Search results for: pathways

Authors: Wan-Ting Kuo, Yi-Wen Liu, Hsiao-Sheng Liu

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Annual incidence of bladder cancer increases in the world and occurs frequently in the male. Most common type is transitional cell carcinoma (TCC) which is treated by transurethral resection followed by intravesical administration of agents. In clinical treatment of bladder cancer, chemotherapeutic drugs-induced apoptosis is always used in patients. However, cancers usually develop resistance to chemotherapeutic drugs and often lead to aggressive tumors with worse clinical outcomes. Approximate 70% TCC recurs and 30% recurrent tumors progress to high-grade invasive tumors, indicating that new therapeutic agents are urgently needed to improve the successful rate of overall treatment. Nonapoptotic program cell death may assist to overcome worse clinical outcomes. Autophagy which is one of the nonapoptotic pathways provides another option for bladder cancer patients. Autophagy is reported as a potent anticancer therapy in some cancers. First of all, we established a mouse orthotopic bladder tumor formation model in order to create a similar tumor microenvironment. IVIS system and micro-ultrasound were utilized to noninvasively monitor tumor formation. In addition, we carried out intravesical treatment in our animal model to be consistent with human clinical treatment. In our study, we carried out intravesical instillation of the autophagy inducer in mouse orthotopic bladder tumor to observe tumor formation by noninvasive IVIS system and micro-ultrasound. Our results showed that bladder tumor formation is suppressed by the autophagy inducer, and there are no significant side effects in the physiology of mice. Furthermore, the autophagy inducer upregulated autophagy in bladder tissues of the treated mice was confirmed by Western blot, immunohistochemistry, and immunofluorescence. In conclusion, we reveal that a novel autophagy inducer with low side effects suppresses bladder tumor formation in our mouse orthotopic bladder tumor model, and it provides another therapeutic approach in bladder cancer patients.

Keywords: bladder cancer, transitional cell carcinoma, orthotopic bladder tumor formation model, autophagy

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Authors: Tarana Siddika, Ilka U. Heinemann, Patrick O’Donoghue

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Protein kinase B (AKT1) is a serine/threonine kinase and central transducer of cell survival pathways. Typical approaches to study AKT1 biology in cells rely on growth factor or insulin stimulation that activates AKT1 via phosphorylation at two key regulatory sites (Threonine308, Serine473), yet cell stimulation also activates many other kinases and fails to differentiate the effect of the two main activating sites of AKT1 on downstream substrate phosphorylation and cell growth. While both AKT1 activating sites are associated with disease and used as clinical markers, in some cancers, high levels of Threonine308 phosphorylation are associated with poor prognosis while in others poor survival correlates with high Serine473 levels. To produce cells with specific AKT1 activity, a system was developed to deliver active AKT1 to human cells. AKT1 phospho-variants were produced from Escherichia coli with programmed phosphorylation by genetic code expansion. Tagging of AKT1 with an N-terminal cell penetrating peptide tag derived from the human immunodeficiency virus trans-activator of transcription (TAT) helped to enter AKT1 proteins in mammalian cells. The TAT-tag did not alter AKT1 kinase activity and was necessary and sufficient to rapidly deliver AKT1 protein variants that persisted in human cells for 24 h without the need to use transfection reagents. TAT-pAKT1T308, TAT-pAKT1S473 and TAT-pAKT1T308S473 proteins induced selective phosphorylation of the known AKT1 substrate GSK-3αβ, and downstream stimulation of the AKT1 pathway as evidenced by phosphorylation of ribosomal protein S6 at Serine240/244 in transfected cells. Increase in cell growth and proliferation was observed due to the transfection of different phosphorylated AKT1 protein variants compared to cells with TAT-AKT1 protein. The data demonstrate efficient delivery of AKT1 with programmed phosphorylation to human cells, thus establishing a cell-based model system to investigate signaling that is dependent on specific AKT1 activity and phosphorylation.

Keywords: cell penetrating peptide, cell signaling, protein kinase b (AKT1), phosphorylation

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Authors: Hala Raslan, Noha Eltaweel, Hanaa Rasmi, Solaf Kamel, May Magdy, Sherif Ismail, Khalda Amr

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Introduction: Rheumatoid arthritis (RA) is an inflammatory, autoimmune disorder with progressive joint damage. Osteoarthritis (OA) is a degenerative disease of the articular cartilage that shows multiple clinical manifestations or symptoms resembling those of RA. Genetic predisposition is believed to be a principal etiological factor for RA and OA. In this study, we aimed to measure the expression of the top deregulated miRNAs that might be the cause of pathogenesis in both diseases, according to our latest NGS analysis. Six of the deregulated miRNAs were selected as they had multiple target genes in the RA pathway, so they are more likely to affect the RA pathogenesis.Methods: Eighty cases were recruited in this study; 45 rheumatoid arthiritis (RA), 30 osteoarthiritis (OA) patients, as well as 20 healthy controls. The selection of the miRNAs from our latest NGS study was done using miRwalk according to the number of their target genes that are members in the KEGG RA pathway. Total RNA was isolated from plasma of all recruited cases. The cDNA was generated by the miRcury RT Kit then used as a template for real-time PCR with miRcury Primer Assays and the miRcury SYBR Green PCR Kit. Fold changes were calculated from CT values using the ΔΔCT method of relative quantification. Results were compared RA vs Controls and OA vs Controls. Target gene prediction and functional annotation of the deregulated miRNAs was done using Mienturnet. Results: Six miRNAs were selected. They were miR-15b-3p, -128-3p, -194-3p, -328-3p, -542-3p and -3180-5p. In RA samples, three of the measured miRNAs were upregulated (miR-194, -542, and -3180; mean Rq= 2.6, 3.8 and 8.05; P-value= 0.07, 0.05 and 0.01; respectively) while the remaining 3 were downregulated (miR-15b, -128 and -328; mean Rq= 0.21, 0.39 and 0.6; P-value= <0.0001, <0.0001 and 0.02; respectively) all with high statistical significance except miR-194. While in OA samples, two of the measured miRNAs were upregulated (miR-194 and -3180; mean Rq= 2.6 and 7.7; P-value= 0.1 and 0.03; respectively) while the remaining 4 were downregulated (miR-15b, -128, -328 and -542; mean Rq= 0.5, 0.03, 0.08 and 0.5; P-value= 0.0008, 0.003, 0.006 and 0.4; respectively) with statistical significance compared to controls except miR-194 and miR-542. The functional enrichment of the selected top deregulated miRNAs revealed the highly enriched KEGG pathways and GO terms. Conclusion: Five of the studied miRNAs were greatly deregulated in RA and OA, they might be highly involved in the disease pathogenesis and so might be future therapeutic targets. Further functional studies are crucial to assess their roles and actual target genes.

Keywords: MiRNAs, expression, rheumatoid arthritis, osteoarthritis

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Authors: Dragos Dragomir-Stanciu, Leon Marsh

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Background As a response to the gaps identified in recent research in the provision of residential care to address co-occurring health needs, including mental health problems and complexities Gamble Aware has facilitated the possibility to provide a new service which would extend the NGTS provision of residential rehabilitation for gambling disorder with complex and co-morbid presentation. Gordon Moody, together with Adferiad have been successful in securing the tender for this service and this presentation aims to introduce FOLD, the resulting model of treatment developed for the delivery of the service. Setting As a partnership, we have come together to coproduce a model which allows us to share our clinical and industry knowledge and build on our reputations as trusted treatment providers. The presentation will outline our expertise share in development of a unified approach to recovery-oriented models of care, clinical governance, risk assessment and management and aftercare and continuous recovery. We will also introduce our innovative specialist referral portal which will offer referring partners the ability to include the service user in planning their own recovery journey. Outcomes Our collaboration has resulted in the development of the FOLD model which includes three agile and flexible treatment packages aimed at offering the most enhanced and comprehensive treatment in UK, to date, for those most affected by gambling harm. The paper will offer insight into each treatment package and all recovery model stages involved, as well as into the partnership work with NGST providers, local mental health and social care providers and lived experience organisation that will enable us to offer support to more 100 people a year who would otherwise get “lost in the system”. Conclusion FOLD offers a great opportunity to develop, implement and evaluate a new, much needed, whole-person and whole-system approach to counter gambling related harms.

Keywords: gambling treatment, partnership working, integrated care pathways, NGTS, complex needs

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Authors: Fitih Ademe, Kibebew Kibret, Sheleme Beyene, Mezgebu Getnet, Gashaw Meteke

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Changes in precipitation, temperature and atmospheric CO2 concentration are expected to alter agricultural productivity patterns worldwide. The interactive effects of soil moisture and nutrient availability are the two key edaphic factors that determine crop yield and are sensitive to climatic changes. The study assessed the potential impacts of climate change on maize yield and corresponding water productivity and nutrient use efficiency under climate change scenarios for the Central Rift Valley of Ethiopia by mid (2041-2070) and end century (2071-2100). Projected impacts were evaluated using climate scenarios generated from four General Circulation Models (GCMs) dynamically downscaled by the Swedish RCA4 Regional Climate Model (RCM) in combination with two Representative Concentration Pathways (RCP 4.5 and RCP8.5). Decision Support System for Agro-technology Transfer cropping system model (DSSAT-CSM) was used to simulate yield, water and nutrient use for the study periods. Results indicate that rainfed maize yield might decrease on average by 16.5 and 23% by the 2050s and 2080s, respectively, due to climate change. Water productivity is expected to decline on average by 2.2 and 12% in the CRV by mid and end centuries with respect to the baseline. Nutrient uptake and corresponding nutrient use efficiency (NUE) might also be negatively affected by climate change. Phosphorus uptake probably will decrease in the CRV on average by 14.5 to 18% by 2050s, while N uptake may not change significantly at Melkassa. Nitrogen and P use efficiency indicators showed decreases in the range between 8.5 to 10.5% and between 9.3 to 10.5%, respectively, by 2050s relative to the baseline average. The simulation results further indicated that a combination of increased water availability and optimum nutrient application might increase both water productivity and nutrient use efficiency in the changed climate, which can ensure modest production in the future. Potential options that can improve water availability and nutrient uptake should be identified for the study locations using a crop modeling approach.

Keywords: crop model, climate change scenario, nutrient uptake, nutrient use efficiency, water productivity

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Authors: Syed Hammad Ali, Rijan Bhakta Kayastha, Danial Hashmi, Richard Armstrong, Ahuti Shrestha, Iram Bano, Javed Hassan

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This paper presents the results of a semi-distributed modified positive degree-day model (MPDDM) for estimating snow and ice melt contributions to discharge from the glacierized Hunza River basin, Pakistan. The model uses daily temperature data, daily precipitation data, and positive degree day factors for snow and ice melt. The model is calibrated for the period 1995-2001 and validated for 2002-2013, and demonstrates close agreements between observed and simulated discharge with Nash–Sutcliffe Efficiencies of 0.90 and 0.88, respectively. Furthermore, the Weather Research and Forecasting model projected temperature, and precipitation data from 2016-2050 are used for representative concentration pathways RCP4.5 and RCP8.5, and bias correction was done using a statistical approach for future discharge estimation. No drastic changes in future discharge are predicted for the emissions scenarios. The aggregate snow-ice melt contribution is 39% of total discharge in the period 1993-2013. Snow-ice melt contribution ranges from 35% to 63% during the high flow period (May to October), which constitutes 89% of annual discharge; in the low flow period (November to April) it ranges from 0.02% to 17%, which constitutes 11 % of the annual discharge. The snow-ice melt contribution to total discharge will increase gradually in the future and reach up to 45% in 2041-2050. From a sensitivity analysis, it is found that the combination of a 2°C temperature rise and 20% increase in precipitation shows a 10% increase in discharge. The study allows us to evaluate the impact of climate change in such basins and is also useful for the future prediction of discharge to define hydropower potential, inform other water resource management in the area, to understand future changes in snow-ice melt contribution to discharge, and offer a possible evaluation of future water quantity and availability.

Keywords: climate variability, future discharge projection, positive degree day, regional climate model, water resource management

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Authors: Ashhar Ahmed Shaikh, Ayush Tandon

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The swift reduction of fossil fuels from nature has crucial need for alternative energy sources to cater vital demand. It is essential to boost alternative energy sources to cover the continuously increasing demand for energy while minimizing the negative environmental impacts. Solar energy is one of the reliable sources that can generate energy. Solar energy is freely available in nature and is completely eco-friendly, and they are considered as the most promising power generating sources due to their easy availability and other advantages for the local power generation. This paper is to review the implementation of power electronic devices through Solar Energy Grid Integration System (SEGIS) to increase the efficiency. This paper will also concentrate on the future grid infrastructure and various other applications in order to make the grid smart. Development and implementation of a power electronic devices such as PV inverters and power controllers play an important role in power supply in the modern energy economy. Solar Energy Grid Integration System (SEGIS) opens pathways for promising solutions for new electronic and electrical components such as advanced innovative inverter/controller topologies and their functions, economical energy management systems, innovative energy storage systems with equipped advanced control algorithms, advanced maximum-power-point tracking (MPPT) suited for all PV technologies, protocols and the associated communications. In addition to advanced grid interconnection capabilities and features, the new hardware design results in small size, less maintenance, and higher reliability. The SEGIS systems will make the 'advanced integrated system' and 'smart grid' evolutionary processes to run in a better way. Since the last few years, there was a major development in the field of power electronics which led to more efficient systems and reduction of the cost per Kilo-watt. The inverters became more efficient and had reached efficiencies in excess of 98%, and commercial solar modules have reached almost 21% efficiency.

Keywords: solar energy grid integration systems, smart grid, advanced integrated system, power electronics

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Authors: Safee Chaudhary, Mahnoor Naseer Gondal, Hira Anees Awan, Abdul Rehman, Ammar Arif, Risham Hussain, Huma Khawar, Zainab Arshad, Muhammad Faizyab Ali Chaudhary, Waleed Ahmed, Muhammad Umer Sultan, Bibi Amina, Salaar Khan, Muhammad Moaz Ahmad, Osama Shiraz Shah, Hadia Hameed, Muhammad Farooq Ahmad Butt, Muhammad Ahmad, Sameer Ahmed, Fayyaz Ahmed, Omer Ishaq, Waqar Nabi, Wim Vanderbauwhede, Bilal Wajid, Huma Shehwana, Muhammad Tariq, Amir Faisal

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Cancer is a manifestation of multifactorial deregulations in biomolecular pathways. These deregulations arise from the complex multi-scale interplay between cellular and extracellular factors. Such multifactorial aberrations at gene, protein, and extracellular scales need to be investigated systematically towards decoding the underlying mechanisms and orchestrating therapeutic interventions for patient treatment. In this work, we propose ‘TISON’, a next-generation web-based multiscale modeling platform for clinical systems oncology. TISON’s unique modeling abstraction allows a seamless coupling of information from biomolecular networks, cell decision circuits, extra-cellular environments, and tissue geometries. The platform can undertake multiscale sensitivity analysis towards in silico biomarker identification and drug evaluation on cellular phenotypes in user-defined tissue geometries. Furthermore, integration of cancer expression databases such as The Cancer Genome Atlas (TCGA) and Human Proteome Atlas (HPA) facilitates in the development of personalized therapeutics. TISON is the next-evolution of multiscale cancer modeling and simulation platforms and provides a ‘zero-code’ model development, simulation, and analysis environment for application in clinical settings.

Keywords: systems oncology, cancer systems biology, cancer therapeutics, personalized therapeutics, cancer modelling

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Authors: Morgane Chatard, Clémentine Puech, Nathalie Perek, Frédéric Roche

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Several neurological disorders are linked to repeated hypoxia. The impact of such repeated hypoxic stress, on endothelial cells function of the blood-brain barrier (BBB) is little studied in the literature. Indeed, the study of hypoxic stress in cellular pathways is complex using hypoxia exposure because HIF 1α (factor induced by hypoxia) has a short half life. Our study presents an innovative induction method of repeated hypoxic stress, more reproducible, which allows us to study its impacts on an in vitro contact co-culture BBB model. Repeated hypoxic stress was induced by hydralazine (a mimetic agent of hypoxia pathway) during two hours and repeated during 24 hours. Then, BBB integrity was assessed by permeability measurements (transendothelial electrical resistance and membrane permeability), tight junction protein expressions (cell-ELISA and confocal microscopy) and by studying expression and activity of efflux transporters. First, this study showed that repeated hypoxic stress leads to a BBB’s dysfunction illustrated by a significant increase in permeability. This loss of membrane integrity was linked to a significant decrease of tight junctions’ protein expressions, facilitating a possible transfer of potential cytotoxic compounds in the brain. Secondly, we demonstrated that brain microvascular endothelial cells had set-up defence mechanism. These endothelial cells significantly increased the activity of their efflux transporters which was associated with a significant increase in their expression. In conclusion, repeated hypoxic stress lead to a loss of BBB integrity with a decrease of tight junction proteins. In contrast, endothelial cells increased the expression of their efflux transporters to fight against cytotoxic compounds brain crossing. Unfortunately, enhanced efflux activity could also lead to reducing pharmacological drugs delivering to the brain in such hypoxic conditions.

Keywords: BBB model, efflux transporters, repeated hypoxic stress, tigh junction proteins

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Authors: Nji Clement Bang, Rosemary Shafack M., Kum Henry Asei, Yaro Loveline Y

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Scholars perceive learner-centered teaching-learning reform as roles and resources in teacher education (TE) and professional outcome with transformative learning (TL) continuum dimensions. But, teaching-learning reform is fast proliferating amidst debilitating stakeholder systemic dichotomies, resources, commitment, resistance and poor quality outcome that necessitate stronger TE and professional continuums. Scholars keep seeking greater understanding of themes in teaching-learning reform, TE and professional outcome as continuums and how policymakers, student-teachers, teacher trainers and local communities concerned with initial TE can promote continuous holistic quality performance. To sustain the debate continuum and answer the overarching question, we use mixed-methods research-design with diverse literature and 409 sample-data. Onset text, interview and questionnaire analyses reveal debilitating teaching-learning reform in TE continuums that need TL revival. Follow-up focus group discussion and teaching considering TL insights reinforce holistic teaching-learning in TE. Therefore, significant increase in diverse prior-experience articulation1; critical reflection-discourse engagement2; teaching-practice interaction3; complex-activity constrain control4 and formative outcome- reintegration5 reinforce teaching-learning in learning-to-teach role-resource pathways and outcomes. Themes reiterate complex teaching-learning in TE programs that suits TL journeys and student-teachers and students cum teachers, workers/citizens become akin, transformative-learners who evolve personal and collective roles-resources towards holistic-lifelong-learning outcomes. The article could assist debate about quality teaching-learning reform through TL dimensions as TE and professional role-resource continuums.

Keywords: transformative learning perspectives, teacher education, initial teacher education, learner-centered pedagogical reform, life-long learning

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Authors: Alexandra K. Diem, Giles Richardson, Roxana O. Carare, Neil W. Bressloff

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Alzheimer's disease (AD) is the most common form of dementia and although it has been researched for over 100 years, there is still no cure or preventive medication. Its onset and progression is closely related to the accumulation of the neuronal metabolite Aβ. This raises the question of how metabolites and waste products are eliminated from the brain as the brain does not have a traditional lymphatic system. In recent years the rapid uptake of Aβ into cerebral artery walls and its clearance along those arteries towards the lymph nodes in the neck has been suggested and confirmed in mice studies, which has led to the hypothesis that interstitial fluid (ISF), in the basement membranes in the walls of cerebral arteries, provides the pathways for the lymphatic drainage of Aβ. This mechanism, however, requires a net reverse flow of ISF inside the blood vessel wall compared to the blood flow and the driving forces for such a mechanism remain unknown. While possible driving mechanisms have been studied using mathematical models in the past, a mechanism for net reverse flow has not been discovered yet. Here, we aim to address the question of the driving force of this reverse lymphatic drainage of Aβ (also called perivascular drainage) by using multi-scale numerical and analytical modelling. The numerical simulation software COMSOL Multiphysics 4.4 is used to develop a fluid-structure interaction model of a cerebral artery, which models blood flow and displacements in the artery wall due to blood pressure changes. An analytical model of a layer of basement membrane inside the wall governs the flow of ISF and, therefore, solute drainage based on the pressure changes and wall displacements obtained from the cerebral artery model. The findings suggest that an active role in facilitating a reverse flow is played by the components of the basement membrane and that stiffening of the artery wall during age is a major risk factor for the impairment of brain lymphatics. Additionally, our model supports the hypothesis of a close association between cerebrovascular diseases and the failure of perivascular drainage.

Keywords: Alzheimer's disease, artery wall mechanics, cerebral blood flow, cerebral lymphatics

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Authors: Joshua W. Edefo, Shafiul Azam, Murray D. Smith

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Introduction: In April 2022, the Welsh Government introduced the six goals for urgent and emergency care programs. One of these goals was to provide access to clinically safe alternatives, leading to the establishment of the Same Day Emergency Care (SDEC) program. The SDEC initiative aims to offer viable options that maintain patient safety while avoiding unnecessary hospital stays. The aim of the study is to determine the duration of patient stay in SDEC and compare it with that of Emergency department (ED) stay to ascertain if one of the objectives of SDEC is achieved. Methods: Patient stays and attendance datasets were constructed from Withybush SDEC and ED patient records. These records were provided by Hywel Dda University Health Board Informatics. Some hypothetical pathways were identified, notably SDEC visits involving a single attendance and ED visits then immediately transferred to SDEC. Descriptive statistics were used to summarise the data, and hypothesis tests for mean differences used the student t-test. Propensity scoring was employed to match a set of ED patient stays to SDEC patient stays which were then used to determine the average treatment effect (ATE) to compare durations of stay in SDEC with ED. Regression methods were used to model the natural logarithm of the duration of SDEC attendance, and the level of statistical significance was set to 0.05. Results: SDEC visits involving a single attendance (170 of 384; 44.3%) is the most frequently observed pathway with patient length of stay at 256 minutes (95%CI 237.4 - 275.1). The next most frequently observed pathway of patient stay was SDEC attendance after presenting to ED (80 of 384; 20.8%) and gave the length of stay of 440 minutes (95%CI 351.6 - 529.2). Time spent in this pathway significantly increased by 184 minutes (95%CI 118.0 - 250.2, support for no difference p<0.001) compared to the most seen pathway. When SDEC data were compared with ED, the estimate for the ATE from SDEC single attendance was -272 minutes (95%CI -334.1 - -210.5; p<0.001), while that of ED then SDEC pathway was -50.6 min (95%CI -182.7-81.5; p=0.453). Conclusion: When patients are admitted to SDEC and successfully discharged, their stays are significantly shorter, approximately 4.5 hours, compared to patients who spend their entire stay in the Emergency Department. That difference vanishes when the patient stay includes a period spent previously in ED before transfer to SDEC.

Keywords: attendance, emergency-department, patient-stay, same-day-emergency-care

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Authors: Rolivhuwa Bishop Ramagoma1*, Lynn Cairncross1, , Saartjie Roux1

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According to the world health organisation, colon cancer is among the most common cancers diagnosed in both men and women. Specifically, it is the second leading cause of cancer related deaths accounting for over 860 000 deaths worldwide in 2018. Currently, chemotherapy has become an essential component of most cancer treatments. Despite progress in cancer drug development over the previous years, traditional chemotherapeutic drugs still have low selectivity for targeting tumour tissues and are frequently constrained by dose-limiting toxicity. The creation of nanoscale delivery vehicles capable of directly directing treatment into cancer cells has recently caught the interest of researchers. Herein, the development of peptide-functionalized polyethylene glycol gold nanoparticles (Peptide-PEG-AuNPs) as a cellular probe and delivery agent is described, with the higher aim to develop a specific diagnostic prototype and assess their specificity not only against cell lines but primary human cells as well. Gold nanoparticles (AuNPs) were synthesized and stabilized through chemical conjugation. The synthesized AuNPs were characterized, stability in physiological solutions was assessed, their cytotoxicity against colon carcinoma and non-carcinoma skin fibroblasts was also studied. Furthermore, genetic effect through real-time polymerase chain reaction (RT-PCR), localization and uptake, peptide specificity were also determined. In this study, different peptide-AuNPs were found to have preferential toxicity at higher concentrations, as revealed by cell viability assays, however, all AuNPs presented immaculate stability for over 3 months following the method of synthesis. The final obtained peptide-PEG-AuNP conjugates showed good biocompatibility in the presence of high ionic solutions and biological media and good cellular uptake. Formulation of colon cancer specific targeting peptide was successful, additionally, the genes/pathways affected by the treatments were determined through RT-PCR. Primary cells study is still on going with promising results thus far.

Keywords: nanotechnology, cancer, diagnosis, therapeutics, gold nanoparticles.

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Authors: Sohail Bawani, Kausar S. Khan, Rozina Karmaliani, Shehnaz Mir

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Action research (AR) is one of the types of health systems research (HSR), and participatory action research (PAR) is known for being effective in health systems strengthening (HSS). The current literature on PAR for HSS cites numerous examples and case studies that led to improve health services; build child health information system; increase knowledge and awareness of people about health problems, and identify pathways for institutional and policy change by engaging people in research. But examples of marginalized communities being agents of change in health governance are not common in health systems research (HSR). This approach to PAR is at the heart of Paolo Freire’s Social Transformation Theory and Critical Consciousness building, which was used to design a community-based PAR study in the Northern/mountainous areas of Pakistan. The purpose of the study was to understand the place and role of marginalized communities in strengthening existing health governance structure (health facility and village health committees and health boards) by taking marginalized communities as partners. Community meetings were carried out to identify who is living at the social, political, cultural and economic margins in 40 different villages. Participatory reflection and analysis (PRA) tools were used during the meeting to facilitate identification. Focus group discussions were conducted with marginalized groups using PRA tools and family ethnographies with marginalized families identified through group discussions. Findings of the study revealed that for the marginalized health systems constitute more than just delivery of health services, but it also embraces social determinants that surround systems and its governance. The paper argues that from Frerian perspective people’s participation should not only be limited to knowledge generation. People must be seen active users of the knowledge that they generate for achieving better health outcomes that they want to achieve in the time to come. PAR provides a pathway to the marginalized in playing a role in health governance. The study dissemination planned shall engage the marginalized in a dialogue with service providers so that together a role for the marginalized can be outlined.

Keywords: participatory action research, health systems, marginalized, health services

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Authors: T. Yasmin, M. A. Farrelly, B. C. Rogers

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Urban water governance in developing countries faces numerous challenges arising from uncontrolled urban population expansion, water pollution, greater economic push and more recently, climate change impact while undergoing transitioning towards a sustainable system. Sustainability transition requires developing adaptive capacities of the socio-ecological and socio-technical system to be able to deal with complexity. Adaptive capacities deliver strategies to connect individuals, organizations, agencies and institutions at multiple levels for dealing with such complexity. Understanding the level of adaptive capacities for sustainability transformation thus has gained significant research attention within developed countries, much less so in developing countries. Filling this gap, this article develops a conceptual framework for analysing the level of adaptive capacities (if any) within a developing context. This framework then applied to the chronological development of urban water governance strategies in Bangladesh for almost two centuries. The chronological analysis of governance interventions has revealed that crisis (public health, food and natural hazards) became the opportunities and thus opened the windows for experimentation and learning to occur as a deviation from traditional practices. Self-organization and networks thus created the platform for development or disruptions to occur for creating change. Leadership (internal or external) is important for nurturing and upscaling theses development or disruptions towards guiding policy vision and targets as well as championing ground implementation. In the case of Bangladesh, the leadership from the international and national aid organizations and targets have always lead the development whereas more often social capital tools (trust, power relations, cultural norms) act as disruptions. Historically, this has been evident in the development pathways of urban water governance in Bangladesh. Overall this research has shown some level of adaptive capacities is growing for sustainable urban growth in big cities, nevertheless unclear regarding the growth in medium and small cities context.

Keywords: adaptive capacity, Bangladesh, sustainability transformation, water governance

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Authors: Israel Ropo Orimoloye, Johanes A. Belle, Olusola Adeyemi, Olusola O. Ololade

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With more than 100,000 orbits during the past 20 years, Terra has significantly improved our knowledge of the Earth's climate and its implications on societies and ecosystems of human activity and natural disasters, including drought events. With Terra instrument's performance and the free distribution of its products, this study utilised Terra MOD13Q1 satellite data to assess drought disaster events and its spatiotemporal patterns over the Free State Province of South Africa between 2001 and 2019 for summer, autumn, winter, and spring seasons. The study also used high-resolution downscaled climate change projections under three representative concentration pathways (RCP). Three future periods comprising the short (the 2030s), medium (2040s), and long term (2050s) compared to the current period are analysed to understand the potential magnitude of projected climate change-related drought. The study revealed that the year 2001 and 2016 witnessed extreme drought conditions where the drought index is between 0 and 20% across the entire province during summer, while the year 2003, 2004, 2007, and 2015 observed severe drought conditions across the region with variation from one part to the another. The result shows that from -24.5 to -25.5 latitude, the area witnessed a decrease in precipitation (80 to 120mm) across the time slice and an increase in the latitude -26° to -28° S for summer seasons, which is more prominent in the year 2041 to 2050. This study emphasizes the strong spatio-environmental impacts within the province and highlights the associated factors that characterise high drought stress risk, especially on the environment and ecosystems. This study contributes to a disaster risk framework to identify areas for specific research and adaptation activities on drought disaster risk and for environmental planning in the study area, which is characterised by both rural and urban contexts, to address climate change-related drought impacts.

Keywords: remote sensing, drought disaster, climate scenario, assessment

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Authors: Aziza S. Al Adhoobi, Amna Al Ruheili, Saud M. Al Jufaili

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This study investigates the potential effects of climate change on the habitat suitability of two Aphaniops species (Teleostei: Aphaniidae) found in the Oman Mountains and the Southwestern Arabian Coast. Aphaniops kruppi, an endemic species, is found in various water bodies such as wadis, springs, aflaj, spring-fed streams, and some coastal backwaters. Aphaniops stoliczkanus, on the other hand, inhabits brackish and freshwater habitats, particularly in the lower parts of wadies and aflaj, and exhibits euryhaline characteristics. Using Maximum Entropy Modeling (MaxEnt) in conjunction with ArcGIS (10.8.2) and CHELSA bioclimatic variables, topographic indices, and other pertinent environmental factors, the study modeled the potential impacts of climate change based on three Representative Concentration Pathways (RCPs 2.6, 7.0, 8.5) for the periods 2011-2040, 2041-2070, and 2071-2100. The model demonstrated exceptional predictive accuracy, achieving AUC values of 0.992 for A. kruppi and 0.983 for A. stoliczkanus. For A. kruppi, the most influential variables were the mean monthly climate moisture index (Cmi_m), the mean diurnal range (Bio2), and the sediment transport index (STI), accounting for 39.9%, 18.3%, and 8.4%, respectively. As for A. stoliczkanus, the key variables were the sediment transport index (STI), stream power index (SPI), and precipitation of the coldest quarter (Bio19), contributing 31%, 20.2%, and 13.3%, respectively. A. kruppi showed an increase in habitat suitability, especially in low and medium suitability areas. By 2071-2100, high suitability areas increased slightly by 0.05% under RCP 2.6, but declined by -0.02% and -0.04% under RCP 7.0 and 8.5, respectively. A. stoliczkanus exhibited a broader range of responses. Under RCP 2.6, all suitability categories increased by 2071-2100, with high suitability areas increasing by 0.01%. However, low and medium suitability areas showed mixed trends under RCP 7.0 and 8.5, with declines of -0.17% and -0.16%, respectively. The study highlights that climatic and topographical factors significantly influence the habitat suitability of Aphaniops species in Oman. Therefore, species-specific conservation strategies are crucial to address the impacts of climate change.

Keywords: Aphaniops kruppi, Aphaniops stoliczkanus, Climate change, Habitat suitability, MaxEnt

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Authors: Swarkar Sharma, Ekta Rai, Ankit Mahajan, Parvinder Kumar, Manoj K Dhar, Sushil Razdan, Kumarasamy Thangaraj, Carol Wise, Shiro Ikegawa M.D., K.K. Pandita M.D.

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Rare disorders are poorly understood hence, remain uncharacterized or patients are misdiagnosed and get poor medical attention. A rare mysterious skeletal disorder that remained unidentified for decades and rendered many people physically challenged and disabled for life has been reported in an isolated remote village ‘Arai’ of Poonch district of Jammu and Kashmir. This village is located deep in mountains and the population residing in the region is highly consanguineous. In our survey of the region, 70 affected people were reported, showing similar phenotype, in the village with a population of approximately 5000 individuals. We were able to collect samples from two multi generational extended families from the village. Through Whole Exome sequencing (WES), we identified a rare variation NM_003880.3:c.156C>A NP_003871.1:p.Cys52Ter, which results in introduction of premature stop codon in WISP3 gene. We found this variation perfectly segregating with the disease in one of the family. However, this variation was absent in other family. Interestingly, a novel splice site mutation at position c.643+1G>A of WISP3 gene, perfectly segregating with the disease was observed in the second family. Thus, exploiting WES and putting different evidences together (familial histories and genetic data, clinical features, radiological and biochemical tests and findings), the disease has finally been diagnosed as a very rare recessive hereditary skeletal disease “Progressive Pseudorheumatoid Arthropathy of Childhood” (PPAC) also known as “Spondyloepiphyseal Dysplasia Tarda with Progressive Arthropathy” (SEDT-PA). This genetic characterization and identification of the disease causing mutations will aid in genetic counseling, critically required to curb this rare disorder and to prevent its appearance in future generations in the population. Further, understanding of the role of WISP3 gene the biological pathways should help in developing treatment for the disorder.

Keywords: whole exome sequencing, Next Generation Sequencing, rare disorders

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Authors: Harika Atmaca, Emir Bozkurt, Latife Merve Oktay, Selim Uzunoglu, Ruchan Uslu, Burçak Karaca

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Microarrays have been developed for highly parallel enzyme-linked immunosorbent assay (ELISA) applications. The most common protein arrays are produced by using multiple monoclonal antibodies, since they are robust molecules which can be easily handled and immobilized by standard procedures without loss of activity. Protein expression profiling with protein array technology allows simultaneous analysis of the protein expression pattern of a large number of proteins. Trabectedin, a tetrahydroisoquinoline alkaloid derived from a Caribbean tunicate, Ecteinascidia turbinata, has been shown to have antitumor effects. Here, we used a novel proteomic approach to explore the mechanism of action of trabectedin in prostate cancer cell line PC-3 by apoptosis antibody microarray. XTT cell proliferation kit and Cell Death Detection Elisa Plus Kit (Roche) was used for measuring cytotoxicity and apoptosis. Human Apoptosis Protein Array (R&D Systems) which consists of 35 apoptosis related proteins was used to assess the omic protein expression pattern. Trabectedin induced cytotoxicity and apoptosis in prostate cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL R2/DR5, TNF R1/TNFRSF1A, FADD were significantly increased by 4.0-, 21.0-, 4.20- and 11.5-fold by trabectedin treatment in PC-3 cells. Moreover, mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, and Cleaved Caspase-3 expressions were induced by 2.68-, 2.07-, 2.8-, and 4.5-fold and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 3.5- and 5.2-fold in PC-3 cells. Proteomic (antibody microarray) analysis suggests that the mechanism of action of trabectedin may be exerted via the induction of both intrinsic and extrinsic apoptotic pathways. The antibody microarray platform can be utilised to explore the molecular mechanism of action of novel anticancer agents.

Keywords: trabectedin, prostate cancer, omic protein expression profile, apoptosis

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Authors: David Mafullul, Jiang Lei, Edward Goacher, Jibin Francis

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PURPOSE: Timely decompressive surgery for cauda equina syndrome (CES) is dependent on efficient referral pathways for patients presenting at local primary or secondary centres to tertiary spinal centres in the United Kingdom (UK). Identifying modifiable points of delay within this process is important as minimising time between presentation and surgery may improve patient outcomes. This study aims to analyse whether adequacy of referral impacts on time to surgery in CES. MATERIALS AND METHODS: Data from all cases of confirmed CES referred to a single tertiary UK hospital between August 2017 to December 2019, via a suspected CES e-referral pathway, were obtained retrospectively. Referral adequacy was defined by the inclusion of sufficient information to determine the presence or absence of several NICE ‘red flags’. Correlation between referral adequacy and delay from referral-to-surgery was then analysed. RESULTS: In total, 118 confirmed CES cases were included. Adequate documentation for saddle anaesthesia was associated with reduced delays of more than 48 hours from referral-to-surgery [X2(1, N=116)=7.12, p=.024], an effect partly attributable to these referrals being accepted sooner [U=16.5; n1=27, n2=4, p=.029, r=.39]. Other red flags had poor association with delay. Referral adequacy was better for somatic red flags [bilateral sciatica (97.5%); severe or progressive bilateral neurological deficit of the legs (95.8%); saddle anaesthesia (91.5%)] compared to autonomic red flags [loss of anal tone (80.5%); urinary retention (79.7%); faecal incontinence or lost sensation of rectal fullness (57.6%)]. Although referral adequacy for urinary retention was 79.7%, only 47.5% of referrals documented a post-void residual numerical value. CONCLUSIONS: Adequate documentation of saddle anaesthesia in e-referrals is associated with reduced delay-to-surgery for confirmed CES, partly attributable to these referrals being accepted sooner. Other red flags had poor association with delay to surgery. Referral adequacy for autonomic red flags, including documentation for post-void residuals, has significant room for improvement.

Keywords: cauda equina, cauda equina syndrome, neurosurgery, spinal surgery, decompression, delay, referral, referral adequacy

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Authors: Misty Attwood, Helgi Schioth

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Transmembrane proteins are important components in many essential cell processes such as signal transduction, cell-cell signalling, transport of solutes, structural adhesion activities, and protein trafficking. Due to their involvement in diverse critical activities, transmembrane proteins are implicated in different disease pathways and hence are the focus of intense interest in understanding functional activities, their pathogenesis in disease, and their potential as pharmaceutical targets. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e., the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. In this in silico bioinformatics analysis, we identify and comprehensively characterize the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). We classify nearly 60 5TM proteins in which 31 are members of ten families that contain two or more family members and all members are predicted to contain the 5TM architecture. Furthermore, nine singlet proteins that contain the 5TM architecture without paralogues detected in humans were also identifying, indicating the evolution of single unique proteins with the 5TM structure. Interestingly, more than half of these proteins function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in sharp contrast with other TM families. Three major 5TM families were identified and include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that acts as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport. About 30% of the proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM regions and provides details of the unique characteristics and application in pharmaceutical development.

Keywords: 5TM, cancer prognostic marker, drug targets, transmembrane protein

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Authors: Jennifer Duffy, Liz Fleming

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Teacher shortage in special education is an American educational problem. Due to the implementation of The No Child Left Behind Act (2001) and The Individuals with Disabilities Education Improvement Act (2004), there has been an increase in the number of students requiring special education services. Consequently, there has been an influx to hire more special education teachers. However, the historic challenge of hiring certified special education teachers has been intensified with this the profession’s increasing demand of positions to fill. Efforts to improve recruitment and entry into the field must be informed by an understanding of the factors that initially inspire special education teachers to choose this career pathway. Hence, an understanding of reasons why teachers select special education as a profession is needed. The purpose of this study was to explore personal, academic, and professional motivations that lead to the selection of special education as a career choice. Using the grounded theory approach, this research investigation examined the factors that were most instrumental in influencing applicants to select special education as a career choice. Over one hundred de-identified graduate school applications to Bay Path University’s Graduate Special Education Programs from 2014- 2017 were qualitatively analyzed. Grounded coding was used to discover themes that emerged in applicants’ admissions essays explaining why he/she was pursuing a career in special education. The central themes that were most influential in applicants’ selection of special education as a career trajectory were (a) personal/familial connections to disability, (b) meaningful paraprofessional experiences working with disabled children, (c) aptitudes for teaching, and (d) finding personal rewards and professional fulfillment by advocating for vulnerable children. Implications from these findings include educating family members of children with disabilities about possible career tracks in special education, designing programs for paraprofessionals to become certified teachers, exposing prospective teacher candidates to the field of special education, and recruiting professionals from the human services field who seek to improve the quality of life and educational opportunities for children with special needs.

Keywords: career choice, professional pathways to teaching children with disabilities, special education, teacher recruitment

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Authors: Michał Jaśkiewicz

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The relation between walkability, place adherence, social relations and quality of life was explored in a Polish context. A considerable number of studies have suggested that environmental factors may influence the quality of life through indirect pathways. The list of possible psychological mediators includes social relations and identity-related variables. Based on the results of Study 1, local identity is a significant mediator in the relationship between neighbourhood walkability and quality of life. It was assumed that pedestrian-oriented neighbourhoods enable residents to interact and that these spontaneous interactions can help to strengthen a sense of local identity, thus influencing the quality of life. We, therefore, conducted further studies, testing the relationship experimentally in studies 2a and 2b. Participants were exposed to (2a) photos of walkable/non-walkable neighbourhoods or (2b) descriptions of high/low-walkable neighbourhoods. They were then asked to assess the walkability of the neighbourhoods and to evaluate their potential social relations and quality of life in these places. In both studies, social relations with neighbours turned out to be a significant mediator between walkability and quality of life. In Study 3, we implemented the measure of overlapping individual and communal identity (fusion with the neighbourhood) and willingness to collective action as mediators. Living in a walkable neighbourhood was associated with identity fusion with that neighbourhood. Participants who felt more fused expressed greater willingness to engage in collective action with other neighbours. Finally, this willingness was positively related to the quality of life in the city. In Study 4, we used commuting time (an aspect of walkability related to the time that people spend travelling to work) as the independent variable. The results showed that a shorter average daily commuting time was linked to more frequent social interactions in the neighbourhood. Individuals who assessed their social interactions as more frequent expressed a stronger city identification, which was in turn related to quality of life. To sum up, our research replicated and extended previous findings on the association between walkability and well-being measures. We introduced potential mediators of this relationship: social interactions in the neighbourhood and identity-related variables.

Keywords: walkability, quality of life, social relations, analysis of mediation

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Authors: Shih-Ping Liu, Cheng-Hsuan Chang, Yu-Chuen Huang, Shih-Yin Chen, Woei-Cherng Shyu

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Embryonic stem cells (ES) and induced pluripotnet stem cells (iPS) are both pluripotent stem cells. For mouse stem cells culture technology, leukemia inhibitory factor (LIF) was used to maintain the pluripotency of stem cells in vitro. However, LIF is an expensive reagent. The goal of this study was to find out a pure compound extracted from Chinese herbal medicine that could maintain stem cells pluripotency to replace LIF and improve the iPS generation efficiency. From 20 candidates traditional Chinese medicine we found that Cordycepsmilitaris triggered the up-regulation of stem cells activating genes (Oct4 and Sox2) expression levels in MEF cells. Cordycepin, a major active component of Cordycepsmilitaris, also could up-regulate Oct4 and Sox2 gene expression. Furthermore, we used ES and iPS cells and treated them with different concentrations of Cordycepin (replaced LIF in the culture medium) to test whether it was useful to maintain the pluripotency. The results showed higher expression levels of several stem cells markers in 10 μM Cordycepin-treated ES and iPS cells compared to controls that did not contain LIF, including alkaline phosphatase, SSEA1, and Nanog. Embryonic body formation and differentiation confirmed that 10 μM Cordycepin-containing medium was capable to maintain stem cells pluripotency after four times passages. For mechanism analysis, microarray analysis indicated extracellular matrix and Jak/Stat signaling pathway as the top two deregulated pathways. In ECM pathway, we determined that the integrin αVβ5 expression levels and phosphorylated Src levels increased after Cordycepin treatment. In addition, the phosphorylated Jak2 and phosphorylated Sat3 protein levels were increased after Cordycepin treatment and suppressed with the Jak2 inhibitor, AG490. The expression of cytokines associated with Jak2/Stat3 signaling pathway were also up-regulated by Q-PCR and ELISA assay. Lastly, we used Oct4-GFP MEF cells to test iPS generation efficiency following Cordycepin treatment. We observed that 10 Μm Cordycepin significantly increased the iPS generation efficiency in day 21. In conclusion, we demonstrated Cordycepin could maintain the pluripotency of stem cells through both of ECM and Jak2/Stat3 signaling pathway and improved iPS generation efficiency.

Keywords: cordycepin, iPS cells, Jak2/Stat3 signaling pathway, molecular biology

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Authors: Saima Saleem, Zubair Abbasi, Abdul Hameed, Mansoor Ahmed Khan, Navid Rashid Qureshi, Abid Azhar

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Oral Squamous Cell Carcinoma (OSCC) is the leading cause of death in the developing countries like Pakistan. This problem aggravates because of the excessive use of available chewing products. In spite of widespread information on their use and purported legislations against their use the Pakistani markets are classical examples of selling chewable carcinogenic mutagens. Reported studies indicated that these products are rich in reactive oxygen species (ROS) and polyphenols. TP53 gene is involved in the suppression of tumor. It has been reported that somatic mutations caused by TP53 gene are the foundation of the cancer. This study aims to find the loss of TP53 functions due to mutation/polymorphism caused by genomic alteration and interaction with tobacco and its related ingredients. Total 260 tissues and blood specimens were collected from OSCC patients and compared with age and sex matched controls. Mutations in exons 2-11 of TP53 were examined by PCR-SSCP. Samples showing mobility shift were directly sequenced. Two mutations were found in exon 4 at nucleotide position 108 and 215 and one in exon 7 at nucleotide position 719 of the coding sequences in patient’s tumor samples. These results show that substitution of proline with arginine at codon 72 and serine with threonine at codon 240 of p53 protein. These polymorphic changes, found in tumor samples of OSCC, could be involved in loss of heterozygocity and apoptotic activity in the binding domain of TP53. The model of the mutated TP53 gene elaborated a nonfunctional unfolded p53 protein, suggesting an important role of these mutations in p53 protein inactivation and malfunction. This nonfunctional 3D model also indicates that exogenous tobacco related carcinogens may act as DNA-damaging agents affecting the structure of DNA. The interpretations could be helpful in establishing the pathways responsible for tumor formation in OSCC patients.

Keywords: TP53 mutation/polymorphism, OSCC, PCR-SSCP, direct DNA sequencing, 3D structure

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Authors: Bui Phuong Linh, Yuki Sakakibara, Ryuto Tanaka, Elizabeth H. Pigney, Taishi Hashiguchi

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NASH is an increasingly prevalent chronic liver disease that can progress to hepatocellular carcinoma and now is attracting interest worldwide. The STAM™ model is a clinically-correlated murine NASH model which shows the same pathological progression as NASH patients and has been widely used for pharmacological and basic research. The multiple parallel hits hypothesis suggests abnormalities in adipocytokines, intestinal microflora, and endotoxins are intertwined and could contribute to the development of NASH. In fact, NASH patients often exhibit gut dysbiosis and dysfunction in adipose tissue and metabolism. However, the analysis of the STAM™ model has only focused on the liver. To clarify whether the STAM™ model can also mimic multiple pathways of NASH progression, we analyzed the organ crosstalk interactions between the liver and the gut and the phenotype of adipose tissue in the STAM™ model. NASH was induced in male mice by a single subcutaneous injection of 200 µg streptozotocin 2 days after birth and feeding with high-fat diet after 4 weeks of age. The mice were sacrificed at NASH stage. Colon samples were snap-frozen in liquid nitrogen and stored at -80˚C for tight junction-related protein analysis. Adipose tissue was prepared into paraffin blocks for HE staining. Blood adiponectin was analyzed to confirm changes in the adipocytokine profile. Tight junction-related proteins in the intestine showed that expression of ZO-1 decreased with the progression of the disease. Increased expression of endotoxin in the blood and decreased expression of Adiponectin were also observed. HE staining revealed hypertrophy of adipocytes. Decreased expression of ZO-1 in the intestine of STAM™ mice suggests the occurrence of leaky gut, and abnormalities in adipocytokine secretion were also observed. Together with the liver, phenotypes in these organs are highly similar to human NASH patients and might be involved in the pathogenesis of NASH.

Keywords: Non-alcoholic steatohepatitis, hepatocellular carcinoma, fibrosis, organ crosstalk, leaky gut

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Authors: Razieh Zarei, Hassan zm, Abolghasem Ajami, Darush Moslemi, Narges Afsary, Amrollah Mostafa-zade

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Introduction: IL-23 is responsible for the differentiation and expansion of Th17/ThIL-17 cells from naive CD4+ T cells. Therefore, may be IL-23/IL17 axis involve in a variety of allergic and autoimmune diseases, such as RA, MS, inflammatory bowel disease (IBD), and asthma. TGF-β is also share for the differentiation Th17 producing IL-17 and CD4+CD25+Foxp3hiT regulatory cells from naïve CD4+ T cells which are involved in the regulation of immune response, maintaining immunological self-tolerance and immune homeostasis ,and the control of autoimmunity and cancer surveillance. Therefore, T regulatory cells play a key role in autoimmunity, allergy, cancer, infectious disease, and the induction of transplantation tolerance. Vitamin A and it's derivatives (retinoids) inhibit or reverse the carcinogenic process in some types of cancers in oral cavity,head and neck, breast, skin, liver, and blood cells. Shark is a murine organism and its cartilage has antitumor peptides to prevent angiogenesis, in vitro. Our purpose is whether simultaneous oral treatment vitamin A and shark cartilage can modulate IL-23/IL-17 and CD4CD25Foxp3 T regulatory cell/TGF-β pathways and Th1/Th2 immunity in patients with gastric cancer. Materials and Methods: First investigated an imbalanced supernatant of cytokines exist in patients with gastric cancer by ELISA. Associated with cytokines measuring such as IL-23,IL-17,TGF-β,IL-4 and γ-IFN, then flow cytometry was employed to determine whether the peripheral blood mononuclear cells such as CD4+CD25+Foxp3highT regulatory cells in patients with gastric cancer were changed correspondingly. Results: An imbalance between IL-17 secretion and TGF-β/Foxp3 t regulatory cell pathway and so, Th1 immunity (γ-IFN production) and TH2 immunity (IL-4 secretion) was not seen in patients with gastric cancer treated by vitamin A and shark cartilage. But, the simultaneously presented down-regulation of IL-23 indicated, at least cytokine level. Conclusion: Il-23, as a pro-angiogenesis cytokine, probably, help to tumor growth. Hence, suggested that down-regulation of IL-23, at least cytokine level, is useful for anti-tumor immune responses in patients with gastric cancer.

Keywords: IL-23/IL17 axis, TGF-β/CD4CD25Foxp3 T regulatory pathway, γ-IFN, IL-4, shark cartilage and gastric cancer

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Authors: Phalla Miech, William Leung, Ty Chhay, Sina Vor, Arata Hidano

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Smallholder pig farms (SPFs) are prevalent in Cambodia but are vulnerable to disease impacts, as evidenced by the recent incursion of African swine fever into the region. As part of the ‘PigFluCam+’ project, we sought to provide an updated picture of pig husbandry and biosecurity practices among SPFs in south-central Cambodia. A multi-stage sampling design was adopted to select study districts and villages within four provinces: Phnom Penh, Kandal, Takeo, and Kampong Speu. Structured interviews were conductedbetween October 2020 - May 2021 among all consenting households keeping pigs in 16 target villages. Recruited SPFs (n=176) kept 6.8 pigs on average (s.d.=7.7), with most (88%) keeping cross-bred varieties of sows (77%), growers/finishers (39%), piglets/weaners (22%), and few keeping boars (5%). Chickens (83%) and waterfowl (56%) were commonly raised and could usually contact pigs directly (79%). Pigs were the primary source of household income for 28% of participants. While pigs tended to be housed individually (40%) or in groups (33%), 13% kept pigs free-ranging/tethered. Pigs were commonly fed agricultural by-products (80%), commercial feed (60%), and, notably, household waste (59%). Under half of SPFs vaccinated their pigs (e.g., against classical swine fever, Aujesky’s, and pasteurellosis, although the target disease was often unknown). Among 20 SPFs who experienced pig morbidities/mortalities within the past 6 months, only 3 (15%) reported to animal health workers, and disease etiology was rarely known. Common biosecurity measures included nets covering pig pens (62%) and restricting access to the site/pens (46%). Boot dips (0.6%) and PPE (1.2%) were rarely used. Pig smallholdings remain an important contributor to rural livelihoods. Current practices and biosecurity challenges increase risk pathways for a range of disease threats of both local and global concern. Ethnographic studies are needed to better understand local determinants and develop context-appropriate strategies.

Keywords: smallholder production, swine, biosecurity practices, Cambodia, African swine fever

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Authors: Meichen He, Xuan Yang

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Background: In the field of psychotherapy, the role of the family of origin is of utmost importance. Over the past few decades, both individual-oriented and family-oriented approaches to child therapy have shown moderate success in reducing children's psychological and behavioral issues. Objective: However, in exploring how the family of origin influences individuals, it has been noted that there is a lack of comprehensive measurement indicators and an absence of an exact model to assess the impact of the family of origin on individual development. Therefore, this study aims to develop a model based on a literature review regarding the influence of the family of origin on children. Specifically, it will examine the effects of factors such as education level, economic status, maternal age, family integration, family violence, marital conflict, parental substance abuse, and alcohol consumption on children's self-confidence and life satisfaction. Through this research, we aim to further investigate the impact of the family of origin on children and provide directions for future research in positive psychology and psychotherapy. Methods: This study will employ a literature review methodology to gather and analyze relevant research articles on the influence of the family of origin on children. Subsequently, we will conduct quantitative analyses to establish a comprehensive model explaining how family of origin factors affect children's psychological and behavioral outcomes. Findings: the research has revealed that family of origin factors, including education level, economic status, maternal age, family integration, family violence, marital conflict, parental drug and alcohol consumption, have an impact on children's self-confidence and life satisfaction. These factors can affect children's psychological well-being and happiness through various pathways. Implications: The results of this study will contribute to a better understanding of the influence of the family of origin on children and provide valuable directions for future research in positive psychology and psychotherapy. This research will enhance awareness of children's psychological well-being and lay the foundation for improving psychotherapeutic methods.

Keywords: family of origion, positive psychology, developmental psychology, family education, social psychology, educational psychology

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Authors: Christina Williams, Mehari Weldemariam, Ann M. Farese, Thomas J. MacVittie, Maureen A. Kane

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Radiation exposure results in dose-dependent and time-dependent multi-organ damage. Drug development of medical countermeasures (MCM) for radiation-induced injury occurs under the FDA Animal Rule because human efficacy studies are not ethical or feasible. The FDA Animal Rule requires the representation of both sexes and describes several uses for biomarkers in MCM drug development studies. Currently, MCMs are limited and there is no FDA-approved biomarker for any radiation injury. Sex as a variable is essential to identifying biomarkers and developing effective MCMs for acute radiation exposure (ARS) and delayed effects of acute radiation exposure (DEARE). These studies aim to address the death of information on sex differences that have not been determined by studies that included only male, single-sex cohorts. Studies have reported differences in radiosensitivity according to sex. As such, biomarker discovery for radiation-induced damage must consider sex as a variable. This study evaluated the plasma proteomic profile of Rhesus macaque non-human primates after different exposures and doses, as well as time points after radiation. Exposures and doses included total body irradiation between 5-7.5 Gy and partial body irradiation with 5% bone marrow sparing at 9, 9.5 and 10 Gy. Timepoints after irradiation included days 1, 3, 60, and 180, which encompassed both acute radiation syndromes and delayed effects of acute radiation exposure. Bottom-up proteomic analyses of plasma included equal numbers of males and females. In the control animals, few proteomic differences are observed between the sexes. In the irradiated animals, there are a few sex differences, with changes mostly consisting of proteins upregulated in the female animals. Multiple canonical pathways were upregulated in irradiated animals relative to the control animals when subjected to pathway analysis, but differential responses between the sexes are limited. These data provide critical baseline differences according to sex and establish sex differences in non-human primate models relevant to drug development of MCM under the FDA Animal Rule.

Keywords: ionizing radiation, sex differences, plasma proteomics, biomarker discovery

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