bluuebunny/crossref_metadata_2025 huggingface dataset:
RESPOND: a programme to prevent secondary falls in older people presenting to the emergency department with a fall: protocol for an economic evaluation
Authors: Morello R T , Morris R L , Hill K D , Haines T P , Arendts G , Redfern J , Etherton-Beer C D , Lowthian J A , Brand C A , Liew D , Watts J J , Barker A L
Published: October 2016

Background

Falls remain common for community-dwelling older people and impose a substantial economic burden to the healthcare system. RESPOND is a novel falls prevention programme that aims to reduce secondary falls and fall injuries among older people who present to a hospital emergency department (ED) with a fall. The present protocol describes a prospective economic evaluation examining the incremental cost-effectiveness of the RESPOND programme, compared with usual care practice, from the Australian health system perspective.

Methods and design

This economic evaluation will recruit 528 participants from two major tertiary hospital EDs in Australia and will be undertaken alongside a multisite randomised controlled trial. Outcome and costing data will be collected for all participants over the 12-month trial. It will compare the RESPOND falls prevention programme with usual care practice (current community-based falls prevention practices) to determine its incremental cost-effectiveness according to three intermediate clinical outcomes: (1) falls prevented, (2) fall injuries prevented and (3) injurious falls prevented. In addition, utilities will be derived from a generic quality-of-life measure (EQ-5D-5L) and used to calculate the ‘incremental cost per quality-adjusted life years gained’.

Discussion

The results of this study will provide healthcare decision makers with evidence to assist with setting spending thresholds for preventive health programmes and inform selection of emergency and community service models of care.

Trial registration number

The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000336684); Pre-results.
Ups and downs of life as a PhD student
Authors: Hill Myfanwy
Published: October 2016

Myfanwy Hill reflects on her coping strategies and recognises her limitations. She has learnt why it is important to relax and recharge
Estimation of ellagic acid and/or repaglinide effects on insulin signaling, oxidative stress, and inflammatory mediators of liver, pancreas, adipose tissue, and brain in insulin resistant/type 2 diabetic rats
Authors: Amin Mohamed M. , Arbid Mahmoud S.
Published: October 2016

Even though ellagic acid has previously been valued in many models of cancer, so far its full mechanistic effect as a natural antiapoptotic agent in the prevention of type 2 diabetes complications has not been completely elucidated, which was the goal of this study. We fed albino rats a high-fat fructose diet (HFFD) for 2 months to induce insulin resistance/type 2 diabetes and then treated the rats with ellagic acid (10 mg/kg body weight, orally) and/or repaglinide (0.5 mg/kg body weight, orally) for 2 weeks. At the serum level, ellagic acid challenged the consequences of HFFD, significantly improving the glucose/insulin balance, liver enzymes, lipid profile, inflammatory cytokines, redox level, adipokines, ammonia, and manganese. At the tissue level (liver, pancreas, adipose tissue, and brain), ellagic acid significantly enhanced insulin signaling, autophosphorylation, adiponectin receptors, glucose transporters, inflammatory mediators, and apoptotic markers. Remarkably, combined treatment with both ellagic acid and repaglinide had a more pronounced effect than treatment with either alone. These outcomes give new insight into the promising molecular mechanisms by which ellagic acid modulates numerous factors induced in the progression of diabetes.
Medicinal mushroom Agaricus subrufescens from Iran shares genetic markers with specimens from China and Thailand
Authors: Mahdizadeh Valiollah , Safaie Naser , Goltapeh Ebrahim Mohammadi , Asef Mohammad Reza , Callac Philippe
Published: October 2016

Agaricus subrufescens Peck is a cosmopolitan species of nutritional and medicinal interest. Three types of internal transcribed spacer (ITS) rDNA sequences were recently characterized for this species. Sequences of types A, B, or both types A and B are found in American and European specimens, while sequences of type C are found in Asian (China and Thailand) and Oceanian (Hawaii) specimens. We report on a collection of this species from Iran, for the first time. Both the morphological features and ITS sequence confirm its identification as A. subrufescens. Its ITS sequence was of type C and even identical to that of specimens previously reported from Hawaii, China, and Thailand. This sequence differed from those of Europe or the Americas, where most current cultivars originate. The discovery of a specimen likely native to Iran extends the known distribution range of the ITS sequence of type C from East Asia to Iran. More collections from West Asia (and elsewhere, for example Africa) would help to better know the distribution area of the different types of ITS sequences and to increase the available germplasm resources of A. subrufescens.
Electrochemical sensor based on rhodium nanoparticles stabilized in zwitterionic surfactant forp-coumaric acid analysis
Authors: Moreira Ferreira Larissa , Dutra de Souza Franciane , Nome Aguilera Faruk Jose , Cruz Vieira Iolanda
Published: October 2016

A new sensor was developed for the analysis of phenolic compounds by coating the surface of a glassy carbon electrode (GCE) with rhodium nanoparticles stabilized in 3-(1-tetradecyl-3-imidazolium) propanesulfonate (ImS3-14), a zwitterionic surfactant. The modifier was found to lower the electron transfer resistance by enhancing the electrical conductivity on the electrode surface. Some phenolic compounds were tested to determine the increase in the electroanalytical response when employing the proposed sensor in comparison to the bare GCE. p-Coumaric acid showed the greatest peak enlargement and, thus, it was selected as the target analyte. Chronocoulometry studies indicated that the increase in the peak is due to the adsorption of the p-coumaric acid on the sensor surface. The optimized analysis conditions were obtained in acetate buffer pH 4.0 employing differential pulse voltammetry, which provided a limit of detection of 472 nmol/L. The recoveries ranged from 98.3% to 104.4%, indicating satisfactory accuracy for the proposed method. The sensor exhibited good repeatability and reproducibility (both intraday and interday) and was applied successfully in the determination of p-coumaric acid in a cellulosic matrix.
Synthesis, physical properties, and chemistry of donor–acceptor-substituted pentacenes
Authors: Lehnherr Dan , Adam Matthias , Murray Adrian H. , McDonald Robert , Hampel Frank , Tykwinski Rik R.
Published: October 2016

Pentacenes bearing electron-donating and (or) -withdrawing groups, namely methoxy-, dialkylamino-, and nitroaryl moieties, are synthesized to afford polarized pentacenes. The optical, electrochemical, and chemical properties of these derivatives are explored. The cycloaddition reaction of selected derivatives with tetracyanoethylene (TCNE) is explored, and the experimental results are rationalized on the basis calculations using density functional theory (DFT). X-ray crystallographic data provides insight into the molecular structure and intermolecular interactions present in the solid state.
Discussion on upper limit of the precision for τ mass measurement
Authors: Mo X. H.
Published: October 2016

[Formula: see text] lepton is one of three charged leptons in nature, the measurements of its mass have been performed since its discovery. The present relative accuracy is already at the level of [Formula: see text]; more factors are still being studied in order to increase the accuracy. However, the available techniques for analysis and expectable luminosity from e[Formula: see text]e[Formula: see text] collider indicate that the precision upper limit of [Formula: see text] mass is almost reached, which means that brand new approaches should be considered if a great improvement is yearned for.
Language, Translation, Trauma
Authors: Pillen Alex
Published: October 2016

Contemporary definitions of trauma and their application remain controversial within anthropology. A survivor's awareness of a parallel, incompatible world of atrocity is understood to bypass language or conscious expression. Such a framework can be compared with ethnographic work on the silence of survivors. Experiences of inhumanity and extreme violence eventually find a discursive niche but nevertheless pose problems of translation. Through the lens of traditional anthropology another realm emerges—a world of vampires, zombies, and cannibals. “Crimes against humanity” can be added to the list, but overall translations seem oriented toward the maintenance of interpretative control, even in contexts of mass dehumanization. Anthropologists are well placed to pay attention to both the complex evidential systems of survivors and the construction of liberal voices. The image of trauma and its untranslatability, however, linger in the background of interventions and point to the vital but endangered bond between language and humanity.
ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
Authors: Muranen Taru , Selfors Laura M. , Hwang Julie , Gallegos Lisa L. , Coloff Jonathan L. , Thoreen Carson C. , Kang Seong A. , Sabatini David M. , Mills Gordon B. , Brugge Joan S.
Published: October 2016

Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell–targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors. Cancer Res; 76(24); 7168–80. ©2016 AACR.
Inhibition by Teriflunomide of Erythrocyte Cell Membrane Scrambling Following Energy Depletion, Oxidative Stress and Ionomycin
Authors: Zierle Jens , Bissinger Rosi , Lang Florian
Published: October 2016

Background/Aims: Teriflunomide, an inhibitor of pyrimidine synthesis and thus proliferation of activated T and B lymphocytes, is successfully used for treatment of inflammatory disease. Teriflunomide has further been shown to trigger apoptosis of tumor cells and has thus been considered for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane with translocation of phosphatidylserine to the erythrocyte surface. Triggers of cell membrane scrambling include energy depletion, oxidative stress and increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored whether teriflunomide modifies eryptosis. Methods: Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, and [Ca2+]i from Fluo3 fluorescence. Results: Oxidative stress (60 min exposure to 0.3 mM tert-butylhydroperoxide), energy depletion (removal of glucose for 48 hours), and exposure to the Ca2+ ionophore ionomycin (1 µM, 60 min) all increased annexin-V-binding, decreased forward scatter and enhanced Fluo3 fluorescence. Teriflunomide (5 µg/ml) did not significantly influence Fluo3 fluorescence, forward scatter and annexin-V-binding under control conditions but significantly blunted the increase of annexin-V-binding following oxidative stress, energy depletion and ionomycin exposure. Teriflunomide further blunted the increase of Fluo3 fluorescence following energy depletion, but did not significantly interfere with increase of Fluo3 fluorescence following oxidative stress and ionomycin exposure. Conclusion: Teriflunomide is a novel inhibitor of suicidal erythrocyte death.
Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores
Authors: Chen Zuolei , Spahn Donat R. , Zhang Xuewei , Liu Yingzhi , Chu Haichen , Liu Zhongkai
Published: October 2016

Background/Aims: The purpose of this study was to investigate the implications of protein kinase C-epsilon (PKCε), Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and mitochondrial permeability transition pore (mPTP) in myocardial protection induced by morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of eight groups. Hearts in time control (TC) group were constantly perfused for 105min. Hearts in ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. εV1-2 (an inhibitor of PKCε) and PD (an inhibitor of ERK1/2) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. I/R injury was assessed by functional parameters, creatine kinase-MB (CK-MB) release and infarct size (IS/AAR). Additional hearts were excised at 20 min following reperfusion to detect the membrane-specific translocation of PKCε, ERK1/2 phosphorylation, mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) release. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of εV1-2 or PD. Compared to TC group, the membrane translocation of PKCε, ERK1/2 phosphorylation, mPTP opening, and Cyt-c release were significantly increased in I/R hearts. MpostC further increased the membrane translocation of PKCε and ERK1/2 phosphorylation, and significantly inhibited mPTP opening and Cyt-c release. However, those protective effects induced by MpostC were abolished by εV1-2 or PD, which, used alone, showed no influence on reperfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against ischemia-reperfusion injury via activating PKCε-ERK1/2 pathway and inhibiting mPTP opening.
ER Stress via CHOP Pathway is Involved in FK506-Induced Apoptosis in Rat Fibroblasts
Authors: Tang Jian , Ge Yingbin , Yang Lei , Xu Xinyu , Sui Tao , Ge Dawei , Que Jun , Cao Xiaojian
Published: October 2016

Background/Aims: Hypertrophic scars (HS) formation results from reduced apoptosis and increased proliferation of fibroblasts. Therefore, apoptosis of fibroblasts is a key target for the development of novel therapeutic strategies for HS. Previous reports demonstrated that FK506 could attenuate scar formation in vivo and FK506 could also induce endoplasmic reticulum stress (ER stress). However, the effects of FK506 on ER stress-mediated apoptosis in fibroblasts remain unclear. Methods: Rat skin fibroblasts were used in the study. Cell viability was examined using cell counting Kit-8. Apoptosis was detected by Annexin V/Propidium Iodide Double Staining. Gene silencing was performed using Small Interfering RNAs (siRNAs) or via lentiviral infection. The expression of apoptosis-related proteins was determined via Western blot. Interaction between proteins was explored by co-immunoprecipitation. Results: FK506 significantly reduced cell viability and induced apoptosis in fibroblasts. Interestingly, ER stress was also activated after FK506 treatment. We further demonstrated that FK506-induced apoptosis was mediated by ER stress via activating CHOP, evidenced by decreased apoptosis after inhibition of ER stress using TUDCA or silencing expression of CHOP. Furthermore, Co-immunoprecipitation results indicated that treatment of FK506 induced disassociation of FKBP12.6 from RyR2 and its translocation from ER membrane to cytosol, consequently promoting ER stress-mediated apoptosis. Conclusion: FK506-induced fibroblasts apoptosis was mediated by ER stress via CHOP signaling pathway.
CO2 and HCO3- Permeability of the Rat Liver Mitochondrial Membrane
Authors: Arias-Hidalgo Mariela , Hegermann Jan , Tsiavaliaris Georgios , Carta Fabrizio , Supuran Claudiu T. , Gros Gerolf , Endeward Volker
Published: October 2016

Background/Aims: Across the mitochondrial membrane an exceptionally intense exchange of O2 and CO2 occurs. We have asked, 1) whether the CO2 permeability, PM,CO2, of this membrane is also exceptionally high, and 2) whether the mitochondrial membrane is sufficiently permeable to HCO3- to make passage of this ion an alternative pathway for exit of metabolically produced CO2. Methods: The two permeabilities were measured using the previously published mass spectrometric 18O exchange technique to study suspensions of mitochondria freshly isolated from rat livers. The mitochondria were functionally and morphologically in excellent condition. Results: The intramitochondrial CA activity was exclusively localized in the matrix. PM,CO2 of the inner mitochondrial membrane was 0.33 (SD ± 0.03) cm/s, which is the highest value reported for any biological membrane, even two times higher than PM,CO2 of the red cell membrane. PM,HCO3- was 2· 10-6 (SD ± 2· 10-6) cm/s and thus extremely low, almost 3 orders of magnitude lower than PM,HCO3- of the red cell membrane. Conclusion: The inner mitochondrial membrane is almost impermeable to HCO3- but extremely permeable to CO2. Since gas channels are absent, this membrane constitutes a unique example of a membrane of very high gas permeability due to its extremely low content of cholesterol.
Thioester-Containing Protein-4 Regulates the Drosophila Immune Signaling and Function against the Pathogen Photorhabdus
Authors: Shokal Upasana , Eleftherianos Ioannis
Published: October 2016

Despite important progress in identifying the molecules that participate in the immune response of Drosophila melanogaster to microbial infections, the involvement of thioester-containing proteins (TEPs) in the antibacterial immunity of the fly is not fully clarified. Previous studies mostly focused on identifying the function of TEP2, TEP3 and TEP6 molecules in the D. melanogaster immune system. Here, we investigated the role of TEP4 in the regulation and function of D. melanogaster host defense against 2 virulent pathogens from the genus Photorhabdus, i.e. the insect pathogenic bacterium Photorhabdus luminescens and the emerging human pathogen P. asymbiotica. We demonstrate that Tep4 is strongly upregulated in adult flies following the injection of Photorhabdus bacteria. We also show that Tep4 loss-of-function mutants are resistant to P. luminescens but not to P. asymbiotica infection. In addition, we find that inactivation of Tep4 results in the upregulation of the Toll and Imd immune pathways, and the downregulation of the Jak/Stat and Jnk pathways upon Photorhabdus infection. We document that loss of Tep4 promotes melanization and phenoloxidase activity in the mutant flies infected with Photorhabdus. Together, these findings generate novel insights into the immune role of TEP4 as a regulator and effector of the D. melanogaster antibacterial immune response.
Peripheral Immune Cell Counts and Advanced Imaging as Biomarkers of Stroke Outcome
Authors: Pagram Heather , Bivard Andrew , Lincz Lisa F. , Levi Christopher
Published: October 2016

Introduction: Circulating neutrophil and lymphocyte levels may be modifiable outcome predictors of ischemic stroke. We sought to compare these immune cell parameters with advanced imaging assessment and the 90-day clinical outcome. Methods: We used a retrospectively collected cohort of consecutive ischemic stroke patients presenting within 4.5 h of symptom onset who had acute CT perfusion and routine blood collection before treatment with intravenous thrombolysis and 24-hour MRI scanning at the John Hunter Hospital. Full blood counts were performed acutely at 24 h and 7 days. Patient outcomes were assed at 90 days after stroke with the modified Rankin Scale (mRS). Results: Overall, 142 patients were assessed during the study period. Patients with a poor outcome (mRS 3-6) had increased neutrophils (44% increase, p = 0.016), decreased lymphocytes (7% decrease, p = 0.491) and an increased lymphocyte-to-neutrophil ratio (196% increase, p < 0.001). Patients with good outcomes (mRS 0-2) did not have significant changes in their full blood counts. There was no relationship between the neutrophil count at 24 h and penumbral volume (r2 = 0.217, p = 0.212), reperfusion (r2 = 0.111, p = 0.085), or core growth (r2 = 0.297, p = 0.107). A backward multivariate analysis containing the 24-hour core volume and 24-hour neutrophil count was strongly related to the 3-month outcome (r2 = 0.477, area under the curve = 0.902, p < 0.001). Conclusions: Peripheral neutrophils have potential as a biomarker of outcome when used in conjunction with advanced imaging. Peripherally measured neutrophil counts change significantly over time after stroke and may be potential targets for immunomodulatory therapy in patients with a severe stroke or a large infarct volume.
Activation of Tryptophan and Phenylalanine Catabolism in the Remission Phase of Allergic Contact Dermatitis: A Pilot Study
Authors: Zinkevičienė Auksė , Kainov Denis , Girkontaitė Irutė , Lastauskienė Eglė , Kvedarienė Violeta , Fu Yu , Anders Simon , Velagapudi Vidya
Published: October 2016

Background: Allergic contact dermatitis (ACD) is an inflammatory skin disease caused by repeated skin exposure to contact allergens. The severity and duration of this disease are associated with many different factors. Some of these factors may represent markers for monitoring disease activity and the individual response to an intervention. Methods: We used a targeted metabolomics approach to find such factors in the serum of individuals with ACD. Metabolomics profiles were examined and compared in the acute phase of the disease and also in the absence of disease activity. Results: Our study identified a significant remission phase of ACD-associated systemic biochemical shifts in 2 metabolic pathways: tryptophan-kynurenine and phenylalanine-tyrosine. Conclusions: Although the responsible mechanisms are unclear, these results suggest that the remission phase of ACD is linked to tryptophan metabolism via kynurenine and phenylalanine-tyrosine pathways. However, further replication studies with a larger number of subjects and their subgroups are necessary to validate our results. These studies may provide a new perspective with which to understand the mechanism of and find potential biomarkers of ACD, as well as a new reference for personalized treatment.
Early Activation of PINCH/ Glycogen-Synthase Kinase 3β/ERK Pathway in Obstructive Nephropathy Rat Model
Authors: Jia Lishan , Li Xiaozhong , Gu Yueqin , Cui Weifeng
Published: October 2016

Background: Despite a previous study showing that PINCH-1 exerts an important role in regulating TGF-β1-mediated mesenchymal transition through its interaction with integrin-linked kinase, relatively little is known about the role of PINCH in the obstructive nephropathy. Methods: To construct a rat model of renal interstitial fibrosis and obstructive nephropathy, unilateral ureteral obstruction (UUO) was used. Hematoxylin and eosin and Masson staining were used in histologic examinations. Quantificational reverse transcription-PCR was used to analyze the mRNA expression level. Western blot and the immunohistochemistry staining were used to detect the protein levels. Results: Histologic examination showed that slight interstitial fibrosis and tubular atrophy existed in the kidney of UUO rats. PINCH, alpha-smooth muscle actin, vascular endothelial growth factor and connective tissue growth factor were markedly induced in the kidney of the UUO rats. However, the expression level of E-cadherin was markedly suppressed in the kidney of the UUO rats. Moreover, both JUN and phosphorylation of JUN proteins were significantly decreased in the kidney of the UUO rats. Conversely, phosphorylation of ERK1/2 and glycogen-synthase kinase 3β (GSK3β) were markedly induced in UUO rats compared to that in sham rats. However, ERK1/2 proteins showed no statistically significant difference between UUO and sham groups. Conclusions: PINCH/GSK3β/ERK pathway was early molecular responses to obstructed kidney induced by UUO in rat.
Neoadjuvant Chemotherapy with Docetaxel, Carboplatin and Weekly Trastuzumab Is Active in HER2-Positive Early Breast Cancer: Results after a Median Follow-Up of over 4 Years
Authors: Kolberg Hans-Christian , Akpolat-Basci Leyla , Stephanou Miltiades , Aktas Bahriye , Hannig Carla Verena , Liedtke Cornelia
Published: October 2016

Introduction: Most patients with HER2-positive breast cancer receive chemotherapy and trastuzumab. Data from adjuvant trials have shown that the combination of docetaxel, carboplatin and weekly trastuzumab (TCH) is well tolerated and as effective as anthracycline-containing regimes. Previous investigations on neoadjuvant treatment with taxanes, platinum salts and trastuzumab showed pathological complete remission (pCR) rates between 43.3 and 76%. To date, the longest published follow-up in this indication is 3 years. Here we present 4-year follow-up data for a cohort of 78 patients treated with neoadjuvant TCH. Methods: Between 2009 and 2014 we treated 78 patients with operable HER2-positive breast cancer with a neoadjuvant schedule of docetaxel (75 mg/m2) and carboplatin (AUC 6) every 3 weeks (q3w) and trastuzumab (4 mg/kg loading dose then 2 mg/kg) q1w. Lymph node involvement was verified by sentinel lymph node or core-cut biopsy. Patients were diagnosed at a mean age of 55.5 years; 65.4% had hormone receptor-positive tumors, 34.6% presented with grade 3 disease and 51.3% of patients were node positive. Patients were monitored every 2 cycles by ultrasound. After 6 cycles of chemotherapy all patients had surgery. Axillary dissection was performed in case of positive lymph node status prior to TCH. After surgery, trastuzumab was continued q3w up to 1 year. Results: No grade III/IV toxicities occurred and no case of congestive heart failure was observed. Neither dose modifications nor dose delays were necessary. 34 of the 78 patients (43.6%) achieved a pCR, 27 of the 40 node-positive patients (67.5%) experienced nodal conversion. After a median follow up of 48.5 months the disease-free survival (DFS) was 84.6%, the distant disease-free survival (DDFS) was 87.2% and the overall survival (OS) was 91%. Only T stage and nodal status at baseline were found to be significantly associated with survival estimates. Conclusion: The anthracycline-free regimen TCH is effective and safe in the neoadjuvant therapy of HER2-positive breast cancer, yielding DFS, DDFS and OS probabilities comparable to the results of adjuvant trials. Our data support the use of TCH as a neoadjuvant therapy regimen for patients with HER2-positive breast cancer. They also strongly encourage the use of taxanes and platinum salts as the chemotherapy backbone in studies investigating dual blockade with trastuzumab and pertuzumab in the neoadjuvant setting.
Paleontologia da fácies arenosa do membro Taquaral (Permiano) no Estado de São Paulo: estado da arte e contribuições adicionais
Authors: Chahud Artur , Petri Setembrino
Published: October 2016

A Formação Irati, Permiano (Cisuraliano) da Bacia do Paraná, destaca-se por importantes características geológicas e paleontológicas. Entre seus fósseis, os crustáceos e répteis Mesosauridae são os mais conhecidos e estudados. Nas fácies arenosas do Membro Taquaral sempre foram citados restos de peixes desarticulados, mas nenhum trabalho foi publicado. Esta lacuna no conhecimento paleontológico foi preenchida com diversas contribuições que serão resumidas neste trabalho. A maior parte dos fósseis são dentes, escamas e partes ósseas indeterminadas de Actinopterygii, porém deve-se aos Chondrichthyes maior diversidade taxonômica, na forma de dentes e espinhos. Os dentes mais abundantes pertencem ao Holocephali Itapyrodus, inicialmente considerado monoespecífico, I. punctatus. Estudos recentes revelaram que diferentes morfotipos identificados como Itapyrodus, podem incluir várias espécies. Os elasmobrânquios são representados por dentes cladodontes, pelo menos três gêneros baseados em espinhos, (Amelacanthus, Sphenacanthus e um indeterminado), uma espécie de Orodontiformes, Orodus ipeunaensis, e Xenacanthiformes, com a espécie Taquaralodus albuquerquei e duas espécies indeterminadas. Outros fósseis também foram registrados; Sarcopterygii (Actinistia, Osteolepiformes), tetrápodes (Temnospondyli), icnofósseis indeterminados e citações de microfósseis (foraminiferos, ostracodes e acritarcas).
Modelo de alojamento do Plúton Cupira, Província Borborema (NE Brasil)
Authors: Miranda Tiago Siqueira de , Mariano Gorki , Correia Paulo de Barros
Published: October 2016

O Plúton Cupira está localizado no Domínio Sul da Província Borborema, possui área aflorante de aproximadamente 300 km2 e forma ovalada com leve alongamento na direção E-W. Com objetivo de determinar o modelo de alojamento do plúton e os alinhamentos magnético-estruturais, foi realizada a integração inédita de estudos de anisotropia de suscetibilidade magnética (ASM) e magnetometria. Os dados de ASM mostram que a susceptibilidade total apresenta variação de 0,105x10-3 SI a 34,618x10-3 SI, indicando caráter ferromagnético. O grau de anisotropia varia de 1,06 a 1,272 e apresenta correlação positiva com a susceptibilidade total. O parâmetro de forma varia de -0,802 a 0,897, com preponderância de elipsoides oblatos sobre prolatos, refletindo trama magnética planar. A maioria das lineações magnéticas possuem direção NE-SW, com caimentos suaves a fortes para NE e para SW. A foliação magnética varia de NE a NNE, com mergulhos moderados a fortes (30° a 86°). A porção central do corpo tem foliações magnéticas e magmáticas essencialmente concêntricas, com mergulhos fortes para o centro do plúton, associadas à lineações com caimento forte, sugerindo ser a zona de alimentação magmática. Os alinhamentos magnéticos reforçam as direções estruturais evidenciadas pela ASM. Estes dados favorecem a proposição de modelo de alojamento do Plúton Cupira a partir de uma zona de alimentação magmática central, com fluxo do magma distribuído de forma concêntrica, com geometria de intrusão similar a um lopólito.
TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcγRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice
Authors: Zhou Yuhang , Abraham Shaji , Renna Stephanie , Edelstein Leonard C. , Dangelmaier Carol A. , Tsygankov Alexander Y. , Kunapuli Satya P. , Bray Paul F. , McKenzie Steven E.
Published: October 2016

Objective—

The objective of this study is to investigate the role of T-cell ubiquitin ligand-2 (TULA-2) in the platelet Fc receptor for IgG IIA (FcγRIIA) pathway and in the pathogenesis of heparin-induced thrombocytopenia (HIT).

Approach and Results—

HIT is a life-threatening thrombotic disease in which IgG antibodies against the heparin–platelet factor 4 complex activate platelets via FcγRIIA. We reported previously differential expression of TULA-2 in human population was linked to FcγRIIA responsiveness. In this study, we investigated the role of TULA-2, a protein phosphatase, in the FcγRIIA pathway and HIT pathogenesis by crossing TULA-2
−
/−
mice with transgenic FcγRIIA
+/+
mice. Ablation of TULA-2 resulted in hyperphosphorylation of spleen tyrosine kinase, linker for the activation of T cells, and phospholipase Cγ2 in platelets via FcγRIIA activation. Platelet integrin activation, granule secretion, phosphatidylserine exposure, and aggregation were also enhanced in TULA-2
−
/−
murine platelets. Compared with wild-type mice, TULA-2
−
/−
mice showed aggravated antibody-mediated thrombocytopenia, augmented thrombin generation, and shortened tail bleeding time. In contrast, there was no significant difference between TULA-2
−
/−
and TULA-2
+/+
platelets in platelet spreading and clot retraction. Of note, heterozygous TULA-2
+/−
mice, whose platelets contained 50% as much protein as the TULA-2
+/+
platelets, showed significantly increased platelet reactivity and more severe thrombocytopenia in vivo compared with TULA-2
+/+
mice.

Conclusions—

Together, the data demonstrate that not only the absence of TULA-2 but also the relative level of TULA-2 expression modulates FcγRIIA-mediated platelet reactivity and HIT in vivo. TULA-2 expression could be a valuable marker for HIT and inhibiting TULA-2 may serve as a potential therapy to reverse the bleeding adverse effect of anticoagulants.
Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo
Authors: Li Peng , Yin Ya-Ling , Guo Tao , Sun Xue-Ying , Ma Hui , Zhu Mo-Li , Zhao Fan-Rong , Xu Ping , Chen Yuan , Wan Guang-Rui , Jiang Fan , Peng Qi-Sheng , Liu Chao , Liu Li-Ying , Wang Shuang-Xi
Published: October 2016

Background:

GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation.

Methods:

Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization.

Results:

We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin.

Conclusions:

Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.
Relationship Between QT Interval and Outcome in Low‐Flow Low‐Gradient Aortic Stenosis With Low Left Ventricular Ejection Fraction
Authors: Dahou Abdellaziz , Toubal Oumhani , Clavel Marie‐Annick , Beaudoin Jonathan , Magne Julien , Mathieu Patrick , Philippon François , Dumesnil Jean G. , Puri Rishi , Ribeiro Henrique B. , Larose Éric , Rodés‐Cabau Josep , Pibarot Philippe
Published: October 2016

Background

QT
interval has been shown to be associated with cardiovascular events. There is no data regarding the association between
QT
interval and left ventricular (
LV
) function and prognosis in patients with low
LV
ejection fraction (
LVEF
), low‐flow, low‐gradient aortic stenosis (
LF
‐
LG AS
). We aimed to examine the relationship between corrected
QT
interval (
QT
c
) and
LV
function and outcome in these patients.

Methods and Results

Ninety‐three patients (73±10 years; 74% men) with
LF
‐
LG AS
(mean gradient <40 mm Hg and indexed aortic valve area ≤0.6 cm
2
/m
2
) and reduced
LVEF
(≤40%) were prospectively included in this analysis and 63 of them underwent aortic valve replacement within 3 months following inclusion. Prolonged
QT
c
was defined as
QT
c
>450 ms in men and >470 ms in women.
LV
global longitudinal strain was measured by speckle tracking and expressed in absolute value |%|.
QT
c
correlated with the following: global longitudinal strain (
r
=−0.40,
P
=0.005),
LVEF
(
r
=−0.27,
P
=0.02), stroke volume (
r
=−0.35,
P
=0.007), and B‐type natriuretic peptide (
r
=0.45,
P
=0.0006). During a median follow‐up of 2.0 years, 49 patients died. Prolonged
QT
c
was associated with a 2‐fold increase in all‐cause mortality (hazard ratio=2.05;
P
=0.01) and cardiovascular mortality (hazard ratio=1.89;
P
=0.04). In multivariable analysis adjusted for Euro
SCORE
, aortic valve replacement, previous myocardial infarction,
LVEF
, and ß‐blocker medication, prolonged
QT
c
was independently associated with all‐cause mortality (hazard ratio=2.56;
P
=0.008) and cardiovascular mortality (hazard ratio=2.50;
P
=0.02).

Conclusions

In patients with
LF
‐
LG AS
and reduced
LVEF
, longer
QT
c
interval was associated with worse
LV
function and increased risk of death. Assessment of
QT
c
may provide a simple and inexpensive tool to enhance risk stratification in
LF
‐
LG AS
patients.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01835028.
The Temperature Paradox and Russell’s Analysis of the Definite Determiner
Authors: Hansen Casper Storm
Published: October 2016

Lasersohn (2005) has argued that the use of Russell’s analysis of the definite determiner in Montague Grammar, which is responsible for giving the correct prediction in the case of the temperature paradox, is also responsible for giving the wrong prediction in the case of the Gupta syllogism. In this article, I argue against this claim and show that the problem with the Gupta syllogism can be solved by making a minor addition to Montague Grammar. This solution is one that Lasersohn discusses but rejects. I show that his critique of it is ill- founded.
Parallel Derivation of Spanish Depictive Secondary Predication
Authors: You Eunjung
Published: October 2016

The depictive secondary predication construction has two subject-predicate relationships in one clause, providing two propositional interpretations. This article proposes that the primary predication, which consists of a main verb, and the secondary predication, made up of a secondary predicate, are simultaneously derived in separate derivational planes; this proposal reflects a property of the secondary predicate that is not included in the θ-grid of the primary predicate. The idea of using Parallel Merge to merge these two planes that share a common element allows us to understand the secondary predication construction in a novel way.
Morphological and molecular characterisation of new and known species of Tripyla Bastian, 1865 (Triplonchida: Tripylidae) from northern Iran, with phylogenetic relationships, compendium and identification key
Authors: Asghari Ramezan , Eskandari Ali , Tanha Maafi Zahra , Álvarez-Ortega Sergio , Zhao Zeng Qi
Published: October 2016

During a nematological survey of the family Tripylidae, two new and two known species of the genusTripyla, namelyT. paraffinissp. n.,T. parafilicaudatasp. n.,T. glomeransandT. setifera, were identified and described from soil samples collected from the rhizosphere of forest trees in northern Iran. Three populations ofT. paraffinissp. n., found in different locations, are described and morphometric data of the type and other populations provided.Tripyla paraffinissp. n. is characterised by its body length of 1.21-1.89 mm, dorsal tooth wedge-shaped and triangular, short outer labial and cephalic sensilla, tail bent ventrad and gradually tapering to the end, horn-shaped spicules bearing a distinct constriction in the middle, and presence of 16-20 ventromedian supplementary papillae.Tripyla parafilicaudatasp. n. is described and illustrated from four different locations. It is characterised by females with a body length of 1.48-1.95 mm, dorsal tooth hook-shaped, vaginal wall with a downward pointing tooth-like projection in the middle, long outer labial and setiform cephalic sensilla, long tail, sausage-shaped spermatozoa, males with horn-shaped spicules and 11-17 ventromedian supplementary papillae.Tripyla glomeransandT. setiferaare new records for the Iranian nematofauna. The results of phylogenetic analyses based on sequences of the partial 18S and D2-D3 expansion segments of 28S rRNA fromT. paraffinissp. n. andT. parafilicaudatasp. n. and other species in the genus clearly support the proposal ofT. paraffinissp. n. andT. parafilicaudatasp. n. as new species, as well as indicating thatTripylashares a more recent common ancestor withTobrilus,Tripylella,Prismatolaimus,Diphtherophoraand two trichodorids,TrichodorusandParatrichodorus. The Tripylidae is placed in a main clade within the Triplonchida.
Putting Behavior into International Cooperation
Authors: Messner Dirk , Guarin Alejandro , Haun Daniel
Published: October 2016

Cooperation among countries to deal with climate change and other global challenges seems almost impossible. However, recent research in the behavioral and evolutionary sciences suggests that people cooperate willingly and perhaps even naturally. Why the contradiction? In this paper we call for the need to think about international relations beyond the assumptions of rational choice and narrow self-interest. We suggest that seemingly intractable international challenges are not only the result of power struggles, but may also reflect the under-provisioning of the key enablers of cooperation—what we call the “cooperation hexagon”: reciprocity, trust, we-identity, enforcement, communication, reputation and fairness.
Phylogenetic relationships among Halymenia (Halymeniaceae, Rhodophyta) species on the Brazilian coast with description of Halymenia cearensis sp. nov.
Authors: AZEVEDO CAROLINA ANGÉLICA ARAÚJO DE , CASSANO VALÉRIA , OLIVEIRA MARIANA CABRAL
Published: October 2016

Phylogenetic relationships and species diversity within the genus Halymenia along the Brazilian coast were investigated through molecular and morphological analyses. Molecular studies included UPA, COI-5P and rbcL markers. A total of five Halymenia species were found: Halymenia cearensis sp. nov., H. ignifera, H. pinnatifida, H. silviae and H. cf. mirabilis. Halymenia cearensis was molecularly distinct from all other Halymenia species included in this study and is morphologically characterized by: cleft, lobate, oblong or obovate blades with broad base; apex irregular in shape; surface with bullations, rugosities, spiny and globular papillae irregularly distributed; abundant and conspicuous ganglionic cells throughout; blades up to 800 µm thick at base; outer cortical cells ellipsoidal or ovoid in shape, higher than broad; and inner cortex cells 4–25 µm in width. Our phylogeny demonstrated that entities attributed to H. floridana and H. elongata occurring in Brazil correspond to two distinct genera, which was also supported by morphological and ecological data. The use of molecular tools was crucial to provide a better understanding of the diversity of Brazilian marine flora.
Херменевтични бележки за библейските псалми
Authors: Койчева [Koĭcheva] Регина [Regina]
Published: October 2016

Some hermeneutical notes on the biblical Psalms The article examines two difficult to interpret verses from the Book of Psalms. The analysis compares the Hebrew text, the Septuagint, the Old Bulgarian text (along with its Church Sla­vonic version) and the Modern Bulgarian synodical translation of the psalms. The proposed reading is based on linguistic, literary and theological observations. In the first analysed verse (Ps. 4:2), semantic illegibility is interpreted as a result of the implicit presence of a specific Hebraism in the translations. In the other case (Ps. 5:9), verbal expression is highly elliptical because of the preference given to the phonetic structure of the verse in the Hebrew original. Hermeneutyczne uwagi o biblijnych PsalmachArtykuł prezentuje dwie różne interpretacje wersów pochodzących z biblijnej Księgi Psal­mów. Autorka porównuje przekłady Psalmów, pochodzące z tekstu hebrajskiego, Septuaginty, tekstu starobułgarskiego (wraz z jego cerkiewnosłowiańską wersją) oraz z pierwszego nowo­bułgarskiego przekładu synodalnego. Zaproponowane odczytanie uwzględnia perspektywę językoznawczą, literaturoznawczą i teologiczną. W pierwszym analizowanym wersie (Ps 4,2) semantyczna nieczytelność jest interpretowana jako wynik bezpośredniej obecności specy­ficznego hebraizmu w komentowanych przekładach. W innym przypadku (Ps 5,9) ekspresja słowna jest niezwykle eliptyczna z powodu zastosowania obecnej w hebrajskim oryginale fonetycznej struktury wersu.
Biblia w kulturze Rusi polsko-litewskiej w XVI wieku
Authors: Naumow Aleksander
Published: October 2016

The Bible in the culture of Polish-Lithuanian Rus’ in the sixteenth centuryBeginning in the mid-fourteenth century, the East Slavic citizens of the Polish-Lithuanian Commonwealth (“Ruthenians,” the “Rutheni”) took active part in a process of multicultural inte­gration. The increase of interests in the biblical text that took place in Europe in that period was not without influence on Ruthenians – both those who remained Orthodox and those who became followers of the Reformation. The article discusses two outstanding figures: Matvej Ioannovič Desjatyj (the biblical codex of Vilnius and Supraśl, 1502–1507) and Francisk Skorina (Prague edi­tion of 23 Books of the Slavonic Bible – Bivlija ruska of 1517–1520, the Vilnius edition of Malaja podorožnaja knižka – The little traveller’s book, 1522, and the Apostolos of 1525). The article also examines how the circle of the Ostroh Academy approached the task of preparing a print edition of the Slavonic Bible (1580–1581) and investigates the viewpoint of those who were influenced by Reformation ideas as well as that of those promoting the usage of prosta/rus’ka mova. This biblical production, which is only a part of the literary activity undertaken in Rus’, testifies to the high level of Ruthenian culture in the Polish-Lithuanian state and shows how Ruthenians were able to match their traditional spirituality with the philologia sacra of the Renaissance. Biblia w kulturze Rusi polsko-litewskiej w XVI wiekuOd połowy XIV wieku wschodniosłowiańscy obywatele Rusi polsko-litewskiej brali czynny udział w procesie wielokulturowej integracji. Wzrost zainteresowania tekstem biblijnym w całej Europie wpłynął zarówno na prawosławnych, jak i sprzyjających reformacji. Artykuł koncentruje się na działalności dwóch wybitnych postaci: Mateusza (Macieja) Joannowicza Dziesiątego (Kodeks biblijny z Wilna i Supraśla z lat 1502–1507) i Franciszka Skoryny („Bivlija ruska” – praskie wydanie 23 ksiąg biblijnych w latach 1517–1520, „Malaja podorožnaja knižka”, wydana w Wilnie w 1522 i „Apostoł”, 1525). Omówiono tu również proces przygotowania w kręgu Akademii Ostrogskiej pierwszej drukowanej Biblii cerkiewnosłowiańskiej (1580–1581), ukazując także punkt widzenia zwolenników reformacji na problem tekstu biblijnego, w tym także propagatorów „prostej/ruśkiej mowy”. Ta biblijna produkcja, stanowiąca jedynie część literackiej piśmienniczej aktywności, świadczy o wysokim poziomie ruskiej kultury w państwie polsko-litewskim i pokazuje, w jaki sposób Rusini byli w stanie połączyć tradycyjną duchowość z renesansową philologia sacra.