bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Strategy for Diagnostic Model Assessment in Capture–Recapture
Authors: McCrea Rachel S. , Morgan Byron J. T. , Gimenez Olivier
Published: November 2016

Common to both diagnostic tests used in capture–recapture and score tests is the idea that starting from a simple base model it is possible to interrogate data to determine whether more complex parameter structures will be supported. Current recommendations advise that diagnostic tests are performed as a precursor to a model selection step. We show that certain well-known diagnostic tests for examining the fit of capture–recapture models to data are in fact score tests. Because of this direct relationship we investigate a new strategy for model assessment which combines the diagnosis of departure from basic model assumptions with a step-up model selection, all based on score tests. We investigate the power of such an approach to detect common reasons for lack of model fit and compare the performance of this new strategy with the existing recommendations by using simulation. We present motivating examples with real data for which the extra flexibility of score tests results in an improved performance compared with diagnostic tests.
How User Fees Influence Contraception in Low and Middle Income Countries: A Systematic Review
Authors: Korachais Catherine , Macouillard Elodie , Meessen Bruno
Published: November 2016

Accessible and quality reproductive health services are critical for low‐ and middle‐income countries (LMICs). After a decade of waning investment in family planning, interest and funding are growing once again. This article assesses whether introducing, removing, or changing user fees for contraception has an effect on contraceptive use. We conducted a search of 14 international databases. We included randomized controlled trials, interrupted‐time series analyses, controlled before‐and‐after study designs, and cohort studies that reported contraception‐related variables as an outcome and a change in the price of contraceptives as an intervention. Four studies were eligible but none was at low risk of bias overall. Most of these, as well as other studies not included in the present research, found that demand for contraception was not cost‐sensitive. We could draw no robust summary of evidence, strongly suggesting that further research in this area is needed.
Curvature determination in the bending test of continuous fibre reinforcements
Authors: Liang B. , Chaudet P. , Boisse P.
Published: November 2016

Bending deformation is one of the main deformation modes in the forming of continuous fibre reinforcements. It is very specific compared to the classical continuous materials. In most textile material forming simulation models, bending stiffness is neglected, but taking into account it would give a more accurate predication, particularly the shape of wrinkles. In the deformation, fibres constituting the reinforcement can slide to each other, resulting in the bending stiffness of reinforcement is not directly related to its in‐plane tensile modulus as the classical continuous materials. Consequently, it is necessary to determine the bending stiffness by the experimental method. A cantilever bending stiffness test approach was proposed to measure the bending stiffness of continuous fibre reinforcements. A CCD camera was used to take the bending deflection shape. To calculate the curvature of bending deflection curve, uniform quartic B‐spline curve was chosen. A detailed process of curvature calculating of deflection curve was given in this paper. A single bending test gives the bending moment as a function of curvature from zero to the maximum value. Bending tests were conducted to validate the capacity of the proposed approach. A smooth curvature plot along the bending deflection curve was obtained for different types of reinforcements, and the non‐linear bending deformation behaviour can be identified with the proposed bending test method.
Discovery of HLA‐B*51:209, a novel HLA‐B*51 variant, in a Taiwanese individual
Authors: Yang K. L. , Lin P. Y.
Published: November 2016

One nucleotide substitution at residue 85 of HLA‐B*51:01:01:01 results in a novel allele, HLA‐B*51:209.
Trademark protection, quality improvement and exports in developing countries
Authors: Yang Lei , Yin Xiaopeng , He Yin
Published: November 2016

Trademarks indicate the inherent quality or other distinguishing features of products. Strong trademark protection can lower consumers' costs of searching for preferred quality characteristics. With weak trademark protection, firms in developing countries may not be willing to provide high‐quality products. With strong trademark protection, firms have an incentive to maintain or improve quality over time in order not to erode the value of their trademarks. By solving the theoretical model, we show that strengthened trademark protection in developing countries may induce domestic firms to become exporters and raise the quality of products on the export market. The welfare analyses show that strengthened trademark protection in developing countries benefits Southern customers and firms producing high‐quality products, but harms firms producing counterfeits and uninformed customers, if firm H charges low prices. Given firm H charges a high price, the strengthened trademark protection only helps firm H and informed customers in the South while leaves the others unaffected.
Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature‐dependent ATP release from human blood and endothelial cells
Authors: Kalsi Kameljit K. , Chiesa Scott T. , Trangmar Steven J. , Ali Leena , Lotlikar Makrand D. , González‐Alonso José
Published: November 2016

New Findings

What is the central question of this study?

Skin and muscle blood flow increases with heating and decreases with cooling, but the temperature‐sensitive mechanisms underlying these responses are not fully elucidated.

What is the main finding and its importance?

We found that local tissue hyperaemia was related to elevations in ATP release from erythrocytes. Increasing intravascular ATP augmented skin and tissue perfusion to levels equal or above thermal hyperaemia. ATP release from isolated erythrocytes was altered by heating and cooling. Our findings suggest that erythrocytes are involved in thermal regulation of blood flow via modulation of ATP release.

Local tissue perfusion changes with alterations in temperature during heating and cooling, but the thermosensitivity of the vascular ATP signalling mechanisms for control of blood flow during thermal interventions remains unknown. Here, we tested the hypotheses that the release of the vasodilator mediator ATP from human erythrocytes, but not from endothelial cells or other blood constituents, is sensitive to both increases and reductions in temperature and that increasing intravascular ATP availability with ATP infusion would potentiate thermal hyperaemia in limb tissues. We first measured blood temperature, brachial artery blood flow and plasma [ATP] during passive arm heating and cooling in healthy men and found that they increased by 3.0 ± 1.2°C, 105 ± 25 ml min−1 °C−1 and twofold, respectively, (all P < 0.05) with heating, but decreased or remained unchanged with cooling. In additional men, infusion of ATP into the brachial artery increased skin and deep tissue perfusion to levels equal or above thermal hyperaemia. In isolated erythrocyte samples exposed to different temperatures, ATP release increased 1.9‐fold from 33 to 39°C (P < 0.05) and declined by ∼50% at 20°C (P < 0.05), but no changes were observed in cultured human endothelial cells, plasma or serum samples. In conclusion, increases in plasma [ATP] and skin and deep tissue perfusion with limb heating are associated with elevations in ATP release from erythrocytes, but not from endothelial cells or other blood constituents. Erythrocyte ATP release is also sensitive to temperature reductions, suggesting that erythrocytes may function as thermal sensors and ATP signalling generators for control of tissue perfusion during thermal interventions.
Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone
Authors: D'Amico Jessica M. , Butler Annie A. , Héroux Martin E. , Cotel Florence , Perrier Jean‐François M. , Butler Jane E. , Gandevia Simon C. , Taylor Janet L.
Published: November 2016

Key points

In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5‐HT1A) receptors at the axon initial segment. We explored whether ingestion of the 5‐HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans.

Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F‐wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii.

Our findings suggest that activation of 5‐HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones.

Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5‐HT1A) receptors and inhibits generation of action potentials. We examined whether activation of 5‐HT1A receptors decreases motoneurone excitability in humans by determining the effects of a 5‐HT1A receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo‐controlled double‐blind study, 10 participants were tested on two occasions where either placebo or 20 mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F‐wave area and persistence, as well as CMEP area, were significantly decreased. The mean post‐pill difference in normalized F‐wave areas and persistence between buspirone and placebo days was –27% (–42, –12; 95% confidence interval) and –9% (–16, –2), respectively. The mean post‐pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was –31% (–60, –2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5‐HT1A receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise.
Resonance Responses of Geometrically Imperfect Functionally Graded Extensible Microbeams
Authors: Ghayesh Mergen H. , Farokhi Hamed , Gholipour Alireza , Hussain Shahid , Arjomandi Maziar
Published: November 2016

This paper aims at analyzing the size-dependent nonlinear dynamical behavior of a geometrically imperfect microbeam made of a functionally graded (FG) material, taking into account the longitudinal, transverse, and rotational motions. The size-dependent property is modeled by means of the modified couple stress theory, the shear deformation and rotary inertia are modeled using the Timoshenko beam theory, and the graded material property in the beam thickness direction is modeled via the Mori–Tanaka homogenization technique. The kinetic and size-dependent potential energies of the system are developed as functions of the longitudinal, transverse, and rotational motions. On the basis of an energy method, the continuous models of the system motion are obtained. Upon application of a weighted-residual method, the reduced-order model is obtained. A continuation method along with an eigenvalue extraction technique is utilized for the nonlinear and linear analyses, respectively. A special attention is paid on the effects of the material gradient index, the imperfection amplitude, and the length-scale parameter on the system dynamical response.
Source depth discrimination with a vertical line array
Authors: Conan Ewen , Bonnel Julien , Chonavel Thierry , Nicolas Barbara
Published: November 2016

Source depth estimation with a vertical line array generally involves mode filtering, then matched-mode processing. Because mode filtering is an ill-posed problem if the water column is not well-sampled, concerns for robustness motivate a simpler approach: source depth discrimination considered as a binary classification problem. It aims to evaluate whether the source is near the surface or submerged. These two hypotheses are formulated in terms of normal modes, using the concept of trapped and free modes. Decision metrics based on classic mode filters are proposed. Monte Carlo methods are used to predict performance and set the parameters of a classifier accordingly.
Creating Entrepreneurial and Innovative Fundraising Opportunities Through Service-Learning
Authors: Meaney Karen S. , Liu Ting , Duke Lara M.
Published: November 2016

The rapidly increasing enrollment in kinesiology programs recognizes the important role of our academic discipline in promoting future professionals within the physical activity, fitness, wellness, education, sport, and allied health domains. Unprecedented growth in student interest in kinesiology offers faculty and administrators in higher education both exciting opportunities and difficult challenges. One significant concern facing kinesiology faculty is maintaining high-quality instruction within growing class sizes. Incorporating service-learning components within kinesiology curricula provides numerous benefits to students, faculty, institutions of higher education, and members of our local and global communities. In addition, service-learning has the potential to initiate innovative and entrepreneurial learning experiences and funding opportunities for students and faculty.
Using Movband Technology to Support Online Learning: An Effective Approach to Maximizing Resources in Kinesiology
Authors: Brock Sheri J. , Wadsworth Danielle , Hollett Nikki , Rudisill Mary E.
Published: November 2016

The School of Kinesiology at Auburn University is using Movband Technology to support online learning in their physical activity program. Active Auburn is a 2-hr credit course that encourages students (n = 2,000/year) to become physically active through online instruction and tracking physical activity using Movband technology. Movband technology allows for uploading and monitoring group physical activity data. The implementation of this technology has allowed the School of Kinesiology to: (a) promote physical activity on our campus, (b) serve a large number of students, (c) reduce demand on classroom/physical activity space, and (d) promote our research and outreach scholarship as well, by collecting physical activity profiles for students enrolled in the course. Students report they enjoy the course and that they appreciate the “freedom to exercise” when it best fits into their schedule. This course generates considerable revenue to support course instruction and much more for the School of Kinesiology.
Optically resonant dielectric nanostructures
Authors: Kuznetsov Arseniy I. , Miroshnichenko Andrey E. , Brongersma Mark L. , Kivshar Yuri S. , Luk’yanchuk Boris
Published: November 2016

A clear approach to nanophotonics

The resonant modes of plasmonic nanoparticle structures made of gold or silver endow them with an ability to manipulate light at the nanoscale. However, owing to the high light losses caused by metals at optical wavelengths, only a small fraction of plasmonics applications have been realized. Kuznetsov
et al.
review how high-index dielectric nanoparticles can offer a substitute for these metals, providing a highly flexible and low-loss route to the manipulation of light at the nanoscale.

Science
, this issue p.
10.1126/science.aag2472
Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against Na
V
Authors: Logan Matthew M. , Toma Tatsuya , Thomas-Tran Rhiannon , Du Bois J.
Published: November 2016

Pluses and minuses of BTX behavior

Batrachotoxin is a potent neurotoxin produced by the endangered Colombian poison dart frog and is an agonist of voltage-gated sodium ion channels (NaVs). Logan
et al.
developed a chemical synthesis of this molecule, denoted (−)-BTX, by taking advantage of a tin hydride–mediated radical cyclization to stitch together the polycyclic framework. Using an analogous route, they also prepared the non-natural mirror image, (+)-BTX. Conversely to the natural product, (+)-BTX antagonized NaVs.

Science
, this issue p.
865
A synthetic pathway for the fixation of carbon dioxide in vitro
Authors: Schwander Thomas , Schada von Borzyskowski Lennart , Burgener Simon , Cortina Niña Socorro , Erb Tobias J.
Published: November 2016

Optimizing designer metabolisms in vitro

Biological carbon fixation requires several enzymes to turn CO
2
into biomass. Although this pathway evolved in plants, algae, and microorganisms over billions of years, many reactions and enzymes could aid in the production of desired chemical products instead of biomass. Schwander
et al.
constructed an optimized synthetic carbon fixation pathway in vitro by using 17 enzymes—including three engineered enzymes—from nine different organisms across all three domains of life (see the Perspective by Gong and Li). The pathway is up to five times more efficient than the in vivo rates of the most common natural carbon fixation pathway. Further optimization of this and other metabolic pathways by using similar approaches may lead to a host of biotechnological applications.

Science
, this issue p.
900
; see also p.
830
The sacral autonomic outflow is sympathetic
Authors: Espinosa-Medina I. , Saha O. , Boismoreau F. , Chettouh Z. , Rossi F. , Richardson W. D. , Brunet J.-F.
Published: November 2016

Sacral neurons reassigned

The autonomic nervous system regulates the function of internal organs such as the gut. The parasympathetic and sympathetic arms of this system tend to operate antagonistically. Espinosa-Medina
et al.
used anatomical and molecular analyses to reevaluate the assignment of neurons in the sacral autonomic nervous system (see the Perspective by Adameyko). Previously categorized as parasympathetic, these neurons are now identified as sympathetic. The results resolve a persistent confusion about how the two systems developed and open the avenue to more predictable outcomes in developing treatments targeted to the pelvic autonomic nervous system.

Science
, this issue p.
893
; see also p.
833
Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice
Authors: Ittner Arne , Chua Sook Wern , Bertz Josefine , Volkerling Alexander , van der Hoven Julia , Gladbach Amadeus , Przybyla Magdalena , Bi Mian , van Hummel Annika , Stevens Claire H. , Ippati Stefania , Suh Lisa S. , Macmillan Alexander , Sutherland Greg , Kril Jillian J. , Silva Ana P. G. , Mackay Joel P. , Poljak Anne , Delerue Fabien , Ke Yazi D. , Ittner Lars M.
Published: November 2016

Tau phosphorylation—not all bad

Alzheimer's disease presents with amyloid-β (Aβ) plaques and tau tangles. The prevailing idea in the field is that Aβ induces phosphorylation of tau, which in turn mediates neuronal dysfunction. Working in Alzheimer's disease mouse models, Ittner
et al.
found evidence for a protective role of tau in early Alzheimer's disease. This protection involves specific tau phosphorylation at threonine 205 at the postsynapse. A protective role of phosphorylated tau in disease challenges the dogma that tau phosphorylation only mediates toxic processes.

Science
, this issue p.
904
Improving photosynthesis and crop productivity by accelerating recovery from photoprotection
Authors: Kromdijk Johannes , Głowacka Katarzyna , Leonelli Lauriebeth , Gabilly Stéphane T. , Iwai Masakazu , Niyogi Krishna K. , Long Stephen P.
Published: November 2016

Faster light adaptation improves productivity

Crop plants protect themselves from excess sunlight by dissipating some light energy as heat, readjusting their systems when shadier conditions prevail. But the photosynthetic systems do not adapt to fluctuating light conditions as rapidly as a cloud passes overhead, resulting in suboptimal photosynthetic efficiency. Kromdijket al.sped up the adaptation process by accelerating interconversion of violaxanthin and zeaxanthin in the xanthophyll cycle and by increasing amounts of a photosystem II subunit. Tobacco plants tested with this system showed about 15% greater plant biomass production in natural field conditions.

Science, this issue p.857
Light-sensing phytochromes feel the heat
Authors: Halliday Karen J. , Davis Seth J.
Published: November 2016

Plant phytochrome activity is governed not just by light, but also by prevailing temperature
Fixing carbon, unnaturally
Authors: Gong Fuyu , Li Yin
Published: November 2016

A synthetic enzymatic pathway is more energy efficient than natural aerobic carbon fixation pathways
An injectable shear-thinning biomaterial for endovascular embolization
Authors: Avery Reginald K. , Albadawi Hassan , Akbari Mohsen , Zhang Yu Shrike , Duggan Michael J. , Sahani Dushyant V. , Olsen Bradley D. , Khademhosseini Ali , Oklu Rahmi
Published: November 2016

An engineered shear-thinning biomaterial is used as an embolic agent for vascular occlusion as treatment for bleeding.
The lung’s defensive line
Authors: Lund Amanda W.
Published: November 2016

Resident memory T cells in human airway tissues encode specialized programs for retention, maintenance, and rapid but controlled effector function.
Size no longer matters
Authors: Shalek Alex K.
Published: November 2016

A method for genome-wide profiling of small RNAs, such as microRNAs, from single cells is developed and applied to human cancer and stem cells.
Visualizing the Essential Role of Complete Virion Assembly Machinery in Efficient Hepatitis C Virus Cell-to-Cell Transmission by a Viral Infection-Activated Split-Intein-Mediated Reporter System
Authors: Zhao Fanfan , Zhao Ting , Deng Libin , Lv Dawei , Zhang Xiaolong , Pan Xiaoyu , Xu Jun , Long Gang
Published: November 2016

Hepatitis C virus (HCV) infects 2 to 3% of the world population and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. Many aspects of HCV study, ranging from molecular virology and antiviral drug development to drug resistance profiling, were supported by straightforward assays of HCV replication and infection. Among these assays, the HCV-dependent fluorescence relocalization (HDFR) system allowed live-cell visualization of infection without modifying the viral genome, but this strategy required careful recognition of the fluorescence relocalization pattern for its high fluorescence background in the cytoplasm. In this study, to achieve background-free visualization of HCV infection, a viral infection-activated split-intein-mediated reporter system (VISI) was devised. Uninfected Huh7.5.1-VISI cells show no background signal, while HCV infection specifically illuminates the nuclei of infected Huh7.5.1-VISI cells with either green fluorescent protein (GFP) or mCherry. Combining VISI-GFP and VISI-mCherry systems, we revisited HCV cell-to-cell transmission with clear-cut distinction of donor and recipient cells in a live-cell manner. Independently of virion assembly, exosomes have been reported to transfer HCV subgenomic RNA to initiate replication in uninfected cells, which suggested an assembly-free pathway. However, our data demonstrated that HCV structural genes and the p7 gene were essential for not only cell-free infectivity but also cell-to-cell transmission. Additionally, depletion of apolipoprotein E (ApoE) from donor cells but not from recipient cells significantly reduced HCV cell-to-cell transmission efficiency. In summary, we developed a background-free cell-based reporter system for convenient live-cell visualization of HCV infection, and our data indicate that complete HCV virion assembly machinery is essential for both cell-free and cell-to-cell transmission.

IMPORTANCE
Hepatitis C virus (HCV) infects hepatocytes via two pathways: cell-free infection and cell-to-cell transmission. Structural modules of the HCV genome are required for production of infectious cell-free virions; however, the role of specific genes within the structural module in cell-to-cell transmission is not clearly defined. Our data demonstrate that deletion of core, E1E2, and p7 genes individually results in no HCV cell-to-cell transmission and that ApoE knockdown from donor cells causes less-efficient cell-to-cell transmission. Thus, this work indicates that the complete HCV assembly machinery is required for HCV cell-to-cell transmission. At last, this work presents an optimized viral infection-activated split-intein-mediated reporter system for easy live-cell monitoring of HCV infection.
Robust Central Nervous System Pathology in Transgenic Mice following Peripheral Injection of α-Synuclein Fibrils
Authors: Ayers Jacob I. , Brooks Mieu M. , Rutherford Nicola J. , Howard Jasie K. , Sorrentino Zachary A. , Riffe Cara J. , Giasson Benoit I.
Published: November 2016

Misfolded α-synuclein (αS) is hypothesized to spread throughout the central nervous system (CNS) by neuronal connectivity leading to widespread pathology. Increasing evidence indicates that it also has the potential to invade the CNS via peripheral nerves in a prion-like manner. On the basis of the effectiveness following peripheral routes of prion administration, we extend our previous studies of CNS neuroinvasion in M83 αS transgenic mice following hind limb muscle (intramuscular [i.m.]) injection of αS fibrils by comparing various peripheral sites of inoculations with different αS protein preparations. Following intravenous injection in the tail veins of homozygous M83 transgenic (M83
+/+
) mice, robust αS pathology was observed in the CNS without the development of motor impairments within the time frame examined. Intraperitoneal (i.p.) injections of αS fibrils in hemizygous M83 transgenic (M83
+/−
) mice resulted in CNS αS pathology associated with paralysis. Interestingly, injection with soluble, nonaggregated αS resulted in paralysis and pathology in only a subset of mice, whereas soluble Δ71-82 αS, human βS, and keyhole limpet hemocyanin (KLH) control proteins induced no symptoms or pathology. Intraperitoneal injection of αS fibrils also induced CNS αS pathology in another αS transgenic mouse line (M20), albeit less robustly in these mice. In comparison, i.m. injection of αS fibrils was more efficient in inducing CNS αS pathology in M83 mice than i.p. or tail vein injections. Furthermore, i.m. injection of soluble, nonaggregated αS in M83
+/−
mice also induced paralysis and CNS αS pathology, although less efficiently. These results further demonstrate the prion-like characteristics of αS and reveal its efficiency to invade the CNS via multiple routes of peripheral administration.

IMPORTANCE
The misfolding and accumulation of α-synuclein (αS) inclusions are found in a number of neurodegenerative disorders and is a hallmark feature of Parkinson's disease (PD) and PD-related diseases. Similar characteristics have been observed between the infectious prion protein and αS, including its ability to spread from the peripheral nervous system and along neuroanatomical tracts within the central nervous system. In this study, we extend our previous results and investigate the efficiency of intravenous (i.v.), intraperitoneal (i.p.), and intramuscular (i.m.) routes of injection of αS fibrils and other protein controls. Our data reveal that injection of αS fibrils via these peripheral routes in αS-overexpressing mice are capable of inducing a robust αS pathology and in some cases cause paralysis. Furthermore, soluble, nonaggregated αS also induced αS pathology, albeit with much less efficiency. These findings further support and extend the idea of αS neuroinvasion from peripheral exposures.
Nuclear Export Signal Masking Regulates HIV-1 Rev Trafficking and Viral RNA Nuclear Export
Authors: Behrens Ryan T. , Aligeti Mounavya , Pocock Ginger M. , Higgins Christina A. , Sherer Nathan M.
Published: November 2016

HIV-1's Rev protein forms a homo-oligomeric adaptor complex linking viral RNAs to the cellular CRM1/Ran-GTP nuclear export machinery through the activity of Rev's prototypical leucine-rich nuclear export signal (NES). In this study, we used a functional fluorescently tagged Rev fusion protein as a platform to study the effects of modulating Rev NES identity, number, position, or strength on Rev subcellular trafficking, viral RNA nuclear export, and infectious virion production. We found that Rev activity was remarkably tolerant of diverse NES sequences, including supraphysiological NES (SNES) peptides that otherwise arrest CRM1 transport complexes at nuclear pores. Rev's ability to tolerate a SNES was both position and multimerization dependent, an observation consistent with a model wherein Rev self-association acts to transiently mask the NES peptide(s), thereby biasing Rev's trafficking into the nucleus. Combined imaging and functional assays also indicated that NES masking underpins Rev's well-known tendency to accumulate at the nucleolus, as well as Rev's capacity to activate optimal levels of late viral gene expression. We propose that Rev multimerization and NES masking regulates Rev's trafficking to and retention within the nucleus even prior to RNA binding.

IMPORTANCE
HIV-1 infects more than 34 million people worldwide causing >1 million deaths per year. Infectious virion production is activated by the essential viral Rev protein that mediates nuclear export of intron-bearing late-stage viral mRNAs. Rev's shuttling into and out of the nucleus is regulated by the antagonistic activities of both a peptide-encoded N-terminal nuclear localization signal and C-terminal nuclear export signal (NES). How Rev and related viral proteins balance strong import and export activities in order to achieve optimal levels of viral gene expression is incompletely understood. We provide evidence that multimerization provides a mechanism by which Rev transiently masks its NES peptide, thereby biasing its trafficking to and retention within the nucleus. Targeted pharmacological disruption of Rev-Rev interactions should perturb multiple Rev activities, both Rev-RNA binding and Rev's trafficking to the nucleus in the first place.
De NovoPyrimidine Biosynthesis Connects Cell Integrity to Amphotericin B Susceptibility in Cryptococcus neoformans
Authors: Banerjee Dithi , Umland Timothy C. , Panepinto John C.
Published: November 2016

Synergy between AmB and nucleotide biosynthetic pathways has been documented, but the mechanism of this interaction has not been delineated. Results from this study suggest a correlation between uridine nucleotide biosynthesis and cell integrity likely mediated through the pool of nucleotide-sugar conjugates, which are precursor molecules for both capsule and cell wall ofC. neoformans. Thus, we propose a mechanism by which structural defects in the cell wall resulting from perturbation of pyrimidine biosynthesis allow faster and increased penetration of AmB molecules into the cell membrane. Overall, our work demonstrates that impairment of pyrimidine biosynthesis inC. neoformanscould be a potential target for antifungal therapy, either alone or in combination with AmB.
Effects of Electroacupuncture at St25 and Bl25 in a Sennae-induced rat model of diarrhoea-predominant irritable bowel syndrome
Authors: Zhu Xianwei , Liu Zhibin , Niu Wenmin , Wang Yuan , Zhang Aimin , Qu Hongyan , Zhou Jing , Bai Lu , Yang Yong , Li Jie
Published: November 2016

Background

Electroacupuncture (EA) may have a role in the treatment of diarrhoea symptoms. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal (GI) tract, which initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. In addition, according to the results of our previous report, EA stimulation mediates GI peristalsis by increasing expression of 5-HT and tryptophan hydroxylase (TPH).

Aim

To investigate the effect of EA at acupuncture points ST25 and BL25 in a rat model of diarrhoea.

Methods

A diarrhoea-predominant irritable bowel syndrome (IBS-D) model was induced by Folium Sennae in 24 rats, which remained untreated (n=6) or received EA at ST25 (n=6), BL25 (n=6) or the combination of ST25 and BL25 (n=6). A control group of healthy rats was also included (n=6). After treatment, changes in loose stool and small intestine transit rates, enterochromaffin (EC) cell number, expression of TPH, and faecal/colonic 5-HT contents were measured.

Results

Loose stool and small intestine transit rates, EC cell numbers, colonic TPH expression and faecal/colonic 5-HT content of IBS-D rats were significantly increased relative to controls (p<0.05) and all these parameters were improved by EA at ST25, BL25, or ST25 and BL25 in combination (all p<0.05 vs untreated IBS-D rats).

Conclusions

EA at ST25 and/or BL25 had a positive effect on objective markers of diarrhoea in a IBS-D rat model and induced changes in EC cell number, colonic TPH and 5-HT contents. The effects of EA stimulation at ST25/BL25 on IBS-D rats may be mediated by excitation of sympathetic nerves.
Retinal vessel calibre measurements by optical coherence tomography angiography
Authors: Ghasemi Falavarjani Khalil , Al-Sheikh Mayss , Darvizeh Fatemeh , Sadun Alfredo A , Sadda Srinivas R
Published: November 2016

Purpose

To compare the vessel calibre measurements between optical coherence tomography angiography (OCTA) and colour fundus photography.

Methods

In this retrospective comparative study, OCTA and colour fundus images of healthy eyes and eyes with optic atrophy were evaluated. The colour fundus image was registered manually using Image J software to the OCTA image of the optic disc. Two independent graders measured the vessel calibre of the widest vein and artery in each peripapillary quadrant on a 3.4 mm diameter circle centred on the optic disc in the same location on both images. The difference in vessel calibre between the two techniques was assessed.

Results

A total of 312 vessels from 29 healthy eyes and 20 eyes with atrophic optic discs were included. There was a high level of agreement between graders for measurement of vessel calibre in both colour fundus (intraclass correlation coefficient=0.93, coefficient of variation=0.07) and OCTA images (intraclass correlation coefficient=0.94, coefficient of variation=0.05). The mean vessel calibre in colour fundus images (94.5±23.2 µm) and OCT images (112.2±26.1 µm) was correlated (r=0.8, p<0.001), but the difference was statistically significant (mean difference: 17.6±1.5 µm, p<0.001). This difference was evident for both arteries (mean difference: 18.2±16.3 µm, p<0.001) and veins (mean difference: 15.1±16.2 µm, p<0.001) individually, with a similar magnitude of difference for both vessel types (p=0.08). In addition, the magnitude of difference between imaging modalities was similar in atrophic and healthy discs (17.1±15.9 vs 18.4±15.2 µm, respectively, p=0.4). The difference, however, was significantly higher in vessels with a calibre of ≤94.5 compared with larger vessels (19.3±16.3 vs 15.6±14.4 µm, respectively, p=0.02).

Conclusions

Vessel calibre measurements were significantly larger in OCTA images compared with colour fundus photographs, particularly for smaller vessels. These differences may need to be accounted for when using OCTA-derived metrics.
Investigating the impact of headaches on the quality of life of patients with glioblastoma multiforme: a qualitative study
Authors: Bennett Samuel Robert , Cruickshank Garth , Lindenmeyer Antje , Morris Simon Rhys
Published: November 2016

Objectives

Headaches and facial pain have been identified as the most prevalent form of pain among patients with glioblastoma multiforme, the most common malignant primary brain tumour. Despite this, minimal research has been undertaken investigating the direct and indirect impact these headaches have on their quality of life. Therefore, in this study, we aimed at gaining a personal insight into the importance and impact that these headaches have on the quality of life of patients with glioblastoma multiforme.

Design

Exploratory study using face-to-face semistructured interviews. Interviews were audio-recorded, transcribed verbatim and then qualitatively analysed using thematic analysis.

Setting

Participants recruited from a tertiary referral hospital in Birmingham, UK.

Participants

Purposive sampling of 14 registered outpatients recently diagnosed with glioblastoma multiforme.

Results

3 themes were identified: (1) an underlying attitude of determination and positivity; (2) impact of headache unpredictability on social interaction; (3) headaches found to act as a springboard onto thoughts regarding their disease and future.

Conclusions

While the quality of life of patients with glioblastoma multiforme is clearly multifactorial, headaches do indeed play a part for some. However, it is not the direct pain of the headache as one might expect that impacts on the quality of life of these patients, but the indirect effect of headaches through limiting patients' social lives and by serving as a painful psychological reminder of having a life-threatening illness. In clinical practice, using headache diaries for these patients may help provide a more comprehensive assessment and further aid management plans. Alongside acting as an important reminder of the potential secondary implications of this disease, suggestions for future research include quantitatively investigating whether headaches can act as a prognostic indicator for quality of life within this patient demographic and determining whether these conclusions also hold true for a wider spectrum of patients with brain tumour.
Complementary feeding and the early origins of obesity risk: a study protocol
Authors: Muniandy Naleena Devi , Allotey Pascale A , Soyiri Ireneous N , Reidpath Daniel D
Published: November 2016

Introduction

The rise in the prevalence of childhood obesity worldwide calls for an intervention earlier in the life cycle. Studies show that nutrition during early infancy may contribute to later obesity. Hence, this study is designed to determine if the variation in complementary feeding practices poses a risk for the development of obesity later in life. A mixed methods approach will be used in conducting this study.

Methods and analysis

The target participants are infants born from January to June 2015 in the South East Asia Community Observatory (SEACO) platform. The SEACO is a Health and Demographic Surveillance System (HDSS) that is established in the District of Segamat in the state of Johor, Malaysia. For the quantitative strand, the sociodemographic data, feeding practices, anthropometry measurement and total nutrient intake will be assessed. The assessment will occur around the time complementary feeding is expected to start (7 Months) and again at 12 months. A 24-hour diet recall and a 2-day food diary will be used to assess the food intake. For the qualitative strand, selected mothers will be interviewed to explore their infant feeding practices and factors that influence their practices and food choices in detail.

Ethics and dissemination

Ethical clearance for this study was sought through the Monash University Human Research and Ethics Committee (application number CF14/3850-2014002010). Subsequently, the findings of this study will be disseminated through peer-reviewed journals, national and international conferences.
Angioplasty and stenting for patients with symptomatic intracranial atherosclerosis: study protocol of a randomised controlled trial
Authors: Cui Xiao-Ping , Lin Min , Mu Jun-Shan , Ye Jian-Xin , He Wen-Qing , Fu Mao-Lin , Li Hua , Fang Jia-Yang , Shen Feng-Feng , Lin Hang
Published: November 2016

Introduction

Whether adding percutaneous transluminal angioplasty and stenting (PTAS) to background medical treatment is effective for decreasing the incidence of stroke or death in patients with symptomatic intracranial atherosclerosis (ICAS) is still controversial. We perform a randomised controlled trial to examine the effectiveness and safety of an improved PTAS procedure for patients with ICAS.

Methods and analysis

A randomised controlled trial will be conducted in three hospitals in China. Eligible patients with ICAS will be randomly assigned to receive medication treatment (MT) plus PTAS or MT alone. The MT will be initiated immediately after randomisation, while the PTAS will be performed when patients report relief of alarm symptoms defined as sudden weakness or numbness. All patients will be followed up at 30 days, 3 and 12 months after randomisation. The primary end point will be the incidence of stroke or death at 30 days after randomisation. Secondary outcomes will be the incidence of ischaemic stroke in the territory of stenosis arteries, the incidence of in-stent restenosis, the Chinese version of the modiﬁed Rankin Scale and the Chinese version of the Stroke-Specific Quality of Life (CSQoL).

Ethics and dissemination

The study protocol is approved by institutional review boards in participating hospitals (reference number FZ20160003, 180PLA20160101 and 476PLA2016007). The results of this study will be disseminated to patients, physicians and policymakers through publication in a peer-reviewed journal or presentations in conferences. It is anticipated that the results of this study will improve the quality of the current PTAS procedure and guide clinical decision-making for patients with ICAS.

Trial registration number

NCT02689037
Prevalence of chemopreventive agent use among hospitalised women at high risk for breast cancer: a cross-sectional study
Authors: Khaliq Waseem , Jelovac Danijela , Wright Scott M
Published: November 2016

Objective

To characterise the current usage of chemoprevention agents among hospitalised women who are at higher risk for breast cancer.

Study design

A cross-sectional study.

Setting

Academic hospital at Baltimore.

Participants

A bedside survey of 250 women aged 50–75 years was conducted who were cancer-free at the time of study enrolment and hospitalised to a general medicine service. Reproductive history, family history for breast cancer, chemopreventive agents use and medical comorbidities data was collected for all patients. χ2and t-tests were used to analyse population characteristics.

Primary outcome measures

Prevalence of women at high risk for developing breast cancer (5-year Gail risk score ≥1.7) and their chemopreventive agent use.

Results

Mean age for the study population was 61.5 years (SD 7.5), and mean 5-year Gail risk score was 1.67 (SD 0.88). A third of study population was at high risk for breast cancer. None of the high-risk women (0%) were taking chemoprevention for breast cancer risk reduction, and 23% were at very high risk with 5-year Gail score ≥3%. These women were not recognised as being high risk by their hospital providers and none were referred to the high-risk breast cancer clinics following discharge.

Conclusions

Many hospitalised women are at high risk for breast cancer and we could not identify even a single woman who was using chemoprevention for risk reduction. Current chemoprevention guidelines may be falling short in their dissemination and implementation. Since women at high risk for breast cancer may only interface with the healthcare system at select points, all healthcare providers must be willing and able to do risk assessment. For those identified to be at high risk, providers must then either engage in chemopreventive counselling or refer patients to providers who are more comfortable working with patients on this critical decision.
High-intensity interval training versus moderate-intensity steady-state training in UK cardiac rehabilitation programmes (HIIT or MISS UK): study protocol for a multicentre randomised controlled trial and economic evaluation
Authors: McGregor Gordon , Nichols Simon , Hamborg Thomas , Bryning Lucy , Tudor-Edwards Rhiannon , Markland David , Mercer Jenny , Birkett Stefan , Ennis Stuart , Powell Richard , Begg Brian , Haykowsky Mark J , Banerjee Prithwish , Ingle Lee , Shave Rob , Backx Karianne
Published: November 2016

Introduction

Current international guidelines for cardiac rehabilitation (CR) advocate moderate-intensity exercise training (MISS, moderate-intensity steady state). This recommendation predates significant advances in medical therapy for coronary heart disease (CHD) and may not be the most appropriate strategy for the ‘modern’ patient with CHD. High-intensity interval training (HIIT) appears to be a safe and effective alternative, resulting in greater improvements in peak oxygen uptake (VO2 peak). To date, HIIT trials have predominantly been proof-of-concept studies in the laboratory setting and conducted outside the UK. The purpose of this multicentre randomised controlled trial is to compare the effects of HIIT and MISS training in patients with CHD attending UK CR programmes.

Methods and analysis

This pragmatic study will randomly allocate 510 patients with CHD to 8 weeks of twice weekly HIIT or MISS training at 3 centres in the UK. HIIT will consist of 10 high-intensity (85–90% peak power output (PPO)) and 10 low-intensity (20–25% PPO) intervals, each lasting 1 min. MISS training will follow usual care recommendations, adhering to currently accepted UK guidelines (ie, >20 min continuous exercise at 40–70% heart rate reserve). Outcome measures will be assessed at baseline, 8 weeks and 12 months. The primary outcome for the trial will be change in VO2 peakas determined by maximal cardiopulmonary exercise testing. Secondary measures will assess physiological, psychosocial and economic outcomes.

Ethics and dissemination

The study protocol V.1.0, dated 1 February 2016, was approved by the NHS Health Research Authority, East Midlands—Leicester South Research Ethics Committee (16/EM/0079). Recruitment will start in August 2016 and will be completed in June 2018. Results will be published in peer-reviewed journals, presented at national and international scientific meetings and are expected to inform future national guidelines for exercise training in UK CR.

Trial registration number

NCT02784873; pre-results.
Differential eligibility of African American and European American lung cancer cases using LDCT screening guidelines
Authors: Ryan Bríd M
Published: November 2016

Introduction

Lung cancer incidence and mortality is higher among African Americans compared with European Americans in the USA where screening guidelines are currently in place and based on age at diagnosis and smoking history. Given the different smoking patterns observed in these populations and the earlier age at which African Americans are diagnosed, it is possible that African Americans will be disproportionally excluded from screening programmes.

Methods

We assessed the capture of African American and EA lung cancer cases using the National Lung Screening Trial, US Preventive Services Task Force and Centers for Medicare and Medicaid Services eligibility guidelines in a population of lung cancer cases diagnosed between 1998 and 2014 in the Baltimore region of Maryland (n=1658).

Results

We found an absolute increase of 3.8% (relative increase: 11.5%) of EA lung cancer cases that fell within the eligible screening guidelines when compared with African Americans. This difference in proportions was not statistically significant (p=0.134). However, differences were more pronounced among women, where an absolute and relative difference of 4.2% and 13.6%, respectively, was observed (p=0.083). As more EA are likely to successfully quit smoking compared with African Americans, the inclusion of the time since quitting variable decreased the relative differences in eligibility.

Conclusions

Current screening guidelines are projected to capture a higher proportion of EA lung cancer cases than African American cases; however, the differences are not statistically significant. Further studies are needed, especially among high-risk populations, to determine if racial differences in eligibility criteria for lung screening will lead to a widening of cancer health disparities.