Search results for: multi-element expression pattern

Authors: Julia Kapr, Andrea Rossi, Haribaskar Ramachandran, Marius Pollet, Ilka Egger, Selina Dangeleit, Katharina Koch, Jean Krutmann, Ellen Fritsche

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It is widely acknowledged that animal models do not always represent human disease. Especially human brain development is difficult to model in animals due to a variety of structural and functional species-specificities. This causes significant discrepancies between predicted and apparent drug efficacies in clinical trials and their subsequent failure. Emerging alternatives based on 3D in vitro approaches, such as human brain spheres or organoids, may in the future reduce and ultimately replace animal models. Here, we present a human induced pluripotent stem cell (hiPSC)-based 3D neural in a vitro disease model for the Cockayne Syndrome B (CSB). CSB is a rare hereditary disease and is accompanied by severe neurologic defects, such as microcephaly, ataxia and intellectual disability, with currently no treatment options. Therefore, the aim of this study is to investigate the molecular and cellular defects found in neural hiPSC-derived CSB models. Understanding the underlying pathology of CSB enables the development of treatment options. The two CSB models used in this study comprise a patient-derived hiPSC line and its isogenic control as well as a CSB-deficient cell line based on a healthy hiPSC line (IMR90-4) background thereby excluding genetic background-related effects. Neurally induced and differentiated brain sphere cultures were characterized via RNA Sequencing, western blot (WB), immunocytochemistry (ICC) and multielectrode arrays (MEAs). CSB-deficiency leads to an altered gene expression of markers for autophagy, focal adhesion and neural network formation. Cell migration was significantly reduced and electrical activity was significantly increased in the disease cell lines. These data hint that the cellular pathologies is possibly underlying CSB. By induction of autophagy, the migration phenotype could be partially rescued, suggesting a crucial role of disturbed autophagy in defective neural migration of the disease lines. Altered autophagy may also lead to inefficient mitophagy. Accordingly, disease cell lines were shown to have a lower mitochondrial base activity and a higher susceptibility to mitochondrial stress induced by rotenone. Since mitochondria play an important role in neurotransmitter cycling, we suggest that defective mitochondria may lead to altered electrical activity in the disease cell lines. Failure to clear the defective mitochondria by mitophagy and thus missing initiation cues for new mitochondrial production could potentiate this problem. With our data, we aim at establishing a disease adverse outcome pathway (AOP), thereby adding to the in-depth understanding of this multi-faced disorder and subsequently contributing to alternative drug development.

Keywords: autophagy, disease modeling, in vitro, pluripotent stem cells

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Authors: Mansour Eslami, Fereshte Habibi

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Limb length discrepancy (LLD), or anisomeric, is defined as a condition in which paired limbs are noticeably unequal. Individuals with LLD during walking use compensatory mechanisms to dynamically lengthen the short limb and shorten the long limb to minimize the displacement of the body center of mass and consequently reduce body energy expenditure. Due to the compensatory movements created, LLD greater than 1 cm increases the odds of creating lumbar problems and hip and knee osteoarthritis. Insoles are non-surgical therapies that are recommended to improve the walking pattern, pain and create greater symmetry between the two lower limbs. However, it is not yet clear what effect insoles have on the variables related to injuries during walking. The aim of the present study was to evaluate the effect of internal and external heel lift insoles on pelvic kinematic in sagittal and frontal planes and lower extremity joint moments in individuals with mild leg length discrepancy during the stance phase of walking. Biomechanical data of twenty-eight men with structural leg length discrepancy of 10-25 mm were collected while they walked under three conditions: shoes without insole (SH), with internal heel lift insoles (IHLI) in shoes, and with external heal lift insole (EHLI). The tests were performed for both short and long legs. The pelvic kinematic and joint moment were measured with a motion capture system and force plate. Five walking trials were performed for each condition. The average value of five successful trials was used for further statistical analysis. Repeated measures ANCOVA with Bonferroni post hoc test were used for between-group comparisons (p ≤ 0.05). In both internal and external heel lift insoles (IHLI, EHLI), there was a significant decrease in the peak values of lateral and anterior pelvic tilts of the long leg, hip, and knee moments of a long leg and ankle moment of short leg (p ≤ 0.05). Furthermore, significant increases in peak values of lateral and anterior pelvic tilt of short leg in IHLI and EHLI were observed as compared to Shoe (SH) condition (p ≤ 0.01). In addition, a significant difference was observed between the IHLI and EHLI conditions in peak anterior pelvic tilt of long leg and plantar flexor moment of short leg (p=0.04; p= 0.04 respectively). Our findings indicate that both IHLI and EHLI can play an important role in controlling excessive pelvic movements in the sagittal and frontal planes in individuals with mild LLD during walking. Furthermore, the EHLI may have a better effect in preventing musculoskeletal injuries compared to the IHLI.

Keywords: kinematic, leg length discrepancy, shoe insole, walking

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Authors: Mohammed El Raey, Moustafa Osman Mohammed

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The spatial-ecological modeling is relating sustainable dispersions with social development. Sustainability with spatial-ecological model gives attention to urban environments in the design review management to comply with Earth’s System. Naturally exchange patterns of ecosystems have consistent and periodic cycles to preserve energy flows and materials in Earth’s System. The probabilistic risk assessment (PRA) technique is utilized to assess the safety of industrial complex. The other analytical approach is the Failure-Safe Mode and Effect Analysis (FMEA) for critical components. The plant safety parameters are identified for engineering topology as employed in assessment safety of industrial ecology. In particular, the most severe accidental release of hazardous gaseous is postulated, analyzed and assessment in industrial region. The IAEA- safety assessment procedure is used to account the duration and rate of discharge of liquid chlorine. The ecological model of plume dispersion width and concentration of chlorine gas in the downwind direction is determined using Gaussian Plume Model in urban and ruler areas and presented with SURFER®. The prediction of accident consequences is traced in risk contour concentration lines. The local greenhouse effect is predicted with relevant conclusions. The spatial-ecological model is also predicted the distribution schemes from the perspective of pollutants that considered multiple factors of multi-criteria analysis. The data extends input–output analysis to evaluate the spillover effect, and conducted Monte Carlo simulations and sensitivity analysis. Their unique structure is balanced within “equilibrium patterns”, such as the biosphere and collective a composite index of many distributed feedback flows. These dynamic structures are related to have their physical and chemical properties and enable a gradual and prolonged incremental pattern. While this spatial model structure argues from ecology, resource savings, static load design, financial and other pragmatic reasons, the outcomes are not decisive in artistic/ architectural perspective. The hypothesis is an attempt to unify analytic and analogical spatial structure for development urban environments using optimization software and applied as an example of integrated industrial structure where the process is based on engineering topology as optimization approach of systems ecology.

Keywords: spatial-ecological modeling, spatial structure orientation impact, composite structure, industrial ecology

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Authors: Bikash Ranjan Mishra, Lopamudra D. Satpathy

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In the wake of the phenomenal surge in international business in the last decades or more, both the developed and developing economies around the world are in massive competition to attract more and more FDI flows. While the developed countries have marched ahead in the race, the developing countries, especially those of Asian economies, have followed them at a rapid pace. While most of the previous studies have analysed the role of institutional quality in the promotion of FDI flows in developing countries, very few studies have taken an integrated approach of examining the comprehensive impact of institutional quality, globalization pattern and domestic financial development on FDI flows. In this context, the paper contributes to the literature in two important ways. Firstly, two composite indices of institutional quality and domestic financial development for the Asian countries are constructed in comparison to earlier studies that resort to a single variable for indicating the institutional quality and domestic financial development. Secondly, the impact of these variables on FDI flows through their interaction with geographical region is investigated. The study uses panel data covering the time period of 1996 to 2012 by selecting twenty Asian developing countries by emphasizing the quality of institutions from the geographical regions of eastern, south-eastern, southern and western Asia. Control of corruption, better rule of law, regulatory quality, effectiveness of the government, political stability and voice and accountability are used as indicators of institutional quality. Besides these, the study takes into account the domestic credits in the hands of public, private sectors and in stock markets as domestic financial indicators. First in the specification of model, a factor analysis is performed to reduce the vast determinants, which are highly correlated with each other, to a manageable size. Afterwards, a reduced version of the model is estimated with the extracted factors in the form of index as independent variables along with a set of control variables. It is found that the institutional quality index and index of globalization exert a significant effect on FDI inflows of the host countries; in contrast, the domestic financial index does not seem to play much worthy role. Finally, some robustness tests are performed to make sure that the results are not sensitive to temporal and spatial unobserved heterogeneity. On the basis of the above study, one general inference can be drawn from the policy prescription point of view that the government of these developing countries should strengthen their domestic institution, both financial and non-financial. In addition to these, welfare policies should also target for rapid globalization. If the financial and non-financial institutions of these developing countries become sound and grow more globalized in the economic, social and political domain, then they can appeal to more amounts of FDI inflows that will subsequently result in advancement of these economies.

Keywords: Asian developing economies, FDI, institutional quality, panel data

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Authors: Akshay B. Pawar, Rohit Y. Parasnis

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Heart Rate Variability (HRV) is a widely used indicator of the regulation between the autonomic nervous system (ANS) and the cardiovascular system. Besides being non-invasive, it also has the potential to predict mortality in cases involving critical injuries. The gold standard method for determining HRV is based on the analysis of RR interval time series extracted from ECG signals. However, because it is much more convenient to obtain photoplethysmogramic (PPG) signals as compared to ECG signals (which require the attachment of several electrodes to the body), many researchers have used pulse cycle intervals instead of RR intervals to estimate HRV. They have also compared this method with the gold standard technique. Though most of their observations indicate a strong correlation between the two methods, recent studies show that in healthy subjects, except for a few parameters, the pulse-based method cannot be a surrogate for the standard RR interval- based method. Moreover, the former tends to overestimate short-term variability in heart rate. This calls for improvements in or alternatives to the pulse-cycle interval method. In this study, besides the systolic peak-peak interval method (PP method) that has been studied several times, four recent PPG-based techniques, namely the first derivative peak-peak interval method (P1D method), the second derivative peak-peak interval method (P2D method), the valley-valley interval method (VV method) and the tangent-intersection interval method (TI method) were compared with the gold standard technique. ECG and PPG signals were obtained from 10 young and healthy adults (consisting of both males and females) seated in the armchair position. In order to de-noise these signals and eliminate baseline drift, they were passed through certain digital filters. After filtering, the following HRV parameters were computed from PPG using each of the five methods and also from ECG using the gold standard method: time domain parameters (SDNN, pNN50 and RMSSD), frequency domain parameters (Very low-frequency power (VLF), Low-frequency power (LF), High-frequency power (HF) and Total power or “TP”). Besides, Poincaré plots were also plotted and their SD1/SD2 ratios determined. The resulting sets of parameters were compared with those yielded by the standard method using measures of statistical correlation (correlation coefficient) as well as statistical agreement (Bland-Altman plots). From the viewpoint of correlation, our results show that the best PPG-based methods for the determination of most parameters and Poincaré plots are the P2D method (shows more than 93% correlation with the standard method) and the PP method (mean correlation: 88%) whereas the TI, VV and P1D methods perform poorly (<70% correlation in most cases). However, our evaluation of statistical agreement using Bland-Altman plots shows that none of the five techniques agrees satisfactorily well with the gold standard method as far as time-domain parameters are concerned. In conclusion, excellent statistical correlation implies that certain PPG-based methods provide a good amount of information on the pattern of heart rate variation, whereas poor statistical agreement implies that PPG cannot completely replace ECG in the determination of HRV.

Keywords: photoplethysmography, heart rate variability, correlation coefficient, Bland-Altman plot

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Authors: Momoka Sunohara, Ashley J. Lemieux, Esther Yakobov, Andrew G. Ryder, Tomas Jurcik

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Immigration brings changes in many aspects of an individual's life, from social support dynamics, to housing and language, as well as difficulties with regards to discrimination, trauma, and loss. Past research has mostly emphasized individual differences in mental health and has neglected the impact of social-ecological context, such as acculturation and ethnic density. Purpose: The present study aimed to assess the relationship between variables associated with social integration such as perceived ethnic density and ways of coping, as well as psychological adjustment in a rapidly growing non-visible minority group of immigrants in Canada. Data: A small subset of an archival data from our previously published study was reanalyzed with additional variables. Data included information from 269 Russian-Speaking immigrants in Montreal, Canada. Method: Canonical correlation analysis (CCA) investigated the relationship between two sets of variables. SAS PROC CANCORR was used to conduct CCA on a set of social integration variables, including ethnic density, discrimination, social support, family functioning, and acculturation, and a set of psychological well-being variables, including distress, depression, self-esteem, and life satisfaction. In addition, canonical redundancy analysis was performed to calculate the proportion of variances of original variables explained by their own canonical variates. Results: Significance tests using Rao’s F statistics indicated that the first two canonical correlations (i.e., r1 = 0.64, r2 = 0.40) were statistically significant (p-value < 0.0001). Additionally, canonical redundancy analysis showed that the first two well-being canonical variates explained separately 62.9% and 12.8% variances of the standardized well-being variables, whereas the first two social integration canonical variates explained separately 14.7% and 16.7% variances of the standardized social integration variables. These results support the selection of the first two canonical correlations. Then, we interpreted the derived canonical variates based on their canonical structure (i.e., correlations with original variables). Two observations can be concluded. First, individuals who have adequate social support, and who, as a family, cope by acquiring social support, mobilizing others and reframing are more likely to have better self-esteem, greater life satisfaction and experience less feelings of depression or distress. Second, individuals who feel discriminated yet rate higher on a mainstream acculturation scale, and who, as a family, cope by acquiring social support, mobilizing others and using spirituality, while using less passive strategies are more likely to have better life satisfaction but also higher degree of depression. Implications: This model may serve to explain the complex interactions that exist between social and emotional adjustment and aid in facilitating the integration of individuals immigrating into new communities. The same group may experience greater depression but paradoxically improved life satisfaction associated with their coping process. Such findings need to be placed in the context of Russian cultural values. For instance, some Russian-speakers may value the expression of negative emotions with significant others during the integration process; this in turn may make negative emotions more salient, but also facilitate a greater sense of family and community connection, as well as life satisfaction.

Keywords: acculturation, ethnic density, mental health, Russian-speaking

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Authors: O. O. Sufyani, M. E. Oraiby, S. A. Qumaiy, A. I. Alaamri, Z. M. Eisa, A. M. Hakami, M. A. Attafi, O. M. Alhassan, W. M. Elsideeg, E. M. Noureldin, Y. A. Hobani, Y. Q. Majrabi, I. A. Khardali, A. B. Maashi, A. A. Al Mane, A. H. Hakami, I. M. Alkhyat, A. A. Sahly, I. M. Attafi

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According to the Food and Agriculture Organization (FAO) Pesticides Use Database, pesticide use in agriculture in Saudi Arabia has more than doubled from 4539 tons in 2009 to 10496 tons in 2019. Among pesticides, pyrethroids is commonly used in Saudi Arabia. Pesticides may increase susceptibility to a variety of diseases, particularly among pesticide workers, due to their extensive use, indiscriminate use, and long-term exposure. Therefore, analyzing blood chemo-profiles and evaluating the detected substances as biomarkers for pyrethroid pesticide exposure may assist to identify and predicting adverse effects of exposure, which may be used for both preventative and risk assessment purposes. The purpose of this study was to (a) analyze chemo-profiling by Gas Chromatography-Mass Spectrometry (GC-MS) analysis, (b) identify the most commonly detected chemicals in a time-exposure-dependent manner using a Venn diagram, and (c) identify their associated disease among pesticide workers using analyzer tools on the Comparative Toxicogenomics Database (CTD) website, (250 healthy male volunteers (20-60 years old) who deal with pesticides in the Jazan region of Saudi Arabia (exposure intervals: 1-2, 4-6, 6-8, more than 8 years) were included in the study. A questionnaire was used to collect demographic information, the duration of pesticide exposure, and the existence of chronic conditions. Blood samples were collected for biochemistry analysis and extracted by solid-phase extraction for gas chromatography-mass spectrometry (GC-MS) analysis. Biochemistry analysis reveals no significant changes in response to the exposure period; however, an inverse association between the albumin level and the exposure interval was observed. The blood chemo-profiling was differentially expressed in an exposure time-dependent manner. This analysis identified the common chemical set associated with each group and their associated significant occupational diseases. While some of these chemicals are associated with a variety of diseases, the distinguishing feature of these chemically associated disorders is their applicability for prevention measures. The most interesting finding was the identification of several chemicals; erucic acid, pelargonic acid, alpha-linolenic acid, dibutyl phthalate, diisobutyl phthalate, dodecanol, myristic Acid, pyrene, and 8,11,14-eicosatrienoic acid, associated with pneumoconiosis, asbestosis, asthma, silicosis and berylliosis. Chemical-disease association study also found that cancer, digestive system disease, nervous system disease, and metabolic disease were the most often recognized disease categories in the common chemical set. The hierarchical clustering approach was used to compare the expression patterns and exposure intervals of the chemicals found commonly. More study is needed to validate these chemicals as early markers of pyrethroid insecticide-related occupational disease, which might assist evaluate and reducing risk. The current study contributes valuable data and recommendations to public health.

Keywords: occupational, toxicology, chemo-profiling, pesticide, pyrethroid, GC-MS

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Authors: Prince S. Campbell, Janine B. Adams, Melusi Thwala, Opeoluwa Oyedele, Paula E. Melariri

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Schistosomiasis, often known as bilharzia, is a parasitic water-borne disease caused by trematode flatworms of the genus Schistosoma. Schistosomiasis infection and prevention have been found to be influenced by a range of socio-cultural risk factors, including human characteristics (e.g., gender, age, education, knowledge, attitude, and practices), as well as environmental and economic elements. Lack of awareness of the disease may also contribute to an individual's tendency to participate in behaviours or activities that heighten their susceptibility to infection. The current study assessed the community knowledge, attitude and practices (KAP) on schistosomiasis and implemented an educational intervention following pre-test interviews. A cross-sectional quasi-experimental research design was used in this quantitative study. Pre- and post-intervention interview format surveys were conducted using a structured questionnaire, targeting individuals aged 18–65 years residing within 5 km of select water bodies. The questionnaire contained 54 close-ended questions about schistosomiasis causes, transmission, and clinical symptoms and the participants were interviewed face-to-face in their homes. Data was captured on Question Pro and analyzed using Microsoft Office Excel 365 (2019) and R (version 4.3.1) software. Overall, 380 individuals completed the pre and post-intervention assessments; 194 and 185 were males (51.1%) and females (48.7%), respectively. A notable 91.3% of participants did not know about schistosomiasis in the pre-intervention phase; however, the mean post-intervention test score (9.4 ± 1.4) for knowledge among participants was higher than the pre-intervention test score (2.2 ± 2.1) indicating a good and improved knowledge of schistosomiasis among the participants. Furthermore, the paired samples t-test results demonstrated that the increase in knowledge levels was statistically significant (p<0.001). Also, the post-intervention improvement of both practice (p<0.001) and attitude (p<0.001) levels was statistically significant. A positive correlation (r=0.23, p<0.001) was found between knowledge and attitude in the pre-intervention stage. Knowledgeable participants had a more positive attitude towards obtaining medical assistance and disease prevention. Moreover, attitudes and practices correlated negatively (r=-0.13, p=0.013) post-intervention; hence, those with positive attitudes did not engage in risky water-related practices, which was the desired outcome. The educational intervention had a favourable impact on the KAP of the study population as the majority were able to recall the disease aetiology, symptoms, transmission pattern, and preventative measures three months post-intervention. Nevertheless, previous research has suggested that participants were unable to recall information about the disease following the intervention. Consequently, research should prioritize behavioural modification strategies that may result in a more persistent outcome in terms of the participants' knowledge, which could ultimately contribute to the development of long-term positive attitudes and practices.

Keywords: educational intervention, knowledge, attitudes and practices, schistosomiasis

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Authors: Jiangbo Hu, Frances Hoyte, Haiquan Huang

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Research identifies that mealtime talk can be a significant learning context that provides children with rich experiences to foster their language and cognitive development. Middle-classed parents create an extended learning discourse for their children through sophisticated vocabulary, narrative and explanation genres at dinner table. However, mealtime opportunities vary with some parents having little interaction with their children and some parents focusing on directive of children’s behaviors. This study investigated five Chinese families’ parent-child interaction during mealtime that was rarely reported in the literature. The five families differ in terms of their living styles. Three families are from professional background where both mothers the fathers work in Australian companies and both of them present at dinner time. The other two families own business. The mothers are housemakers and the fathers are always absent at dinner time due to their busy business life. Employing case study method, the five Chinese families’ parent-child interactions at dinner table were recorded using a video camera. More than 3000 clauses were analyzed with the framework of 'systems of clause complexing' from systemic functional linguistic theory. The finding shows that mothers played a critical role in the interaction with their children by initiating most conversations. The three mothers from professional background tended to use more language in extending and expanding pattern that is beneficial for children’s language development and high level of thinking (e.g., logical thinking). The two house making mothers’ language focused more on the directive of their children’s social manners and dietary behaviors. The fathers though seemed to be less active, contributing to the richness of the conversation through their occasional props such as asking open questions or initiating a new topic. In general, the families from professional background were more advantaged in providing learning opportunities for their children at dinner table than the families running business were. The home experiences of Chinese children is an important topic in research due to the rapidly increasing number of Chinese children in Australia and other English speaking countries. Such research assist educators in the education of Chinese children with more awareness of Chinese children experiences at home that could be very unlike the settings in English schools. This study contributes to the research in this area through the analysis of language in parent-child interaction during mealtime, which is very different from previous research that mainly investigated Chinese families through survey and interview. The finding of different manners in language use between the professional families and business families has implication for the understanding of the variation of Chinese children’s home experiences that is influenced not only by parents’ socioeconomic status but their lifestyles.

Keywords: Chinese children, Chinese parents, mealtime talk, parent-child interaction

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Authors: Abid Hussain, Binay Kumar

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Environment-friendly lead-free Na₀.₅₂K₀.₄₄Li₀.₀₄Nb₀.₈₄Ta₀.₁₀Sb₀.₀₆O₃ (NKLNTS) ceramic was synthesized by solid-state reaction method in search of a potential candidate to replace lead-based ceramics such as PbZrO₃-PbTiO₃ (PZT), Pb(Mg₁/₃Nb₂/₃)O₃-PbTiO₃ (PMN-PT) etc., for various applications. The ceramic was calcined at temperature 850 ᵒC and sintered at 1090 ᵒC. The powder X-Ray Diffraction (XRD) pattern revealed the formation of pure perovskite phase having tetragonal symmetry with space group P4mm of the synthesized ceramic. The surface morphology of the ceramic was studied using Field Emission Scanning Electron Microscopy (FESEM) technique. The well-defined grains with homogeneous microstructure were observed. The average grain size was found to be ~ 0.6 µm. A very large value of piezoelectric charge coefficient (d₃₃ ~ 754 pm/V) was obtained for the synthesized ceramic which indicated its potential for use in transducers and actuators. In dielectric measurements, a high value of ferroelectric to paraelectric phase transition temperature (Tm~305 ᵒC), a high value of maximum dielectric permittivity ~ 2110 (at 1 kHz) and a very small value of dielectric loss ( < 0.6) were obtained which suggested the utility of NKLNTS ceramic in high-temperature ferroelectric devices. Also, the degree of diffuseness (γ) was found to be 1.61 which confirmed a relaxor ferroelectric behavior in NKLNTS ceramic. P-E hysteresis loop was traced and the value of spontaneous polarization was found to be ~11μC/cm² at room temperature. The pyroelectric coefficient was obtained to be very high (p ∼ 1870 μCm⁻² ᵒC⁻¹) for the present case indicating its applicability in pyroelectric detector applications including fire and burglar alarms, infrared imaging, etc. NKLNTS ceramic showed fatigue free behavior over 107 switching cycles. Remanent hysteresis task was performed to determine the true-remanent (or intrinsic) polarization of NKLNTS ceramic by eliminating non-switchable components which showed that a major portion (83.10 %) of the remanent polarization (Pr) is switchable in the sample which makes NKLNTS ceramic a suitable material for memory switching devices applications. Time-Dependent Compensated (TDC) hysteresis task was carried out which revealed resistive leakage free nature of the ceramic. The performance of NKLNTS ceramic was found to be superior to many lead based piezoceramics and hence can effectively replace them for use in piezoelectric, pyroelectric and long duration ferroelectric applications.

Keywords: dielectric properties, ferroelectric properties , lead free ceramic, piezoelectric property, solid state reaction, true-remanent polarization

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Authors: Kibrom Hadush

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Countries like Ethiopia, whose economy is mainly rain-fed dependent agriculture, are highly vulnerable to climate variability and weather extremes. Sub-seasonal (monthly) and dekadal forecasts are hence critical for crop production and water resource management. Therefore, this paper was conducted to study the predictability and variability of Kiremt rainfall over the northern half of Ethiopia on monthly and dekadal time scales in association with global Sea Surface Temperature (SST) at different lag time. Trends in rainfall have been analyzed on annual, seasonal (Kiremt), monthly, and dekadal (June–September) time scales based on rainfall records of 36 meteorological stations distributed across four homogenous zones of the northern half of Ethiopia for the period 1992–2017. The results from the progressive Mann–Kendall trend test and the Sen’s slope method shows that there is no significant trend in the annual, Kiremt, monthly and dekadal rainfall total at most of the station's studies. Moreover, the rainfall in the study area varies spatially and temporally, and the distribution of the rainfall pattern increases from the northeast rift valley to northwest highlands. Methods of analysis include graphical correlation and multiple linear regression model are employed to investigate the association between the global SSTs and Kiremt rainfall over the homogeneous rainfall zones and to predict monthly and dekadal (June-September) rainfall using SST predictors. The results of this study show that in general, SST in the equatorial Pacific Ocean is the main source of the predictive skill of the Kiremt rainfall variability over the northern half of Ethiopia. The regional SSTs in the Atlantic and the Indian Ocean as well contribute to the Kiremt rainfall variability over the study area. Moreover, the result of the correlation analysis showed that the decline of monthly and dekadal Kiremt rainfall over most of the homogeneous zones of the study area are caused by the corresponding persistent warming of the SST in the eastern and central equatorial Pacific Ocean during the period 1992 - 2017. It is also found that the monthly and dekadal Kiremt rainfall over the northern, northwestern highlands and northeastern lowlands of Ethiopia are positively correlated with the SST in the western equatorial Pacific, eastern and tropical northern the Atlantic Ocean. Furthermore, the SSTs in the western equatorial Pacific and Indian Oceans are positively correlated to the Kiremt season rainfall in the northeastern highlands. Overall, the results showed that the prediction models using combined SSTs at various ocean regions (equatorial and tropical) performed reasonably well in the prediction (With R2 ranging from 30% to 65%) of monthly and dekadal rainfall and recommends it can be used for efficient prediction of Kiremt rainfall over the study area to aid with systematic and informed decision making within the agricultural sector.

Keywords: dekadal, Kiremt rainfall, monthly, Northern Ethiopia, sea surface temperature

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Authors: Antonela Matana, Dubravka Brdar, Vesela Torlak, Marijana Popovic, Ivana Gunjaca, Ozren Polasek, Vesna Boraska Perica, Maja Barbalic, Ante Punda, Caroline Hayward, Tatijana Zemunik

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Parathyroid hormone (PTH) plays a critical role in the regulation of bone mineral metabolism and calcium homeostasis. Higher PTH levels are associated with heart failure, hypertension, coronary artery disease, cardiovascular mortality and poorer bone health. A twin study estimated that 60% of the variation in PTH concentrations is genetically determined. Only one GWAS of PTH concentration has been reported to date. Identified loci explained 4.5% of the variance in circulating PTH, suggesting that additional genetic variants remain undiscovered. Therefore, the aim of this study was to identify novel genetic variants associated with PTH levels in a general population. We have performed a GWAS meta-analysis on 2596 individuals originating from three Croatian cohorts: City of Split and the Islands of Korčula and Vis, within a large-scale project of “10,001 Dalmatians”. A total of 7 411 206 variants, imputed using the 1000 Genomes reference panel, with minor allele frequency ≥ 1% and Rsq ≥ 0.5 were analyzed for the association. GWAS within each data set was performed under an additive model, controlling for age, gender and relatedness. Meta-analysis was conducted using the inverse-variance fixed-effects method. Furthermore, to identify sex-specific effects, we have conducted GWAS meta-analyses analyzing males and females separately. In addition, we have performed biological pathway analysis. Four SNPs, representing one locus, reached genome-wide significance. The most significant SNP was rs11099476 on chromosome 4 (P=1.15x10-8), which explained 1.14 % of the variance in PTH. The SNP is located near the protein-coding gene RASGEF1B. Additionally, we detected suggestive association with SNPs, rs77178854 located on chromosome 2 in the DPP10 gene (P=2.46x10-7) and rs481121 located on chromosome 1 (P=3.58x10-7) near the GRIK1 gene. One of the top hits detected in the main meta-analysis, intron variant rs77178854 located within DPP10 gene, reached genome-wide significance in females (P=2.21x10-9). No single locus was identified in the meta-analysis in males. Fifteen biological pathways were functionally enriched at a P<0.01, including muscle contraction, ion homeostasis and cardiac conduction as the most significant pathways. RASGEF1B is the guanine nucleotide exchange factor, known to be associated with height, bone density, and hip. DPP10 encodes a membrane protein that is a member of the serine proteases family, which binds specific voltage-gated potassium channels and alters their expression and biophysical properties. In conclusion, we identified 2 novel loci associated with PTH levels in a general population, providing us with further insights into the genetics of this complex trait.

Keywords: general population, genome-wide association analysis, parathyroid hormone, single nucleotide polymorphisms.

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Authors: Husham Bayazed

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Purpose of Presentation: Obesity and overweight are among the biggest health challenges of the 21st century, according to the WHO. Obviously, obese individuals suffer different courses of disease – from infections and allergies to cancer- and even respond differently to some treatment options. Of note, obesity often seems to predispose and triggers several secondary diseases such as diabetes, arteriosclerosis, or heart attacks. Since decades it seems that immunological signals gear inflammatory processes among obese individuals with the aforementioned conditions. This review aims to shed light how obesity sparks or rewire the immune system and predisposes to such unpleasant health outcomes. Moreover, lessons from the Covid-19 pandemic ascertain that people living with pre-existing conditions such as obesity can develop severe acute respiratory syndrome (SARS), which needs to be elucidated how obesity and its adjuvant inflammatory process distortion contribute to enhancing severe COVID-19 consequences. Recent Findings: In recent clinical studies, obesity was linked to alter and sparks the immune system in different ways. Adipose tissue (AT) is considered as a secondary immune organ, which is a reservoir of tissue-resident of different immune cells with mediator release, making it a secondary immune organ. Adipocytes per se secrete several pro-inflammatory cytokines (IL-6, IL-4, MCP-1, and TNF-α ) involved in activation of macrophages resulting in chronic low-grade inflammation. The correlation between obesity and T cells dysregulation is pivotal in rewiring the immune system. Of note, autophagy occurrence in adipose tissues further rewire the immune system due to flush and outburst of leptin and adiponectin, which are cytokines and influencing pro-inflammatory immune functions. These immune alterations among obese individuals are collectively incriminated in triggering several metabolic disorders and playing role in increasing cancers incidence and susceptibility to different infections. During COVID-19 pandemic, it was verified that patients with pre-existing obesity being at greater risk of suffering severe and fatal clinical outcomes. Beside obese people suffer from increased airway resistance and reduced lung volume, ACE2 expression in adipose tissue seems to be high and even higher than that in lungs, which spike infection incidence. In essence, obesity with pre-existence of pro-inflammatory cytokines such as LI-6 is a risk factor for cytokine storm and coagulopathy among COVID-19 patients. Summary: It is well documented that obesity is associated with chronic systemic low-grade inflammation, which sparks and alter different pillars of the immune system and triggers different metabolic disorders, and increases susceptibility of infections and cancer incidence. The pre-existing chronic inflammation in obese patients with the augmented inflammatory response against the viral infection seems to increase the susceptibility of these patients to developing severe COVID-19. Although the new weight loss drugs and bariatric surgery are considered as breakthrough news for obesity treatment, but preventing is easier than treating it once it has taken hold. However, obesity and immune system link new insights dispute the role of immunotherapy and regulating immune cells treating diet-induced obesity.

Keywords: immunity, metabolic disorders, cancer, COVID-19

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Authors: Osman Turkoglu, Alvin Estilo, Ritu Gupta, Liliam Pineda-Salgado, Rajesh Pandey

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Background: Hepatotoxicity can be linked to a variety of clinical symptoms and histopathological signs, posing a great challenge in the surveillance of suspected drug-induced liver injury (DILI) cases in the safety database. Additionally, the majority of such cases are rare, idiosyncratic, highly unpredictable, and tend to demonstrate unique individual susceptibility; these qualities, in turn, lend to a pharmacovigilance monitoring process that is often tedious and time-consuming. Objective: Develop a multifactorial algorithm to assist pharmacovigilance physicians in identifying high-risk hepatotoxicity cases associated with DILI from the sponsor’s safety database (Argus). Methods: Multifactorial selection criteria were established using Structured Query Language (SQL) and the TIBCO Spotfire® visualization tool, via a combination of word fragments, wildcard strings, and mathematical constructs, based on Hy’s law criteria and pattern of injury (R-value). These criteria excluded non-eligible cases from monthly line listings mined from the Argus safety database. The capabilities and limitations of these criteria were verified by comparing a manual review of all monthly cases with system-generated monthly listings over six months. Results: On an average, over a period of six months, the algorithm accurately identified 92% of DILI cases meeting established criteria. The automated process easily compared liver enzyme elevations with baseline values, reducing the screening time to under 15 minutes as opposed to multiple hours exhausted using a cognitively laborious, manual process. Limitations of the algorithm include its inability to identify cases associated with non-standard laboratory tests, naming conventions, and/or incomplete/incorrectly entered laboratory values. Conclusions: The newly developed multifactorial algorithm proved to be extremely useful in detecting potential DILI cases, while heightening the vigilance of the drug safety department. Additionally, the application of this algorithm may be useful in identifying a potential signal for DILI in drugs not yet known to cause liver injury (e.g., drugs in the initial phases of development). This algorithm also carries the potential for universal application, due to its product-agnostic data and keyword mining features. Plans for the tool include improving it into a fully automated application, thereby completely eliminating a manual screening process.

Keywords: automation, drug-induced liver injury, pharmacovigilance, post-marketing

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Authors: Jessica To

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Feedback is one of the powerful levers for enhancing students’ performance. However, some students are under-engaged with feedback because they lack responsibility for feedback uptake. To resolve this conundrum, recent literature proposes feedback partnerships in which students and teachers share the power and responsibilities to co-construct feedback. During feedback co-construction, students express feedback needs to teachers, and teachers respond to individuals’ needs in return. Though this approach can increase students’ feedback ownership, its application is lagging as the field lacks conceptual clarity and implementation guide. This presentation aims to discuss the conceptual framework of feedback partnerships and feedback co-construction strategies. It identifies the components of feedback partnerships and strategies which could facilitate feedback co-construction. A systematic literature review was conducted to answer the questions. The literature search was performed using ERIC, PsycINFO, and Google Scholar with the keywords “assessment partnership”, “student as partner,” and “feedback engagement”. No time limit was set for the search. The inclusion criteria encompassed (i) student-teacher partnerships in feedback, (ii) feedback engagement in higher education, (iii) peer-reviewed publications, and (iv) English as the language of publication. Those without addressing conceptual understanding and implementation strategies were excluded. Finally, 65 publications were identified and analysed using thematic analysis. For the procedure, the texts relating to the questions were first extracted. Then, codes were assigned to summarise the ideas of the texts. Upon subsuming similar codes into themes, four themes emerged: students’ responsibilities, teachers’ responsibilities, conditions for partnerships development, and strategies. Their interrelationships were examined iteratively for framework development. Establishing feedback partnerships required different responsibilities of students and teachers during feedback co-construction. Students needed to self-evaluate performance against task criteria, identify inadequacies and communicate their needs to teachers. During feedback exchanges, they interpreted teachers’ comments, generated self-feedback through reflection, and co-developed improvement plans with teachers. Teachers had to increase students’ understanding of criteria and evaluation skills and create opportunities for students’ expression of feedback needs. In feedback dialogue, teachers responded to students’ needs and advised on the improvement plans. Feedback partnerships would be best grounded in an environment with trust and psychological safety. Four strategies could facilitate feedback co-construction. First, students’ understanding of task criteria could be increased by rubrics explanation and exemplar analysis. Second, students could sharpen evaluation skills if they participated in peer review and received teacher feedback on the quality of peer feedback. Third, provision of self-evaluation checklists and prompts and teacher modeling of self-assessment process could aid students in articulating feedback needs. Fourth, the trust could be fostered when teachers explained the benefits of feedback co-construction, showed empathy, and provided personalised comments in dialogue. Some strategies were applied in interactive cover sheets in which students performed self-evaluation and made feedback requests on a cover sheet during assignment submission, followed by teachers’ response to individuals’ requests. The significance of this presentation lies in unpacking the conceptual framework of feedback partnerships and outlining feedback co-construction strategies. With a solid foundation in theory and practice, researchers and teachers could better enhance students’ engagement with feedback.

Keywords: conceptual framework, feedback co-construction, feedback partnerships, implementation strategies

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Authors: A. K. Tursunova, O. V. Chebonenko, A. Zh. Amirkulova, A. O. Abaildayev, O. A. Sapko, Y. M. Dyo, A. Sh. Utarbaeva

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Fusarium solani and its variants cause root and stem rot of plants. Dry rot is the most common disease of potato tubers during storage. The causative agents of fusariosis in contact with plants behave as antagonists, growth stimulants or parasites. The diversity of host-parasite relationships is explained by the parasite’s ability to produce a wide spectrum of biologically active compounds including toxins, enzymes, oligosaccharides, antibiotic substances, enniatins and gibberellins. Many of these metabolites contribute to the creation of compatible relations; others behave as elicitors, inducing various protective responses in plants. An important part of the strategy for developing plant resistance against pathogens is the activation of protein synthesis to produce protective ‘pathogenesis-related’ proteins. The family of PR-proteins known to confer the most protective response is chitinases (EC 3.2.1.14, Cht) and β-1,3-glucanases (EC 3.2.1.39, Glu). PR-proteins also include a large multigene family of peroxidases (EC 1.11.1.7, Pod), and increased activity of Pod and expression of the Pod genes leads to the development of resistance to a broad class of pathogens. Despite intensive research on the role of PR-proteins, the question of their participation in the mechanisms of formation of the F.solani–S.tuberosum pathosуstem is not sufficiently studied. Our aim was to investigate the effect of different classes of F. solani metabolites on the activity of chitinase, β-1,3-glucanases and peroxidases in tubers of Solanum tuberosum. Metabolite culture filtrate (CF) and cytoplasmic components were fractionated by extraction of the mycelium with organic solvents, salting out techniques, dialysis, column chromatography and ultrafiltration. Protein, lipid, carbohydrate and polyphenolic fractions of fungal metabolites were derived. Using enzymatic hydrolysis we obtained oligo glycans from fungal cell walls with different molecular weights. The activity of the metabolites was tested using potato tuber discs (d = 16mm, h = 5mm). The activity of PR-proteins of tubers was analyzed in a time course of 2–24 hours. The involvement of the analysed metabolites in the modulation of both early non-specific and late related to pathogenesis reactions was demonstrated. The most effective inducer was isolated from the CF (fraction of total phenolic compounds including naphtazarins). Induction of PR-activity by this fraction was: chitinase - 340-360%, glucanase - 435-450%, soluble forms of peroxidase - 400-560%, related forms of peroxidase - 215-237%. High-inducing activity was observed by the chloroform and acetonitrile extracts of the mycelium (induction of chitinase and glucanase activity was 176-240%, of soluble and bound forms of peroxidase - 190-400%). The fraction of oligo glycans mycelium cell walls of 1.2 kDa induced chitinase and β-1,3-glucanase to 239-320%; soluble forms and related peroxidase to 198-426%. Oligo glycans cell walls of 5-10 kDa had a weak suppressor effect - chitinase (21-25%) and glucanase (25-28%) activity; had no effect on soluble forms of peroxidase, but induced to 250-270% activity related forms. The CF polysaccharides of 8.5 kDa and 3.1 kDa inhibited synchronously the glucanase and chitinase specific response in step (after 24 hours at 42-50%) and the step response induced nonspecific peroxidase activity: soluble forms 4.8 -5.2 times, associated forms 1.4-1.6 times.

Keywords: fusarium solani, PR-proteins, peroxidase, solanum tuberosum

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Authors: Mohamed Hendawy Mousa, Warda Youssef Mohamed Morsy

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Background: Sepsis is a major cause of mortality and morbidity in trauma patients. Body mass index as an indicator of nutritional status was reported as a predictor of injury pattern and complications among critically ill injured patients. Aim: The aim of this study is to investigate the relationship between body mass index and the development of sepsis, systemic inflammatory response syndrome among adult trauma patients at emergency hospital - Cairo University. Research design: Descriptive correlational research design was utilized in the current study. Research questions: Q1. What is the body mass index profile of adult trauma patients admitted to the emergency hospital at Cairo University over a period of 6 months?, Q2. What is the frequency of systemic inflammatory response syndrome and sepsis among adult trauma patients admitted to the emergency hospital at Cairo University over a period of 6 months?, and Q3. What is the relationship between the development of sepsis, systemic inflammatory response syndrome and body mass index among adult trauma patients admitted to the emergency hospital at Cairo University over a period of 6 months?. Sample: A purposive sample of 52 adult male and female trauma patients with revised trauma score 10 to 12. Setting: The Emergency Hospital affiliated to Cairo University. Tools: Four tools were utilized to collect data pertinent to the study: Socio demographic and medical data tool, Systemic inflammatory response syndrome assessment tool, Revised Trauma Score tool, and Sequential organ failure assessment tool. Results: The current study revealed that, (61.5 %) of the studied subjects had normal body mass index, (25 %) were overweight, and (13.5 %) were underweight. 84.6% of the studied subjects had systemic inflammatory response syndrome and 92.3% were suffering from mild sepsis. No significant statistical relationship was found between body mass index and occurrence of Systemic inflammatory response syndrome (2= 2.89 & P = 0.23). However, Sequential organ failure assessment scores were affected significantly by body mass index was found mean of initial and last Sequential organ failure assessment score for underweight, normal and obese where t= 7.24 at p = 0.000, t= 16.49 at p = 0.000 and t= 9.80 at p = 0.000 respectively. Conclusion: Underweight trauma patients showed significantly higher rate of developing sepsis as compared to patients with normal body weight and obese. Recommendations: based on finding of this study the following are recommended: replication of the study on a larger probability sample from different geographical locations in Egypt; Carrying out of further studies in order to assess the other risk factors influencing trauma outcome and incidence of its complications; Establishment of standardized guidelines for managing underweight traumatized patients with sepsis.

Keywords: body mass index, sepsis, systemic inflammatory response syndrome, adult trauma

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Authors: Obasanjo Afolabi Bolarinwa

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This study assesses the levels of knowledge of sexually transmitted infections among unmarried youths in Nigeria; examines the pattern of high risk sex among unmarried youths in Nigeria; investigate the socio-demographic factors (age, place of residence, religion, level of education, wealth index and employment status) affecting the practice of high-risk sexual behaviour and ascertain the relationships between knowledge of sexually transmitted infections and practice of high risk sex. The goal of the study is to identify the factors associated with the practice of high risk sex among youth. These were with a view to identifying critical actions needed to reduce high risk sexual behaviour among youths. The study employed secondary data. The data for the study were extracted from the 2013 Nigeria Demographic and Health Survey (NDHS). The 2013 NDHS collected information from 38,948 Women ages 15-49 years and 17,359 men ages 15-49. A total of 7,744 female and 6,027 male respondents were utilized in the study. In order to adjust for the effect of oversampling of the population, the weighting factor provided by Measure DHS was applied. The data were analysed using frequency distribution and logistic regression. The results show that both male (92.2%) and female (93.6%) have accurate knowledge of sexually transmitted infections. The study also revealed that prevalence of high risk sexual behavior is high among Nigerian youths; this is evident as 77.7% (female) and 78.4% (male) are engaging in high risk sexual behavior. The bivariate analysis shows that age of respondent (χ2=294.2; p < 0.05), religion (χ2=136.64; p < 0.05), wealth index (χ2=17.38; p < 0.05), level of education (χ2=34.73; p < 0.05) and employment status (χ2=94.54; p < 0.05) were individual factors significantly associated with high risk sexual behaviour among male while age of respondent (χ2=327.07; p < 0.05), place of residence (χ2=6.71; p < 0.05), religion (χ2=81.04; p < 0.05), wealth index (χ2=7.41; p < 0.05), level of education (χ2=18.12; p < 0.05) and employment status (χ2=51.02; p < 0.05) were individual factors significantly associated with high risk sexual behaviour among female. Furthermore, the study shows that there is a relationship between knowledge of sexually transmitted infections and high risk sex among male (χ2=38.32; p < 0.05) and female (χ2=18.37; p < 0.05). At multivariate level, the study revealed that individual characteristics such as age, religion, place of residence, wealth index, levels of education and employment status were statistically significantly related with high risk sexual behaviour among male and female (p < 0.05). Lastly, the study shows that knowledge of sexually transmitted infection was significantly related to high risk sexual behaviour among youths (p < 0.05). The study concludes that there is a high level of knowledge of sexually transmitted infections among unmarried youths in Nigeria. The practice of high risk sex is high among unmarried youths but higher among male youths. The prevalence of high risk sexual activity is higher for males when they are at disadvantage and higher for females when they are at advantage. Socio-demographic factors like age of respondents, religion, wealth index, place of residence, employment status and highest level of education are factors influencing high risk sexual behaviour among youths.

Keywords: high risk sex, wealth index, sexual behaviour, knowledge

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Authors: Vaicekauskiene G., Nabazaite E.

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This study analyses the rise of global populism in Western democracies, focusing primarily on the populist rhetoric. Populist rhetoric is based on anti-pluralist ideas, opposing a “homogeneous nation” against “dangerous others” who are pushed out of the nation by populists, and can be citizens from both in-groups and out-groups. This study will examine the case of the elections of Parliament of the Republic of Lithuania of 2024. Fifteen candidate lists of parties and coalitions participated in the elections to the Lithuanian Parliament in 2024. Focus group methodology will be used to analyse the narratives of party supporters actively engaged in politics, trying to identify public support/opposition to populism. Liberal democracy is experiencing a crisis in both the US and Western democracies in Europe. The election results of recent years are increasingly announcing populist victories or the creation of new populist parties. Far-right parties lead the governments in three countries – Hungary, Slovakia, and Italy, and they are part of the ruling coalition in Sweden, Finland, and the Netherlands. It will become clear in the USA whether Donald Trump will be re-elected as president in November of this year. Trump’s victory in 2016 was named by political scientists as the apotheosis of populism. Influential politicians consolidate all bad manners and social categorization in the digital era of demagoguery. The research shows that a significant proportion of democratic societies also support this divisive discourse. Citizens, as consumers of information, often approve of populist communication themselves. New parliament elections were held in Lithuania in October 2024. Ideas that polarize society were amplified in the public space, negativism increased, and with it distrust towards the state, its institutions, and democratically elected politicians, “enemies” were sought and conspiracy theories were created. Problem of the Study. This study analyses the global rise of populism from the perspective of Lithuania with various groups of society, trying to understand the relationship of citizens with democracy through believing in populists, approval/disapproval of the expression of populism. Opinions are an important challenge when trying to find the truth in the age of populism, because democratic societies are based on the culture of discussion and the idea of consensus. Methodology. This study will deconstruct the narratives of Lithuanian citizens from the point of view of populism. Fifteen focus group discussions will be held with supporters of the party lists that participated in the Parliament elections of the Republic of Lithuania during November-December 2024. The main unifying criterion for focus group participants is their political activity, while the distinguishing criteria are age, gender and place of residence. Fifteen focus groups were chosen due to the fact that fifteen candidate lists of parties and coalitions participated in the elections and seeking to ensure the variety of participants. This study aims to emphasize populism as a communication phenomenon in Lithuania. Public testimonies and experiences will reveal new meanings about the understanding of populism and support/opposition towards it.

Keywords: democracy, narratives in populist rhetoric, populist rhetoric, populism

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Authors: Morgan Johansson, Joosef Leppanen, Mathias Flansbjer, Fabio Lozano, Josef Makdesi

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Concrete is commonly used for protective structures and how impact loading affects different types of concrete structures is an important issue. Often the knowledge gained from static loading is also used in the design of impulse loaded structures. A large plastic deformation capacity is essential to obtain a large energy absorption in an impulse loaded structure. However, the structural response of an impact loaded concrete beam may be very different compared to a statically loaded beam. Consequently, the plastic deformation capacity and failure modes of the concrete structure can be different when subjected to dynamic loads; and hence it is not sure that the observations obtained from static loading are also valid for dynamic loading. The aim of this paper is to investigate the residual plastic deformation capacity in reinforced concrete beams subjected to drop weight impact tests. A test-series consisting of 18 simply supported beams (0.1 x 0.1 x 1.18 m, ρs = 0.7%) with a span length of 1.0 m and subjected to a point load in the beam mid-point, was carried out. 2x6 beams were first subjected to drop weight impact tests, and thereafter statically tested until failure. The drop in weight had a mass of 10 kg and was dropped from 2.5 m or 5.0 m. During the impact tests, a high-speed camera was used with 5 000 fps and for the static tests, a camera was used with 0.5 fps. Digital image correlation (DIC) analyses were conducted and from these the velocities of the beam and the drop weight, as well as the deformations and crack propagation of the beam, were effectively measured. Additionally, for the static tests, the applied load and midspan deformation were measured. The load-deformation relations for the beams subjected to an impact load were compared with 6 reference beams that were subjected to static loading only. The crack pattern obtained were compared using DIC, and it was concluded that the resulting crack formation depended much on the test method used. For the static tests, only bending cracks occurred. For the impact loaded beams, though, distinctive diagonal shear cracks also formed below the zone of impact and less wide shear cracks were observed in the region half-way to the support. Furthermore, due to wave propagation effects, bending cracks developed in the upper part of the beam during initial loading. The results showed that the plastic deformation capacity increased for beams subjected to drop weight impact tests from a high drop height of 5.0 m. For beams subjected to an impact from a low drop height of 2.5 m, though, the plastic deformation capacity was in the same order of magnitude as for the statically loaded reference beams. The beams tested were designed to fail due to bending when subjected to a static load. However, for the impact tested beams, one beam exhibited a shear failure at a significantly reduced load level when it was tested statically; indicating that there might be a risk of reduced residual load capacity for impact loaded structures.

Keywords: digital image correlation (DIC), drop weight impact, experiments, plastic deformation capacity, reinforced concrete

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Authors: Mariam Khaled, Noha Farag, Ghada Mohamed Abdel Salam, Khaled Abu-Aisha, Mohamed El-Azizi

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Gastric and colorectal cancers are among the most frequent causes of cancer-associated mortalities in Africa. They have been considered as a global public health concern, as nearly one million new cases are reported per year. IL-1β is a pro-inflammatory cytokine-produced by activated macrophages and monocytes- and a member of the IL-1 family. The inactive IL-1β precursor is cleaved and activated by caspase-1 enzyme, which itself is activated by the assembly of intracellular structures defined as NLRP3 (Nod Like receptor P3) inflammasomes. Activated IL-1β stimulates the Interleukin-1 receptor type-1 (IL-1R1), which is responsible for the initiation of a signal transduction pathway leading to cell proliferation. It has been proven that the IL-1β gene is a highly polymorphic gene in which single nucleotide polymorphisms (SNPs) may affect its expression. It has been previously reported that SNPs including base transitions between C and T at positions, -511 (C-T; dbSNP: rs16944) and -31 (C-T; dbSNP: rs1143627), from the transcriptional start site, contribute to the pathogenesis of gastric and colorectal cancers by affecting IL-1β levels. Altered production of IL-1β due to such polymorphisms is suspected to stimulate an amplified inflammatory response and promote Epithelial Mesenchymal Transition leading to malignancy. Allele frequency distribution of the IL-1β-31 and -511 SNPs, in different populations, and their correlation to the incidence of gastric and colorectal cancers, has been intriguing to researchers worldwide. The current study aims to investigate allele distributions of the IL-1β SNPs among gastric and colorectal cancers Egyptian patients. In order to achieve to that, 89 Biopsy and surgical specimens from the antrum and corpus mucosa of chronic gastritis subjects and gastric and colorectal carcinoma patients was collected for DNA extraction followed by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The amplified PCR products of IL-1β-31C > T and IL-1β-511T > C were digested by incubation with the restriction endonuclease enzymes ALu1 and Ava1. Statistical analysis was carried out to determine the allele frequency distribution in the three studied groups. Also, the effect of the IL-1β -31 and -511 SNPs on nuclear factor binding was analyzed using Fluorescence Electrophoretic Mobility Shift Assay (EMSA), preceded by nuclear factor extraction from gastric and colorectal tissue samples and LPS stimulated monocytes. The results of this study showed that a significantly higher percentage of Egyptian gastric cancer patients have a homozygous CC genotype at the IL-1β-31 position and a heterozygous TC genotype at the IL-1β-511 position. Moreover, a significantly higher percentage of the colorectal cancer patients have a homozygous CC genotype at the IL-1β-31 and -511 positions as compared to the control group. In addition, the EMSA results showed that IL-1β-31C/T and IL-1β-511T/C SNPs do not affect nuclear factor binding. Results of this study suggest that the IL-1β-31 C/T and IL-1β-511 T/C may be correlated to the incidence of gastric cancer in Egyptian patients; however, similar findings couldn’t be proven in the colorectal cancer patients group for the IL-1β-511 T/C SNP. This is the first study to investigate IL-1β -31 and -511 SNPs in the Egyptian population.

Keywords: colorectal cancer, Egyptian patients, gastric cancer, interleukin-1β, single nucleotide polymorphisms

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Authors: P. Naderi, M. N. Ouarzazi, S. C. Hirata, H. Ben Hamed, H. Beji

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The stability of mixed convection in a Newtonian fluid medium heated from below and cooled from above, also known as the Poiseuille-Rayleigh-Bénard problem, has been extensively investigated in the past decades. To our knowledge, mixed convection in porous media has received much less attention in the published literature. The present paper extends the mixed convection problem in porous media for the case of a viscoelastic fluid flow owing to its numerous environmental and industrial applications such as the extrusion of polymer fluids, solidification of liquid crystals, suspension solutions and petroleum activities. Without a superimposed through-flow, the natural convection problem of a viscoelastic fluid in a saturated porous medium has already been treated. The effects of the viscoelastic properties of the fluid on the linear and nonlinear dynamics of the thermoconvective instabilities have also been treated in this work. Consequently, the elasticity of the fluid can lead either to a Hopf bifurcation, giving rise to oscillatory structures in the strongly elastic regime, or to a stationary bifurcation in the weakly elastic regime. The objective of this work is to examine the influence of the main horizontal flow on the linear and characteristics of these two types of instabilities. Under the Boussinesq approximation and Darcy's law extended to a viscoelastic fluid, a temporal stability approach shows that the conditions for the appearance of longitudinal rolls are identical to those found in the absence of through-flow. For the general three-dimensional (3D) perturbations, a Squire transformation allows the deduction of the complex frequencies associated with the 3D problem using those obtained by solving the two-dimensional one. The numerical resolution of the eigenvalue problem concludes that the through-flow has a destabilizing effect and selects a convective configuration organized in purely transversal rolls which oscillate in time and propagate in the direction of the main flow. In addition, by using the mathematical formalism of absolute and convective instabilities, we study the nature of unstable three-dimensional disturbances. It is shown that for a non-vanishing through-flow, general three-dimensional instabilities are convectively unstable which means that in the absence of a continuous noise source these instabilities are drifted outside the porous medium, and no long-term pattern is observed. In contrast, purely transversal rolls may exhibit a transition to absolute instability regime and therefore affect the porous medium everywhere including in the absence of a noise source. The absolute instability threshold, the frequency and the wave number associated with purely transversal rolls are determined as a function of the Péclet number and the viscoelastic parameters. Results are discussed and compared to those obtained from laboratory experiments in the case of Newtonian fluids.

Keywords: instability, mixed convection, porous media, and viscoelastic fluid

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Authors: Michelle Mansfield

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Introduction: This paper uses the work of Deleuze and Guattari to consider the street art practice of youth in the Indonesian city of Yogyakarta, a hub of arts and culture in Central Java. Around the world young people have taken to city streets to populate the new informal exhibition spaces outside the galleries of official art institutions. However, rarely is the focus outside the urban metropolis of the ‘Global North.' This paper looks at these practices in a ‘Global South’ Asian context. Space and place are concepts central to understanding youth cultural expression as it emerges on the streets. Deleuze and Guattari’s notion of assemblage enriches understanding of this complex spatial and creative relationship. Yogyakarta street art combines global patterns and motifs with local meanings, symbolism, and language to express local youth voices that convey a unique sense of place on the world stage. Street art has developed as a global urban youth art movement and is theorised as a way in which marginalised young people reclaim urban space for themselves. Methodologies: This study utilised a variety of qualitative methodologies to collect and analyse data. This project took a multi-method approach to data collection, incorporating the qualitative social research methods of ethnography, nongkrong (deep hanging out), participatory action research, online research, in-depth interviews and focus group discussions. Both interviews and focus groups employed photo-elicitation methodology to stimulate rich data gathering. To analyse collected data, rhizoanalytic approaches incorporating discourse analysis and visual analysis were utilised. Street art practice is a fluid and shifting phenomenon, adding to the complexity of inquiry sites. A qualitative approach to data collection and analysis was the most appropriate way to map the components of the street art assemblage and to draw out complexities of this youth cultural practice in Yogyakarta. Major Findings: The rhizoanalytic approach devised for this study proved a useful way of examining in the street art assemblage. It illustrated the ways in which the street art assemblage is constructed. Especially the interaction of inspiration, materials, creative techniques, audiences, and spaces operate in the creations of artworks. The study also exposed the generational tensions between the senior arts practitioners, the established art world, and the young artists. Conclusion: In summary, within the spatial processes of the city, street art is inextricably linked with its audience, its striving artistic community and everyday life in the smooth rather than the striated worlds of the state and the official art world. In this way, the anarchic rhizomatic art practice of nomadic urban street crews can be described not only as ‘becoming-artist’ but as constituting ‘nomos’, a way of arranging elements which are not dependent on a structured, hierarchical organisation practice. The site, streets, crews, neighbourhood and the passers by can all be examined with the concept of assemblage. The assemblage effectively brings into focus the complexity, dynamism, and flows of desire that is a feature of street art practice by young people in Yogyakarta.

Keywords: assemblage, Indonesia, street art, youth

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Authors: Netalie Shloim, Brian Brown, Siobhan Hugh-Jones, Jane Plastow, Diana Setiyawati, Anna Madill

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In June 2021, the World Health Organization launched its guidance and technical packages on community mental health services, stressing a human rights-based approach to care. This initiative stems from an increasing acknowledgment of the role mental health plays in achieving the Sustainable Development Goals. Nevertheless, mental health remains a relatively neglected research area and the estimates for untreated mental disorders in low-and-middle-income countries (LMICs) are as high as 78% for adults. Moreover, the development sector and research programs too often side-line mental health as a privilege in the face of often immediate threats to life and livelihood. As a way of addressing this problem, this study aimed to examine past or ongoing GCRF projects to see if there were opportunities where mental health impact could have been achieved without compromising a study's main aim and without overburdening a project. Projects funded by the UKRI Global Challenges Research Fund (GCRF) were analyzed. This program was initiated in 2015 to support cutting-edge research that addresses the challenges faced by developing countries. By the end of May 2020, a total of 15,279 projects were funded of which only 3% had an explicit mental health focus. A sample of 36 non-mental-health-focused projects was then sampled for diversity across research council, challenge portfolio and world region. Each of these 36 projects was coded by two coders for opportunities to embed mental health impact. To facilitate coding, the literature was inspected for dimensions relevant to LMIC settings. Three main psychological and three main social dimensions were identified: promote a positive sense of self; promote positive emotions, safe expression and regulation of challenging emotions, coping strategies, and help-seeking; facilitate skills development; and facilitate community-building; preserve sociocultural identity; support community mobilization. Coding agreement was strong on missed opportunities for mental health impact on the three social dimensions: support community mobilization (92%), facilitate community building (83%), preserve socio-cultural identity (70%). Coding agreement was reasonably strong on missed opportunities for mental health impact on the three psychological dimensions: promote positive emotions (67%), facilitate skills development (61%), positive sense of self (58%). In order of frequency, the agreed perceived opportunities from the highest to lowest are: support community mobilization, facilitate community building, facilitate skills development, promote a positive sense of self, promote positive emotions, preserve sociocultural identity. All projects were considered to have an opportunity to support community mobilization and to facilitate skills development by at least one coder. Findings provided support that there were opportunities to embed mental health impact in research across the range of development sectors and identifies what kind of missed opportunities are most frequent. Hence, mainstreaming mental health has huge potential to tackle the lack of priority and funding it has attracted traditionally. The next steps are to understand the barriers to mainstreaming mental health and to work together to overcome them.

Keywords: GCRF, mental health, psychosocial wellbeing, LMIC

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Authors: Meiling Yu, Nadia Rouatbi, Khuloud T. Al-Jamal

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Background: Treatment of neurological disorders with modern medical and surgical approaches remains difficult. Gene therapy, allowing the delivery of genetic materials that encodes potential therapeutic molecules, represents an attractive option. The treatment of brain diseases with gene therapy requires the gene-editing tool to be delivered efficiently to the central nervous system. In this study, we explored the efficiency of different delivery routes, namely intravenous (i.v.), intra-cranial (i.c.), and intra-nasal (i.n.), to deliver stable nucleic acid-lipid particles (SNALPs) containing gene-editing tools namely Cas9 mRNA and sgRNA encoding for GFP as a reporter protein. We hypothesise that SNALPs can reach the brain and perform gene-editing to different extents depending on the administration route. Intranasal administration (i.n.) offers an attractive and non-invasive way to access the brain circumventing the blood–brain barrier. Successful delivery of gene-editing tools to the brain offers a great opportunity for therapeutic target validation and nucleic acids therapeutics delivery to improve treatment options for a range of neurodegenerative diseases. In this study, we utilised Rosa26-Cas9 knock-in mice, expressing GFP, to study brain distribution and gene-editing efficiency of SNALPs after i.v.; i.c. and i.n. routes of administration. Methods: Single guide RNA (sgRNA) against GFP has been designed and validated by in vitro nuclease assay. SNALPs were formulated and characterised using dynamic light scattering. The encapsulation efficiency of nucleic acids (NA) was measured by RiboGreen™ assay. SNALPs were incubated in serum to assess their ability to protect NA from degradation. Rosa26-Cas9 knock-in mice were i.v., i.n., or i.c. administered with SNALPs to test in vivo gene-editing (GFP knockout) efficiency. SNALPs were given as three doses of 0.64 mg/kg sgGFP following i.v. and i.n. or a single dose of 0.25 mg/kg sgGFP following i.c.. knockout efficiency was assessed after seven days using Sanger Sequencing and Inference of CRISPR Edits (ICE) analysis. In vivo, the biodistribution of DiR labelled SNALPs (SNALPs-DiR) was assessed at 24h post-administration using IVIS Lumina Series III. Results: Serum-stable SNALPs produced were 130-140 nm in diameter with ~90% nucleic acid loading efficiency. SNALPs could reach and stay in the brain for up to 24h following i.v.; i.n. and i.c. administration. Decreasing GFP expression (around 50% after i.v. and i.c. and 20% following i.n.) was confirmed by optical imaging. Despite the small number of mice used, ICE analysis confirmed GFP knockout in mice brains. Additional studies are currently taking place to increase mice numbers. Conclusion: Results confirmed efficient gene knockout achieved by SNALPs in Rosa26-Cas9 knock-in mice expressing GFP following different routes of administrations in the following order i.v.= i.c.> i.n. Each of the administration routes has its pros and cons. The next stages of the project involve assessing gene-editing efficiency in wild-type mice and replacing GFP as a model target with therapeutic target genes implicated in Motor Neuron Disease pathology.

Keywords: CRISPR, nanoparticles, brain diseases, administration routes

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Authors: Alireza Shams, Ali Zamanian, Atefehe Shamosi, Farnaz Ghorbani

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Introduction: Although the application of a new strategy remains a remarkable challenge for treatment of disabilities due to neuronal defects, progress in Nanomedicine and tissue engineering, suggesting the new medical methods. One of the promising strategies for reconstruction and regeneration of nervous tissue is replacing of lost or damaged cells by specific scaffolds after Compressive, ischemic and traumatic injuries of central nervous system. Furthermore, ultrastructure, composition, and arrangement of tissue scaffolds are effective on cell grafts. We followed implantation and differentiation of mesenchyme stem cells to neural cells on Gelatin Polylactic-co-glycolic acid (PLGA) scaffolds coated with iron nanoparticles. The aim of this study was to evaluate the capability of stem cells to differentiate into motor neuron-like cells under topographical cues and morphogenic factors. Methods and Materials: Bone marrow mesenchymal stem cells (BMMSCs) was obtained by primary cell culturing of adult rat bone marrow got from femur bone by flushing method. BMMSCs were incubated with DMEM/F12 (Gibco), 15% FBS and 100 U/ml pen/strep as media. Then, BMMSCs seeded on Gel/PLGA scaffolds and tissue culture (TCP) polystyrene embedded and incorporated by Fe Nano particles (FeNPs) (Fe3o4 oxide (M w= 270.30 gr/mol.). For neuronal differentiation, 2×10 5 BMMSCs were seeded on Gel/PLGA/FeNPs scaffolds was cultured for 7 days and 0.5 µ mol. Retinoic acid, 100 µ mol. Ascorbic acid,10 ng/ml. Basic fibroblast growth factor (Sigma, USA), 250 μM Iso butyl methyl xanthine, 100 μM 2-mercaptoethanol, and 0.2 % B27 (Invitrogen, USA) added to media. Proliferation of BMMSCs was assessed by using MTT assay for cell survival. The morphology of BMMSCs and scaffolds was investigated by scanning electron microscopy analysis. Expression of neuron-specific markers was studied by immunohistochemistry method. Data were analyzed by analysis of variance, and statistical significance was determined by Turkey’s test. Results: Our results revealed that differentiation and survival of BMMSCs into motor neuron-like cells on Gel/PLGA/FeNPs as a biocompatible and biodegradable scaffolds were better than those cultured in Gel/PLGA in absence of FeNPs and TCP scaffolds. FeNPs had raised physical power but decreased capacity absorption of scaffolds. Well defined oriented pores in scaffolds due to FeNPs may activate differentiation and synchronized cells as a mechanoreceptor. Induction effects of magnetic FeNPs by One way flow of channels in scaffolds help to lead the cells and can facilitate direction of their growth processes. Discussion: Progression of biological properties of BMMSCs and the effects of FeNPs spreading under magnetic field was evaluated in this investigation. In vitro study showed that the Gel/PLGA/FeNPs scaffold provided a suitable structure for motor neuron-like cells differentiation. This could be a promising candidate for enhancing repair and regeneration in neural defects. Dynamic and static magnetic field for inducing and construction of cells can provide better results for further experimental studies.

Keywords: differentiation, mesenchymal stem cells, nano particles, neuronal defects, Scaffolds

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Authors: Deepti Kumari, Upamanyu Hore

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Cities are an example of a human-modified environment with few fragments of urban green spaces, which are widely considered for urban biodiversity. The study aims to address the avifaunal diversity in urban parks based on the park size and their urbanization intensity. Also, understanding the key factors affecting species composition and structure as birds are a good indicator of a healthy ecosystem, and they are sensitive to changes in the environment. A 50 m-long line-transect method is used to survey birds in 39 urban parks in Delhi, India. Habitat variables, including vegetation (percentage of non-native trees, percentage of native trees, top canopy cover, sub-canopy cover, diameter at breast height, ground vegetation cover, shrub height) were measured using the quadrat method along the transect, and disturbance variables (distance from water, distance from road, distance from settlement, park area, visitor rate, and urbanization intensity) were measured using ArcGIS and google earth. We analyzed species data for diversity and richness. We explored the relation of species diversity and richness to habitat variables using the multi-model inference approach. Diversity and richness are found significant in different park sizes and their urbanization intensity. Medium size park supports more diversity, whereas large size park has more richness. However, diversity and richness both declined with increasing urbanization intensity. The result of CCA revealed that species composition in urban parks was positively associated with tree diameter at breast height and distance from the settlement. On the model selection approach, disturbance variables, especially distance from road, urbanization intensity, and visitors are the best predictors for the species richness of birds in urban parks. In comparison, multiple regression analysis between habitat variables and bird diversity suggested that native tree species in the park may explain the diversity pattern of birds in urban parks. Feeding guilds such as insectivores, omnivores, carnivores, granivores, and frugivores showed a significant relation with vegetation variables, while carnivores and scavenger bird species mainly responded with disturbance variables. The study highlights the importance of park size in urban areas and their urbanization intensity. It also indicates that distance from the settlement, distance from the road, urbanization intensity, visitors, diameter at breast height, and native tree species can be important determining factors for bird richness and diversity in urban parks. The study also concludes that the response of feeding guilds to vegetation and disturbance in urban parks varies. Therefore, we recommend that park size and surrounding urban matrix should be considered in order to increase bird diversity and richness in urban areas for designing and planning.

Keywords: diversity, feeding guild, urban park, urbanization intensity

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Authors: Fernanda Piculo, Giovana Vesentini, Gabriela Marini, Debora Cristina Damasceno, Angelica Mercia Pascon Barbosa, Marilza Vieira Cunha Rudge

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Introduction: Women with previous gestational diabetes mellitus (GDM) were significantly more likely to have urinary incontinence (UI) and pelvic floor muscle dysfunction compared to non-diabetic women two years after a cesarean section. Additional results demonstrated that induced diabetes causes detrimental effects on pregnant rat urethral muscle. These results indicate the need for exploration of the mechanistic role of a recovery factor in female UI. Chemokine ligand 7 (CCL7) was significantly over expressed in rat serum, urethral and vaginal tissues immediately following induction of stress UI in a rat model simulating birth trauma. CCL7 over expression has shown potency for stimulating targeted stem cell migration and provide a translational link (clinical measurement) which further provide opportunities for treatment. The aim of this study was to investigate the CCL7 levels profile in diabetic pregnant women with urinary incontinence during pregnancy over the first year postpartum. Methods: This study was conducted in the Perinatal Diabetes Research Center of the Botucatu Medical School/UNESP, and was approved by the Research Ethics Committee of the Institution (CAAE: 20639813.0.0000.5411). The diagnosis of GDM was established between 24th and 28th gestational weeks, by the 75 g-OGTT test according to ADA’s criteria. Urinary incontinence was defined according to the International Continence Society and the CCL7 levels was measured by ELISA (R&D Systems, Catalog Number DCC700). Two hundred twelve women were classified into four study groups: normoglycemic continent (NC), normoglycemic incontinent (NI), diabetic continent (DC) and diabetic incontinent (DI). They were evaluated at six-time-points: 12-18, 24-28 and 34-38 gestational weeks, 24-48 hours, 6 weeks and 6-12 months postpartum. Results: At 12-18 weeks, it was possible to consider only two groups, continent and incontinent, because at this early gestational period has not yet been the diagnosis of GDM. The group with GDM and UI (DI group) showed lower levels of CCL7 in all time points during pregnancy and postpartum, compared to normoglycemic groups (NC and NI), indicating that these women have not recovered from child birth induced UI during the 6-12 months postpartum compared to their controls, and that the progression of UI and/or lack of recovery throughout the first postpartum year can be related with lower levels of CCL7. Instead, serum CCL7 was significantly increased in the NC group. Taken together, these findings of overexpression of CCL7 in the NC group and decreased levels in the DI group, could confirm that diabetes delays the recovery from child birth induced UI, and that CCL7 could potentially be used as a serum marker of injury. Conclusion: This study demonstrates lower levels of CCL7 in the DI group during pregnancy and postpartum and suggests that the progression of UI in diabetic women and/or lack of recovery throughout the first postpartum year can be related with low levels of CCL7. This provides a translational potential where CCL7 measurement could be used as a surrogate for injury after delivery. Successful controlled CCL7 mediated stem cell homing to the lower urinary tract could one day introduce the potential for non-operative treatment or prevention of stress urinary incontinence.

Keywords: CCL7, gestational diabetes, pregnancy, urinary incontinence

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Authors: Sajana Suwal, Ganesh R. Nhemafuki

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Evaluation of ground response under earthquake shaking is crucial in geotechnical earthquake engineering. Damage due to seismic excitation is mainly correlated to local geological and geotechnical conditions. It is evident from the past earthquakes (e.g. 1906 San Francisco, USA, 1923 Kanto, Japan) that the local geology has strong influence on amplitude and duration of ground motions. Since then significant studies has been conducted on ground motion amplification revealing the importance of influence of local geology on ground. Observations from the damaging earthquakes (e.g. Nigata and San Francisco, 1964; Irpinia, 1980; Mexico, 1985; Kobe, 1995; L’Aquila, 2009) divulged that non-uniform damage pattern, particularly in soft fluvio-lacustrine deposit is due to the local amplification of seismic ground motion. Non-uniform damage patterns are also observed in Kathmandu Valley during 1934 Bihar Nepal earthquake and recent 2015 Gorkha earthquake seemingly due to the modification of earthquake ground motion parameters. In this study, site effects resulting from amplification of soft soil in Kathmandu are presented. A large amount of subsoil data was collected and used for defining the appropriate subsoil model for the Kathamandu valley. A comparative study of one-dimensional total-stress equivalent linear and non-linear site response is performed using four strong ground motions for six sites of Kathmandu valley. In general, one-dimensional (1D) site-response analysis involves the excitation of a soil profile using the horizontal component and calculating the response at individual soil layers. In the present study, both equivalent linear and non-linear site response analyses were conducted using the computer program DEEPSOIL. The results show that there is no significant deviation between equivalent linear and non-linear site response models until the maximum strain reaches to 0.06-0.1%. Overall, it is clearly observed from the results that non-linear site response model perform better as compared to equivalent linear model. However, the significant deviation between two models is resulted from other influencing factors such as assumptions made in 1D site response, lack of accurate values of shear wave velocity and nonlinear properties of the soil deposit. The results are also presented in terms of amplification factors which are predicted to be around four times more in case of non-linear analysis as compared to equivalent linear analysis. Hence, the nonlinear behavior of soil prevails the urgent need of study of dynamic characteristics of the soft soil deposit that can specifically represent the site-specific design spectra for the Kathmandu valley for building resilient structures from future damaging earthquakes.

Keywords: deep soil, equivalent linear analysis, non-linear analysis, site response

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Authors: Ram Sharma, Esha Chatterjee, Santosh Kumar Guru, Kunal Nepali

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A tractable anti-lung cancer agent was identified via the installation of a Ring C expanded synthetic analogue of the alkaloid vasicinone [7,8,9,10-tetrahydroazepino[2,1-b] quinazolin-12(6H)-one (TAZQ)] as a surface recognition part in the HDAC inhibitory three-component model. Noteworthy to mention that the candidature of TAZQ was deemed suitable for accommodation in HDAC inhibitory pharmacophore as per the results of the fragment recruitment process conducted by our laboratory. TAZQ was pinpointed through the fragment screening program as a synthetically flexible fragment endowed with some moderate cell growth inhibitory activity against the lung cancer cell lines, and it was anticipated that the use of the aforementioned fragment to generate hydroxamic acid functionality (zinc-binding motif) bearing HDAC inhibitors would boost the antitumor efficacy of TAZQ. Consistent with our aim of applying epigenetic targets to the treatment of lung cancer, a strikingly potent anti-lung cancer scaffold (compound 6) was pinpointed through a series of in-vitro experiments. Notably, the compounds manifested a magnificent activity profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80 - 0.96 µM), and the effects were found to be mediated through preferential HDAC6 inhibition (IC50 = 12.9 nM). In addition to HDAC6 inhibition, the compounds also elicited HDAC1 and HDAC3 inhibitory activity with an IC50 value of 49.9 nM and 68.5 nM, respectively. The HDAC inhibitory ability of compound 6 was also confirmed from the results of the western blot experiment that revealed its potential to decrease the expression levels of HDAC isoforms (HDAC1, HDAC3, and HDAC6). Noteworthy to mention that complete downregulation of the HDAC6 isoform was exerted by compound 6 at 0.5 and 1 µM. Moreover, in another western blot experiment, treatment with hydroxamic acid 6 led to upregulation of H3 acK9 and α-Tubulin acK40 levels, ascertaining its inhibitory activity toward both the class I HDACs and Class II B HDACs. The results of other assays were also encouraging as treatment with compound 6 led to the suppression of the colony formation ability of A549 cells, induction of apoptosis, and increase in autophagic flux. In silico studies led us to rationalize the results of the experimental assay, and some key interactions of compound 6 with the amino acid residues of HDAC isoforms were identified. In light of the impressive activity spectrum of compound 6, a pH-responsive nanocarrier (hyaluronic acid-compound 6 nanoparticles) was prepared. The dialysis bag approach was used for the assessment of the nanoparticles under both normal and acidic circumstances, and the pH-sensitive nature of hyaluronic acid-compound 6 nanoparticles was confirmed. Delightfully, the nanoformulation was devoid of cytotoxicity against the L929 mouse fibroblast cells (normal settings) and exhibited selective cytotoxicity towards the A549 lung cancer cell lines. In a nutshell, compound 6 appears to be a promising adduct, and a detailed investigation of this compound might yield a therapeutic for the treatment of lung cancer.

Keywords: HDAC inhibitors, lung cancer, scaffold, hyaluronic acid, nanoparticles

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