Search results for: gene regulation

Authors: Sridhar A. Malkaram, Tamer E. Fandy

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Purpose: 5-Azacytidine (5AC) and decitabine (DC) are DNA hypomethylating agents. We recently demonstrated that both drugs increase the enzymatic activity of the histone deacetylase enzyme SIRT6. Accordingly, we are comparing the changes H3K9 acetylation changes in the whole genome induced by both drugs using leukemia cells. Description of Methods & Materials: Mononuclear cells from the bone marrow of six de-identified naive acute myeloid leukemia (AML) patients were cultured with either 500 nM of DC or 5AC for 72 h followed by ChIP-Seq analysis using a ChIP-validated acetylated-H3K9 (H3K9ac) antibody. Chip-Seq libraries were prepared from treated and untreated cells using SMARTer ThruPLEX DNA- seq kit (Takara Bio, USA) according to the manufacturer’s instructions. Libraries were purified and size-selected with AMPure XP beads at 1:1 (v/v) ratio. All libraries were pooled prior to sequencing on an Illumina HiSeq 1500. The dual-indexed single-read Rapid Run was performed with 1x120 cycles at 5 pM final concentration of the library pool. Sequence reads with average Phred quality < 20, with length < 35bp, PCR duplicates, and those aligning to blacklisted regions of the genome were filtered out using Trim Galore v0.4.4 and cutadapt v1.18. Reads were aligned to the reference human genome (hg38) using Bowtie v2.3.4.1 in end-to-end alignment mode. H3K9ac enriched (peak) regions were identified using diffReps v1.55.4 software using input samples for background correction. The statistical significance of differential peak counts was assessed using a negative binomial test using all individuals as replicates. Data & Results: The data from the six patients showed significant (Padj<0.05) acetylation changes at 925 loci after 5AC treatment versus 182 loci after DC treatment. Both drugs induced H3K9 acetylation changes at different chromosomal regions, including promoters, coding exons, introns, and distal intergenic regions. Ten common genes showed H3K9 acetylation changes by both drugs. Approximately 84% of the genes showed an H3K9 acetylation decrease by 5AC versus 54% only by DC. Figures 1 and 2 show the heatmaps for the top 100 genes and the 99 genes showing H3K9 acetylation decrease after 5AC treatment and DC treatment, respectively. Conclusion: Despite the similarity in hypomethylating activity and chemical structure, the effect of both drugs on H3K9 acetylation change was significantly different. More changes in H3K9 acetylation were observed after 5 AC treatments compared to DC. The impact of these changes on gene expression and the clinical efficacy of these drugs requires further investigation.

Keywords: DNA methylation, leukemia, decitabine, 5-Azacytidine, epigenetics

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Authors: W. Mohammedsaeed, A. J. Mcbain, S. M. Cruickshank, C. A. O’Neill

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Many studies have demonstrated the importance of probiotics and their potential therapeutic effects within the gut. Recently, the possible therapeutic effects of probiotics in other tissues have also begun to be investigated. Comparatively few studies have evaluated the use of topical probiotics in relation to the skin. In this study, we have conducted preliminary investigations into whether a well-known probiotic, Lactobacillus rhamnosus GG (LGG), can increase the rate of re-epithelialization in a model wound. Full-thickness skin was obtained from individuals undergoing elective cosmetic surgery. This skin was wounded using excisional punch and cultured using a serum-free medium, either in the presence or absence of L. rhamnosus GG lysate. Histological staining of the sections was performed with Haematoxylin& Eosin E to quantify “epithelial tongue length”. This is the length of the new epithelial ‘tongue’ that grows and covers the exposed dermis at the inner wound edges. The length of the new epithelial ‘tongue’ was compared in untreated section and section treated with and L. rhamnosus GG made using108CFU/ml bacterial cells. L. rhamnosus GG lysate enhanced significantly the re-epithelialisation of treated wounds compared with that of untreated wounds (P=0.005, n=3). Tongue length, at day 1 was 7.55μm 0.15, at day 3 it was 18.5μm 0.25 and at day 7 was 22.9μm 0.35. These results can be compared with untreated cultures in which tongue length was 3.25μm 0.35, day 3 was 9.65μm 0.25 and day 7 was 13.5μm 0.15 post-wounding. In ex-vivo proliferation and migration cells were measured by determining the expression of nuclear proliferation marker Ki-67 and the expression of Phosphorylated cortactin respectively demonstrated that L. rhamnosus GG significantly increased NHEK proliferation and migration rates relative to controls. However, the dominant mechanism was migration because in ex-vivo skin treated with the L. rhamnosus GG up-regulated the gene expression of the chemokine receptor and ligands CXCR2 and CXCL2 comparing with controls (P=0.02, P=0.03 respectively, n=3). High levels of CXCL2/CXCL2 have already been implicated in multiple aspects of stimulation of wound healing through activation of keratinocyte migration. These data demonstrate that lysates from Lactobacillus rhamnosus GG increase re-epithelialization by stimulation of keratinocyte migration. The current study identifies the partial mechanism that contribute to stimulating the wound-healing process ex vivo in response to L. rhamnosus GG lysate is an increase in the production of CXCL2/ CXCR2 in ex vivo models. The use of probiotic lysates potentially offers new options to develop treatments that could improve wound healing.

Keywords: Lactobacillus rhamnosus GG, wounds, migration, lysate

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Authors: Dalal Alghawas, Jetty Lee, Kaisa Poutanen, Hani El-Nezami

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Oat β-glucan a water soluble non starch linear polysaccharide has been approved as a cholesterol lowering agent by various food safety administrations and is commonly used to reduce the risk of heart disease. The molecular weight of oat β-glucan can vary depending on the extraction and fractionation methods. It is not clear whether the molecular weight has a significant impact at reducing the acceleration of atherosclerosis. The aim of this study was to investigate three different oat β-glucan fractionations on the development of atherosclerosis in vivo. With special focus on plaque stability and the intestinal barrier function. To test this, ApoE-/- female mice were fed a high fat diet supplemented with oat bran, high molecular weight (HMW) oat β-glucan fractionate and low molecular weight (LMW) oat β-glucan fractionate for 16 weeks. Atherosclerosis risk markers were measured in the plasma, heart and aortic tree. Plaque size was measured in the aortic root and aortic tree. ICAM-1, VCAM-1, E-Selectin, P-Selectin, protein levels were assessed from the aortic tree to determine plaque stability at 16 weeks. The expression of p22phox at the aortic root was evaluated to study the NADPH oxidase complex involved in nitric oxide bioavailability and vascular elasticity. The tight junction proteins E-cadherin and beta-catenin from western blot analyses were analysed as an intestinal barrier function test. Plasma LPS, intestinal D-lactate levels and hepatic FMO gene expression were carried out to confirm whether the compromised intestinal barrier lead to endotoxemia. The oat bran and HMW oat β-glucan diet groups were more effective than the LMW β-glucan diet group at reducing the plaque size and showed marked improvements in plaque stability. The intestinal barrier was compromised for all the experimental groups however the endotoxemia levels were higher in the LMW β-glucan diet group. The oat bran and HMW oat β-glucan diet groups were more effective at attenuating the development of atherosclerosis. Reasons for this could be due to the LMW oat β-glucan diet group’s low viscosity in the gut and the inability to block the reabsorption of cholesterol. Furthermore the low viscosity may allow more bacterial endotoxin translocation through the impaired intestinal barrier. In future food technologists should carefully consider how to incorporate LMW oat β-glucan as a health promoting food.

Keywords: Atherosclerosis, beta glucan, endotoxemia, intestinal barrier function

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Authors: Sung-Hee Nam, Kwang-Gill Lee, You-Young Jo, HaeYong Kweon

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Entomopathogenic fungi is a Cordyceps species that is isolated from dead silkworm and cicada. Fungi on cicadas were described in old Chinese medicinal books and From ancient times, vegetable wasps and plant worms were widely known to have active substance and have been studied for pharmacological use. Among many fungi belonging to the genus Cordyceps, Cordyceps sinensis have been demonstrated to yield natural products possessing various biological activities and many bioactive components. Generally, It is commonly used to replenish the kidney and soothe the lung, and for the treatment of fatigue. Due to their commercial and economic importance, the demand for Cordyceps has been rapidly increased. However, a supply of Cordyceps specimen could not meet the increasing demand because of their sole dependence on field collection and habitat destruction. Because it is difficult to obtain many insect hosts in nature and the edibility of host insect needs to be verified in a pharmacological aspect. Recently, this setback was overcome that P. tenuipes was able to be cultivated in a large scale using silkworm as host. Pharmacological effects of P. tenuipes cultured on silkworm such as strengthening immune function, anti-fatigue, anti-tumor activity and controlling liver etc have been proved. They are widely commercialized. In this study, we attempted to establish a method for stable growth inhibition of P. tenuipes on silkworm hosts and an optimal condition for synnemata formation. To determine optimum culturing conditions, temperature and light conditions were varied. The length and number of synnemata was highest at 25℃ temperature and 100~300 lux illumination. On an average, the synnemata of wild P. tenuipes measures 70 ㎜ in length and 20 in number; those of the cultured strain were relatively shorter and more in number. The number of synnemata may have increased as a result of inoculating the host with highly concentrated conidia, while the length may have decreased due to limited nutrition per individual. It is not able that changes in light illumination cause morphological variations in the synnemata. However, regulation of only light and temperature could not produce stromata like perithecia, asci, and ascospores. Yamanaka reported that although a complete fruiting body can be produced under optimal culture conditions, it should be regarded as synnemata because it does not develop into an ascoma bearing ascospores.

Keywords: paecilomyces tenuipes, entomopathogenic fungi, silkworm larva, bombyx mori

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Authors: Shiri Shinan-Altman, Tanya Lavrinenko

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Purpose: Prolonged mechanical ventilation (PMV) places significant emotional, physical, and social burdens on family caregivers. Despite these challenges, limited attention has been given to their subjective well-being (SWB). The aim of this study was to explore the factors associated with SWB among family caregivers of hospitalized PMV patients, utilizing the Self-Regulation Model as a theoretical framework. Specifically, we examined how illness representations and coping resources—sense of coherence and perceived social support—are associated with SWB. Methods: The study involved 134 family caregivers who completed validated questionnaires measuring SWB, illness representations, sense of coherence, and perceived social support. Path analysis was employed to investigate the direct and indirect effects of illness representations on SWB and the mediating role of coping resources. Results: Positive illness representations, such as perceptions of shorter illness timelines and greater treatment control, were linked to higher SWB through a higher sense of coherence and social support. Conversely, negative representations, including severe perceived consequences and heightened emotional responses, negatively impacted SWB. Symptom burden and illness understanding did not significantly influence coping resources or SWB. Path analysis highlighted significant indirect effects, demonstrating the importance of coping resources in mediating these relationships. Conclusion: The findings highlight the need for interventions targeting adaptive illness representations and strengthening caregivers' coping resources. Enhancing the sense of coherence and social support can mitigate caregiver burden and improve SWB. Healthcare professionals should focus on developing tailored intervention programs aimed at reframing caregivers' illness perceptions, providing psychoeducational support, and fostering coping skills. Specific strategies could include structured support groups to enhance social networks, resilience-building workshops, and psychoeducational sessions on managing emotional responses to PMV care. Additionally, regular assessments of caregiver well-being and proactive referrals to support services should be integrated into the care plans of PMV patients. By implementing these strategies, healthcare providers can not only improve caregivers' quality of life but also contribute to better outcomes for patients and their families.

Keywords: well-being, illness representations, coping resources, prolonged mechanical ventilation

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Authors: Şule Yanık, Emel Ertürk-Mustul, Zerrin Turan, Hasan Gürgür

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It is known that there are policies that will support the early special education (ESE) for children requiring special care including the children with hearing loss (CHL) in many countries that give importance to early childhood (0-6 years) education, accordingly ESE services have been gradually increasing and these services provide positive contributions to the child and family. These services begin with medical diagnostics, provision of the use of assistive technologies for hearing and the orientation of children towards early education program (EEP) for the CHL. In 0-3 years of age EEP, education and support services are provided to the children and their families. In 3-6 years of age, children are supported in a pre-school education program (PSE) in which their peers and teachers are present. Therefore, the children with hearing loss and their families are going through a series of medical, educational and social transition process after diagnosed with hearing loss. Depending on their age and development, CHL also go through a transition period from hospital to home, from home to EEP and from EEP to PSE. It is seen that there is no legal regulation regarding the transition process in Turkey and hence different processes have been carried out in the transition process from EEP to PSE. The aim of this study is to reveal the problems confronted by the CHL during the transition period from EEP to PSE and the solution proposals for these problems. In this study, a document review was made by reviewing the national and international studies about transition processes of the CHL in Turkey from EEP to PSE. Accordingly, in the study carried out in two stages, firstly, a review of the body of literature was performed by creating key words related to the subject. Secondly, the problems confronted by the CHL in Turkey during the transition period from EEP to PSE and the solution proposals for these problems were demonstrated by analyzing the obtained data. According to the body of literature, it is seen that there are no laws concerning the transition processes of the children who require special care including the CHL in Turkey from EEP (sending) to PSE (receiving), and correspondingly numerous problems have been experienced during the transition period. It seems that the EEP adopts family-centered approaches for strengthening the families of the CHL. However, PSE program aims to prepare the children to school life by focusing on their social and academical development rather with the adoption of children-centered approaches. Therefore, while the families feel an inseparable part of the team in EEP, they indicated that they felt like a stranger in the school team after their children have started to PSE. Therefore, families find the transition processes worrisome and state that they are not satisfied with the process. We discovered that in the process of transition from EEP to PSE, families are not informed, there is a limited number of PSE options available, children cannot adapt to the new educational environment and cannot benefit from the existing PSE.

Keywords: early education program, early special education, children with hearing loss, transition

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Authors: Sujata Sharma, Avinash Singh, Lovely Gautam, Pradeep Sharma, Mau Sinha, Asha Bhushan, Punit Kaur, Tej P. Singh

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Peptidyl-tRNA hydrolase (Pth) Pth is an essential bacterial enzyme that catalyzes the release of free tRNA and peptide moeities from peptidyl tRNAs during stalling of protein synthesis. In order to design inhibitors of Pth from Pseudomonas aeruginosa (PaPth), we have determined the structures of PaPth in its native state and in the bound states with two compounds, amino acylate-tRNA analogue (AAtA) and 5-azacytidine (AZAC). The peptidyl-tRNA hydrolase gene from Pseudomonas aeruginosa was amplified by Phusion High-Fidelity DNA Polymerase using forward and reverse primers, respectively. The E. coliBL21 (λDE3) strain was used for expression of the recombinant peptidyl-tRNA hydrolase from Pseudomonas aeruginosa. The protein was purified using a Ni-NTA superflow column. The crystallization experiments were carried out using hanging drop vapour diffusion method. The crystals diffracted to 1.50 Å resolution. The data were processed using HKL-2000. The polypeptide chain of PaPth consists of 194 amino acid residues from Met1 to Ala194. The centrally located β-structure is surrounded by α-helices from all sides except the side that has entrance to the substrate binding site. The structures of the complexes of PaPth with AAtA and AZAC showed the ligands bound to PaPth in the substrate binding cleft and interacted with protein atoms extensively. The residues that formed intermolecular hydrogen bonds with the atoms of AAtA included Asn12, His22, Asn70, Gly113, Asn116, Ser148, and Glu161 of the symmetry related molecule. The amino acids that were involved in hydrogen bonded interactions in case of AZAC included, His22, Gly113, Asn116, and Ser148. As indicated by fittings of two ligands and the number of interactions made by them with protein atoms, AAtA appears to be a more compatible with the structure of the substrate binding cleft. However, there is a further scope to achieve a better stacking than that of O-tyrosyl moiety because it is not still ideally stacked. These observations about the interactions between the protein and ligands have provided the information about the mode of binding of ligands, nature and number of interactions. This information may be useful for the design of tight inhibitors of Pth enzymes.

Keywords: peptidyl tRNA hydrolase, Acinetobacter baumannii, Pth enzymes, O-tyrosyl

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Authors: Mehrnaz Mostafavi

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Nanoliposomes, minute lipid-based vesicles at the nano-scale, show promise in the realm of photothermal therapy (PTT). This study presents an extensive overview of nanoliposomes in PTT, exploring their distinct attributes and the significant progress in this therapeutic methodology. The research delves into the fundamental traits of nanoliposomes, emphasizing their adaptability, compatibility with biological systems, and their capacity to encapsulate diverse therapeutic substances. Specifically, it examines the integration of light-absorbing materials, like gold nanoparticles or organic dyes, into nanoliposomal formulations, enabling their efficacy as proficient agents for photothermal treatment Additionally, this paper elucidates the mechanisms involved in nanoliposome-mediated PTT, highlighting their capability to convert light energy into localized heat, facilitating the precise targeting of diseased cells or tissues. This precise regulation of light absorption and heat generation by nanoliposomes presents a non-invasive and precisely focused therapeutic approach, particularly in conditions like cancer. The study explores advancements in nanoliposomal formulations aimed at optimizing PTT outcomes. These advancements include strategies for improved stability, enhanced drug loading, and the targeted delivery of therapeutic agents to specific cells or tissues. Furthermore, the paper discusses multifunctional nanoliposomal systems, integrating imaging components or targeting elements for real-time monitoring and improved accuracy in PTT. Moreover, the review highlights recent preclinical and clinical trials showcasing the effectiveness and safety of nanoliposome-based PTT across various disease models. It also addresses challenges in clinical implementation, such as scalability, regulatory considerations, and long-term safety assessments. In conclusion, this paper underscores the substantial potential of nanoliposomes in advancing PTT as a promising therapeutic approach. Their distinctive characteristics, combined with their precise ability to convert light into heat, offer a tailored and efficient method for treating targeted diseases. The encouraging outcomes from preclinical studies pave the way for further exploration and potential clinical applications of nanoliposome-based PTT.

Keywords: nanoliposomes, photothermal therapy, light absorption, heat conversion, therapeutic agents, targeted delivery, cancer therapy

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Authors: Hani M. Alothaid, Louise Robson, Richmond Muimo

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Cystic fibrosis (CF) is a disease that affects respiratory function and in EU it affects about 1 in 2,500 live births with an average 40-year life expectancy. This disease caused by mutations within the gene encoding the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) chloride channel leading to dysregulation of epithelial fluid transport and chronic lung inflammation, suggesting functional alterations of immune cells. In airways, CFTR been found to form a functional complex with S100A10 and AnxA2 in a cAMP/PKA dependent manner. The multiprotein complex of AnxA2-S100A10 and CFTR is also regulated by calcineurin. The aim of this study was i) to investigate whether chloride ion (Cl−) channels are activated by Pseudomonas aeruginosa lipopolysaccharide (LPS from PA), ii) if this activation is regulated by cAMP/PKA/calcineurin pathway and iii) to investigate the role of LPS-activated Cl− channels in the release of pro-inflammatory cytokines by immune cells. Human peripheral blood monocytes were used in the study. Whole-cell patch records showed that LPS from PA can activate Cl− channels, including CFTR and outwardly-rectifying Cl− channel (ORCC). This activation appears to require an intact PKA/calcineurin signalling pathway. The Gout in the presence of LPS was significantly inhibited by diisothiocyanatostilbene-disulfonic acid (DIDS), an ORCC blocker (p<0.001). The Gout was further suppressed by CFTR(inh)-172, a specific inhibitor for CFTR channels (p<0.001). Monocytes pre-incubated with PKA inhibitor or calcineurin inhibitor before stimulated with LPS from PA that were resulted in DIDS and CFTR(inh)-172 insensitive currents. Activation of both ORCC and CFTR was however, observed in response to monocytes exposure to LPS. Additionally, ELISA showed that the CFTR and ORCC play a role in mediating the release of pro-inflammatory cytokines such as IL-1β upon exposure of monocytes to LPS. However, this secretion was significantly inhibited due to CFTR and ORCC inhibition. However, Cl− may play a role in IL-1β release independent of cAMP/PKA/calcineurin signalling due to the enhancement of IL-1β secretion even when cAMP/PKA/calcineurin pathway was inhibited. In conclusion, our data confirmed that LPS from PA activates Cl− channels in human peripheral blood monocytes. Our data also confirmed that Cl− channels were involved in IL-1β release in monocytes upon exposure to LPS. However, it has been found that PKA and calcineurin does not seem to influence the Cl− dependent cytokine release.

Keywords: cystic fibrosis, CFTR, Annexin A2, S100A10, PP2B, PKA, outwardly-rectifying Cl− channel, Pseudomonas aeruginosa

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Authors: Ellis Kofi Akwaa-Sekyi, Jordi Moreno Gené

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Managerial actions which negatively profile banks and impair corporate reputation are addressed through effective internal control systems. Disregard for acceptable standards and procedures for granting credit have affected bank loan portfolios and could be cited for the crises in some European countries. The study intends to determine the effectiveness of internal control systems, investigate whether perceived agency problems exist on the part of board members and to establish the relationship between internal controls and credit risk among listed banks in the European Union. Drawing theoretical support from the behavioural compliance and agency theories, about seventeen internal control variables (drawn from the revised COSO framework), bank-specific, country, stock market and macro-economic variables will be involved in the study. A purely quantitative approach will be employed to model internal control variables covering the control environment, risk management, control activities, information and communication and monitoring. Panel data from 2005-2014 on listed banks from 28 European Union countries will be used for the study. Hypotheses will be tested and the Generalized Least Squares (GLS) regression will be run to establish the relationship between dependent and independent variables. The Hausman test will be used to select whether random or fixed effect model will be used. It is expected that listed banks will have sound internal control systems but their effectiveness cannot be confirmed. A perceived agency problem on the part of the board of directors is expected to be confirmed. The study expects significant effect of internal controls on credit risk. The study will uncover another perspective of internal controls as not only an operational risk issue but credit risk too. Banks will be cautious that observing effective internal control systems is an ethical and socially responsible act since the collapse (crisis) of financial institutions as a result of excessive default is a major contagion. This study deviates from the usual primary data approach to measuring internal control variables and rather models internal control variables in a quantitative approach for the panel data. Thus a grey area in approaching the revised COSO framework for internal controls is opened for further research. Most bank failures and crises could be averted if effective internal control systems are religiously adhered to.

Keywords: agency theory, credit risk, internal controls, revised COSO framework

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Authors: Turban Kar, Maitree Bhattacharyya

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Curcumin, a dietary antioxidant has been identified as a wonder molecule to possess therapeutic properties protecting the cellular macromolecules from oxidative damage. In our experimental study, we have explored the effectiveness of curcumin in protecting the structural paradigm of Human Serum Albumin (HSA) when exposed to gamma irradiation. HSA, being an important transport protein of the circulatory system, is involved in binding of variety of metabolites, drugs, dyes and fatty acids due to the presence of hydrophobic pockets inside the structure. HSA is also actively involved in the transportation of drugs and metabolites to their targets, because of its long half-life and regulation of osmotic blood pressure. Gamma rays, in its increasing concentration, results in structural alteration of the protein and superoxide radical generation. Curcumin, on the other hand, mitigates the damage, which has been evidenced in the following experiments. Our study explores the possibility for protection by curcumin during the molecular and conformational changes of HSA when exposed to gamma irradiation. We used a combination of spectroscopic methods to probe the conformational ensemble of the irradiated HSA and finally evaluated the extent of restoration by curcumin. SDS - PAGE indicated the formation of cross linked aggregates as a consequence of increasing exposure of gamma radiation. CD and FTIR spectroscopy inferred significant decrease in alpha helix content of HSA from 57% to 15% with increasing radiation doses. Steady state and time resolved fluorescence studies complemented the spectroscopic measurements when lifetime decay was significantly reduced from 6.35 ns to 0.37 ns. Hydrophobic and bityrosine study showed the effectiveness of curcumin for protection against radiation induced free radical generation. Moreover, bityrosine and hydrophobic profiling of gamma irradiated HSA in presence and absence of curcumin provided light on the formation of ROS species generation and the protective (magical) role of curcumin. The molecular mechanism of curcumin protection to HSA from gamma irradiation is yet unknown, though a possible explanation has been proposed in this work using Thioflavin T assay. It was elucidated, that when HSA is irradiated at low dose of gamma radiation in presence of curcumin, it is capable of retaining the native characteristic properties to a greater extent indicating stabilization of molecular structure. Thus, curcumin may be utilized as a therapeutic strategy to protect cellular proteins.

Keywords: Bityrosine content, conformational change, curcumin, gamma radiation, human serum albumin

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Authors: Peter C. St. John, Michael F. Crowley, Yannick J. Bomble

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Production of chemicals from engineered organisms in a batch culture typically involves a trade-off between productivity, yield, and titer. However, strategies for strain design typically involve designing mutations to achieve the highest yield possible while maintaining growth viability. Such approaches tend to follow the principle of designing static networks with minimum metabolic functionality to achieve desired yields. While these methods are computationally tractable, optimum productivity is likely achieved by a dynamic strategy, in which intracellular fluxes change their distribution over time. One can use multi-stage fermentations to increase either productivity or yield. Such strategies would range from simple manipulations (aerobic growth phase, anaerobic production phase), to more complex genetic toggle switches. Additionally, some computational methods can also be developed to aid in optimizing two-stage fermentation systems. One can assume an initial control strategy (i.e., a single reaction target) in maximizing productivity - but it is unclear how close this productivity would come to a global optimum. The calculation of maximum theoretical yield in metabolic engineering can help guide strain and pathway selection for static strain design efforts. Here, we present a method for the calculation of a maximum theoretical productivity of a batch culture system. This method follows the traditional assumptions of dynamic flux balance analysis: that internal metabolite fluxes are governed by a pseudo-steady state and external metabolite fluxes are represented by dynamic system including Michealis-Menten or hill-type regulation. The productivity optimization is achieved via dynamic programming, and accounts explicitly for an arbitrary number of fermentation stages and flux variable changes. We have applied our method to succinate production in two common microbial hosts: E. coli and A. succinogenes. The method can be further extended to calculate the complete productivity versus yield Pareto surface. Our results demonstrate that nearly optimal yields and productivities can indeed be achieved with only two discrete flux stages.

Keywords: A. succinogenes, E. coli, metabolic engineering, metabolite fluxes, multi-stage fermentations, succinate

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Authors: Rosa S. Wong, Keith T.S. Tung, H.W. Tsang, Frederick K. Ho, Patrick Ip

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Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention and hyperactive-impulsive behavior. Evidence shows that ADHD and mood problems such as depression and anxiety often co-occur and yet not everyone with ADHD reported elevated emotional problems. Given that cholesterol is essential for healthy brain development including the regions governing emotion regulation, reports found lower cholesterol levels in patients with major depressive disorder and those with suicide attempt behavior compared to healthy subjects. This study explored whether ADHD adolescents experienced more emotional problems and whether emotional problems correlated with cholesterol levels in these adolescents. This study used a portion of data from the longitudinal cohort study which was designed to investigate the long-term impact of family socioeconomic status on child development. In 2018/19, parents of 300 adolescents (average age: 12.57+/-0.49 years) were asked to rate their children’s emotional problems and report whether their children had doctor-diagnosed psychiatric diseases. We further collected blood samples from 263 children to study their lipid profile (total cholesterol, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol). Regression analyses were performed to test the relationships between variables of interest. Among 300 children, 27 (9%) had ADHD diagnosis. Analysis based on overall sample found no association between ADHD and emotional problems, but when investigating the relationship by gender, there was a significant interaction effect of ADHD and gender on emotional problems (p=0.037), with ADHD males displaying more emotional problems than ADHD females. Further analyses based on 263 children (21 with ADHD diagnosis) found significant interaction effect of ADHD and gender on total cholesterol (p=0.038) and low LDL-cholesterol levels (p=0.013) after adjusting for the child’s physical disease history. Specifically, ADHD males had significantly lower total cholesterol and low lipoprotein-cholesterol levels than ADHD females. In ADHD males, more emotional problems were associated with lower LDL-cholesterol levels (B = -4.26, 95%CI (-7.46, -1.07), p=0.013). We found preliminary support for the association between more emotional problems and lower cholesterol levels in ADHD children, especially among males. Although larger prospective studies are needed to substantiate these claims, the evidence highlights the importance of healthy lifestyle to keep cholesterol levels in normal range which can have positive effects on physical and mental health.

Keywords: attention-deficit hyperactivity disorder, cholesterol, emotional problems, adolescents

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Authors: Gela Gelashvili, David Gelenidze, Sulkhan Nanobashvili, Irakli Nanobashvili, George Tavkhelidze, Tsiuri Sitchinava

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Development of new highly efficient plasma arc combustion system of pulverized coal is presented. As it is well-known, coal is one of the main energy carriers by means of which electric and heat energy is produced in thermal power stations. The quality of the extracted coal decreases very rapidly. Therefore, the difficulties associated with its firing and complete combustion arise and thermo-chemical preparation of pulverized coal becomes necessary. Usually, other organic fuels (mazut-fuel oil or natural gas) are added to low-quality coal for this purpose. The fraction of additional organic fuels varies within 35-40% range. This decreases dramatically the economic efficiency of such systems. At the same time, emission of noxious substances in the environment increases. Because of all these, intense development of plasma combustion systems of pulverized coal takes place in whole world. These systems are equipped with Non-Transferred Plasma Arc Torches. They allow practically complete combustion of pulverized coal (without organic additives) in boilers, increase of energetic and financial efficiency. At the same time, emission of noxious substances in the environment decreases dramatically. But, the non-transferred plasma torches have numerous drawbacks, e.g. complicated construction, low service life (especially in the case of high power), instability of plasma arc and most important – up to 30% of energy loss due to anode cooling. Due to these reasons, intense development of new plasma technologies that are free from these shortcomings takes place. In our proposed system, pulverized coal-air mixture passes through plasma arc area that burns between to carbon electrodes directly in pulverized coal muffler burner. Consumption of the carbon electrodes is low and does not need a cooling system, but the main advantage of this method is that radiation of plasma arc directly impacts on coal-air mixture that accelerates the process of thermo-chemical preparation of coal to burn. To ensure the stability of the plasma arc in such difficult conditions, we have developed a power source that provides fixed current during fluctuations in the arc resistance automatically compensated by the voltage change as well as regulation of plasma arc length over a wide range. Our combustion system where plasma arc acts directly on pulverized coal-air mixture is simple. This should allow a significant improvement of pulverized coal combustion (especially low-quality coal) and its economic efficiency. Preliminary experiments demonstrated the successful functioning of the system.

Keywords: coal combustion, plasma arc, plasma torches, pulverized coal

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Authors: Diana Islam, Juan Fang, Vito Fanelli, Bing Han, Julie Khang, Jianfeng Wu, Arthur S. Slutsky, Haibo Zhang

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Introduction: MSC delivery in preclinical models of ARDS has demonstrated significant improvements in lung function and recovery from acute injury. However, the role of MSC delivery in ARDS associated pulmonary fibrosis is not well understood. Some animal studies using bleomycin, asbestos, and silica-induced pulmonary fibrosis show that MSC delivery can suppress fibrosis. While other animal studies using radiation induced pulmonary fibrosis, liver, and kidney fibrosis models show that MSC delivery can contribute to fibrosis. Hypothesis: The beneficial and deleterious effects of MSC in ARDS are modulated by the lung microenvironment at the time of MSC delivery. Methods: To induce ARDS a two-hit mouse model of Hydrochloric acid (HCl) aspiration (day 0) and mechanical ventilation (MV) (day 2) was used. HCl and injurious MV generated fibrosis within 14-28 days. 0.5x106 mouse MSCs were delivered (via both intratracheal and intravenous routes) either in the active inflammatory phase (day 2) or during the remodeling phase (day 14) of ARDS (mouse fibroblasts or PBS used as a control). Lung injury accessed using inflammation score and elastance measurement. Pulmonary fibrosis was accessed using histological score, tissue collagen level, and collagen expression. In addition alveolar epithelial (E) and mesenchymal (M) marker expression profile was also measured. All measurements were taken at day 2, 14, and 28. Results: MSC delivery 2 days after HCl exacerbated lung injury and fibrosis compared to HCl alone, while the day 14 delivery showed protective effects. However in the absence of HCl, MSC significantly reduced the injurious MV-induced fibrosis. HCl injury suppressed E markers and up-regulated M markers. MSC delivery 2 days after HCl further amplified M marker expression, indicating their role in myofibroblast proliferation/activation. While with 14-day delivery E marker up-regulation was observed indicating their role in epithelial restoration. Conclusions: Early MSC delivery can be protective of injurious MV. Late MSC delivery during repair phase may also aid in recovery. However, early MSC delivery during the exudative inflammatory phase of HCl-induced ARDS can result in pro-fibrotic profiles. It is critical to understand the interaction between MSC and the lung microenvironment before MSC-based therapies are utilized for ARDS.

Keywords: acute respiratory distress syndrome (ARDS), mesenchymal stem cells (MSC), hydrochloric acid (HCl), mechanical ventilation (MV)

Procedia PDF Downloads 673

Authors: Hanouf A. S. Al Nuwaysir, Nadine Moubayed, Abir Ben Bacha, Islem Abid

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Consumption of waste water continues to cause significant problems for human health in both developed and developing countries. Many regulations have been implied by different world authorities controlling water quality for the presence of coliforms used as standard indicators of water quality deterioration and historically leading health protection concept. In this study, the European directive for the detection of Escherichia coli, ISO 9308-1, was applied to examine and monitor coliforms in water samples collected from Wadi Hanifa and neighboring wells, Riyadh governorate, kingdom of Saudi Arabia, which is used for irrigation and industrial purposes. Samples were taken from different locations for 8 months consecutively, chlorine concentration ranging from 0.1- 0.4 mg/l, was determined using the DPD FREE CHLORINE HACH kit. Water samples were then analyzed following the ISO protocol which relies on the membrane filtration technique (0.45µm, pore size membrane filter) and a chromogenic medium TTC, a lactose based medium used for the detection and enumeration of total coliforms and E.coli. Data showed that the number of bacterial isolates ranged from 60 to 300 colonies/100ml for well and surface water samples respectively; where higher numbers were attributed to the surface samples. Organisms which apparently ferment lactose on TTC agar plates, appearing as orange colonies, were selected and additionally cultured on EMB and MacConkey agar for a further differentiation among E.coli and coliform bacteria. Two additional biochemical tests (Cytochrome oxidase and indole from tryptophan) were also investigated to detect and differentiate the presence of E.coli from other coliforms, E. coli was identified in an average of 5 to 7colonies among 25 selected colonies.On the other hand, a more rapid, specific and sensitive analytical molecular detection namely single colony PCR was also performed targeting hha gene to sensitively detect E.coli, giving more accurate and time consuming identification of colonies considered presumptively as E.coli. Comparative methodologies, such as ultrafiltration and direct DNA extraction from membrane filters (MoBio, Grermany) were also applied; however, results were not as accurate as the membrane filtration, making it a technique of choice for the detection and enumeration of water coliforms, followed by sufficiently specific enzymatic confirmatory stage.

Keywords: coliform, cytochrome oxidase, hha primer, membrane filtration, single colony PCR

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Authors: Elif Gencturk, Ekin Yurdakul, Ahmet Y. Celik, Senol Mutlu, Kutlu O. Ulgen

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Yeast cells are generally used as a model system of eukaryotes due to their complex genetic structure, rapid growth ability in optimum conditions, easy replication and well-defined genetic system properties. Thus, yeast cells increased the knowledge of the principal pathways in humans. During fermentation, carbohydrates (hexoses and pentoses) degrade into some toxic by-products such as 5-hydroxymethylfurfural (5-HMF or HMF) and furfural. HMF influences the ethanol yield, and ethanol productivity; it interferes with microbial growth and is considered as a potent inhibitor of bioethanol production. In this study, yeast single cell behavior under HMF application was monitored by using a continuous flow single phase microfluidic platform. Microfluidic device in operation is fabricated by hot embossing and thermo-compression techniques from cyclo-olefin polymer (COP). COP is biocompatible, transparent and rigid material and it is suitable for observing fluorescence of cells considering its low auto-fluorescence characteristic. The response of yeast cells was recorded through Red Fluorescent Protein (RFP) tagged Nop56 gene product, which is an essential evolutionary-conserved nucleolar protein, and also a member of the box C/D snoRNP complexes. With the application of HMF, yeast cell proliferation continued but HMF slowed down the cell growth, and after HMF treatment the cell proliferation stopped. By the addition of fresh nutrient medium, the yeast cells recovered after 6 hours of HMF exposure. Thus, HMF application suppresses normal functioning of cell cycle but it does not cause cells to die. The monitoring of Nop56 expression phases of the individual cells shed light on the protein and ribosome synthesis cycles along with their link to growth. Further computational study revealed that the mechanisms underlying the inhibitory or inductive effects of HMF on growth are enriched in functional categories of protein degradation, protein processing, DNA repair and multidrug resistance. The present microfluidic device can successfully be used for studying the effects of inhibitory agents on growth by single cell tracking, thus capturing cell to cell variations. By metabolic engineering techniques, engineered strains can be developed, and the metabolic network of the microorganism can thus be manipulated such that chemical overproduction of target metabolite is achieved along with the maximum growth/biomass yield.  

Keywords: COP, HMF, ribosome biogenesis, thermoplastic microbioreactor, yeast

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Authors: Gergely G. Karacsony

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Fundamental rights are the result of thousand years’ progress of legislation, adjudication and legal practice. They serve as the framework of peaceful cohabitation of people, protecting the individual from any abuse by the government or violation by other people. Artificial intelligence, however, is the development of the very recent past, being one of the most important prospects to the future. Artificial intelligence is now capable of communicating and performing actions the same way as humans; such acts are sometimes impossible to tell from actions performed by flesh-and-blood people. In a world, where human-robot interactions are more and more common, a new framework of peaceful cohabitation is to be found. Artificial intelligence, being able to take part in almost any kind of interaction where personal presence is not necessary without being recognized as a non-human actor, is now able to break the law, violate people’s rights, and disturb social peace in many other ways. Therefore, a code of peaceful coexistence is to be found or created. We should consider the issue, whether human rights can serve as the code of ethical and rightful conduct in the new era of artificial intelligence and human coexistence. In this paper, we will examine the applicability of fundamental rights to human-robot interactions as well as to the actions of artificial intelligence performed without human interaction whatsoever. Robot ethics has been a topic of discussion and debate of philosophy, ethics, computing, legal sciences and science fiction writing long before the first functional artificial intelligence has been introduced. Legal science and legislation have approached artificial intelligence from different angles, regulating different areas (e.g. data protection, telecommunications, copyright issues), but they are only chipping away at the mountain of legal issues concerning robotics. For a widely acceptable and permanent solution, a more general set of rules would be preferred to the detailed regulation of specific issues. We argue that human rights as recognized worldwide are able to be adapted to serve as a guideline and a common basis of coexistence of robots and humans. This solution has many virtues: people don’t need to adjust to a completely unknown set of standards, the system has proved itself to withstand the trials of time, legislation is easier, and the actions of non-human entities are more easily adjudicated within their own framework. In this paper we will examine the system of fundamental rights (as defined in the most widely accepted source, the 1966 UN Convention on Human Rights), and try to adapt each individual right to the actions of artificial intelligence actors; in each case we will examine the possible effects on the legal system and the society of such an approach, finally we also examine its effect on the IT industry.

Keywords: human rights, robot ethics, artificial intelligence and law, human-robot interaction

Procedia PDF Downloads 245

Authors: Joana Mourão

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Transition to a low carbon economy requires changes in consumption and production patterns, including the improvement of existing buildings’ environmental performance. Urban rehabilitation is a top policy priority in Europe, creating an opportunity to increase this performance. However, urban rehabilitation comprises different typologies of interventions with distinct levels of consideration for cultural urban heritage values and for environmental values, thus with different impacts. Cities rely on both material and non-material forms of heritage that are deep-rooted and resilient. One of the most relevant parts of that urban heritage is the historical pre-industrial housing stock, with an extensive presence in many European cities, as Lisbon. This stock is rehabilitated and transformed at the framework of urban management and local governance traditions, as well as the framework of the global economy, and in that context, faces opportunities and threats that need evaluation and control. The scope of this article is to define methodological bases and research lines for the assessment of impacts that urban rehabilitation initiatives set on the vulnerable and historical pre-industrial urban housing stock, considering it as an environmental and cultural unreplaceable material value and resource. As a framework, this article reviews the concepts of urban regeneration, urban renewal, current buildings conservation and refurbishment, and energy refurbishment of buildings, seeking to define key typologies of urban rehabilitation that represent different approaches to the urban fabric, in terms of scope, actors, and priorities. Moreover, main types of interventions - basing on a case-study in a XVIII century neighborhood in Lisbon - are defined and analyzed in terms of the elements lost in each type of intervention, and relating those to urbanistic, architectonic and constructive values of urban heritage, as well as to environmental and energy efficiency. Further, the article overviews environmental cultural heritage assessment and life-cycle assessment tools, selecting relevant and feasible impact assessment criteria for urban buildings rehabilitation regulation, focusing on multi-level urban heritage integrity. Urbanistic, architectonic, constructive and energetic integrity are studied as criteria for impact assessment and specific indicators are proposed. The role of these criteria in sustainable urban management is discussed. Throughout this article, the key challenges for urban rehabilitation planning and management, concerning urban built heritage as a resource for sustainability, are discussed and clarified.

Keywords: urban rehabilitation, impact assessment criteria, buildings integrity, embodied energy

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Authors: Satendra Pal Singh, Dalip Kr. Kakru, Jyoti Mishra, Rajesh Thakur, Tarana Sarwat

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COVID-19 is still an intrigue as far as morbidity or mortality is concerned. The rate of recovery varies from person to person, & it depends upon the accessibility of the healthcare system and the roles played by the physicians and caregivers. It is envisaged that with the passage of time, people would become immune to this virus, and those who are vulnerable would sustain themselves with the help of vaccines. The proposed study deals with the severeness of COVID-19 is associated with some specific biomarkers linked to correlate age and gender. We will be assessing the overall homeostasis of the persons who were affected by the coronavirus infection and also of those who recovered from it. Some people show more severe effects, while others show very mild symptoms, however, they show low CT values. Thus far, it is unclear why the new strain of Covid has different effects on different people in terms of age, gender, and ABO blood typing. According to data, the fatality rate with heart disease was 10.5 percent, 7.3 percent were diabetic, and 6 percent who are already infected from other comorbidities. However, some COVID-19 cases are worse than others & it is not fully explainable as of date. Overall data show that the ABO blood group is effective or prone to the risk of SARS-COV2 infection, while another study also shows the phenotypic effects of the blood group related to covid. It is an accepted fact that females have more strong immune systems than males, which may be related to the fact that females have two ‘X’ chromosomes, which might contain a more effective immunity booster gene on the X chromosome, and are capable to protect the female. Also specific sex hormones also induce a better immune response in a specific gender. This calls for in-depth analysis to be able to gain insight into this dilemma. COVID-19 is still not fully characterized, and thus we are not very familiar with its biology, mode of infection, susceptibility, and overall viral load in the human body. How many virus particles are needed to infect a person? How, then, comorbidity contribute to coronavirus infection? Since the emergence of this virus in 2020, a large number of papers have been published, and seemingly, vaccines have been prepared. But still, a large number of questions remain unanswered. The proneness of humans for infection by covid-19 needs to be established to be able to develop a better strategy to fight this virus. Our study will be on the Impact of demography on the Severity of covid-19 infection & at the same time, will look into gender-specific sensitivity of Covid-19 and the Operational variation of different biochemical markers in Covid-19 positive patients. Besides, we will be studying the co-relation, if any, of COVID severity & ABO Blood group type and the occurrence of the most common blood group type amongst positive patience.

Keywords: coronavirus, ABO blood group, age, gender

Procedia PDF Downloads 102

Authors: Omer Zvi Shaked

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Intimate Partner Violence (IPV) is a widespread social problem. Since the 1970's, and due to political changes resulting from the feminist movement, western society has been changing its attitude towards the phenomenon and has been taking an active approach to reduce its magnitude. Enterprises in the form of legislation, awareness and prevention campaigns, women's shelters, and community intervention programs became more prevalent as years progressed. Although many initiatives were found to be productive, the effectiveness of one, however, remained questionable throughout the years: intervention programs for men's intimate violence. Surveys outline two main intervention models for men's intimate violence. The first is the Duluth model, which argued that men are socialized to be dominant - while women are socialized to be subordinate - and men are therefore required by social imperative to enforce, physically if necessary, their dominance. The Duluth model became the chief authorized intervention program, and some states in the US even regulated it as the standard criminal justice program for men's intimate violence. However, meta-analysis findings demonstrated that based on a partner's reports, Duluth treatment completers have 44% recidivism rate, and between 40% and 85% dropout range. The second model is the Cognitive-Behavioral Model (CBT), which is a highly accepted intervention worldwide. The model argues that cognitive misrepresentations of intimate situations precede violent behaviors frequently when anger predisposition exists. Since anger dysregulation mediates between one's cognitive schemes and violent response, anger regulation became the chief purpose of the intervention. Yet, a meta-analysis found only a 56% risk reduction for CBT interventions. It is, therefore, crucial to understand the background behind the domination of both the Duluth model and CBT interventions. This presentation will discuss the ways in which theoretical conceptualizations of men's intimate violence, as well as ideologies, had contributed to the above-mentioned interventions' wide acceptance, despite known lack of scientific and evidential support. First, the presentation will review the prominent interventions for male intimate violence, the Duluth model, and CBT. Second, the presentation will review the prominent theoretical models explaining men's intimate violence: The Patriarchal model, the Abusive Personality model, and the Post-Traumatic Stress model. Third, the presentation will discuss the interrelation between theory and practice, and the nature of affinity between research and practice regarding men's intimate violence. Finally, the presentation will set new directions for further research, aiming to improve intervention's efficiency with men's intimate violence and advance social work practice in the field.

Keywords: intimate partner violence, theory and practice relationship, Duluth, CBT, abusive personality, post-traumatic stress

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Authors: Danni Cheng

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Background: Preclinical and epidemiological studies have reported potential protective effects of low-density lipoprotein cholesterol (LDL-C) lowering drugs on head and neck squamous cell cancer (HNSCC) survival, but the causality was not consistent. Genetic variants associated with LDL-C lowering drug targets can predict the effects of their therapeutic inhibition on disease outcomes. Objective: We aimed to evaluate the causal association of genetically proxied cholesterol-lowering drug targets and circulating lipid traits with cancer survival in HNSCC patients stratified by human papillomavirus (HPV) status using two-sample Mendelian randomization (MR) analyses. Method: Single-nucleotide polymorphisms (SNPs) in gene region of LDL-C lowering drug targets (HMGCR, NPC1L1, CETP, PCSK9, and LDLR) associated with LDL-C levels in genome-wide association study (GWAS) from the Global Lipids Genetics Consortium (GLGC) were used to proxy LDL-C lowering drug action. SNPs proxy circulating lipids (LDL-C, HDL-C, total cholesterol, triglycerides, apoprotein A and apoprotein B) were also derived from the GLGC data. Genetic associations of these SNPs and cancer survivals were derived from 1,120 HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) and 2,570 non-HPV-driven HNSCC patients in VOYAGER program. We estimated the causal associations of LDL-C lowering drugs and circulating lipids with HNSCC survival using the inverse-variance weighted method. Results: Genetically proxied HMGCR inhibition was significantly associated with worse overall survival (OS) in non-HPV-drive HNSCC patients (inverse variance-weighted hazard ratio (HR IVW), 2.64[95%CI,1.28-5.43]; P = 0.01) but better OS in HPV-positive OPSCC patients (HR IVW,0.11[95%CI,0.02-0.56]; P = 0.01). Estimates for NPC1L1 were strongly associated with worse OS in both total HNSCC (HR IVW,4.17[95%CI,1.06-16.36]; P = 0.04) and non-HPV-driven HNSCC patients (HR IVW,7.33[95%CI,1.63-32.97]; P = 0.01). A similar result was found that genetically proxied PSCK9 inhibitors were significantly associated with poor OS in non-HPV-driven HNSCC (HR IVW,1.56[95%CI,1.02 to 2.39]). Conclusion: Genetically proxied long-term HMGCR inhibition was significantly associated with decreased OS in non-HPV-driven HNSCC and increased OS in HPV-positive OPSCC. While genetically proxied NPC1L1 and PCSK9 had associations with worse OS in total and non-HPV-driven HNSCC patients. Further research is needed to understand whether these drugs have consistent associations with head and neck tumor outcomes.

Keywords: Mendelian randomization analysis, head and neck cancer, cancer survival, cholesterol, statin

Procedia PDF Downloads 103

Authors: Christopher R. Triggle, Hong Ding, Khaled Machaca, Gnanapragasam Arunachalam

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The antidiabetic drug, metformin, has been in clinical use for over 50 years and remains the first choice drug for the treatment of type two diabetes. In addition to its effectiveness as an oral anti-hyperglycaemic drug metformin also possesses vasculoprotective effects that are assumed to be secondary to its ability to reduce insulin resistance and control glycated hemoglobin levels; however, recent data from our laboratory indicate that metformin also has direct vasoprotective effects that are mediated, at least in part, via the anti-ageing gene, SIRT1. Diabetes is a major risk factor for the development of cardiovascular disease (CVD) and it is also well established that tobacco use further enhances the risk of CVD; however, it is not known whether treatment with metformin can offset the negative effects of diabetes and tobacco use on cardiac function. The current study was therefore designed to investigate 1: the effects of hyperglycaemia (HG) either alone or in the presence of elevated fatty acids (palmitate) and nicotine on the protein expression levels of the deacetylase sirtuin 1 (the protein product of SIRT1), anti-apoptotic Bcl-2, pro-apoptotic BIM and the pro-apoptotic, tumour suppressor protein, acetylated p53 in cardiomyocytes. 2: the ability of metformin to prevent the detrimental effects of HG, palmitate and nicotine on cardiomyocyte survival. Cell culture protocols were designed using a rat cardiomyocyte cell line, H9c2, either under normal glycaemic (NG) conditions of 5.5mM glucose, or hyperglycaemic conditions (HG) of 25mM glucose with, or without, added palmitate (250μM) or nicotine (1.0mM) for 24h. Immuno-blotting was used to detect the expression of sirtuin 1, Bcl-2, BIM, acetylated (Ac)-p53, p53 with β-actin used as the reference protein. Exposure to HG, palmitate, or nicotine alone significantly reduced expression of sirtuin1, Bcl-2 and raised the expression levels of acetylated p53 and BIM; however, the combination of HG, palmitate and nicotine had a synergistic effect to significantly suppress the expression levels of sirtuin 1 and Bcl-2, but further enhanced the expression of Ac-p53, and BIM. The inclusion of 1000μM, but not 50μM, metformin in the H9c2 cell culture protocol prevented the effects of HG, palmitate and nicotine on the pro-apoptotic pathways. Collectively these data indicate that metformin, in addition to its anti-hyperglycaemic and vasculoprotective properties, also has direct cardioprotective actions that offset the negative effects of hyerglycaemia, elevated free fatty acids and nicotine on cardiac cell survival. These data are of particular significance for the treatment of patients with diabetes who are also smokers as the inclusion of metformin in their therapeutic treatment plan should help reduce cardiac-related morbidity and mortality.

Keywords: apoptosis, cardiac muscle, diabetes, metformin, nicotine

Procedia PDF Downloads 321

Authors: Dong Zhao

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Abstract—Extensive research on obtaining applicable room temperature superconductors meets the major barrier, and the record Tc of 135 K achieved via cuprate has been idling for decades. Even though, the accomplishment of higher Tc than the cuprate was made through pressurizing certain compounds composed of light elements, such as for the LaH10 and for the metallic hydrogen. Room temperature superconductivity under ambient pressure is still the preferred approach and is believed to be the ultimate solution for many applications. While racing to find the breakthrough method to achieve this room temperature Tc milestone in superconducting research, a report stated a discovery of a possible high-temperature superconductor, i.e., the thorium sulfide ThS. Apparently, ThS’s Tc can be at room temperature or even higher. This is because ThS revealed an unusual property of the ‘coexistence of high electrical conductivity and diamagnetism’. Noticed that this property of coexistence of high electrical conductivity and diamagnetism is in line with superconductors, meaning ThS is also at its superconducting state. Surprisingly, ThS owns the property of superconductivity at least at room temperature and under atmosphere pressure. Further study of the ThS’s electrical and magnetic properties in comparison with thorium di-iodide ThI2 concluded its molecular configuration as [Th4+(e-)2]S. This means the ThS’s cation is composed of a [Th4+(e-)2]2+ cation core. It is noticed that this cation core is built by an oxidation state +4 of thorium atom plus an electron pair on this thorium atom that resulted in an oxidation state +2 of this [Th4+(e-)2]2+ cation core. This special construction of [Th4+(e-)2]2+ cation core may lead to the ThS’s room temperature superconductivity because of this characteristic electron lone pair residing on the thorium atom. Since the study of thorium chemistry was carried out in the period of before 1970s. the exploration about ThS’s possible room temperature superconductivity would require resynthesizing ThS. This re-preparation of ThS will provide the sample and enable professionals to verify the ThS’s room temperature superconductivity. Regrettably, the current regulation prevents almost everyone from getting access to thorium metal or thorium compounds due to the radioactive nature of thorium-232 (Th-232), even though the radioactive level of Th-232 is extremely low with its half-life of 14.05 billion years. Consequently, further confirmation of ThS’s high-temperature superconductivity through experiments will be impossible unless the use of corresponding thorium metal and related thorium compounds can be deregulated. This deregulation would allow researchers to obtain the necessary starting materials for the study of ThS. Hopefully, the confirmation of ThS’s room temperature superconductivity can not only establish a method to obtain applicable superconductors but also to pave the way for fully understanding the mechanism of superconductivity.

Keywords: co-existence of high electrical conductivity and diamagnetism, electron pairing and electron lone pair, room temperature superconductivity, the special molecular configuration of thorium sulfide ThS

Procedia PDF Downloads 53

Authors: Azzaya Enkhjargal

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Context: The mining industry has a long history of human rights abuses, including forced labor, environmental pollution, and displacement of communities. In recent years, there has been growing international pressure to hold mining companies accountable for these abuses. Research Aim: This study explores the legal liabilities of mining companies for human rights abuses. The study specifically examines the case of Erdenet Mining Corporation (EMC), a large mining company in Mongolia that has been accused of human rights abuses. Methodology: The study used a mixed-methods approach, which included a review of legal literature, interviews with community members and NGOs, and a case study of EMC. Findings: The study found that mining companies can be held liable for human rights abuses under a variety of regulatory frameworks, including soft law and self-regulatory instruments in the mining industry, international law, national law, and corporate law. The study also found that there are a number of challenges to holding mining companies accountable for human rights abuses, including the lack of effective enforcement mechanisms and the difficulty of proving causation. Theoretical Importance: The study contributes to the growing body of literature on the legal liabilities of mining companies for human rights abuses. The study also provides insights into the challenges of holding mining companies accountable for human rights abuses. Data Collection: The data for the study was collected through a variety of methods, including a review of legal literature, interviews with community members and NGOs, and a case study of EMC. Analysis Procedures: The data was analyzed using a variety of methods, including content analysis, thematic analysis, and case study analysis. Conclusion: The study concludes that mining companies can be held liable for human rights abuses under a variety of legal and regulatory frameworks. There are positive developments in ensuring greater accountability and protection of affected communities and the environment in countries with a strong economy. Regrettably, access to avenues of redress is reasonably low in less developed countries, where the governments have not implemented a robust mechanism to enforce liability requirements in the mining industry. The study recommends that governments and mining companies take more ambitious steps to enhance corporate accountability.

Keywords: human rights, human rights abuses, ESG, litigation, Erdenet Mining Corporation, corporate social responsibility, soft law, self-regulation, mining industry, parent company liability, sustainability, environment, UN

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Authors: Salma A. Mahmoud

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Epigenetic, or alteration in gene expression influenced by extragenetic factors, has emerged as one of the most promising areas that will address some of the gaps in our current knowledge in understanding patterns of human variation. In the last decade, the research investigating epigenetic mechanisms in many fields has flourished and witnessed significant progress. It paved the way for a new era of integrated research especially between anthropology/archeology and life sciences. Skeletal remains are considered the most significant source of information for studying human variations across history, and by utilizing these valuable remains, we can interpret the past events, cultures and populations. In addition to archeological, historical and anthropological importance, studying bones has great implications in other fields such as medicine and science. Bones also can hold within them the secrets of the future as they can act as predictive tools for health, society characteristics and dietary requirements. Bones in their basic forms are composed of cells (osteocytes) that are affected by both genetic and environmental factors, which can only explain a small part of their variability. The primary objective of this project is to examine the epigenetic landscape/signature within bones of archeological remains as a novel marker that could reveal new ways to conceptualize chronological events, gender differences, social status and ecological variations. We attempted here to address discrepancies in common variants such as methylome as well as novel epigenetic regulators such as chromatin remodelers, which to our best knowledge have not yet been investigated by anthropologists/ paleoepigenetists using plethora of techniques (biological, computational, and statistical). Moreover, extracting epigenetic information from bones will highlight the importance of osseous material as a vector to study human beings in several contexts (social, cultural and environmental), and strengthen their essential role as model systems that can be used to investigate and construct various cultural, political and economic events. We also address all steps required to plan and conduct an epigenetic analysis from bone materials (modern and ancient) as well as discussing the key challenges facing researchers aiming to investigate this field. In conclusion, this project will serve as a primer for bioarcheologists/anthropologists and human biologists interested in incorporating epigenetic data into their research programs. Understanding the roles of epigenetic mechanisms in bone structure and function will be very helpful for a better comprehension of their biology and highlighting their essentiality as interdisciplinary vectors and a key material in archeological research.

Keywords: epigenetics, archeology, bones, chromatin, methylome

Procedia PDF Downloads 111

Authors: Tanima Chatterjee, Maitree Bhattacharyya

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The global challenge of type 2 diabetes mellitus is a major health concern in this millennium, and researchers are continuously exploring new targets to develop a novel therapeutic strategy. Type 2 diabetes mellitus (T2DM) is often coupled with dyslipidemia increasing the risks for cardiovascular (CVD) complications. Enhanced oxidative and nitrosative stresses appear to be the major risk factors underlying insulin resistance, dyslipidemia, β-cell dysfunction, and T2DM pathogenesis. Autophagy emerges to be a promising defense mechanism against stress-mediated cell damage regulating tissue homeostasis, cellular quality control, and energy production, promoting cell survival. In this study, we have attempted to explore the pivotal role of autophagy in T2DM subjects with or without dyslipidemia in peripheral blood mononuclear cells and insulin-resistant HepG2 cells utilizing flow cytometric platform, confocal microscopy, and molecular biology techniques like western blotting, immunofluorescence, and real-time polymerase chain reaction. In the case of T2DM with dyslipidemia higher population of autophagy, positive cells were detected compared to patients with the only T2DM, which might have resulted due to higher stress. Autophagy was observed to be triggered both by oxidative and nitrosative stress revealing a novel finding of our research. LC3 puncta was observed in peripheral blood mononuclear cells and periphery of HepG2 cells in the case of the diabetic and diabetic-dyslipidemic conditions. Increased expression of ATG5, LC3B, and Beclin supports the autophagic pathway in both PBMC and insulin-resistant Hep G2 cells. Upon blocking autophagy by 3-methyl adenine (3MA), the apoptotic cell population increased significantly, as observed by caspase‐3 cleavage and reduced expression of Bcl2. Autophagy has also been evidenced to control oxidative stress-mediated up-regulation of inflammatory markers like IL-6 and TNF-α. To conclude, this study elucidates autophagy to play a protective role in the case of diabetes mellitus with dyslipidemia. In the present scenario, this study demands to have a significant impact on developing a new therapeutic strategy for diabetic dyslipidemic subjects by enhancing autophagic activity.

Keywords: autophagy, apoptosis, dyslipidemia, reactive oxygen species, reactive nitrogen species, Type 2 diabetes

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Authors: Ankita Singh, Chandan Gorain, Amirul I. Mallick

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Successful adherence of the mucosal epithelial cells is the key early step for Campylobacter jejuni pathogenesis (C. jejuni). A set of Surface Exposed Colonization Proteins (SECPs) are among the major factors involved in host cell adherence and invasion of C. jejuni. Among them, constitutively expressed surface-exposed lipoprotein adhesin of C. jejuni, JlpA, interacts with intestinal heat shock protein 90 (hsp90α) and contributes in disease progression by triggering pro-inflammatory response via activation of NF-κB and p38 MAP kinase pathway. Together with its ability to express in the bacterial surface, higher sequence conservation and predicted predominance of several B cells epitopes, JlpA protein reserves its potential to become an effective vaccine candidate against wide range of Campylobacter sps including C. jejuni. Given that chickens are the primary sources for C. jejuni and persistent gut colonization remain as major cause for foodborne pathogenesis to humans, present study explicitly used chickens as model to test the immune-protective efficacy of JlpA protein. Taking into account that gastrointestinal tract is the focal site for C. jejuni colonization, to extrapolate the benefit of mucosal (intragastric) delivery of JlpA protein, a food grade Nisin inducible Lactic acid producing bacteria, Lactococcus lactis (L. lactis) was engineered to express recombinant JlpA protein (rJlpA) in the surface of the bacteria. Following evaluation of optimal surface expression and functionality of recombinant JlpA protein expressed by recombinant L. lactis (rL. lactis), the immune-protective role of intragastric administration of live rL. lactis was assessed in commercial broiler chickens. In addition to the significant elevation of antigen specific mucosal immune responses in the intestine of chickens that received three doses of rL. lactis, marked upregulation of Toll-like receptor 2 (TLR2) gene expression in association with mixed pro-inflammatory responses (both Th1 and Th17 type) was observed. Furthermore, intragastric delivery of rJlpA expressed by rL. lactis, but not the injectable form, resulted in a significant reduction in C. jejuni colonization in chickens suggesting that mucosal delivery of live rL. lactis expressing JlpA serves as a promising vaccine platform to induce strong immune-protective responses against C. jejuni in chickens.

Keywords: chickens, lipoprotein adhesion of Campylobacter jejuni, immuno-protection, Lactococcus lactis, mucosal delivery

Procedia PDF Downloads 143

Authors: Amira Mabrouk

Abstract:

This paper deals with the acceptability of urban toll in Tunisia. The price-based regulation, i.e. urban toll, is the outcome of a political process hampered by three-fold objectives: effectiveness, equity and social acceptability. This produces both economic interest groups and functions that are of incongruent preferences. The plausibility of this speculation goes hand in hand with the fact that these economic interest groups are also taxpayers who undeniably perceive urban toll as an additional charge. This wariness is coupled with an inquiry about the conditions of usage, the redistribution of the collected tax revenue and the idea of the leviathan state completes the picture. In a nutshell, if researches related to road congestion proliferate, no de facto legitimacy can be pleaded. Nonetheless, the theory on urban tolls engenders economists’ questioning of ways to reduce negative external effects linked to it. Only then does the urban toll appear to bear an answer to these issues. Undeniably, the urban toll suggests inherent conflicts due to the apparent no-payment principal of a public asset as well as to the social perception of the new measure as a mere additional charge. However, when the main concern is effectiveness is its broad sense and the social well-being, the main factors that determine the acceptability of such a tariff measure along with the type of incentives should be the object of a thorough, in-depth analysis. Before adopting this economic role, one has to recognize the factors that intervene in the acceptability of a congestion toll which brought about a copious number of articles and reports that lacked mostly solid theoretical content. It is noticeable that nowadays uncertainties float over the exact nature of the acceptability process. Accepting a congestion tariff could differ from one era to another, from one region to another and from one population to another, etc. Notably, this article, within a convenient time frame, attempts at bringing into focus a link between the social acceptability of the urban congestion toll and the value of time through a survey method barely employed in Tunisia, that of stated preference method. How can the urban toll, as a tax, be defined, justified and made acceptable? How can an equitable and effective tariff of congestion toll be reached? How can the costs of this urban toll be covered? In what way can we make the redistribution of the urban toll revenue visible and economically equitable? How can the redistribution of the revenue of urban toll compensate the disadvantaged while introducing such a tariff measure? This paper will offer answers to these research questions and it follows the line of contribution of JULES DUPUIT in 1844.

Keywords: congestion charge, social perception, acceptability, stated preferences

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Authors: Edouard Ngor Sarr, Abel Diatta, Serigne Mor Toure, Ousmane Sall, Lamine Faty

Abstract:

Thanks to Web 2, we are witnessing a form of democratization of the spoken word, an exponential increase in the number of users on the web, but also, and above all, the accumulation of a daily flow of content that is becoming, at times, uncontrollable. Added to this is the rise of a violent social fabric characterised by hateful and racial comments, insults, and other content that contravenes social rules and the platforms' terms of use. Consequently, managing and regulating this mass of new content is proving increasingly difficult, requiring substantial human, technical, and technological resources. Without regulation and with the complicity of anonymity, this toxic content can pollute discussions and make these online spaces highly conducive to abuse, which very often has serious consequences for certain internet users, ranging from anxiety to suicide, depression, or withdrawal. The toxicity of a comment is defined as anything that is rude, disrespectful, or likely to cause someone to leave a discussion or to take violent action against a person or a community. Two levels of measures are needed to deal with this deleterious situation. The first measures are being taken by governments through draft laws with a dual objective: (i) to punish the perpetrators of these abuses and (ii) to make online platforms accountable for the mistakes made by their users. The second measure comes from the platforms themselves. By assessing the content left by users, they can set up filters to block and/or delete content or decide to suspend the user in question for good. However, the speed of discussions and the volume of data involved mean that platforms are unable to properly monitor the moderation of content produced by Internet users. That's why they use human moderators, either through recruitment or outsourcing. Moderating comments on the web means assessing and monitoring users‘ comments on online platforms in order to strike the right balance between protection against abuse and users’ freedom of expression. It makes it possible to determine which publications and users are allowed to remain online and which are deleted or suspended, how authorised publications are displayed, and what actions accompany content deletions. In this study, we look at the problem of automatic moderation of toxic comments in the face of local African languages and, more specifically, on social network comments in Senegal. We review the state of the art, highlighting the different approaches, algorithms, and tools for moderating comments. We also study the issues and challenges of moderation in the face of web ecosystems with lesser-known languages, such as local languages.

Keywords: moderation, local languages, Senegal, toxic comments

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