bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence
Authors: Nguyen Minh Thu , Götz Friedrich
Published: August 2016

Since the discovery in 1973 of the first of the bacterial lipoproteins (Lpp) in
Escherichia coli
, Braun's lipoprotein, the ever-increasing number of publications indicates the importance of these proteins. Bacterial Lpp belong to the class of lipid-anchored proteins that in Gram-negative bacteria are anchored in both the cytoplasmic and outer membranes and in Gram-positive bacteria are anchored only in the cytoplasmic membrane. In contrast to the case for Gram-negative bacteria, in Gram-positive bacteria lipoprotein maturation and processing are not vital. Physiologically, Lpp play an important role in nutrient and ion acquisition, allowing particularly pathogenic species to better survive in the host. Bacterial Lpp are recognized by Toll-like receptor 2 (TLR2) of the innate immune system. The important role of Lpp in Gram-positive bacteria, particularly in the phylum
Firmicutes
, as key players in the immune response and pathogenicity has emerged only in recent years. In this review, we address the role of Lpp in signaling and modulating the immune response, in inflammation, and in pathogenicity. We also address the potential of Lpp as promising vaccine candidates.
Enterovirus infection of human islets of Langerhans affects β-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure
Authors: Hodik M , Skog O , Lukinius A , Isaza-Correa J M , Kuipers J , Giepmans B N G , Frisk G
Published: August 2016

Aims/hypothesis

In type 1 diabetes (T1D), most insulin-producing β cells are destroyed, but the trigger is unknown. One of the possible triggers is a virus infection and the aim of this study was to test if enterovirus infection affects glucose stimulated insulin secretion and the effect of virus replication on cellular macromolecules and organelles involved in insulin secretion.

Methods

Isolated human islets were infected with different strains of coxsackievirus B (CVB) virus and the glucose-stimulated insulin release (GSIS) was measured in a dynamic perifusion system. Classical morphological electron microscopy, large-scale electron microscopy, so-called nanotomy, and immunohistochemistry were used to study to what extent virus-infected β cells contained insulin, and real-time PCR was used to analyze virus induced changes of islet specific genes.

Results

In islets infected with CVB, GSIS was reduced in correlation with the degree of virus-induced islet disintegration. The expression of the gene encoding insulin was decreased in infected islets, whereas the expression of glucagon was not affected. Also, in islets that were somewhat disintegrated, there were uninfected β cells. Ultrastructural analysis revealed that virus particles and virus replication complexes were only present in β cells. There was a significant number of insulin granules remaining in the virus-infected β cells, despite decreased expression of insulin mRNA. In addition, no typical Golgi apparatus was detected in these cells. Exposure of islets to synthetic dsRNA potentiated glucose-stimulated insulin secretion.

Conclusions/interpretation

Glucose-stimulated insulin secretion; organelles involved in insulin secretion and gene expression were all affected by CVB replication in β cells.
Ocular screening adherence across Hispanic/Latino heritage groups with diabetes: results from the Ocular SOL ancillary to the Miami site of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Tannenbaum Stacey L , McClure Laura A , Zheng D Diane , Lam Byron L , Arheart Kristopher L , Joslin Charlotte E , Talavera Gregory A , Lee David J
Published: August 2016

Objective

The objective of this study was to examine the prevalence and correlates of ocular screening adherence among select Hispanics/Latinos living with diabetes.

Research design and methods

Data were obtained through an ancillary study of the Hispanic Community Health Study/Study of Latinos (Miami site). Participants included Hispanics/Latinos aged 40+ years who underwent a baseline examination/risk factor assessment (2008–2011) and then completed a survey on vision health/knowledge (conducted October 2011–September 2013; sample n=1235; diabetic subsample=264). The dependent variable was having a dilated eye examination within the past 12 months. Covariate candidate selection for entry into sequential multivariable logistic regression models was guided by Anderson's Behavioral Model of Health Services Use and the Behavioral Model for Vulnerable Populations.

Results

Participants aged 65+ were more likely to have dilated eye examinations (OR 2.62, 95% CI 1.22 to 5.60) compared with those aged 40–54 years. Participants less likely to have dilated examinations had a high school degree or general educational development (GED) (OR 0.30, 95% CI 0.10 to 0.96, compared to no degree) and those currently uninsured or never insured ((OR 0.34, 95% CI 0.14 to 0.83) and (OR 0.19, 95% CI 0.07 to 0.51)) compared to those currently insured. Participants who heard or saw something about eye health from two or more sources (eg, media outlets, doctor's office, relatives/friends) compared to those who reported no sources in the past 12 months were more likely to have a dilated eye examination (OR 2.82, 95% CI 1.26 to 6.28).

Conclusions

Lack of health insurance is strongly associated with low screening uptake in Hispanics/Latinos living with diabetes. Health promotion strategies stressing the importance of annual dilated eye examinations and increasing sources of information on eye health are other potential strategies to increase screening uptake in Hispanics/Latinos.
The QuickWee trial: protocol for a randomised controlled trial of gentle suprapubic cutaneous stimulation to hasten non-invasive urine collection from infants
Authors: Kaufman Jonathan , Fitzpatrick Patrick , Tosif Shidan , Hopper Sandy M , Bryant Penelope A , Donath Susan M , Babl Franz E
Published: August 2016

Introduction

Urinary tract infections (UTIs) are common in young children. Urine sample collection is required to diagnose or exclude UTI; however, current collection methods for pre-continent children all have limitations and guidelines vary. Clean catch urine (CCU) collection is a common and favoured non-invasive collection method, despite its high contamination rates and time-consuming nature. This study aims to establish whether gentle suprapubic cutaneous stimulation with cold fluid-soaked gauze can improve the rate of voiding for CCU within 5 min in young pre-continent children.

Methods and analysis

This study is a randomised controlled trial of 354 infants (aged 1–12 months) who require urine sample collection, conducted in a single emergency department in a tertiary paediatric hospital in Melbourne, Australia. After standard urogenital cleaning, patients will be randomised to either a novel technique of suprapubic cutaneous stimulation using cold saline-soaked gauze in circular motions or no stimulation. The study period is 5 min, after which care is determined by the treating clinician if a urine sample has not been collected. Primary outcome: whether the child voids within 5 min (yes/no). Secondary outcomes: parental and clinician satisfaction with the method, success in catching a urine sample if the child voids, and sample contamination rates. This trial will allow the definitive assessment of this novel technique, gentle suprapubic cutaneous stimulation with cold saline-soaked gauze, and its utility to hasten non-invasive urine collection in infants.

Ethics and dissemination

The study has hospital ethics approval and is registered with the Australian New Zealand Clinical Trials Registry—ACTRN12615000754549. The results of the study will be published in a peer-reviewed journal.

Trial registration number

ACTRN12615000754549; Pre-results.
Reporting of financial and non-financial conflicts of interest by authors of systematic reviews: a methodological survey
Authors: Hakoum Maram B , Anouti Sirine , Al-Gibbawi Mounir , Abou-Jaoude Elias A , Hasbani Divina Justina , Lopes Luciane Cruz , Agarwal Arnav , Guyatt Gordon , Akl Elie A
Published: August 2016

Background

Conflicts of interest may bias the findings of systematic reviews. The objective of this methodological survey was to assess the frequency and different types of conflicts of interest that authors of Cochrane and non-Cochrane systematic reviews report.

Methods

We searched for systematic reviews using the Cochrane Database of Systematic Reviews and Ovid MEDLINE (limited to the 119 Core Clinical Journals and the year 2015). We defined a conflict of interest disclosure as the reporting of whether a conflict of interest exists or not, and used a framework to classify conflicts of interest into individual (financial, professional and intellectual) and institutional (financial and advocatory) conflicts of interest. We conducted descriptive and regression analyses.

Results

Of the 200 systematic reviews, 194 (97%) reported authors' conflicts of interest disclosures, typically in the main document, and in a few cases either online (2%) or on request (5%). Of the 194 Cochrane and non-Cochrane reviews, 49% and 33%, respectively, had at least one author reporting any type of conflict of interest (p=0.023). Institutional conflicts of interest were less frequently reported than individual conflicts of interest, and Cochrane reviews were more likely to report individual intellectual conflicts of interest compared with non-Cochrane reviews (19% and 5%, respectively, p=0.004). Regression analyses showed a positive association between reporting of conflicts of interest (at least one type of conflict of interest, individual financial conflict of interest, institutional financial conflict of interest) and journal impact factor and between reporting individual financial conflicts of interest and pharmacological versus non-pharmacological intervention.

Conclusions

Although close to half of the published systematic reviews report that authors (typically many) have conflicts of interest, more than half report that they do not. Authors reported individual conflicts of interest more frequently than institutional and non-financial conflicts of interest.
Evaluating the experiences and support needs of people living with chronic cancer: development and initial validation of the Chronic Cancer Experiences Questionnaire (CCEQ)
Authors: Harley Clare , Pini Simon , Kenyon Lucille , Daffu-O'Reilly Amrit , Velikova Galina
Published: August 2016

Background

Many advanced cancers are managed as chronic diseases, yet there are currently no international guidelines for the support of patients living with chronic cancer. It is important to understand whether care and service arrangements meet the needs of this rapidly growing patient group. This study aimed to develop and validate a questionnaire to capture patients' experiences of living with chronic cancer and their views of clinical and support services.

Methods

The research was carried out between 1 July 2010 and 21 February 2013. A conceptual framework and initial item bank were derived from prior interviews with 56 patients with chronic cancer. Items were reviewed by 4 oncologists and 1 clinical nurse specialist and during 2 focus groups with 9 patients. Pilot questionnaires were completed by 416 patients across 5 cancer units. Item selection and scale reliability was explored using descriptive data, exploratory factor analysis, internal consistency analyses, multitrait scaling analyses and known-groups comparisons.

Results

The final Chronic Cancer Experiences Questionnaire (CCEQ) includes 75 items. 62 items contribute to 14 subscales with internal consistency between α 0·68–0·88 and minimal scaling errors. Known-groups comparisons confirmed subscale utility in distinguishing between patient groups. Subscales were labelled: managing appointments, coordination of care, general practitioner involvement, clinical trials, information and questions, making treatment decisions, symptom non-reporting, key worker, limitations, sustaining normality, financial advice, worries and anxieties, sharing feelings with others, and accessing support. 13 items assessing symptom experiences were retained as single items.

Conclusions

The CCEQ has the potential to be used as a clinical instrument to assess patient experiences of chronic cancer or to screen for patient needs. It may also be used as an outcome measure for evaluating programmes and models of care and may identify areas for service development that could ultimately improve the care and support received by patients with chronic cancer.
In vitro comparison of intracranial stent visibility using various concentrations of gadolinium contrast agent under 1.5 T and 3 T MR angiography
Authors: Chiang Chen-Hua , Tseng Ying-Chi , Chen Ai-Chi , Huang Yen-Lin , Chen David Yen-Ting , Chen Chi-Jen , Lin Yen-Kuang , Hsu Hui-Ling
Published: August 2016

Background and purpose

MR angiography (MRA) is an increasingly used evaluation method following intracranial stenting. However, the various artifacts created by the stent limit this technique. The purpose of this study was to investigate the effects of various concentrations of gadolinium contrast agent on the visibility and signal characteristics of two stents using the a contrast enhanced MRA technique.

Material and method

Two intracranial stents (Enterprise and Helistent) were placed in polyvinyl chloride tubes as vascular phantoms. They were filled with six different doses of gadolinium contrast agent (1.0, 2.0, 4.0, 6.0, 8.0, and 10.0 mmol/L dimeglumine gadopentetate, respectively) and imaged using 3 T and 1.5 T MR systems. Relative in-stent signal (RIS) was calculated and artificial luminal narrowing (ALN) was obtained using pixel by pixel analysis.

Result

The Enterprise stent, performed in both 1.5 T and 3 T MR systems, showed mean RIS values much less than those for the Helistent for all different doses of gadolinium solution. Increased gadolinium concentration resulted in a gradual reduction in RIS values in the Enterprise group. Also, ALN in the Enterprise group showed no or little change with various gadolinium doses.

Conclusions

The Enterprise stent demonstrated good luminal visibility regardless of gadolinium concentration. The relative in-stent signals were more predictable in the Enterprise stent with various doses of gadolinium. Therefore, the Enterprise stent has been shown to provide better in-stent visibility compared with the Helistent using various gadolinium doses.
Oxytocin versus carbetocin administered to cows after uncomplicated calvings and subsequent fertility
Authors: Robinson Natalie , Brennan Marnie
Published: August 2016

BestBETs for Vets are generated by the Centre for Evidence‐based Veterinary Medicine at the University of Nottingham to help answer specific questions and assist in clinical decision making. Although evidence is often limited, they aim to find, present and draw conclusions from the best available evidence, using a standardised framework. A more detailed description of how BestBETs for Vets are produced was published in VR, April 4, 2015, vol 176, pp 354‐356.
Phylogenetics of extant and fossil Pinaceae: methods for increasing topological stability
Authors: Gernandt David S. , Holman Garth , Campbell Christopher , Parks Matthew , Mathews Sarah , Raubeson Linda A. , Liston Aaron , Stockey Ruth A. , Rothwell Gar W.
Published: August 2016

Relationships of living and fossil Pinaceae were inferred using parsimony and Bayesian inference of morphological characters and plastid and nuclear DNA sequences. When considering extant taxa only, adding molecular to morphological characters resulted in markedly increased resolution and branch support compared with analysis of morphology alone. Including 45 fossil taxa resulted in drastically decreased resolution in morphology-based consensus trees. We evaluated the effect on branch support and resolution of including DNA sequences, deleting fossils lacking information for cone scale apices and seeds, using reduced consensus methods, and using implied weighting, and found that the greatest improvements were found by including DNA sequences and using implied weighting. The tree topologies from parsimony and Bayesian inference confirm previous findings that the fossil genus Pseudoaraucaria and a few species of Pityostrobus from the Lower Cretaceous are related to abietoid genera, and that other species of Pityostrobus are pinoid and closely related to Pinus. Focusing phylogenetic analyses on the most complete fossil cones, specifically those that are anatomically preserved and include both cone scale apices and seeds, and taking into account homoplasy, resulted in the clearest hypotheses for the timing and sequence of diversification in the family.
Integrating taxonomic and trait analyses to assess the impact of damming on fish communities in a northern cold region river
Authors: Lima Ana Carolina , Sayanda Diogo , Soares Amadeu M.V.M. , Wrona Frederick J. , Monaghan Kieran A.
Published: August 2016

Dams are considered one of the most important threats to freshwater ecosystems. To date, assessments of the impact of riverine impoundments are based primarily on taxonomic approaches where little can be inferred about functional ecological change. We assessed the impact of damming in a cold region river fish community in Alberta, Canada, by integrating taxonomic and trait-based approaches over time (before, during the first 5 years, and after 5 years of dam construction), considering the longitudinal habitat and environmental change created by reservoir formation (downstream, reservoir, and upstream). Integrating both approaches was found to be informative, as alterations to taxonomic composition in fish communities provided initial clues to a functional response in a spatiotemporal context. Biomonitoring should therefore explicitly consider longitudinal spatial gradients in the design, implementation, and evaluation of management actions. Understanding the underlying environmental causes of why the combination of some traits are connected to the risk of species loss or a decline in their distribution is an important step towards the development of better conservation and mitigation strategies.
Code Comment Quality Analysis and Improvement Recommendation: An Automated Approach
Authors: Sun Xiaobing , Geng Qiang , Lo David , Duan Yucong , Liu Xiangyue , Li Bin
Published: August 2016

Program comprehension is one of the first and most frequently performed activities during software maintenance and evolution. In a program, there are not only source code, but also comments. Comments in a program is one of the main sources of information for program comprehension. If a program has good comments, it will be easier for developers to understand it. Unfortunately, for many software systems, due to developers’ poor coding style or hectic work schedule, it is often the case that a number of methods and classes are not written with good comments. This can make it difficult for developers to understand the methods and classes, when they are performing future software maintenance tasks. To deal with this problem, in this paper we propose an approach which assesses the quality of a code comment and generates suggestions to improve comment quality. A user study is conducted to assess the effectiveness of our approach and the results show that our comment quality assessments are similar to the assessments made by our user study participants, the suggestions provided by our approach are useful to improve comment quality, and our approach can improve the accuracy of the previous comment quality analysis approaches.
Directing the Development of Constraint Languages by Checking Constraints on RDF Data
Authors: Hartmann Thomas , Zapilko Benjamin , Wackerow Joachim , Eckert Kai
Published: August 2016

For research institutes, data libraries, and data archives, validating RDF data according to predefined constraints is a much sought-after feature, particularly as this is taken for granted in the XML world. Based on our work in two international working groups on RDF validation and jointly identified requirements to formulate constraints and validate RDF data, we have published 81 types of constraints that are required by various stakeholders for data applications.

In this paper, we evaluate the usability of identified constraint types for assessing RDF data quality by (1) collecting and classifying 115 constraints on vocabularies commonly used in the social, behavioral, and economic sciences, either from the vocabularies themselves or from domain experts, and (2) validating 15,694 data sets (4.26 billion triples) of research data against these constraints. We classify each constraint according to (1) the severity of occurring violations and (2) based on which types of constraint languages are able to express its constraint type. Based on the large-scale evaluation, we formulate several findings to direct the further development of constraint languages.
Goal-Based Semantic Queries for Dynamic Processes in the Internet of Things
Authors: Huber Steffen , Seiger Ronny , Kühnert André , Theodorou Vasileios , Schlegel Thomas
Published: August 2016

Internet of Things-aware process execution imposes new requirements on process modeling that are outside the scope of current modeling languages. Internet of Things (IoT) devices may vanish, appear or stay unknown during process execution, which renders process resource allocation at design time infeasible. Devices’ capabilities are often only available in a particular real-world context at runtime. This is not considered by current approaches that use services for encapsulating device functionality. We propose a novel approach to enable both service discovery and invocation for IoT-aware processes based on users’ goals that are defined as part of a process. We apply the Tropos goal modeling methodology to represent the dependencies between these goals and IoT device capabilities. Furthermore, we present a Semantic Access Layer (SAL) to transform these goals into service invocations using generated SPARQL queries. The SAL executes the queries on a knowledge base representing runtime domain knowledge about IoT services, their capabilities, and context. As a result, it invokes the identified IoT services and transfers the responses back to the process engine. The evaluation of our approach within several Smart Home scenarios shows an increase of flexibility and separation of concerns for scalable, IoT-aware process execution.
ODoST
Authors: Yu Ting , Bradley Chris , Sinnen Oliver
Published: August 2016

Dynamic biomedical systems are mathematically described by Ordinary Differential Equations (ODEs) and their solution is often one of the most computationally intensive parts in biomedical simulations. With high inherent parallelism, hardware acceleration based on Field-Programmable Gate Arrays (FPGAs) has great potential to increase the computational performance of the model simulations, while being very power-efficient. However, the manual hardware implementation is complex and time consuming. The advantages of FPGA designs can only be realised if there is a general solution to automate the process. In this article, we propose a domain-specific high-level synthesis tool called ODoST that automatically generates an FPGA-based Hardware Accelerator Module (HAM) from a high-level description. In this direct approach, ODE equations are directly mapped to processing pipelines without any intermediate architecture layer of processing elements. We evaluate the generated HAMs on real hardware based on their resource usage, processing speed, and power consumption, and compare them with CPUs and a GPU. The results show that FPGA implementations can achieve 15.3 times more speedup compared to a single core CPU solution and perform similarly to an auto-generated GPU solution, while the FPGA implementations can achieve 14.5 times more power efficiency than the CPU and 3.1 times compared to the
optimised
GPU solution. Improved speedups are foreseeable based on further optimisations.
Hierarchical Dynamic Thermal Management Method for High-Performance Many-Core Microprocessors
Authors: Wang Hai , Ma Jian , Tan Sheldon X.-D. , Zhang Chi , Tang He , Huang Keheng , Zhang Zhenghong
Published: August 2016

It is challenging to manage the thermal behavior of many-core microprocessors while still keeping them running at high performance since the control complexity increases as the core number increases. In this article, a novel hierarchical dynamic thermal management method is proposed to overcome this challenge. The new method employs model predictive control (MPC) with task migration and a DVFS scheme to ensure smooth control behavior and negligible computing performance sacrifice. In order to be scalable to many-core systems, the hierarchical control scheme is designed with two levels. At the lower level, the cores are spatially clustered into blocks, and local task migration is used to match current power distribution with the optimal distribution calculated by MPC. At the upper level, global task migration is used with the unmatched powers from the lower level. A modified iterative minimum cut algorithm is used to assist the task migration decision making if the power number is large at the upper level. Finally, DVFS is applied to regulate the remaining unmatched powers. Experiments show that the new method outperforms existing methods and is very scalable to manage many-core microprocessors with small performance degradation.
Error-Correcting Sample Preparation with Cyberphysical Digital Microfluidic Lab-on-Chip
Authors: Poddar Sudip , Ghoshal Sarmishtha , Chakrabarty Krishnendu , Bhattacharya Bhargab B.
Published: August 2016

Digital (droplet-based) microfluidic technology offers an attractive platform for implementing a wide variety of biochemical laboratory protocols, such as point-of-care diagnosis, DNA analysis, target detection, and drug discovery. A digital microfluidic biochip consists of a patterned array of electrodes on which tiny fluid droplets are manipulated by electrical actuation sequences to perform various fluidic operations, for example, dispense, transport, mix, or split. However, because of the inherent uncertainty of fluidic operations, the outcome of biochemical experiments performed on-chip can be erroneous even if the chip is tested a priori and deemed to be defect-free. In this article, we address an important error recoverability problem in the context of sample preparation. We assume a cyberphysical environment, in which the physical errors, when detected online at selected checkpoints with integrated sensors, can be corrected through recovery techniques. However, almost all prior work on error recoverability used checkpointing-based
rollback
approach, that is, re-execution of certain portions of the protocol starting from the previous checkpoint. Unfortunately, such techniques are expensive both in terms of assay completion time and reagent cost, and can never ensure full error-recovery in deterministic sense. We consider imprecise droplet mix-split operations and present a novel
roll-forward
approach where the erroneous droplets, thus produced, are used in the error-recovery process, instead of being discarded or remixed. All erroneous droplets participate in the dilution process and they mutually cancel or reduce the concentration-error when the target droplet is reached. We also present a rigorous analysis that reveals the role of volumetric-error on the concentration of a sample to be prepared, and we describe the layout of a lab-on-chip that can execute the proposed cyberphysical dilution algorithm. Our analysis reveals that fluidic errors caused by unbalanced droplet splitting can be classified as being either
critical
or
non-critical
, and only those of the former type require correction to achieve error-free sample dilution. Simulation experiments on various sample preparation test cases demonstrate the effectiveness of the proposed method.
Causal Relationship Detection in Archival Collections of Product Reviews for Understanding Technology Evolution
Authors: Zhang Yating , Jatowt Adam , Tanaka Katsumi
Published: August 2016

Technology progress is one of the key reasons behind today's rapid changes in lifestyles. Knowing how products and objects evolve can not only help with understanding the evolutionary patterns in our society but can also provide clues on effective product design and can offer support for predicting the future. We propose a general framework for analyzing technology's impact on our lives through detecting cause--effect relationships, where causes represent changes in technology while effects are changes in social life, such as new activities or new ways of using products. We address the challenge of viewing technology evolution through the “social impact lens” by mining causal relationships from the long-term collections of product reviews. In particular, we first propose dividing vocabulary into two groups: terms describing product features (called
physical terms
) and terms representing product usage (called
conceptual terms
). We then search for two kinds of changes related to the appearance of terms: frequency-based and context-based changes. The former indicate periods when a word was significantly more frequently used, whereas the latter indicate periods of high change in the word's context. Based on the detected changes, we then search for causal term pairs such that the change in the physical term triggers the change in the conceptual term. We next extend our approach to finding causal relationships between word groups such as a group of words representing the same technology and causing a given conceptual change or group of words representing two different technologies that simultaneously “co-cause” a conceptual change. We conduct experiments on different product types using the Amazon Product Review Dataset, which spans 1995 to 2013, and we demonstrate that our approaches outperform state-of-the-art baselines.
Vacuolar H+-ATPase in the nuclear membranes regulates nucleo-cytosolic proton gradients
Authors: Santos Julianna Maria , Martínez-Zaguilán Raul , Facanha Arnoldo Rocha , Hussain Fazle , Sennoune Souad R.
Published: August 2016

The regulation of the luminal pH of each organelle is crucial for its function and must be controlled tightly. Nevertheless, it has been assumed that the nuclear pH is regulated by the cytoplasmic proton transporters via the diffusion of H+ across the nuclear pores because of their large diameter. However, it has been demonstrated that ion gradients exist between cytosol and nucleus, suggesting that the permeability of ions across the nuclear pores is restricted. Vacuolar H+-ATPase (V-H+-ATPase) is responsible for the creation and maintenance of trans-membrane electrochemical gradient. We hypothesize that V-H+-ATPase located in the nuclear membranes functions as the primary mechanism to regulate nuclear pH and generate H+ gradients across the nuclear envelope. We studied the subcellular heterogeneity of H+ concentration in the nucleus and cytosol using ratio imaging microscopy and SNARF-1, a pH indicator, in prostate cells. Our results indicate that there are proton gradients across the nuclear membranes that are generated by V-H+-ATPase located in the outer and inner nuclear membranes. We demonstrated that these gradients are mostly dissipated by inhibiting V-H+-ATPase. Immunoblots and V-H+-ATPase activity corroborated the existence of V-H+-ATPase in the nuclear membranes. This study demonstrates that V-H+-ATPase is functionally expressed in nuclear membranes and is responsible for nuclear H+ gradients that may promote not only the coupled transport of substrates, but also most electrochemically driven events across the nuclear membranes. This study represents a paradigm shift that the nucleus can regulate its own pH microenvironment, providing new insights into nuclear ion homeostasis and signaling.
The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation
Authors: Bilodeau Philippe A. , Coyne Erin S. , Wing Simon S.
Published: August 2016

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.
Legumain is activated in macrophages during pancreatitis
Authors: Edgington-Mitchell Laura E. , Wartmann Thomas , Fleming Alicia K. , Gocheva Vasilena , van der Linden Wouter A. , Withana Nimali P. , Verdoes Martijn , Aurelio Luigi , Edgington-Mitchell Daniel , Lieu TinaMarie , Parker Belinda S. , Graham Bim , Reinheckel Thomas , Furness John B. , Joyce Johanna A. , Storz Peter , Halangk Walter , Bogyo Matthew , Bunnett Nigel W.
Published: August 2016

Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68+ macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer.
α4-Containing nicotinic receptors contribute to the effects of perinatal nicotine on ventilatory and metabolic responses of neonatal mice to ambient cooling
Authors: Avraam Joanne , Cummings Kevin J. , Frappell Peter B.
Published: August 2016

Among numerous studies, perinatal nicotine exposure (PN) has had variable effects on respiratory control in the neonatal period. The effects of acute nicotine exposure on breathing are largely mediated by α4-containing nicotine acetylcholine receptors (nAChRs). These receptors are also involved in thermoregulatory responses induced by both acetylcholine and nicotine. We therefore hypothesized that α4-containing nAChRs would mediate the effects of PN on the metabolic and ventilatory responses of neonates to modest cold exposure. Wild-type (WT) and α4 knockout (KO) mice were exposed to 6 mg·kg−1·day−1 nicotine or vehicle from embryonic day 14. At postnatal day (P) 7 mice were cooled from an ambient temperature (TA) of 32 to 20°C. Body temperature (TB), rate of O2 consumption (V̇o2), ventilation (V̇e), respiratory frequency (FB), and tidal volume (VT) were continually monitored. An absence of α4 had no effect on the metabolic response to ambient cooling. Surprisingly, PN selectively increased the metabolic response of KO pups to cooling. Regardless, KO pups became hypothermic to the same degree as WT pups, and for both genotypes the drop in TB was exacerbated by PN. PN led to hyperventilation in WT pups caused by an increase in VT, an effect that was absent in α4 KO littermates. We show that PN interacts with α4-containing nAChRs in unique ways to modulate the control of breathing and thermoregulation in the early postnatal period.
An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease
Authors: Gu Chunyan , Zhang Jiandong , Noble Nancy A. , Peng Xiao-Rong , Huang Yufeng
Published: August 2016

While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-β1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22. Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover.
FloWave.US: validated, open-source, and flexible software for ultrasound blood flow analysis
Authors: Coolbaugh Crystal L. , Bush Emily C. , Caskey Charles F. , Damon Bruce M. , Towse Theodore F.
Published: August 2016

Automated software improves the accuracy and reliability of blood velocity, vessel diameter, blood flow, and shear rate ultrasound measurements, but existing software offers limited flexibility to customize and validate analyses. We developed FloWave.US —open-source software to automate ultrasound blood flow analysis—and demonstrated the validity of its blood velocity (aggregate relative error, 4.32%) and vessel diameter (0.31%) measures with a skeletal muscle ultrasound flow phantom. Compared with a commercial, manual analysis software program, FloWave.US produced equivalent in vivo cardiac cycle time-averaged mean (TAMean) velocities at rest and following a 10-s muscle contraction (mean bias <1 pixel for both conditions). Automated analysis of ultrasound blood flow data was 9.8 times faster than the manual method. Finally, a case study of a lower extremity muscle contraction experiment highlighted the ability of FloWave.US to measure small fluctuations in TAMean velocity, vessel diameter, and mean blood flow at specific time points in the cardiac cycle. In summary, the collective features of our newly designed software—accuracy, reliability, reduced processing time, cost-effectiveness, and flexibility—offer advantages over existing proprietary options. Further, public distribution of FloWave.US allows researchers to easily access and customize code to adapt ultrasound blood flow analysis to a variety of vascular physiology applications.
The destination defines the journey: an examination of the kinematics of hand-to-mouth movements
Authors: Flindall Jason W. , Gonzalez Claudia L. R.
Published: August 2016

Long-train electrical stimulation of the motor and premotor cortices of nonhuman primates can produce either hand-to-mouth or grasp-to-inspect movements, depending on the precise location of stimulation. Furthermore, single-neuron recording studies identify discrete neuronal populations in the inferior parietal and ventral premotor cortices that respond uniquely to either grasp-to-eat or grasp-to-place movements, despite their identical mechanistic requirements. These studies demonstrate that the macaque motor cortex is organized around producing functional, goal-oriented movements, rather than simply fulfilling muscular prerequisites of action. In humans, right-handed hand-to-mouth movements have a unique kinematic signature; smaller maximum grip apertures are produced when grasping to eat than when grasping to place identical targets. This is evidence that the motor cortex in humans is also organized around producing functional movements. However, in both macaques and humans, grasp-to-eat/hand-to-mouth movements have always been elicited using edible targets and have (necessarily) been paired with mouth movement. It is therefore unknown whether the kinematic distinction is a natural result of grasping food and/or is simply attributable to concurrent opening of the mouth while grasping. In experiment 1, we used goal-differentiated grasping tasks, directed toward edible and inedible targets, to show that the unique kinematic signature is present even with inedible targets. In experiment 2, we used the same goal-differentiated grasping tasks, either coupled with or divorced from an open-mouth movement, to show that the signature is not attributable merely to a planned opening of the mouth during the grasp. These results are discussed in relation to the role of hand-to-mouth movements in human development, independently of grasp-to-eat behavior.
Sciatic nerve stimulation activates the retrotrapezoid nucleus in anesthetized rats
Authors: Kanbar Roy , Stornetta Ruth L. , Guyenet Patrice G.
Published: August 2016

Retrotrapezoid nucleus (RTN) neurons sustain breathing automaticity. These neurons have chemoreceptor properties, but their firing is also regulated by multiple synaptic inputs of uncertain function. Here we test whether RTN neurons, like neighboring presympathetic neurons, are excited by somatic afferent stimulation. Experiments were performed in Inactin-anesthetized, bilaterally vagotomized, paralyzed, mechanically ventilated Sprague-Dawley rats. End-expiratory CO2(eeCO2) was varied between 4% and 10% to modify rate and amplitude of phrenic nerve discharge (PND). RTN and presympathetic neurons were recorded extracellularly below the facial motor nucleus with established criteria. Sciatic nerve stimulation (SNstim, 1 ms, 0.5 Hz) slightly increased blood pressure (6.6 ± 1.6 mmHg) and heart rate and, at low eeCO2(<5.5%), entrained PND. Ipsi- and contralateral SNstim produced the known biphasic activation of presympathetic neurons. SNstim evoked a similar but weaker biphasic response in up to 67% of RTN neurons and monophasic excitation in the rest. At low eeCO2,RTN neurons were silent and responded more weakly to SNstim than at high eeCO2. RTN neuron firing was respiratory modulated to various degrees. The phasic activation of RTN neurons elicited by SNstim was virtually unchanged at high eeCO2when PND entrainment to the stimulus was disrupted. Thus RTN neuron response to SNstim did not result from entrainment to the central pattern generator. Overall, SNstim shifted the relationship between RTN firing and eeCO2upward. In conclusion, somatic afferent stimulation increases RTN neuron firing probability without altering their response to CO2.This pathway may contribute to the hyperpnea triggered by nociception, exercise (muscle metabotropic reflex), or hyperthermia.
Ion Channels in Endothelial Responses to Fluid Shear Stress
Authors: Gerhold Kristin A. , Schwartz Martin A.
Published: August 2016

Fluid shear stress is an important environmental cue that governs vascular physiology and pathology, but the molecular mechanisms that mediate endothelial responses to flow are only partially understood. Gating of ion channels by flow is one mechanism that may underlie many of the known responses. Here, we review the literature on endothelial ion channels whose activity is modulated by flow with an eye toward identifying important questions for future research.
Regulatory Roles of Fluctuation-Driven Mechanotransduction in Cell Function
Authors: Suki Béla , Parameswaran Harikrishnan , Imsirovic Jasmin , Bartolák-Suki Erzsébet
Published: August 2016

Cells in the body are exposed to irregular mechanical stimuli. Here, we review the so-called fluctuation-driven mechanotransduction in which stresses stretching cells vary on a cycle-by-cycle basis. We argue that such mechanotransduction is an emergent network phenomenon and offer several potential mechanisms of how it regulates cell function. Several examples from the vasculature, the lung, and tissue engineering are discussed. We conclude with a list of important open questions.
The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease
Authors: Berridge Michael J.
Published: August 2016

Many cellular functions are regulated by calcium (Ca2+) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5-trisphosphate/calcium (InsP3/Ca2+) signaling pathway that operates through either primary or modulatory mechanisms. In its primary role, it generates the Ca2+that acts directly to control processes such as metabolism, secretion, fertilization, proliferation, and smooth muscle contraction. Its modulatory role occurs in excitable cells where it modulates the primary Ca2+signal generated by the entry of Ca2+through voltage-operated channels that releases Ca2+from ryanodine receptors (RYRs) on the internal stores. In carrying out this modulatory role, the InsP3/Ca2+signaling pathway induces subtle changes in the generation and function of the voltage-dependent primary Ca2+signal. Changes in the nature of both the primary and modulatory roles of InsP3/Ca2+signaling are a contributory factor responsible for the onset of a large number human diseases.