bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical Loading of Cartilage Explants with Compression and Sliding Motion Modulates Gene Expression of Lubricin and Catabolic Enzymes
Authors: Schätti Oliver R. , Marková Michala , Torzilli Peter A. , Gallo Luigi M. 
Published: April 2015

Objective Translation of the contact zone in articulating joints is an important component of joint kinematics, yet rarely investigated in a biological context. This study was designed to investigate how sliding contact areas affect cartilage mechanobiology. We hypothesized that higher sliding speeds would lead to increased extracellular matrix mechanical stress and the expression of catabolic genes. Design A cylindrical Teflon indenter was used to apply 50 or 100 N normal forces at 10, 40, or 70 mm/s sliding speed. Mechanical parameters were correlated with gene expressions using a multiple linear regression model. Results In both loading groups there was no significant effect of sliding speed on any of the mechanical parameters (strain, stress, modulus, tangential force). However, an increase in vertical force (from 50 to 100 N) led to a significant increase in extracellular matrix strain and stress. For 100 N, significant correlations between gene expression and mechanical parameters were found for TIMP-3 (r2 = 0.89), ADAMTS-5 (r2 = 0.73), and lubricin (r2 = 0.73). Conclusions The sliding speeds applied do not have an effect on the mechanical response of the cartilage, this could be explained by a partial attainment of the “elastic limit” at and above a sliding speed of 10 mm/s. Nevertheless, we still found a relationship between sliding speed and gene expression when the tissue was loaded with 100 N normal force. Thus despite the absence of speed-dependent mechanical changes (strain, stress, modulus, tangential force), the sliding speed had an influence on gene expression.
Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor–expressing T cells
Authors: Lynn Rachel C. , Poussin Mathilde , Kalota Anna , Feng Yang , Low Philip S. , Dimitrov Dimiter S. , Powell Daniel J. 
Published: April 2015

Key PointsHuman FRβ-specific CAR T cells target AML in vitro and in vivo without toxicity against healthy bone marrow HSCs. Combination with ATRA-mediated receptor upregulation may augment FRβ-directed CAR therapy of AML.
Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing
Authors: Kurtz David M. , Green Michael R. , Bratman Scott V. , Scherer Florian , Liu Chih Long , Kunder Christian A. , Takahashi Kazuhiro , Glover Cynthia , Keane Colm , Kihira Shingo , Visser Brendan , Callahan Jason , Kong Katherine A. , Faham Malek , Corbelli Karen S. , Miklos David , Advani Ranjana H. , Levy Ronald , Hicks Rodney J. , Hertzberg Mark , Ohgami Robert S. , Gandhi Maher K. , Diehn Maximilian , Alizadeh Ash A. 
Published: April 2015

Key PointsDLBCL can be detected in the blood by immunoglobulin high-throughput sequencing (Ig-HTS) with high specificity. Although DLBCL can be detected in leukocytes or plasma by Ig-HTS, plasma has greater sensitivity and more accurately reflects disease.
Addressing challenges of training a new generation of clinician‐innovators through an interdisciplinary medical technology design program: Bench‐to‐Bedside
Authors: Loftus Patrick D , Elder Craig T , D’Ambrosio Troy , Langell John T 
Published: April 2015

AbstractGraduate medical education has traditionally focused on training future physicians to be outstanding clinicians with basic and clinical science research skills. This focus has resulted in substantial knowledge gains, but a modest return on investment based on direct improvements in clinical care. In today's shifting healthcare landscape, a number of important challenges must be overcome to not only improve the delivery of healthcare, but to prepare future physicians to think outside the box, focus on and create healthcare innovations, and navigate the complex legal, business and regulatory hurdles of bringing innovation to the bedside. We created an interdisciplinary and experiential medical technology design competition to address these challenges and train medical students interested in moving new and innovative clinical solutions to the forefront of medicine. Medical students were partnered with business, law, design and engineering students to form interdisciplinary teams focused on developing solutions to unmet clinical needs. Over the course of six months teams were provided access to clinical and industry mentors, $500 prototyping funds, development facilities, and non‐mandatory didactic lectures in ideation, design, intellectual property, FDA regulatory requirements, prototyping, market analysis, business plan development and capital acquisition. After four years of implementation, the program has supported 396 participants, seen the development of 91 novel medical devices, and launched the formation of 24 new companies. From our perspective, medical education programs that develop innovation training programs and shift incentives from purely traditional basic and clinical science research to also include high‐risk innovation will see increased student engagement in improving healthcare delivery and an increase in the quality and quantity of innovative solutions to medical problems being brought to market.
Mutant human torsinA, responsible for early-onset dystonia, dominantly suppresses GTPCH expression, dopamine levels and locomotion inDrosophila melanogaster
Authors: Wakabayashi-Ito Noriko , Ajjuri Rami R. , Henderson Benjamin W. , Doherty Olugbenga M. , Breakefield Xandra O. , O'Donnell Janis M. , Ito Naoto 
Published: April 2015

Dystonia represents the third most common movement disorder in humans with over 20 genetic loci identified. TOR1A (DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. Most cases of DYT1 dystonia are caused by a 3 bp (ΔGAG) deletion that results in the loss of a glutamic acid residue (ΔE302/303) in the carboxyl terminal region of torsinA. This torsinAΔE mutant protein has been speculated to act in a dominant-negative manner to decrease activity of wild type torsinA. Drosophila melanogaster has a single torsin-related gene, dtorsin. Null mutants of dtorsin exhibited locomotion defects in third instar larvae. Levels of dopamine and GTP cyclohydrolase (GTPCH) proteins were severely reduced in dtorsin-null brains. Further, the locomotion defect was rescued by the expression of human torsinA or feeding with dopamine.Here, we demonstrate that human torsinAΔE dominantly inhibited locomotion in larvae and adults when expressed in neurons using a pan-neuronal promoter Elav. Dopamine and tetrahydrobiopterin (BH4) levels were significantly reduced in larval brains and the expression level of GTPCH protein was severely impaired in adult and larval brains. When human torsinA and torsinAΔE were co-expressed in neurons in dtorsin-null larvae and adults, the locomotion rates and the expression levels of GTPCH protein were severely reduced. These results support the hypothesis that torsinAΔE inhibits wild type torsinA activity. Similarly, neuronal expression of a Drosophila DtorsinΔE equivalent mutation dominantly inhibited larval locomotion and GTPCH protein expression. These results indicate that both torsinAΔE and DtorsinΔE act in a dominant-negative manner. We also demonstrate that Dtorsin regulates GTPCH expression at the post-transcriptional level. This Drosophila model of DYT1 dystonia provides an important tool for studying the differences in the molecular function between the wild type and the mutant torsin proteins.
PKA and cAMP/CNG Channels Independently Regulate the Cholinergic Ca2+-Response ofDrosophilaMushroom Body Neurons
Authors: Pavot Pierre , Carbognin Elena , Martin Jean-René 
Published: April 2015

AbstractThe mushroom bodies (MBs), one of the main structures in the adult insect brain, play a critical role in olfactory learning and memory. Though historical genes such asdunceandrutabaga, which regulate the level of cAMP, were identified more than 30 years ago, theirin vivoeffects on cellular and physiological mechanisms and particularly on the Ca2+-responses still remain largely unknown. In this work, performed inDrosophila, we took advantage ofin vivobioluminescence imaging, which allowed real-time monitoring of the entire MBs (both the calyx/cell-bodies and the lobes) simultaneously. We imaged neuronal Ca2+-activity continuously, over a long time period, and characterized the nicotine-evoked Ca2+-response. Using both genetics and pharmacological approaches to interfere with different components of the cAMP signaling pathway, we first show that the Ca2+-response is proportional to the levels of cAMP. Second, we reveal that an acute change in cAMP levels is sufficient to trigger a Ca2+-response. Third, genetic manipulation of protein kinase A (PKA), a direct effector of cAMP, suggests that cAMP also has PKA-independent effects through the cyclic nucleotide-gated Ca2+-channel (CNG). Finally, the disruption of calmodulin, one of the main regulators of therutabagaadenylate cyclase (AC), yields different effects in the calyx/cell-bodies and in the lobes, suggesting a differential and regionalized regulation of AC. Our results provide insights into the complex Ca2+-response in the MBs, leading to the conclusion that cAMP modulates the Ca2+-responses through both PKA-dependent and -independent mechanisms, the latter through CNG-channels.
Inferring causal metabolic signals that regulate the dynamic TORC1‐dependent transcriptome
Authors: Oliveira Ana Paula , Dimopoulos Sotiris , Busetto Alberto Giovanni , Christen Stefan , Dechant Reinhard , Falter Laura , Haghir Chehreghani Morteza , Jozefczuk Szymon , Ludwig Christina , Rudroff Florian , Schulz Juliane Caroline , González Asier , Soulard Alexandre , Stracka Daniele , Aebersold Ruedi , Buhmann Joachim M , Hall Michael N , Peter Matthias , Sauer Uwe , Stelling Jörg 
Published: April 2015

AbstractCells react to nutritional cues in changing environments via the integrated action of signaling, transcriptional, and metabolic networks. Mechanistic insight into signaling processes is often complicated because ubiquitous feedback loops obscure causal relationships. Consequently, the endogenous inputs of many nutrient signaling pathways remain unknown. Recent advances for system‐wide experimental data generation have facilitated the quantification of signaling systems, but the integration of multi‐level dynamic data remains challenging. Here, we co‐designed dynamic experiments and a probabilistic, model‐based method to infer causal relationships between metabolism, signaling, and gene regulation. We analyzed the dynamic regulation of nitrogen metabolism by the target of rapamycin complex 1 (TORC1) pathway in budding yeast. Dynamic transcriptomic, proteomic, and metabolomic measurements along shifts in nitrogen quality yielded a consistent dataset that demonstrated extensive re‐wiring of cellular networks during adaptation. Our inference method identified putative downstream targets of TORC1 and putative metabolic inputs of TORC1, including the hypothesized glutamine signal. The work provides a basis for further mechanistic studies of nitrogen metabolism and a general computational framework to study cellular processes.
Differential genetic interactions of yeast stress response MAPK pathways
Authors: Martin Humberto , Shales Michael , Fernandez‐Piñar Pablo , Wei Ping , Molina Maria , Fiedler Dorothea , Shokat Kevan M , Beltrao Pedro , Lim Wendell , Krogan Nevan J 
Published: April 2015

AbstractGenetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large‐scale genetic interaction analysis in Saccharomyces cerevisiae involving approximately 49 × 1,200 double mutants in the presence of five different stress conditions, including osmotic, oxidative and cell wall‐altering stresses. This resulted in the generation of a differential E‐MAP (or dE‐MAP) comprising over 250,000 measurements of conditional interactions. We found an extensive number of conditional genetic interactions that recapitulate known stress‐specific functional associations. Furthermore, we have also uncovered previously unrecognized roles involving the phosphatase regulator Bud14, the histone methylation complex COMPASS and membrane trafficking complexes in modulating the cell wall integrity pathway. Finally, the osmotic stress differential genetic interactions showed enrichment for genes coding for proteins with conditional changes in phosphorylation but not for genes with conditional changes in gene expression. This suggests that conditional genetic interactions are a powerful tool to dissect the functional importance of the different response mechanisms of the cell.
A Phase Ib Study of Safety and Pharmacokinetics of Ramucirumab in Combination With Paclitaxel in Patients With Advanced Gastric Adenocarcinomas
Authors: Ueda Shinya , Satoh Taroh , Gotoh Masahiro , Gao Ling , Doi Toshihiko 
Published: April 2015

Abstract

Lessons Learned
The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies. This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated.

Background.
This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum.

Methods.
Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6).

Results.
No dose-limiting toxicities occurred in the first cycle. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ≥3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4–42.7 weeks) and 12.2 weeks (range: 11.0–41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ∼0.017 L/hour, half-life (t1/2) was 138 to 225 hours, and steady-state volume of distribution (Vss) was ∼3 L.

Conclusion.
The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated.
Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD
Authors: Bazick Jessica , Donithan Michele , Neuschwander-Tetri Brent A. , Kleiner David , Brunt Elizabeth M. , Wilson Laura , Doo Ed , Lavine Joel , Tonascia James , Loomba Rohit 
Published: April 2015

OBJECTIVEApproximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment.RESEARCH DESIGN AND METHODSThis study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI.RESULTSThe mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m2, respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75–0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76–0.85, P &lt; 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis.CONCLUSIONSRoutinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists.
Cardiovascular and All-Cause Mortality Over a 23-Year Period Among Chinese With Newly Diagnosed Diabetes in the Da Qing IGT and Diabetes Study
Authors: An Yali , Zhang Ping , Wang Jinping , Gong Qiuhong , Gregg Edward W. , Yang Wenying , Li Hui , Zhang Bo , Shuai Ying , Chen Yanyan , Engelgau Michael M. , Cheng Yiling , Hu Yinghua , Bennett Peter H. , Li Guangwei 
Published: April 2015

OBJECTIVE
Despite its growing prevalence in China, the extent to which diabetes leads to excess cardiovascular disease (CVD) mortality and all-cause mortality is unclear.

RESEARCH DESIGN AND METHODS
We compared death rates and causes of death among 630 people with newly diagnosed diabetes (NDD) and 519 with normal glucose tolerance (NGT) who, in 1986, were identified as a result of screening 110,660 adults aged 25–74 years for diabetes in Da Qing, China.

RESULTS
During 23 years of follow-up, 338 (56.5%) participants with NDD and 100 (20.3%) with NGT died. CVD was the predominant cause of death in those with diabetes (47.5% in men and 49.7% in women), almost half of which was due to stroke (52.3% in men and 42.3% in women). The age-standardized incidence of all-cause death was three times as high in those with NDD as in those with NGT with incidences (per 1,000 person-years) of 36.9 (95% CI 31.5–42.3) vs. 13.3 (10.2–16.5) in men (P &lt; 0.0001) and 27.1 (22.9–31.4) vs. 9.2 (7.8–10.6) in women (P &lt; 0.0001). The incidence of CVD deaths in men and women with NDD (17.5 [13.8–21.2] vs. 13.5 [10.5–16.5]) did not differ significantly. Significantly higher death rates attributable to renal disease and infection were also found in the NDD group.

CONCLUSIONS
Diabetes is associated with a substantially increased risk of death in Chinese adults, especially from CVD, almost half of which is due to stroke.
The Passion of Faith and the Work of Love: Barrett, Augustine, and Kierkegaard
Authors: Russell Helene 
Published: April 2015

Abstract: Is the core of Christianity about loving the neighbour or justification by grace? Kierkegaard and Augustine answer this question with a resounding yes, refusing to give in to one side or the other. This article uses Lee C. Barrett's newest book on the intersections of these two giants of Christianity, Eros and Self-Emptying, to examine this issue. Using a shared metaphor of a road for the reality of faith, and a common understanding of divine love as self-emptying, Barrett reveals insightful ways in which these cardinal thinkers refuse to reduce Christian salvation to grace alone or to love alone. For Augustine, the unquenchable passion and love for God leads to becoming conformed to God's likeness in self-emptying love for the other. And Kierkegaard's theology of love as the human response to God's grace suggests that the works of love toward the neighbour is the follow-through to faith. Salvation for both Augustine and Kierkegaard is a journey of the fruits of grace ripening in fulfilling the command to love the neighbour. Both insist that being a Christian is simultaneously a gift and a task. Further, this integration is not forcing together two opposing positions. Instead each thinker's formulation entwines the work of love and the grace of faith in the practice of Christian living.
The Intersections of Augustine and Kierkegaard Revisited
Authors: Barrett Lee C. 
Published: April 2015

Abstract: The essayists included here are in agreement that Augustine and Kierkegaard were primarily rhetorical theologians, and that they shared much in common concerning the role of desire for God in the Christian life. Most of the authors stress certain aspects of Augustine's and Kierkegaard's theological vision, and they are right to do so. However, both Augustine and Kierkegaard were dialectical thinkers, and often contrapuntal themes, different from those emphasized by our essayists, can be discerned in their works. Augustine and Kierkegaard were both capable of asserting different things in different contexts in order to pursue different edifying purposes.
Churches in the Ukrainian Public Square
Authors: Hovorun Cyril 
Published: April 2015

Abstract: During the winter of 2013–2014, hundreds of thousands protested in Kyiv against the regime of Viktor Yanukovych. As a result of the clashes with police, over one hundred civil protesters lost their lives, and hundreds were wounded by the troops loyal to the president, who eventually had to run away from Ukraine. Those events, which have been branded as “the revolution of dignity,” are unthinkable without the presence of the churches at the Maidan—the central square of the Ukrainian capital. Any picture of the Maidan missing the churches would be incomplete and incorrect. The Maidan was not only a political and social event, but also a religious phenomenon. It explained itself in religious terms and articulated its demands through religious symbols. More importantly and less obviously, it created a new matrix of relationship between the churches and society in Ukraine. This article explores some aspects of the new matrix. The role of the Ukrainian churches in creating a new model of their relationship with the public square, which was shaped by the Maidan, is rather passive. Most churches failed to fit religious expectations of the Maidan. Reactions of some of them are still inadequate to the social awakening of the Ukrainian people: instead of embracing the changes that the Maidan brought to Ukrainian society, they closed themselves in self-imposed ghettos, and preserved in those ghettos the pre-Maidan ethos. The churches received and still receive the Maidan and its outcomes differently. Their differentiation in this regard widens the existing gap between them. New strategies of rapprochement of the churches with the Ukrainian public square and between each other should be elaborated. This article concludes with suggestions for such new strategies.