bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of an integrated engine-hydro-mechanical transmission control algorithm for a tractor
Authors: Ahn Sunghyun , Choi Jingyu , Kim Suchul , Lee Jinwoong , Choi Changhyun , Kim Hyunsoo
Published: July 2015

This article presents an integrated engine-hydro-mechanical transmission control algorithm for a tractor considering the engine-hydro-mechanical transmission efficiency. First, the hydro-mechanical transmission efficiency was obtained by network analysis based on the hydrostatic unit efficiency constructed from the test. Using the hydro-mechanical transmission efficiency map and the thermal efficiency of the engine, an engine-hydro-mechanical transmission optimal operating line was obtained, which provides higher total system efficiency. Based on the optimal operating line, an integrated engine-hydro-mechanical transmission control algorithm was proposed, which provides higher total powertrain system efficiency. To evaluate the performance of the proposed control algorithm, an AMESim-MATLAB/Simulink-based co-simulator was developed. From the simulation results for the plow working, it was found that the integrated engine-hydro-mechanical transmission control provides improved fuel economy by 7.5% compared with the existing engine optimal operating line control. The performance of the integrated engine-hydro-mechanical transmission control was also validated using the test bench.
Performance of water source heat pump system using high-density polyethylene tube heat exchanger wound with square copper wire
Authors: Zhang Xin Wen , Oh Geun-Sug , Jung Gun-Joo
Published: July 2015

Surface water source heat pump system is an energy-efficient heat pump system. Surface water heat exchanger is an important part of heat pump system that can affect the performance of the system. In order to enhance the performance of the system, the overall heat transfer coefficient (U value) of the water exchanger using a 32A square copper coiled high-density polyethylene tube was researched. Comparative experiments were conducted between the performance of the coiled high-density polyethylene tube and the 32A smooth high-density polyethylene tube. At the same time, the coefficient of performance of the heat pump was investigated. According to the result, the U value of the coiled tube was 18% higher than that of the smooth tube in natural convection and 19% higher in forced convection. The coefficient of performance of the heat pump with the coiled tube is higher than that with the smooth tube. The economic evaluation of the coiled tube was also investigated.
Numerical analysis and parametric study of multilayered microchannel heat sinks
Authors: Lin Lin , Deng Min-Xin , Zhang Xin-Xin , Wang Xiao-Dong
Published: July 2015

A three-dimensional solid–fluid conjugated model is used to investigate and optimize the performances of two-, three-, and four-layered microchannel heat sinks. In the optimization process, constraints of fixed total pumping power and fixed total channel height are adopted, and the thermal resistance and bottom wall temperature uniformity are taken as the objective functions. The flow configuration, channel height, and pumping power in each layer are optimized. The results show that more uniform temperature distribution and lower thermal resistance occur at flow configuration (0, 1) for the two-layered microchannel heat sink, (0, 1, 1) for the three-layered microchannel heat sink, and (0, 1, 1, 1) for the four-layered microchannel heat sink. The channel height and pumping power in the bottom layer are dominant over those in the other layers. The optimal design requires a smaller bottom channel height and a higher pumping power than the average value in each layer. The multilayered microchannel heat sink with more layer numbers can achieve a more uniform bottom wall temperature and can also lead to a reduction in the thermal resistance.
Dual-Bézier path smoothing and interpolation for five-axis linear tool path in workpiece coordinate system
Authors: Jin Yongqiao , Bi Qingzhen , Wang Yuhan
Published: July 2015

The tool path composed of consecutive short linear segments (G01 blocks) is still the widespread tool path representation form in five-axis machining. The inherent shortcoming of linear tool path is first-order discontinuity at the corner, which is the bottleneck to achieve high-speed and high-accuracy machining. In this article, a dual-Bézier path smoothing algorithm for five-axis linear tool path in workpiece coordinate system is proposed. There are three steps involved in our method. First, the corner error distribution model is introduced to assign the given tolerance to the smoothing approximation error constraint and the chord error constraint to ensure the interpolation trajectory error within the given tolerance. Second, segment junctions of the linear tool path in workpiece coordinate system are smoothed by double G2 continuous cubic Bézier curves. One cubic Bézier curve is used to round the corner of the tool tip point path, and the other Bézier curve is used to round the corner of the tool axis point path. This algorithm takes the conditions of approximation error constraint, the parameterized synchronization constraint, and continuous curvature constraint into consideration. Hence, the tangency and curvature continuities are both guaranteed in the new path. Third, an adaptive feedrate scheduling method is introduced to interpolate the new path. Simulation and experiment are performed to verify the effectiveness of the proposed method in five-axis tool path smoothing, speed smoothing, and trajectory accuracy controlling.
Improvement of hydro-turbine draft tube efficiency using vortex generator
Authors: Tian Xiaoqing , Pan Huachen , Hong Shuli , Zheng Yuan
Published: July 2015

Computational fluid dynamics simulation was employed in a hydraulic turbine (from inlet tube to draft tube). The calculated turbine efficiencies were compared with measured results, and the relative error is 1.12%. In order to improve the efficiency of the hydraulic turbine, 15 kinds of vortex generators were installed at the vortex development section of the draft tube, and all of them were simulated using the same method. Based on the turbine efficiencies, distribution of streamlines, velocities, and pressures in the draft tube, an optimal draft tube was found, which can increase the efficiency of this hydraulic turbine more than 1.5%. The efficiency of turbine with the optimal draft tube, draft tube with four pairs of middle-sized vortex generator, and draft tube without vortex generator under different heads of turbine (5–14 m) was calculated, and it was verified that these two kinds of draft tubes can increase the efficiency of this turbine in every situation.
Error analysis on assembly and alignment of laser optical unit
Authors: Xiong Zhao , Wang Hui , Cao Tingfen , Yuan Xiaodong , Yao Chao , Zhang Zheng , Zhou Minxing , Ma Guohui
Published: July 2015

As one of largest optical units used in high-power laser inertial confinement fusion facility, the large-aperture transport mirror’s misalignment error can have a very negative impact on the targeting performance of laser beams. In this article, we have carried out a fundamental analysis on the mounting and misalignment errors of transport mirror. An integrated simulated assembly station is proposed to align the mirror precisely, and the design of transport mirror unit is optimized to satisfy the stringent specifications. Finally, methods that integrated theoretical modeling, numerical simulation, and field experiments are used to evaluate the mirror’s alignment, and the results indicate a more robust and precise alignment performance of new design.
Utility of home blood pressure monitoring to evaluate postprandial blood pressure in treated hypertensive patients
Authors: Alfie José
Published: July 2015

Postprandial hypotension, defined as a fall in systolic blood pressure (SBP) of 20 mmHg or greater within 2  hours after a meal, is a risk factor for stroke, coronary events and mortality. The clinical suspicion is typically raised by episodes of postprandial syncope or falls, whereas asymptomatic postprandial hypotension is mostly neglected. The magnitude of the postprandial fall in SBP, as detected by 24-hour recording in apparently healthy middle-aged to elderly subjects, was proportional to the severity of the silent cerebrovascular damage. Postprandial hypotension can also be detected by self-measured blood pressure before and within 2 hours after meals using automatic devices. The review highlights the value of home blood pressure monitoring (HBPM) as a screening test for asymptomatic postprandial hypotension in hypertensive patients. Using a HBPM protocol that included duplicated blood pressure measurements before and after three consecutive lunches, we detected unsuspected postprandial hypotension in 27.4% of the 230 hypertensive patients screened. The prevalence of postprandial hypotension was 13.2% in controlled and 42.2% in uncontrolled hypertensive patients ( p < 0.001), raising the dilemma of further lowering blood pressure in the setting of postprandial hypotension. The inclusion of preprandial and postprandial measurements in the protocol of HBPM is useful to identify hypertensive patients with postprandial hypotension and may guide adjustments in antihypertensive treatment according to postprandial blood pressure.
Conceptualisation of patient satisfaction: a systematic narrative literature review
Authors: Batbaatar Enkhjargal , Dorjdagva Javkhlanbayar , Luvsannyam Ariunbat , Amenta Pietro
Published: July 2015

Aim:

Patient satisfaction concept is widely measured due to its appropriateness to health service; however, evidence suggests that it is a poorly developed concept. This article is a first part of a two-part series of research with a goal to review a current conceptual framework of patient satisfaction and to bring the concept for further operationalisation procedures. The current article aimed to review a theoretical framework that helps the next article to review determinants of patient satisfaction for designing a measurement system.

Method:

The study used a systematic review method, meta-narrative review, based on the RAMESES guideline with the phases of screening evidence, appraisal evidence, data extraction and synthesis. Patient satisfaction theoretical articles were searched on the two databases MEDLINE and CINAHL. Inclusion criteria were articles published between 1980 and 2014, and English language papers only. There were 36 articles selected for the synthesis.

Results:

Results showed that most of the patient satisfaction theories and formulations are based on marketing theories and defined as how well health service fulfils patient expectations. However, review demonstrated that a relationship between expectation and satisfaction is unclear and the concept expectation itself is not distinctly theorised as well.

Conclusions:

Researchers brought satisfaction theories from other fields to the current healthcare literature without much adaptation. Thus, there is a need to attempt to define the patient satisfaction concept from other perspectives or to learn how patients evaluate the care rather than struggling to describe it by consumerist theories.
Challenges in the management of nutritional disorders and communicable diseases in child day care centers: a quantitative and qualitative approach
Authors: Konstantyner Tulio , Konstantyner Thais Cláudia Roma de Oliveira , Toloni Maysa Helena Aguiar , Longo-Silva Giovana , Taddei José Augusto de Aguiar Carrazedo
Published: July 2015

In Brazil, although many children from low income families attend day care centers with appropriate hygiene practices and food programs, they have nutritional disorders and communicable diseases. This quantitative and qualitative cross-sectional study identified staff challenges in child day care centers and suggested alternative activity management to prevent nutritional disorders and communicable diseases. The study included 71 nursery teachers and 270 children from public and philanthropic day care centers (teacher to child ratios of 1:2.57 and 1:6.40, respectively). Interviews and focus groups were conducted with teachers and parents, and anthropometry and blood samples were drawn from the children by digital puncture. Children in philanthropic child day care centers were more likely to be hospitalized due to communicable diseases. Teachers from philanthropic child day care centers had lower age, income and education and higher work responsibilities based on the number of children and working time. The focus groups characterized institutions with organized routines, standard food practices, difficulties with caretaking, and lack of training to provide healthcare to children. Strategies to improve children’s health in day care settings should focus on training of teachers about healthcare and nutrition.
Diseño de un programa basado en la promoción del desarrollo positivo en la infancia para la prevención temprana de la violencia en Colombia
Authors: Hernández Holguín Dora M. , Páez Zapata Esteban , Múnera Restrepo Laura M. , Duque Ramírez Luis F.
Published: July 2015

Aunque algunos informes identifiquen a Colombia como ejemplo de un país que ha logrado revertir los niveles crecientes de violencia, estos siguen siendo altos. Por este motivo se han convocado acciones de promoción de la convivencia y prevención de la violencia, a las cuales responde el programa que presentamos en este artículo. Este programa está basado en la perspectiva contextual-evolutiva del modelo ecológico y en la educación para la salud, tendiente al cuidado de sí en los padres o cuidadores, y al ejercicio de una crianza, centrada en los derechos de los niños, el desarrollo infantil y la promoción de la salud mental, con el fin de promover el desarrollo saludable y prevenir comportamientos agresivos en los niños; éste es presentado como una alternativa de orientación psicosocial para el fortalecimiento de estrategias y programas dirigidos a la primera infancia.
Strategic initiatives to maintain pharmaceutical care and clinical pharmacists sufficiency in Saudi Arabia
Authors: Albekairy Abdulkareem M , Khalidi Nabil , Alkatheri Abdulmalik M , Althiab Khalifa , Alharbi Shmeylan , Aldekhael Saleh , Qandil Amjad M , Alknawy Bandar
Published: July 2015

Objectives:

The shortage of clinical pharmacists in Saudi Arabia has limited the full implementation of pharmaceutical care in most of its hospitals. The National Guard Health Affairs hospitals. This work discussed the Department of Pharmaceutical Care, and the King Saud Bin Abdulaziz University for Health Sciences College of Pharmacy four initiatives that were planned in 2009–2010 to develop and recruit clinical pharmacists, practitioners, or faculty.

Methods:

The combined initiatives were aimed at (1) instituting a 4-year clinical skills development career ladder, (2) expanding the National Guard Health Affairs postgraduate residency program, (3) offering scholarships to qualified pharmacy graduates to pursue the PharmD degree and a PGY-1 residency training in the United States, and (4) recruiting non-Saudi clinical pharmacists educated and trained in the United States to ameliorate the current shortage of practitioner.

Results:

The current number of clinical pharmacists practicing at the National Guard Health Affairs at central region is 24, most of whom are Board Certified by the American Pharmacists Association Board of Pharmacy Specialties.

Conclusions:

The four initiatives, based on current trends, suggest that 60–65 positions will be added by 2017–2018, barring attrition. Saudi Arabia and many developing countries will continue to experience a shortage in clinical pharmacists due to the high demand for clinical pharmacy services. A multifaceted approach is recommended to address the problem.
Safety, efficacy, and immunogenicity of Flublok in the prevention of seasonal influenza in adults
Authors: Cox Manon M. J. , Izikson Ruvim , Post Penny , Dunkle Lisa
Published: July 2015

Flublok is the first recombinant hemagglutinin (HA) vaccine licensed by the US Food and Drugs Administration for the prevention of influenza in adults aged 18 and older. The HA proteins produced in insect cell culture using the baculovirus expression system technology are exact analogues of wild type circulating influenza virus HAs. The universal HA manufacturing process that has been successfully scaled to the 21,000L contributes to rapid delivery of a substantial number of doses. This review discusses the immunogenicity, efficacy and safety data from five pivotal clinical studies used to support licensure of trivalent Flublok for adults 18 years of age and older in the United States. The trial data demonstrate that the higher antigen content in Flublok results in improved immunogenicity. Data further suggest improved efficacy and a slightly lower local reactogenicity compared with standard inactivated influenza vaccine, despite the presence of more antigen (statistically significant). Flublok influenza vaccine can include HAs designed to mimic ‘drift’ in influenza viruses as the process of predicting antigenic drift advances and, at a minimum, could address late appearing influenza viruses. The implementation of the latter will require support from regulatory authorities.
Theory-based strategies for enhancing the impact and usage of digital health behaviour change interventions: A review
Authors: Morrison Leanne G
Published: July 2015

There is growing evidence that digital interventions can successfully effect meaningful changes in health-related behaviour. However, optimisation of digital intervention delivery is challenged by low usage, high attrition and small effect sizes. Whilst a number of conceptual frameworks and models exist to guide intervention planning and development, insufficient attention has been paid to how existing psychological theory could inform the optimal implementation and delivery of the design features commonly used in digital health behaviour change interventions. This paper provides a critical review of psychological theories and models in order to consider their implications for the design of digital interventions. The theories reviewed include theories of: persuasion and attitude change; motivation; volition and self-regulation; patient preferences for participation in medical decision making; and social support. A set of theory-based guidelines is provided to inform the development of future interventions.
Development of an integrated staircase lift for home access
Authors: Mattie Johanne L , Borisoff Jaimie F , Leland Danny , Miller William C
Published: July 2015

Purpose

Stairways into buildings present a significant environmental barrier for those with mobility impairments. A number of home access solutions that allow users to safely enter and exit the home exist; however, these all have some limitations. The purpose of this work was to develop a novel, inclusive home access solution that integrates a staircase and a lift into one device.

Method

We developed an integrated staircase lift following a structured protocol with stakeholders providing feedback at various stages in the design process, consistent with rehabilitation engineering design methods.

Results

A novel home access device was developed. The integrated staircase-lift has the following features: inclusivity, by a design that provides an option for either use of stairs or a lift; constant availability, with a lift platform always ready for use on either level; and potential aesthetic advantages when integrating the device into an existing home. The potential also exists for emergency descent during a power outage, and self-powered versions.

Conclusions

By engaging stakeholders in a user-centred design process, we were able to gain insight into the limitations of existing home access solutions and get specific feedback on our lift concept. This information strengthened the development of a novel home access device.
Longer-Term Outcomes of Geriatric Odontoid Fracture Nonunion
Authors: Raudenbush Brandon , Molinari Robert
Published: July 2015

Introduction:

Longer-term outcomes of patients with geriatric type II odontoid fracture nonunion remain unclear.

Methods:

Thirty-four consecutive geriatric patients (>70 years old) with minimally displaced (<50% displacement) type II odontoid fractures were treated 24 hours a day for 12 weeks with rigid collar immobilization between the years 2003 and 2011. Radiographic and medical record reviews were performed on all 34 patients. Additionally, 7 patients were available for clinical longer-term follow-up (>4 years).

Results:

In all, 30 (88%) of the 34 patients had nonunion after 12 weeks of treatment, 2 (6%) patients had union, and 2 (6%) patients died during the first 12 weeks. Twenty-one of the 30 patients with nonunion had a displaced or mobile nonunion (70%), and 4 (12%) patients were lost to follow-up. At longer-term follow-up, 23 (68%) patients had died. The average time death occurred was 3.8 years with a range of 0.17 years to 9.42 years postinjury. Twenty of the 23 deaths were attributed to medical comorbidities not related to the patient’s odontoid nonunion. We were unable to determine the cause of death in 3 patients. None of the patients who died had identifiable clinical myelopathy prior to their death on chart review. Of the 7 patients who were alive, all were determined to have odontoid nonunion, of which 5 (70%) were mobile odontoid nonunion. Visual Analog Scale (VAS) and Neck Disability Index (NDI) scores were low (VAS averaged 0.57 and NDI averaged 6.9%) and treatment satisfaction was high (averaged 9.7 of 10). Scores for pain and function did not differ significantly when compared to age-matched controls ( P = .08, t test).

Conclusion:

Rates of odontoid nonunion are high in patients with geriatric odontoid fractures that are treated with continuous rigid collar for 12 weeks. The majority of patients with nonunion appear to achieve high functional outcomes. In this study, mortality did not appear to be related to adverse neurologic events after treatment.
Bougainvillea spectabilis Exhibits Antihyperglycemic and Antioxidant Activities in Experimental Diabetes
Authors: Chauhan Pratibha , Mahajan Sunil , Kulshrestha Archana , Shrivastava Sadhana , Sharma Bechan , Goswamy H. M. , Prasad G. B. K. S.
Published: July 2015

The study investigates the effects of aqueous extract of Bougainvillea spectabilis leaves on blood glucose, glycosylated hemoglobin, lipid profile, oxidative stress, and on DNA damage, if any, as well as on liver and kidney functions in streptozotocin-induced diabetes in Wistar rats. Daily administration of the aqueous extract of B spectabilis leaves for 28 days resulted in significant reduction in hyperglycemia and hyperlipidemia as evident from restoration of relevant biochemical markers following extract administration. The extract also exhibited significant antioxidant activity as evidenced from the enzymatic and nonenzymatic responses and DNA damage markers. The extract restored kidney and liver functions to normal and proved to be nontoxic. A marked improvement in the histological changes of tissues was also observed. The present study documented antihyperglycemic, antihyperlipidemic, and antioxidative potentials of the aqueous extract of B spectabilis leaves without any toxicity in streptozotocin-treated Wistar rats.
Is Homesickness a Mini-Grief? Development of a Dual Process Model
Authors: Stroebe Margaret , Schut Henk , Nauta Maaike H.
Published: July 2015

Homesickness (HS) is associated with mental and physical health problems and is thus of clinical concern. In some highly influential theoretical models and widely used questionnaires, HS spans home-related losses and new-locality adjustments. A differentiated approach is needed: Evidence suggests that distinct manifestations are associated with these two domains. Collapsing home- and new-place-related phenomena has impeded understanding of separation-from-home-specific aspects. Thus, we propose a dual process model of coping with HS (DPM-HS). According to this framework, HS is fundamentally a separation phenomenon, a “mini-grief,” involving different (though possibly mutually exacerbating) stressors from new place ones. It follows that HS should be narrowly defined; separate examination of home–new place stressors, correlates, and consequences is mandatory; regulatory cognitive-emotional processes and incremental effects due to new place stressors need charting. Following DPM-HS principles, HS prevention and treatment should not only focus on distraction and adjustment, but also pay attention to missing home aspects and emotion-regulation strategies.
Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition
Authors: Jacque Nathalie , Ronchetti Anne Marie , Larrue Clément , Meunier Godelieve , Birsen Rudy , Willems Lise , Saland Estelle , Decroocq Justine , Maciel Thiago Trovati , Lambert Mireille , Poulain Laury , Hospital Marie Anne , Sujobert Pierre , Joseph Laure , Chapuis Nicolas , Lacombe Catherine , Moura Ivan Cruz , Demo Susan , Sarry Jean Emmanuel , Recher Christian , Mayeux Patrick , Tamburini Jérôme , Bouscary Didier
Published: July 2015

Key Points

Genetic- or compound CB-839–induced GAC inhibition reduces OXPHOS and has antileukemic activity in AML. GAC inhibition synergizes with BCL-2 inhibition by compound ABT-199.
Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation
Authors: Cheng Hui , Hao Sha , Liu Yanfeng , Pang Yakun , Ma Shihui , Dong Fang , Xu Jing , Zheng Guoguang , Li Shaoguang , Yuan Weiping , Cheng Tao
Published: July 2015

Key Points

Increased quiescence of HSCs and HPCs in leukemogenesis, and reversible suppression of HSCs was observed in leukemic bone marrow. A novel inhibitory role of Egr3 in HSC proliferation was revealed by leukemic infiltration in bone marrow.
The biology of pediatric acute megakaryoblastic leukemia
Authors: Gruber Tanja A. , Downing James R.
Published: July 2015

Acute megakaryoblastic leukemia (AMKL) comprises between 4% and 15% of newly diagnosed pediatric acute myeloid leukemia patients. AMKL in children with Down syndrome (DS) is characterized by a founding GATA1 mutation that cooperates with trisomy 21, followed by the acquisition of additional somatic mutations. In contrast, non–DS-AMKL is characterized by chimeric oncogenes consisting of genes known to play a role in normal hematopoiesis. CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in this subset of patients and confers a poor prognosis.
The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator
Authors: Richard Arianne C , Ferdinand John R , Meylan Francoise , Hayes Erika T , Gabay Odile , Siegel Richard M
Published: July 2015

Originally described in 2002 as a T cell-costimulatory cytokine, the tumor necrosis factor family member TNF-like factor 1A (TL1A), encoded by the TNFSF15 gene, has since been found to affect multiple cell lineages through its receptor, death receptor 3 (DR3, encoded by TNFRSF25) with distinct cell-type effects. Genetic deficiency or blockade of TL1A-DR3 has defined a number of disease states that depend on this cytokine-receptor pair, whereas excess TL1A leads to allergic gastrointestinal inflammation through stimulation of group 2 innate lymphoid cells. Noncoding variants in the TL1A locus are associated with susceptibility to inflammatory bowel disease and leprosy, predicting that the level of TL1A expression may influence host defense and the development of autoimmune and inflammatory diseases.
Spatiotemporal dynamics of effector CD8+ T cell responses within the liver
Authors: Inverso Donato , Iannacone Matteo
Published: July 2015

CD8+ T cells play a critical role in controlling hepatotropic viral infections, such as those caused by hepatitis B and hepatitis C viruses. The capacity of these cells to protect against such pathogens is mediated by antigen-experienced effector cells and relies on their ability to home to the liver, recognize pathogen-derived antigens, and deploy effector functions. Here, we review how dynamic imaging of hepatic effector CD8+ T cell migration and function in mouse models of hepatitis B virus pathogenesis has recently revealed a unique and novel mode of adaptive immune surveillance. Circulating effector CD8+ T cells initially arrest within liver sinusoids by docking onto adherent platelets and then actively crawl along the liver vasculature, probing hepatocytes for the presence of antigens by extending protrusions through the fenestrated sinusoidal endothelial cells. Hepatocellular antigen recognition and effector functions occur while CD8+ T cells are still confined to the intravascular space and are inhibited by the pathologic processes that characterize liver fibrosis. A detailed understanding of the spatiotemporal dynamics of effector CD8+ T cells within the liver is important for the rational design of targeted immunotherapeutic approaches for chronic liver infections.
Paradoxical changes in innate immunity in aging: recent progress and new directions
Authors: Montgomery Ruth R , Shaw Albert C
Published: July 2015

Immunosenescence, describing alterations, including decline of immune responses with age, is comprised of inappropriate elevations, decreases, and dysregulated immune responses, leading to more severe consequences of bacterial and viral infections and reduced responses to vaccination. In adaptive immunity, these changes include increased proportions of antigen-experienced B and T cells at the cost of naïve cell populations. Innate immune changes in aging are complex in spanning multiple cell types, activation states, and tissue context. Innate immune responses are dampened in aging, yet there is also a paradoxical increase in certain signaling pathways and cytokine levels. Here, we review recent progress and highlight novel directions for expected advances that can lead the aging field to a new era of discovery that will embrace the complexity of aging in human populations.
Transcriptome of pancreas-specificBmpr1a-deleted islets links to TPH1–5-HT axis
Authors: Jiang Fang-Xu , Mishina Yuji , Baten Akma , Morahan Grant , Harrison Leonard C.
Published: July 2015

Bone morphogenetic protein (BMP) signaling is crucial for the development and function of numerous organs, but its role on the function of pancreatic islets is not completely clear. To explore this question, we applied the high throughput transcriptomic analyses on the islets isolated from mice with a pancreas-specific deletion of the gene, Bmpr1a, encoding the type 1a BMP receptor. Consistently, these pBmpr1aKO mice had impaired glucose homeostasis at 3 months, and were more severely affected at 12 months of age. These had lower fasting blood insulin concentrations, with reduced expression of several key regulators of β-cell function. Importantly, transcriptomic profiling of 3-month pBmpr1aKO islets and bioinformatic analyses revealed abnormal expression of 203 metabolic genes. Critically among these, the tryptophan hydroxylase 1 gene (Tph1), encoding the rate-limiting enzyme for the production of 5-hydroxytryptamine (5-HT) was the highest over-expressed one. 5-HT is an important regulator of insulin secretion from β cells. Treatment with excess 5-HT inhibited this secretion. Thus our transcriptomic analysis links two highly conserved molecular pathways the BMP signaling and the TPH1–5-HT axis on glucose homeostasis.
Evolutionarily conserved sites in yeast tropomyosin function in cell polarity, transport and contractile ring formation
Authors: Cranz-Mileva Susanne , MacTaggart Brittany , Russell Jacquelyn , Hitchcock-DeGregori Sarah E.
Published: July 2015

Tropomyosin is a coiled-coil protein that binds and regulates actin filaments. The tropomyosin gene in Schizosaccharomyces pombe, cdc8, is required for formation of actin cables, contractile rings, and polar localization of actin patches. The roles of conserved residues were investigated in gene replacement mutants. The work validates an evolution-based approach to identify tropomyosin functions in living cells and sites of potential interactions with other proteins. A cdc8 mutant with near-normal actin affinity affects patch polarization and vacuole fusion, possibly by affecting Myo52p, a class V myosin, function. The presence of labile residual cell attachments suggests a delay in completion of cell division and redistribution of cell patches following cytokinesis. Another mutant with a mild phenotype is synthetic negative with GFP-fimbrin, inferring involvement of the mutated tropomyosin sites in interaction between the two proteins. Proteins that assemble in the contractile ring region before actin do so in a mutant cdc8 strain that cannot assemble condensed actin rings, yet some cells can divide. Of general significance, LifeAct-GFP negatively affects the actin cytoskeleton, indicating caution in its use as a biomarker for actin filaments.
Cooperation of the BTB-Zinc finger protein, Abrupt, with cytoskeletal regulators inDrosophilaepithelial tumorigenesis
Authors: Turkel Nezaket , Portela Marta , Poon Carole , Li Jason , Brumby Anthony M. , Richardson Helena E.
Published: July 2015

The deregulation of cell polarity or cytoskeletal regulators is a common occurrence in human epithelial cancers. Moreover, there is accumulating evidence in human epithelial cancer that BTB-ZF genes, such as Bcl6 and ZBTB7A, are oncogenic. From our previous studies in the vinegar fly, Drosophila melanogaster, we have identified a cooperative interaction between a mutation in the apico-basal cell polarity regulator Scribble (Scrib) and overexpression of the BTB-ZF protein Abrupt (Ab). Herein, we show that co-expression of ab with actin cytoskeletal regulators, RhoGEF2 or Src64B, in the developing eye-antennal epithelial tissue results in the formation of overgrown amorphous tumours, whereas ab and DRac1 co-expression leads to non-cell autonomous overgrowth. Together with ab, these genes affect the expression of differentiation genes, resulting in tumours locked in a progenitor cell fate. Finally, we show that the expression of two mammalian genes related to ab, Bcl6 and ZBTB7A, which are oncogenes in mammalian epithelial cancers, significantly correlate with the upregulation of cytoskeletal genes or downregulation of apico-basal cell polarity neoplastic tumour suppressor genes in colorectal, lung and other human epithelial cancers. Altogether, this analysis has revealed that upregulation of cytoskeletal regulators cooperate with Abrupt in Drosophila epithelial tumorigenesis, and that high expression of human BTB-ZF genes, Bcl6 and ZBTB7A, shows significant correlations with cytoskeletal and cell polarity gene expression in specific epithelial tumour types. This highlights the need for further investigation of the cooperation between these genes in mammalian systems.
Critical role of TRPC6 in maintaining the stability of HIF-1α in glioma cells under hypoxia
Authors: Li Shanshan , Wang Jinkui , Wei Yi , Liu Yongjian , Ding Xia , Dong Bin , Xu Yinghui , Wang Yizheng
Published: July 2015

Hypoxia-inducible factor-1 (HIF-1) is a key transcriptional factor responsible for the expression of a broad range of genes that facilitate acclimatization to hypoxia. Its stability is predominantly controlled by rapid hydroxylation of two prolines on its α subunit. However, how the rapid hydroxylation of HIF-1α is regulated is not fully understood. Here, we report that transient receptor potential canonical (TRPC) 6 channels control hydroxylation and stability of HIF-1α in human glioma cells under hypoxia. TRPC6 was rapidly activated by IGF-1R-PLCγ-IP3R pathway in hypoxia. Inhibition of TRPC6 enhanced the levels of α-ketoglutarate (α-KG) and promoted hydroxylation of HIF-1α to suppress HIF-1α accumulation without affecting its transcription or translation. Dimethyloxalylglycine N-(methoxyoxoacetyl)-glycine methyl ester (DMOG), an analog of α-KG, reversed the inhibition of HIF-1α accumulation. Moreover, TRPC6 regulated GLUT1 expression depending on HIF-1α accumulation to affect glucose uptake in hypoxia. Our results suggest that TRPC6 regulates metabolism to affect HIF-1α stability and consequent glucose metabolism in human glioma cells under hypoxia.
Promotion of periostin expression contributes to the migration of Schwann cells
Authors: Sonnenberg-Riethmacher Eva , Miehe Michaela , Riethmacher Dieter
Published: July 2015

Neuregulin ligands and their erbB receptors are important for the development of Schwann cells (SCs), the glial cells of the peripheral nervous system (PNS). ErbB3 deficiency is characterized by a complete loss of SCs along axons of the peripheral nerves, impaired fasciculation and neuronal cell death. We performed comparative gene expression analysis of dorsal root ganglia (DRG) explant cultures from erbB3 deficient and wild type mice to identify genes that are involved in SC development and migration. The extracellular matrix (ECM) gene periostin was found to exhibit the most prominent down regulation in erbB3 deficient DRG. Expression analysis revealed that the periostin expressing cell population in the PNS corresponds to SC precursors and SCs and is particularly high in migratory SCs. Furthermore; stimulation of SCs with neuregulin‑1 (NRG1) or transforming growth factor β (TGFβ) resulted in an upregulation of periostin expression. Interestingly, DRG explant cultures of periostin deficient mice revealed a significant reduction of the number of migrating SCs. These data demonstrate that the expression of periostin is stimulated by erbB ligand NRG1 and influences the migration of SC precursors.
Expression of CRISPR/Cas single guide RNAs using small tRNA promoters
Authors: Mefferd Adam L. , Kornepati Anand V.R. , Bogerd Hal P. , Kennedy Edward M. , Cullen Bryan R.
Published: July 2015

The in vivo application of CRISPR/Cas-based DNA editing technology will require the development of efficient delivery methods that likely will be dependent on adeno-associated virus (AAV)-based viral vectors. However, AAV vectors have only a modest, ∼4.7-kb packaging capacity, which will necessitate the identification and characterization of highly active Cas9 proteins that are substantially smaller than the prototypic Streptococcus pyogenes Cas9 protein, which covers ∼4.2 kb of coding sequence, as well as the development of single guide RNA (sgRNA) expression cassettes substantially smaller than the current ∼360 bp size. Here, we report that small, ∼70-bp tRNA promoters can be used to express high levels of tRNA:sgRNA fusion transcripts that are efficiently and precisely cleaved by endogenous tRNase Z to release fully functional sgRNAs. Importantly, cells stably expressing functional tRNA:sgRNA precursors did not show a detectable change in the level of endogenous tRNA expression. This novel sgRNA expression strategy should greatly facilitate the construction of effective AAV-based Cas9/sgRNA vectors for future in vivo use.
Characterization of the role of HCN channels in β3-adrenoceptor mediated rat bladder relaxation
Authors: Kashyap Mahendra , Yoshimura Naoki , P. Smith Phillip , Chancellor Michael , Tyagi Pradeep
Published: July 2015

Objective: The second messenger cAMP is involved in both β3 adrenoceptor (β3-AR) mediated detrusor relaxation and the kinetics of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Here we characterized the effect HCN channel activation and possible interaction with β3-AR in bladder.
Methods: Bladder tissues from Sprague-Dawley rats and Human organ donors obtained for studying species-specific expression of HCN channels by real-time QPCR and Western Blot. Effect of β3-agonist on rat bladder Strips (0.5 x 0.5 x 7 mm in size) was studied during activation and blockade of HCN channels by Lamotrigine and ZD7288, respectively.
Results: Expression of all four genes encoding for HCN channels (HCN1-4) was detected separately in bladder mucosa and detrusor from human and rat bladders. Species based differences shown by relatively higher expression of HCN4 isoform in human bladder and that of HCN1 in rat bladder. Western blot confirmed the findings at mRNA level. Cumulative application β3-AR agonist CL316,243 produced a concentration dependent decrease in resting tension of rat bladder strips expressed as integral of mechanical activity. Pre-incubation of HCN channel blocker ZD 7288 opposed the relaxant effect of CL316,243, whereas co-administration of lamotrigine with CL316,243 at equal molar concentrations caused an additive decrease in resting tension. Cumulative addition of ZD7288 and lamotrigine in absence of CL316,243 showed opposing effects on detrusor contractility
Conclusions: Species-specific differences noted in expression of HCN channels in bladder. Opposing effects ZD7288 and Lamotrigine in the action of β3-AR agonist demonstrate possible functional interaction of HCN channels and β3-AR in detrusor contractility.
Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients
Authors: Rostomyan Liliya , Daly Adrian F , Petrossians Patrick , Nachev Emil , Lila Anurag R , Lecoq Anne-Lise , Lecumberri Beatriz , Trivellin Giampaolo , Salvatori Roberto , Moraitis Andreas G , Holdaway Ian , Kranenburg - van Klaveren Dianne J , Chiara Zatelli Maria , Palacios Nuria , Nozieres Cecile , Zacharin Margaret , Ebeling Tapani , Ojaniemi Marja , Rozhinskaya Liudmila , Verrua Elisa , Jaffrain-Rea Marie-Lise , Filipponi Silvia , Gusakova Daria , Pronin Vyacheslav , Bertherat Jerome , Belaya Zhanna , Ilovayskaya Irena , Sahnoun-Fathallah Mona , Sievers Caroline , Stalla Gunter K , Castermans Emilie , Caberg Jean-Hubert , Sorkina Ekaterina , Auriemma Renata Simona , Mittal Sachin , Kareva Maria , Lysy Philippe A , Emy Philippe , De Menis Ernesto , Choong Catherine S , Mantovani Giovanna , Bours Vincent , De Herder Wouter , Brue Thierry , Barlier Anne , Neggers Sebastian J C M M , Zacharieva Sabina , Chanson Philippe , Shah Nalini Samir , Stratakis Constantine A , Naves Luciana A , Beckers Albert
Published: July 2015

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2s.d.above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23,P=0.02).AIPmutations occurred in 29%; microduplication at Xq26.3 – X-linked acrogigantism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG,AIPmutated and genetically negative patient groups.AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden.AIPmutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer
Authors: Eggemann Holm , Ignatov Tanja , Burger Elke , Kantelhardt Eva Johanna , Fettke Franziska , Thomssen Christoph , Costa Serban Dan , Ignatov Atanas
Published: July 2015

Overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis in breast cancer and predicts response to anti-HER2 therapy in breast cancer. The prognostic relevance of moderate expression of HER2 is unclear. Data of 9872 patients with primary nonmetastatic breast cancer from the cancer registries of Magdeburg and Halle, Germany, were analyzed retrospectively. A total of 5907 patients with complete data sets including follow-up were eligible for analysis. HER2 status was determined as recommended by international guidelines. Of 5907 patients investigated, 5023 (68.4%) had HER2 0 and 1+ expression and 884 (12.0%) had HER2 (2+)/HER2−expression. Patients with hormone receptor positive (HR+) and HER2 (2+) tumors had a shorter median disease-free survival (DFS;P<0.0001) and breast cancer specific survival (BCSS;P=0.019) than HR+ patients with HER2 (0/1+) tumors. Among patients with HR− breast cancer there was no significant difference between HER2 (2+) and HER2 (0/1+) tumors. In multivariate analysis after adjustment for other prognostic factors, HER2 (2+) status remained an unfavorable prognostic factor for DFS (hazard ratio (HR)=1.217, 95% CI=1.052–1.408;P=0.008) but not for BCSS (HR=1.045, 95% CI=0.926–1.178;P=0.474). The HER2 (2+) status is an unfavorable prognostic factor for survival of patients with HR+ breast cancer. The impact of anti-HER2 therapy in this group of patients should be evaluated.
Cardiometabolic and reproductive benefits of early dietary energy restriction and voluntary exercise in an obese PCOS-prone rodent model
Authors: Diane Abdoulaye , Kupreeva Maria , Borthwick Faye , Proctor Spencer D , Pierce W David , Vine Donna F
Published: July 2015

Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age characterized by ovulatory dysfunction, hyperandrogenism and cardiometabolic risk. The overweight-obese PCOS phenotype appears to have exacerbated reproductive dysfunction and cardiometabolic risk. In overweight-obese adult women with PCOS, exercise and energy restricted diets have shown limited and inconsistent effects on both cardiometabolic indices and reproductive outcomes. We hypothesized that an early lifestyle intervention involving exercise and dietary energy restriction to prevent or reduce the propensity for adiposity would modulate reproductive indices and cardiometabolic risk in an obese PCOS-prone rodent model. Weanling obese PCOS-prone and Lean-Control JCR:LA-cp rodents were given a chow dietad libitumor an energy-restricted diet combined with or without voluntary exercise (4 h/day) for 8 weeks. Dietary energy restriction and exercise lowered total body weight gain and body fat mass by 30% compared to free-fed sedentary or exercising obese PCOS-prone animals (P<0.01). Energy restriction induced an increase in exercise intensity compared to free-feeding plus exercise conditions. Energy restriction and exercise decreased fasting plasma triglycerides and apoB48 concentrations in obese PCOS-prone animals compared to free-fed and exercise or sedentary groups. The energy restriction and exercise combination in obese PCOS-prone animals significantly increased plasma sex-hormone binding globulin, hypothalamic cocaine-and amphetamine-regulated transcript (CART) and Kisspeptin mRNA expression to levels of the Lean-Control group, and this was further associated with improvements in estrous cyclicity. The combination of exercise and dietary energy restriction when initiated in early life exerts beneficial effects on cardiometabolic and reproductive indices in an obese PCOS-prone rodent model, and this may be associated with normalization of the hypothalamic neuropeptides, Kisspeptin and CART.