Search results for: T. J Parkinson

Authors: Srishty Gulati, Anju Singh, Shrikant Kukreti

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The manifestation of structural polymorphism in DNA depends on the sequence and surrounding environment. Ample of folded DNA structures have been found in the cellular system out of which DNA hairpins are very common, however, are indispensable due to their role in the replication initiation sites, recombination, transcription regulation, and protein recognition. We enumerate this approach in our study, where the two base substitutions and change in temperature embark destabilization of DNA structure and misbalance the equilibrium between two structures of a sequence present at the overlapping region of the human COMT gene and MIR4761 gene. COMT and MIR4761 gene encodes for catechol-O-methyltransferase (COMT) enzyme and microRNAs (miRNAs), respectively. Environmental changes and errors during cell division lead to genetic abnormalities. The COMT gene entailed in dopamine regulation fosters neurological diseases like Parkinson's disease, schizophrenia, velocardiofacial syndrome, etc. A 19-mer deoxyoligonucleotide sequence 5'-AGGACAAGGTGTGCATGCC-3' (COMT19) is located at exon-4 on chromosome 22 and band q11.2 at the intersection of COMT and MIR4761 gene. Bioinformatics studies suggest that this sequence is conserved in humans and few other organisms and is involved in recognition of transcription factors in the vicinity of 3'-end. Non-denaturating gel electrophoresis and CD spectroscopy of COMT sequences indicate the formation of hairpin type DNA structures. Temperature-dependent CD studies revealed an unusual shift in the slipped DNA-Hairpin DNA equilibrium with the change in temperature. Also, UV-thermal melting techniques suggest that the two base substitutions on the complementary strand of COMT19 did not affect the structure but reduces the stability of duplex. This study gives insight about the possibility of existing structurally polymorphic transient states within DNA segments present at the intersection of COMT and MIR4761 gene.

Keywords: base-substitution, catechol-o-methyltransferase (COMT), hairpin-DNA, structural polymorphism

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Authors: Ahdab H. Mahdaly, Debajyoti Pati, Sharran Parkinson, Lee S. Duemer

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The importance of providing employed mothers with the right physical environment inside the home is not an easy task, especially when the culture is involved. This study examines the typical Saudi home as a personal, emotional, social and cultural setting, especially on the interactions between the physical design and perceived control of working mothers. However, owing to the scarcity of published literature on Saudi homes, American employed mothers were included in the study to provide a baseline. With the ongoing transformations in women’s role in Saudi Arabia, there is a perception that traditional home designs may not afford the appropriate sense of control inside the home. Saudi Arabia has numerous interacting layers of socio-cultural-religious forces that affect residential design, and understanding the moderating role of the Saudi home is vital to the ongoing national policy transition on women. The study investigated one narrow, albeit critical, influence of home design on ones sense of control – direct visual and physical accessibility between sets of rooms. Ten subjects, five Saudis and five American, examined visual and physical access between 171 room sets, and provided qualitative responses on how each access influences their sense of control. Three main themes emerged, with potential effects on control: 1- Openness, 2- Proximity, and 3- Separation. Data suggest that although the Saudi home is a substantially more complex setting than the American ones, a class of spaces that can be termed as ‘Neutral Rooms’ serving as cultural separators may represent the ideal solution for optimizing sense of control, without ignoring cultural-religious traditions, during the transition of the Saudi women.

Keywords: direct physical accessibility, home environment, sense of control, visual accessibility, working mothers

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Authors: Younus Mohammad, Anita B. Fallah, Ben J. Boyd, Shakila B. Rizwan

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N-acylethanolamines (NAEs) are endogenous lipids, which have neuromodulatory properties. NAEs have shown neuroprotective properties in various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and ischemic stroke. However, NAEs are eliminated rapidly in vivo by enzymatic hydrolysis. We propose to encapsulate NAEs in liquid crystalline nanoparticles (cubosomes) to increase their biological half-life and explore their therapeutic potential. Recently, we have reported the co-formulation and nanostructural characterization of cubosomes containing the NAE, oleoylethanolamide and a synthetic cubosome forming lipid phytantriol. Here, we report on the formulation of cubosomes with the NAE, linoleoylethanolamide (LEA) as the core cubosome forming lipid. LEA-cubosomes were formulated in the presence of three different steric stabilisers: two brain targeting ligands, Tween 80 and Pluronic P188 and a control, Pluronic F127. Size, morphology and internal structure of formulations were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo–TEM) and small angle X–ray scattering (SAXS), respectively. Chemical stability of LEA in formulations was investigated using high-performance liquid chromatography (HPLC). Cytotoxicity of formulations towards human cerebral microvascular endothelial cell line (hCMEC/D3) was also investigated using an MTT (3-[4, 5- dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide) assay. All cubosome formulations had mean particle size of less than 250 nm and were uniformly distributed with polydispersity indices less than 0.2. Cubosomes produced had a bicontinuous cubic internal structure with an Im3m space group but different lattice parameters, indicating the different modes of interaction between the stabilisers and LEA. LEA in formulations was found to be chemically stable. At concentrations of up to 20 µg/mL LEA in the presence of all the stabilisers, greater than 80% cell viability was observed.

Keywords: blood-brain barrier, cubosomes, linoleoyl ethanolamide, N-acylethanolamines (NAEs)

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Authors: Shay Kee Tan, Kok Haur Ng, Jennifer So-Kuen Chan

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This paper extends the conditional autoregressive range (CARR) model to multivariate CARR (MCARR) model and further to the two-stage MCARR-return model to model and forecast volatilities, correlations and returns of multiple financial assets. The first stage model fits the scaled realised Parkinson volatility measures using individual series and their pairwise sums of indices to the MCARR model to obtain in-sample estimates and forecasts of volatilities for these individual and pairwise sum series. Then covariances are calculated to construct the fitted variance-covariance matrix of returns which are imputed into the stage-two return model to capture the heteroskedasticity of assets’ returns. We investigate different choices of mean functions to describe the volatility dynamics. Empirical applications are based on the Standard and Poor 500, Dow Jones Industrial Average and Dow Jones United States Financial Service Indices. Results show that the stage-one MCARR models using asymmetric mean functions give better in-sample model fits than those based on symmetric mean functions. They also provide better out-of-sample volatility forecasts than those using CARR models based on two robust loss functions with the scaled realised open-to-close volatility measure as the proxy for the unobserved true volatility. We also find that the stage-two return models with constant means and multivariate Student-t errors give better in-sample fits than the Baba, Engle, Kraft, and Kroner type of generalized autoregressive conditional heteroskedasticity (BEKK-GARCH) models. The estimates and forecasts of value-at-risk (VaR) and conditional VaR based on the best MCARR-return models for each asset are provided and tested using Kupiec test to confirm the accuracy of the VaR forecasts.

Keywords: range-based volatility, correlation, multivariate CARR-return model, value-at-risk, conditional value-at-risk

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Authors: R. Bužgová, R. Kozáková, M. Škutová, M. Bar, P. Ressner, P. Bártová

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Introduction: Currently, there has been an increasing concern about the provision of palliative care in non-oncological patients in both professional literature and clinical practice. However, there is not much scientific information on how to provide neurological and palliative care together. The main objective of the project is to create and to verify a concept of neuro-palliative and rehabilitative care for patients with selected neurological diseases in an advanced stage of the disease and also to evaluate bio-psychosocial and spiritual needs of these patients and their caregivers related to the quality of life using created standardized tools. Methodology: Triangulation of research methods (qualitative and quantitative) will be used. A concept of care and assessment tools will be developed by analyzing interviews and focus groups. Qualitative data will be analyzed using grounded theory. The concept of care will be tested in the context of the intervention study. Using quantitative analysis, we will assess the effect of an intervention provided on the saturation of needs, quality of life, and quality of care. A research sample will be made up of the patients with selected neurological diseases (Parkinson´s syndrome, motor neuron disease, multiple sclerosis, Huntington’s disease), together with patients´ family members. Based on the results, educational materials and a certified course for health care professionals will be created. Findings: Based on qualitative data analysis, we will propose the concept of integrated care model combining neurological, rehabilitative and specialist palliative care for patients with selected neurological diseases in different settings of care and services. Patients´ needs related to quality of life will be described by newly created and validated measuring tools before the start of intervention (application of neuro-palliative and palliative approach) and then in the time interval. Conclusion: Based on the results, educational materials and a certified course for doctors and health care professionals will be created.

Keywords: multidisciplinary approach, neuropalliative care, research, quality of life

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Authors: Hajar Zarei, AliAkbar Zarenejadatashgah, Vuk Uskoković, Hiroshi Watabe

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The reactive oxygen species (ROS) generated by radiation in nuclear diagnostic imaging and radiotherapy could damage the structure of the proteins in noncancerous cells surrounding the tumor. The critical factor in many age-related diseases, such as Alzheimer, Parkinson, or Huntington diseases, is the oxidation of proteins by the ROS as molecular triggers of the given pathologies. Our studies by spectroscopic experiments showed doses close to therapeutic ones (1 to 5 Gy) could lead to changes of secondary and tertiary structures in BSA protein macromolecule as a protein model as well as the aggregation of polypeptide chain but without the fragmentation. For this reason, we investigated the radioprotective effects of natural (vitamin C and E) and synthetic materials (CNPs and FIOMPs) on the structural changes in BSA protein induced by gamma irradiation at a therapeutic dose (3Gy). In the presence of both vitamins and synthetic materials, the spectroscopic studies revealed that irradiated BSA was protected from the structural changes caused by ROS, according to in vitro research. The radioprotective property of CNPs and FIOMPs arises from enzyme mimetic activities (catalase, superoxide dismutase, and peroxidase) and their antioxidant capability against hydroxyl radicals. In the case of FIOMPs, a porous structure also leads to increased ROS recombination with each other in the same radiolytic track and subsequently decreased encounters with BSA. The hydrophilicity of vitamin C resulted in the major scavenging of ROS in the solvent, whereas hydrophobic vitamin E localized on the nonpolar patches of the BSA surface, where it did not only neutralize them thanks to the moderate BSA binding constant but also formed a barrier for diffusing ROS. To the best of our knowledge, there has been a persistent lack of studies investigating the radioactive effect of mentioned materials on proteins. Therefore, the results of our studies can open a new widow for application of these common dietary ingredients and new synthetic NPs in improving the safety of radiotherapy.

Keywords: reactive oxygen species, spectroscopy, bovine serum albumin, gamma radiation, radioprotection

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Authors: Tanakrit Doltanakarn

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Introduction: These days, cannabis is being accepted in many countries due to the fact that cannabis could be use in medical. The medical cannabis is used to treat and reduce the pain many diseases. For example, neuropathic pain, Parkinson, autism disorders, cancer pain reduce the adverse effect of chemotherapy, diabetes, and migraine. Active ingredients in cannabis that modulate patients' perceptions of their conditions include Δ9‐tetrahydrocannabinol (THC), cannabidiol (CBD), flavonoids, and terpenes. However, there is an adverse effect of cannabis, cardiovascular effects, psychosis, schizophrenia, mood disorder, and cognitive alternation. These effects are from the THC and CBD ingredients in the cannabis. The metabolize processes of delta-9 THC to 11-OH-delta 9 -THC (inactive form), THC were cause of adverse effects. Interestingly, the distributions of CYP2C9 gene (CYP2C9*2 and CYP2C9*3, poor metabolizer) that might affect incidences of adverse effects in patients who treated with medical cannabis. Objective: The aim of this study we want to investigate the association between genetic polymorphism of CYP2C9 frequency and Thai patients who treated with medical cannabis. Materials and Methods:We recruited sixty-five unrelated Thai patients from the College of Pharmacy, Rangsit University. DNA were extracted using Genomic DNA Mini Kit. Genotyping of CYP2C9*2 (430C>T, rs1799853) and CYP2C9*3 (1075A>C, rs1057910) were genotyped by the TaqMan Real-time PCR assay. Results: Among these 31 medicals cannabis-induced ADRs patients, they were diagnosed with 22 (33.85%) tachycardia and 3 (4.62%) arrhythmia. There were 34 (52.31%) medical cannabis-tolerant controls who were included in this study.40 (61.53%) Thai patients were female, and 25 (38.46%) were male, with median age of 57 (range 27 – 87) years. In this study, we found none of the medical cannabis-induced ADRs carried CYP2C9*2 variant along with medical cannabis-tolerant control group. CYP2C9*3 variant (intermediate metabolizer, IM) was found just only one of thirty-one (3.23%) in the medical cannabis-induced ADRs and two of thirty-fourth (5.88%) in the tolerant controls. Conclusions: Thus, the distribution of CYP2C9 alleles offer a comprehensive view of pharmacogenomics marker in Thai population that could be used as a reference for worldwide to investigate the pharmacogenomics application.

Keywords: medical cannabis, adverse effect, CYP2C9, thai patients

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Authors: Sandra Baez, Mariana Pino, Mildred Berrio, Hernando Santamaria-Garcia, Lucas Sedeno, Adolfo Garcia, Sol Fittipaldi, Agustin Ibanez

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Schadenfreude refers to the perceiver’s experience of pleasure at another’s misfortune. This is a multidetermined emotion which can be evoked by hostile feelings and envy. The experience of Schadenfreude engages mechanisms implicated in diverse social cognitive processes. For instance, Schadenfreude involves heightened reward processing, accompanied by increased striatal engagement and it interacts with mentalizing and perspective-taking abilities. Patients with Huntington's disease (HD) exhibit reductions of Schadenfreude experience, suggesting a role of striatal degeneration in such an impairment. However, no study has directly assessed the relationship between regional brain atrophy in HD and reduced Schadenfreude. This study investigated whether gray matter (GM) atrophy in HD patients correlates with ratings of Schadenfreude. First, we compared the performance of 20 HD patients and 23 controls on an experimental task designed to trigger Schadenfreude and envy (another social emotion acting as a control condition). Second, we compared GM volume between groups. Third, we examined brain regions where atrophy might be associated with specific impairments in the patients. Results showed that while both groups showed similar ratings of envy, HD patients reported lower Schadenfreude. The latter pattern was related to atrophy in regions of the reward system (ventral striatum) and the mentalizing network (precuneus and superior parietal lobule). Our results shed light on the intertwining of reward and socioemotional processes in Schadenfreude, while offering novel evidence about their neural correlates. In addition, our results open the door to future studies investigating social emotion processing in other clinical populations characterized by striatal or mentalizing network impairments (e.g., Parkinson’s disease, schizophrenia, autism spectrum disorders).

Keywords: envy, Gray matter atrophy, Huntigton's disease, Schadenfreude, social emotions

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Authors: Cornelia-Eugenia Munteanu

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The goal of this paper is to present the diagnostic contribution that the screening instrument, Mini-Mental State Examination-2: Expanded Version (MMSE-2:EV), brings in detecting the cognitive impairment or in monitoring the progress of degenerative disorders. The diagnostic signification is underlined by the interpretation of the MMSE-2:EV scores, resulted from the test application to patients with mild and major neurocognitive disorders. The original MMSE is one of the most widely used screening tools for detecting the cognitive impairment, in clinical settings, but also in the field of neurocognitive research. Now, the practitioners and researchers are turning their attention to the MMSE-2. To enhance its clinical utility, the new instrument was enriched and reorganized in three versions (MMSE-2:BV, MMSE-2:SV and MMSE-2:EV), each with two forms: blue and red. The MMSE-2 was adapted and used successfully in Romania since 2013. The cases were selected from current practice, in order to cover vast and significant neurocognitive pathology: mild cognitive impairment, Alzheimer’s disease, vascular dementia, mixed dementia, Parkinson’s disease, conversion of the mild cognitive impairment into Alzheimer’s disease. The MMSE-2:EV version was used: it was applied one month after the initial assessment, three months after the first reevaluation and then every six months, alternating the blue and red forms. Correlated with age and educational level, the raw scores were converted in T scores and then, with the mean and the standard deviation, the z scores were calculated. The differences of raw scores between the evaluations were analyzed from the point of view of statistic signification, in order to establish the progression in time of the disease. The results indicated that the psycho-diagnostic approach for the evaluation of the cognitive impairment with MMSE-2:EV is safe and the application interval is optimal. The alternation of the forms prevents the learning phenomenon. The diagnostic accuracy and efficient therapeutic conduct derive from the usage of the national test norms. In clinical settings with a large flux of patients, the application of the MMSE-2:EV is a safe and fast psycho-diagnostic solution. The clinicians can draw objective decisions and for the patients: it doesn’t take too much time and energy, it doesn’t bother them and it doesn’t force them to travel frequently.

Keywords: MMSE-2, dementia, cognitive impairment, neuropsychology

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Authors: Bright Chukwunwike Uzuegbunam, Wojciech Paslawski, Hans Agren, Christer Halldin, Wolfgang Weber, Markus Luster, Thomas Arzberger, Behrooz Hooshyar Yousefi

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There is a need to develop a PET tracer that will enable to diagnosis and track the progression of Alpha-synucleinopathies (Parkinson’s disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA]) in living subjects over time. Alpha-synuclein aggregates (a-syn), which are present in all the stages of disease progression, for instance, in PD, are a suitable target for in vivo PET imaging. For this reason, we have developed some promising a-syn tracers based on a disarylbisthiazole (DABTA) scaffold. The precursors are synthesized via a modified Hantzsch thiazole synthesis. The precursors were then radiolabeled via one- or two-step radiofluorination methods. The ligands were initially screened using a combination of molecular dynamics and quantum/molecular mechanics approaches in order to calculate the binding affinity to a-syn (in silico binding experiments). Experimental in vitro binding assays were also performed. The ligands were further screened in other experiments such as log D, in vitro plasma protein binding & plasma stability, biodistribution & brain metabolite analyses in healthy mice. Radiochemical yields were up to 30% - 72% in some cases. Molecular docking revealed possible binding sites in a-syn and also the free energy of binding to those sites (-28.9 - -66.9 kcal/mol), which correlated to the high binding affinity of the DABTAs to a-syn (Ki as low as 0.5 nM) and selectivity (> 100-fold) over Aβ and tau, which usually co-exist with a-synin some pathologies. The log D values range from 2.88 - 2.34, which correlated with free-protein fraction of 0.28% - 0.5%. Biodistribution experiments revealed that the tracers are taken up (5.6 %ID/g - 7.3 %ID/g) in the brain at 5 min (post-injection) p.i., and cleared out (values as low as 0.39 %ID/g were obtained at 120 min p.i. Analyses of the mice brain 20 min p.i. Revealed almost no radiometabolites in the brain in most cases. It can be concluded that in silico study presents a new venue for the rational development of radioligands with suitable features. The results obtained so far are promising and encourage us to further validate the DABTAs in autoradiography, immunohistochemistry, and in vivo imaging in non-human primates and humans.

Keywords: alpha-synuclein aggregates, alpha-synucleinopathies, PET imaging, tracer development

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Authors: Semyachkina-Glushkovskaya Oxana, Fedosov Ivan, Blokhina Inna, Terskov Andrey, Evsukova Arina, Elovenko Daria, Adushkina Viktoria, Dubrovsky Alexander, Jürgen Kurths

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In modern neurobiology, sleep is considered a novel biomarker and a promising therapeutic target for brain diseases. This is due to recent discoveries of the nighttime activation of the brain lymphatic system (BLS), playing an important role in the removal of wastes and toxins from the brain and contributes neuroprotection of the central nervous system (CNS). In our review, we discuss that night stimulation of BLS might be a breakthrough strategy in a new treatment of Alzheimer’s and Parkinson’s disease, stroke, brain trauma, and oncology. Although this research is in its infancy, however, there are pioneering and promising results suggesting that night transcranial photostimulation (tPBM) stimulates more effectively lymphatic removal of amyloid-beta from mouse brain than daily tPBM that is associated with a greater improvement of the neurological status and recognition memory of animals. In our previous study, we discovered that tPBM modulates the tone and permeability of the lymphatic endothelium by stimulating NO formation, promoting lymphatic clearance of wastes and toxins from the brain tissues. We also demonstrate that tPBM can also lead to angio- and lymphangiogenesis, which is another mechanism underlying tPBM-mediated stimulation of BLS. Thus, photo-augmentation of BLS might be a promising therapeutic target for preventing or delaying brain diseases associated with BLS dysfunction. Here we present pioneering technology for simultaneous tPBM in humans and sleep monitoring for stimulation of BLS to remove toxins from CNS and modulation of brain immunity. The wireless-controlled gadget includes a flexible organic light-emitting diode (LED) source that is controlled directly by a sleep-tracking device via a mobile application. The designed autonomous LED source is capable of providing the required therapeutic dose of light radiation at a certain region of the patient’s head without disturbing of sleeping patient. To minimize patients' discomfort, advanced materials like flexible organic LEDs were used. Acknowledgment: This study was supported by RSF project No. 23-75-30001.

Keywords: brain diseases, brain lymphatic system, phototherapy, sleep

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Authors: David Martinez-Pernia, Alvaro Rivera-Rei, Alejandro Troncoso, Gonzalo Forno, Andrea Slachevsky, David Huepe, Victoria Silva-Mack, Jorge Calderon, Mayte Vergara, Valentina Carrera

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Background: Recent theories in the field of emotions have taken the relevance of motor control beyond a system related to personal autonomy (walking, running, grooming), and integrate it into the emotional dimension. However, to our best knowledge, there are no studies that specifically investigate how emotional stimuli related to motor control modify emotional states in terms of postural control and phenomenological experience. Objective: The main aim of this work is to investigate the emotions produced by stimuli of bodily imbalance (neutral, pleasant and unpleasant) in the postural control and the phenomenological experience of young, healthy adults. Methodology: 46 healthy young people are shown emotional videos (neutral, pleasant, motor unpleasant, and non-motor unpleasant) related to the body imbalance. During the period of stimulation of each of the videos (60 seconds) the participant is standing on a force platform to collect temporal and spatial data of postural control. In addition, the electrophysiological activity of the heart and electrodermal activity is recorded. In relation to the two unpleasant conditions (motor versus non-motor), a phenomenological interview is carried out to collect the subjective experience of emotion and body perception. Results: Pleasant and unpleasant emotional videos have significant changes with respect to the neutral condition in terms of greater area, higher mean velocity, and greater mean frequency power on the anterior-posterior axis. The results obtained with respect to the electrodermal response was that the pleasurable and unpleasant conditions produced a significant increase in the phasic component with respect to the neutral condition. Regarding the electrophysiology of the heart, no significant change was found in any condition. Phenomenological experiences in the two unpleasant conditions differ in body perception and the emotional meaning of the experience. Conclusion: Emotional stimuli related to bodily imbalance produce changes in postural control, electrodermal activity, and phenomenological experience. This experimental setting could be relevant to be implemented in people with motor disorders (Parkinson, Stroke, TBI) to know how emotions affect motor control.

Keywords: body imbalance stimuli, emotion, phenomenological experience, postural control

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Authors: M. L. W. P. De Silva, R. A. C. Rabel, N. Smith, L. McIntyre, T. J Parkinson, K. A. N. Wijayawardhane

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Curricular integration is an important concept in medical education for developing students’ ability to create connections between different medical disciplines. Problem-Based Learning (PBL) is one of the vehicles through which such integration can be achieved. During the recent review of the veterinary curriculum at the University of Peradeniya, a series of courses in Integrative Veterinary Science (IVS) were introduced, in which PBL was the primary teaching methodology. The objectives of this study were to evaluate students’ opinions on PBL as a teaching method: it should be noted that, within the context of secondary and tertiary education in Sri Lanka, this would be an entirely novel learning experience for the students. Opinions were sought at the conclusion of IVS sessions where students of semesters 2, 4, 6, and 7 (of an 8-semester program) were exposed to a two, 2-hour PBL-based case scenario. The PBL-based case scenario in semesters 2, 4, and 7 were delivered using material previously developed by an experienced PBL practitioner, whilst material for semester 6 was prepared de novo by a less experienced practitioner. Each student (semesters 2: n=38, 4: n=37, 6: n=55, and 7: n=40) completed a questionnaire which asked whether: (i) the course had improved their critical thinking skills; (ii) the learning environment was sufficiently comfortable to express/share student’s opinion; (iii) there was sufficient facilitator guidance; (iv) the online study environment enhanced learning; and (v) the students were overall satisfied with the PBL approach and IVS concept. Responses were given on a 5-point Likert-scale (strongly agree (SA), agree (A), neutral (N), disagree (D), and strongly disagree (SD)). SA and A responses were summed to provide an overall ‘satisfactory’ response. Results were subjected to frequency-distribution statistical analysis. A total of 88.5% of students gave SA+A scores to their overall satisfaction. The proportion of SA+A scores differed between different semesters, such that 95% of semester 2, 4, and 7 students gave SA+A scores, whereas only 69% of semester 6 students did so for their respective sessions. Overall, 96% of the students gave SA+A scores to the question relating to the improvement of critical thinking skills: semester 6 students’ scores were marginally, but not significantly, lower (91% SA+A) than those in other semesters. The difference of scores between semester 6 and the other semesters may be attributed to the different PBL-material used and/or the different experience levels of the practitioners that developed the study material. The use of PBL as a means of teaching IVS curriculum-integration courses was well-received by the students in terms of their overall satisfaction and their perceptions of improved critical thinking skills. Importantly, this was achieved in the face of a methodology that was entirely novel to the students. Finally, the delivery of the PBL medium was readily mastered by the practitioner to whom it was also a novel methodology.

Keywords: critical thinking skills, integration, problem based learning, veterinary education

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Authors: Kate Parkinson

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A Family Group Conference (FGC) is a family-led decision-making process through which a family/kinship group, rather than the professionals involved, is asked to develop a plan for the care or the protection of children in the family. In England and Wales, FGCs are used in 76% of local authorities and in recent years, have tended to be used in cases where the local authority are considering the court process to remove children from their immediate family, to explore kinship alternatives to local authority care. Some local authorities offer the service much earlier, when families first come to the attention of children's social care, in line with research that suggests the earlier an FGC is held, the more likely they are to be successful. Family plans that result from FGCs are different from professional plans in that they are unique to a family and, as a result, reflect the diversity of families. Despite the fact that FGCs are arguable the most researched area of social work globally, there is a dearth of research that examines the nature of family plans and their substance. This paper presents the findings of a documentary analysis of 42 Early Help FGC plans from local authorities in England, with the aim of exploring the level and type of support that family members offer at a FGC. A thematic analysis identified 5 broad areas of support: Practical Support, Building Relationships, Child-care Support, Emotional Support and Social Support. In the majority of cases, family members did not want or ask for any formal support from the local authority or other agencies. Rather, the families came together to agree a plan of support, which was within the parameters of the resources that they as a family could provide. Perhaps then the role of the Early Help professional should be one of a facilitating and enabling role, to support families to develop plans that address their own specific difficulties, rather than the current default option, which is to either close the case because the family do not meet service thresholds or refer to formal support if they do, which may offer very specific support, have rigid referral criteria, long waiting lists and may not reflect the diverse and unique nature of families. FGCs are argued to be culturally appropriate social work practices in that they are appropriate for families from a range of cultural backgrounds and can be adapted to meet particular cultural needs. Furthermore, research on the efficacy of FGCs at an Early Help Level has demonstrated that Early Help FGCs have the potential to address difficulties in family life and prevent the need for formal support services, which are potentially stigmatising and do not reflect the uniqueness and diversity of families. The paper concludes with a recommendation for the use of FGCs across Early Help Services in England and Wales.

Keywords: family group conferences, family led decision making, early help, prevention

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Authors: Marcin Stasiulewicz, Sebastian Filipkowski, Aneta Panuszko

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Background: The hallmark of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, is an aggregation of the abnormal forms of peptides and proteins. Water is essential to functioning biomolecules, and it is one of the key factors influencing protein folding and misfolding. However, the hydration studies of proteins are complicated due to the complexity of protein systems. The use of model compounds can facilitate the interpretation of results involving larger systems. Objectives: The goal of the research was to characterize the properties of the hydration water surrounding the two three-residue K peptide fragments INS (Isoleucine - Asparagine - Serine) and NSR (Asparagine - Serine - Arginine). Methods: Fourier-transform infrared spectra of aqueous solutions of the tripeptides were recorded on Nicolet 8700 spectrometer (Thermo Electron Co.) Measurements were carried out at 25°C for varying molality of solute. To remove oscillation couplings from water spectra and, consequently, obtain narrow O-D semi-heavy water bands (HDO), the isotopic dilution method of HDO in H₂O was used. The difference spectra method allowed us to isolate the tripeptide-affected HDO spectrum. Results: The structural and energetic properties of water affected by the tripeptides were compared to the properties of pure water. The shift of the values of the gravity center of bands (related to the mean energy of water hydrogen bonds) towards lower values with respect to the ones corresponding to pure water suggests that the energy of hydrogen bonds between water molecules surrounding tripeptides is higher than in pure water. A comparison of the values of the mean oxygen-oxygen distances in water affected by tripeptides and pure water indicates that water-water hydrogen bonds are shorter in the presence of these tripeptides. The analysis of differences in oxygen-oxygen distance distributions between the tripeptide-affected water and pure water indicates that around the tripeptides, the contribution of water molecules with the mean energy of hydrogen bonds decreases, and simultaneously the contribution of strong hydrogen bonds increases. Conclusions: It was found that hydrogen bonds between water molecules in the hydration sphere of tripeptides are shorter and stronger than in pure water. It means that in the presence of the tested tripeptides, the structure of water is strengthened compared to pure water. Moreover, it has been shown that in the vicinity of the Asparagine - Serine - Arginine, water forms stronger and shorter hydrogen bonds. Acknowledgments: This work was funded by the National Science Centre, Poland (grant 2017/26/D/NZ1/00497).

Keywords: amyloids, K-peptide, hydration, FTIR spectroscopy

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Authors: Sulalit Bandyopadhyay, Muhammad Awais Ashfaq Alvi, Anuvansh Sharma, Wilhelm R. Glomm

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Release of drugs from nanogels and nanogel-based systems can occur under the influence of external stimuli like temperature, pH, magnetic fields and so on. pNIPAm-AAc nanogels respond to the combined action of both temperature and pH, the former being mostly determined by hydrophilic-to-hydrophobic transitions above the volume phase transition temperature (VPTT), while the latter is controlled by the degree of protonation of the carboxylic acid groups. These nanogels based systems are promising candidates in the field of drug delivery. Combining nanogels with magneto-plasmonic nanoparticles (NPs) introduce imaging and targeting modalities along with stimuli-response in one hybrid system, thereby incorporating multifunctionality. Fe@Au core-shell NPs possess optical signature in the visible spectrum owing to localized surface plasmon resonance (LSPR) of the Au shell, and superparamagnetic properties stemming from the Fe core. Although there exist several synthesis methods to control the size and physico-chemical properties of pNIPAm-AAc nanogels, yet, there is no comprehensive study that highlights the dependence of incorporation of one or more layers of NPs to these nanogels. In addition, effective determination of volume phase transition temperature (VPTT) of the nanogels is a challenge which complicates their uses in biological applications. Here, we have modified the swelling-collapse properties of pNIPAm-AAc nanogels, by combining with Fe@Au NPs using different solution based methods. The hydrophilic-hydrophobic transition of the nanogels above the VPTT has been confirmed to be reversible. Further, an analytical method has been developed to deduce the average VPTT which is found to be 37.3°C for the nanogels and 39.3°C for nanogel coated Fe@Au NPs. An opposite swelling –collapse behaviour is observed for the latter where the Fe@Au NPs act as bridge molecules pulling together the gelling units. Thereafter, Cyt C, a model protein drug and L-Dopa, a drug used in the clinical treatment of Parkinson’s disease were loaded separately into the nanogels and nanogel coated Fe@Au NPs, using a modified breathing-in mechanism. This gave high loading and encapsulation efficiencies (L Dopa: ~9% and 70µg/mg of nanogels, Cyt C: ~30% and 10µg/mg of nanogels respectively for both the drugs. The release kinetics of L-Dopa, monitored using UV-vis spectrophotometry was observed to be rather slow (over several hours) with highest release happening under a combination of high temperature (above VPTT) and acidic conditions. However, the release of L-Dopa from nanogel coated Fe@Au NPs was the fastest, accounting for release of almost 87% of the initially loaded drug in ~30 hours. The chemical structure of the drug, drug incorporation method, location of the drug and presence of Fe@Au NPs largely alter the drug release mechanism and the kinetics of these nanogels and Fe@Au NPs coated with nanogels.

Keywords: controlled release, nanogels, volume phase transition temperature, l-dopa

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Authors: M. Roberts

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We Are Undefeatable - is a mass marketing behaviour change campaign that aims to support the least active people living with long term health conditions to be more active. This is an important issue to address because people with long term conditions are an historically underserved community for the sport and physical activity sector and the least active of those with long term conditions have the most to gain in health and wellbeing benefits. The campaign has generated a significant change in the way physical activity is communicated and people with long term conditions are represented in the media and marketing. The goal is to create a social norm around being active. The campaign is led by a unique partnership of organisations: the Richmond Group of Charities (made up of Age UK, Alzheimer’s Society, Asthma + Lung UK, Breast Cancer Now, British Heart Foundation, British Red Cross, Diabetes UK, Macmillan Cancer Support, Rethink Mental Illness, Royal Voluntary Service, Stroke Association, Versus Arthritis) along with Mind, MS Society, Parkinson’s UK and Sport England, with National Lottery Funding. It is underpinned by the COM-B model of behaviour change. It draws on the lived experience of people with multiple long term conditions to shape the look and feel of the campaign and all the resources available. People with long term conditions are the campaign messengers, central to the ethos of the campaign by telling their individual stories of overcoming barriers to be active with their health conditions. The central messaging is about finding a way to be active that works for the individual. We Are Undefeatable is evaluated through a multi-modal approach, including regular qualitative focus groups and a quantitative evaluation tracker undertaken three times a year. The campaign has highlighted the significant barriers to physical activity for people with long term conditions. This has changed the way our partnership talks about physical activity but has also had an impact on the wider sport and physical activity sector, prompting an increasing departure from traditional messaging and marketing approaches for this audience of people with long term conditions. The campaign has reached millions of people since its launch in 2019, through multiple marketing and partnership channels including primetime TV advertising and promotion through health professionals and in health settings. Its diverse storytellers make it relatable to its target audience and the achievable activities highlighted and inclusive messaging inspire our audience to take action as a result of seeing the campaign. The We Are Undefeatable campaign is a blueprint for physical activity campaigns; it not only addresses individual behaviour change but plays a role in addressing systemic barriers to physical activity by sharing the lived experience insight to shape policy and professional practice.

Keywords: behaviour change, long term conditions, partnership, relatable

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Authors: Su Yin Chiam, Zhipeng Ding, Guang Yang, Danny Jian Hang Tng, Peiyi Song, Geok Ing Ng, Ken-Tye Yong, Qing Xin Zhang

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Brain-machine interfaces (BMI) is a ground rich of exploration opportunities where manipulation of neural activity are used for interconnect with myriad form of external devices. These research and intensive development were evolved into various areas from medical field, gaming and entertainment industry till safety and security field. The technology were extended for neurological disorders therapy such as obsessive compulsive disorder and Parkinson’s disease by introducing current pulses to specific region of the brain. Nonetheless, the work to develop a real-time observing, recording and altering of neural signal brain-machine interfaces system will require a significant amount of effort to overcome the obstacles in improving this system without delay in response. To date, feature size of interface devices and the density of the electrode population remain as a limitation in achieving seamless performance on BMI. Currently, the size of the BMI devices is ranging from 10 to 100 microns in terms of electrodes’ diameters. Henceforth, to accommodate the single cell level precise monitoring, smaller and denser Nano-scaled nanowire electrode arrays are vital in fabrication. In this paper, we would like to showcase the fabrication of high aspect ratio of vertical silicon nanowire electrodes arrays using microelectromechanical system (MEMS) method. Nanofabrication of the nanowire electrodes involves in deep reactive ion etching, thermal oxide thinning, electron-beam lithography patterning, sputtering of metal targets and bottom anti-reflection coating (BARC) etch. Metallization on the nanowire electrode tip is a prominent process to optimize the nanowire electrical conductivity and this step remains a challenge during fabrication. Metal electrodes were lithographically defined and yet these metal contacts outline a size scale that is larger than nanometer-scale building blocks hence further limiting potential advantages. Therefore, we present an integrated contact solution that overcomes this size constraint through self-aligned Nickel silicidation process on the tip of vertical silicon nanowire electrodes. A 4 x 4 array of vertical silicon nanowires electrodes with the diameter of 290nm and height of 3µm has been successfully fabricated.

Keywords: brain-machine interfaces, microelectromechanical systems (MEMS), nanowire, nickel silicide

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Authors: Brianne Nichols, John A. Parkinson

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Positive Psychology has provided a rich understanding of the beneficial effects of positive emotions in relation to optimal functioning, and research has been devoted to promote states of positive feeling and thinking. While this is a worthwhile pursuit, positive emotions are not useful in all contexts - some situations may require the individual to make use of their negative emotions to reach a desired end state. To account for the potential value of a wider range of emotional experiences that are common to the human condition, Positive Psychology needs to expand its horizons and investigate how individuals achieve positive outcomes using varied means. The current research seeks to understand the positive psychology of fear of failure (FF), which is a commonly experienced negative emotion relevant to most life domains. On the one hand, this emotion has been linked with avoidance motivation and self-handicap behaviours, on the other; FF has been shown to act as a drive to move the individual forward. To fully capture the depth of this highly subjective emotional experience and understand the circumstances under which FF may be adaptive, this study adopted a mixed methods design using SenseMaker; a web-based tool that combines the richness of narratives with the objectivity of numerical data. Two hundred participants consisting mostly of undergraduate university students shared a story of a time in the recent past when they feared failure of achieving a valued goal. To avoid researcher bias in the interpretation of narratives, participants self-signified their stories in a tagging system that was based on researchers’ aim to explore the role of past failures, the cognitive, emotional and behavioural profile of individuals high and low in FF, and the relationship between these factors. In addition, the role of perceived personal control and self-esteem were investigated in relation to FF using self-report questionnaires. Results from quantitative analyses indicated that individuals with high levels of FF, compared to low, were strongly influenced by past failures and preoccupied with their thoughts and emotions relating to the fear. This group also reported an unwillingness to accept their internal experiences, which in turn was associated with withdrawal from goal pursuit. Furthermore, self-esteem was found to mediate the relationship between perceived control and FF, suggesting that self-esteem, with or without control beliefs, may have the potential to buffer against high FF. It is hoped that the insights provided by the current study will inspire future research to explore the ways in which ‘acceptance’ may help individuals keep moving towards a goal despite the presence of FF, and whether cultivating a non-contingent self-esteem is the key to resilience in the face of failures.

Keywords: fear of failure, goal-pursuit, negative emotions, optimal functioning, resilience

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Authors: Tatjana Pekmezovic, Milica Jecmenica-Lukic, Igor Petrovic, Vladimir Kostic

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Background: A group of atypical parkinsonian syndromes (APS) includes a variety of rare neurodegenerative disorders characterized by reduced life expectancy, increasing disability, and considerable impact on health-related quality of life (HRQoL). Aim: In this study we wanted to answer two questions: a) which demographic and clinical factors are main contributors of HRQoL in our cohort of patients with APS, and b) how does quality of life of these patients change over 1-year follow-up period. Patients and Methods: We conducted a prospective cohort study in hospital settings. The initial study comprised all consecutive patients who were referred to the Department of Movement Disorders, Clinic of Neurology, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade (Serbia), from January 31, 2000 to July 31, 2013, with the initial diagnoses of ‘Parkinson’s disease’, ‘parkinsonism’, ‘atypical parkinsonism’ and ‘parkinsonism plus’ during the first 8 months from the appearance of first symptom(s). The patients were afterwards regularly followed in 4-6 month intervals and eventually the diagnoses were established for 46 patients fulfilling the criteria for clinically probable progressive supranuclear palsy (PSP) and 36 patients for probable multiple system atrophy (MSA). The health-related quality of life was assessed by using the SF-36 questionnaire (Serbian translation). Hierarchical multiple regression analysis was conducted to identify predictors of composite scores of SF-36. The importance of changes in quality of life scores of patients with APS between baseline and follow-up time-point were quantified using Wilcoxon Signed Ranks Test. The magnitude of any differences for the quality of life changes was calculated as an effect size (ES). Results: The final models of hierarchical regression analysis showed that apathy measured by the Apathy evaluation scale (AES) score accounted for 59% of the variance in the Physical Health Composite Score of SF-36 and 14% of the variance in the Mental Health Composite Score of SF-36 (p<0.01). The changes in HRQoL were assessed in 52 patients with APS who completed 1-year follow-up period. The analysis of magnitude for changes in HRQoL during one-year follow-up period have shown sustained medium ES (0.50-0.79) for both Physical and Mental health composite scores, total quality of life as well as for the Physical Health, Vitality, Role Emotional and Social Functioning. Conclusion: This study provides insight into new potential predictors of HRQoL and its changes over time in patients with APS. Additionally, identification of both prognostic markers of a poor HRQoL and magnitude of its changes should be considered when developing comprehensive treatment-related strategies and health care programs aimed at improving HRQoL and well-being in patients with APS.

Keywords: atypical parkinsonian syndromes, follow-up study, quality of life, APS

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Authors: Irina Veselova, Maria Makedonskaya, Olga Eremina, Alexandr Sidorov, Eugene Goodilin, Tatyana Shekhovtsova

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Such catecholamines as dopamine, norepinephrine, and epinephrine are the principal neurotransmitters in the sympathetic nervous system. Catecholamines and their metabolites are considered to be important markers of socially significant diseases such as atherosclerosis, diabetes, coronary heart disease, carcinogenesis, Alzheimer's and Parkinson's diseases. Currently, neurotransmitters can be studied via electrochemical and chromatographic techniques that allow their characterizing and quantification, although these techniques can only provide crude spatial information. Besides, the difficulty of catecholamine determination in biological materials is associated with their low normal concentrations (~ 1 nM) in biomaterials, which may become even one more order lower because of some disorders. In addition, in blood they are rapidly oxidized by monoaminooxidases from thrombocytes and, for this reason, the determination of neurotransmitter metabolism indicators in an organism should be very rapid (15—30 min), especially in critical states. Unfortunately, modern instrumental analysis does not offer a complex solution of this problem: despite its high sensitivity and selectivity, HPLC-MS cannot provide sufficiently rapid analysis, while enzymatic biosensors and immunoassays for the determination of the considered analytes lack sufficient sensitivity and reproducibility. Fluorescent and SERS-sensors remain a compelling technology for approaching the general problem of selective neurotransmitter detection. In recent years, a number of catecholamine sensors have been reported including RNA aptamers, fluorescent ribonucleopeptide (RNP) complexes, and boronic acid based synthetic receptors and the sensor operated in a turn-off mode. In this work we present the fluorescent and SERS turn-on sensor systems based on the bio- or chemorecognizing nanostructured films {chitosan/collagen-Tb/Eu/Cu-nanoparticles-indicator reagents} that provide the selective recognition, visualization, and sensing of the above mentioned catecholamines on the level of nanomolar concentrations in biomaterials (cell cultures, tissue etc.). We have (1) developed optically transparent porous films and gels of chitosan/collagen; (2) ensured functionalization of the surface by molecules-'recognizers' (by impregnation and immobilization of components of the indicator systems: biorecognizing and auxiliary reagents); (3) performed computer simulation for theoretical prediction and interpretation of some properties of the developed materials and obtained analytical signals in biomaterials. We are grateful for the financial support of this research from Russian Foundation for Basic Research (grants no. 15-03-05064 a, and 15-29-01330 ofi_m).

Keywords: biomaterials, fluorescent and SERS-recognition, neurotransmitters, solid-phase turn-on sensor system

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Authors: Sylwia Krawiec, Joanna Cabaj, Karol Malecha

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Nowadays, progress in the field of the analytical methods is of great interest for reliable biological research and medical diagnostics. Classical techniques of chemical analysis, despite many advantages, do not permit to obtain immediate results or automatization of measurements. Chemical sensors have displaced the conventional analytical methods - sensors combine precision, sensitivity, fast response and the possibility of continuous-monitoring. Biosensor is a chemical sensor, which except of conventer also possess a biologically active material, which is the basis for the detection of specific chemicals in the sample. Each biosensor device mainly consists of two elements: a sensitive element, where is recognition of receptor-analyte, and a transducer element which receives the signal and converts it into a measurable signal. Through these two elements biosensors can be divided in two categories: due to the recognition element (e.g immunosensor) and due to the transducer (e.g optical sensor). Working of optical sensor is based on measurements of quantitative changes of parameters characterizing light radiation. The most often analyzed parameters include: amplitude (intensity), frequency or polarization. Changes in the optical properties one of the compound which reacts with biological material coated on the sensor is analyzed by a direct method, in an indirect method indicators are used, which changes the optical properties due to the transformation of the testing species. The most commonly used dyes in this method are: small molecules with an aromatic ring, like rhodamine, fluorescent proteins, for example green fluorescent protein (GFP), or nanoparticles such as quantum dots (QDs). Quantum dots have, in comparison with organic dyes, much better photoluminescent properties, better bioavailability and chemical inertness. These are semiconductor nanocrystals size of 2-10 nm. This very limited number of atoms and the ‘nano’-size gives QDs these highly fluorescent properties. Rapid and sensitive detection of dopamine is extremely important in modern medicine. Dopamine is very important neurotransmitter, which mainly occurs in the brain and central nervous system of mammals. Dopamine is responsible for the transmission information of moving through the nervous system and plays an important role in processes of learning or memory. Detection of dopamine is significant for diseases associated with the central nervous system such as Parkinson or schizophrenia. In developed optical biosensor for detection of dopamine, are used graphene quantum dots (GQDs). In such sensor dopamine molecules coats the GQD surface - in result occurs quenching of fluorescence due to Resonance Energy Transfer (FRET). Changes in fluorescence correspond to specific concentrations of the neurotransmitter in tested sample, so it is possible to accurately determine the concentration of dopamine in the sample.

Keywords: biosensor, dopamine, fluorescence, quantum dots

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Authors: Urvi Panwar, Kanchan Mishra, Kanjaksha Ghosh, ShankerLal Kothari

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Background: Day-by-day the increasing prevalence of neurodegenerative diseases have become a global issue to manage them by medical sciences. The adult neural stem cells are rare and require an invasive and painful procedure to obtain it from central nervous system. Mesenchymal stem cell (MSCs) therapies have shown remarkable application in treatment of various cell injuries and cell loss. MSCs can be derived from various sources like adult tissues, human bone marrow, umbilical cord blood and cord tissue. MSCs have similar proliferation and differentiation capability, but the human umbilical cord-derived mesenchymal stem cells (hUCMSCs) are proved to be more beneficial with respect to cell procurement, differentiation to other cells, preservation, and transplantation. Material and method: Human umbilical cord is easily obtainable and non-controversial comparative to bone marrow and other adult tissues. The umbilical cord can be collected after delivery of baby, and its tissue can be cultured using explant culture method. Cell culture medium such as DMEMF12+10% FBS and DMEMF12+Neural growth factors (bFGF, human noggin, B27) with antibiotics (Streptomycin/Gentamycin) were used to culture and differentiate mesenchymal stem cells into neural cells, respectively. The characterisations of MSCs were done with Flow Cytometer for surface markers CD90, CD73 and CD105 and colony forming unit assay. The differentiated various neural cells will be characterised by fluorescence markers for neurons, astrocytes, and oligodendrocytes; quantitative PCR for genes Nestin and NeuroD1 and Western blotting technique for gap43 protein. Result and discussion: The high quality and number of MSCs were isolated from human umbilical cord via explant culture method. The obtained MSCs were differentiated into neural cells like neurons, astrocytes and oligodendrocytes. The differentiated neural cells can be used to treat neural injuries and neural cell loss by delivering cells by non-invasive administration via cerebrospinal fluid (CSF) or blood. Moreover, the MSCs can also be directly delivered to different injured sites where they differentiate into neural cells. Therefore, human umbilical cord is demonstrated to be an inexpensive and easily available source for MSCs. Moreover, the hUCMSCs can be a potential source for neural cell therapies and neural cell regeneration for neural cell injuries and neural cell loss. This new way of research will be helpful to treat and manage neural cell damages and neurodegenerative diseases like Alzheimer and Parkinson. Still the study has a long way to go but it is a promising approach for many neural disorders for which at present no satisfactory management is available.

Keywords: bone marrow, cell therapy, explant culture method, flow cytometer, human umbilical cord, mesenchymal stem cells, neurodegenerative diseases, neuroprotective, regeneration

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Authors: Joanna Gerszon, Aleksandra Rodacka

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In the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, protein and peptide aggregation processes play a vital role in contributing to the formation of intracellular and extracellular protein deposits. One of the major components of these deposits is the oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Therefore, the purpose of this research was to answer the question whether piceatannol, a stilbene derivative, counteracts and/or slows down oxidative stress-induced GAPDH aggregation. The study also aimed to determine if this natural occurring compound prevents unfavorable nuclear translocation of GAPDH in hippocampal cells. The isothermal titration calorimetry (ITC) analysis indicated that one molecule of GAPDH can bind up to 8 molecules of piceatannol (7.3 ± 0.9). As a consequence of piceatannol binding to the enzyme, the loss of activity was observed. Parallel with GAPDH inactivation the changes in zeta potential, and loss of free thiol groups were noted. Nevertheless, the ligand-protein binding does not influence the secondary structure of the GAPDH. Precise molecular docking analysis of the interactions inside the active center allowed to presume that these effects are due to piceatannol ability to assemble a covalent binding with nucleophilic cysteine residue (Cys149) which is directly involved in the catalytic reaction. Molecular docking also showed that simultaneously 11 molecules of ligand can be bound to dehydrogenase. Taking into consideration obtained data, the influence of piceatannol on level of GAPDH aggregation induced by excessive oxidative stress was examined. The applied methods (thioflavin-T binding-dependent fluorescence as well as microscopy methods - transmission electron microscopy, Congo Red staining) revealed that piceatannol significantly diminishes level of GAPDH aggregation. Finally, studies involving cellular model (Western blot analyses of nuclear and cytosolic fractions and confocal microscopy) indicated that piceatannol-GAPDH binding prevents GAPDH from nuclear translocation induced by excessive oxidative stress in hippocampal cells. In consequence, it counteracts cell apoptosis. These studies demonstrate that by binding with GAPDH, piceatannol blocks cysteine residue and counteracts its oxidative modifications, that induce oligomerization and GAPDH aggregation as well as it prevents hippocampal cells from apoptosis by retaining GAPDH in the cytoplasm. All these findings provide a new insight into the role of piceatannol interaction with GAPDH and present a potential therapeutic strategy for some neurological disorders related to GAPDH aggregation. This work was supported by the by National Science Centre, Poland (grant number 2017/25/N/NZ1/02849).

Keywords: glyceraldehyde-3-phosphate dehydrogenase, neurodegenerative disease, neuroprotection, piceatannol, protein aggregation

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Authors: Susan Hall, Gary D. Grant, Catherine McDermott, Devinder Arora

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Introduction /Aim: The kynurenine pathway is thought to play an important role in the pathophysiology of numerous neurodegenerative diseases including depression, Alzheimer’s disease, and Parkinson’s disease. Numerous neuroactive compounds, including the neurotoxic 3-hydroxyanthranilic acid, 3-hydroxykynurenine and quinolinic acid and the neuroprotective kynurenic acid and picolinic acid, are produced through the metabolism of kynurenine and are thought to be the causative agents responsible for neurodegeneration. The toxicity of 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid has been widely evaluated and demonstrated in primary cell cultures but to date only 3-hydroxykynurenine and 3-hydroxyanthranilic acid have been shown to cause toxicity in immortal tumour cells. The aim of this study was to evaluate the toxicity of kynurenine metabolites, both individually and in combination, on SH-SY5Y neuroblastoma cells after 24 and 72 h exposure in order to explore a cost-effective model to study their neurotoxic effects and potential protective agents. Methods: SH-SY5Y neuroblastoma cells were exposed to various concentrations of the neuroactive kynurenine metabolites, both individually and in combination, for 24 and 72 h, and viability was subsequently evaluated using the Resazurin (Alamar blue) proliferation assay. Furthermore, the effects of these compounds, alone and in combination, on specific death pathways including apoptosis, necrosis and free radical production was evaluated using various assays. Results: Consistent with literature, toxicity was shown with short-term 24-hour treatments at 1000 μM concentrations for both 3-hydroxykynurenine and 3-hydroxyanthranilic acid. Combinations of kynurenine metabolites showed modest toxicity towards SH-SY5Y neuroblastoma cells in a concentration-dependent manner. Specific cell death pathways, including apoptosis, necrosis and free radical production were shown to be increased after both 24 and 72 h exposure of SH-SY5Y neuroblastoma cells to 3-hydroxykynurenine and 3-hydroxyanthranilic acid and various combinations of neurotoxic kynurenine metabolites. Conclusion: It is well documented that neurotoxic kynurenine metabolites show toxicity towards primary human neurons in the nanomolar to low micromolar concentration range. Results show that the concentrations required to show significant cell death are in the range of 1000 µM for 3-hydroxykynurenine and 3-hydroxyanthranilic acid and toxicity of quinolinic acid towards SH-SY5Y was unable to be shown. This differs significantly from toxicities observed in primary human neurons. Combinations of the neurotoxic metabolites were shown to have modest toxicity towards these cells with increased toxicity and activation of cell death pathways observed after 72 h exposure. This study suggests that the 24 h model is unsuitable for use in neurotoxicity studies, however, the 72 h model better represents the observations of the studies using primary human neurons and may provide some benefit in providing a cost-effective model to assess possible protective agents against kynurenine metabolite toxicities.

Keywords: kynurenine metabolites, neurotoxicity, quinolinic acid, SH-SY5Y neuroblastoma

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Authors: Mariia A. Parfenenko, Ilya S. Dantsev, Sergei V. Bochenkov, Natalia V. Vinogradova, Olga S. Groznova, Victoria Yu. Voinova

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Introduction: Autism is the most common neurodevelopmental disorder. Autism is characterized by difficulties in social interaction and adherence to stereotypic behavioral patterns and frequently co-occurs with epilepsy, intellectual disabilities, connective tissue disorders, and other conditions. CHD8 codes for chromodomain-helicase-DNA-binding protein 8 - a chromatin remodeler that regulates cellular proliferation and neurodevelopment in embryogenesis. CHD8 is one of the genes most frequently involved in autism. Patients and methods: 2 unrelated male patients, P3 and P12, aged 3 and 12 years old, underwent whole genome sequencing, which determined that they both had different likely pathogenic variants, both previously undescribed in literature. Sanger sequencing later determined that P12 inherited the variant from his affected mother. Results: P3 and P12 presented with autism, a developmental delay, ataxia, sleep disorders, overgrowth, and macrocephaly, as well as other clinical features typically present in patients with causative variants in CHD8. The mother of P12 also has autistic traits, as well as ataxia, hypotonia, sleep disorders, and other symptoms. However, P3 and P12 also have different cardiac abnormalities. P3 had signs of a repolarization disorder: a flattened T wave in the III and aVF derivations and a negative T wave in the V1-V2 derivations. He also had structural valve anomalies with associated regurgitation, local contractility impairment of the left ventricular, and diastolic dysfunction of the right ventricle. Meanwhile, P12 had Wolff-Parkinson-White syndrome and underwent radiofrequency ablation at the age of 2 years. At the time of observation, P12 had mild sinus arrhythmia and an incomplete right bundle branch block, as well as arterial hypertension. Discussion: Cardiac abnormalities were not previously reported in patients with causative variants in CHD8. The underlying mechanism for the formation of those abnormalities is currently unknown. However, the two hypotheses are either a disordered interaction with CHD7 – another chromodomain remodeler known to be directly involved in the cardiophenotype of CHARGE syndrome – a rare condition characterized by coloboma, heart defects and growth abnormalities, or the disrupted functioning of CHD8 as an A-Kinase Anchoring Protein, which are known to modulate cardiac function. Conclusion: We observed 2 unrelated autistic males with likely pathogenic variants in CHD8 that presented with typical symptoms of CHD8-related neurodevelopmental disorder, as well as cardiac abnormalities. Cardiac abnormalities have, until now, been considered uncharacteristic for patients with causative variants in CHD8. Further accumulation of data, including experimental evidence of the involvement of CHD8 in heart formation, will elucidate the mechanism underlying the cardiophenotype of those patients. Acknowledgements: Molecular genetic testing of the patients was made possible by the Charity Fund for medical and social genetic aid projects «Life Genome.»

Keywords: autism spectrum disorders, chromodomain-helicase-DNA-binding protein 8, neurodevelopmental disorder, cardio phenotype

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Authors: Rajesh Kumar Gautam, Debabrata Seth

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Thioflavin-T (ThT) play a key role of an important biologically active fluorescent sensor for amyloid fibrils. ThT molecule has been developed a method to detect the analysis of different type of diseases such as neurodegenerative disorders, Alzheimer’s, Parkinson’s, and type II diabetes. ThT was used as a fluorescent marker to detect the formation of amyloid fibril. In the presence of amyloid fibril, ThT becomes highly fluorescent. ThT undergoes twisting motion around C-C bonds of the two adjacent benzothiazole and dimethylaniline aromatic rings, which is predominantly affected by the micro-viscosity of the local environment. The present study articulates photophysics and torsional dynamics of biologically active molecule ThT in the presence of deep-eutectic solvents (DESs). DESs are environment-friendly, low cost and biodegradable alternatives to the ionic liquids. DES resembles ionic liquids, but the constituents of a DES include a hydrogen bond donor and acceptor species, in addition to ions. Due to the presence of the H-bonding network within a DES, it exhibits structural heterogeneity. Herein, we have prepared two different DESs by mixing urea with choline chloride and N, N-diethyl ethanol ammonium chloride at ~ 340 K. It was reported that deep eutectic mixture of choline chloride with urea gave a liquid with a freezing point of 12°C. We have experimented by taking two different concentrations of ThT. It was observed that at higher concentration of ThT (50 µM) it forms aggregates in DES. The photophysics of ThT as a function of temperature have been explored by using steady-state, and picoseconds time-resolved fluorescence emission spectroscopic techniques. From the spectroscopic analysis, we have observed that with rising temperature the fluorescence quantum yields and lifetime values of ThT molecule gradually decreases; this is the cumulative effect of thermal quenching and increase in the rate of the torsional rate constant. The fluorescence quantum yield and fluorescence lifetime decay values were always higher for DES-II (urea & N, N-diethyl ethanol ammonium chloride) than those for DES-I (urea & choline chloride). This was mainly due to the presence of structural heterogeneity of the medium. This was further confirmed by comparison with the activation energy of viscous flow with the activation energy of non-radiative decay. ThT molecule in less viscous media undergoes a very fast twisting process and leads to deactivation from the photoexcited state. In this system, the torsional motion increases with increasing temperature. We have concluded that beside bulk viscosity of the media, structural heterogeneity of the medium play crucial role to guide the photophysics of ThT in DESs. The analysis of the experimental data was carried out in the temperature range 288 ≤ T = 333K. The present articulate is to obtain an insight into the DESs as media for studying various photophysical processes of amyloid fibrils sensing molecule of ThT.

Keywords: deep eutectic solvent, photophysics, Thioflavin T, the torsional rate constant

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Authors: Ved Vrat Verma, Rani Gupta, Manisha Goel

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γ-glutamyltranspeptidase (GGT: EC 2.3.2.2) is an N-terminal nucleophile hydrolase conserved in all three domains of life. GGT plays a key role in glutathione metabolism where it catalyzes the breakage of the γ-glutamyl bonds and transfer of γ-glutamyl group to water (hydrolytic activity) or amino acids or short peptides (transpeptidase activity). GGTs from bacteria, archaea, and eukaryotes (human, rat and mouse) are homologous proteins sharing >50% sequence similarity and conserved four layered αββα sandwich like three dimensional structural fold. These proteins though similar in their structure to each other, are quite diverse in their enzyme activity: some GGTs are better at hydrolysis reactions but poor in transpeptidase activity, whereas many others may show opposite behaviour. GGT is known to be involved in various diseases like asthma, parkinson, arthritis, and gastric cancer. Its inhibition prior to chemotherapy treatments has been shown to sensitize tumours to the treatment. Microbial GGT is known to be a virulence factor too, important for the colonization of bacteria in host. However, all known inhibitors (mimics of its native substrate, glutamate) are highly toxic because they interfere with other enzyme pathways. However, a few successful efforts have been reported previously in designing species specific inhibitors. We aim to leverage the diversity seen in GGT family (pathogen vs. eukaryotes) for designing specific inhibitors. Thus, in the present study, we have used DIVERGE software to identify sites in GGT proteins, which are crucial for the functional and structural divergence of these proteins. Since, type II divergence sites vary in clade specific manner, so type II divergent sites were our focus of interest throughout the study. Type II divergent sites were identified for pathogen vs. eukaryotes clusters and sites were marked on clade specific representative structures HpGGT (2QM6) and HmGGT (4ZCG) of pathogen and eukaryotes clade respectively. The crucial divergent sites within 15 A radii of the binding cavity were highlighted, and in-silico mutations were performed on these sites to delineate the role of these sites on the mechanism of catalysis and protein folding. Further, the amino acid network (AAN) analysis was also performed by Cytoscape to delineate assortative mixing for cavity divergent sites which could strengthen our hypothesis. Additionally, molecular dynamics simulations were performed for wild complexes and mutant complexes close to physiological conditions (pH 7.0, 0.1 M ionic strength and 1 atm pressure) and the role of putative divergence sites and structural integrities of the homologous proteins have been analysed. The dynamics data were scrutinized in terms of RMSD, RMSF, non-native H-bonds and salt bridges. The RMSD, RMSF fluctuations of proteins complexes are compared, and the changes at protein ligand binding sites were highlighted. The outcomes of our study highlighted some crucial divergent sites which could be used for novel inhibitors designing in a species-specific manner. Since, for drug development, it is challenging to design novel drug by targeting similar protein which exists in eukaryotes, so this study could set up an initial platform to overcome this challenge and help to deduce the more effective targets for novel drug discovery.

Keywords: γ-glutamyltranspeptidase, divergence, species-specific, drug design

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Authors: Kelly S. Parkinson, Katherine Y. Teh-White

Abstract:

Futureye has a bespoke social licence to operate methodology which has successfully secured community approval and commercial return for fisheries which have faced regulatory and financial risk. This unique approach to fisheries management focuses on delivering improved social and environmental outcomes to support the fishing industry make steps towards achieving the United Nations SDGs. An SLO is the community’s implicit consent for a business or project to exist. An SLO must be earned and maintained alongside regulatory licences. In current and new operations, it helps you to anticipate and measure community concerns around your operations – leading to more predictable and sensible policy outcomes that will not jeopardise your commercial returns. Rising societal expectations and increasing activist sophistication mean the international fishing industry needs to resolve community concerns at each stage their supply chain. Futureye applied our tested social licence to operate (SLO) methodology to help Austral Fisheries who was being attacked by activists concerned about the sustainability of Patagonian Toothfish. Austral was Marine Stewardship Council certified, but pirates were making the overall catch unsustainable. Austral wanted to be carbon neutral. SLO provides a lens on the risk that helps industries and companies act before regulatory and political risk escalates. To do this assessment, we have a methodology that assesses the risk that we can then translate into a process to create a strategy. 1) Audience: we understand the drivers of change and the transmission of those drivers across all audience segments. 2) Expectation: we understand the level of social norming of changing expectations. 3) Outrage: we understand the technical and perceptual aspects of risk and the opportunities to mitigate these. 4) Inter-relationships: we understand the political, regulatory, and reputation system so that we can understand the levers of change. 5) Strategy: we understand whether the strategy will achieve a social licence through bringing the internal and external stakeholders on the journey. Futureye’s SLO methodologies helped Austral to understand risks and opportunities to enhance its resilience. Futureye reviewed the issues, assessed outrage and materiality and mapped SLO threats to the company. Austral was introduced to a new way that it could manage activism, climate action, and responsible consumption. As a result of Futureye’s work, Austral worked closely with Sea Shepherd who was campaigning against pirates illegally fishing Patagonian Toothfish as well as international governments. In 2016 Austral launched the world’s first carbon neutral fish which won Austral a thirteen percent premium for tender on the open market. In 2017, Austral received the prestigious Banksia Foundation Sustainability Leadership Award for seafood that is sustainable, healthy and carbon neutral. Austral’s position as a leader in sustainable development has opened doors for retailers all over the world. Futureye’s SLO methodology can identify the societal, political and regulatory risks facing fisheries and position them to proactively address the issues and become an industry leader in sustainability.

Keywords: carbon neutral, fisheries management, risk communication, social licence to operate, sustainable development

Procedia PDF Downloads 120

Authors: John Lachapelle

Abstract:

Introduction: Neural stimulation is increasingly targeted toward treatment of back pain, PTSD, Parkinson’s disease, and for sensory perception. Sensory recording during stimulation is important in order to examine neural response to stimulation. Most neural amplifiers (headstages) focus on noise efficiency factor (NEF). Conversely, neural headstages need to handle artifacts from several sources including power lines, movement (EMG), and neural stimulation itself. In this work a layered approach to artifact rejection is used to reduce corruption of the neural ENG signal by 60dBv, resulting in recovery of sensory signals in rats and primates that would previously not be possible. Methods: The approach combines analog techniques to reduce and handle unwanted signal amplitudes. The methods include optimized (1) sensory electrode placement, (2) amplifier configuration, and (3) artifact blanking when necessary. The techniques together are like concentric moats protecting a castle; only the wanted neural signal can penetrate. There are two conditions in which the headstage operates: unwanted artifact < 50mV, linear operation, and artifact > 50mV, fast-settle gain reduction signal limiting (covered in more detail in a separate paper). Unwanted Signals at the headstage input: Consider: (a) EMG signals are by nature < 10mV. (b) 60 Hz power line signals may be > 50mV with poor electrode cable conditions; with careful routing much of the signal is common to both reference and active electrode and rejected in the differential amplifier with <50mV remaining. (c) An unwanted (to the neural recorder) stimulation signal is attenuated from stimulation to sensory electrode. The voltage seen at the sensory electrode can be modeled Φ_m=I_o/4πσr. For a 1 mA stimulation signal, with 1 cm spacing between electrodes, the signal is <20mV at the headstage. Headstage ASIC design: The front end ASIC design is designed to produce < 1% THD at 50mV input; 50 times higher than typical headstage ASICs, with no increase in noise floor. This requires careful balance of amplifier stages in the headstage ASIC, as well as consideration of the electrodes effect on noise. The ASIC is designed to allow extremely small signal extraction on low impedance (< 10kohm) electrodes with configuration of the headstage ASIC noise floor to < 700nV/rt-Hz. Smaller high impedance electrodes (> 100kohm) are typically located closer to neural sources and transduce higher amplitude signals (> 10uV); the ASIC low-power mode conserves power with 2uV/rt-Hz noise. Findings: The enhanced neural processing ASIC has been compared with a commercial neural recording amplifier IC. Chronically implanted primates at MGH demonstrated the presence of commercial neural amplifier saturation as a result of large environmental artifacts. The enhanced artifact suppression headstage ASIC, in the same setup, was able to recover and process the wanted neural signal separately from the suppressed unwanted artifacts. Separately, the enhanced artifact suppression headstage ASIC was able to separate sensory neural signals from unwanted artifacts in mouse-implanted peripheral intrafascicular electrodes. Conclusion: Optimizing headstage ASICs allow observation of neural signals in the presence of large artifacts that will be present in real-life implanted applications, and are targeted toward human implantation in the DARPA HAPTIX program.

Keywords: ASIC, biosensors, biomedical signal processing, biomedical sensors

Procedia PDF Downloads 330