bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different contributions of primary motor cortex, reticular formation, and spinal cord to fractionated muscle activation
Authors: Zaaimi Boubker , Dean Lauren R. , Baker Stuart N. 
Published: October 2017

Coordinated movement requires patterned activation of muscles. In this study, we examined differences in selective activation of primate upper limb muscles by cortical and subcortical regions. Five macaque monkeys were trained to perform a reach and grasp task, and electromyogram (EMG) was recorded from 10 to 24 muscles while weak single-pulse stimuli were delivered through microelectrodes inserted in the motor cortex (M1), reticular formation (RF), or cervical spinal cord (SC). Stimulus intensity was adjusted to a level just above threshold. Stimulus-evoked effects were assessed from averages of rectified EMG. M1, RF, and SC activated 1.5 ± 0.9, 1.9 ± 0.8, and 2.5 ± 1.6 muscles per site (means ± SD); only M1 and SC differed significantly. In between recording sessions, natural muscle activity in the home cage was recorded using a miniature data logger. A novel analysis assessed how well natural activity could be reconstructed by stimulus-evoked responses. This provided two measures: normalized vector length L, reflecting how closely aligned natural and stimulus-evoked activity were, and normalized residual R, measuring the fraction of natural activity not reachable using stimulus-evoked patterns. Average values for M1, RF, and SC were L = 119.1 ± 9.6, 105.9 ± 6.2, and 109.3 ± 8.4% and R = 50.3 ± 4.9, 56.4 ± 3.5, and 51.5 ± 4.8%, respectively. RF was significantly different from M1 and SC on both measurements. RF is thus able to generate an approximation to the motor output with less activation than required by M1 and SC, but M1 and SC are more precise in reaching the exact activation pattern required. Cortical, brainstem, and spinal centers likely play distinct roles, as they cooperate to generate voluntary movements. NEW & NOTEWORTHY Brainstem reticular formation, primary motor cortex, and cervical spinal cord intermediate zone can all activate primate upper limb muscles. However, brainstem output is more efficient but less precise in producing natural patterns of motor output than motor cortex or spinal cord. We suggest that gross muscle synergies from the reticular formation are sculpted and refined by motor cortex and spinal circuits to reach the finely fractionated output characteristic of dexterous primate upper limb movements.
RUNX1 Upregulation by Cytotoxic Drugs Promotes Apoptosis
Authors: Speidel Daniel , Wellbrock Jasmin , Abas Melissa 
Published: October 2017

Abstract
Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia, and myelodysplastic syndromes. However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated posttranscriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine in vitro. Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any antiproliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between RUNX1 mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacologic modulation of RUNX1 might be an attractive new approach to treat hematologic malignancies. Cancer Res; 77(24); 6818–24. ©2017 AACR.
Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence
Authors: Sharma Chandan , Wang Hong-Xing , Li Qinglin , Knoblich Konstantin , Reisenbichler Emily S. , Richardson Andrea L. , Hemler Martin E. 
Published: October 2017

AbstractDHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (antitumor macrophages, natural killer cells) associated with clearance of senescent tumors. These antitumor effects were reversed upon reconstitution with wild-type, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence. Cancer Res; 77(24); 6880–90. ©2017 AACR.
Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol
Authors: Pearson Hannah E. , Iida Mari , Orbuch Rachel A. , McDaniel Nellie K. , Nickel Kwangok P. , Kimple Randall J. , Arbiser Jack L. , Wheeler Deric L. 
Published: October 2017

Abstract
Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non–small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo. There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro. Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204–14. ©2017 AACR.
Mitral Leaflet Changes Following Myocardial Infarction
Authors: Beaudoin Jonathan , Dal-Bianco Jacob P. , Aikawa Elena , Bischoff Joyce , Guerrero J. Luis , Sullivan Suzanne , Bartko Philipp Emanuel , Handschumacher Mark D. , Kim Dae-Hee , Wylie-Sears Jill , Aaron Jacob , Levine Robert A. 
Published: October 2017

Background—
Ischemic mitral regurgitation (MR) is classically ascribed to functional restriction of normal leaflets, but recent studies have suggested post–myocardial infarction (MI) mitral valve (MV) leaflet fibrosis and thickening, challenging valve normality. Progression of leaflet thickness post-MI has not been studied. We hypothesized that excessive MV remodeling post-MI contributes to MR. Our objectives are to characterize MV changes after MI and relate them to MR.

Methods and Results—

Three groups of 40 patients with serial echocardiograms over a mean of 23.4 months were identified from an echocardiography database: patients first studied early (6±12 days) and late (12±7 years) after an inferior MI and normal controls. MV thickness was correlated with MR. We studied the mechanisms for MV changes in a sheep model (6 apical MI versus 6 controls) followed for 8 weeks, with MV cellular and histopathologic analyses. Early post-MI, leaflet thickness was found to be similar to controls (2.6±0.5 vs 2.5±0.4 mm;
P
=0.23) but significantly increased over time (2.5±0.4 to 2.9±0.4 mm;
P
<0.01). In this group, patients tolerating maximal doses of renin–angiotensin blocking agents had less thickening (25% of patients;
P
<0.01). The late-MI group had increased thickness (3.2±0.5 vs 2.5±0.4 mm;
P
<0.01) without progression. At follow-up, 48% of post-MI patients had more than mild MR. Increased thickness was independently associated with MR. Experimentally, 8 weeks post-MI, MVs were 2-fold thicker than controls, with increased collagen, profibrotic transforming growth factor-β, and endothelial-to-mesenchymal transformation, confirmed by flow cytometry.

Conclusions—
MV thickness increases post-MI and correlates with MR, suggesting an organic component to ischemic MR. MV fibrotic remodeling can indicate directions for future therapy.
The Biblical Hebrew “Store Cities” and an Amarna Gloss
Authors: Baranowski Krzysztof J. 
Published: October 2017

Abstract
The word מסכנות used in the phrase ערי מסכנות “store cities” is commonly considered a loanword from the Neo-Assyrian word maškattu, “account, deposit, storehouse.” The current loan hypothesis does not account for the difficulties of the Akkadian evidence and does not take into consideration a gloss in Amarna letter no. 306. This gloss shows that the Canaanite scribes of the Late Bronze Age were familiar with the Akkadian plural form maškanātu and used it with the meaning “granaries, storage areas.” This technical term was borrowed into a Canaanite dialect and was subsequently transmitted to Biblical Hebrew as מסכנות.
Separation and Creation in Genesis 1 and Psalm 104, A Continuation of the Discussion of the Verb ברא
Authors: van Wolde Ellen 
Published: October 2017

Abstract
The meaning of the verb ברא is the subject of fierce discussions. Conventionally it has been rendered by biblicists and Hebraists as “to create,” but this traditional interpretation fails to explain adequately numerous linguistic and conceptual aspects of the verb’s usage. Historical solutions of these problems are discussed. The alternative hypothesis defended here is that the verb ברא Qal designates “to separate.” It is considered to be a spatial concept, not a concept that figures in the domain of construction. In the present article I present further analyses of the verb ברא in Gen 1 and explain the significance for the idea of creation it represents, and of the most famous creation psalm, Ps 104, and especially of vv. 26-30 in which the term ברא is used. The similarities and dissimilarities between these two texts demonstrate that each context of usage of ברא must be independently investigated and appreciated.
On the Frontier between Eastern and Western Yiddish: Sources from Burgenland
Authors: Schäfer Lea 
Published: October 2017

Abstract
Burgenland, the smallest state of current Austria, located on the border with Hungary, once had seven vibrant Jewish communities under the protection of the Hungarian Eszterházy family. There is next to nothing known about the Yiddish variety spoken in these communities. This article brings together every single piece of evidence of this language to get an impression of its structure. This article shows that Yiddish from Burgenland can be integrated into the continuum between Eastern and Western Yiddish and is part of a gradual transition zone between these two main varieties.
Acculturation and severity of depression among first-generation Vietnamese outpatients in Germany
Authors: Nguyen Main Huong , Hahn Eric , Wingenfeld Katja , Graef-Calliess Iris T , von Poser Anita , Stopsack Malte , Burian Hannah , Dreher Annegret , Wolf Simon , Dettling Michael , Burian Ronald , Diefenbacher Albert , Ta Thi Minh Tam 
Published: October 2017

Background: Challenges of migration, particularly concerning the process of acculturation are associated with an increased risk of mental illness. Vietnamese migrants constitute the largest Southeast Asian migrant group in Germany, yet there is no data on the relationship between the mental health status and acculturation among this population. Aims: Therefore, the present study examines the relationship between two well-established dimensions of acculturation, that is, dominant society immersion (DSI) and ethnic society immersion (ESI), the four resulting acculturation strategies (integration, assimilation, separation and marginalization), and severity of depression. Methods: A sample of N = 113 first-generation Vietnamese outpatients from a psychiatric outpatient clinic for Vietnamese migrants in Germany was studied regarding their self-reported depressive symptoms (Beck Depression Inventory-II (BDI-II)) and acculturation (Stephenson Multigroup Acculturation Scale (SMAS)). Results: Consistent with the hypotheses, patients reported less severe depressive symptoms, when they reported higher orientation toward the German and the Vietnamese society. Moreover, the results showed that integrated patients reported a lower severity of depression compared to marginalized patients, who reported the highest severity of depression. Conclusions: The findings indicate that among a sample of first-generation Vietnamese patients with depression, an orientation to both, the mainstream society and one’s heritage society might serve as a potential resource. The rejection of any orientation to any society is associated with an increased risk for depression.
Effect of aminaphtone on in vitro vascular permeability and capillary-like maintenance
Authors: Felice Francesca , Belardinelli Ester , Frullini Alessandro , Santoni Tatiana , Imbalzano Egidio , Di Stefano Rossella 
Published: October 2017

Objectives Aminaphtone, a naphtohydrochinone used in the treatment of capillary disorders, may affect oedema in chronic venous insufficiency. Aim of study is to investigate the effect of aminaphtone on vascular endothelial permeability in vitro and its effects on three-dimensional capillary-like structures formed by human umbilical vein endothelial cells. Method Human umbilical vein endothelial cells were treated with 50 ng/ml VEGF for 2 h and aminaphtone for 6 h. Permeability assay, VE-cadherin expression and Matrigel assay were performed. Results VEGF-induced permeability was significantly decreased by aminaphtone in a range concentration of 1–20 µg/ml. Aminaphtone restored VE-cadherin expression. Finally, 6 h pre-treatment with aminaphtone significantly preserved capillary-like structures formed by human umbilical vein endothelial cells on Matrigel up to 48 h compared to untreated cells. Conclusions Aminaphtone significantly protects endothelium permeability and stabilises endothelial cells organised in capillary-like structures, modulating VE-cadherin expression. These data might explain the clinical benefit of aminaphtone on chronic venous insufficiency.
Contrast-enhanced spectral mammography in patients with MRI contraindications
Authors: Richter Vivien , Hatterman Valerie , Preibsch Heike , Bahrs Sonja D , Hahn Markus , Nikolaou Konstantin , Wiesinger Benjamin 
Published: October 2017

Background Contrast-enhanced spectral mammography (CESM) is a novel breast imaging technique providing comparable diagnostic accuracy to breast magnetic resonance imaging (MRI). Purpose To show that CESM in patients with MRI contraindications is feasible, accurate, and useful as a problem-solving tool, and to highlight its limitations. Material and Methods A total of 118 patients with MRI contraindications were examined by CESM. Histology was obtained in 94 lesions and used as gold standard for diagnostic accuracy calculations. Imaging data were reviewed retrospectively for feasibility, accuracy, and technical problems. The diagnostic yield of CESM as a problem-solving tool and for therapy response evaluation was reviewed separately. Results CESM was more accurate than mammography (MG) for lesion categorization (r = 0.731, P < 0.0001 vs. r = 0.279, P = 0.006) and for lesion size estimation (r = 0.738 vs. r = 0.689, P < 0.0001). Negative predictive value of CESM was significantly higher than of MG (85.71% vs. 30.77%, P < 0.0001). When used for problem-solving, CESM changed patient management in 2/8 (25%) cases. Superposition artifacts and timing problems affected diagnostic utility in 3/118 (2.5%) patients. Conclusion CESM is a feasible and accurate alternative for patients with MRI contraindications, but it is necessary to be aware of the method’s technical limitations.
Persistency of Biologic Therapies for Plaque Psoriasis in 2 Large Community Practices
Authors: Verma Luvneet , Mayba Julia N. , Gooderham Melinda J. , Verma Ankush , Papp Kim A. 
Published: October 2017

Background: Biologics have transformed the management of moderate to severe psoriasis. The persistency of biologics lacks real-world data. Objectives: To quantify drug survival of infliximab (IFX), adalimumab (ADA), etanercept (ETA), and ustekinumab (UST) and to identify potential factors affecting drug survival. Methods: An observational, retrospective 2-centre study consisting of 906 patients from private practices in Ontario between July 2003 and June 13, 2016, was conducted, including patients with plaque psoriasis receiving commercial treatment with ADA, ETA, IFX, and UST. Paper and electronic records of each patient were reviewed. Results: Median survival times for UST, IFX, ADA, and ETA were respectively, in months, 68, 23, 33, and 28. Female sex was determined to be a statistically significant positive predictor of drug survival. Our study was consistent with the literature in that UST had the highest survival rate compared to the other biologics, and the shape of our drug survival curve suggested that loss of drug efficacy is a stochastic occurrence. Compared to other studies, our data exhibited lower survival rates at various time points for all the biologics studied, and female sex did not predict drug survival in other studies. We also investigated potential reasons for differences in biologic survival times between different practices; the main differentiator was drug dosage, as higher dosages were associated with greater survival. Conclusion: UST has a higher drug survival rate than ADA, ETA, and IFX, as observed in other studies. When practice patterns are compared, dosage difference is the main factor that may cause differing survival rates.
Seven years’ follow-up of comparative study between stenting and medication for treatment of symptomatic vertebrobasilar artery stenosis
Authors: Wang Jun , Zhong Changyang , Zhang Yan , Wei Yingnan , Liu Huili , Wu Chunli , Yan Yongxing 
Published: October 2017

Objective Endovascular stent-assistant angioplasty (ESAA) is a valid treatment for symptomatic vertebrobasilar artery stenosis (SVAS), but the long-term effect and the improvement of condition compared with medication treatment are unknown. This study investigated the long-term efficacy of ESAA in patients with moderate and severe SVAS, and compared the efficacy with medication treatment. Materials and methods We conducted a retrospective analysis of clinical data of 43 patients with moderate and severe SVAS hospitalized in our department. According to different treatment methods they were divided into 29 cases in an ESAA group and 14 cases in a medication treatment group. During the follow-up period, the degree of vascular stenosis, vascular blood flow velocity, restenosis rate, recovery of neurological function and the incidence of cerebral ischemic events in the two groups were analyzed. Results The average clinical follow-up period was 89.4 ± 10.2 months. Before treatment, the stenosis rate and average blood flow velocity of the two groups were not statistically significant ( p > 0.05). During the follow-up period, both were significantly lower than the medication treatment group ( p < 0.01). In the ESAA group, three cases of stent stenosis, and three cases in the medication treatment group were completely occluded. The total ischemic events in ESAA group were three cases, compared with nine cases in the medication treatment group; the difference was statistically significant ( p < 0.05). Conclusion ESAA has a long-term effect in the treatment of symptomatic moderate and severe vertebrobasilar artery stenosis. It is superior to medication therapy in preventing posterior circulation ischemia (PCI), but a larger sample size is still needed to confirm the study.
Usefulness for the combination of G protein- and β-arrestin-biased ligands of μ-opioid receptors: Prevention of antinociceptive tolerance
Authors: Mori Tomohisa , Kuzumaki Naoko , Arima Takamichi , Narita Michiko , Tateishi Ryunosuke , Kondo Takashige , Hamada Yusuke , Kuwata Hirotsugu , Kawata Miho , Yamazaki Mitsuaki , Sugita Kazuyuki , Matsuzawa Akinobu , Baba Kanae , Yamauchi Takayasu , Higashiyama Kimio , Nonaka Miki , Miyano Kanako , Uezono Yasuhito , Narita Minoru 
Published: October 2017

Background µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid–opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for µ-opioid receptors, TRV130, which has an antinociceptive effect without β-arrestin-dependent µ-opioid receptor internalization, and its combination with fentanyl using µ-opioid receptor-expressing cells and mice. Results In the present study, we confirmed that fentanyl produced a profound increase in β-arrestin-2 recruitment accompanied by µ-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of β-arrestin-2 or µ-opioid receptor internalization in µ-opioid receptor-expressing cells. Under these conditions, β-arrestin-2 recruitment accompanied by µ-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cyclic adenosine monophosphate formation by fentanyl in µ-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development of its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. Conclusions These findings provide evidence that activation of the G protein-biased pathway through µ-opioid receptors can alter signaling in the β-arrestin-2 pathway linked to the stimulation of µ-opioid receptors. Furthermore, the combination of G protein-biased and β-arrestin-biased ligands of µ-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.