bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Submandibular Gland Synucleinopathy in Parkinson’s Disease, Dementia with Lewy Bodies and other Lewy Body Disorders
Authors: Beach Thomas G. , Adler Charles H. , Serrano Geidy , Sue Lucia I. , Walker D.G. , Dugger Brittany N. , Shill Holly A. , Driver-Dunckley Erika , Caviness John N. , Intorcia Anthony , Filon Jessica , Scott Sarah , Garcia Angelica , Hoffman Brittany , Belden Christine M. , Davis Kathryn J. , Sabbagh Marwan N. ,   and the Arizona Parkinson’s Disease Consortium
Published: April 2016

Background: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson’s disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders.

Objective: To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders.

Methods: Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer’s disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA).

Results: Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects.

Conclusions: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.
Creative Thinking, Professional Artists, and Parkinson’s Disease
Authors: Canesi Margherita , Rusconi Maria Luisa , Moroni Federica , Ranghetti Alessandra , Cereda Emanuele , Pezzoli Gianni
Published: April 2016

Background: An increase in artistic-like production in Parkinson’s disease (PD) has been associated with compulsive and repetitive behaviours after the introduction of dopaminergic treatment (DT). Recent data suggest that it could be due to the emergence of artistic-like skills triggered by DT.

Objective: In order to evaluate whether artistic production and creative thinking are influenced by DT or linked to artistic-like skills, we characterize creativity features in PD and healthy controls (HC) including professional artists.

Methods: Three groups of PD out-patients were included consecutively: professional artists (PD-A), patients with (PD-C) and without artistic-like production (PD-NC). Twenty-four gender and age-matched HC were included: professional artists (HC-A) and non-artists (HC-NC). All patients were evaluated by means of a) a battery of neuropsychological tests and a semi-structured interview; b) the Abbreviated Torrance Test for Adults (ATTA) for creative thinking; c) the Minnesota Impulsive Disorders Interview (mMIDI) and a screening for impulse control disorders (ICDs) for compulsive behaviour.

Results: ATTA total score was significantly higher in HC-A and PD-A than in the other groups. Although PD-NC showed the lowest ATTA total score the difference vs HC-NC was not significant. ATTA scores were not significantly correlated with DT dosage and duration. mMIDI tests were positive only in PD. There were no differences in ICDs among PD groups.

Conclusions: Our results do not support a relationship between DT and the emergence of artistic creativity. We believe that DT may increase the drive to create and that further studies in “on” and “off” medication are needed to clarify this issue.
Multimodal Swallowing Evaluation with High-Resolution Manometry Reveals Subtle Swallowing Changes in Early and Mid-Stage Parkinson Disease
Authors: Jones Corinne A. , Ciucci Michelle R.
Published: April 2016

Background: Parkinson disease (PD) has detrimental effects on swallowing function. Treatment options are largely behavioral; thus, patients would benefit from an earlier start to therapy. Early swallowing changes in PD are not well-known, so patients do not typically receive swallowing treatment until later in the progression of PD.

Objective: We used predictive modeling to determine what quantitative swallowing variables best differentiate individuals with early to mid-stage PD from healthy controls.

Methods: Participants included twenty-six individuals with early to mid-stage PD and 26 healthy, age- and sex-matched controls. Swallowing was evaluated by simultaneous high-resolution manometry and videofluoroscopy as well as the Sydney Swallow Questionnaire (SSQ). Binomial logistic regression was performed on 4 sets of data: 1) high-resolution manometry only; 2) videofluoroscopy only; 3) SSQ only; and 4) all data combined.

Results: A model from a combined data set had the highest accuracy in differentiating individuals with PD from controls. The model included maximum pressure in the velopharynx (soft palate), pressure variability in the velopharynx, and the SSQ item concerning difficulty with swallowing saliva. No significant models could be generated using the videofluoroscopy data.

Conclusions: Individuals with PD show quantitative changes in pressure generation and are able to self-assess aspects of swallowing function in the early and mid-stages of PD, even in the absence of swallowing changes seen on videofluoroscopy. A multimodal approach for the assessment of swallowing may be more accurate for determining subtle swallowing changes that occur in the early stages of PD.
An Efficient Procedure for Removal and Inactivation of Alpha-Synuclein Assemblies from Laboratory Materials
Authors: Bousset Luc , Brundin Patrik , Böckmann Anja , Meier Beat , Melki Ronald
Published: April 2016

Background: Preformed α-synuclein fibrils seed the aggregation of soluble α-synuclein in cultured cells and in vivo. This, and other findings, has kindled the idea that α-synuclein fibrils possess prion-like properties.

Objective: As α-synuclein fibrils should not be considered as innocuous, there is a need for decontamination and inactivation procedures for laboratory benches and non-disposable laboratory material.

Methods: We assessed the effectiveness of different procedures designed to disassemble α-synuclein fibrils and reduce their infectivity. We examined different commercially available detergents to remove α-synuclein assemblies adsorbed on materials that are not disposable and that are most found in laboratories (e.g. plastic, glass, aluminum or stainless steel surfaces).

Results: We show that methods designed to decrease PrP prion infectivity neither effectively remove α-synuclein assemblies adsorbed to different materials commonly used in the laboratory nor disassemble the fibrillar form of the protein with efficiency. In contrast, both commercial detergents and SDS detached α-synuclein assemblies from contaminated surfaces and disassembled the fibrils.

Conclusions: We describe three cleaning procedures that effectively remove and disassemble α-synuclein seeds. The methods rely on the use of detergents that are compatible with most non-disposable tools in a laboratory. The procedures are easy to implement and significantly decrease any potential risks associated to handling α-synuclein assemblies.
Profile of Neuropsychiatric Symptoms in Parkinson’s Disease: Surgical Candidates Compared to Controls
Authors: Lamberti Valérie M.J. , Pereira Bruno , Lhommée Eugénie , Bichon Amélie , Schmitt Emmanuelle , Pelissier Pierre , Kistner Andrea , Fraix Valérie , Castrioto Anna , Esselink Rianne A. J. , Durif Frank , Krack Paul
Published: April 2016

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson’s disease (PD) and motor complications of dopaminergic treatment. Whether STN-DBS should be considered when PD patients experience neuropsychiatric symptoms is controversial. Lack of systematic behavioral evaluation at baseline hampers the understanding of postoperative neuropsychiatric outcomes.

Objective: This study compares the behavioral profile of a surgical population to that in general PD.

Methods: Single center data from 234 PD surgical candidates were compared to data from 260 non-demented PD patients consulting in 13 PD expert centers at different stages of disease. The latter were considered representative of the general PD population. Neuropsychiatric symptoms were assessed using the Ardouin Scale of Behavior in PD, a guided interview quantifying changes in severity of 21 neuropsychiatric symptoms, classified into psychic non-motor fluctuations, hypo- and hyperdopaminergic behaviors. Multivariate analyses were performed to study differences in behavioral items between the two groups.

Results: Surgical candidates were younger, had longer disease duration and used significantly higher doses of dopaminergic drugs. After adjustment for covariates, dopaminergic addiction (OR 10.83; p = 0.002), nocturnal hyperactivity (OR 1.87; p = 0.04), excessive hobbyism (OR 2.37; p = 0.008), “excess in motivation” (OR 4.02; p <  0.001), psychic OFF (2.87; p <  0.001) and psychic ON (2.10; p = 0.001) fluctuations were more frequent in the surgical candidates. Depressed mood prevailed in the general PD population (OR 0.53; p = 0.045).

Conclusion: Behavioral complications of dopaminergic treatment are frequent in PD patients candidates for STN-DBS. They cannot be considered as contraindications for STN-DBS but must be taken into account in postoperative management.
Safinamide as Add-On Therapy to Levodopa in Mid- to Late-Stage Parkinson’s Disease Fluctuating Patients: Post hoc Analysesof Studies 016 and SETTLE
Authors: Cattaneo Carlo , Sardina Marco , Bonizzoni Ermino
Published: April 2016

Background: Studies 016 and SETTLE showed that safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms.

Objective: To evaluate the clinical effects of safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE.

Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of safinamide versus placebo on individual cardinal PD symptoms during ON time.

Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, safinamide improved bradykinesia, rigidity, tremor and gait.

Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.
Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition
Authors: Barrett Matthew J. , Koeppel Alexander F. , Flanigan Joseph L. , Turner Stephen D. , Worrall Bradford B.
Published: April 2016

Background: Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated.

Objective: The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD).

Methods: Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score.

Results: In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE <  24) in PD subjects >  70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects≤70 years old.

Conclusions: Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.
Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson’s Disease
Authors: Hacker Mallory L. , Currie Amanda D. , Molinari Anna L. , Turchan Maxim , Millan Sarah M. , Heusinkveld Lauren E. , Roach Jonathon , Konrad Peter E. , Davis Thomas L. , Neimat Joseph S. , Phibbs Fenna T. , Hedera Peter , Byrne Daniel W. , Charles David
Published: April 2016

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson’s disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT).

Objective: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs.

Methods: Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS.

Results: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months ( p <  0.05; OR = 0.2; 95% CI: 0.04–0.97).

Conclusions: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD.
Lille Apathy Rating Scale and MDS-UPDRS for Screening Apathy in Parkinson’s Disease
Authors: Weintraut Rita , Karádi Kázmér , Lucza Tivadar , Kovács Márton , Makkos Attila , Janszky József , Kovács Norbert
Published: April 2016

Background: Apathy is a syndrome characterized primarily by lack of motivation which may be associated with cognitive, affective and behavioral changes. Although the Lille Apathy Scale (LARS) has been extensively utilized in PD for detecting apathy and testing the effectiveness of specific therapeutic interventions, the highly variable cut-off values (between –11 and –22 points) ensures the applicability of the LARS degree of difficulty as a superb screening tool.

Objective: The aim of this study is to determine more reliable threshold values based on the neuropsychiatric status of patients.

Methods: Depression was assessed utilizing the Montgomery-Asberg Depression Rating Scale and neurocognitive status by Addenbrooke’s Cognitive Examination. The presence of apathy was assessed by the proposed diagnostic criteria of Drijgers et al, and graded by both LARS and the ‘Apathy’ item of MDS-UPDRS.

Results: Based on multivariate regression analysis, we revealed the neurocognitive status, severity of depression, and also gender while applying dosage of dopamine agonists to determine the degree of patient apathy. Based on whether or not depression and neurocognitive disorders were indeed present, we established four different threshold values for the LARS: patients with normal cognition and without depression: –22.5; patients with normal cognition and with depression: –18.5; patients with NCD and without depression: –19.5; patients with NCD and with depression: –14.5.

Conclusions: The LARS and the ‘Apathy’ item of MDS-UPDRS were confirmed to be potentially operational, beneficial and easy-to-assess instruments for detecting apathy syndrome in PD. However, there is no universal threshold value for the LARS suitable in all types of Parkinson’s patients.
Transcriptomic Profiling of Extracellular RNAs Present in Cerebrospinal Fluid Identifies Differentially Expressed Transcripts in Parkinson’s Disease
Authors: Hossein-nezhad Arash , Fatemi Roya Pedram , Ahmad Rili , Peskind Elaine R. , Zabetian Cyrus P. , Hu Shu-Ching , Shi Min , Wahlestedt Claes , Zhang Jing , Faghihi Mohammad Ali
Published: April 2016

Background: Parkinson’s disease (PD) is a debilitating neurological disorder for which prognostic and diagnostic biomarkers are lacking. Cerebrospinal fluid (CSF) is an accessible body fluid that comes into direct contact with the central nervous system (CNS) and acts as a nuclease-free repository where RNA transcripts shed by brain tissues can reside for extended periods of time.

Objective: We studied the RNA species present in the CSF of PD patients to identify novel diagnostic biomarkers.

Methods: Small volumes of CSF from 27 PD patients and 30 healthy age- and sex-matched controls were used for RNA extraction followed by next-generation sequencing (RNA-seq) using the Illumina platform. CSF contains a number of fragmented RNA species that were individually sequenced and analyzed. Comparing PD to control subjects, we observed a pool of dysregulated sequencing tags that were further analyzed and validated by quantitative real-time PCR (qRT-PCR).

Results: A total of 201 differentially expressed sequencing tags (DETs), including 92 up-regulated and 109 down-regulated DETs were identified. We validated the following DETs by real time PCR in the patient samples: Dnmt1, Ezh2, CCR3, SSTR5,PTPRC, UBC, NDUFV2, BMP7, SCN9, SCN9 antisense ( AC010127.3), and long noncoding RNAs AC079630 and UC001lva.4 (close to the LRRK2 gene locus), as potential PD biomarkers.

Conclusions: The CSF is a unique environment that contains many species of RNA. Our work demonstrates that CSF can potentially be used to identify biomarkers for the detection and tracking of disease progression and evaluation of therapeutic outcomes.
Decoding Parkinson’s Disease Pathogenesis: The Role of Deregulated mRNA Translation
Authors: Martin Ian
Published: April 2016

Mutations in a number of genes cause rare familial forms of Parkinson’s disease and provide profound insight into potential mechanisms governing disease pathogenesis. Recently, a role for translation and metabolism of mRNA has emerged in the development of various neurodegenerative disorders including Parkinson’s disease (PD). In PD, preliminary evidence supports a role for aberrant translation in the disease process stemming from mutations in several genes. Translation control is central to maintaining organism homeostasis under variable environmental conditions and deregulation of this may predispose to certain stressors. Hypothetically, deregulated translation may be detrimental to neuronal viability in PD through the misexpression of a subset of transcripts or through the impact of excessive bulk translation on energy consumption and burden on protein homeostatic mechanisms. While compelling preliminary evidence exists to support a role for translation in PD, much more work is required to identify specific mechanisms linking altered translation to the disease process.
Impact of Mood and Behavioral Disorders on Quality of Life in Parkinson’s disease
Authors: Rieu Isabelle , Houeto Jean Luc , Pereira Bruno , De Chazeron Ingrid , Bichon Amélie , Chéreau Isabelle , Ulla Miguel , Brefel-Courbon Christine , Ory-Magne Fabienne , Dujardin Kathy , Tison François , Krack Paul , Durif Franck
Published: April 2016

Background: Mood symptoms negatively affect quality of life of Parkinson’s disease (PD); however little is known about the impact of behavioral disorders such as impulse control disorders, and non-motor fluctuations on quality of life.

Objective: To assess the impact of mood and behavioral disorders on quality of life in PD.

Methods: 136 (84% male) PD were included (mean age: 61±8y; mean duration of disease: 8.8±5.4y). Mood symptoms, behavioral disorders and non-motor fluctuations were detected and quantified using the recently validated “Ardouin Scale of Behavior in Parkinson’s Disease”. Motor symptoms were assessed using UPDRS and quality of life with the “39-item Parkinson’s Disease Questionnaire”.

Results: Both motor and non-motor factors significantly affected the quality of life of PD patients. Multivariate regression of the relationship between items of the quality of life questionnaire and the Ardouin Scale showed that alteration of patients’ quality of life was strongly correlated with the presence of mood symptoms (such as depression, anxiety ...) and with non-motor fluctuations (especially in the OFF period). A significant correlation was also found between the number of symptoms and their severity, and the quality of life deterioration. Some behavioral disorders (compulsive buying / eating behavior) also negatively affected patient’s quality of life to a lesser extent. Alternatively, excess in motivation and hobbyism behaviors had a positive impact on mobility and emotional well-being dimensions respectively of quality of life.

Conclusions: This study shows the main impact of mood symptoms and non-motor fluctuations on worsening quality of life in PD.
Retrograde Axonal Degeneration in Parkinson Disease
Authors: Tagliaferro Patricia , Burke Robert E.
Published: April 2016

In spite of tremendous research efforts we have not yet achieved two of our principal therapeutic goals in the treatment of Parkinson’s disease (PD), to prevent its onward progression and to provide restoration of systems that have already been damaged by the time of diagnosis. There are many possible reasons for our inability to make progress. One possibility is that our efforts thus far may not have been directed towards the appropriate cellular compartments. Up until now research has been largely focused on the loss of neurons in the disease. Thus, neuroprotection approaches have been largely aimed at blocking mechanisms that lead to destruction of the neuronal cell body. Attempts to provide neurorestoration have been almost entirely focused on replacement of neurons. We herein review the evidence that the axonal component of diseased neuronal systems merit more of our attention. Evidence from imaging studies, from postmortem neurochemical studies, and from genetic animal models suggests that the axons of the dopaminergic system are involved predominantly and early in PD. Since the mechanisms of axonal destruction are distinct from those of neuron cell body degeneration, a focus on axonal neurobiology will offer new opportunities for preventing their degeneration. At present these mechanisms remain largely obscure. However, defining them is likely to offer new opportunities for neuroprotection. In relation to neurorestoration, while it has been classically believed that neurons of the adult central nervous system are incapable of new axon growth, recent evidence shows that this is not true for the dopaminergic projection. In conclusion, the neurobiology of axons is likely to offer many new approaches to protective and restorative therapeutics.
Alterations in Activity-Dependent Neuroprotective Protein in Sporadic and Experimental Parkinson’s Disease
Authors: Chu Yaping , Morfini Gerardo A. , Kordower Jeffrey H.
Published: April 2016

Background: Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and neuronal survival. It is possible that intracellular alpha-synuclein ( α-syn) inclusions may be due to, or may cause, down-regulation of ADNP expression.

Objective: This study were to determine whether ADNP protein levels are altered in nigral dopaminergic neurons, establish whether ADNP alterations are associated with α-syn accumulation, and evaluate potential correlations between levels of ADNP expression and axonal transport motor proteins in sporadic and experimental Parkinson’s disease (PD).

Methods: Twenty human brains from PD ( n = 12) and age-matched controls ( n = 8) and sixteen rat brains received α-synuclein gene ( n = 8) or empty vector ( n = 8) were analyzed using immunohistochemistry. The number of ADNP labeled nigral neurons were estimated with stereology and the levels of ADNP were determined using densitometry.

Results: Compared to age-matched controls, a marked reduction in ADNP protein levels was observed in neuromelanin-containing nigral neurons of PD. Reduced ADNP levels did no relate to the progression of PD symptoms, but instead occurred at early PD stages, before reductions in tyrosine hydroxylase could be detected. Reductions in ADNP were also positively correlated with alterations in axonal transport motor protein. Reductions in ADNP levels were recapitulated in a rat model of PD based on viral over-expression of human wild-type α-synuclein, suggesting that ADNP reductions in PD are a direct result of α-synuclein overexpression.

Conclusion: These findings demonstrate that the down-regulation of protein ADNP is an early pathological alteration and may contribute to dopaminergic neurodegeneration in PD.
Impact of Climate Change on Natural Snow Reliability, Snowmaking Capacities, and Wind Conditions of Ski Resorts in Northeast Turkey: A Dynamical Downscaling Approach
Authors: Demiroglu Osman , Turp Mustafa , Ozturk Tugba , Kurnaz Mehmet
Published: April 2016

Many ski resorts worldwide are going through deteriorating snow cover conditions due to anthropogenic warming trends. As the natural and the artificially supported, i.e., technical, snow reliability of ski resorts diminish, the industry approaches a deadlock. For this reason, impact assessment studies have become vital for understanding vulnerability of ski tourism. This study considers three resorts at one of the rapidly emerging ski destinations, Northeast Turkey, for snow reliability analyses. Initially one global circulation model is dynamically downscaled by using the regional climate model RegCM4.4 for 1971–2000 and 2021–2050 periods along the RCP4.5 greenhouse gas concentration pathway. Next, the projected climate outputs are converted into indicators of natural snow reliability, snowmaking capacity, and wind conditions. The results show an overall decline in the frequencies of naturally snow reliable days and snowmaking capacities between the two periods. Despite the decrease, only the lower altitudes of one ski resort would face the risk of losing natural snow reliability and snowmaking could still compensate for forming the base layer before the critical New Year’s week. On the other hand, adverse high wind conditions improve as to reduce the number of lift closure days at all resorts. Overall, this particular region seems to be relatively resilient against climate change.
The NF-κB Pathway and Cancer Stem Cells
Authors: Rinkenbaugh Amanda , Baldwin Albert
Published: April 2016

The NF-κB transcription factor pathway is a crucial regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been identified in many types of cancer. Downstream of key oncogenic pathways, such as RAS, BCR-ABL, and Her2, NF-κB regulates transcription of target genes that promote cell survival and proliferation, inhibit apoptosis, and mediate invasion and metastasis. The cancer stem cell model posits that a subset of tumor cells (cancer stem cells) drive tumor initiation, exhibit resistance to treatment, and promote recurrence and metastasis. This review examines the evidence for a role for NF-κB signaling in cancer stem cell biology.
The Regulation of Cellular Responses to Mechanical Cues by Rho GTPases
Authors: Hoon Jing , Tan Mei , Koh Cheng-Gee
Published: April 2016

The Rho GTPases regulate many cellular signaling cascades that modulate cell motility, migration, morphology and cell division. A large body of work has now delineated the biochemical cues and pathways, which stimulate the GTPases and their downstream effectors. However, cells also respond exquisitely to biophysical and mechanical cues such as stiffness and topography of the extracellular matrix that profoundly influence cell migration, proliferation and differentiation. As these cellular responses are mediated by the actin cytoskeleton, an involvement of Rho GTPases in the transduction of such cues is not unexpected. In this review, we discuss an emerging role of Rho GTPase proteins in the regulation of the responses elicited by biophysical and mechanical stimuli.
High-Spin Chains and Crowns from Double-Exchange Mechanism
Authors: Chilkuri Vijay , Suaud Nicolas , Guihéry Nathalie
Published: April 2016

This article addresses the question of the possibility of obtaining high-spin chains and crowns of magnetic units s = 1 from doped (by a hole) antiferromagnetic architectures. It aims at determining the range of values of the double-exchange model interactions for which these molecules exhibit a high-spin ground state. Several chains and crowns of sizes varying between three to seven magnetic sites have been studied using a refined double-exchange model. It is shown that, for physical values of the parameters, linear chains of three, four and five sites are likely to adopt the highest spin state. For chains of six sites, small values of magnetic couplings are needed to get the highest spin, but it would be easy to get an S = 3/2 ground state. For systems of seven (or slightly more) sites, the highest spin state becomes non accessible but S = 5/2 states are likely to be obtained. Surprisingly, the physics of crowns is substantially different. The same trends are observed for even-number systems but with a larger double-exchange regime. At variance, odd-number systems do not exhibit a double-exchange mechanism for low values of the magnetic couplings. These observations are rationalized from an analysis of the computed spectra and wave functions.
Quantum Heat Machines Equivalence, Work Extraction beyond Markovianity, and Strong Coupling via Heat Exchangers
Authors: Uzdin Raam , Levy Amikam , Kosloff Ronnie
Published: April 2016

Various engine types are thermodynamically equivalent in the quantum limit of small “engine action”. Our previous derivation of the equivalence is restricted to Markovian heat baths and to implicit classical work repository (e.g., laser light in the semi-classical approximation). In this paper, all the components, baths, batteries, and engines, are explicitly taken into account. To neatly treat non-Markovian dynamics, we use mediating particles that function as a heat exchanger. We find that, on top of the previously observed equivalence, there is a higher degree of equivalence that cannot be achieved in the Markovian regime. Next, we focus on the quality of the battery charging process. A condition for positive energy increase and zero entropy increase (work) is given. Moreover, it is shown that, in the strong coupling regime, it is possible to super-charge a battery. With super-charging, the energy of the battery is increased while its entropy is being reduced at the same time.
Robot Motion Planning Using Adaptive Hybrid Sampling in Probabilistic Roadmaps
Authors: Kannan Ashwin , Gupta Prashant , Tiwari Rishabh , Prasad Shubham , Khatri Apurv , Kala Rahul
Published: April 2016

Motion planning deals with finding a collision-free trajectory for a robot from the current position to the desired goal. For a high-dimensional space, sampling-based algorithms are widely used. Different sampling algorithms are used in different environments depending on the nature of the scenario and requirements of the problem. Here, we deal with the problems involving narrow corridors, i.e., in order to reach its destination the robot needs to pass through a region with a small free space. Common samplers used in the Probabilistic Roadmap are the uniform-based sampler, the obstacle-based sampler, maximum clearance-based sampler, and the Gaussian-based sampler. The individual samplers have their own advantages and disadvantages; therefore, in this paper, we propose to create a hybrid sampler that uses a combination of sampling techniques for motion planning. First, the contribution of each sampling technique is deterministically varied to create time efficient roadmaps. However, this approach has a limitation: The sampling strategy cannot adapt as per the changing configuration spaces. To overcome this limitation, the sampling strategy is extended by making the contribution of each sampler adaptive, i.e., the sampling ratios are determined on the basis of the nature of the environment. In this paper, we show that the resultant sampling strategy is better than commonly used sampling strategies in the Probabilistic Roadmap approach.
Critical Filler Concentration in Sulfated Titania-Added Nafion™ Membranes for Fuel Cell Applications
Authors: Sgambetterra Mirko , Brutti Sergio , Allodi Valentina , Mariotto Gino , Panero Stefania , Navarra Maria
Published: April 2016

In this communication we present a detailed study of Nafion™ composite membranes containing different amounts of nanosized sulfated titania particles, synthesized through an optimized one-step synthesis procedure. Functional membrane properties, such as ionic exchange capacity and water uptake (WU) ability will be described and discussed, together with thermal analysis, atomic force microscopy and Raman spectroscopy data. Also electrochemical properties such as proton conductivity and performances in hydrogen fuel cells will be presented. It has been demonstrated that a critical concentration of filler particles can boost the fuel cell performance at low humidification, exhibiting a significant improvement of the maximum power and current density delivered under 30% low-relative humidity (RH) and 70 °C with respect to bare Nafion™-based systems.
MicroRNA and Heart Failure
Authors: Wong Lee , Wang Juan , Liew Oi , Richards Arthur , Chen Yei-Tsung
Published: April 2016

Heart failure (HF) imposes significant economic and public health burdens upon modern society. It is known that disturbances in neurohormonal status play an important role in the pathogenesis of HF. Therapeutics that antagonize selected neurohormonal pathways, specifically the renin-angiotensin-aldosterone and sympathetic nervous systems, have significantly improved patient outcomes in HF. Nevertheless, mortality remains high with about 50% of HF patients dying within five years of diagnosis thus mandating ongoing efforts to improve HF management. The discovery of short noncoding microRNAs (miRNAs) and our increasing understanding of their functions, has presented potential therapeutic applications in complex diseases, including HF. Results from several genome-wide miRNA studies have identified miRNAs differentially expressed in HF cohorts suggesting their possible involvement in the pathogenesis of HF and their potential as both biomarkers and as therapeutic targets. Unravelling the functional relevance of miRNAs within pathogenic pathways is a major challenge in cardiovascular research. In this article, we provide an overview of the role of miRNAs in the cardiovascular system. We highlight several HF-related miRNAs reported from selected cohorts and review their putative roles in neurohormonal signaling.
Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma
Authors: Shaikh Atik , Li Fangfei , Li Min , He Bing , He Xiaojuan , Chen Guofen , Guo Baosheng , Li Defang , Jiang Feng , Dang Lei , Zheng Shaowei , Liang Chao , Liu Jin , Lu Cheng , Liu Biao , Lu Jun , Wang Luyao , Lu Aiping , Zhang Ge
Published: April 2016

Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%–75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma.
Expression of Castor LPAT2 Enhances Ricinoleic Acid Content at the sn-2 Position of Triacylglycerols in Lesquerella Seed
Authors: Chen Grace , Van Erp Harrie , Martin-Moreno Jose , Johnson Kumiko , Morales Eva , Browse John , Eastmond Peter , Lin Jiann-Tsyh
Published: April 2016

Lesquerella is a potential industrial oilseed crop that makes hydroxy fatty acid (HFA). Unlike castor its seeds are not poisonous but accumulate lesquerolic acid mostly at the sn-1 and sn-3 positions of triacylglycerol (TAG), whereas castor contains ricinoleic acid (18:1OH) at all three positions. To investigate whether lesquerella can be engineered to accumulate HFAs in the sn-2 position, multiple transgenic lines were made that express castor lysophosphatidic acid acyltransferase 2 (RcLPAT2) in the seed. RcLPAT2 increased 18:1OH at the sn-2 position of TAGs from 2% to 14%–17%, which resulted in an increase of tri-HFA-TAGs from 5% to 13%–14%. Our result is the first example of using a LPAT to increase ricinoleic acid at the sn-2 position of seed TAG. This work provides insights to the mechanism of HFA-containing TAG assembly in lesquerella and directs future research to optimize this plant for HFA production.
UPLC-MS/MS-Based Profiling of Eicosanoids in RAW264.7 Cells Treated with Lipopolysaccharide
Authors: Lee Jae , Mok Hyuck , Lee Dae-Young , Park Seung , Ban Myeong , Choi Jehun , Park Chun , Ahn Young-Sup , Kim Kwang , Kim Hyung
Published: April 2016

While both the pro- and anti-inflammatory effects of several eicosanoids have been widely studied, the degree of inflammation in cells that results from various eicosanoids has yet to be comprehensively studied. The objective of this study was to assess the effect of lipopolysaccharide (LPS) treatment on eicosanoid content in RAW264.7 cells. An Ultra performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based profiling method was used to analyze the eicosanoid contents of RAW264.7 cells treated with different LPS concentrations. The profiling data were subjected to statistical analyses, such as principal component analysis (PCA) and hierarchical clustering analysis. LPS treatment increased nitric oxide production and secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, in a concentration-dependent manner. In total, 79 eicosanoids were identified in the cells. RAW264.7 cells treated with different LPS concentrations were well differentiated in the PCA score plot. A heatmap was used to identify the eicosanoids that were up- or down-regulated according to the degree of inflammation and LPS concentration. Thirty-nine eicosanoids were upregulated and seven were down-regulated by LPS treatment in a concentration-dependent manner. Our novel UPLC-MS/MS technique can profile eicosanoids, and can evaluate the correlations between inflammation and eicosanoid metabolism.
Cytotoxicity of Nanoparticles Contained in Food on Intestinal Cells and the Gut Microbiota
Authors: Fröhlich Esther , Fröhlich Eleonore
Published: April 2016

Toxicity of nanoparticles (NPs) upon oral exposure has been studied in animals using physiological changes, behavior, histology, and blood analysis for evaluation. The effects recorded include the combination of the action on cells of the exposed animal and the reaction of the microorganisms that populate the external and internal surfaces of the body. The importance of these microorganisms, collectively termed as microbiota, for the health of the host has been widely recognized. They may also influence toxicity of NPs but these effects are difficult to differentiate from toxicity on cells of the gastrointestinal tract. To estimate the likelihood of preferential damage of the microbiota by NPs the relative sensitivity of enterocytes and bacteria was compared. For this comparison NPs with antimicrobial action present in consumer products were chosen. The comparison of cytotoxicity with Escherichia coli as representative for intestinal bacteria and on gastrointestinal cells revealed that silver NPs damaged bacteria at lower concentrations than enterocytes, while the opposite was true for zinc oxide NPs. These results indicate that silver NPs may cause adverse effects by selectively affecting the gut microbiota. Fecal transplantation from NP-exposed animals to unexposed ones offers the possibility to verify this hypothesis.
The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions
Authors: Wu Shaowei , Fu Xiong , Brennan Margaret , Brennan Charles , Chun Chen
Published: April 2016

Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 104 Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent.
Can International Human Rights Law Help Restore Access to Justice for Disabled Workers?
Authors: Harwood Rupert
Published: April 2016

The research literature indicates that legislative changes in recent years, including the introduction of tribunal fees, have made it harder for workers in general to enforce their rights under UK employment laws. Drawing on the author’s qualitative study, conducted in 2015 and with information from 265 participants, this paper finds that these legislative changes could be having disproportionate adverse impacts on disabled workers. Of particular note, fees had deterred substantial numbers from submitting discrimination claims; and it appeared that this reluctance to take legal action had in turn emboldened some employers to commit what might have been found to constitute unlawful acts if taken to tribunal. The paper goes onto consider whether these adverse impacts on disabled workers could render fees unlawful under UK and European equality and human rights law and/or could entail violations of rights under the United Nations Convention on the Rights of Persons with Disabilities. The paper concludes that the intent behind UK laws might (in relation to the lawfulness of fees) have been frustrated in the domestic courts and that the impact of any future successes in the domestic courts, or under international law, might be dependent upon public opinion and political expediency. The paper also briefly compares developments in Britain with developments in neighbouring and other comparable jurisdictions.
Application of Direct Current Atmospheric Pressure Glow Microdischarge Generated in Contact with a Flowing Liquid Solution for Synthesis of Au-Ag Core-Shell Nanoparticles
Authors: Dzimitrowicz Anna , Jamroz Piotr , Nyk Marcin , Pohl Pawel
Published: April 2016

A direct current atmospheric pressure glow microdischarge (dc-μAPGD) generated between an Ar nozzle microjet and a flowing liquid was applied to produce Au-Ag core-shell nanoparticles (Au@AgCSNPs) in a continuous flow system. Firstly, operating dc-μAPGD with the flowing solution of the Au(III) ions as the cathode, the Au nanoparticles (AuNPs) core was produced. Next, to produce the core-shell nanostructures, the collected AuNPs solution was immediately mixed with an AgNO3 solution and passed through the system with the reversed polarity to fabricate the Ag nanoshell on the AuNPs core. The formation of Au@AgCSNPs was confirmed using ultraviolet-visible (UV-Vis) absorbance spectrophotometry, transmission electron microscopy (TEM), and energy-dispersive X-ray spectroscopy (EDS). Three localized surface plasmon resonance absorption bands with wavelengths centered at 372, 546, and 675 nm were observed in the UV-Vis spectrum of Au@AgCSNPs, confirming the reduction of both the Au(III) and Ag(I) ions. The right configuration of metals in Au@AgCSNPs was evidenced by TEM. The Au core diameter was 10.2 ± 2.0 nm, while the thickness of the Ag nanoshell was 5.8 ± 1.8 nm. The elemental composition of the bimetallic nanoparticles was also confirmed by EDS. It is possible to obtain 90 mL of a solution containing Au@AgCSNPs per hour using the applied microdischarge system.