Search results for: excretion pathways

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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Authors: Liqin Zhi, Lin Xu, Wenxia Wei, Yaqi Cai

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Recently, replacing some of the methyl groups in polydimethylsiloxanes with other functional groups has been extensively explored to obtain modified polymethylsiloxanes with special properties that enable new industrial applications. Fluorinated polysiloxanes, one type of these modified polysiloxanes, are based on a siloxane backbone with fluorinated groups attached to the side chains of polysiloxanes. As a commercially significant material, poly[methyl(trifluoropropyl)siloxane] (PMTFPS) has sufficient fluorine content to be useful as a fuel-and oil-resistant elastomer, which combines both the chemical and solvent resistance of fluorocarbons and the wide temperature range applicability of organosilicones. PMTFPS products can be used in many applications in which resistance to fuel, oils and hydrocarbon solvents is required, including use as lubricants in bearings, sealants, and elastomers for aerospace and automotive fuel systems. Fluorinated methylsiloxanes, a type of modified methylsiloxane, include tris(trifluoropropyl)trimethylcyclotrisiloxane (D3F) and tetrakis(trifluoropropyl)tetramethylcyclotetrasiloxane (D4F), both of which contain trifluoropropyl groups in the side chains of cyclic methylsiloxanes. D3F, as an important monomer in the manufacture of PMTFPS, is often present as an impurity in PMTFPS. In addition, the synthesis of PMTFPS from D3F could form other fluorinated methylsiloxanes with low molecular weights (such as D4F). The yearly demand and production volumes of D3F increased rapidly all over world. Fluorinated methylsiloxanes might be released into the environment via different pathways during the production and application of PMTFPS. However, there is a lack of data concerning the emission, environmental occurrence and potential environmental impacts of fluorinated methylsiloxanes. Here, we report fluorinated methylsiloxanes (D3F and D4F) in surface water and sediment samples collected near a fluorinated methylsiloxane manufacturing plant in Weihai, China. The concentrations of D3F and D4F in surface water ranged from 3.29 to 291 ng/L and from 7.02 to 168 ng/L, respectively. The concentrations of D3F and D4F in sediment ranged from 11.8 to 5478 ng/g and from 17.2 to 6277 ng/g, respectively. In simulation experiment, the half-lives of D3F and D4F at different pH values (5.2, 6.4, 7.2, 8.3 and 9.2) varied from 80.6 to 154 h and from 267 to 533 h respectively. CF₃(CH₂)₂MeSi(OH)₂ was identified as one of the main hydrolysis products of fluorinated methylsiloxanes. It was also detected in the river samples at concentrations of 72.1-182.9 ng/L. In addition, the slow rearrangement of D3F (spiked concentration = 500 ng/L) to D4F (concentration = 11.0-22.7 ng/L) was also found during 336h hydrolysis experiment.

Keywords: fluorinated methylsiloxanes, environmental matrices, hydrolysis, sediment

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Authors: Jun Sun, Tsz Tin Yu, Maryam Mirabediny, Matthew Lee, Adele Jones, Denis M. O’Carroll, Michael J. Manefield, Björn Åkermark, Biswanath Das, Naresh Kumar

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Reductive defluorination has emerged as a sustainable approach to clean water from Per and polyfluoroalkyl substances (PFASs), also known as forever organic containments. For last few decades, nano zero valent metals (nZVMs) have been intensively applied in the reductive remediation of groundwater contaminated with chlorinated organic compounds due to its low redox potential, easy application, and low production cost. However, there is inadequate information on the effective reductive defluorination of linear or branched PFAS using nZVMs as reductants because of the lack of suitable catalysts. CoII-5,10,15,20-Tetraphenyl-21H,23H-porphyrin (CoTPP) has been recently reported for effective catalyzing reductive defluorination of branched (br-) perfluorooctane sulfonate (PFOS) by using TiIII citrate as reductant. However, the low water solubility of CoTPP limited its applicability. Here, we explored a series of structurally related soluble cobalt porphyrin catalysts based on our previously reported best performing CoTPP. All soluble porphyrins [[meso-tetra(4-carboxyphenyl)porphyrinato]cobalt(III)]Cl·₇H₂O (CoTCPP), [[meso-tetra(4-sulfonatophenyl) porphyrinato]cobalt(III)]·9H2O (CoTPPS), and [[meso-tetra(4-N-methylpyridyl) porphyrinato]cobalt(II)](I)₄·₄H₂O (CoTMpyP) displayed better defluorination efficiencies than CoTPP. Especially, CoTMpyP presented the best defluorination efficiency for br-PFOS (94 %), branched perfluorooctanoic acid (PFOA) (89 %), and 3,7-Perfluorodecanoic acid (PFDA) (60 %) after 1 day at 70 0C. CoTMpyP-nZn0 system showed 88-164 times higher defluorination rate than VB12-nZn0 system in terms of all investigated br-PFASs. The CoTMpyP-nZn0 also performed effectively at room temperature, demonstrating the potential prospect for in-situ reductive systems. Based on the analysis of the intermediate products, the calculated bond dissociation energies (BDEs) and possible first interaction between CoTMpyP and PFAS, degradation pathways of 3,7-PFDA and 6-PFOS are proposed.

Keywords: cationic, soluble porphyrin, cobalt, vitamin b12, pfas, reductive defluorination

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Authors: Larry O. Awo, George N. Duru

Abstract:

There is growing public and mental health concerns over the availability of gambling platforms and shops in Nigeria and the high level of youth involvement in gambling. Early theorizing maintained that gambling involvement driven by the quest for resource gains. However, evidences show that the economic model of gambling tend to explain the involvement of the gambling business owners (sport lottery operators: SLOs) as most gamblers lose more than they win. This loss, according to the law of effect, ought to discourage decisions to gamble. However, the quest to recover loses has often initiated and prolonged gambling sessions. Therefore, the need to investigate mental contemplations (such as counterfactual reasoning (upward versus downward) of what “would, should, or could” have been, and feeling of the illusion of control; IOC) over gambling outcome as risk or protective factors in gambling decisions became pertinent. The present study sought to understand the differential contributions and conditional effects of upward versus downward counterfactual reasoning as pathways through which the association between IOC and gambling decision of Nigerian youths (N = 120, mean age = 18.05, SD = 3.81) could be explained. The study adopted a randomized group design, and data were obtained by means of stimulus material (the Gambling Episode; GE) and self-report measures of IOC and Gambling Decision. One-way analysis of variance (ANOVA) result showed that participants in the upward counterfactual reasoning group (M = 22.08) differed from their colleagues in the downward counterfactual reasoning group (M = 17.33) on the decision to gamble, and this difference was significant [F(1,112) = 23, P < .01]. HAYES PROCESS macro moderation analysis results showed that 1) IOC and upward counterfactual reasoning were positively associated with the decision to gamble (B = 14.21, t = 6.10, p < .01 and B = 7.22, t = 2.07, p < .01), 3) upward counterfactual reasoning did not moderate the association between IOC and gambling decision (p > .05), and 4) downward counterfactual reasoning negatively moderated the association between IOC and gambling decision (B = 07, t = 2.18, p < .05) such that the association was strong at a low level of downward counterfactual, but wane at high levels of downward counterfactual reasoning. The implication of these findings are that IOC and upward counterfactual reasoning were risk factors and promote gambling behavior, while downward counterfactual reasoning protects individuals from gambling activities. Thus, it is concluded that downward counterfactual reasoning strategies should be included in gambling therapy and treatment packages as it could diminish feelings of both IOC and negative feelings of missed positive outcomes and the urge to gamble.

Keywords: counterfactual reasoning, gambling cognition, gambling decision, nigeria, youths

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Authors: Attila Kiss, Erzsébet Némedi, Zoltán Naár

Abstract:

Due to the rapidly growing number of conscious customers in the recent years, more and more people look for products with positive physiological effects which may contribute to the preservation of their health. In response to these demands Food Science Research Institute of Budapest develops and introduces into the market new functional foods of guaranteed positive effect that contain bioactive agents. New, efficient technologies are also elaborated in order to preserve the maximum biological effect of the produced foods. The main objective of our work was the development of new functional biscuits fortified with physiologically beneficial ingredients. Bakery products constitute the base of the food nutrients’ pyramid, thus they might be regarded as foodstuffs of the largest consumed quantity. In addition to the well-known and certified physiological benefits of lysine, as an essential amino acid, a series of antioxidant type compounds is formed as a consequence of the occurring Maillard-reaction. Progress of the evoked Maillard-reaction was studied by applying diverse sugars (glucose, fructose, saccharose, isosugar) and lysine at several temperatures (120-170°C). Interval of thermal treatment was also varied (10-30 min). The composition and production technologies were tailored in order to reach the maximum of the possible biological benefits, so as to the highest antioxidant capacity in the biscuits. Out of the examined sugar components, theextent of the Maillard-reaction-driven transformation of glucose was the most pronounced at both applied temperatures. For the precise assessment of the antioxidant activity of the products FRAP and DPPH methods were adapted and optimised. To acquire an authentic and extensive mechanism of the occurring transformations, Maillard-reaction products were identified, and relevant reaction pathways were revealed. GC-MS and HPLC-MS techniques were applied for the analysis of the 60 generated MRPs and characterisation of actual transformation processes. 3 plausible major transformation routes might have been suggested based on the analytical result and the deductive sequence of possible occurring conversions between lysine and the sugars.

Keywords: Maillard-reaction, lysine, antioxidant activity, GC-MS and HPLC-MS techniques

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Authors: Janneth Gonzalez, Andrés Pinzon Velasco, Maria Angarita

Abstract:

Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatorypathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, broad studies with a systemic point of view on the neurodegenerative role of PA and the neuro-protective mechanisms of tibolone are lacking. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also applied a control theory approach to identify those reactions that exert more control in the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a switch in energy source use through inhibition of folate cycle and fatty acid β‐oxidation and upregulation of ketone bodies formation. We found 25 metabolic switches under PA‐mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation of metabolic pathways that may increase neurotoxicity and represent potential treatment targets. Finally, the overall framework of our approach facilitates the understanding of complex metabolic regulation, and it can be used for in silico exploration of the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases.

Keywords: astrocytes, data integration, palmitic acid, computational model, multi-omics

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Authors: Salina Yahya Saddick

Abstract:

Ovarian cancer remains the most lethal gynecological malignancy due to the lack of highly sensitive and specific screening tools for detection of early-stage disease. The OSE provides the progenitor cells for 90% of human ovarian cancers. Recent morphologic, immunohistochemical and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer (EOC) based on a ualistic model of carcinogenesis that divides EOC into two broad categories designated Types I and II which are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN PIK3CA, ARID1A, and PPPR1A, which target specific cell signaling pathways. Type 1 tumors rarely harbor TP53. type I tumors are relatively genetically stable and typically display a variety of somatic sequence mutations that include KRAS, BRAF, PTEN, PIK3CA CTNNB1 (the gene encoding beta catenin), ARID1A and PPP2R1A but very rarely TP53 . The cancer stem cell (CSC) hypothesis postulates that the tumorigenic potential of CSCs is confined to a very small subset of tumor cells and is defined by their ability to self-renew and differentiate leading to the formation of a tumor mass. Potential protein biomarker miRNA, are promising biomarkers as they are remarkably stable to allow isolation and analysis from tissues and from blood in which they can be found as free circulating nucleic acids and in mononuclear cells. Recently, genomic anaylsis have identified biomarkers and potential therapeutic targets for ovarian cancer namely, FGF18 which plays an active role in controlling migration, invasion, and tumorigenicity of ovarian cancer cells through NF-κB activation, which increased the production of oncogenic cytokines and chemokines. This review summarizes update information on epithelial ovarian cancers and point out to the most recent ongoing research.

Keywords: epithelial ovarian cancers, somatic sequence mutations, cancer stem cell (CSC), potential protein, biomarker, genomic analysis, FGF18 biomarker

Procedia PDF Downloads 380

Authors: Ghebremedhin Tsegay, Weldu Tesfagaber, Yuanmao Zhu, Xijun He, Wan Wang, Zhenjiang Zhang, Encheng Sun, Jinya Zhang, Yuntao Guan, Fang Li, Renqiang Liu, Zhigao Bu, Dongming Zhao*

Abstract:

African swine fever (ASF) is a highly infectious viral disease of pigs, resulting in significant economic loss worldwide. As there is no approved vaccines and treatments, the control of ASF entirely depends on early diagnosis and culling of infected pigs. Thus, highly specific and sensitive diagnostic assays are required for accurate and early diagnosis of ASF virus (ASFV). Currently, only a few recombinant proteins have been tested and validated for use as reagents in ASF diagnostic assays. The most promising ones for ASFV antibody detection were p72, p30, p54, and pp62. So far, three ELISA kits based on these recombinant proteins have been commercialized. Due to the complex nature of the virus and variety forms of the disease, robust serodiagnostic assays are still required. ASFV p22 protein, encoded by KP177R gene, is located in the inner membrane of viral particle and appeared transiently in the plasma membrane early after virus infection. The p22 protein interacts with numerous cellular proteins, involved in processes of phagocytosis and endocytosis through different cellular pathways. However, p22 does not seem to be involved in virus replication or swine pathogenicity. In this study, E.coli expressed recombinant p22 protein was used to generate a monoclonal antibody (mAb), and its potential use for the development of blocking ELISA (bELISA) was evaluated. A total of 806 pig serum samples were tested to evaluate the bELISA. Acording the ROC (Reciever operating chracteristic) analysis, 100% sensitivity and 98.10% of specificity was recorded when the PI cut-off value was set at 47%. The novel assay was able to detect the antibodies as early as 9 days post infection. Finaly, a highly sensitive, specific and rapid novel p22-mAb based bELISA assay was developed, and optimized for detection of antibodies against genotype I and II ASFVs. It is a promising candidate for an early and acurate detection of the antibodies and is highly expected to have a valuable role in the containment and prevention of ASF.

Keywords: ASFV, blocking ELISA, diagnosis, monoclonal antibodies, sensitivity, specificity

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Authors: Jean Paul M. Milambo

Abstract:

Purpose: Aromatase inhibitors (AIs) are indicated in the treatment of hormone-receptive breast cancer in postmenopausal women in various settings. Studies have shown cardiovascular events in some developed countries. To date the data is sparce for evidence-based recommendations in African clinical settings due to lack of cancer registries, capacity building and surveillance systems. Therefore, this study was conducted to assess the feasibility of HyBeacon® probe genotyping adjunctive to standard care for timely prediction and diagnosis of Aromatase inhibitors (AIs) associated adverse events in breast cancer survivors in Africa. Methods: Cross sectional study was conducted to assess the knowledge of POCT among six African countries using online survey and telephonically contacted. Incremental cost effectiveness ratio (ICER) was calculated, using diagnostic accuracy study. This was based on mathematical modeling. Results: One hundred twenty-six participants were considered for analysis (mean age = 61 years; SD = 7.11 years; 95%CI: 60-62 years). Comparison of genotyping from HyBeacon® probe technology to Sanger sequencing showed that sensitivity was reported at 99% (95% CI: 94.55% to 99.97%), specificity at 89.44% (95% CI: 87.25 to 91.38%), PPV at 51% (95%: 43.77 to 58.26%), and NPV at 99.88% (95% CI: 99.31 to 100.00%). Based on the mathematical model, the assumptions revealed that ICER was R7 044.55. Conclusion: POCT using HyBeacon® probe genotyping for AI-associated adverse events maybe cost effective in many African clinical settings. Integration of preventive measures for early detection and prevention guided by different subtype of breast cancer diagnosis with specific clinical, biomedical and genetic screenings may improve cancer survivorship. Feasibility of POCT was demonstrated but the implementation could be achieved by improving the integration of POCT within primary health cares, referral cancer hospitals with capacity building activities at different level of health systems. This finding is pertinent for a future envisioned implementation and global scale-up of POCT-based initiative as part of risk communication strategies with clear management pathways.

Keywords: breast cancer, diagnosis, point of care, South Africa, aromatase inhibitors

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Authors: Koryukaeva Ksenia, Jinfeng Sun

Abstract:

Europe has been a traditional importer of Russian natural gas for more than 50 years. In 2021, Russian state-owned company Gazprom supplied about a third of all gas consumed in Europe. The Russia-Europe mutual dependence in terms of natural gas supplies has been causing many concerns about the energy security of the two sides for a long period of time. These days the issue has become more urgent than ever considering recent Russian invasion in Ukraine followed by increased large-scale geopolitical conflicts, making the future of Russian natural gas supplies and global gas markets as well highly uncertain. Hence, the main purpose of this study is to get insight into the possible futures of Russian pipeline natural gas exports by a scenario planning method based on Monte-Carlo simulation within LUSS model framework, and propose Russian pipeline natural gas export strategies based on the obtained scenario planning results. The scenario analysis revealed that recent geopolitical disputes disturbed the traditional, longstanding model of Russian pipeline gas exports, and, as a result, the prospects and the pathways for Russian pipeline gas on the world markets will differ significantly from those before 2022. Specifically, our main findings show, that (i) the events of 2022 generated many uncertainties for the long-term future of Russian pipeline gas export perspectives on both western and eastern supply directions, including geopolitical, regulatory, economic, infrastructure and other uncertainties; (ii) according to scenario modelling results, Russian pipeline exports will face many challenges in the future, both on western and eastern directions. A decrease in pipeline gas exports will inevitably affect country’s natural gas production and significantly reduce fossil fuel export revenues, jeopardizing the energy security of the country; (iii) according to proposed strategies, in order to ensure the long-term stable export supplies in the changing environment, Russia may need to adjust its traditional export strategy by performing export flows and product diversification, entering new markets, adapting its contracting mechanism, increasing competitiveness and gaining a reputation of a reliable gas supplier.

Keywords: Russian natural gas, Pipeline natural gas, Uncertainty, Scenario simulation, Export strategy

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Authors: Ábrám Zoltán

Abstract:

Introduction: Climate change is now a major health risk, and its environmental and health effects have become frequently discussed topics. The consequences of climate change are clearly visible in natural disasters and excess deaths caused by extreme weather conditions. Global warming and the increasingly frequent extreme weather events have direct, immediate effects or long-term, indirect effects on health. For this reason, it is a need to teach the health effects of climate change in medical schools. Material and methods: We looked for various surveys, studies, and reports on the main pathways through which global warming affects health. Medical schools face the challenge of teaching the health implications of climate change and integrating knowledge about the health effects of climate change into medical training. For this purpose, there were organised World Café workshops for three target groups: medical students, academic staff, and practising medical doctors. Results: Among the goals of the research is the development of a detailed curriculum for medical students, which serves to expand their knowledge in basic education. At the same time, the project promotes the increase of teacher motivation and the development of methodological guidelines for university teachers; it also provides further training for practicing doctors. The planned teaching materials will be developed in a format suitable for traditional face-to-face teaching, as well as e-learning teaching materials. CLIMATEMED is a project based on the cooperation of six universities and institutions from four countries, the aim of which is to improve the curriculum and expand knowledge about the health effects of climate change at medical universities. Conclusions: In order to assess the needs, summarize the proposals, to develop the necessary strategy, World Café type, one-and-a-half to two-hour round table discussions will take place separately for medical students, academic staff, and practicing doctors. The CLIMATEMED project can facilitate the integration of knowledge about the health effects of climate change into curricula and can promote practical use. The avoidance of the unwanted effects of global warming and climate change is not only a public matter, but it is also a challenge to change our own lifestyle. It is the responsibility of all of us to protect the Earth's ecosystem and the physical and mental health of ourselves and future generations.

Keywords: climate change, health effects, medical schools, World Café, medical students

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Authors: Sami Khan, Kripa Varanasi

Abstract:

Corrosion is a widespread problem in several industries and developing surfaces that resist corrosion has been an area of interest since the last several decades. Superhydrophobic surfaces that combine hydrophobic coatings along with surface texture have been shown to improve corrosion resistance by creating voids filled with air that minimize the contact area between the corrosive liquid and the solid surface. However, these air voids can incorporate corrosive liquids over time, and any mechanical faults such as cracks can compromise the coating and provide pathways for corrosion. As such, there is a need for self-healing corrosion-resistance surfaces. In this work, the anti-corrosion properties of textured surfaces impregnated with a lubricant have been systematically studied. Since corrosion resistance depends on the area and physico-chemical properties of the material exposed to the corrosive medium, lubricant-impregnated surfaces (LIS) have been designed based on the surface tension, viscosity and chemistry of the lubricant and its spreading coefficient on the solid. All corrosion experiments were performed in a standard three-electrode cell using iron, which readily corrodes in a 3.5% sodium chloride solution. In order to obtain textured iron surfaces, thin films (~500 nm) of iron were sputter-coated on silicon wafers textured using photolithography, and subsequently impregnated with lubricants. Results show that the corrosion rate on LIS is greatly reduced, and offers an over hundred-fold improvement in corrosion protection. Furthermore, it is found that the spreading characteristics of the lubricant are significant in ensuring corrosion protection: a spreading lubricant (e.g., Krytox 1506) that covers both inside the texture, as well as the top of the texture, provides a two-fold improvement in corrosion protection as compared to a non-spreading lubricant (e.g., Silicone oil) that does not cover texture tops. To enhance corrosion protection of surfaces coated with a non-spreading lubricant, pyramid-shaped textures have been developed that minimize exposure to the corrosive solution, and a consequent twenty-fold increased in corrosion protection is observed. An increase in viscosity of the lubricant scales with greater corrosion protection. Finally, an equivalent cell-circuit model is developed for the lubricant-impregnated systems using electrochemical impedance spectroscopy. Lubricant-impregnated surfaces find attractive applications in harsh corrosive environments, especially where the ability to self-heal is advantageous.

Keywords: lubricant-impregnated surfaces, self-healing surfaces, wettability, nano-engineered surfaces

Procedia PDF Downloads 136

Authors: Shveta Bathla, Preeti Rawat, Sudarshan Kumar, Rubina Baithalu, Jogender Singh Rana, Tushar Kumar Mohanty, Ashok Kumar Mohanty

Abstract:

Pregnancy is a complex process which includes series of events such as fertilization, formation of blastocyst, implantation of embryo, placental formation and development of fetus. The success of these events depends on various interactions which are synchronized by endocrine interaction between a receptive dam and competent embryo. These interactions lead to change in expression of hormones and proteins. But till date no protein biomarker is available which can be used to detect successful completion of these events. We employed quantitative proteomics approach to develop putative serological biomarker which has diagnostic applicability for early detection of pregnancy in cows. For this study, sera were collected from control (non-pregnant, n=6) and pregnant animals on successive days of pregnancy (7, 19, 45, n=6). The sera were subjected to depletion for removal of albumin using Norgen depletion kit. The tryptic peptides were labeled with iTRAQ. The peptides were pooled and fractionated using bRPLC over 80 min gradient. Then 12 fractions were injected to nLC for identification and quantitation in DDA mode using ESI. Identification using Mascot search revealed 2056 proteins out of which 352 proteins were differentially expressed. Twenty proteins were upregulated and twelve proteins were down-regulated with fold change > 1.5 and < 0.6 respectively (p < 0.05). The gene ontology studies of DEPs using Panther software revealed that majority of proteins are actively involved in catalytic activities, binding and enzyme regulatory activities. The DEP'S such as NF2, MAPK, GRIPI, UGT1A1, PARP, CD68 were further subjected to pathway analysis using KEGG and Cytoscape plugin Cluego that showed involvement of proteins in successful implantation, maintenance of pluripotency, regulation of luteal function, differentiation of endometrial macrophages, protection from oxidative stress and developmental pathways such as Hippo. Further efforts are continuing for targeted proteomics, western blot to validate potential biomarkers and development of diagnostic kit for early pregnancy diagnosis in cows.

Keywords: bRPLC, Cluego, ESI, iTRAQ, KEGG, Panther

Procedia PDF Downloads 462

Authors: Ozlem Oral, Emre Taskin, Aysel Yuce, Serap Dokmeci, Devrim Gozuacik

Abstract:

Autophagy is an evolutionary conserved lysosome-dependent catabolic pathway, responsible for the degradation of long-lived proteins, abnormal aggregates and damaged organelles which cannot be degraded by the ubiquitin-proteasome system. Lysosomes degrade the substrates through the activity of lysosomal hydrolases and lysosomal membrane-bound proteins. Mutations in the coding region of these proteins cause malfunctional lysosomes, which contributes to the pathogenesis of lysosomal storage diseases. Gaucher disease is a lysosomal storage disease resulting from the mutation of a lysosomal membrane-associated glycoprotein called glucocerebrosidase and its cofactor saposin C. The disease leads to intracellular accumulation of glucosylceramide and other glycolipids. Because of the essential role of lysosomes in autophagic degradation, Gaucher disease may directly be linked to this pathway. In this study, we investigated the expression of autophagy and/or lysosome-related genes and proteins in fibroblast cells isolated from patients with different mutations. We carried out confocal microscopy analysis and examined autophagic flux by utilizing the differential pH sensitivities of RFP and GFP in mRFP-GFP-LC3 probe. We also evaluated lysosomal pH by active lysosome staining and lysosomal enzyme activity. Beside lysosomes, we also performed proteasomal activity and cell death analysis in patient samples. Our data showed significant attenuation in the expression of key autophagy-related genes and accumulation of their proteins in mutant cells. We found decreased the ability of autophagosomes to fuse with lysosomes, associated with elevated lysosomal pH and reduced lysosomal enzyme activity. Proteasomal degradation and cell death analysis showed reduced proteolytic activity of the proteasome, which consequently leads to increased susceptibility to cell death. Our data indicate that the major degradation pathways are affected by multifunctional lysosomes in mutant patient cells and may underlie in the mechanism of clinical severity of Gaucher patients. (This project is supported by TUBITAK-3501-National Young Researchers Career Development Program, Project No: 112T130).

Keywords: autophagy, Gaucher's disease, glucocerebrosidase, mutant fibroblasts

Procedia PDF Downloads 325

Authors: Larry O. Awo, George N. Duru

Abstract:

There are growing public and mental health concerns over the availability of gambling platforms and shops in Nigeria and the high level of youth involvement in gambling. Early theorizing maintained that gambling involvement was driven by a quest for resource gains. However, evidence shows that the economic model of gambling tends to explain the involvement of the gambling business owners (sport lottery operators: SLOs) as most gamblers lose more than they win. This loss, according to the law of effect, ought to discourage decisions to gamble. However, the quest to recover losses has often initiated prolonged gambling sessions. Therefore, the need to investigate mental contemplations (such as counterfactual reasoning (upward versus downward) of what “would, should, or could” have been, and feeling of the illusion of control; IOC) over gambling outcomes as risk or protective factors in gambling decisions became pertinent. The present study sought to understand the differential contributions and conditional effects of upward versus downward counterfactual reasoning as pathways through which the association between IOC and gambling decisions of Nigerian youths (N = 120, mean age = 18.05, SD = 3.81) could be explained. The study adopted a randomized group design, and data were obtained by means of stimulus material (the Gambling Episode; GE) and self-report measures of IOC and Gambling Decision. One-way analysis of variance (ANOVA) result showed that participants in the upward counterfactual reasoning group (M = 22.08) differed from their colleagues in the downward counterfactual reasoning group (M = 17.33) on the decision to gamble, and this difference was significant [F(1,112) = 23, P < .01]. HAYES PROCESS macro moderation analysis results showed that 1) IOC and upward counterfactual reasoning were positively associated with the decision to gamble (B = 14.21, t = 6.10, p < .01 and B = 7.22, t = 2.07, p <.05, respectively), 2) downward counterfactual reasoning was negatively associated with the decision to gamble more to recover losses (B = 10.03, t = 3.21, p < .01), 3) upward counterfactual reasoning did not moderate the association between IOC and gambling decision (p > .05), and 4) downward counterfactual reasoning negatively moderated the association between IOC and gambling decision (B = 07, t = 2.18, p < .05) such that the association was strong at the low level of downward counterfactual, but wane at high levels of downward counterfactual reasoning. The implication of these findings is that IOC and upward counterfactual reasoning were risk factors and promoted gambling behavior, while downward counterfactual reasoning protects individuals from gambling activities. Thus, it is concluded that downward counterfactual reasoning strategies should be included in gambling therapy and treatment packages as it could diminish feelings of both IOC and negative feelings of missed positive outcomes and the urge to gamble.

Keywords: counterfactual reasoning, gambling cognition, gambling decision, Nigeria, youths

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Authors: Yelin Zhao, Xinxiu Li, Martin Smelik, Oleg Sysoev, Firoj Mahmud, Dina Mansour Aly, Mikael Benson

Abstract:

Background: Early diagnosis of pancreatic cancer is clinically challenging due to vague, or no symptoms, and lack of biomarkers. Polygenic risk score (PRS) scores may provide a valuable tool to assess increased or decreased risk of PC. This study aimed to develop such PRS by filtering genetic variants identified by GWAS using transcriptional programs identified by single-cell RNA sequencing (scRNA-seq). Methods: ScRNA-seq data from 24 pancreatic ductal adenocarcinoma (PDAC) tumor samples and 11 normal pancreases were analyzed to identify differentially expressed genes (DEGs) in in tumor and microenvironment cell types compared to healthy tissues. Pathway analysis showed that the DEGs were enriched for hundreds of significant pathways. These were clustered into 40 “programs” based on gene similarity, using the Jaccard index. Published genetic variants associated with PDAC were mapped to each program to generate program PRSs (pPRSs). These pPRSs, along with five previously published PRSs (PGS000083, PGS000725, PGS000663, PGS000159, and PGS002264), were evaluated in a European-origin population from the UK Biobank, consisting of 1,310 PDAC participants and 407,473 non-pancreatic cancer participants. Stepwise Cox regression analysis was performed to determine associations between pPRSs with the development of PC, with adjustments of sex and principal components of genetic ancestry. Results: The PDAC genetic variants were mapped to 23 programs and were used to generate pPRSs for these programs. Four distinct pPRSs (P1, P6, P11, and P16) and two published PRSs (PGS000663 and PGS002264) were significantly associated with an increased risk of developing PC. Among these, P6 exhibited the greatest hazard ratio (adjusted HR[95% CI] = 1.67[1.14-2.45], p = 0.008). In contrast, P10 and P4 were associated with lower risk of developing PC (adjusted HR[95% CI] = 0.58[0.42-0.81], p = 0.001, and adjusted HR[95% CI] = 0.75[0.59-0.96], p = 0.019). By comparison, two of the five published PRS exhibited an association with PDAC onset with HR (PGS000663: adjusted HR[95% CI] = 1.24[1.14-1.35], p < 0.001 and PGS002264: adjusted HR[95% CI] = 1.14[1.07-1.22], p < 0.001). Conclusion: Compared to published PRSs, scRNA-seq-based pPRSs may be used not only to assess increased but also decreased risk of PDAC.

Keywords: cox regression, pancreatic cancer, polygenic risk score, scRNA-seq, UK biobank

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Authors: Ayesha Waqar Khan, Mariam Altaf, Jamil Ahmad, Shaheen Shahzad

Abstract:

Kidney fibrosis is an anticipated outcome of possibly all types of progressive chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) signaling pathway is responsible for production of matrix-producing fibroblasts and myofibroblasts in diseased kidney. In this study, a discrete model of TGF-beta (transforming growth factor) and CTGF (connective tissue growth factor) was constructed using Rene Thomas formalism to investigate renal fibrosis turn over. The kinetic logic proposed by Rene Thomas is a renowned approach for modeling of Biological Regulatory Networks (BRNs). This modeling approach uses a set of constraints which represents the dynamics of the BRN thus analyzing the pathway and predicting critical trajectories that lead to a normal or diseased state. The molecular connection between TGF-beta, Smad 2/3 (transcription factor) phosphorylation and CTGF is modeled using GenoTech. The order of BRN is CTGF, TGF-B, and SMAD3 respectively. The predicted cycle depicts activation of TGF-B (TGF-β) via cleavage of its own pro-domain (0,1,0) and presentation to TGFR-II receptor phosphorylating SMAD3 (Smad2/3) in the state (0,1,1). Later TGF-B is turned off (0,0,1) thereby activating SMAD3 that further stimulates the expression of CTGF in the state (1,0,1) and itself turns off in (1,0,0). Elevated CTGF expression reactivates TGF-B (1,1,0) and the cycle continues. The predicted model has generated one cycle and two steady states. Cyclic behavior in this study represents the diseased state in which all three proteins contribute to renal fibrosis. The proposed model is in accordance with the experimental findings of the existing diseased state. Extended cycle results in enhanced CTGF expression through Smad2/3 and Smad4 translocation in the nucleus. The results suggest that the system converges towards organ fibrogenesis if CTGF remains constructively active along with Smad2/3 and Smad 4 that plays an important role in kidney fibrosis. Therefore, modeling regulatory pathways of kidney fibrosis will escort to the progress of therapeutic tools and real-world useful applications such as predictive and preventive medicine.

Keywords: CTGF, renal fibrosis signaling pathway, system biology, qualitative modeling

Procedia PDF Downloads 180

Authors: Evangelia-Chrysanthi Kouklari, Evdokia Tagkouli, Vassiliki Ntre, Artemios Pehlivanidis, Stella Tsermentseli, Gerasimos Kolaitis, Katerina Papanikolaou

Abstract:

Executive Function (EF) is a set of goal-directed cognitive skills essentially needed in problem-solving and social behavior. Developmental EF research has indicated that EF emerges early in life and marks dramatic changes before the age of 5. Research evidence has suggested that it may continue to develop up to adolescence as well, following the development of the prefrontal cortex. Over the last decade, research evidence has suggested distinguished domains of cool and hot EF, but traditionally the development of EF in Autism Spectrum Disorder (ASD) has been examined mainly with tasks that address the “cool” cognitive aspects of EF. Thus, very little is known about the development of “hot” affective EF processes and whether the cross-sectional developmental pathways of cool and hot EF present similarities in ASD. Cool EF has also been proven to have a strong correlation with Theory of Mind (ToM) in young and middle childhood in typical development and in ASD, but information about the relationship of hot EF to ToM skills is minimal. The present study’s objective was to explore the age-related changes of cool and hot EF in ASD participants from middle childhood to adolescence, as well as their relationship to ToM. This study employed an approach of cross-sectional developmental trajectories to investigate patterns of cool and hot EF relative to chronological age within ASD. Eighty-two participants between 7 and 16 years of age were recruited to undertake measures that assessed cool EF (working memory, cognitive flexibility, planning & inhibition), hot EF (affective decision making & delay discounting) and ToM (false belief and mental state/emotion recognition). Results demonstrated that trajectories of all cool EF presented age-related changes in ASD (improvements with age). With regards to hot EF, affective decision-making presented age-related changes, but for delay discounting, there were no statistically significant changes found across younger and older ASD participants. ToM was correlated only to cool EF. Theoretical implications are discussed as the investigation of the cross-sectional developmental trajectories of the broader EF (cool and hot domains) may contribute to better defining cognitive phenotypes in ASD. These findings highlight the need to examine developmental trajectories of both hot and cool EF in research and clinical practice as they may aid in enhancing diagnosis or better-informed intervention programs.

Keywords: autism spectrum disorder, developmental trajectories, executive function, theory of mind

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