bluuebunny/crossref_metadata_2025 huggingface dataset:
A time series analysis of alcohol-related presentations to emergency departments in Queensland following the increase in alcopops tax
Authors: Kisely Steve , Lawrence David
Published: September 2015

Background

Raising duty on alcohol across the board can reduce morbidity, mortality and other adverse consequences of alcohol use. However, effectiveness is less certain for measures that target specific types of alcohol beverage in isolation. One example from Australia was the increase in tax on alcopops favoured by young people to curb risky drinking in this demographic.

Methods

We measured alcohol-related health harms in 15–29-year-olds presenting to emergency departments (EDs) in Queensland following the tax increase. These presentations were compared with following ED controls: (1) 15–29-year-olds with asthma or appendicitis; and (2) 30–49-year-olds presenting with alcohol-related harms. We analysed data over a 5-year period (April 2005–April 2010) using a time series analysis. This covered 3 years before, and 2 years after, the tax increase. We investigated both mental and behavioural consequences (F10 codes), and intentional/unintentional injuries (S and T codes).

Results

We fitted an ARIMA (autoregressive integrated moving average) model to test for a change following the increased ‘alcopops’ tax in April 2008. There was no significant decrease in alcohol-related ED presentations in 15–29-year-olds compared to any of the controls. We found similar results for males and females, narrow and broad definitions of alcohol-related harms, under-19s and ED presentations at night-time and weekends.

Conclusions

The increase in tax on ‘alcopops’ did not result in any reduction in alcohol-related harms in this population. Targeting particular alcoholic drinks may therefore not be as effective as more comprehensive policies such as minimum unit pricing for alcohol.
Temperature-dependent performance as a driver of warm-water fish species replacement along the river continuum
Authors: Troia Matthew J. , Denk Michael A. , Gido Keith B.
Published: September 2015

Replacement of fish species by their congeners along gradients of stream size is common in warm-water streams, but the causative environmental factors driving this turnover are not fully understood. We used laboratory experiments to test for differences in temperature-dependent egg hatch success and age-0 food ration size for three congeneric cyprinids that differ in abundance along temperature–stream size gradients. Headwater species (Pimephales promelas and Pimephales notatus) had lower thermal optima and narrower thermal breadths for hatch success compared with a river mainstem species (Pimephales vigilax). Temperature sensitivity of ration size was lowest for P. promelas, intermediate for P. notatus, and highest for P. vigilax. Using an empirical stream temperature model, we predicted water temperatures and projected hatch success and ration size for 7974 stream segments in Kansas, USA. Projected hatch success from May to July and ration size from July to September generally matched abundance–stream size patterns, suggesting that increasing temperature along the river continuum may drive replacements among Pimephales species. Our findings combined with evaluations of timing and duration of spawning seasons will improve mechanistic understanding of species replacements along the river continuum.
Sex-specific vascular responses of the rat aorta: effects of moderate term (intermediate stage) streptozotocin-induced diabetes
Authors: Han Xiaoyuan , Shaligram Sonali , Zhang Rui , Anderson Leigh , Rahimian Roshanak
Published: September 2015

Hyperglycemia affects male and female vascular beds differently. We have previously shown that 1 week after the induction of diabetes with streptozotocin (STZ), male and female rats exhibit differences in aortic endothelial function. To examine this phenomenon further, aortic responses were studied in male and female rats 8 weeks after the induction of diabetes (intermediate stage). Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh) was measured in phenylephrine (PE) pre-contracted rat aortic rings. Concentration response curves to PE were generated before and after L-NAME, a nitric oxide synthase (NOS) inhibitor. Furthermore, mRNA expression of endothelial nitric oxide synthase (eNOS) and NADPH oxidase subunit (Nox1) were determined. At 8 weeks, diabetes impaired EDV to a greater extent in female than male aortae. Furthermore, the responsiveness to PE was significantly enhanced only in female diabetic rats, and basal NO, as indicated by the potentiation of the response to PE after L-NAME, was reduced in female diabetic rat aortae to the same levels as in males. In addition, eNOS mRNA expression was decreased, while the Nox1 expression was significantly enhanced in diabetic female rats. These results suggest that aortic function in female diabetic rats after 8 weeks exhibits a more prominent impairment and that NO may be involved.
AP-1-Targeted Inhibition of Macrophage Function and Lipopolysaccharide/D-Galactosamine-Induced Hepatitis by Phyllanthus acidus Methanolic Extract
Authors: Hossen Muhammad Jahangir , Kim Mi-Yeon , Kim Jong-Hoon , Cho Jae Youl
Published: September 2015

Traditionally, Phyllanthus acidus (Phyllanthaceae) has been used for the treatment of rheumatism, bronchitis, asthma, respiratory disorders, and hepatitis. Recently, we showed that a methanol extract of Phyllanthaceae (Pa-ME) has a potent anti-inflammatory activity in RAW264.7 cells and strongly ameliorates HCl / EtOH -induced gastric ulcers in mice by targeting the Src/Syk of NF-κB. In the present study, we explored the molecular mechanism of Pa-ME on the AP-1 activation pathway and evaluated its potential hepatoprotective effects. To do this, we employed lipopolysaccharide (LPS)-stimulated RAW264.7 cells and U937 cells and an LPS/D-galactosamine (D- GaIN )-induced acute hepatitis mouse model. We utilized a multitude of assays, including immunoblotting analysis, reporter gene assays, and mRNA expression analysis, to determine the effect of Pa-ME on the AP-1 pathway. Pa-ME strikingly suppressed the production of LPS-induced pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Furthermore, Pa-ME also strongly inhibited activator protein-1 (AP-1) activation and mitogen-activated protein kinase (MAPK) phosphorylation in LPS-stimulated RAW264.7 macrophages cells and the U937 monocyte like human cell line. Moreover, pre-treatment with Pa-ME exhibited strong hepatoprotective and curative effects in an LPS/D-Gal-induced mouse hepatitis model as evidenced by a decrease in elevated serum AST and ALT levels and the amelioration of histological damage. Taken together, our data suggest that Pa-ME might play a crucial ethnopharmacological role as a hepatoprotective herbal remedy by suppressing MAPK signaling and the activity of the downstream transcription factor AP-1.
The experimental study of Cr6+ contaminated water remediation by zero-valent nano-Fe
Authors: Sun X. N. , Liu A. P. , Chen Q. F. , Wang X.
Published: September 2015

In recent years, researchers have developed a number of new types of zero-valent nano-Fe remediation materials applied in the remediation of contaminated soil and water, which has attracted wide attentions. This paper selected soil leaching wastewater severely contaminated by chromium as target of the study and chose zero-valent nano-Fe, [Formula: see text] and [Formula: see text] for comparison experiments to study the effects on removing [Formula: see text] under experimental conditions of different pH values, dosages and reaction times. As is shown in the experiments, zero-valent nano-Fe has the highest removal rates for [Formula: see text], while the reaction of [Formula: see text] is the slowest under the same conditions. However, both removal rates are prone to be stable after 10 min. Dosages do not make a distinct difference and the pH value has the least effect on the repair of zero-valent nano-Fe.
Levitation forces of a bulk YBCO superconductor in gradient varying magnetic fields
Authors: Jiang J. , Gong Y. M. , Wang G. , Zhou D. J. , Zhao L. F. , Zhang Y. , Zhao Y.
Published: September 2015

The levitation forces of a bulk YBCO superconductor in gradient varying high and low magnetic fields generated from a superconducting magnet were investigated. The magnetic field intensity of the superconducting magnet was measured when the exciting current was 90 A. The magnetic field gradient and magnetic force field were both calculated. The YBCO bulk was cooled by liquid nitrogen in field-cooling (FC) and zero-field-cooling (ZFC) condition. The results showed that the levitation forces increased with increasing the magnetic field intensity. Moreover, the levitation forces were more dependent on magnetic field gradient and magnetic force field than magnetic field intensity.
Photovoltaic performance of dye-sensitized solar cells using TiO2 nanotubes aggregates produced by hydrothermal synthesis
Authors: Chen Qiufan , Sun Xiaonan , Liu Anping , Zhang Qifeng , Cao Guozhong , Zhou Xiaoyuan
Published: September 2015

This paper reports the synthesis, detailed structural characterization of aggregated [Formula: see text] nanotubes and the application of such aggregated [Formula: see text] nanotubes as photoelectrodes in solar cells (dye sensitized DSCs). A maximum overall conversion efficiency of 7.9% has been achieved, which use conventional dyes without any additional chemical treatments under circumstances of an open-circuit voltage of 710 mV, a short-circuit current density of [Formula: see text], and a fill factor of 66%. This impressive performance is believed to attribute to the micron-sized aggregate structure which may be favorable for light harvesting, the desired high specific surface area and pure anatase phase for dye absorption. This significant improvement in the conversion efficiency indicates that DSCs based on aggregated [Formula: see text] nanotubes are a promising alternative to semiconductor-based solar cells.
Abandoned, Removed and Moved Object Classification
Authors: Fitzsimons Jack , Dawson-Howe Kenneth
Published: September 2015

This paper extends the problem of abandoned/removed object classification in video surveillance to encompass the closely related (but to date ignored) problem of moved object classification. Existing abandoned/removed region classification techniques are shown to arbitrarily classify such localized object movements as either abandonment or removal. Our new approach correctly classifies abandoned and removed objects, and also correctly classified 90% of moved objects.
Curvature properties of some class of warped product manifolds
Authors: Deszcz Ryszard , Głogowska Małgorzata , Jełowicki Jan , Zafindratafa Georges
Published: September 2015

We prove that warped product manifolds with [Formula: see text]-dimensional base, [Formula: see text] satisfy some pseudosymmetry type curvature conditions. These conditions are formed from the metric tensor [Formula: see text], the Riemann–Christoffel curvature tensor [Formula: see text], the Ricci tensor [Formula: see text] and the Weyl conformal curvature [Formula: see text] of the considered manifolds. The main result of the paper states that if [Formula: see text] and the fiber is a semi-Riemannian space of constant curvature (when [Formula: see text] is greater or equal to 5) then the [Formula: see text]-tensors [Formula: see text] and [Formula: see text] of such warped products are proportional to the [Formula: see text]-tensor [Formula: see text] and the tensor [Formula: see text] is a linear combination of some Kulkarni–Nomizu products formed from the tensors [Formula: see text] and [Formula: see text]. We also obtain curvature properties of this kind of quasi-Einstein and 2-quasi-Einstein manifolds, and in particular, of the Goedel metric, generalized spherically symmetric metrics and generalized Vaidya metrics.
A novel indicator of vibration damage in concrete
Authors: Braithwaite Colin J. R. , Heath Rachel A.
Published: September 2015

Open cracks in concrete contain crystals nucleated on the fracture walls, together with fragments of crystals and structures that resemble ooids that cannot have been derived from the host concrete. The fact that similar ooids, occurring in both marine and freshwater modern-day environments, typically form in response to oscillatory water movements strongly suggests that these bodies have also been subject to oscillation. It is concluded that this movement was driven by vibration within the concrete and that this has been responsible for the formation of the ooids and potentially for the propagation of the cracks in which they are found.
The location of pacemakers in the uteri of pregnant guinea pigs and rats
Authors: Lammers Wim J. E. P. , Stephen Betty , Al-Sultan Mahmood Ahmed , Subramanya Sandeep B. , Blanks Andrew M.
Published: September 2015

The pregnant uterus is a smooth muscle organ whose pattern of contraction is dictated by the propagation of electrical impulses. Such electrical activity may originate from one or more pacemakers, but the location of these sites has not yet been determined. To detect the location of the pacemaker in the gravid uterus, two approaches were used: 1) determine the site from where the contraction started using isolated uteri from the pregnant guinea pig, and videotape their contractions; and 2) record, in isolated uteri from pregnant term rats, with 240 extracellular electrodes simultaneously, and determine where the electrical bursts started. In both the contractile and electrophysiological experiments, there was not a single, specific pacemaker area. However, most contractions (guinea pig 87%) and bursts (rat 76%) started close to the mesometrial border (mean 2.7 ± 4.0 mm SD in guinea pigs and 1.3 ± 1.4 mm in rats). In addition, in the rat, most sites of initiations were located closer to the ovarial end of the horn (mean distance from the ovarial end 6.0 ± 6.2 mm SD), whereas such an orientation was not seen in the guinea pig. In both guinea pig and rat uteri at term, there is not one specific pacemaker area. Rather, contractile and electrical activity may arise from any site, with the majority starting close to the mesometrial border. Furthermore, in the rat, most activities started at the ovarial end of the horn. This may suggest a slightly different pattern of contraction in both species.
Accelerated age-related decline in renal and vascular function in female rats following early-life growth restriction
Authors: Black M. Jane , Lim Kyungjoon , Zimanyi Monika A. , Sampson Amanda K. , Bubb Kristen J. , Flower Rebecca L. , Parkington Helena C. , Tare Marianne , Denton Kate M.
Published: September 2015

Many studies report sexual dimorphism in the fetal programming of adult disease. We hypothesized that there would be differences in the age-related decline in renal function between male and female intrauterine growth-restricted rats. Early-life growth restriction was induced in rat offspring by administering a low-protein diet (LPD; 8.7% casein) to dams during pregnancy and lactation. Control dams were fed a normal-protein diet (NPD; 20% casein). Mean arterial pressure (MAP) and renal structure and function were assessed in 32- and 100-wk-old offspring. Mesenteric artery function was examined at 100 wk using myography. At 3 days of age, body weight was ∼24% lower ( P < 0.0001) in LPD offspring; this difference was still apparent at 32 wk but not at 100 wk of age. MAP was not different between the male NPD and LPD groups at either age. However, MAP was greater in LPD females compared with NPD females at 100 wk of age (∼10 mmHg; P < 0.001). Glomerular filtration rate declined with age in the NPD male, LPD male and LPD female offspring (∼45%, all P < 0.05), but not in NPD female offspring. Mesenteric arteries in the aged LPD females had reduced sensitivity to nitric oxide donors compared with their NPD counterparts, suggesting that vascular dysfunction may contribute to the increased risk of disease in aged females. In conclusion, females growth-restricted in early life were no longer protected from an age-related decline in renal and arterial function, and this was associated with increased arterial pressure without evidence of renal structural damage.
Role of FQQI motif in the internalization, trafficking, and signaling of guanylyl-cyclase/natriuretic peptide receptor-A in cultured murine mesangial cells
Authors: Mani Indra , Garg Renu , Pandey Kailash N.
Published: September 2015

Binding of the cardiac hormone atrial natriuretic peptide (ANP) to transmembrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), produces the intracellular second messenger cGMP in target cells. To delineate the critical role of an endocytic signal in intracellular sorting of the receptor, we have identified a FQQI (Phe790, Gln791, Gln792, and Ile793) motif in the carboxyl-terminal region of NPRA. Mouse mesangial cells (MMCs) were transiently transfected with the enhanced green fluorescence protein (eGFP)-tagged wild-type (WT) and mutant constructs of eGFP-NPRA. The mutation FQQI/AAAA, in the eGFP-NPRA cDNA sequence, markedly attenuated the internalization of mutant receptors by almost 49% compared with the WT receptor. Interestingly, we show that the μ1B subunit of adaptor protein-1 binds directly to a phenylalanine-based FQQI motif in the cytoplasmic tail of the receptor. However, subcellular trafficking indicated that immunofluorescence colocalization of the mutated receptor with early endosome antigen-1 (EEA-1), lysosome-associated membrane protein-1 (LAMP-1), and Rab 11 marker was decreased by 57% in early endosomes, 48% in lysosomes, and 42% in recycling endosomes, respectively, compared with the WT receptor in MMCs. The receptor containing the mutated motif (FQQI/AAAA) also produced a significantly decreased level of intracellular cGMP during subcellular trafficking than the WT receptor. The coimmunoprecipitation assay confirmed a decreased level of colocalization of the mutant receptor with subcellular compartments during endocytic processes. The results suggest that the FQQI motif is essential for the internalization and subcellular trafficking of NPRA during the hormone signaling process in intact MMCs.
Double transduction of a Cre/LoxP lentiviral vector: a simple method to generate kidney cell-specific knockdown mice
Authors: Nam Bo Young , Kim Dong Ki , Park Jung Tak , Kang Hye-Young , Paeng Jisun , Kim Seonghun , Park Jimin , Um Jae Eun , Oh Hyung Jung , Han Seung Hyeok , Yoo Tae-Hyun , Kang Shin-Wook
Published: September 2015

In a lentivirus-based gene delivery system, the incorporated gene is continuously expressed for a long time. In this study, we devised a simple way to knock down a specific gene in a kidney cell-specific pattern in adult mice by lentivirus-assisted transfer of short hairpin RNA (shRNA). Kidney collecting duct (CD)-specific aquaporin-3 (AQP3)-knockdown mice were generated by consecutive injection of Hoxb7-Cre-expressing lentivirus (LV-Hoxb7 Cre) and loxP-AQP3 shRNA-expressing lentivirus (LV-loxP shAQP3) in adult C57BL6/J mice. LV-Hoxb7 Cre was designed to express mCherry, while LV-loxP shAQP3 was designed with a floxed enhanced green fluorescent protein (EGFP)-tagged stop sequence, and thus EGFP would be expressed only in the absence of Cre recombination. In mice treated with LV-Hoxb7 Cre alone, mCherry protein expression, which indicates the presence of Cre recombinase, occurred only in CD cells. However, LV-loxP shAQP3 injection alone resulted in an increase in EGFP expression in all kidney cells, indicating the transcription of the floxed region. When LV-Hoxb7 Cre and LV-loxP shAQP3 were sequentially transduced, EGFP expression was attenuated while mCherry expression was sustained in CD cells, demonstrating a CD cell-specific recombination of the floxed region. AQP3 expression in mice injected with LV-Hoxb7 Cre or LV-loxP shAQP3 alone did not differ, but consecutive injection of LV-Hoxb7 Cre and LV-loxP shAQP3 significantly reduced AQP3 expression in CD cells. However, the expression levels of AQP3 were not altered in other cell types. Double transduction of Cre- and loxP-based lentivirus can easily generate kidney cell-specific knockdown mice, and this method might be applicable to other species.
Insights into decision making using choice probability
Authors: Crapse Trinity B. , Basso Michele A.
Published: September 2015

A long-standing question in systems neuroscience is how the activity of single neurons gives rise to our perceptions and actions. Critical insights into this question occurred in the last part of the 20th century when scientists began linking modulations of neuronal activity directly to perceptual behavior. A significant conceptual advance was the application of signal detection theory to both neuronal activity and behavior, providing a quantitative assessment of the relationship between brain and behavior. One metric that emerged from these efforts was choice probability (CP), which provides information about how well an ideal observer can predict the choice an animal makes from a neuron's discharge rate distribution. In this review, we describe where CP has been studied, locational trends in the values found, and why CP values are typically so low. We discuss its dependence on correlated activity among neurons of a population, assess whether it arises from feedforward or feedback mechanisms, and investigate what CP tells us about how many neurons are required for a decision and how they are pooled to do so.
Spatial phase sensitivity of complex cells in primary visual cortex depends on stimulus contrast
Authors: Meffin H. , Hietanen M. A. , Cloherty S. L. , Ibbotson M. R.
Published: September 2015

Neurons in primary visual cortex are classified as simple, which are phase sensitive, or complex, which are significantly less phase sensitive. Previously, we have used drifting gratings to show that the phase sensitivity of complex cells increases at low contrast and after contrast adaptation while that of simple cells remains the same at all contrasts (Cloherty SL, Ibbotson MR. J Neurophysiol 113: 434–444, 2015; Crowder NA, van Kleef J, Dreher B, Ibbotson MR. J Neurophysiol 98: 1155–1166, 2007; van Kleef JP, Cloherty SL, Ibbotson MR. J Physiol 588: 3457–3470, 2010). However, drifting gratings confound the influence of spatial and temporal summation, so here we have stimulated complex cells with gratings that are spatially stationary but continuously reverse the polarity of the contrast over time (contrast-reversing gratings). By varying the spatial phase and contrast of the gratings we aimed to establish whether the contrast-dependent phase sensitivity of complex cells results from changes in spatial or temporal processing or both. We found that most of the increase in phase sensitivity at low contrasts could be attributed to changes in the spatial phase sensitivities of complex cells. However, at low contrasts the complex cells did not develop the spatiotemporal response characteristics of simple cells, in which paired response peaks occur 180° out of phase in time and space. Complex cells that increased their spatial phase sensitivity at low contrasts were significantly overrepresented in the supragranular layers of cortex. We conclude that complex cells in supragranular layers of cat cortex have dynamic spatial summation properties and that the mechanisms underlying complex cell receptive fields differ between cortical layers.
Adaptation-induced modification of motion selectivity tuning in visual tectal neurons of adult zebrafish
Authors: Hollmann Vanessa , Lucks Valerie , Kurtz Rafael , Engelmann Jacob
Published: September 2015

In the developing brain, training-induced emergence of direction selectivity and plasticity of orientation tuning appear to be widespread phenomena. These are found in the visual pathway across different classes of vertebrates. Moreover, short-term plasticity of orientation tuning in the adult brain has been demonstrated in several species of mammals. However, it is unclear whether neuronal orientation and direction selectivity in nonmammalian species remains modifiable through short-term plasticity in the fully developed brain. To address this question, we analyzed motion tuning of neurons in the optic tectum of adult zebrafish by calcium imaging. In total, orientation and direction selectivity was enhanced by adaptation, responses of previously orientation-selective neurons were sharpened, and even adaptation-induced emergence of selectivity in previously nonselective neurons was observed in some cases. The different observed effects are mainly based on the relative distance between the previously preferred and the adaptation direction. In those neurons in which a shift of the preferred orientation or direction was induced by adaptation, repulsive shifts (i.e., away from the adapter) were more prevalent than attractive shifts. A further novel finding for visually induced adaptation that emerged from our study was that repulsive and attractive shifts can occur within one brain area, even with uniform stimuli. The type of shift being induced also depends on the difference between the adapting and the initially preferred stimulus direction. Our data indicate that, even within the fully developed optic tectum, short-term plasticity might have an important role in adjusting neuronal tuning functions to current stimulus conditions.
Dynamics of visual receptive fields in the macaque frontal eye field
Authors: Mayo J. Patrick , DiTomasso Amie R. , Sommer Marc A. , Smith Matthew A.
Published: September 2015

Neuronal receptive fields (RFs) provide the foundation for understanding systems-level sensory processing. In early visual areas, investigators have mapped RFs in detail using stochastic stimuli and sophisticated analytical approaches. Much less is known about RFs in prefrontal cortex. Visual stimuli used for mapping RFs in prefrontal cortex tend to cover a small range of spatial and temporal parameters, making it difficult to understand their role in visual processing. To address these shortcomings, we implemented a generalized linear model to measure the RFs of neurons in the macaque frontal eye field (FEF) in response to sparse, full-field stimuli. Our high-resolution, probabilistic approach tracked the evolution of RFs during passive fixation, and we validated our results against conventional measures. We found that FEF neurons exhibited a surprising level of sensitivity to stimuli presented as briefly as 10 ms or to multiple dots presented simultaneously, suggesting that FEF visual responses are more precise than previously appreciated. FEF RF spatial structures were largely maintained over time and between stimulus conditions. Our results demonstrate that the application of probabilistic RF mapping to FEF and similar association areas is an important tool for clarifying the neuronal mechanisms of cognition.
Cell swelling increases the severity of spreading depression inLocusta migratoria
Authors: Spong Kristin E. , Chin Brittany , Witiuk Kelsey L. M. , Robertson R. Meldrum
Published: September 2015

Progressive accumulation of extracellular potassium ions can trigger propagating waves of spreading depression (SD), which are associated with dramatic increases in extracellular potassium levels ([K+]o) and arrest in neural activity. In the central nervous system the restricted nature of the extracellular compartment creates an environment that is vulnerable to disturbances in ionic homeostasis. Here we investigate how changes in the size of the extracellular space induced by alterations in extracellular osmolarity affect locust SD. We found that hypotonic exposure increased susceptibility to experimentally induced SD evidenced by a decrease in the latency to onset and period between individual events. Hypertonic exposure was observed to delay the onset of SD or prevent the occurrence altogether. Additionally, the magnitude of extracellular K+concentration ([K+]o) disturbance during individual SD events was significantly greater and they were observed to propagate more quickly under hypotonic conditions compared with hypertonic conditions. Our results are consistent with a conclusion that hypotonic exposure reduced the size of the extracellular compartment by causing cell swelling and thus facilitated the accumulation of K+ions. Lastly, we found that pharmacologically reducing the accumulation of extracellular K+using the K+channel blocker tetraethylammonium slowed the rate of SD propagation while increasing [K+]othrough inhibition of the Na-K-2Cl cotransporter increased propagation rates. Overall our findings indicate that treatments or conditions that act to reduce the accumulation of extracellular K+help to protect against the development of SD and attenuate the spread of ionic disturbance adding to the evidence that diffusion of K+is a leading event during locust SD.
Histone Deacetylases in Bone Development and Skeletal Disorders
Authors: Bradley Elizabeth W. , Carpio Lomeli R. , van Wijnen Andre J. , McGee-Lawrence Meghan E. , Westendorf Jennifer J.
Published: September 2015

Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn2+for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2+. Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of this knowledge for orthopedic applications and bone tissue engineering.
The Stress Kinase p38α as a Target for Cancer Therapy
Authors: Igea Ana , Nebreda Angel R.
Published: September 2015

p38α is a ubiquitous protein kinase strongly activated by stress signals, inflammatory cytokines, and many other stimuli, which has been implicated in the modulation of multiple cellular processes. There is good evidence in the literature that p38α plays an important tumor-suppressor role by interfering with malignant cell transformation. This is mainly based on the ability of the p38α pathway to regulate tissue homeostasis by integrating signals that balance cell proliferation and differentiation or induce apoptosis. However, recent reports have also illustrated protumorigenic functions for p38α. Thus, p38α signaling may facilitate the survival and proliferation of tumor cells contributing to the progression of some tumor types. In addition, p38α activation helps tumor cells to survive chemotherapeutic treatments. In all these cases, the inhibition of p38α has a potential therapeutic interest. Further elucidation of the context-dependent functions of p38α signaling in tumoral processes is of obvious importance for the use of inhibitors of this pathway in cancer therapy. Cancer Res; 75(19); 3997–4002. ©2015 AACR.
A Newly Identified Susceptibility Locus nearFOXP1Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus
Authors: Dai James Y. , de Dieu Tapsoba Jean , Buas Matthew F. , Onstad Lynn E. , Levine David M. , Risch Harvey A. , Chow Wong-Ho , Bernstein Leslie , Ye Weimin , Lagergren Jesper , Bird Nigel C. , Corley Douglas A. , Shaheen Nicholas J. , Wu Anna H. , Reid Brian J. , Hardie Laura J. , Whiteman David C. , Vaughan Thomas L.
Published: September 2015

Background: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure–disease associations is unclear.

Methods: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma.

Results: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91–7.56), 3.56 (2.85–4.44), and 3.97 (2.47–6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index.

Conclusion: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1.

Impact: The novel gene–exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 24(11); 1739–47. ©2015 AACR.
A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation
Authors: Arai Sally , Pidala Joseph , Pusic Iskra , Chai Xiaoyu , Jaglowski Samantha , Khera Nandita , Palmer Jeanne , Chen George L. , Jagasia Madan H. , Mayer Sebastian A. , Wood William A. , Green Michael , Hyun Teresa S. , Inamoto Yoshihiro , Storer Barry E. , Miklos David B. , Shulman Howard M. , Martin Paul J. , Sarantopoulos Stefanie , Lee Stephanie J. , Flowers Mary E.D.
Published: September 2015

Purpose: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.

Experimental design: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m2 i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.

Results: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%–43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%–44%) randomized to rituximab. Six (17%; 95% CI, 7%–34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%–29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27+) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.

Conclusions: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab. Clin Cancer Res; 22(2); 319–27. ©2015 AACR.
Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model
Authors: Sandulache Vlad C. , Chen Yunyun , Skinner Heath D. , Lu Tongtong , Feng Lei , Court Laurence E. , Myers Jeffrey N. , Meyn Raymond E. , Fuller Clifton D. , Bankson James A. , Lai Stephen Y.
Published: September 2015

Ionizing radiation is the primary nonsurgical treatment modality for solid tumors. Its effectiveness is impacted by temporal constraints such as fractionation, hypoxia, and development of radioresistant clones. Biomarkers of acute radiation response are essential to developing more effective clinical algorithms. We hypothesized that acute perturbations in tumor lactate levels act as a surrogate marker of radiation response. In vitro experiments were carried out using validated human-derived cell lines from three histologies: anaplastic thyroid carcinoma (ATC), head and neck squamous cell carcinoma (HNSCC), and papillary thyroid carcinoma (PTC). Cellular metabolic activity was measured using standard biochemical assays. In vivo validation was performed using both an orthotopic and a flank derivative of a previously established ATC xenograft murine model. Irradiation of cells and tumors triggered a rapid, dose-dependent, transient decrease in lactate levels that was reversed by free radical scavengers. Acute lactate perturbations following irradiation could identify hypoxic conditions and correlated with hypoxia-induced radioresistance. Mutant TP53 cells and cells in which p53 activity was abrogated (shRNA) demonstrated a blunted lactate response to irradiation, consistent with a radioresistant phenotype. Lactate measurements therefore rapidly detected both induced (i.e., hypoxia) and intrinsic (i.e., mutTP53-driven) radioresistance. We conclude that lactate is a quantitative biomarker of acute genotoxic stress, with a temporal resolution that can inform clinical decision making. Combined with the spatial resolution of newly developed metabolic imaging platforms, this biomarker could lead to the development of truly individualized treatment strategies. Mol Cancer Ther; 14(12); 2901–8. ©2015 AACR.
FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL
Authors: Consolaro Francesca , Ghaem-Maghami Sadaf , Bortolozzi Roberta , Zona Stefania , Khongkow Mattaka , Basso Giuseppe , Viola Giampietro , Lam Eric W.-F.
Published: September 2015

Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.

Implications: FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells. Mol Cancer Res; 13(12); 1578–90. ©2015 AACR.
Pharmacokinetics of Levodopa before and after Gastrointestinal Resection in Parkinson's Disease
Authors: Nagayama Hiroshi , Kajimoto Yusuke , Kumagai Tomoaki , Nishiyama Yasuhiro , Mishina Masahiro , Kimura Kazumi
Published: September 2015

Introduction: Levodopa (LD) is important in the clinical treatment of Parkinson's disease (PD), and the changes of its pharmacokinetics may affect the clinical outcome. LD is mainly absorbed in the upper intestine; thus, the pharmacokinetics of LD may change after gastrointestinal operation. Here, we present the case of a patient who underwent resection of the intestine and compared his LD pharmacokinetics before and after resection. Case Presentation: A 72-year-old Japanese male PD patient developed jaundice and was diagnosed with cholangiocarcinoma. Pancreaticoduodenectomy was performed and part of the stomach, total duodenum, and part of the jejunum were resected. The patient had been treated with LD, and his pharmacokinetics was checked twice at the age of 68 years. Because LD is absorbed in the duodenum and jejunum, we checked his pharmacokinetics again after the operation. The results before the operation were almost similar; however, in comparison, the area under the curve and peak drug concentration was reduced, and the time-to-peak drug concentration and elimination halftime were elongated after the operation. Conclusion: Physicians must pay attention to the change of LD pharmacokinetics after gastrointestinal operation.
Hsp27 Acts as a Master Molecular Chaperone and Plays an Essential Role in Hepatocellular Carcinoma Progression
Authors: Cheng Jun , Lv Zhen , Weng Xiaoyu , Ye Sunyi , Shen Kezhen , Li Mansheng , Qin Yunsheng , Hu Chen , Zhang Chenxi , Wu Jian , Zheng Shusen
Published: September 2015

Aims: Hsp27, a master molecular chaperone, plays an important role in cancer. However, the specific co-chaperones that partner with Hsp27 and the role of Hsp27 in hepatocellular carcinoma (HCC) are not fully enumerated. The present study focuses on the role of Hsp27 in HCC and explores its potential co-chaperones in HCC development. Methods: Gene overexpression or knockdown was used to observe the role of Hsp27 in HCC. Co-immunoprecipitation and mass spectrometry were used to explore apoptosis resistance by regulating multiple co-chaperones of Hsp27. Hsp27 protein-protein interaction (PPI) networks were constructed by the MetaCore software. Results: Hsp27 was upregulated in HCC tissues, and Hsp27 overexpression significantly facilitated formation of HCC cell colony and invasion in normoxia and tolerance in hypoxia by interacting with HIF-1α. Next, the analysis of microarrays revealed that Hsp27 regulated several cellular signaling pathways, including Wnt, ErbB and TGF-β signaling. Moreover, we characterized the Hsp27 PPI map, which indicated that Hsp27 along with its co-chaperones formed different complexes and exerts transcription regulation activity by activating sp1, c-Myc, p53 and ESR1. Conclusions: Hsp27 along with its co-chaperones was related to the development of HCC by regulating multiple signaling pathways, and drugs that target Hsp27 along with its co-chaperones may be a potential therapy for HCC.
The Role of School Social Environment on Dental Caries Experience in 8- to 12-Year-Old Brazilian Children: A Multilevel Analysis
Authors: Fernández María Raquel , Goettems Marília L. , Ardenghi Thiago M. , Demarco Flávio F. , Correa Marcos Britto
Published: September 2015

Aim: Although children spend most of their time involved in activities related to school, few studies have focused on the association between school social environment and oral health. This cross-sectional study assessed individual and school-related social environment correlates of dental caries in Brazilian schoolchildren aged 8-12 years. Methods: A sample of children from 20 private and public schools (n = 1,211) was selected. Socio-economic data were collected from parents, and data regarding children characteristics were collected from children using a questionnaire. Dental examinations were performed to assess the presence of dental plaque: dental caries experience (DMFT ≥1) and dental caries severity (mean dmf-t/DMF-T). The social school environment was assessed by a questionnaire administered to school coordinators. Multilevel Poisson regression was used to investigate the association between school social environment and dental caries prevalence and experience. Results: The dental caries prevalence was 32.4% (95% confidence interval: 29.7-35.2) and the mean dmf-t/DMF-T was 1.84 (standard deviation: 2.2). Multilevel models showed that the mean dmf-t/DMF-T and DMFT ≥1 were associated with lower maternal schooling and higher levels of dental plaque. For contextual variables, schools offering after-hours sports activities were associated with a lower prevalence of dental caries and a lower mean of dmf-t/DMF-T, while the occurrence of violence and theft episodes was positively associated with dental caries. Conclusions: The school social environment has an influence on dental caries in children. The results suggest that strategies focused on the promotion of healthier environments should be stimulated to reduce inequalities in dental caries.
Alternative to LRRK2-IN-1 for Pharmacological Studies of Parkinson's Disease
Authors: Koshibu Kyoko , van Asperen Judith , Gerets Helga , Garcia-Ladona Javier , Lorthioir Olivier , Courade Jean-Phillippe
Published: September 2015

Background/Aims: LRRK2 (leucine-rich repeat protein kinase 2) is one of the most commonly accepted genes associated with Parkinson's disease (PD). The overexpression of disease-associated mutations in LRRK2 is toxic to the cells, while reduction or elimination of LRRK2 expression promotes cell health and growth. Thus, the identification of an LRRK2 inhibitor with good physiochemical and pharmacokinetic properties is of great interest for the treatment of PD. Methods: In this study, we have investigated LRRK2 compounds, LRRK2-IN-1 and Compound 1, in vitro and in vivo to determine how suitable they are as a selective LRRK2 tool compound. Results: We report that Compound 1, patented by GSK, is a potent and selective LRRK2 inhibitor with good blood-brain barrier permeability as reflected by its high brain to plasma ratio in rats. In addition, Compound 1 can significantly promote neurite outgrowth in a primary cortical culture, indicating an optimistic cellular function of this compound in a biological system. In contrast, LRRK2-IN-1 is a less selective LRRK2 inhibitor and has low brain penetration. Furthermore, LRRK2-IN-1 is cyto- and genotoxic, while Compound 1 does not exhibit any toxicity. Conclusions: These results suggest that Compound 1 may be a superior tool compound than LRRK2-IN-1 to advance future pharmacological research on LRRK2.