specifically, we generated two independent excisions of nemy that differentially affect the expression of nemy isoforms. We show that the nemy 45 excision, which specifically reduces the expression of the longest splice form of nemy , leads to an increase in stimulus evoked transmitter release and altered synaptic plasticity at the NMJ. Conversely, the nemy 26.2 excision, which appears to reduce the expression of all splice forms except the longest splice isoform, shows a reduction in stimulus evoked transmitter release, and enhanced synaptic plasticity. We further show that nemy 45 mutants have reduced levels of amidated peptides similar to that observed in peptidyl-glycine hydryoxylating mono-oxygenase (PHM) mutants. In contrast, nemy 26.2 mutants show no defects in peptide amidation but rather display a decrease in Tyramine β hydroxylase activity (TβH). Taken together, these results show non-redundant roles for the different nemy isoforms and shed light on the complex regulation of neuromodulators.

Description: by Davide Bolignano, Graziella D’Arrigo, Anna Pisano, Giuseppe Coppolino Background Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this agent may be helpful for anemia management also in CKD patients is still object of debate. Study Design Systematic review and meta-analysis. Population Adults with CKD (any KDOQI stage, including ESKD patients on regular dialysis) and anemia (Hb

Description: by Yukihiko Hiroshima, Ming Zhao, Yong Zhang, Nan Zhang, Ali Maawy, Takashi Murakami, Sumiyuki Mii, Fuminari Uehara, Mako Yamamoto, Shinji Miwa, Shuya Yano, Masashi Momiyama, Ryutaro Mori, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Yasushi Ichikawa, Michael Bouvet, Itaru Endo, Robert M. Hoffman A patient-derived nude-mouse model of soft-tissue sarcoma has been established and treated in the following groups: (1) untreated controls; (2) gemcitabine (GEM) (80 mg/kg, ip, weekly, 3 weeks); (3) Pazopanib (100 mg/kg, orally, daily, 3 weeks) and (4) Salmonella typhimurium A1-R (5 × 10 7 CFU/body, ip, weekly, 3 weeks). The sarcoma was resistant to GEM (p = 0.879). Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was no significant difference (p = 0.115). S . typhimurium A1-R significantly inhibited tumor growth compared to the untreated mice (p = 0.001). S . typhimurium A1-R was the only effective treatment for the soft-tissue sarcoma nude mouse model among all treatments including a newly approved multiple tyrosine kinase inhibitor; Pazopanib. These results suggest tumor-targeting S . typhimurium A1-R is a promising treatment for chemo-resistant soft-tissue sarcoma.

Description: by Fangqun OuYang, Jian-Feng Mao, Junhui Wang, Shougong Zhang, Yue Li The mechanisms by which different light spectra regulate plant shoot elongation vary, and phytohormones respond differently to such spectrum-associated regulatory effects. Light supplementation can effectively control seedling growth in Norway spruce. However, knowledge of the effective spectrum for promoting growth and phytohormone metabolism in this species is lacking. In this study, 3-year-old Norway spruce clones were illuminated for 12 h after sunset under blue or red light-emitting diode (LED) light for 90 d, and stem increments and other growth traits were determined. Endogenous hormone levels and transcriptome differences in the current needles were assessed to identify genes related to the red and blue light regulatory responses. The results showed that the stem increment and gibberellin (GA) levels of the seedlings illuminated by red light were 8.6% and 29.0% higher, respectively, than those of the seedlings illuminated by blue light. The indoleacetic acid (IAA) level of the seedlings illuminated by red light was 54.6% lower than that of the seedlings illuminated by blue light, and there were no significant differences in abscisic acid (ABA) or zeatin riboside [ZR] between the two groups of seedlings. The transcriptome results revealed 58,736,166 and 60,555,192 clean reads for the blue-light- and red-light-illuminated samples, respectively. Illumina sequencing revealed 21,923 unigenes, and 2744 (approximately 93.8%) out of 2926 differentially expressed genes (DEGs) were found to be upregulated under blue light. The main KEGG classifications of the DEGs were metabolic pathway (29%), biosynthesis of secondary metabolites (20.49%) and hormone signal transduction (8.39%). With regard to hormone signal transduction, AUXIN-RESISTANT1 ( AUX1 ), AUX/IAA genes, auxin-inducible genes, and early auxin-responsive genes [( auxin response factor ( ARF ) and small auxin-up RNA ( SAUR )] were all upregulated under blue light compared with red light, which might have yielded the higher IAA level. DELLA and phytochrome-interacting factor 3 (PIF3), involved in negative GA signaling, were also upregulated under blue light, which may be related to the lower GA level. Light quality also affects endogenous hormones by influencing secondary metabolism. Blue light promoted phenylpropanoid biosynthesis, phenylalanine metabolism, flavonoid biosynthesis and flavone and flavonol biosynthesis, accompanied by upregulation of most of the genes in their pathways. In conclusion, red light may promote stem growth by regulating biosynthesis of GAs, and blue light may promote flavonoid, lignin, phenylpropanoid and some hormones (such as jasmonic acid) which were related to plant defense in Norway spruce, which might reduce the primary metabolites available for plant growth.

Description: by Diane I. Schroeder, Kartika Jayashankar, Kory C. Douglas, Twanda L. Thirkill, Daniel York, Pete J. Dickinson, Lawrence E. Williams, Paul B. Samollow, Pablo J. Ross, Danika L. Bannasch, Gordon C. Douglas, Janine M. LaSalle Over the last 20-80 million years the mammalian placenta has taken on a variety of morphologies through both divergent and convergent evolution. Recently we have shown that the human placenta genome has a unique epigenetic pattern of large partially methylated domains (PMDs) and highly methylated domains (HMDs) with gene body DNA methylation positively correlating with level of gene expression. In order to determine the evolutionary conservation of DNA methylation patterns and transcriptional regulatory programs in the placenta, we performed a genome-wide methylome (MethylC-seq) analysis of human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow placentas as well as opossum extraembryonic membrane. We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues. Higher relative gene body methylation was the conserved feature across all mammalian placentas, despite differences in PMD/HMDs and absolute methylation levels. Specifically, higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification was observed compared with the rest of the genome. As in human placenta, higher methylation is associated with higher gene expression and is predictive of genic location across species. Analysis of DNA methylation in oocytes and preimplantation embryos shows a conserved pattern of gene body methylation similar to the placenta. Intriguingly, mouse and cow oocytes and mouse early embryos have PMD/HMDs but their placentas do not, suggesting that PMD/HMDs are a feature of early preimplantation methylation patterns that become lost during placental development in some species and following implantation of the embryo.