Search results for: differential gene expression

Authors: Khodzhaberdi Allaberdiev

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In order to understand the interactions on the interface polyamide fibers and epoxy matrix in fiber- reinforced composites were investigated industrial aramid fibers: armos, svm, terlon using individual epoxy matrix components, epoxies: diglycidyl ether of bisphenol A (DGEBA), three- and diglycidyl derivatives of m, p-amino-, m, p-oxy-, o, m,p-carboxybenzoic acids, the models: curing agent, aniline and the compound, that depict of the structure the primary addition reaction the amine to the epoxy resin, N-di (oxyethylphenoxy) aniline. The chemical structure of the surface of untreated and treated polyamide fibers analyzed using Fourier transform infrared spectroscopy (FTIR). The impregnation of fibers with epoxy matrix components and N-di (oxyethylphenoxy) aniline has been carried out by heating 150˚C (6h). The optimum fiber loading is at 65%.The result a thermal treatment is the covalent bonds formation , derived from a combined of homopolymerization and crosslinking mechanisms in the interfacial region between the epoxy resin and the surface of fibers. The reactivity of epoxy resins on interface in microcomposites (MC) also depends from processing aids treated on surface of fiber and the absorbance moisture. The influences these factors as evidenced by the conversion of epoxy groups values in impregnated with DGEBA of the terlons: industrial, dried (in vacuum) and purified samples: 5.20 %, 4.65% and 14.10%, respectively. The same tendency for svm and armos fibers is observed. The changes in surface composition of these MC were monitored by X-ray photoelectron spectroscopy (XPS). In the case of the purified fibers, functional groups of fibers act as well as a catalyst and curing agent of epoxy resin. It is found that the value of the epoxy groups conversion for reinforced formulations depends on aromatic polyamides nature and decreases in the order: armos >svm> terlon. This difference is due of the structural characteristics of fibers. The interfacial interactions also examined between polyglycidyl esters substituted benzoic acids and polyamide fibers in the MC. It is found that on interfacial interactions these systems influences as well as the structure and the isomerism of epoxides. The IR-spectrum impregnated fibers with aniline showed that the polyamide fibers appreciably with aniline do not react. FTIR results of treated fibers with N-di (oxyethylphenoxy) aniline fibers revealed dramatically changes IR-characteristic of the OH groups of the amino alcohol. These observations indicated hydrogen bondings and covalent interactions between amino alcohol and functional groups of fibers. This result also confirms appearance of the exo peak on Differential Scanning Calorimetry (DSC) curve of the MC. Finally, the theoretical evaluation non-covalent interactions between individual epoxy matrix components and fibers has been performed using the benzanilide and its derivative contaning the benzimidazole moiety as a models of terlon and svm,armos, respectively. Quantum-topological analysis also demonstrated the existence hydrogen bond between amide group of models and epoxy matrix components.All the results indicated that on the interface polyamide fibers and epoxy matrix exist not only covalent, but and non-covalent the interactions during the preparation of MC.

Keywords: epoxies, interface, modeling, polyamide fibers

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Authors: Delphine Morales, Florian Lombart, Agathe Truchot, Pauline Maire, Pascale Vigneron, Antoine Galmiche, Catherine Lok, Muriel Vayssade

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Targeted therapy molecules are used as a first-line treatment for metastatic melanoma with B-Raf mutation. Nevertheless, these molecules can cause side effects to patients and are efficient on 50 to 60 % of them. Indeed, melanoma cell sensitivity to targeted therapy molecules is dependent on tumor microenvironment (cell-cell and cell-extracellular matrix interactions). To better unravel factors modulating cell sensitivity to B-Raf inhibitor, we have developed and compared several melanoma models: from metastatic melanoma cells cultured as monolayer (2D) to a co-culture in a 3D dermal equivalent. Cell response was studied in different melanoma cell lines such as SK-MEL-28 (mutant B-Raf (V600E), sensitive to Vemurafenib), SK-MEL-3 (mutant B-Raf (V600E), resistant to Vemurafenib) and a primary culture of dermal human fibroblasts (HDFn). Assays have initially been performed in a monolayer cell culture (2D), then a second time on a 3D dermal equivalent (dermal human fibroblasts embedded in a collagen gel). All cell lines were treated with Vemurafenib (a B-Raf inhibitor) for 48 hours at various concentrations. Cell sensitivity to treatment was assessed under various aspects: Cell proliferation (cell counting, EdU incorporation, MTS assay), MAPK signaling pathway analysis (Western-Blotting), Apoptosis (TUNEL), Cytokine release (IL-6, IL-1α, HGF, TGF-β, TNF-α) upon Vemurafenib treatment (ELISA) and histology for 3D models. In 2D configuration, the inhibitory effect of Vemurafenib on cell proliferation was confirmed on SK-MEL-28 cells (IC50=0.5 µM), and not on the SK-MEL-3 cell line. No apoptotic signal was detected in SK-MEL-28-treated cells, suggesting a cytostatic effect of the Vemurafenib rather than a cytotoxic one. The inhibition of SK-MEL-28 cell proliferation upon treatment was correlated with a strong expression decrease of phosphorylated proteins involved in the MAPK pathway (ERK, MEK, and AKT/PKB). Vemurafenib (from 5 µM to 10 µM) also slowed down HDFn proliferation, whatever cell culture configuration (monolayer or 3D dermal equivalent). SK-MEL-28 cells cultured in the dermal equivalent were still sensitive to high Vemurafenib concentrations. To better characterize all cell population impacts (melanoma cells, dermal fibroblasts) on Vemurafenib efficacy, cytokine release is being studied in 2D and 3D models. We have successfully developed and validated a relevant 3D model, mimicking cutaneous metastatic melanoma and tumor microenvironment. This 3D melanoma model will become more complex by adding a third cell population, keratinocytes, allowing us to characterize the epidermis influence on the melanoma cell sensitivity to Vemurafenib. In the long run, the establishment of more relevant 3D melanoma models with patients’ cells might be useful for personalized therapy development. The authors would like to thank the Picardie region and the European Regional Development Fund (ERDF) 2014/2020 for the funding of this work and Oise committee of "La ligue contre le cancer".

Keywords: 3D human skin model, melanoma, tissue engineering, vemurafenib efficiency

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Authors: Roni Ramon-Gonen, Amir Dori, Shahar Shelly

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Background and objectives: Healthcare professionals produce abundant textual information in their daily clinical practice. The extraction of insights from all the gathered information, mainly unstructured and lacking in normalization, is one of the major challenges in computational medicine. In this respect, text mining assembles different techniques to derive valuable insights from unstructured textual data, so it has led to being especially relevant in Medicine. Neurological patient’s history allows the clinician to define the patient’s symptoms and along with the result of the nerve conduction study (NCS) and electromyography (EMG) test, assists in formulating a differential diagnosis. Past medical history (PMH) helps to direct the latter. In this study, we aimed to identify relevant PMH, understand which PMHs are common among patients in the referral cohort and documented by the medical staff, and examine the differences by sex and age in a large cohort based on textual format notes. Methods: We retrospectively identified all patients with abnormal NCS between May 2016 to February 2022. Age, gender, and all NCS attributes reports were recorded, including the summary text. All patients’ histories were extracted from the text report by a query. Basic text cleansing and data preparation were performed, as well as lemmatization. Very popular words (like ‘left’ and ‘right’) were deleted. Several words were replaced with their abbreviations. A bag of words approach was used to perform the analyses. Different visualizations which are common in text analysis, were created to easily grasp the results. Results: We identified 5282 unique patients. Three thousand and five (57%) patients had documented PMH. Of which 60.4% (n=1817) were males. The total median age was 62 years (range 0.12 – 97.2 years), and the majority of patients (83%) presented after the age of forty years. The top two documented medical histories were diabetes mellitus (DM) and surgery. DM was observed in 16.3% of the patients, and surgery at 15.4%. Other frequent patient histories (among the top 20) were fracture, cancer (ca), motor vehicle accident (MVA), leg, lumbar, discopathy, back and carpal tunnel release (CTR). When separating the data by sex, we can see that DM and MVA are more frequent among males, while cancer and CTR are less frequent. On the other hand, the top medical history in females was surgery and, after that, DM. Other frequent histories among females are breast cancer, fractures, and CTR. In the younger population (ages 18 to 26), the frequent PMH were surgery, fractures, trauma, and MVA. Discussion: By applying text mining approaches to unstructured data, we were able to better understand which medical histories are more relevant in these circumstances and, in addition, gain additional insights regarding sex and age differences. These insights might help to collect epidemiological demographical data as well as raise new hypotheses. One limitation of this work is that each clinician might use different words or abbreviations to describe the same condition, and therefore using a coding system can be beneficial.

Keywords: abnormal studies, healthcare analytics, medical history, nerve conduction studies, text mining, textual analysis

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Authors: Sandra Christina Gressler

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Resting is essentially the physical and mental relaxation. So, can behaviors that go beyond the merely physical relaxation to some extent be understood as a behavior of restoration? Studies on restorative environments emphasize the physical, mental and social benefits that some environments can provide and suggest that activities in natural environments reduce the stress of daily lives, promoting recovery against the daily wear. These studies, though specific in their results, do not unify the different possibilities of restoration. Considering the importance of restorative environments by promoting well-being, this research aims to verify the applicability of the theory on restorative environments in a Brazilian context, inquiring about the environment/behavior of rest. The research sought to achieve its goals by; a) identifying daily ways of how participants interact/connect with nature; b) identifying the resting environments/behavior; c) verifying if rest strategies match the restorative environments suggested by restorative studies; and d) verifying different rest strategies related to time. Workers from different companies in which certain functions require focused attention, and high school students from different schools, participated in this study. An interview was used to collect data and information. The data obtained were compared with studies of attention restoration theory and stress recovery. The collected data were analyzed through the basic descriptive inductive statistics and the use of the software ALCESTE® (Analyse Lexicale par Contexte d'un Ensemble de Segments de Texte). The open questions investigate perception of nature on a daily basis – analysis using ALCESTE; rest periods – daily, weekends and holidays – analysis using ALCESTE with tri-croisé; and resting environments and activities – analysis using a simple descriptive statistics. According to the results, environments with natural characteristics that are compatible with personal desires (physical aspects and distance) and residential environments when they fulfill the characteristics of refuge, safety, and self-expression, characteristics of primary territory, meet the requirements of restoration. Analyzes suggest that the perception of nature has a wide range that goes beyond the objects nearby and possible to be touched, as well as observation and contemplation of details. The restoration processes described in the studies of attention restoration theory occur gradually (hierarchically), starting with being away, following compatibility, fascination, and extent. They are also associated with the time that is available for rest. The relation between rest behaviors and the bio-demographic characteristics of the participants are noted. It reinforces, in studies of restoration, the need to insert not only investigations regarding the physical characteristics of the environment but also behavior, social relationship, subjective reactions, distance and time available. The complexity of the theme indicates the necessity for multimethod studies. Practical contributions provide subsidies for developing strategies to promote the welfare of the population.

Keywords: attention restoration theory, environmental psychology, rest behavior, restorative environments

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Authors: Tomohiko Utsuki, Kyoka Sato

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In emergency medicine, it is recognized that brain resuscitation is very important for the reduction of mortality rate and neurological sequelae. Especially, the control of brain temperature (BT), intracranial pressure (ICP), and cerebral blood flow (CBF) are most required for stabilizing brain’s physiological state in the treatment for such as brain injury, stroke, and encephalopathy. However, the manual control of BT, ICP, and CBF frequently requires the decision and operation of medical staff, relevant to medication and the setting of therapeutic apparatus. Thus, the integration and the automation of the control of those is very effective for not only improving therapeutic effect but also reducing staff burden and medical cost. For realizing such integration and automation, a mathematical model of brain physiological state is necessary as the controlled object in simulations, because the performance test of a prototype of the control system using patients is not ethically allowed. A model of cerebral blood circulation has already been constructed, which is the most basic part of brain physiological state. Also, a migration model of extracellular fluid in brain has been constructed, however the condition that the total volume of intracranial cavity is almost changeless due to the hardness of cranial bone has not been considered in that model. Therefore, in this research, the dynamic migration model of extracellular fluid in brain was constructed on the consideration of the changelessness of intracranial cavity’s total volume. This model is connectable to the cerebral blood circulation model. The constructed model consists of fourteen compartments, twelve of which corresponds to perfused area of bilateral anterior, middle and posterior cerebral arteries, the others corresponds to cerebral ventricles and subarachnoid space. This model enable to calculate the migration of tissue fluid from capillaries to gray matter and white matter, the flow of tissue fluid between compartments, the production and absorption of cerebrospinal fluid at choroid plexus and arachnoid granulation, and the production of metabolic water. Further, the volume, the colloid concentration, and the tissue pressure of/in each compartment are also calculable by solving 40-dimensional non-linear simultaneous differential equations. In this research, the obtained model was analyzed for its validation under the four condition of a normal adult, an adult with higher cerebral capillary pressure, an adult with lower cerebral capillary pressure, and an adult with lower colloid concentration in cerebral capillary. In the result, calculated fluid flow, tissue volume, colloid concentration, and tissue pressure were all converged to suitable value for the set condition within 60 minutes at a maximum. Also, because these results were not conflict with prior knowledge, it is certain that the model can enough represent physiological state of brain under such limited conditions at least. One of next challenges is to integrate this model and the already constructed cerebral blood circulation model. This modification enable to simulate CBF and ICP more precisely due to calculating the effect of blood pressure change to extracellular fluid migration and that of ICP change to CBF.

Keywords: dynamic model, cerebral extracellular migration, brain resuscitation, automatic control

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Authors: Vaidehi Raipat

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A city is an expression of coexistence between its users and built environment. The way in which its spaces are animated signify the quality of this coexistence. Urban sustainability is the ability of a city to respond efficiently towards its people, culture, environment, visual image, history, visions and identity. The quality of built environment determines the quality of our lifestyles, but poor ability of the built environment to adapt and sustain itself through the changes leads to degradation of cities. Ranchi was created in November 2000, as the capital of the newly formed state Jharkhand, located on eastern side of India. Before this Ranchi was known as summer capital of Bihar and was a little larger than a town in terms of development. But since then it has been vigorously expanding in size, infrastructure as well as population. This sudden expansion has created a stress on existing built environment. The large forest covers, agricultural land, diverse culture and pleasant climatic conditions have degraded and decreased to a large extent. Narrow roads and old buildings are unable to bear the load of the changing requirements, fast improving technology and growing population. The built environment has hence been rendered unsustainable and unadaptable through fastidious changes of present era. Some of the common hazards that can be easily spotted in the built environment are half-finished built forms, pedestrians and vehicles moving on the same part of the road. Unpaved areas on street edges. Over-sized, bright and randomly placed hoardings. Negligible trees or green spaces. The old buildings have been poorly maintained and the new ones are being constructed over them. Roads are too narrow to cater to the increasing traffic, both pedestrian and vehicular. The streets have a large variety of activities taking place on them, but haphazardly. Trees are being cut down for road widening and new constructions. There is no space for greenery in the commercial as well as old residential areas. The old infrastructure is deteriorating because of poor maintenance and the economic limitations. Pseudo understanding of functionality as well as aesthetics drive the new infrastructure. It is hence necessary to evaluate the extent of sustainability of existing built environment of the city and create or regenerate the existing built environment into a more sustainable and adaptable one. For this purpose, research titled “Sustainability of the Built Environment of Ranchi District” has been carried out. In this research the condition of the built environment of Ranchi are explored so as to figure out the problems and shortcomings existing in the city and provide for design strategies that can make the existing built-environment sustainable. The built environment of Ranchi that include its outdoor spaces like streets, parks, other open areas, its built forms as well as its users, has been analyzed in terms of various urban design parameters. Based on which strategies have been suggested to make the city environmentally, socially, culturally and economically sustainable.

Keywords: adaptable, built-environment, sustainability, urban

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Authors: Shamim Mushtaq, Moazzam Shahid

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Breast cancer (BC) claims the lives of half a million women every year and is the most common cause of death in the developing world. In 2019, it was estimated that BC alone accounts for 15% of all cancer deaths in younger women (aged < 45 years old) with advanced-stage lung metastasis. According to the World Health Organization & International Union against Cancer, in Asia, a high number of cancer-related deaths will be observed in 2020, whereas the burden will be reduced in Western countries due to awareness about the disease, better health facilities and advanced treatments. In the last 15 years, it has been reported that the incidence of BC has increased by 1.1% among Asian compared to the US population from 2003 to 2012. To date, several BC biological subtypes have been reported so far, which are associated with different treatment responses. The heterogeneity and diversity of BC reflected these different subtypes, including Luminal A (23.7% prevalence) and B (38.8% prevalence) that have pathological estrogen receptor (ER+)-positive tumors, the human epidermal growth factor receptor 2 (HER2) (11.2% prevalence) and triple-negative breast cancer (TNBC) (25% prevalence). According to Shaukat Khanum Memorial Cancer Hospital and Research Centre – Pakistan, ten years of data showed that among 636 BC patients, 30.5% had TNBC who were <40 years of age, which is an extremely alarming situation. Therefore, there is a dire need to explore and develop therapeutic targets for the treatment of early TNBC. Since the last decade, unfortunately, there has been little success in understanding the complexity of TNBC and in discovering new biological therapeutic targets. However, conventional chemotherapy is the only choice of treatment for TNBC patients. Many investigators revealed advances in multi-omics (multiple "omes", e.g., genome, proteome, transcriptome, epigenome, and microbiome) which were later identified as actionable targets and increased prevalence in TNBC patients. However, various drugs have been identified so far which are related to a particular diagnostic and prognostic biomarker. For example, Epidermal growth factor receptor ( EGFR or ErbB-1), HER-2/neu (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4). Protein Transglin-2 (TAGLN 2 ) and Profilins-1 (Pfn-1 ) are the ubiquitously expressed large family of proteins present in all eukaryotes, enabling actin cytoskeletal reorganization. It is known that the oncogenic transformation of cells is accompanied by alteration in the actin cytoskeleton. There are causal connections between altered expression of actin cytoskeletal regulators and cancer progression. Our case-control study identified TAGLN-2 and Pfn-1 proteins in TNBC blood by mass spectrometry. Both TAGLN-2 and Pfn-1 proteins are differentially expressed in early and advanced stages of TNBS patients, which could be potential predictors or therapeutic targets for TNBC.

Keywords: TNBC, blood biomarkers, mass spectrometry, qPCR, ELISA

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Authors: Sudipta Garai

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Films as a cultural, social practice remains a dominant space for creation and destruction of ideologies and practices which make the sociological viewing, analysis, and interpretation of the same a complex affair. It remains the doorway between the interpretations and understanding of the writer/director and the reader/viewer. India, being a multi-linguistic culture, the media plays a much intriguing role than that of newspaper, books, stories, novels or any other medium of expression. Known to be the largest democracy, the State seem to guarantee and safeguard people’s choices and life of dignity through its Fundamental Rights and Directives. However, the laws contradict themselves when it comes to IPC 377 criminalizing anything except penovaginal sexual intercourse restricting alternative sexual preferences and practices questioning its sense of ‘democracy.' In this context, the issue of homosexuality came up in bits and pieces through various representations in ‘popular’ cinema mostly with sudden references of mockery and laughter where the explicit narratives of ‘queer’ seemed missing. Rituparno Ghosh, an eminent film maker of Bengal, came up as the ‘queer’ face in Kolkata specifically through his ‘queer’ trilogy (Memories in March, 2010; Arekti Premer Golpo, 2010; Chitrangada: A Crowning Wish, 2012) coming out of his own closet and speaking about his own sexual choices not only through the explicit narratives in films but also in person which made these films an important point of departure in Bengali film history. A sociological reading of these films through a discourse analysis is being done with the critical questions of ‘choice,' ’freedom,' ‘love and marriage’ and most importantly the ‘change.' This study not only focuses on the films and its analysis of content but also to engage with its audience, queer and not in order to extend beyond the art form into the actual vulnerabilities of life and experiences through informal interviews, focused group discussions and engaging with the real life narratives. A research of this kind is always looked upon as a medium of change hoping for a better world wiping away the discrimination and ‘shame’ the ‘queer’ faces in their everyday life, but a social science research is limited but its ‘time’ and academic boundary where the hope of change might be initiated but not fulfilled. The experiences and reflections of the ‘queer’ not only redefined the narratives of the films but also me as a researcher. The perspectives of the ‘hetero-normative’ informants gave a broader picture of the study and the socio-cultural complications that are intrigued with the ideas of resistance and change. The issues on subjectivity, power, and position couldn’t be wiped out in a study of this kind as both politics and aesthetics become integrated with each other in the creation of any art form be it films or a study of research.

Keywords: cinema, alternative sexualities, narratives, sexual choices, state and society

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Authors: Mitali Saha, Soma Das

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The fabrication of nanoscale materials for use in chemical sensing, biosensing and biological analyses has proven a promising avenue in the last few years. Cholesterol has aroused considerable interest in recent years on account of its being an important parameter in clinical diagnosis. There is a strong positive correlation between high serum cholesterol level and arteriosclerosis, hypertension, and myocardial infarction. Enzyme-based electrochemical biosensors have shown high selectivity and excellent sensitivity, but the enzyme is easily denatured during its immobilization procedure and its activity is also affected by temperature, pH, and toxic chemicals. Besides, the reproducibility of enzyme-based sensors is not very good which further restrict the application of cholesterol biosensor. It has been demonstrated that carbon nanotubes could promote electron transfer with various redox active proteins, ranging from cytochrome c to glucose oxidase with a deeply embedded redox center. In continuation of our earlier work on the synthesis and applications of carbon and metal based nanoparticles, we have reported here the synthesis of carbon nanotubes (CCNT) by burning coconut oil under insufficient flow of air using an oil lamp. The soot was collected from the top portion of the flame, where the temperature was around 6500C which was purified, functionalized and then characterized by SEM, p-XRD and Raman spectroscopy. The SEM micrographs showed the formation of tubular structure of CCNT having diameter below 100 nm. The XRD pattern indicated the presence of two predominant peaks at 25.20 and 43.80, which corresponded to (002) and (100) planes of CCNT respectively. The Raman spectrum (514 nm excitation) showed the presence of 1600 cm-1 (G-band) related to the vibration of sp2-bonded carbon and at 1350 cm-1 (D-band) responsible for the vibrations of sp3-bonded carbon. A nonenzymatic cholesterol biosensor was then fabricated on an insulating Teflon material containing three silver wires at the surface, covered by CCNT, obtained from coconut oil. Here, CCNTs worked as working as well as counter electrodes whereas reference electrode and electric contacts were made of silver. The dimensions of the electrode was 3.5 cm×1.0 cm×0.5 cm (length× width × height) and it is ideal for working with 50 µL volume like the standard screen printed electrodes. The voltammetric behavior of cholesterol at CCNT electrode was investigated by cyclic voltammeter and differential pulse voltammeter using 0.001 M H2SO4 as electrolyte. The influence of the experimental parameters on the peak currents of cholesterol like pH, accumulation time, and scan rates were optimized. Under optimum conditions, the peak current was found to be linear in the cholesterol concentration range from 1 µM to 50 µM with a sensitivity of ~15.31 μAμM−1cm−2 with lower detection limit of 0.017 µM and response time of about 6s. The long-term storage stability of the sensor was tested for 30 days and the current response was found to be ~85% of its initial response after 30 days.

Keywords: coconut oil, CCNT, cholesterol, biosensor

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Authors: Drago Bratkovic, Curtis Gravance, David Ketteridge, Ravi Krishnan, Michael Imperiale

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The mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases that have a common defect in the catabolism of glycosaminoglycans (GAGs). MPS I is the most common of the MPS diseases. Manifestations of MPS I include coarsening of facial features, corneal clouding, developmental delay, short stature, skeletal manifestations, hearing loss, cardiac valve disease, hepatosplenomegaly, and umbilical and inguinal hernias. Treatments for MPS I restore or activate the missing or deficient enzyme in the case of enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT). Pentosan polysulfate sodium (PPS) is a potential treatment to improve bone and joint manifestations of MPS I. The mechanisms of action of PPS that are relevant to the treatment of MPS I are the ability to: (i) Reduce systemic and accumulated GAG, (ii) Reduce inflammatory effects via the inhibition of NF-kB, resulting in the reduction in pro-inflammatory mediators. (iii) Reduce the expression of the pain mediator nerve growth factor in osteocytes from degenerating joints. (iv) Inhibit the cartilage degrading enzymes related to joint dysfunction in MPS I. PPS is being evaluated as an adjunctive therapy to ERT and/or HSCT in an open-label, single-centre, phase 2 study. Patients are ≥ 5 years of age with a diagnosis of MPS I and previously received HSCT and/or ERT. Three white, female, patients with MPS I-Hurler, ages 14, 15, and 19 years, and one, white male patient aged 15 years are enrolled. All were diagnosed at ≤2 years of age. All patients received HSCT ≤ 6 months after diagnosis. Two of the patients were treated with ERT prior to HSCT, and 1 patient received ERT commencing 3 months prior to HSCT. Two patients received 0.75mg/kg and 2 patients received 1.5mg/kg of PPS. PPS was well tolerated at doses of 0.75 and 1.5 mg/kg to 47 weeks of continuous dosing. Of the 19 adverse events (AEs), 2 were related to PPS. One AE was moderate (pre-syncope) and 1 was mild (injection site bruising), experienced in the same patient. All AEs were reported as mild or moderate. There have been no SAEs. One subject experienced a COVID-19 infection and PPS was interrupted. The MPS I signature GAG fragments, sulfated disaccharide and UA-HNAc S, tended to decrease in 3 patients from baseline through Week 25. Week 25 GAG data are pending for the 4th patient. Overall, most biomarkers (inflammatory, cartilage degeneration, and bone turnover) evaluated in the 3 patients with 25-week assessments have indicated either no change or a reduction in levels compared to baseline. In 3 patients, there was a trend toward improvement in the 2MWT from baseline to Week 48 with > 100% increase in 1 patient (01-201). In the 3 patients that had Week 48 assessments, patients and proxies reported improvement in PGIC, including “worthwhile difference” (n=1), or “made all the difference” (n=2).

Keywords: MPS I, pentosan polysulfate sodium, clinical study, 2MWT, QoL

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Authors: Navid Mosallaei, Mahmoud Reza Jaafari, Mohammad Yahya Hanafi-Bojd, Shiva Golmohammadzadeh, Bizhan Malaekeh-Nikouei

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Background: Docetaxel (DTX), a potent anticancer drug derived from the European yew tree, is effective against various human cancers by inhibiting microtubule depolymerization. Solid lipid nanoparticles (SLNs) have gained attention as drug carriers for enhancing drug effectiveness and safety. SLNs, submicron-sized lipid-based particles, can passively target tumors through the "enhanced permeability and retention" (EPR) effect, providing stability, drug protection, and controlled release while being biocompatible. Methods: The SLN formulation included biodegradable lipids (Compritol and Precirol), hydrogenated soy phosphatidylcholine (H-SPC) as a lipophilic co-surfactant, and Poloxamer 188 as a non-ionic polymeric stabilizer. Two SLN preparation techniques, probe sonication and microemulsion, were assessed. Characterization encompassed SLNs' morphology, particle size, zeta potential, matrix, and encapsulation efficacy. In-vitro cytotoxicity and cellular uptake studies were conducted using mouse colorectal (C-26) and human malignant melanoma (A-375) cell lines, comparing SLN-DTX with Taxotere®. In-vivo studies evaluated tumor inhibitory efficacy and survival in mice with colorectal (C-26) tumors, comparing SLNDTX withTaxotere®. Results: SLN-DTX demonstrated stability, with an average size of 180 nm and a low polydispersity index (PDI) of 0.2 and encapsulation efficacy of 98.0 ± 0.1%. Differential scanning calorimetry (DSC) suggested amorphous encapsulation of DTX within SLNs. In vitro studies revealed that SLN-DTX exhibited nearly equivalent cytotoxicity to Taxotere®, depending on concentration and exposure time. Cellular uptake studies demonstrated superior intracellular DTX accumulation with SLN-DTX. In a C-26 mouse model, SLN-DTX at 10 mg/kg outperformed Taxotere® at 10 and 20 mg/kg, with no significant differences in body weight changes and a remarkably high survival rate of 60%. Conclusion: This study concludes that SLN-DTX, prepared using the probe sonication, offers stability and enhanced therapeutic effects. It displayed almost same in vitro cytotoxicity to Taxotere® but showed superior cellular uptake. In a mouse model, SLN-DTX effectively inhibited tumor growth, with 10 mg/kg outperforming even 20 mg/kg of Taxotere®, without adverse body weight changes and with higher survival rates. This suggests that SLN-DTX has the potential to reduce adverse effects while maintaining or enhancing docetaxel's therapeutic profile, making it a promising drug delivery strategy suitable for industrialization.

Keywords: docetaxel, Taxotere®, solid lipid nanoparticles, enhanced permeability and retention effect, drug delivery, cancer chemotherapy, cytotoxicity, cellular uptake, tumor inhibition

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Authors: Changhan Ouyang, Zhonglin Xie

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In response to proatherosclerotic factors such as oxidized lipids, or to therapeutic interventions such as angioplasty, stents, or bypass surgery, vascular smooth muscle cells (VSMCs) migrate from the media to the intima, resulting in intimal hyperplasia, restenosis, graft failure, or atherosclerosis. These proatherosclerotic factors also activate autophagy in VSMCs. However, the functional role of autophagy in vascular health and disease remains poorly understood. In the present study, we determined the role of autophagy in the regulation of VSMC migration. Autophagy activity in cultured human aortic smooth muscle cells (HASMCs) and mouse carotid arteries was measured by Western blot analysis of microtubule-associated protein 1 light chain 3 B (LC3B) and P62. The VSMC migration was determined by scratch wound assay and transwell migration assay. Ex vivo smooth muscle cell migration was determined using aortic ring assay. The in vivo SMC migration was examined by staining the carotid artery sections with smooth muscle alpha actin (alpha SMA) after carotid artery ligation. To examine the relationship between autophagy and neointimal hyperplasia, C57BL/6J mice were subjected to carotid artery ligation. Seven days after injury, protein levels of Atg5, Atg7, Beclin1, and LC3B drastically increased and remained higher in the injured arteries three weeks after the injury. In parallel with the activation of autophagy, vascular injury-induced neointimal hyperplasia as estimated by increased intima/media ratio. The en face staining of carotid artery showed that vascular injury enhanced alpha SMA staining in the intimal cells as compared with the sham operation. Treatment of HASMCs with platelet-derived growth factor (PDGF), one of the major factors for vascular remodeling in response to vascular injury, increased Atg7 and LC3 II protein levels and enhanced autophagosome formation. In addition, aortic ring assay demonstrated that PDGF treated aortic rings displayed an increase in neovessel formation compared with control rings. Whole mount staining for CD31 and alpha SMA in PDGF treated neovessels revealed that the neovessel structures were stained by alpha SMA but not CD31. In contrast, pharmacological and genetic suppression of autophagy inhibits VSMC migration. Especially, gene silencing of Atg7 inhibited VSMC migration induced by PDGF. Furthermore, three weeks after ligation, markedly decreased neointimal formation was found in mice treated with chloroquine, an inhibitor of autophagy. Quantitative morphometric analysis of the injured vessels revealed a marked reduction in the intima/media ratio in the mice treated with chloroquine. Conclusion: Autophagy activation increases VSMC migration while autophagy suppression inhibits VSMC migration. These findings suggest that autophagy suppression may be an important therapeutic strategy for atherosclerosis and intimal hyperplasia.

Keywords: autophagy, vascular smooth muscle cell, migration, neointimal formation

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Authors: Tomasz Lewinski

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The right to know becomes gradually recognised as an increasing number of states adopts national legislations regarding access to state-held information. Laws differ from each other in the scope of the right to information (hereinafter: RTI). In all regimes of RTI, there are exceptions from the general notion of the right. States’ authorities too often use exceptions to justify refusals to requests for state-held information. This paper sets out how states hamper RTI basing on the notion of exception and by not providing an effective procedure that could redress unlawful denials. This paper bases on two selected examples of RTI incorporation into the national legal regime, United Kingdom, and South Africa. It succinctly outlines the international standard given in Article 19 of the International Covenant on Civil and Political Rights (hereinafter: ICCPR) and its influence on the RTI in selected countries. It shortly demonstrates as a background to further analysis the Human Rights Committee’s jurisprudence and standards articulated by successive Special Rapporteurs on freedom of opinion and expression. Subsequently, it presents a brief comparison of these standards with the regional standards, namely the African Charter on Human and Peoples' Rights and the European Convention on Human Rights. It critically discusses the regimes of exceptions in RTI legislations in respective national laws. It shows how excessive these regimes are, what implications they have for the transparency in general. Also, the objective is to divide exceptions enumerated in legislations of selected states in relation to exceptions provided in Article 19 of the ICCPR. Basing on the established division of exceptions by its natures, it compares both regimes of exceptions related to the principle of national security. That is to compare jurisprudence of domestic courts, and overview practices of states’ authorities applied to RTI requests. The paper evaluates remedies available in legislations, including contexts of the length and costs of the subsequent proceedings. This provides a general assessment of the given mechanisms and present potential risks of its ineffectiveness. The paper relies on examination of the national legislations, comments of the credible non-governmental organisations (e.g. The Public's Right to Know Principles on Freedom of Information Legislation by the Article 19, The Tshwane Principles on National Security and the Right to Information), academics and also the research of the relevant judgements delivered by domestic and international courts. Conclusion assesses whether selected countries’ legislations go in line with international law and trends, whether the jurisprudence of the regional courts provide appropriate benchmarks for national courts to address RTI issues effectively. Furthermore, it identifies the largest disadvantages of current legislations and to what outcomes it leads in domestic courts jurisprudences. In the end, it provides recommendations and policy arguments for states to improve transparency and support local organisations in their endeavours to establish more transparent states and societies.

Keywords: access to information, freedom of information, national security, right to know, transparency

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Authors: Joseph Falzon, Margaret Nelson

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Background: Regeneration and re-use of abandoned historic buildings present a continuous challenge for policy makers and stakeholders in the tourism and leisure industry. Obsolete historic buildings provide great potential for tourism and leisure accommodation, presenting unique heritage experiences to travellers and host communities. Contemporary demands in the hospitality industry continuously require higher standards, some of which are in conflict with heritage conservation principles. Objective: The aim of this research paper is to critically discuss regeneration policies with stakeholders of the tourism and leisure industry and to examine current practices in policy development and the resultant impact of policies on the Maltese tourism and leisure industry. Research Design: Six semi-structured interviews with stakeholders involved in the tourism and leisure industry participated in the research. A number of measures were taken to reduce bias and thus improve trustworthiness. Clear statements of the purpose of the research study were provided at the start of each interview to reduce expectancy bias. The interviews were semi-structured to minimise interviewer bias. Interviewees were allowed to expand and elaborate as necessary, with only necessary probing questions, to allow free expression of opinion and practices. Interview guide was submitted to participants at least two weeks before the interview to allow participants to prepare for the interview and prevent recall bias during the interview as much as possible. Interview questions and probes contained both positive and negative aspects to prevent interviewer bias. Policy documents were available during the interview to prevent recall bias. Interview recordings were transcribed ‘intelligent’ verbatim. Analysis was carried out using thematic analysis with the coding frame developed independently by two researchers. All phases of the study were governed by research ethics. Findings: Findings were grouped in main themes: financing of regeneration, governance, legislation and policies. Other key issues included value of historic buildings and approaches for regeneration. Whist regeneration of historic buildings was noted, participants discussed a number of barriers that hindered regeneration. Stakeholders identified gaps in policies and gaps at policy implementation stages. European Union funding policies facilitated regeneration initiatives but funding criteria based on economic deliverables presented the intangible heritage gap. Stakeholders identified niche markets for heritage tourism accommodation. Lack of research-based policies was also identified. Conclusion: Potential of regeneration is hindered by inadequate legal framework that supports contemporary needs of the tourism industry. Policies should be developed by active stakeholder participation. Adequate funding schemes have to support the tangible and intangible components of the built heritage.

Keywords: governance, historic buildings, policy, tourism

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Authors: Smita Lahkar

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Sattriya, the youngest of the eight principal Classical Indian dance traditions, has undergone too many changes and modifications to arrive at its present stage of performing art form extracting itself from age-old religious confinement. Although some of the other traditions have been revived in the recent past, Sattriya has a living tradition since its inception in the 15th century by Srimanta Sankardeva, the great Vaishnavite saint, poet, playwright, lyricist, painter, singer and dancer of Assam, a primary north-eastern state of India. This living dance tradition from the Sattras, the Vaishnavite monasteries, has been practiced for over five hundred years by celibate male monks, as a powerful medium for propagating the Vaishnava religious faith. Sankardeva realised the potential of the vocalised word integrated with the visual image as a powerful medium of expression and communication. So he used this principal medium for propagating his newly found message of devotion among the people of his time. Earlier, Sattriya was performed by male monks alone in monasteries (Sattras) as a part of daily rituals. The females were not even allowed to learn this art form. But, in present time, Sattriya has come out from the Sattras to proscenium stage, performed mostly by female as well as few male dancers also. The technique of performing movements, costumes, ornaments, music and style of performance too have experienced too many changes and modifications. For example, earlier and even today in Sattra, the ‘Pataka’ hand gesture is depicted in conformity with the original context (religious) of creation of the dance form. But, today stage-performers prefer the instructions of the scripture ‘Srihastamuktavali’ and depict the ‘Pataka’ in a sophisticated manner affecting decontextualisation to a certain extent. This adds aesthetic beauty to the dance form as an art distancing it from its context of being a vehicle for propagating Vaishnava religion. The Sattriya dance today stands at the crossroads of past and future, tradition and modernity, devotion and display, spirituality and secularism. The traditional exponents trained under the tutelage of Sattra maestros and imbibing a devotionally inspired rigour of the religion, try to retain the traditional nuances; while the young artists being trained outside the monasteries are more interested in taking up the discipline purely from the perspective of ‘performing arts’ bereft of the philosophy of religion or its sacred associations. Hence, this paper will be an endeavor to establish the hypothesis that the Sattriya, whose origin was for propagating Vaishnava faith, has now entered the world of performing arts with highly aesthetical components. And as a transformed art form, Sattriya may be expected to carve a niche in world dance arena. This will be done with the help of historical evidences, observations from the recorded past and expert rendezvous.

Keywords: dance, performing art, religion, Sattriya

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Authors: M. Cardenas-Garcia, P. P. Gonzalez-Perez

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Intercellular communication is a necessary condition for cellular functions and it allows a group of cells to survive as a population. Throughout this interaction, the cells work in a coordinated and collaborative way which facilitates their survival. In the case of cancerous cells, these take advantage of intercellular communication to preserve their malignancy, since through these physical unions they can send signs of malignancy. The Wnt/β-catenin signaling pathway plays an important role in the formation of intercellular communications, being also involved in a large number of cellular processes such as proliferation, differentiation, adhesion, cell survival, and cell death. The modeling and simulation of cellular signaling systems have found valuable support in a wide range of modeling approaches, which cover a wide spectrum ranging from mathematical models; e.g., ordinary differential equations, statistical methods, and numerical methods– to computational models; e.g., process algebra for modeling behavior and variation in molecular systems. Based on these models, different simulation tools have been developed from mathematical ones to computational ones. Regarding cellular and molecular processes in cancer, its study has also found a valuable support in different simulation tools that, covering a spectrum as mentioned above, have allowed the in silico experimentation of this phenomenon at the cellular and molecular level. In this work, we simulate and explore the complex interaction patterns of intercellular communication in cancer cells using the Cellulat bioinformatics tool, a computational simulation tool developed by us and motivated by two key elements: 1) a biochemically inspired model of self-organizing coordination in tuple spaces, and 2) the Gillespie’s algorithm, a stochastic simulation algorithm typically used to mimic systems of chemical/biochemical reactions in an efficient and accurate way. The main idea behind the Cellulat simulation tool is to provide an in silico experimentation environment that complements and guides in vitro experimentation in intra and intercellular signaling networks. Unlike most of the cell signaling simulation tools, such as E-Cell, BetaWB and Cell Illustrator which provides abstractions to model only intracellular behavior, Cellulat is appropriate for modeling both intracellular signaling and intercellular communication, providing the abstractions required to model –and as a result, simulate– the interaction mechanisms that involve two or more cells, that is essential in the scenario discussed in this work. During the development of this work we made evident the application of our computational simulation tool (Cellulat) for the modeling and simulation of intercellular communication between normal and cancerous cells, and in this way, propose key molecules that may prevent the arrival of malignant signals to the cells that surround the tumor cells. In this manner, we could identify the significant role that has the Wnt/β-catenin signaling pathway in cellular communication, and therefore, in the dissemination of cancer cells. We verified, using in silico experiments, how the inhibition of this signaling pathway prevents that the cells that surround a cancerous cell are transformed.

Keywords: cancer cells, in silico approach, intercellular communication, key molecules, modeling and simulation

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Authors: Jesús Horacio, Alfredo Ollero, Víctor Bouzas-Blanco, Augusto Pérez-Alberti

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Rivers have traditionally been classified, assessed and managed in terms of hydrological, chemical and / or biological criteria. Geomorphological classifications had in the past a secondary role, although proposals like River Styles Framework, Catchment Baseline Survey or Stroud Rural Sustainable Drainage Project did incorporate geomorphology for management decision-making. In recent years many studies have been attracted to the geomorphological component. The geomorphological processes and their associated forms determine the structure of a river system. Understanding these processes and forms is a critical component of the sustainable rehabilitation of aquatic ecosystems. The fluvial auto-classification approach suggests that a river is a self-built natural system, with processes and forms designed to effectively preserve their ecological function (hydrologic, sedimentological and biological regime). Fluvial systems are formed by a wide range of elements with multiple non-linear interactions on different spatial and temporal scales. Besides, the fluvial auto-classification concept is built using data from the river itself, so that each classification developed is peculiar to the river studied. The variables used in the classification are specific stream power and mean grain size. A discriminant analysis showed that these variables are the best characterized processes and forms. The statistical technique applied allows to get an individual discriminant equation for each geomorphological type. The geomorphological classification was developed using sites with high naturalness. Each site is a control point of high ecological and geomorphological quality. The changes in the conditions of the control points will be quickly recognizable, and easy to apply a right management measures to recover the geomorphological type. The study focused on Galicia (NW Spain) and the mapping was made analyzing 122 control points (sites) distributed over eight river basins. In sum, this study provides a method for fluvial geomorphological classification that works as an open and flexible tool underlying the fluvial auto-classification concept. The hydrographic mapping is the visual expression of the results, such that each river has a particular map according to its geomorphological characteristics. Each geomorphological type is represented by a particular type of hydraulic geometry (channel width, width-depth ratio, hydraulic radius, etc.). An alteration of this geometry is indicative of a geomorphological disturbance (whether natural or anthropogenic). Hydrographic mapping is also dynamic because its meaning changes if there is a modification in the specific stream power and/or the mean grain size, that is, in the value of their equations. The researcher has to check annually some of the control points. This procedure allows to monitor the geomorphology quality of the rivers and to see if there are any alterations. The maps are useful to researchers and managers, especially for conservation work and river restoration.

Keywords: fluvial auto-classification concept, mapping, geomorphology, river

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Authors: Lucas Derks, Christine Beenhakker, Michiel Brandt, Gert Arts, Ruud van Langeveld

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Background: The method Depression in Awareness Space (DAS) is a psychotherapeutic intervention technique based on the principles of spatial cognition and imagination therapy with spatial components. The basic assumptions are: mental space is the primary organizing principle in the mind, and all psychological issues can be treated by first locating and by next relocating the conceptualizations involved. The most clinical experience was gathered over the last 20 years in the area of social issues (with the social panorama model). The latter work led to the conclusion that a mental object (image) gains emotional impact when it is placed more central, closer and higher in the visual field – and vice versa. Changing the locations of mental objects in space thus alters the (socio-) emotional meaning of the relationships. The experience of depression seems always associated with darkness. Psychologists tend to see the link between depression and darkness as a metaphor. However, clinical practice hints to the existence of more literal forms of darkness. Aims: The aim of the method Depression in Awareness Space is to reduce the distress of clients with depression in the clinical counseling practice, as a reliable alternative method of psychological therapy for the treatment of depression. The method Depression in Awareness Space aims at making dark areas smaller, lighter and more transparent in order to identify the problem or the cause of the depression which lies behind the darkness. It was hypothesized that the darkness is a subjective side-effect of the neurological process of repression. After reducing the dark clouds the real problem behind the depression becomes more visible, allowing the client to work on it and in that way reduce their feelings of depression. This makes repression of the issue obsolete. Results: Clients could easily get into their 'sadness' when asked to do so and finding the location of the dark zones proved pretty easy as well. In a recent pilot study with five participants with mild depressive symptoms (measured on two different scales and tested against an untreated control group with similar symptoms), the first results were also very promising. If the mental spatial approach to depression can be proven to be really effective, this would be very good news. The Society of Mental Space Psychology is now looking for sponsoring of an up scaled experiment. Conclusions: For spatial cognition and the research into spatial psychological phenomena, the discovery of dark areas can be a step forward. Beside out of pure scientific interest, it is great to know that this discovery has a clinical implication: when darkness can be connected to depression. Also, darkness seems to be more than metaphorical expression. Progress can be monitored over measurement tools that quantify the level of depressive symptoms and by reviewing the areas of darkness.

Keywords: depression, spatial cognition, spatial imagery, social panorama

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Authors: Fengjuan Wang, Azilawati Jamaludin

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Developmental Dyscalculia (DD) is defined as a particular learning difficulty with continuous challenges in learning requisite math skills that cannot be explained by intellectual disability or educational deprivation. Recent studies have increasingly recognized that DD is a heterogeneous, instead of monolithic, learning disorder with not only cognitive and behavioral deficits but so too neural dysfunction. In recent years, neuroimaging studies employed group comparison to explore the neural underpinnings of DD, which contradicted the heterogenous nature of DD and may obfuscate critical individual differences. This research aimed to investigate the neural heterogeneity of DD using case studies with functional near-infrared spectroscopy (fNIRS). A total of 54 aged 6-7 years old of children participated in this study, comprising two comprehensive cognitive assessments, an 8-minute resting state, and an 8-minute one-digit addition task. Nine children met the criteria of DD and scored at or below 85 (i.e., the 16th percentile) on the Mathematics or Math Fluency subtest of the Wechsler Individual Achievement Test, Third Edition (WIAT-III) (both subtest scores were 90 and below). The remaining 45 children formed the typically developing (TD) group. Resting-state data and brain activation in the inferior frontal gyrus (IFG), superior frontal gyrus (SFG), and intraparietal sulcus (IPS) were collected for comparison between each case and the TD group. Graph theory was used to analyze the brain network under the resting state. This theory represents the brain network as a set of nodes--brain regions—and edges—pairwise interactions across areas to reveal the architectural organizations of the nervous network. Next, a single-case methodology developed by Crawford et al. in 2010 was used to compare each case’s brain network indicators and brain activation against 45 TD children’s average data. Results showed that three out of the nine DD children displayed significant deviation from TD children’s brain indicators. Case 1 had inefficient nodal network properties. Case 2 showed inefficient brain network properties and weaker activation in the IFG and IPS areas. Case 3 displayed inefficient brain network properties with no differences in activation patterns. As a rise above, the present study was able to distill differences in architectural organizations and brain activation of DD vis-à-vis TD children using fNIRS and single-case methodology. Although DD is regarded as a heterogeneous learning difficulty, it is noted that all three cases showed lower nodal efficiency in the brain network, which may be one of the neural sources of DD. Importantly, although the current “brain norm” established for the 45 children is tentative, the results from this study provide insights not only for future work in “developmental brain norm” with reliable brain indicators but so too the viability of single-case methodology, which could be used to detect differential brain indicators of DD children for early detection and interventions.

Keywords: brain activation, brain network, case study, developmental dyscalculia, functional near-infrared spectroscopy, graph theory, neural heterogeneity

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Authors: Rafael Santos, Clara Pimenta Do Vale, Barbara Bogoni, Poul Henning Kirkegaard

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In the last decades, the relevance of hand drawing has decreased in the scope of architectural education. However, some schools continue to recognize its decisive role, not only in the architectural design teaching, but in the whole of architectural training. With this paper it is intended to present the results of a research developed on the following problem: the practise of hand drawing as a premier form of representation in architectural design teaching. The research had as its object the educational model of the Faculty of Architecture of the University of Porto (FAUP) and was led by three main objectives: to identify the circumstance that promoted hand drawing as a form of representation in FAUP's model; to characterize the types of hand drawing and their role in that model; to determine the particularities of hand drawing as a premier form of representation in architectural design teaching. Methodologically, the research was conducted according to a qualitative embedded single-case study design. The object – i.e., the educational model – was approached in FAUP case considering its Context and three embedded unities of analysis: the educational Purposes, Principles and Practices. In order to guide the procedures of data collection and analysis, a Matrix for the Characterization (MCC) was developed. As a methodological tool, the MCC allowed to relate the three embedded unities of analysis with the three main sources of evidence where the object manifests itself: the professors, expressing how the model is Assumed; the architectural design classes, expressing how the model is Achieved; and the students, expressing how the model is Acquired. The main research methods used were the naturalistic and participatory observation, in-person-interview and documentary and bibliographic review. The results reveal that the educational model of FAUP – following the model of the former Porto School – was largely due to the methodological foundations created with the hand drawing teaching-learning processes. In the absence of a culture of explicit theoretical elaboration or systematic research, hand drawing was the support for the continuity of the school, an expression of a unified thought about what should be the reflection and practice of architecture. As a form of representation, hand drawing plays a transversal role in the entire educational model, since its purposes are not limited to the conception of architectural design – it is also a means for perception, analysis and synthesis. Regarding the architectural design teaching, there seems to be an understanding of three complementary dimensions of didactics: the instrumental, methodological and propositional dimension. At FAUP, hand drawing is recognized as the common denominator among these dimensions, according to the idea of "globality of drawing". It is expected that the knowledge base developed in this research may have three main contributions: to contribute to the maintenance and valorisation of FAUP’s model; through the precise description of the methodological procedures, to contribute by transferability to similar studies; through the critical and objective framework of the problem underlying the hand drawing in architectural design teaching, to contribute to the broader discussion concerning the contemporary challenges on architectural education.

Keywords: architectural design teaching, architectural education, forms of representation, hand drawing

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Authors: Taher Abofol, Eldad Yechiam, Thorsten Pachur

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In four studies, we examined whether seller and buyers differ not only in subjective price levels for objects (i.e., the endowment effect) but also in their relative accuracy given objects varying in expected value. If, as has been proposed, sellers stand to accrue a more substantial loss than buyers do, then their pricing decisions should be more sensitive to expected-value differences between objects. This is implied by loss aversion due to the steeper slope of prospect theory’s value function for losses than for gains, as well as by loss attention account, which posits that losses increase the attention invested in a task. Both accounts suggest that losses increased sensitivity to relative values of different objects, which should result in better alignment of pricing decisions to the objective value of objects on the part of sellers. Under loss attention, this characteristic should only emerge under certain boundary conditions. In Study 1 a published dataset was reanalyzed, in which 152 participants indicated buying or selling prices for monetary lotteries with different expected values. Relative EV sensitivity was calculated for participants as the Spearman rank correlation between their pricing decisions for each of the lotteries and the lotteries' expected values. An ANOVA revealed a main effect of perspective (sellers versus buyers), F(1,150) = 85.3, p < .0001 with greater EV sensitivity for sellers. Study 2 examined the prediction (implied by loss attention) that the positive effect of losses on performance emerges particularly under conditions of time constraints. A published dataset was reanalyzed, where 84 participants were asked to provide selling and buying prices for monetary lotteries in three deliberations time conditions (5, 10, 15 seconds). As in Study 1, an ANOVA revealed greater EV sensitivity for sellers than for buyers, F(1,82) = 9.34, p = .003. Importantly, there was also an interaction of perspective by deliberation time. Post-hoc tests revealed that there were main effects of perspective both in the condition with 5s deliberation time, and in the condition with 10s deliberation time, but not in the 15s condition. Thus, sellers’ EV-sensitivity advantage disappeared with extended deliberation. Study 3 replicated the design of study 1 but administered the task three times to test if the effect decays with repeated presentation. The results showed that the difference between buyers and sellers’ EV sensitivity was replicated in repeated task presentations. Study 4 examined the loss attention prediction that EV-sensitivity differences can be eliminated by manipulations that reduce the differential attention investment of sellers and buyers. This was carried out by randomly mixing selling and buying trials for each participant. The results revealed no differences in EV sensitivity between selling and buying trials. The pattern of results is consistent with an attentional resource-based account of the differences between sellers and buyers. Thus, asking people to price, an object from a seller's perspective rather than the buyer's improves the relative accuracy of pricing decisions; subtle changes in the framing of one’s perspective in a trading negotiation may improve price accuracy.

Keywords: decision making, endowment effect, pricing, loss aversion, loss attention

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Authors: D. Cole, S. Mahootian, P. Medlock

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This research contributes to existing knowledge of the complexities surrounding women’s relationship to beauty standards by examining their lived experiences. While there is much academic work on the effects of culturally imposed and largely unattainable beauty standards, the arguments tend to fall into two paradigms. On the one hand is the radical feminist perspective that argues that women are subjected to absolute oppression within the patriarchal system in which beauty standards have been constructed. This position advocates for a complete restructuring of social institutions to liberate women from all types of oppression. On the other hand, there are liberal feminist arguments that focus on choice, arguing that women’s agency in how to present themselves is empowerment. These arguments center around what women do within the patriarchal system in order to liberate themselves. However, there is very little research on the lived experiences of women negotiating these two realms: the complex negotiation between the pressure to adhere to cultural beauty standards and the agency of self-expression and empowerment. By exploring beauty standards through the intersection of societal messages (including macro-level processes such as social media and advertising as well as smaller-scale interactions such as families and peers) and lived experiences, this study seeks to provide a nuanced understanding of how women navigate and negotiate their own presentation and sense of self-identity. Current research sees a rise in incidents of body dysmorphia, depression and anxiety since the advent of social media. Approximately 91% of women are unhappy with their bodies and resort to dieting to achieve their ideal body shape, but only 5% of women naturally possess the body type often portrayed by Americans in movies and media. It is, therefore, crucial we begin talking about the processes that are affecting self-image and mental health. A question that arises is that, given these negative effects, why do companies continue to advertise and target women with standards that very few could possibly attain? One obvious answer is that keeping beauty standards largely unattainable enables the beauty and fashion industries to make large profits by promising products and procedures that will bring one up to “standard”. The creation of dissatisfaction for some is profit for others. This research utilizes qualitative methods: interviews, questionnaires, and focus groups to investigate women’s relationships to beauty standards and empowerment. To this end, we reached out to potential participants through a video campaign on social media: short clips on Instagram, Facebook, and TikTok and a longer clip on YouTube inviting users to take part in the study. Participants are asked to react to images, videos, and other beauty-related texts. The findings of this research have implications for policy development, advocacy and interventions aimed at promoting healthy inclusivity and empowerment of women.

Keywords: women, beauty, consumerism, social media

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Authors: Daniel O. Kleinsman

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The 2019 terrorist attack on two masjidain in Christchurch, New Zealand, was a shocking demonstration of the harm that can be caused by hate crime. As legal and governmental responses to the attack struggle to provide effective remedies to its victims, restorative justice has emerged as a tool that can assist, in terms of both meeting victims’ needs and discharging the obligations of the state under the International Covenant on Civil and Political Rights (ICCPR), arts 2(3), 26, 27. Restorative justice is a model that emphasizes the repair of harm caused or revealed by unjust behavior. It also prioritises the facilitation of dialogue, the restoration of equitable relationships, and the prevention of future harm. Returning to the case study, in the remarks of the sentencing judge, the terrorist’s actions were described as a hate crime of vicious malevolence that the Court was required to decisively reject, as anathema to the values of acceptance, tolerance and mutual respect upon which New Zealand’s inclusive society is based and which the country strives to maintain. This was one of the reasons for which the terrorist received a life sentence with no possibility of parole. However, in the report of the Royal Commission of Inquiry into the Attack, it was found that victims felt the attack occurred within the context of widespread racism, discrimination and Islamophobia, where hostile behaviors, including hate-based threats and attacks, were rarely recorded, analysed or acted on. It was also found that the Government had inappropriately concentrated intelligence resources on the risk of ‘Islamist’ terrorism and had failed to adequately respond to concerns raised about threats against the Muslim community. In this light, the remarks of the sentencing judge can be seen to reflect a criminal justice system that, in the absence of other remedies, denies systemic accountability and renders hate crime an isolated incident rather than an expression of more widespread discrimination and hate to be holistically addressed. One of the recommendations of the Royal Commission was to explore with victims the desirability and design of restorative justice processes. This presents an opportunity for victims to meet with state representatives and pursue effective remedies (ICCPR art 2(3)) not only for the harm caused by the terrorist but the harm revealed by a system that has exposed the minority Muslim community in New Zealand to hate in all forms, including but not limited to violent extremism. In this sense, restorative justice can also assist the state in discharging its wider obligations to protect all persons from discrimination (art 26) and allow ethnic and religious minorities to enjoy their own culture and profess and practice their own religion (art 27). It can also help give effect to the law and its purpose as a remedy to hate crime, as expressed in this case study by the sentencing judge.

Keywords: hate crime, restorative justice, minorities, victims' rights

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Authors: M. Nerantzaki, I. Koliakou, D. Bikiaris

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This study evaluates the hypothesis that the incorporation of fibrous hydroxyapatite nanoparticles (nHA) with high crystallinity and high aspect ratio, synthesized by hydrothermal method, into Poly(butylene succinate) (PBSu), improves the bioactivity of the aliphatic polyester and affects new bone growth inhibiting resorption and enhancing bone formation. Hydroxyapatite nanorods were synthesized using a simple hydrothermal procedure. First, the HPO42- -containing solution was added drop-wise into the Ca2+-containing solution, while the molar ratio of Ca/P was adjusted at 1.67. The HA precursor was then treated hydrothermally at 200°C for 72 h. The resulting powder was characterized using XRD, FT-IR, TEM, and EDXA. Afterwards, PBSu nanocomposites containing 2.5wt% (nHA) were prepared by in situ polymerization technique for the first time and were examined as potential scaffolds for bone engineering applications. For comparison purposes composites containing either 2.5wt% micro-Bioglass (mBG) or 2.5wt% mBG-nHA were prepared and studied, too. The composite scaffolds were characterized using SEM, FTIR, and XRD. Mechanical testing (Instron 3344) and Contact Angle measurements were also carried out. Enzymatic degradation was studied in an aqueous solution containing a mixture of R. Oryzae and P. Cepacia lipases at 37°C and pH=7.2. In vitro biomineralization test was performed by immersing all samples in simulated body fluid (SBF) for 21 days. Biocompatibility was assessed using rat Adipose Stem Cells (rASCs), genetically modified by nucleofection with DNA encoding SB100x transposase and pT2-Venus-neo transposon expression plasmids in order to attain fluorescence images. Cell proliferation and viability of cells on the scaffolds were evaluated using fluoresce microscopy and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay. Finally, osteogenic differentiation was assessed by staining rASCs with alizarine red using cetylpyridinium chloride (CPC) method. TEM image of the fibrous HAp nanoparticles, synthesized in the present study clearly showed the fibrous morphology of the synthesized powder. The addition of nHA decreased significantly the contact angle of the samples, indicating that the materials become more hydrophilic and hence they absorb more water and subsequently degrade more rapidly. In vitro biomineralization test confirmed that all samples were bioactive as mineral deposits were detected by X-ray diffractometry after incubation in SBF. Metabolic activity of rASCs on all PBSu composites was high and increased from day 1 of culture to day 14. On day 28 metabolic activity of rASCs cultured on samples enriched with bioceramics was significantly decreased due to possible differentiation of rASCs to osteoblasts. Staining rASCs with alizarin red after 28 days in culture confirmed our initial hypothesis as the presence of calcium was detected, suggesting osteogenic differentiation of rACS on PBSu/nHAp/mBG 2.5% and PBSu/mBG 2.5% composite scaffolds.

Keywords: biomaterials, hydroxyapatite nanorods, poly(butylene succinate), scaffolds

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Authors: Chung-Yuan Wang, Min Hsu, Bo-Ya Juan, Hsiv Ching Lin, Hsveh Min Lin, Hsiu-Fang Yeh

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The success of Taiwan's National Health Insurance (NHI) system attracts widespread praise from the international society. However, the availability of medical care in a emote area is limited. Without the convenient public transportation system and mature social welfare policy, these people are difficult to regain their health and prevent disability. Preterm children have more risk to get development delay. Preterm children in a remote area have the human right to get rehabilitation resources as those in the city area. Therefore, the aim of this study was to show the importance of development screening to preterm children in a remote area and a tract the government to notice the issue. In Pingtung, children who are suspected development delay would be suggested to take a skillful screening evaluation in our hospital. Those preterm children (within 1-year-old) visited our pediatric clinic would also be referred to take the development evaluation. After the physiatrist’s systemic evaluation, the subjects would be scheduled to take the development evaluation. Gross motor, fine motor, speech comprehension/expression and mental study were included. The evaluation was in-charged by a physical therapist, occupational therapy, speech therapist and pediatric psychologist. The tools were Peabody developmental scale, Bayley Scales of Infant and Toddler Development (Bayley-III) and Wechsler Preschool & Primary Scale of Intelligence-Revised (WPPSI-R). In 2013, 459 children received the service in our hospital. Among these children, fifty-seven were noted with preterm baby history (gestation within 37 weeks). Thirty-six of these preterm children, who had never receive development evaluation, were included in this study. Thirty-six subjects (twenty-six male and ten female) were included. Nineteen subjects were found development delay. Six subjects were found suspected development delay. In gross motor, six subjects were development delay and eight were suspected development delay. In fine motor, five subjects were development delay and three were suspected development delay. In speech, sixteen subjects were development delay and six were suspected development delay. In our study, through the provision of development evaluation service, 72.2% preterm baby were found their development delay or suspected delay. They need further early intervention rehabilitation service. We made their parents realize that when development delay was recognized at the early stage, they are often reversible. No only the patients but also their families were improved their health status. The number of the subjects was limited in our study. Further study might be needed. Compared with 770 physical therapist (PT) and 370 occupational therapy (OT) in Taipei, there are only 108 PT and 54 OT in Pingtung. Further, there are much fewer therapists working on the field of pediatric rehabilitation. Living healthy is a human's right, no matter where does he live. For those development delay children in remote area, particularly preterm children, early detection, and early intervention rehabilitation service could play an important role in decreasing their disability and improving their quality of life. Through this study, we suggest the government to add more national resources on the development evaluation to preterm children in a remote area.

Keywords: development, early intervention, preterm children, rehabilitation

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Authors: P. Asiabi, M. Shahhoseini, R. Favaedi, F. Hassani, N. Nassiri, B. Movaghar, L. Karimian, P. Eftekhariyazdi

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Introduction: Polycystic Ovary Syndrome is a common gynecologic disorder. Many factors including environment, metabolism, hormones and genetics are involved in etiopathogenesis of PCOS. Of genes that have altered expression in human reproductive system disorders are HOX family genes which act as transcription factors in regulation of cell proliferation, differentiation, adhesion and migration. Since recent evidences consider epigenetic factors as causative mechanisms of PCOS, evaluation of association between known epigenetic marks of acetylation/methylation of histone 3 (H3K9ac/me) with regulatory regions of these genes can represent better insight about PCOS. In the current study, cumulus cells (CCs) which have critical roles during folliculogenesis, oocyte maturation, ovulation and fertilization were aimed to monitor epigenetic alterations of HOX genes. Material and methods: CCs were collected from 20 PCOS patients and 20 fertile women (18-36 year) with male infertility problems referred to the Royan Institute to have ICSI under GnRH antagonist protocol. Informed consents were obtained from the participants. Thirty six hours after hCG injection, ovaries were punctured and cumulus oocyte complexes were dissected. Soluble chromatin were extracted from CCs and Chromatin Immune precipitation (ChIP) coupled with Real Time PCR was performed to quantify the epigenetic marks of histone H3K9 acetylation/methylation (H3K9ac/me) on regulatory regions of 15 members of HOX genes from A-D subfamily. Results: Obtained data showed significant increase of H3K9ac epigenetic mark on regulatory regions of HOXA1, HOXB2, HOXC4, HOXD1, HOXD3 and HOXD4 (P < 0.01) and HOXC5 (P < 0.05) and also significant decrease of H3K9ac into regulatory regions of HOXA2, HOXA4, HOXA5, HOXB1 and HOXB5 (P < 0.01) and HOXB3 (P<0.05) in PCOS patients vs. control group. On the other side, there was a significant decrease in incorporation of H3K9me level on regulatory region of HOXA2, HOXA3, HOXA4, HOXA5, HOXB3 and HOXC4 (P≤0.01) and HOXB5 (P < 0.05) in PCOS patients vs. control group. This epigenetic mark (H3K9me2) has significant increase on regulatory region of HOXB1, HOXB2, HOXC5, HOXD1, HOXD3 and HOXD4 (P ≤ 0.01) and HOXB4 (P < 0.05) in patients vs. control group. There were no significant changes in acetylation/methylation levels of H3K9 on regulatory regions of the other studied genes. Conclusion: Current study suggests that epigenetic alterations of HOX genes can be correlated with PCOS and consequently female infertility. This finding might offer additional definitions of PCOS, and eventually provides insight for novel treatments with epidrugs for this disease.

Keywords: epigenetic, HOX genes, PCOS, female infertility

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Authors: Soma Ghosh, Balaram Mohapatra, Pinaki Sar, Abhijeet Mukherjee

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Microbial role in arsenic (As) mobilization in the groundwater aquifers of Brahmaputra river basin (BRB) in India, severely threatened by high concentrations of As, remains largely unknown. The present study, therefore, is a molecular and ecophysiological characterization of an indigenous bacterium strain IIIJ3-1 isolated from As contaminated groundwater of BRB and application of this strain in several microcosm set ups differing in their organic carbon (OC) source and terminal electron acceptors (TEA), to understand its role in As dissolution under aerobic and anaerobic conditions. Strain IIIJ3-1 was found to be a new facultative anaerobic, gram-positive, endospore-forming strain capable of arsenite (As3+) oxidation and dissimilatory arsenate (As5+) reduction. The bacterium exhibited low genomic (G+C)% content (45 mol%). Although, its 16S rRNA gene sequence revealed a maximum similarity of 99% with Bacillus cereus ATCC 14579(T) but the DNA-DNA relatedness of their genomic DNAs was only 49.9%, which remains well below the value recommended to delimit different species. Abundance of fatty acids iC17:0, iC15:0 and menaquinone (MK) 7 though corroborates its taxonomic affiliation with B. cereus sensu-lato group, presence of hydroxy fatty acids (HFAs), C18:2, MK5 and MK6 marked its uniqueness. Besides being highly As resistant (MTC=10mM As3+, 350mM As5+), metabolically diverse, efficient aerobic As3+ oxidizer; it exhibited near complete dissimilatory reduction of As5+ (1 mM). Utilization of various carbon sources with As5+ as TEA revealed lactate to serve as the best electron donor. Aerobic biotransformation assay yielded a lower Km for As3+ oxidation than As5+ reduction. Arsenic homeostasis was found to be conferred by the presence of arr, arsB, aioB, and acr3(1) genes. Scanning electron microscopy (SEM) coupled with energy dispersive X-ray (EDX) analysis of this bacterium revealed reduction in cell size upon exposure to As and formation of As-rich electron opaque dots following growth with As3+. Incubation of this strain with sediment (sterilised) collected from BRB aquifers under varying OC, TEA and redox conditions revealed that the strain caused highest As mobilization from solid to aqueous phase under anaerobic condition with lactate and nitrate as electron donor and acceptor, respectively. Co-release of highest concentrations of oxalic acid, a well known bioweathering agent, considerable fold increase in viable cell counts and SEM-EDX and X-ray diffraction analysis of the sediment after incubation under this condition indicated that As release is consequent to microbial bioweathering of the minerals. Co-release of other elements statistically proves decoupled release of As with Fe and Zn. Principle component analysis also revealed prominent role of nitrate under aerobic and/or anaerobic condition in As release by strain IIIJ3-1. This study, therefore, is the first to isolate, characterize and reveal As mobilization property of a strain belonging to the Bacillus cereus sensu lato group isolated from highly As contaminated aquifers of Brahmaputra River Basin.

Keywords: anaerobic microcosm, arsenic rich electron opaque dots, Arsenic release, Bacillus strain IIIJ3-1

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Authors: Jelena Kovačević Vorgučin, Sibila Petenji Arbutina

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The postmodern age brings a rapid development of technology which inevitably leads to man's need to adapt to modern lifestyle. On the one hand, technological achievements have made human life easier, but there are numerous risks involved. Moreover, man's awareness and perception is changing and adapting unconsciously to the world we live in, while communication in the 21st century is predominantly based on the consumption of images. This paper presents sociological aspects of a community which is confined due to turbulent political-economic circumstances and its impact on the development of media literacy in Serbia. Previous researches led to the conclusion that the media culture is on an extremely low level, and that it can have a strong influence on the general development of the society, starting from the youngest segment of the population. Our aim is to use the conceptual authorial photographs inspired by the obtained research results to emphasize the importance that the impact of visual art has in delivering the message, its role in education and in raising awareness of universal social problems. The paper presents a number of stages involved in the conceptual project which is designed to last over a longer period of time in order to facilitate dissemination of information. First, a survey was carried out in several preschool institutions. This resulted in obtaining the necessary information on the habitual use of the medium of television in children and their carers-parents. The second stage focused on the relationship between the parent and the child in TV consumption. Further, an overview of the visual part of the project was made, which consisted of photographs in various dimensions, ranging from miniature to large dimensions, and following various exhibition principles in both gallery and alternative spaces. This stage of the project placed particular emphasis on the non-standard exhibiting formats and alternative exhibition principles which are increasingly present in all kinds of visual art aimed at achieving a higher level of information noticing and memorizing. The motif on the authorial photographs is children's portraits taken while they are watching different television contents, with emphasis on their emotional response. The importance of the medium of TV is particularly emphasized due to the fact that its consumption is the highest, even though there are newer and more advanced information-technological achievements. The already realized part of the project was used for an analysis of the results in the last stage of the project, which led to the conclusion that the response to the entire visual expression campaign was extremely positive, and action as such very useful indeed. The results obtained speak in favour of widening and continuation of the project, both on a greater number of sites locally as well as in other communities in Serbia with the aim of guiding people towards meaningful consumption of the television medium.

Keywords: alternative space exhibiting, children and TV, conceptual portrait photography, media literacy

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Authors: Georges Ghazi, Magali Gelhaye, Ruxandra Botez

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Over the years, the Flight Management System (FMS) has experienced a continuous improvement of its many features, to the point of becoming the pilot’s primary interface for flight planning operation on the airplane. With the assistance of the FMS, the concept of distance and time has been completely revolutionized, providing the crew members with the determination of the optimized route (or flight plan) from the departure airport to the arrival airport. To accomplish this function, the FMS needs an accurate Aircraft Performance Model (APM) of the aircraft. In general, APMs that equipped most modern FMSs are established before the entry into service of an individual aircraft, and results from the combination of a set of ordinary differential equations and a set of performance databases. Unfortunately, an aircraft in service is constantly exposed to dynamic loads that degrade its flight characteristics. These degradations endow two main origins: airframe deterioration (control surfaces rigging, seals missing or damaged, etc.) and engine performance degradation (fuel consumption increase for a given thrust). Thus, after several years of service, the performance databases and the APM associated to a specific aircraft are no longer representative enough of the actual aircraft performance. It is important to monitor the trend of the performance deterioration and correct the uncertainties of the aircraft model in order to improve the accuracy the flight management system predictions. The basis of this research lies in the new ability to continuously update an Aircraft Performance Model (APM) during flight using an adaptive lookup table technique. This methodology was developed and applied to the well-known Cessna Citation X business aircraft. For the purpose of this study, a level D Research Aircraft Flight Simulator (RAFS) was used as a test aircraft. According to Federal Aviation Administration the level D is the highest certification level for the flight dynamics modeling. Basically, using data available in the Flight Crew Operating Manual (FCOM), a first APM describing the variation of the engine fan speed and aircraft fuel flow w.r.t flight conditions was derived. This model was next improved using the proposed methodology. To do that, several cruise flights were performed using the RAFS. An algorithm was developed to frequently sample the aircraft sensors measurements during the flight and compare the model prediction with the actual measurements. Based on these comparisons, a correction was performed on the actual APM in order to minimize the error between the predicted data and the measured data. In this way, as the aircraft flies, the APM will be continuously enhanced, making the FMS more and more precise and the prediction of trajectories more realistic and more reliable. The results obtained are very encouraging. Indeed, using the tables initialized with the FCOM data, only a few iterations were needed to reduce the fuel flow prediction error from an average relative error of 12% to 0.3%. Similarly, the FCOM prediction regarding the engine fan speed was reduced from a maximum error deviation of 5.0% to 0.2% after only ten flights.

Keywords: aircraft performance, cruise, trajectory optimization, adaptive lookup tables, Cessna Citation X

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Authors: P. J. Sweeney, T. Ahtoniemi, J. Puoliväli, T. Laitinen, K. Lehtimäki, A. Nurmi, D. Wells

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Duchenne muscular dystrophy (DMD) is caused by an X linked mutation in the dystrophin gene; lack of dystrophin causes a progressive muscle necrosis which leads to a progressive decrease in mobility in those suffering from the disease. The MDX mouse, a mutant mouse model which displays a frank dystrophinopathy, is currently widely employed in pre clinical efficacy models for treatments and therapies aimed at DMD. In general the end-points examined within this model have been based on invasive histopathology of muscles and serum biochemical measures like measurement of serum creatine kinase (sCK). It is established that a “critical period” between 4 and 6 weeks exists in the MDX mouse when there is extensive muscle damage that is largely sub clinical but evident with sCK measurements and histopathological staining. However, a full characterization of the MDX model remains largely incomplete especially with respect to the ability to aggravate of the muscle damage beyond the critical period. The purpose of this study was to attempt to aggravate the muscle damage in the MDX mouse and to create a wider, more readily translatable and discernible, therapeutic window for the testing of potential therapies for DMD. The study consisted of subjecting 15 male mutant MDX mice and 15 male wild-type mice to an intense chronic exercise regime that consisted of bi-weekly (two times per week) treadmill sessions over a 12 month period. Each session was 30 minutes in duration and the treadmill speed was gradually built up to 14m/min for the entire session. Baseline plasma creatine kinase (pCK), treadmill training performance and locomotor activity were measured after the “critical period” at around 10 weeks of age and again at 14 weeks of age, 6 months, 9 months and 12 months of age. In addition, kinematic gait analysis was employed using a novel analysis algorithm in order to compare changes in gait and fine motor skills in diseased exercised MDX mice compared to exercised wild type mice and non exercised MDX mice. In addition, a morphological and metabolic profile (including lipid profile), from the muscles most severely affected, the gastrocnemius muscle and the tibialis anterior muscle, was also measured at the same time intervals. Results indicate that by aggravating or exacerbating the underlying muscle damage in the MDX mouse by exercise a more pronounced and severe phenotype in comes to light and this can be picked up earlier by kinematic gait analysis. A reduction in mobility as measured by open field is not apparent at younger ages nor during the critical period, but changes in gait are apparent in the mutant MDX mice. These gait changes coincide with pronounced morphological and metabolic changes by non-invasive anatomical MRI and proton spectroscopy (1H-MRS) we have reported elsewhere. Evidence of a progressive asymmetric pathology in imaging parameters as well as in the kinematic gait analysis was found. Taken together, the data show that chronic exercise regime exacerbates the muscle damage beyond the critical period and the ability to measure through non-invasive means are important factors to consider when performing preclinical efficacy studies in the MDX mouse.

Keywords: Gait, muscular dystrophy, Kinematic analysis, neuromuscular disease

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