bluuebunny/crossref_metadata_2025 huggingface dataset:
A priori-defined diet quality indices, biomarkers and risk for type 2 diabetes in five ethnic groups: the Multiethnic Cohort
Authors: Jacobs Simone , Boushey Carol J. , Franke Adrian A. , Shvetsov Yurii B. , Monroe Kristine R. , Haiman Christopher A. , Kolonel Laurence N. , Le Marchand Loic , Maskarinec Gertraud
Published: September 2017

Dietary indices have been related to risk for type 2 diabetes (T2D) predominantly in white populations. The present study evaluated this association in the ethnically diverse Multiethnic Cohort and examined four diet quality indices in relation to T2D risk, homoeostatic model assessment-estimated insulin resistance (HOMA-IR) and biomarkers of dyslipidaemia, inflammation and adipokines. The T2D analysis included 166 550 white, African American, Native Hawaiian, Japanese American and Latino participants (9200 incident T2D cases). Dietary intake was assessed at baseline using a quantitative FFQ and T2D status was based on three self-reports and confirmed by administrative data. Biomarkers were assessed about 10 years later in a biomarker subcohort (n10 060). Sex- and ethnicity-specific hazard ratios were calculated for the Healthy Eating Index-2010 (HEI-2010), the alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED) and the Dietary Approaches to Stop Hypertension (DASH). Multivariable-adjusted means of biomarkers were compared across dietary index tertiles in the biomarker subcohort. The AHEI-2010, aMED (in men only) and DASH scores were related to a 10–20 % lower T2D risk, with the strongest associations in whites and the direction of the relationships mostly consistent across ethnic groups. Higher scores on the four indices were related to lower HOMA-IR, TAG and C-reactive protein concentrations, not related to leptin, and the DASH score was directly associated with adiponectin. The AHEI-2010 and DASH were directly related to HDL-cholesterol in women. Potential underlying biological mechanisms linking diet quality and T2D risk are an improved lipid profile and reduced systemic inflammation and, with regards to DASH alone, an improved adiponectin profile.
La figure du cercle vertueux comme aspect essentiel de la causalité créatrice. Une lecture critique de Bergson
Authors: HWANG SU-YOUNG
Published: September 2017

Cet article met l’accent sur la notion de création, entendue comme cercle vertueux dans l’œuvre de Bergson. La figure du cercle vertueux désigne un processus qui tire de soi rétrospectivement son identité à travers les événements présents. Nous montrerons que ce schème est à l’œuvre dans l’acte libre, puis dans l’action des vivants, et surtout au niveau du processus évolutif lui-même. Nous verrons ensuite s’il est possible d’élargir la perspective au-delà de ce schème traditionnel amené par le spiritualisme bergsonien. Nous montrerons que, contrairement à ce que souhaitait Bergson, nous pouvons en élargir l’extension au monde matériel lui-même.
The relationship between tinnitus pitch and parameters of audiometry and distortion product otoacoustic emissions
Authors: Keppler H , Degeest S , Dhooge I
Published: September 2017

Objectives:

Chronic tinnitus is associated with reduced auditory input, which results in changes in the central auditory system. This study aimed to examine the relationship between tinnitus pitch and parameters of audiometry and distortion product otoacoustic emissions. For audiometry, the parameters represented the edge frequency of hearing loss, the frequency of maximum hearing loss and the frequency range of hearing loss. For distortion product otoacoustic emissions, the parameters were the frequency of lowest distortion product otoacoustic emission amplitudes and the frequency range of reduced distortion product otoacoustic emissions.

Method:

Sixty-seven patients (45 males, 22 females) with subjective chronic tinnitus, aged 18 to 73 years, were included.

Results:

No correlation was found between tinnitus pitch and parameters of audiometry and distortion product otoacoustic emissions. However, tinnitus pitch fell mostly within the frequency range of hearing loss.

Conclusion:

The current study seems to confirm the relationship between tinnitus pitch and the frequency range of hearing loss, thus supporting the homeostatic plasticity model.
Facets of Conscientiousness and risk of dementia
Authors: Sutin A. R. , Stephan Y. , Terracciano A.
Published: September 2017

Background

Multiple studies have found Conscientiousness to be protective against dementia. The purpose of this study is to identify which specific aspects, or facets, of Conscientiousness are most protective against cognitive impairment and whether these associations are moderated by demographic factors and/or genetic risk.

Methods

Health and Retirement Study participants were selected for analysis if they completed the facets of Conscientiousness measure, scored in the range of normal cognitive functioning at the baseline personality assessment, and had at least one follow-up assessment of cognition over the up to 6-year follow-up (N = 11 181). Cox regression was used to test for risk of incident dementia and risk of incident cognitive impairment not dementia (CIND).

Results

Over the follow-up, 278 participants developed dementia and 2186 participants developed CIND. The facet of responsibility had the strongest and most consistent association with dementia risk: every standard deviation increase in this facet was associated with a nearly 35% decreased risk of dementia; self-control and industriousness were also protective. Associations were generally similar when controlling for clinical, behavioral, and genetic risk factors. These three facets were also independent predictors of decreased risk of CIND.

Conclusions

The present research indicates that individuals who see themselves as responsible, able to control their behavior, and hard workers are less likely to develop CIND or dementia and that these associations persist after accounting for some common clinical, behavioral, and genetic risk factors.
Adolescent mental health and behavioural predictors of being NEET: a prospective study of young adults not in employment, education, or training
Authors: Rodwell L. , Romaniuk H. , Nilsen W. , Carlin J. B. , Lee K. J. , Patton G. C.
Published: September 2017

Background

Young adults who are not in employment, education, or training (NEET) are at risk of long-term economic disadvantage and social exclusion. Knowledge about risk factors for being NEET largely comes from cross-sectional studies of vulnerable individuals. Using data collected over a 10-year period, we examined adolescent predictors of being NEET in young adulthood.

Methods

We used data on 1938 participants from the Victorian Adolescent Health Cohort Study, a community-based longitudinal study of adolescents in Victoria, Australia. Associations between common mental disorders, disruptive behaviour, cannabis use and drinking behaviour in adolescence, and NEET status at two waves of follow-up in young adulthood (mean ages of 20.7 and 24.1 years) were investigated using logistic regression, with generalised estimating equations used to account for the repeated outcome measure.

Results

Overall, 8.5% of the participants were NEET at age 20.7 years and 8.2% at 24.1 years. After adjusting for potential confounders, we found evidence of increased risk of being NEET among frequent adolescent cannabis users [adjusted odds ratio (ORadj) = 1.74; 95% confidence interval (CI) 1.10–2.75] and those who reported repeated disruptive behaviours (ORadj= 1.71; 95% CI 1.15–2.55) or persistent common mental disorders in adolescence (ORadj= 1.60; 95% CI 1.07–2.40). Similar associations were present when participants with children were included in the same category as those in employment, education, or training.

Conclusions

Young people with an early onset of mental health and behavioural problems are at risk of failing to make the transition from school to employment. This finding reinforces the importance of integrated employment and mental health support programmes.
Ultrastructural, Elemental and Mineralogical Analysis of Vascular Calcification in Atherosclerosis
Authors: Perrotta Ida , Perri Edoardo
Published: September 2017

Over the past few decades, remarkable progress has been achieved in terms of understanding the molecular and cellular mechanisms of atherosclerotic vascular calcification and the important role of matrix vesicles in initiating and propagating pathologic tissue mineralization has been widely recognized. Despite these recent advances, however, no definitive data are currently available regarding the texture and composition of the minerals that grow in the vessel wall during the course of the disease. Using different electron microscopy imaging and analysis, we demonstrate that vascular cells can produce and secrete more than one type of matrix vesicles which act as sites for initial mineral deposition independently of their structural features. Our results reveal that apatite formation in the atherosclerotic lesions of the human aorta occur through the deposition of amorphous calcium phosphate that matures over time, transforms into crystalline hydroxyapatite, and radiates towards the lumen of the vesicles, finally forming the calcified spherules. Elemental and mineralogical analyses also demonstrate that the presence of mature and stable amorphous calcium phosphate deposits in the affected tissues is linked to the incorporation of magnesium, which probably delay the conversion to the crystalline phase. Though more rarely, the presence of calcium oxalate crystals has been also documented.
IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation
Authors: Chevrier Stéphane , Kratina Tobias , Emslie Dianne , Tarlinton David M , Corcoran Lynn M
Published: September 2017

Bcl6 (B‐cell lymphoma 6) is a transcriptional repressor and critical mediator of the germinal center reaction during a T‐cell‐dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B‐cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post‐transcriptional levels, and in particular a strong signal through the B‐cell receptor causes rapid proteasomal degradation of Bcl6. Despite the importance of Bcl6 in both immunity and cancer, little is known about how other extrinsic factors regulate Bcl6 in B cells. Here we show that Bcl6 is indeed highly unstable in B cells after a B‐cell receptor (BCR) signal, but that the T‐cell‐derived cytokines interleukin 4 (IL4) and IL21 counteract BCR‐mediated degradation, preserving Bcl6 protein levels. Stat6, downstream of IL4, can induce Bcl6 transcription directly. In vivo, B‐cell intrinsic loss of IL4 or IL21 signaling reduces the magnitude or duration of the GC response, respectively, while their combined loss almost completely eliminates the GC response. This work provides key insights into the effect mediated by T‐follicular helper cytokines on Bcl6 regulation.
The life and death of immune cell types: the role of BCL‐2 anti‐apoptotic molecules
Authors: Carrington Emma M , Tarlinton David M , Gray Daniel H , Huntington Nicholas D , Zhan Yifan , Lew Andrew M
Published: September 2017

Targeting survival mechanisms of immune cells may provide an avenue for immune intervention to dampen unwanted responses (e.g. autoimmunity, immunopathology and transplant rejection) or enhance beneficial ones (e.g. immune deficiency, microbial defence and cancer immunotherapy). The selective survival mechanisms of the various immune cell types also avails the possibility of specific tailoring of such interventions. Here, we review the role of the BCL‐2 anti‐apoptotic family members (BCL‐2, BCL‐XL, BCL‐W, MCL‐1 and A1) on cell death/survival of the major immune cell types, for example, T, NK, B, dendritic cell (DC) lineages. There is both selectivity and redundancy among this family. Selectivity comes partly from the expression levels in each of the cell types. For example, plasmacytoid DC express abundant BCL‐2 and are susceptible to BCL‐2 antagonism or deficiency, whereas conventional DC express abundant A1 and are susceptible to A1 deficiency. There is, however, also functional redundancy; for example, overexpression of MCL‐1 can override BCL‐2 antagonism in plasmacytoid DC. Moreover, susceptibility to another anti‐apoptotic family member can be unmasked, when one or other member is removed. These dual principles of selectivity and redundancy should guide the use of antagonists for manipulating immune cells.
Correction: Corrigendum: p120-catenin prevents multinucleation through control of MKLP1-dependent RhoA activity during cytokinesis
Authors: van de Ven Robert A. H. , de Groot Jolien S. , Park Danielle , van Domselaar Robert , de Jong Danielle , Szuhai Karoly , van der Wall Elsken , Rueda Oscar M. , Ali H. Raza , Caldas Carlos , van Diest Paul J. , Hetzer Martin W. , Sahai Erik , Derksen Patrick W. B.
Published: September 2017

Nature Communications 7: Article number: 13874 (2016); Published 22 December 2016; Updated 6 September 2017 The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the National Institutes of Health grants R01GM098749 and National Institutes of Health Transformative Research Award R01NS096786.
Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella
Authors: Eckhard Ulrich , Bandukwala Hina , Mansfield Michael J. , Marino Giada , Cheng Jiujun , Wallace Iain , Holyoak Todd , Charles Trevor C. , Austin John , Overall Christopher M. , Doxey Andrew C.
Published: September 2017

Bacterial flagella are cell locomotion and occasional adhesion organelles composed primarily of the polymeric protein flagellin, but to date have not been associated with any enzymatic function. Here, we report the bioinformatics-driven discovery of a class of enzymatic flagellins that assemble to form proteolytically active flagella. Originating by a metallopeptidase insertion into the central flagellin hypervariable region, this flagellin family has expanded to at least 74 bacterial species. In the pathogen, Clostridium haemolyticum, metallopeptidase-containing flagellin (which we termed flagellinolysin) is the second most abundant protein in the flagella and is localized to the extracellular flagellar surface. Purified flagellar filaments and recombinant flagellin exhibit proteolytic activity, cleaving nearly 1000 different peptides. With ~ 20,000 flagellin copies per  ~ 10-μm flagella this assembles the largest proteolytic complex known. Flagellum-mediated extracellular proteolysis expands our understanding of the functional plasticity of bacterial flagella, revealing this family as enzymatic biopolymers that mediate interactions with diverse peptide substrates.
Region-specific differential corneal and scleral mRNA expressions of MMP2, TIMP2, and TGFB2 in highly myopic-astigmatic chicks
Authors: Xi Lisa Yan-yan , Yip Shea Ping , Shan Sze Wan , Summers-Rada Jody , Kee Chea-su
Published: September 2017

Myopia and astigmatism, two common refractive errors frequently co-exist, are affecting vision at all working distances in the affected populations worldwide. Eyeballs having these refractive errors are known to exhibit abnormal eye shape at the anterior and posterior eye segments, but whether the outer coats of these abnormal eyeballs, cornea anteriorly and sclera posteriorly, are regulated by region-specific molecular mechanism remains unclear. Here we presented the changes in mRNA expression levels of three genes (MMP2,TIMP2, andTGFB2), all known to participate in extracellular matrix organization, at five regions of the cornea and sclera in chickens developing high myopia and astigmatism induced by form deprivation. We found that, compared to normal chicks, the highly myopic-astigmatic chicks had significantly higher expression of all three genes in the superior sclera (Mann-Whitney tests, all p ≤ 0.05), as well as higherTIMP2expression in the central cornea and nasal sclera (Mann-Whitney tests, both p ≤ 0.05). Strikingly, the superior scleral region stood out as showing the strongest and most widespread correlations between mRNA expression and biometry parameters including axial and astigmatic components (r = + 0.52~ + 0.85, all p < 0.05). These results imply that local molecular mechanism may manipulate the eye shape remodeling across the globe during refractive-error development.
Development of novel Meju starter culture using plant extracts with reduced Bacillus cereus counts and enhanced functional properties
Authors: Shukla Shruti , Park Juyeon , Park Jung Hyun , Lee Jong Suk , Kim Myunghee
Published: September 2017

We developed a novel type of Meju starter culture using single and combined extracts of Allium sativum (garlic clove), Nelumbo nucifera (lotus leaves), and Ginkgo biloba (ginkgo leaves) to improve the quality and functionality of Meju-based fermented products. Meju samples fermented with plant extracts (10 mg/ml) showed phenolic contents of 11.4–31.6 mg/g (gallic acid equivalents). Samples of extracts (garlic clove, lotus leaves, ginkgo leaves and their combination) fermented with Meju strongly inhibited tyrosinase, α-glucosidase, and elastase activities by 36.43–64.34%, 45.08–48.02%, and 4.52–10.90%, respectively. Specifically, ginkgo leaves extract added to fermented Meju samples at different concentrations (1% and 10%) strongly inhibited tyrosinase, α-glucosidase, and elastase activities and exhibited a potent antibacterial effect against Bacillus cereus with a significant reduction in bacterial counts compared with the effects observed for garlic clove and lotus leaf added to Meju samples. Scanning electron microscopy revealed severe morphological alterations of the B. cereus cell wall in response to ginkgo leaf extracts. Gas chromatographic mass spectroscopic analysis of plant extract-supplemented Meju samples and control Meju samples identified 113 bioactive compounds representing 98.44–99.98% total extract. The proposed approach may be useful for the development of various fermented functional foods at traditional and commercial levels.
Electrical properties and thermal stability in stack structure of HfO2/Al2O3/InSb by atomic layer deposition
Authors: Baik Min , Kang Hang-Kyu , Kang Yu-Seon , Jeong Kwang-Sik , An Youngseo , Choi Seongheum , Kim Hyoungsub , Song Jin-Dong , Cho Mann-Ho
Published: September 2017

Changes in the electrical properties and thermal stability of HfO2 grown on Al2O3-passivated InSb by atomic layer deposition (ALD) were investigated. The deposited HfO2 on InSb at a temperature of 200 °C was in an amorphous phase with low interfacial defect states. During post-deposition annealing (PDA) at 400 °C, In–Sb bonding was dissociated and diffusion through HfO2 occurred. The diffusion of indium atoms from the InSb substrate into the HfO2 increased during PDA at 400 °C. Most of the diffused atoms reacted with oxygen in the overall HfO2 layer, which degraded the capacitance equivalent thickness (CET). However, since a 1-nm-thick Al2O3 passivation layer on the InSb substrate effectively reduced the diffusion of indium atoms, we could significantly improve the thermal stability of the capacitor. In addition, we could dramatically reduce the gate leakage current by the Al2O3 passivation layer. Even if the border traps measured by C–V data were slightly larger than those of the as-grown sample without the passivation layer, the interface trap density was reduced by the Al2O3 passivation layer. As a result, the passivation layer effectively improved the thermal stability of the capacitor and reduced the interface trap density, compared with the sample without the passivation layer.
Partitioning the roles of CYP6G1 and gut microbes in the metabolism of the insecticide imidacloprid in Drosophila melanogaster
Authors: Fusetto Roberto , Denecke Shane , Perry Trent , O’Hair Richard A. J. , Batterham Philip
Published: September 2017

Resistance to insecticides through enhanced metabolism is a worldwide problem. The Cyp6g1 gene of the vinegar fly, Drosophila melanogaster, is a paradigm for the study of metabolic resistance. Constitutive overexpression of this gene confers resistance to several classes of insecticides, including the neonicotinoid imidacloprid (IMI). The metabolism of IMI in this species has been previously shown to yield oxidative and nitro-reduced metabolites. While levels of the oxidative metabolites are correlated with CYP6G1 expression, nitro-reduced metabolites are not, raising the question of how these metabolites are produced. Some IMI metabolites are known to be toxic, making their fate within the insect a second question of interest. These questions have been addressed by coupling the genetic tools of gene overexpression and CRISPR gene knock-out with the mass spectrometric technique, the Twin-Ion Method (TIM). Analysing axenic larvae indicated that microbes living within D. melanogaster are largely responsible for the production of the nitro-reduced metabolites. Knock-out of Cyp6g1 revealed functional redundancy, with some metabolites produced by CYP6G1 still detected. IMI metabolism was shown to produce toxic products that are not further metabolized but readily excreted, even when produced in the Central Nervous System (CNS), highlighting the significance of transport and excretion in metabolic resistance.
Nanograin size effects on the strength of biphase nanolayered composites
Authors: Huang Sixie , Beyerlein Irene J. , Zhou Caizhi
Published: September 2017

In this work, we employ atomic-scale simulations to uncover the interface-driven deformation mechanisms in biphase nanolayered composites. Two internal boundaries persist in these materials, the interlayer crystalline boundaries and intralayer biphase interfaces, and both have nanoscale dimensions. These internal surfaces are known to control the activation and motion of dislocations, and despite the fact that most of these materials bear both types of interfaces. From our calculations, we find that the first defect event, signifying yield, is controlled by the intralayer spacing (grain size, d), and not the intralayer biphase spacing (layer thickness, h). The interplay of two internal sizes leads to a very broad transition region from grain boundary sliding dominated flow, where the material is weak and insensitive to changes in h, to grain boundary dislocation emission and glide dominated flow, where the material is strong and sensitive to changes in h. Such a rich set of states and size effects are not seen in idealized materials with one of these internal surfaces removed. These findings provide some insight into how changes in h and d resulting from different synthesis processes can affect the strength of nanolayered materials.
Uniformly dispersed platinum-cobalt alloy nanoparticles with stable compositions on carbon substrates for methanol oxidation reaction
Authors: Liu Hui , Li Chengyin , Chen Dong , Cui Penglei , Ye Feng , Yang Jun
Published: September 2017

Alloying platinum (Pt) with suitable transition metals is effective way to enhance their catalytic performance for methanol oxidation reaction, and reduce their cost at mean time. Herein, we report our investigation on the synthesis of bimetallic platinum-cobalt (PtCo) alloy nanoparticles, their activation, as well as the catalytic evaluation for methanol oxidation reaction. The strategy starts with the synthesis of PtCo alloy nanoparticles in an organic medium, followed by loading on carbon substrates. We then remove the capping agent by refluxing the carbon-supported PtCo particles in acetic acid before electrochemical measurements. We emphasize the change in composition of the alloys during refluxing process, and the initial PtCo alloys with Pt/Co ratio of 1/2 turns into stable alloys with Pt/Co ratio of 3/1. The final Pt3Co particles have uniform distribution on carbon substrates, and exhibit activity with 2.4 and 1.5 times of that for commercial Pt/C and PtRu/C for methanol oxidation reaction.
Programmed Self-Assembly of a Biochemical and Magnetic Scaffold to Trigger and Manipulate Microtubule Structures
Authors: Ducasse Rémi , Wang Wei-An , Navarro Marina Garcia-Jove , Debons Nicolas , Colin Alexandra , Gautier Jérémie , Guigner Jean-Michel , Guyot François , Gueroui Zoher
Published: September 2017

Artificial bio-based scaffolds offer broad applications in bioinspired chemistry, nanomedicine, and material science. One current challenge is to understand how the programmed self-assembly of biomolecules at the nanometre level can dictate the emergence of new functional properties at the mesoscopic scale. Here we report a general approach to design genetically encoded protein-based scaffolds with modular biochemical and magnetic functions. By combining chemically induced dimerization strategies and biomineralisation, we engineered ferritin nanocages to nucleate and manipulate microtubule structures upon magnetic actuation. Triggering the self-assembly of engineered ferritins into micrometric scaffolds mimics the function of centrosomes, the microtubule organizing centres of cells, and provides unique magnetic and self-organizing properties. We anticipate that our approach could be transposed to control various biological processes and extend to broader applications in biotechnology or material chemistry.
Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry
Authors: Sapkota Yadav , Vivo Immaculata De , Steinthorsdottir Valgerdur , Fassbender Amelie , Bowdler Lisa , Buring Julie E. , Edwards Todd L. , Jones Sarah , O Dorien , Peterse Daniëlle , Rexrode Kathryn M. , Ridker Paul M. , Schork Andrew J. , Thorleifsson Gudmar , Wallace Leanne M. ,   iPSYCH-SSI-Broad Group, Werge Thomas M. , Thompson Wesley K. , Kraft Peter , Morris Andrew P. , Nyholt Dale R. , Edwards Digna R. Velez , Nyegaard Mette , D’Hooghe Thomas , Chasman Daniel I. , Stefansson Kari , Missmer Stacey A. , Montgomery Grant W.
Published: September 2017

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10−9) in GREB1 at 2p25.1 — a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.
A new mild hyperthermia device to treat vascular involvement in cancer surgery
Authors: Ware Matthew J. , Nguyen Lam P. , Law Justin J. , Krzykawska-Serda Martyna , Taylor Kimberly M. , Cao Hop S. Tran , Anderson Andrew O. , Pulikkathara Merlyn , Newton Jared M. , Ho Jason C. , Hwang Rosa , Rajapakshe Kimal , Coarfa Cristian , Huang Shixia , Edwards Dean , Curley Steven A. , Corr Stuart J.
Published: September 2017

Surgical margin status in cancer surgery represents an important oncologic parameter affecting overall prognosis. The risk of disease recurrence is minimized and survival often prolonged if margin-negative resection can be accomplished during cancer surgery. Unfortunately, negative margins are not always surgically achievable due to tumor invasion into adjacent tissues or involvement of critical vasculature. Herein, we present a novel intra-operative device created to facilitate a uniform and mild heating profile to cause hyperthermic destruction of vessel-encasing tumors while safeguarding the encased vessel. We use pancreatic ductal adenocarcinoma as an in vitro and an in vivo cancer model for these studies as it is a representative model of a tumor that commonly involves major mesenteric vessels. In vitro data suggests that mild hyperthermia (41–46 °C for ten minutes) is an optimal thermal dose to induce high levels of cancer cell death, alter cancer cell’s proteomic profiles and eliminate cancer stem cells while preserving non-malignant cells. In vivo and in silico data supports the well-known phenomena of a vascular heat sink effect that causes high temperature differentials through tissues undergoing hyperthermia, however temperatures can be predicted and used as a tool for the surgeon to adjust thermal doses delivered for various tumor margins.
YeeJ is an inverse autotransporter from Escherichia coli that binds to peptidoglycan and promotes biofilm formation
Authors: Martinez-Gil Marta , Goh Kelvin G. K. , Rackaityte Elze , Sakamoto Chizuko , Audrain Bianca , Moriel Danilo G. , Totsika Makrina , Ghigo Jean-Marc , Schembri Mark A. , Beloin Christophe
Published: September 2017

Escherichia coli is a commensal or pathogenic bacterium that can survive in diverse environments. Adhesion to surfaces is essential for E. coli colonization, and thus it is important to understand the molecular mechanisms that promote this process in different niches. Autotransporter proteins are a class of cell-surface factor used by E. coli for adherence. Here we characterized the regulation and function of YeeJ, a poorly studied but widespread representative from an emerging class of autotransporter proteins, the inverse autotransporters (IAT). We showed that the yeeJ gene is present in ~40% of 96 completely sequenced E. coli genomes and that YeeJ exists as two length variants, albeit with no detectable functional differences. We demonstrated that YeeJ promotes biofilm formation in different settings through exposition at the cell-surface. We also showed that YeeJ contains a LysM domain that interacts with peptidoglycan and thus assists its localization into the outer membrane. Additionally, we identified the Polynucleotide Phosphorylase PNPase as a repressor of yeeJ transcription. Overall, our work provides new insight into YeeJ as a member of the recently defined IAT class, and contributes to our understanding of how commensal and pathogenic E. coli colonise their environments.
Large strain synergetic material deformation enabled by hybrid nanolayer architectures
Authors: Li Jianjun , Lu Wenjun , Zhang Siyuan , Raabe Dierk
Published: September 2017

Nanolayered metallic composites are much stronger than pure nanocrystalline metals due to their high density of hetero-interfaces. However, they are usually mechanically instable due to the deformation incompatibility among the soft and hard constituent layers promoting shear instability. Here we designed a hybrid material with a heterogeneous multi-nanolayer architecture. It consists of alternating 10 nm and 100 nm-thick Cu/Zr bilayers which deform compatibly in both stress and strain by utilizing the layers’ intrinsic strength, strain hardening and thickness, an effect referred to as synergetic deformation. Micropillar tests show that the 6.4 GPa-hard 10 nm Cu/Zr bilayers and the 3.3 GPa 100 nm Cu layers deform in a compatible fashion up to 50% strain. Shear instabilities are entirely suppressed. Synergetic strengthening of 768 MPa (83% increase) compared to the rule of mixture is observed, reaching a total strength of 1.69 GPa. We present a model that serves as a design guideline for such synergetically deforming nano-hybrid materials.
FCN1 (M-ficolin), which directly associates with immunoglobulin G1, is a molecular target of intravenous immunoglobulin therapy for Kawasaki disease
Authors: Okuzaki Daisuke , Ota Kaori , Takatsuki Shin-ichi , Akiyoshi Yukari , Naoi Kazuyuki , Yabuta Norikazu , Saji Tsutomu , Nojima Hiroshi
Published: September 2017

Kawasaki disease (KD), an acute systemic vasculitis of early childhood, is of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is an effective treatment, but its molecular target remains elusive. DNA microarray analysis of peripheral blood mononuclear cells (PBMCs) revealed that at least 21 genes are drastically down-regulated after IVIG treatment in most KD patients. qRT-PCR analysis confirmed that the mRNA levels of five of these genes were considerably reduced in almost all KD patients after IVIG treatment. Western blot (Wb) of PBMC extracts revealed that levels of FCN1 (M-ficolin), a protein of the complement system that defends against infectious agents, were reduced after IVIG treatment in many KD patients. In another set of KD patients, Wb confirmed that levels of both FCN1 were greatly reduced after IVIG therapy. Wb revealed that the collagen-like domain of FCN1 directly bound to IgG1 in vitro through a portion of the CH1 and CH3 domains, and synthetic peptides corresponding to these domains of IgG1 efficiently inhibited these associations. These results suggest that FCN1 is a molecular target of intravenous IVIG in KD patients. We propose that these peptides and a humanized monoclonal antibody against FCN1 could be useful in combination therapy with IVIG.
A broadband photodetector based on Rhodamine B-sensitized ZnO nanowires film
Authors: Bai Zheng Qi , Liu Ze Wen
Published: September 2017

A broadband photodetector has been developed on the basis of ZnO nanowires (NWs)/Rhodamine B (RhB) hybrid system. The device is fabricated by spraying NWs on to gold interdigital electrodes followed by modifying the NWs via an RhB solution-casting process. Measurements show that the as-fabricated device demonstrates photoresponsivity ranging from 300 nm to 700 nm with a bandwidth as large as 400 nm. The role of the dye sensitizer adsorbed on the surface of NWs is modeled to alter the transportation path of photo-generated carriers. The calculations based on the measurements reveal that the device exhibits a prominent responsivity in the interested band with maximum responsivity of 5.5 A/W for ultraviolet (UV) light and 3 A/W for visible (VIS) light under 8 V bias, respectively. The sensitization not only widens the response spectrum with external quantum efficiency leaping up to 771% at VIS but also improves UV responsivity with maximum 51% enhancement. From the time–dependent photo-current measurement, it is found that the response time (rise and decay times in total) of the device largely reduced from 17.5 s to 3.3 s after sensitization. A comparison of the obtained photodetector with other ZnO-based photodetectors is summarized from the view point of responsivity and bandwidth.
Long noncoding RNAs in the model species Brachypodium distachyon
Authors: De Quattro Concetta , Pè Mario Enrico , Bertolini Edoardo
Published: September 2017

Eukaryotic genomes are pervasively transcribed and only a small portion of the transcribed sequences belongs to protein coding genes. High-throughput sequencing technology contributed to consolidate this perspective, allowing the identification of numerous noncoding RNAs with key roles in biological processes. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nt with limited phylogenetic conservation, expressed at low levels and characterized by tissue/organ specific expression profiles. Although a large set of lncRNAs has been identified, the functional roles of lncRNAs are only beginning to be recognized and the molecular mechanism of lncRNA-mediated gene regulation remains largely unexplored, particularly in plants where their annotation and characterization are still incomplete. Using public and proprietary poly-(A)+RNA-seq data as well as a collection of full length ESTs from several organs, developmental stages and stress conditions in threeBrachypodium distachyoninbred lines, we describe the identification and the main features of thousands lncRNAs. Here we provide a genome-wide characterization of lncRNAs, highlighting their intraspecies conservation and describing their expression patterns among several organs/tissues and stress conditions. This work represents a fundamental resource to deepen our knowledge on long noncoding RNAs in C3cereals, allowing theBrachypodiumcommunity to exploit these results in future research programs.
Arf6 in lymphatic endothelial cells regulates lymphangiogenesis by controlling directional cell migration
Authors: Lin Yueh-Chien , Ohbayashi Norihiko , Hongu Tsunaki , Katagiri Naohiro , Funakoshi Yuji , Lee Hsinyu , Kanaho Yasunori
Published: September 2017

The small GTPase Arf6 plays pivotal roles in a wide variety of cellular events such as endocytosis, exocytosis, and actin cytoskeleton reorganization. However, the physiological functions of Arf6 at the whole animal level have not yet been thoroughly understood. Here, we show that Arf6 regulates developmental and tumor lymphangiogenesis in mice. Lymphatic endothelial cell (LEC)-specific Arf6 conditional knockout (LEC-Arf6 cKO) mouse embryos exhibit severe skin edema and impairment in the formation of lymphatic vessel network at the mid-gestation stage. Knockdown of Arf6 in human LECs inhibits in vitro capillary tube formation and directed cell migration induced by vascular endothelial growth factor-C (VEGF-C) by inhibiting VEGF-C-induced internalization of β1 integrin. Finally, we found that LEC-Arf6 cKO mice transplanted with B16 melanoma cells attenuated tumor lymphangiogenesis and progression. Collectively, these results demonstrate that Arf6 in LECs plays a crucial role in physiological and pathological lymphangiogenesis.
In situ vocal fold properties and pitch prediction by dynamic actuation of the songbird syrinx
Authors: Düring Daniel N. , Knörlein Benjamin J. , Elemans Coen P. H.
Published: September 2017

The biomechanics of sound production forms an integral part of the neuromechanical control loop of avian vocal motor control. However, we critically lack quantification of basic biomechanical parameters describing the vocal organ, the syrinx, such as material properties of syringeal elements, forces and torques exerted on, and motion of the syringeal skeleton during song. Here, we present a novel marker-based 3D stereoscopic imaging technique to reconstruct 3D motion of servo-controlled actuation of syringeal muscle insertions sites in vitro and focus on two muscles controlling sound pitch. We furthermore combine kinematic analysis with force measurements to quantify elastic properties of sound producing medial labia (ML). The elastic modulus of the zebra finch ML is 18 kPa at 5% strain, which is comparable to elastic moduli of mammalian vocal folds. Additionally ML lengthening due to musculus syringealis ventralis (VS) shortening is intrinsically constraint at maximally 12% strain. Using these values we predict sound pitch to range from 350–800 Hz by VS modulation, corresponding well to previous observations. The presented methodology allows for quantification of syringeal skeleton motion and forces, acoustic effects of muscle recruitment, and calibration of computational birdsong models, enabling experimental access to the entire neuromechanical control loop of vocal motor control.
The neural basis of spatial vision losses in the dysfunctional visual system
Authors: Huang Jinfeng , Zhou Yifeng , Liu Caiyuan , Liu Zhongjian , Luan Chunmeng , Tzvetanov Tzvetomir
Published: September 2017

Human vision relies on correct information processing from the eye to various visual areas. Disturbances in the visual perception of simple features are believed to come from low-level network (e.g., V1) disruptions. In the present study, we modelled monocular losses in spatial vision through plausible multiple network modifications in early visual coding. We investigated perceptual deficits in anisometropic amblyopia and used the monocular tilt illusion as a probe of primary visual cortex orientation coding and inhibitory interactions. The psychophysical results showed that orientation misperception was higher in amblyopic eyes (AE) than in the fellow and neurotypical eyes and was correlated with the subject’s AE peak contrast sensitivity. The model fitted to the experimental results allowed to split these observations between different network characteristics by showing that these observations were explained by broader orientation tuning widths in AEs and stronger lateral inhibition in abnormal amblyopic system that had strong contrast sensitivity losses. Through psychophysics measures and computational modelling of V1, our study links multiple perceptual changes with localized modifications in the primary visual cortex.
Dextromethorphan Exhibits Anti-inflammatory and Immunomodulatory Effects in a Murine Model of Collagen-Induced Arthritis and in Human Rheumatoid Arthritis
Authors: Chen Der-Yuan , Lin Chi-Chien , Chen Yi-Ming , Chao Ya-Hsuan , Yang Deng-Ho
Published: September 2017

Dextromethorphan (d-3-methoxy-17-methylmorphinan, DXM) is a commonly used antitussive with a favorable safety profile. Previous studies have demonstrated that DXM has anti-inflammatory and immunomodulatory properties; however, the effect of DXM in rheumatoid arthritis (RA) remains unknown. Herein, we found that DXM treatment attenuated arthritis severity and proinflammatory cytokine expression levels, including TNF-α, IL-6, and IL-17A, in paw tissues of CIA mice. DXM treatment also reduced serum TNF-α, IL-6, and IL-17A levels of CIA mice and patients with RA. DXM further decreased the production of anti-CII IgG, IFN-γ, and IL-17A in collagen-reactive CD4+T cells extracted from the lymph nodes of CIA mice.In vitroincubation of bone marrow–derived dendritic cells with DXM limited CD4+T-cell proliferation and inflammatory cytokine secretion. In conclusion, our results showed that DXM attenuated arthritis symptoms in CIA mice and significantly reduced proinflammatory cytokines in patients with RA, suggesting that it can be used as an anti-arthritic agent.
Transgenerational exposure of North Atlantic bivalves to ocean acidification renders offspring more vulnerable to low pH and additional stressors
Authors: Griffith Andrew W. , Gobler Christopher J.
Published: September 2017

While early life-stage marine bivalves are vulnerable to ocean acidification, effects over successive generations are poorly characterized. The objective of this work was to assess the transgenerational effects of ocean acidification on two species of North Atlantic bivalve shellfish, Mercenaria mercenaria and Argopecten irradians. Adults of both species were subjected to high and low pCO2 conditions during gametogenesis. Resultant larvae were exposed to low and ambient pH conditions in addition to multiple, additional stressors including thermal stress, food-limitation, and exposure to a harmful alga. There were no indications of transgenerational acclimation to ocean acidification during experiments. Offspring of elevated pCO2-treatment adults were significantly more vulnerable to acidification as well as the additional stressors. Our results suggest that clams and scallops are unlikely to acclimate to ocean acidification over short time scales and that as coastal oceans continue to acidify, negative effects on these populations may become compounded and more severe.
Synthesis and Evaluation of GM2-Monophosphoryl Lipid A Conjugate as a Fully Synthetic Self-Adjuvant Cancer Vaccine
Authors: Zhou Zhifang , Mandal Satadru S. , Liao Guochao , Guo Jiatong , Guo Zhongwu
Published: September 2017

An efficient method was developed for the synthesis of a GM2 derivative suitable for the conjugation with various biomolecules. This GM2 derivative was covalently linked to keyhole limpet hemocyanin (KLH) and monophosphoryl lipid A (MPLA) to form novel therapeutic cancer vaccines. Immunological evaluations of the resultant conjugates in mice revealed that they elicited robust GM2-specific overall and IgG antibody responses. Moreover, the GM2-MPLA conjugate was disclosed to elicit strong immune responses without the use of an adjuvant, proving its self-adjuvant property. The antisera of both conjugates showed strong binding and mediated similarly effective complement-dependent cytotoxicity to GM2-expressing cancer cell line MCF-7. Based on these results, it was concluded that both GM2-MPLA and GM2-KLH are promising candidates as therapeutic cancer vaccines, whereas fully synthetic GM2-MPLA, which has homogeneous and well-defined structure and self-adjuvant property, deserves more attention and studies.
A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model
Authors: Daly Conor , Shine Lisa , Heffernan Theresa , Deeti Sudhakar , Reynolds Alison L. , O’Connor John J. , Dillon Eugène T. , Duffy David J. , Kolch Walter , Cagney Gerard , Kennedy Breandán N.
Published: September 2017

Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dye
ucd6
model, we determined if treatment with HDACi can rescue cone photoreceptor-mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (~43 fold, p < 0.001) and visualmotor (VMR) (~3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue in our dataset. Co-treatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness.
Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency
Authors: Di Meo Ivano , Colombelli Cristina , Srinivasan Balaji , de Villiers Marianne , Hamada Jeffrey , Jeong Suh Y. , Fox Rachel , Woltjer Randall L. , Tepper Pieter G. , Lahaye Liza L. , Rizzetto Emanuela , Harrs Clara H. , de Boer Theo , van der Zwaag Marianne , Jenko Branko , Čusak Alen , Pahor Jerca , Kosec Gregor , Grzeschik Nicola A. , Hayflick Susan J. , Tiranti Valeria , Sibon Ody C. M.
Published: September 2017

Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4′-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.