Search results for: peroxide initiation

Authors: Natalie Hoyer

Abstract:

Usually, steel structures are designed for the upper region of the steel toughness-temperature curve. To address the reduced toughness properties in the temperature transition range, additional safety assessments based on fracture mechanics are necessary. These assessments enable the appropriate selection of steel materials to prevent brittle fracture. In this context, recommendations were established in 2011 to regulate the appropriate selection of steel grades for bridge bearing components. However, these recommendations are no longer fully aligned with more recent insights: Designing bridge bearings and their components in accordance with DIN EN 1337 and the relevant sections of DIN EN 1993 has led to an increasing trend of using large plate thicknesses, especially for long-span bridges. However, these plate thicknesses surpass the application limits specified in the national appendix of DIN EN 1993-2. Furthermore, compliance with the regulations outlined in DIN EN 1993-1-10 regarding material toughness and through-thickness properties requires some further modifications. Therefore, these standards cannot be directly applied to the material selection for bearings without additional information. In addition, recent findings indicate that certain bridge bearing components are subjected to high fatigue loads, necessitating consideration in structural design, material selection, and calculations. To address this issue, the German Center for Rail Traffic Research initiated a research project aimed at developing a proposal to enhance the existing standards. This proposal seeks to establish guidelines for the selection of steel materials for bridge bearings to prevent brittle fracture, particularly for thick plates and components exposed to specific fatigue loads. The results derived from theoretical analyses, including finite element simulations and analytical calculations, are verified through component testing on a large-scale. During these large-scale tests, where a brittle failure is deliberately induced in a bearing component, an artificially generated defect is introduced into the specimen at the predetermined hotspot. Subsequently, a dynamic load is imposed until the crack initiation process transpires, replicating realistic conditions akin to a sharp notch resembling a fatigue crack. To stop the action of the dynamic load in time, it is important to precisely determine the point at which the crack size transitions from stable crack growth to unstable crack growth. To achieve this, the potential drop measurement method is employed. The proposed paper informs about the choice of measurement method (alternating current potential drop (ACPD) or direct current potential drop (DCPD)), presents results from correlations with created FE models, and may proposes a new approach to introduce beach marks into the fracture surface within the framework of potential drop measurement.

Keywords: beach marking, bridge bearing design, brittle fracture, design for fatigue, potential drop

Procedia PDF Downloads 13

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

Abstract:

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

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

Procedia PDF Downloads 101

Authors: N. Rambabu, H. Gururaj, Reynold Washington, Oommen George

Abstract:

Motivation: Under the USAID Strengthening Health Outcomes through Private Sector (SHOPS-TB) initiative, Karnataka Health Promotion Trust (KHPT) with technical support of Abt associates is implementing a TB prevention and care model in Karnataka State, South India. KHPT is the interface agency between the public and private sectors, and providers and the target community facilitating early TB case detection and enhancing treatment compliance through private health care providers (pHCP) engagement in RNTCP. The project coverage is 0.84 million urban poor from 663 slums in 12 districts of Karnataka. Problem Statement: India with the highest burden of global TB (26%) and two million cases annually, accounts for approximately one fifth of the global incidence. WHO estimates 300,000 people die from TB annually in India. India expanded the coverage of Directly Observed Treatment, Short-course chemotherapy (DOTS) to the entire country as early as 2006. However, the performance of RNTCP has not been uniform across states. While the national annual new smear-positive (NSP) case notification rate is 53, it is much lower at 47 in Karnataka. A third of TB patients in India reside in urban slums. Approach: Under SHOPS, KHPT actively engages with communities through key opinion leaders and community structures. Interpersonal communication, by Outreach workers through house-to-house visits and at aggregation points, is the primary method used for communication about TB and its management and to increase demand for sputum examination and DOTS. pHCP are mapped, trained and mentored by KHPT. ORWs also provide patient and family counseling on TB treatment, side effects and adherence, screen close contacts of index patients especially children under 6 years of age and screen co-morbidities including HIV, diabetes and malnutrition and risk factors including alcoholism, tobacco use, occupational hazards making appropriate accompanied or documented referrals. A treatment ‘buddy’ system for the patients involving close friends or family members, ICT-based support, DOTS Prerana (inspiration) groups of TB patients, family members and community, DOTS Mitra (friend) helpline services are also used for care and support services. Results: The intervention educated 39988 slum dwellers, referred 1731 chest symptomatics, tested 1061 patients and initiated 248 patients on anti-TB treatment within three months of intervention through continuous community engagement. Conclusions: The intervention’s potential to increase access to preferred health care providers, reduce patient and health system delays in diagnosis and initiation of treatment, improve health seeking behaviour and enhance compliance of pHCPs to standard treatment protocols is being monitored. Initial results are promising.

Keywords: DOTS, KHPT, health outcomes, public and private sector

Procedia PDF Downloads 294

Authors: Mark McGuire, Eric Shannon, John Parmigiani

Abstract:

Timber harvesting increasingly involves mechanized equipment. This has increased the efficiency of harvesting, but has also introduced worker-safety concerns. One such concern arises from the use of harvesters. During operation, harvesters subject saw chain to large dynamic mechanical stresses. These stresses can, under certain conditions, cause the saw chain to fracture. The high speed of harvester saw chain can cause the resulting open chain loop to fracture a second time due to the dynamic loads placed upon it as it travels through space. If a second fracture occurs, it can result in a projectile consisting of one-to-several chain links. This projectile is referred to as a chain shot. It has speeds similar to a bullet but typically has greater mass and is a significant safety concern. Numerous examples exist of chain shots penetrating bullet-proof barriers and causing severe injury and death. Improved harvester-cab barriers can help prevent injury however a comprehensive scientific understanding of chain shot is required to consistently reduce or prevent it. Obtaining this understanding requires a test machine with the capability to cause chain shot to occur under carefully controlled conditions and accurately measure the response. Worldwide few such test machine exist. Those that do focus on validating the ability of barriers to withstand a chain shot impact rather than obtaining a scientific understanding of the chain shot event itself. The purpose of this paper is to describe the design, fabrication, and use of a test machine capable of a comprehensive scientific investigation of chain shot. The capabilities of this machine are to test all commercially-available saw chains and bars at chain tensions and speeds meeting and exceeding those typically encountered in harvester use and accurately measure the corresponding key technical parameters. The test machine was constructed inside of a standard shipping container. This provides space for both an operator station and a test chamber. In order to contain the chain shot under any possible test conditions, the test chamber was lined with a base layer of AR500 steel followed by an overlay of HDPE. To accommodate varying bar orientations and fracture-initiation sites, the entire saw chain drive unit and bar mounting system is modular and capable of being located anywhere in the test chamber. The drive unit consists of a high-speed electric motor with a flywheel. Standard Ponsse harvester head components are used to bar mounting and chain tensioning. Chain lubrication is provided by a separate peristaltic pump. Chain fracture is initiated through ISO standard 11837. Measure parameters include shaft speed, motor vibration, bearing temperatures, motor temperature, motor current draw, hydraulic fluid pressure, chain force at fracture, and high-speed camera images. Results show that the machine is capable of consistently causing chain shot. Measurement output shows fracture location and the force associated with fracture as a function of saw chain speed and tension. Use of this machine will result in a scientific understanding of chain shot and consequently improved products and greater harvester operator safety.

Keywords: chain shot, safety, testing, timber harvesters

Procedia PDF Downloads 127

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

Abstract:

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

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

Procedia PDF Downloads 115

Authors: Khin Thi Htun, James Jain, Tim Andrews

Abstract:

This study examines the under-researched phenomenon of crowdfunding use and effectiveness in developing non-western markets. More precisely, using an institutional theoretical lens, the research explores the attitudes, motivations, and practice surrounding the initiation, development, and receipt of crowdfunding campaignsin a business context symptomatic of widely dissimilar regulatory, normative cognitive institutional ‘pillars’ to those studied – and utilized in practice - to date. As, in essence, a form of alternative finance, crowdfunding is used primarily to fund a wide range of projects through the securement of small amounts of money from a large pool of investors/participants. Being tied almost inextricably to e-commerce channels, the practice of crowdfunding typically sources its means and communicates the purpose of each venture mainly, though not exclusively, online. The wide range of projects supported to date span social entrepreneurship, community benefits initiatives, creative and artistic endeavors, assistance to disadvantaged social cohorts, and small business start-ups. Adopting a longitudinal, comparative approach, the study reported here embodies an investigation centered on six case start-up campaigns within the Thai societal context, covering a range of fundings calls and cause choices. Data was sourced from a variety of respondents using semi-structured interviews, observation (direct and participant), and company information. Results suggest that the motives and effectiveness of crowdfunding campaigns differ significantly in non-western consumer contexts from the norms that have evolved to date in mature Western contexts(particularly the US and UK). Specifically, whereas data on the different regulatory pressures showed relatively insignificant variation, the results regarding cognitive and, especially, normative dissimilarities between the Thai and US/UK institutional profiles surfaced potentially important differences with far-reaching implications. Particular issuesto emerge from our data concerned consumer motivation in terms of support and engagement with different types of campaigns. This was found to stem from social norms symptomatic of ‘collectivist’ and ‘relations based/particularist’ cultural assistance behavior, in turn, linked to deeply-held societal values regarding interpersonal network (‘in group’) reciprocity. This research serves to refine and extend the limited body of knowledge to date on crowdfunding by exploring the phenomenon in a non-western, non-developed country contextswhere social norms and values differ. This was achieved through uncovering and explicating the effects of cultural dissimilarity on motivation, decision-making, construed ethics, and general engagement with crowdfunding ideas. Implications for theory into e-marketing and cross-cultural marketing, as well as for practitioners seeking to develop effective crowdfunding campaigns in a Southeast Asian cultural environment, are discussed to conclude the paper.

Keywords: crowdfunding, national culture, e-marketing, cross-cultural business

Procedia PDF Downloads 129

Authors: Javier Enciso-Benavides, Fredy Fabian, Carlos Castaneda, Luis Alfaro, Alex Choque, Aparicio Aguilar, Javier Enciso

Abstract:

Background: The use of biomarkers in breast cancer diagnosis, therapy, and prognosis has gained increasing interest. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and may cause relapse. Therefore, due to the importance of diagnosis, therapy, and prognosis, several biomarkers that characterize CSCs have been identified; however, in treatment-naïve triple-negative breast tumors, there is an urgent need to identify new biomarkers and therapeutic targets. According to this, the aim of this study was to identify serum proteins associated with cancer stem cells and pluripotency in women with triple-negative breast tumors in order to subsequently identify a biomarker for this type of breast tumor. Material and Methods: Whole blood samples from 12 women with histopathologically diagnosed triple-negative breast tumors were used after obtaining informed consent from the patient. Blood serum was obtained by conventional procedure and frozen at -80ºC. Identification of cancer stem cell-associated proteins was performed by matrix-assisted laser desorption/ionisation-assisted laser desorption/ionisation mass spectrometry (MALDI-TOF MS), protein analysis was obtained using the AB Sciex TOF/TOF™ 5800 system (AB Sciex, USA). Sequences not aligned by ProteinPilot™ software were analyzed by Protein BLAST. Results: The following proteins related to pluripotency and cancer stem cells were identified by MALDI TOF/TOF mass spectrometry: A-chain, Serpin A12 [Homo sapiens], AIEBP [Homo sapiens], Alpha-one antitrypsin, AT {internal fragment} [human, partial peptide, 20 aa] [Homo sapiens], collagen alpha 1 chain precursor variant [Homo sapiens], retinoblastoma-associated protein variant [Homo sapiens], insulin receptor, CRA_c isoform [Homo sapiens], Hydroxyisourate hydrolase [Streptomyces scopuliridis], MUCIN-6 [Macaca mulatta], Alpha-actinin-3 [Chrysochloris asiatica], Polyprotein M, CRA_d isoform, partial [Homo sapiens], Transcription factor SOX-12 [Homo sapiens]. Recommendations: The serum proteins identified in this study should be investigated in the exosome of triple-negative breast cancer stem cells and in the blood serum of women without breast cancer. Subsequently, proteins found only in the blood serum of women with triple-negative breast cancer should be identified in situ in triple-negative breast cancer tissue in order to identify a biomarker to study the evolution of this type of cancer, or that could be a therapeutic target. Conclusions: Eleven cancer stem cell-related serum proteins were identified in 12 women with triple-negative breast cancer, of which MUCIN-6, retinoblastoma-associated protein variant, transcription factor SOX-12, and collagen alpha 1 chain are the most representative and have not been studied so far in this type of breast tumor. Acknowledgement: This work was supported by Proyecto CONCYTEC–Banco Mundial “Mejoramiento y Ampliacion de los Servicios del Sistema Nacional de Ciencia Tecnología e Innovacion Tecnologica” 8682-PE (104-2018-FONDECYT-BM-IADT-AV).

Keywords: triple-negative breast cancer, MALDI TOF/TOF MS, serum proteins, cancer stem cells

Procedia PDF Downloads 188

Authors: Mahla Azimi

Abstract:

Introduction: Post-bladder catheter infection is a common and significant healthcare-associated infection that affects individuals with indwelling urinary catheters. These infections can lead to various complications, including urinary tract infections (UTIs), bacteremia, sepsis, and increased morbidity and mortality rates. This article aims to provide a comprehensive review of post-bladder catheter infections, including their causes, risk factors, clinical presentation, diagnosis, treatment options, and preventive measures. Causes and Risk Factors: Post-bladder catheter infections primarily occur due to the colonization of microorganisms on the surface of the urinary catheter. The most common pathogens involved are Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus species. Several risk factors contribute to the development of these infections, such as prolonged catheterization duration, improper insertion technique, poor hygiene practices during catheter care, compromised immune system function in patients with underlying conditions or immunosuppressive therapy. Clinical Presentation: Patients with post-bladder catheter infections may present with symptoms such as fever, chills, malaise, suprapubic pain or tenderness, and cloudy or foul-smelling urine. In severe cases or when left untreated for an extended period of time, patients may develop more severe symptoms like hematuria or signs of systemic infection. Diagnosis: The diagnosis of post-bladder catheter infection involves a combination of clinical evaluation and laboratory investigations. Urinalysis is crucial in identifying pyuria (presence of white blood cells) and bacteriuria (presence of bacteria). A urine culture is performed to identify the causative organism(s) and determine its antibiotic susceptibility profile. Treatment Options: Prompt initiation of appropriate antibiotic therapy is essential in managing post-bladder catheter infections. Empirical treatment should cover common pathogens until culture results are available. The choice of antibiotics should be guided by local antibiogram data to ensure optimal therapy. In some cases, catheter removal may be necessary, especially if the infection is recurrent or associated with severe complications. Preventive Measures: Prevention plays a vital role in reducing the incidence of post-bladder catheter infections. Strategies include proper hand hygiene, aseptic technique during catheter insertion and care, regular catheter maintenance, and timely removal of unnecessary catheters. Healthcare professionals should also promote patient education regarding self-care practices and signs of infection. Conclusion: Post-bladder catheter infections are a significant healthcare concern that can lead to severe complications and increased healthcare costs. Early recognition, appropriate diagnosis, and prompt treatment are crucial in managing these infections effectively. Implementing preventive measures can significantly reduce the incidence of post-bladder catheter infections and improve patient outcomes. Further research is needed to explore novel strategies for prevention and management in this field.

Keywords: post-bladder catheter infection, urinary tract infection, bacteriuria, indwelling urinary catheters, prevention

Procedia PDF Downloads 55

Authors: Tracey Woods

Abstract:

In the ever-evolving landscape of academia, the traditional role of the librarian has undergone a remarkable transformation. Once considered as custodians of books and gatekeepers of information, librarians have the potential to take on the vital role of facilitators of cross and inter-disciplinary projects. This shift is driven by the growing recognition of the value of interdisciplinary collaboration in addressing complex research questions in pursuit of novel solutions to real-world problems. This paper shall explore the potential of the academic librarian’s role in facilitating innovative, multi-disciplinary projects, both recognising and validating the vital role that the librarian plays in a somewhat underplayed profession. Academic libraries support teaching, the strengthening of knowledge discourse, and, potentially, the development of innovative practices. As the role of the library gradually morphs from a quiet repository of books to a community-based information hub, a potential opportunity arises. The academic librarian’s role is to build knowledge across a wide span of topics, from the advancement of AI to subject-specific information, and, whilst librarians are generally not offered the research opportunities and funding that the traditional academic disciplines enjoy, they are often invited to help build research in support of the academic. This identifies that one of the primary skills of any 21st-century librarian must be the ability to collaborate and facilitate multi-disciplinary projects. In universities seeking to develop research diversity and academic performance, there is an increasing awareness of the need for collaboration between faculties to enable novel directions and advancements. This idea has been documented and discussed by several researchers; however, there is not a great deal of literature available from recent studies. Having a team based in the library that is adept at creating effective collaborative partnerships is valuable for any academic institution. This paper outlines the development of such a project, initiated within and around an identified library-specific need: the replication of fragile special collections for object-based learning. The research was developed as a multi-disciplinary project involving the faculties of engineering (digital twins lab), architecture, design, and education. Centred around methods for developing a fragile archive into a series of tactile objects furthers knowledge and understanding in both the role of the library as a facilitator of projects, chairing and supporting, alongside contributing to the research process and innovating ideas through the bank of knowledge found amongst the staff and their liaising capabilities. This paper shall present the method of project development from the initiation of ideas to the development of prototypes and dissemination of the objects to teaching departments for analysis. The exact replication of artefacts is also balanced with the adaptation and evolutionary speculations initiated by the design team when adapted as a teaching studio method. The dynamic response required from the library to generate and facilitate these multi-disciplinary projects highlights the information expertise and liaison skills that the librarian possesses. As academia embraces this evolution, the potential for groundbreaking discoveries and innovative solutions across disciplines becomes increasingly attainable.

Keywords: Liaison librarian, multi-disciplinary collaborations, library innovations, librarian stakeholders

Procedia PDF Downloads 40

Authors: Taghrid Asfar, Olusanya J. Oluwole, Michael Schmidt, Alejandra Casas, Zoran Bursac, Wasim Maziak.

Abstract:

Waterpipe (WP) smoking (a.k.a. hookah) has increased dramatically in the US mainly due to the misperception that it is safer than cigarette smoking. Mounting evidence show that WP smoking is addictive and harmful. Health warning labels (HWLs) are effective in communicating smoking-related risks. Currently, the FDA requires that WP tobacco packages have a textual HWL about nicotine. While this represents a good step, it is inadequate given the established harm of WP smoking beyond addiction and the superior performance of pictorial HWLs over text-only ones. We developed 24 WP pictorial HWLs in a Delphi study among international expert panel. HWLs were grouped into 6 themes: addiction, harm compared to cigarettes, harm to others, health effects, quitting, and specific harms. This study aims to compare the effect of the pictorial HWLs compared to the FDA HWL, and 2) the effect of pictorial HWLs between the 6 themes. A 2x7 between/within subject online factorial experimental study was conducted among a national convenience sample of 300 (50% current WP smokers; 50% nonsmokers) US adults (females 71.1%; mean age of 31.1±3.41 years) in March 2022. The first factor varied WP smoking status (smokers, nonsmokers). The second factor varied the HWL theme and type (text, pictorial). Participants were randomized to view and rate 7 HWLs: 1 FDA text HWL (control) and 6 HWLs, one from each of the 6 themes, all presented in random order. HWLs were rated based on the message impact framework into five categories: attention, reaction (believability, relevance, fear), perceived effectiveness, intentions to quit WP among current smokers, and intention to not initiate WP among nonsmokers. measures were assessed on a 5-point Likert scale (1=not at all to 5=very much) for attention and reaction and on a 7-point Likert scale (1=not at all to 7=very much) for the perceived effectiveness and intentions to quit or not initiate WP smoking. Means and SDs of outcome measures for each HWL type and theme were calculated. Planned comparisons using Friedman test followed by pairwise Wilcoxon signed-rank test for multiple comparisons were used to examine distributional differences of outcomes between the HWL type and themes. Approximately 74.4 % of participants were non-Hispanic Whites, 68.4% had college degrees, and 41.5% were under the poverty level. Participants reported starting WTS on average at 20.3±8.19 years. Compared with the FDA text HWL, pictorial HWLs elicited higher attention (p<0.0001), fear (p<0.0001), harm perception (p<0.0003), perceived effectiveness (p<0.0001), and intentions to quit (p=0.0014) and not initiate WP smoking (p<0.0003). HWLs in theme 3 (harm to others) achieved the highest rating in attention (4.14±1), believability (4.15±0.95), overall perceived effectiveness (7.60±2.35), harm perception (7.53±2.43), and intentions to quit (7.35±2.57). HWLs in theme 2 (WP harm compared to cigarettes) achieved the highest rating in discouraging WP smoking initiation (7.32±2.54). Pictorial HWLs were superior to the FDA text-only for several communication outcomes. Pictorial HWLs related to WP harm to others and WP harm compared to cigarette are promising. These findings provide strong evidence for the potential implementation of WP-specific pictorial HWLs.

Keywords: health communication, waterpipe smoking, factorial experiment, reaction, harm perception, tobacco regulations

Procedia PDF Downloads 88

Authors: Adiba Matin, Daniel Cabrera, Javiera Bellolio, Jasmine Stewart, Dana Gerberi (librarian), Nathan Cummins, Fernanda Bellolio

Abstract:

OBJECTIVES: Artificial intelligence (AI) tools are becoming more prevalent in healthcare settings, particularly for diagnostic and therapeutic recommendations, with an expected surge in the incoming years. The bedside use of this technology for clinicians opens the possibility of disagreements between the recommendations from AI algorithms and clinicians’ judgment. There is a paucity in the literature analyzing nature and possible outcomes of these potential conflicts, particularly related to ethical considerations. The goal of this scoping review is to identify, analyze and classify current themes and potential strategies addressing ethical conflicts originating from the conflict between AI and human recommendations. METHODS: A protocol was written prior to the initiation of the study. Relevant literature was searched by a medical librarian for the terms of artificial intelligence, healthcare and liability, ethics, or conflict. Search was run in 2021 in Ovid Cochrane Central Register of Controlled Trials, Embase, Medline, IEEE Xplore, Scopus, and Web of Science Core Collection. Articles describing the role of AI in healthcare that mentioned conflict between humans and AI were included in the primary search. Two investigators working independently and in duplicate screened titles and abstracts and reviewed full-text of potentially eligible studies. Data was abstracted into tables and reported by themes. We followed methodological guidelines for Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). RESULTS: Of 6846 titles and abstracts, 225 full texts were selected, and 48 articles included in this review. 23 articles were included as original research and review papers. 25 were included as editorials and commentaries with similar themes. There was a lack of consensus in the included articles on who would be held liable for mistakes incurred by following AI recommendations. It appears that there is a dichotomy of the perceived ethical consequences depending on if the negative outcome is a result of a human versus AI conflict or secondary to a deviation from standard of care. Themes identified included transparency versus opacity of recommendations, data bias, liability of outcomes, regulatory framework, and the overall scope of artificial intelligence in healthcare. A relevant issue identified was the concern by clinicians of the “black box” nature of these recommendations and the ability to judge appropriateness of AI guidance. CONCLUSION AI clinical tools are being rapidly developed and adopted, and the use of this technology will create conflicts between AI algorithms and healthcare workers with various outcomes. In turn, these conflicts may have legal, and ethical considerations. There is limited consensus about the focus of ethical and liability for outcomes originated from disagreements. This scoping review identified the importance of framing the problem in terms of conflict between standard of care or not, and informed by the themes of transparency/opacity, data bias, legal liability, absent regulatory frameworks and understanding of the technology. Finally, limited recommendations to mitigate ethical conflicts between AI and humans have been identified. Further work is necessary in this field.

Keywords: ethics, artificial intelligence, emergency medicine, review

Procedia PDF Downloads 70

Authors: Neelofar, Khursheed Alam, Jamal Ahmad

Abstract:

Protein modification in diabetes mellitus may lead to early glycation products (EGPs) or amadori product as well as advanced glycation end products (AGEs). Early glycation involves the reaction of glucose with N-terminal and lysyl side chain amino groups to form Schiff’s base which undergoes rearrangements to form more stable early glycation product known as Amadori product. After Amadori, the reactions become more complicated leading to the formation of advanced glycation end products (AGEs) that interact with various AGE receptors, thereby playing an important role in the long-term complications of diabetes. Millard reaction or nonenzymatic glycation reaction accelerate in diabetes due to hyperglycation and alter serum protein’s structure, their normal functions that lead micro and macro vascular complications in diabetic patients. In this study, Human Serum Albumin (HSA) with a constant concentration was incubated with different concentrations of glucose at 370C for a week. At 4th day, Amadori product was formed that was confirmed by colorimetric method NBT assay and TBA assay which both are authenticate early glycation product. Conformational changes in native as well as all samples of Amadori albumin with different concentrations of glucose were investigated by various biophysical and biochemical techniques. Main biophysical techniques hyperchromacity, quenching of fluorescence intensity, FTIR, CD and SDS-PAGE were used. Further conformational changes were observed by biochemical assays mainly HMF formation, fructoseamine, reduction of fructoseamine with NaBH4, carbonyl content estimation, lysine and arginine residues estimation, ANS binding property and thiol group estimation. This study find structural and biochemical changes in Amadori modified HSA with normal to hyperchronic range of glucose with respect to native HSA. When glucose concentration was increased from normal to chronic range biochemical and structural changes also increased. Highest alteration in secondary and tertiary structure and conformation in glycated HSA was observed at the hyperchronic concentration (75mM) of glucose. Although it has been found that Amadori modified proteins is also involved in secondary complications of diabetes as AGEs but very few studies have been done to analyze the conformational changes in Amadori modified proteins due to early glycation. Most of the studies were found on the structural changes in Amadori protein at a particular glucose concentration but no study was found to compare the biophysical and biochemical changes in HSA due to early glycation with a range of glucose concentration at a constant incubation time. So this study provide the information about the biochemical and biophysical changes occur in Amadori modified albumin at a range of glucose normal to chronic in diabetes. Although many implicates currently in use i.e. glycaemic control, insulin treatment and other chemical therapies that can control many aspects of diabetes. However, even with intensive use of current antidiabetic agents more than 50 % of diabetic patient’s type 2 suffers poor glycaemic control and 18 % develop serious complications within six years of diagnosis. Experimental evidence related to diabetes suggests that preventing the nonenzymatic glycation of relevant proteins or blocking their biological effects might beneficially influence the evolution of vascular complications in diabetic patients or quantization of amadori adduct of HSA by authentic antibodies against HSA-EGPs can be used as marker for early detection of the initiation/progression of secondary complications of diabetes. So this research work may be helpful for the same.

Keywords: diabetes mellitus, glycation, albumin, amadori, biophysical and biochemical techniques

Procedia PDF Downloads 249

Authors: Michal Kielbik, Izabela Szulc-Kielbik, Anna Brzostek, Jaroslaw Dziadek, Magdalena Klink

Abstract:

The goal of many research groups in the world is to find new components that are important for survival of mycobacteria in the host cells. Mycobacterium tuberculosis (Mtb) possesses a number of enzymes degrading cholesterol that are considered to be an important factor for its survival and persistence in host macrophages. One of them - cholesterol oxidase (ChoD), although not being essential for cholesterol degradation, is discussed as a virulence compound, however its involvement in macrophages’ response to Mtb is still not sufficiently determined. The recognition of tubercle bacilli antigens by pathogen recognition receptors is crucial for the initiation of the host innate immune response. An important receptor that has been implicated in the recognition and/or uptake of Mtb is Toll-like receptor type 2 (TLR2). Engagement of TLR2 results in the activation and phosphorylation of intracellular signaling proteins including IRAK-1 and -4, TRAF-6, which in turn leads to the activation of target kinases and transcription factors responsible for bactericidal and pro-inflammatory response of macrophages. The aim of these studies was a detailed clarification of the role of Mtb cholesterol oxidase as a virulence factor affecting the TLR2 signaling pathway in human macrophages. As human macrophages the THP-1 differentiated cells were applied. The virulent wild-type Mtb strain (H37Rv), its mutant lacking a functional copy of gene encoding cholesterol oxidase (∆choD), as well as complimented strain (∆choD–choD) were used. We tested the impact of Mtb strains on the expression of TLR2-depended signaling proteins (mRNA level, cytosolic level and phosphorylation status). The cytokine and bactericidal response of THP-1 derived macrophages infected with Mtb strains in relation to TLR2 signaling pathway dependence was also determined. We found that during the 24-hours of infection process the wild-type and complemented Mtb significantly reduced the cytosolic level and phosphorylation status of IRAK-4 and TRAF-6 proteins in macrophages, that was not observed in the case of ΔchoD mutant. Decreasement of TLR2-dependent signaling proteins, induced by wild-type Mtb, was not dependent on the activity of proteasome. Blocking of TLR2 expression, before infection, effectively prevented the induced by wild-type strain reduction of cytosolic level and phosphorylation of IRAK-4. None of the strains affected the surface expression of TLR2. The mRNA level of IRAK-4 and TRAF-6 genes were significantly increased in macrophages 24 hours post-infection with either of tested strains. However, the impact of wild-type Mtb strain on both examined genes was significantly stronger than its ΔchoD mutant. We also found that wild-type strain stimulated macrophages to release high amount of immunosuppressive IL-10, accompanied by low amount of pro-inflammatory IL-8 and bactericidal nitric oxide in comparison to mutant lacking cholesterol oxidase. The influence of wild-type Mtb on this type of macrophages' response strongly dependent on fully active IRAK-1 and IRAK-4 signaling proteins. In conclusion, Mtb using cholesterol oxidase causes the over-activation of TLR2 signaling proteins leading to the reduction of their cytosolic level and activity resulting in the modulation of macrophages response to allow its intracellular survival. Supported by grant: 2014/15/B/NZ6/01565, National Science Center, Poland

Keywords: Mycobacterium tuberculosis, cholesterol oxidase, macrophages, TLR2-dependent signaling pathway

Procedia PDF Downloads 397

Authors: Rita Sassine, Yassine Hassani, Mohamad Al Omari, Stéphanie Guibert

Abstract:

Building Information Modelling (BIM) is the process of creating, managing, and centralizing information during the building lifecycle. BIM can be used all over a construction project, from the initiation phase to the planning and execution phases to the maintenance and lifecycle management phase. For existing buildings, BIM can be used for specific applications such as lifecycle management. However, most of the existing buildings don’t have a BIM model. Creating a compatible BIM for existing buildings is very challenging. It requires special equipment for data capturing and efforts to convert these data into a BIM model. The main difficulties for such projects are to define the data needed, the level of development (LOD), and the methodology to be adopted. In addition to managing information for an existing building, studying the impact of the built environment is a challenging topic. So, integrating the existing terrain that surrounds buildings into the digital model is essential to be able to make several simulations as flood simulation, energy simulation, etc. Making a replication of the physical model and updating its information in real-time to make its Digital Twin (DT) is very important. The Digital Terrain Model (DTM) represents the ground surface of the terrain by a set of discrete points with unique height values over 2D points based on reference surface (e.g., mean sea level, geoid, and ellipsoid). In addition, information related to the type of pavement materials, types of vegetation and heights and damaged surfaces can be integrated. Our aim in this study is to define the methodology to be used in order to provide a 3D BIM model for the site and the existing building based on the case study of “Ecole Spéciale des Travaux Publiques (ESTP Paris)” school of engineering campus. The property is located on a hilly site of 5 hectares and is composed of more than 20 buildings with a total area of 32 000 square meters and a height between 50 and 68 meters. In this work, the campus precise levelling grid according to the NGF-IGN69 altimetric system and the grid control points are computed according to (Réseau Gédésique Français) RGF93 – Lambert 93 french system with different methods: (i) Land topographic surveying methods using robotic total station, (ii) GNSS (Global Network Satellite sytem) levelling grid with NRTK (Network Real Time Kinematic) mode, (iii) Point clouds generated by laser scanning. These technologies allow the computation of multiple building parameters such as boundary limits, the number of floors, the floors georeferencing, the georeferencing of the 4 base corners of each building, etc. Once the entry data are identified, the digital model of each building is done. The DTM is also modeled. The process of altimetric determination is complex and requires efforts in order to collect and analyze multiple data formats. Since many technologies can be used to produce digital models, different file formats such as DraWinG (DWG), LASer (LAS), Comma-separated values (CSV), Industry Foundation Classes (IFC) and ReViT (RVT) will be generated. Checking the interoperability between BIM models is very important. In this work, all models are linked together and shared on 3DEXPERIENCE collaborative platform.

Keywords: building information modeling, digital terrain model, existing buildings, interoperability

Procedia PDF Downloads 80

Authors: Natasa Ilic, Alisa Gruden-Movsesijan, Maja Kosanovic, Sofija Glamoclija, Marina Bekic, Ljiljana Sofronic-Milosavljevic, Sergej Tomic

Abstract:

As a very promising candidate for modulation of immune response in the sense of biasing the inflammatory towards an anti-inflammatory type of response, Trichinella spiralis infection was shown to successfully alleviate the severity of experimental autoimmune encephalomyelitis, the animal model of human disease multiple sclerosis. This effect is achieved via its excretory-secretory muscle larvae (ES L1) products which affect the maturation status and function of dendritic cells (DCs) by inducing the tolerogenic status of DCs, which leads to the mitigation of the Th1 type of response and the activation of a regulatory type of immune response both in vitro and in vivo. ES L1 alone or via treated DCs successfully mitigated EAE in the same manner as the infection itself. On the other hand, it has been shown that T. spiralis infection slows down the tumour growth and significantly reduces the tumour size in the model of mouse melanoma, while ES L1 possesses a pro-apoptotic and anti-survival effect on melanoma cells in vitro. Hence, although the mechanisms still need to be revealed, T. spiralis infection and its ES L1 products have a bit of controversial potential to modulate both inflammatory diseases and malignancies. The recent discovery of T. spiralis extracellular vesicles (TsEVs) suggested that the induction of complex regulation of the immune response requires simultaneous delivery of different signals in nano-sized packages. This study aimed to explore whether TsEVs bare the similar potential as ES L1 to influence the status of DCs in initiation, progression and regulation of immune response, but also to investigate the effect of both ES L1 and TsEVs on myeloid derived suppressor cells (MDSC) which present the regular tumour tissue environment. TsEVs were enriched from the conditioned medium of T. spiralis muscle larvae by differential centrifugation and used for the treatment of human monocyte-derived DCs and MDSC. On DCs, TsEVs induced low expression of HLA DR and CD40, moderate CD83 and CD86, and increased expression of ILT3 and CCR7 on treated DCs, i.e., they induced tolerogenic DCs. Such DCs possess the capacity to polarize T cell immune response towards regulatory type, with an increased proportion of IL-10 and TGF-β producing cells, similarly to ES L1. These findings indicated that the ability of TsEVs to induce tolerogenic DCs favoring anti-inflammatory responses may be helpful in coping with diseases that involve Th1/Th17-, but also Th2-mediated inflammation. In MDSC in vitro model, although both ES L1 and TsEVs had the same impact on MDSC phenotype i.e., they acted suppressive, ES L1 treated MDSC, unlike TsEVs treated ones, induced T cell response characterized by the increased RoRγT and IFN-γ, while the proportion of regulatory cells was decreased followed by the decrease in IL-10 and TGF-β positive cells proportion within this population. These findings indicate the interesting ability of ES L1 to modulate T cells response via MDSC towards pro-inflamatory type, suggesting that, unlike TsEVs which consistently demonstrate the suppresive effect on inflammatory response, it could be used also for the development of new approaches aimed for the treatment of malignant diseases. Acknowledgment: This work was funded by the Promis project – Nano-MDCS-Thera, Science Fund, Republic of Serbia.

Keywords: dendritic cells, myeloid derived suppressor cells, immunomodulation, Trichinella spiralis

Procedia PDF Downloads 181

Authors: Imen Asma Mbarek, Alexis Rusinek, Etienne Petit, Guy Sutter, Gautier List

Abstract:

Over the past two decades, the automotive, aerospace and army industries have been paying an increasing attention to Finite Elements (FE) numerical simulations of the fracture process of their structures. Thanks to the numerical simulations, it is nowadays possible to analyze several problems involving costly and dangerous extreme loadings safely and at a reduced cost such as blast or ballistic impact problems. The present paper is concerned with ballistic impact and perforation problems involving ductile fracture of thin armor steel targets. The target fracture process depends usually on various parameters: the projectile nose shape, the target thickness and its mechanical properties as well as the impact conditions (friction, oblique/normal impact...). In this work, the investigations are concerned with the normal impact of a conical head-shaped projectile on thin armor steel targets. The main aim is to establish a comparative study of four fracture criteria that are commonly used in the fracture process simulations of structures subjected to extreme loadings such as ballistic impact and perforation. Usually, the damage initiation results from a complex physical process that occurs at the micromechanical scale. On a macro scale and according to the following fracture models, the variables on which the fracture depends are mainly the stress triaxiality ƞ, the strain rate, temperature T, and eventually the Lode angle parameter Ɵ. The four failure criteria are: the critical strain to failure model, the Johnson-Cook model, the Wierzbicki model and the Modified Hosford-Coulomb model MHC. Using the SEM, the observations of the fracture facies of tension specimen and of armor steel targets impacted at low and high incident velocities show that the fracture of the specimens is a ductile fracture. The failure mode of the targets is petalling with crack propagation and the fracture facies are covered with micro-cavities. The parameters of each ductile fracture model have been identified for three armor steels and the applicability of each criterion was evaluated using experimental investigations coupled to numerical simulations. Two loading paths were investigated in this study, under a wide range of strain rates. Namely, quasi-static and intermediate uniaxial tension and quasi-static and dynamic double shear testing allow covering various values of stress triaxiality ƞ and of the Lode angle parameter Ɵ. All experiments were conducted on three different armor steel specimen under quasi-static strain rates ranging from 10-4 to 10-1 1/s and at three different temperatures ranging from 297K to 500K, allowing drawing the influence of temperature on the fracture process. Intermediate tension testing was coupled to dynamic double shear experiments conducted on the Hopkinson tube device, allowing to spot the effect of high strain rate on the damage evolution and the crack propagation. The aforementioned fracture criteria are implemented into the FE code ABAQUS via VUMAT subroutine and they were coupled to suitable constitutive relations allow having reliable results of ballistic impact problems simulation. The calibration of the four damage criteria as well as a concise evaluation of the applicability of each criterion are detailed in this work.

Keywords: armor steels, ballistic impact, damage criteria, ductile fracture, SEM

Procedia PDF Downloads 292

Authors: Shereen Ismail Fawaz, Shin-Ichi Izumi, Nouran Mohamed Salah, Heba G. Saber, Ibrahim Mohamed Roushdi

Abstract:

Background: Multiple sclerosis (MS) is a chronic, inflammatory, mainly demyelinating disease of the central nervous system, more common in young adults. Cerebellar involvement is one of the most disabling lesions in MS and is usually a sign of disease progression. It plays a major role in the planning, initiation, and organization of movement via its influence on the motor cortex and corticospinal outputs. Therefore, it contributes to controlling movement, motor adaptation, and motor learning, in addition to its vast connections with other major pathways controlling balance, such as the cerebellopropriospinal pathways and cerebellovestibular pathways. Hence, trying to stimulate the cerebellum by facilitatory protocols will add to our motor control and balance function. Non-invasive brain stimulation, both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), has recently emerged as effective neuromodulators to influence motor and nonmotor functions of the brain. Anodal tDCS has been shown to improve motor skill learning and motor performance beyond the training period. Similarly, rTMS, when used at high frequency (>5 Hz), has a facilitatory effect on the motor cortex. Objective: Our aim was to determine the effect of high-frequency rTMS over the cerebellum in improving balance and functional ambulation of multiple sclerosis patients with Ataxia. Patients and methods: This was a randomized single-blinded placebo-controlled prospective trial on 40 patients. The active group (N=20) received real rTMS sessions, and the control group (N=20) received Sham rTMS using a placebo program designed for this treatment. Both groups received 12 sessions of high-frequency rTMS over the cerebellum, followed by an intensive exercise training program. Sessions were given three times per week for four weeks. The active group protocol had a frequency of 10 Hz rTMS over the cerebellar vermis, work period 5S, number of trains 25, and intertrain interval 25s. The total number of pulses was 1250 pulses per session. The control group received Sham rTMS using a placebo program designed for this treatment. Both groups of patients received an intensive exercise program, which included generalized strengthening exercises, endurance and aerobic training, trunk abdominal exercises, generalized balance training exercises, and task-oriented training such as Boxing. As a primary outcome measure the Modified ICARS was used. Static Posturography was done with: Patients were tested both with open and closed eyes. Secondary outcome measures included the expanded Disability Status Scale (EDSS) and 8 Meter walk test (8MWT). Results: The active group showed significant improvements in all the functional scales, modified ICARS, EDSS, and 8-meter walk test, in addition to significant differences in static Posturography with open eyes, while the control group did not show such differences. Conclusion: Cerebellar high-frequency rTMS could be effective in the functional improvement of balance in MS patients with ataxia.

Keywords: brain neuromodulation, high frequency rTMS, cerebellar stimulation, multiple sclerosis, balance rehabilitation

Procedia PDF Downloads 59

Authors: Kartik Gupta, Virendra Kumar, Sanjeev Sinha, N. Jagannathan

Abstract:

Introduction: A significant number of patients having human immunodeficiency virus (HIV) infection show a neurocognitive decline (NCD) ranging from minor cognitive impairment to severe dementia. The possible causes of NCD in HIV-infected patients include brain injury by HIV before cART, neurotoxic viral proteins and metabolic abnormalities. In the present study, we compared the level of NCD in asymptomatic HIV-infected patients with changes in brain metabolites measured by using magnetic resonance spectroscopy (MRS). Methods: 43 HIV-positive patients (30 males and 13 females) coming to ART center of the hospital and HIV-seronegative healthy subjects were recruited for the study. All the participants completed MRI and MRS examination, detailed clinical assessments and a battery of neuropsychological tests. All the MR investigations were carried out at 3.0T MRI scanner (Ingenia/Achieva, Philips, Netherlands). MRI examination protocol included the acquisition of T2-weighted imaging in axial, coronal and sagittal planes, T1-weighted, FLAIR, and DWI images in the axial plane. Patients who showed any apparent lesion on MRI were excluded from the study. T2-weighted images in three orthogonal planes were used to localize the voxel in left frontal lobe white matter (FWM) and left basal ganglia (BG) for single voxel MRS. Single voxel MRS spectra were acquired with a point resolved spectroscopy (PRESS) localization pulse sequence at an echo time (TE) of 35 ms and a repetition time (TR) of 2000 ms with 64 or 128 scans. Automated preprocessing and determination of absolute concentrations of metabolites were estimated using LCModel by water scaling method and the Cramer-Rao lower bounds for all metabolites analyzed in the study were below 15\%. Levels of total N-acetyl aspartate (tNAA), total choline (tCho), glutamate + glutamine (Glx), total creatine (tCr), were measured. Cognition was tested using a battery of tests validated for Indian population. The cognitive domains tested were the memory, attention-information processing, abstraction-executive, simple and complex perceptual motor skills. Z-scores normalized according to age, sex and education standard were used to calculate dysfunction in these individual domains. The NCD was defined as dysfunction with Z-score ≤ 2 in at least two domains. One-way ANOVA was used to compare the difference in brain metabolites between the patients and healthy subjects. Results: NCD was found in 23 (53%) patients. There was no significant difference in age, CD4 count and viral load between the two groups. Maximum impairment was found in the domains of memory and simple motor skills i.e., 19/43 (44%). The prevalence of deficit in attention-information processing, complex perceptual motor skills and abstraction-executive function was 37%, 35%, 33% respectively. Subjects with NCD had a higher level of Glutamate in the Frontal region (8.03 ± 2.30 v/s. 10.26 ± 5.24, p-value 0.001). Conclusion: Among newly diagnosed, ART-naïve retroviral disease patients from India, cognitive decline was found in 53\% patients using tests validated for this population. Those with neurocognitive decline had a significantly higher level of Glutamate in the left frontal region. There was no significant difference in age, CD4 count and viral load at initiation of ART between the two groups.

Keywords: HIV, neurocognitive decline, neurometabolites, magnetic resonance spectroscopy

Procedia PDF Downloads 176

Authors: Ankur Chaudhuri, Sibani Sen Chakraborty

Abstract:

In human, glutaminyl cyclase activity is highly abundant in neuronal and secretory tissues and is preferentially restricted to hypothalamus and pituitary. The N-terminal modification of β-amyloids (Aβs) peptides by the generation of a pyro-glutamyl (pGlu) modified Aβs (pE-Aβs) is an important process in the initiation of the formation of neurotoxic plaques in Alzheimer’s disease (AD). This process is catalyzed by glutaminyl cyclase (QC). The expression of QC is characteristically up-regulated in the early stage of AD, and the hallmark of the inhibition of QC is the prevention of the formation of pE-Aβs and plaques. A computer-aided drug design (CADD) process was employed to give an idea for the designing of potentially active compounds to understand the inhibitory potency against human glutaminyl cyclase (QC). This work elaborates the ligand-based and structure-based pharmacophore exploration of glutaminyl cyclase (QC) by using the known inhibitors. Three dimensional (3D) quantitative structure-activity relationship (QSAR) methods were applied to 154 compounds with known IC50 values. All the inhibitors were divided into two sets, training-set, and test-sets. Generally, training-set was used to build the quantitative pharmacophore model based on the principle of structural diversity, whereas the test-set was employed to evaluate the predictive ability of the pharmacophore hypotheses. A chemical feature-based pharmacophore model was generated from the known 92 training-set compounds by HypoGen module implemented in Discovery Studio 2017 R2 software package. The best hypothesis was selected (Hypo1) based upon the highest correlation coefficient (0.8906), lowest total cost (463.72), and the lowest root mean square deviation (2.24Å) values. The highest correlation coefficient value indicates greater predictive activity of the hypothesis, whereas the lower root mean square deviation signifies a small deviation of experimental activity from the predicted one. The best pharmacophore model (Hypo1) of the candidate inhibitors predicted comprised four features: two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. The Hypo1 was validated by several parameters such as test set activity prediction, cost analysis, Fischer's randomization test, leave-one-out method, and heat map of ligand profiler. The predicted features were then used for virtual screening of potential compounds from NCI, ASINEX, Maybridge and Chembridge databases. More than seven million compounds were used for this purpose. The hit compounds were filtered by drug-likeness and pharmacokinetics properties. The selective hits were docked to the high-resolution three-dimensional structure of the target protein glutaminyl cyclase (PDB ID: 2AFU/2AFW) to filter these hits further. To validate the molecular docking results, the most active compound from the dataset was selected as a reference molecule. From the density functional theory (DFT) study, ten molecules were selected based on their highest HOMO (highest occupied molecular orbitals) energy and the lowest bandgap values. Molecular dynamics simulations with explicit solvation systems of the final ten hit compounds revealed that a large number of non-covalent interactions were formed with the binding site of the human glutaminyl cyclase. It was suggested that the hit compounds reported in this study could help in future designing of potent inhibitors as leads against human glutaminyl cyclase.

Keywords: glutaminyl cyclase, hit lead, pharmacophore model, simulation

Procedia PDF Downloads 115

Authors: Michael R. Shurin, Galina Shurin, Vladimir A. Kirichenko

Abstract:

Background. Visibility of hepatic malignancies is poor on non-contrast imaging for daily verification of liver malignancies prior to radiation therapy on MRI-guided Linear Accelerators (MR-Linac). Ferumoxytol® (Feraheme, AMAG Pharmaceuticals, Waltham, MA) is a SPION agent that is increasingly utilized off-label as hepatic MRI contrast. This agent has the advantage of providing a functional assessment of the liver based upon its uptake by hepatic Kupffer cells proportionate to vascular perfusion, resulting in strong T1, T2 and T2* relaxation effects and enhanced contrast of malignant tumors, which lack Kupffer cells. The latter characteristic has been recently utilized for MRI-guided radiotherapy planning with precision targeting of liver malignancies. However potential radiotoxicity of SPION has never been addressed for its safe use as an MRI-contrast agent during liver radiotherapy on MRI-Linac. This study defines the radiomodulating properties of SPIONs in vitro on human monocyte and macrophage cell lines exposed to 60Go gamma-rays within clinical radiotherapy dose range. Methods. Human monocyte and macrophages cell line in cultures were loaded with a clinically relevant concentration of Ferumoxytol (30µg/ml) for 2 and 24 h and irradiated to 3Gy, 5Gy and 10Gy. Cells were washed and cultured for additional 24 and 48 h prior to assessing their phenotypic activation by flow cytometry and function, including viability (Annexin V/PI assay), proliferation (MTT assay) and cytokine expression (Luminex assay). Results. Our results reveled that SPION affected both human monocytes and macrophages in vitro. Specifically, iron oxide nanoparticles decreased radiation-induced apoptosis and prevented radiation-induced inhibition of human monocyte proliferative activity. Furthermore, Ferumoxytol protected monocytes from radiation-induced modulation of phenotype. For instance, while irradiation decreased polarization of monocytes to CD11b+CD14+ and CD11bnegCD14neg phenotype, Ferumoxytol prevented these effects. In macrophages, Ferumoxytol counteracted the ability of radiation to up-regulate cell polarization to CD11b+CD14+ phenotype and prevented radiation-induced down-regulation of expression of HLA-DR and CD86 molecules. Finally, Ferumoxytol uptake by human monocytes down-regulated expression of pro-inflammatory chemokines MIP-1α (Macrophage inflammatory protein 1α), MIP-1β (CCL4) and RANTES (CCL5). In macrophages, Ferumoxytol reversed the expression of IL-1RA, IL-8, IP-10 (CXCL10) and TNF-α, and up-regulates expression of MCP-1 (CCL2) and MIP-1α in irradiated macrophages. Conclusion. SPION agent Ferumoxytol increases resistance of human monocytes to radiation-induced cell death in vitro and supports anti-inflammatory phenotype of human macrophages under radiation. The effect is radiation dose-dependent and depends on the duration of Feraheme uptake. This study also finds strong evidence that SPIONs reversed the effect of radiation on the expression of pro-inflammatory cytokines involved in initiation and development of radiation-induced liver damage. Correlative translational work at our institution will directly assess the cyto-protective effects of Ferumoxytol on human Kupfer cells in vitro and ex vivo analysis of explanted liver specimens in a subset of patients receiving Feraheme-enhanced MRI-guided radiotherapy to the primary liver tumors as a bridge to liver transplant.

Keywords: superparamagnetic iron oxide nanoparticles, radioprotection, magnetic resonance imaging, liver

Procedia PDF Downloads 52

Authors: Paul J. McKay

Abstract:

Large-scale genome-wide association studies (GWAS) investigating genetic contributions to sexual orientation and gender identity are largely lacking and may reduce stigma experienced in the LGBTQ+ community by providing an underlying biological explanation for queerness. While there is a growing consensus within the scientific community that genetic makeup contributes – at least in part – to sexual orientation and gender identity, there is a marked lack of genomics research exploring polygenic contributions to queerness. Based on recent (2019) findings from a large-scale GWAS investigating the genetic architecture of same-sex sexual behavior, and various additional peer-reviewed publications detailing novel insights into the molecular mechanisms of sexual orientation and gender identity, we hypothesize that sexual orientation and gender identity are complex, multifactorial, and polygenic; meaning that many genetic factors contribute to these phenomena, and environmental factors play a possible role through epigenetic modulation. In recent years, large-scale GWAS studies have been paramount to our modern understanding of many other complex human traits, such as in the case of autism spectrum disorder (ASD). Despite possible benefits of such research, including reduced stigma towards queer people, improved outcomes for LGBTQ+ in familial, socio-cultural, and political contexts, and improved access to healthcare (particularly for trans populations); important risks and considerations remain surrounding this type of research. To mitigate possibilities such as invalidation of the queer identities of existing LGBTQ+ individuals, genetic discrimination, or the possibility of euthanasia of embryos with a genetic predisposition to queerness (through reproductive technologies like IVF and/or gene-editing in utero), we propose a community-engaged research (CER) framework which emphasizes the privacy and confidentiality of research participants. Importantly, the historical legacy of scientific research attempting to pathologize queerness (in particular, falsely equating gender variance to mental illness) must be acknowledged to ensure any future research conducted in this realm does not propagate notions of homophobia, transphobia or stigma against queer people. Ultimately, in a world where same-sex sexual activity is criminalized in 69 UN member states, with 67 of these states imposing imprisonment, 8 imposing public flogging, 6 (Brunei, Iran, Mauritania, Nigeria, Saudi Arabia, Yemen) invoking the death penalty, and another 5 (Afghanistan, Pakistan, Qatar, Somalia, United Arab Emirates) possibly invoking the death penalty, the importance of this research cannot be understated, as finding a biological basis for queerness would directly oppose the harmful rhetoric that “being LGBTQ+ is a choice.” Anti-trans legislation is similarly widespread: In the United States in 2022 alone (as of Oct. 13), 155 anti-trans bills have been introduced preventing trans girls and women from playing on female sports teams, barring trans youth from using bathrooms and locker rooms that align with their gender identity, banning access to gender affirming medical care (e.g., hormone-replacement therapy, gender-affirming surgeries), and imposing legal restrictions on name changes. Understanding that a general lack of knowledge about the biological basis of queerness may be a contributing factor to the societal stigma faced by gender and sexual orientation minorities, we propose the initiation of large-scale GWAS studies investigating the genetic basis of gender identity and sexual orientation.

Keywords: genome-wide association studies (GWAS), sexual and gender minorities (SGM), polygenicity, community-engaged research (CER)

Procedia PDF Downloads 48

Authors: M. M. Hassani, S. Ammann, F. K. Wittel, P. Niemz, H. J. Herrmann

Abstract:

Application of engineered wood, especially in the form of glued-laminated timbers has increased significantly. Recent progress in plywood made of high strength and high stiffness hardwoods, like European beech, gives designers in general more freedom by increased dimensional stability and load-bearing capacity. However, the strong hygric dependence of basically all mechanical properties renders many innovative ideas futile. The tendency of hardwood for higher moisture sorption and swelling coefficients lead to significant residual stresses in glued-laminated configurations, cross-laminated patterns in particular. These stress fields cause initiation and evolution of cracks in the bond-lines resulting in: interfacial de-bonding, loss of structural integrity, and reduction of load-carrying capacity. Subsequently, delamination of glued-laminated timbers made of hardwood elements can be considered as the dominant failure mechanism in such composite elements. In addition, long-term creep and mechano-sorption under changing environmental conditions lead to loss of stiffness and can amplify delamination growth over the lifetime of a structure even after decades. In this study we investigate the delamination process of adhesively bonded hardwood (European beech) elements subjected to changing climatic conditions. To gain further insight into the long-term performance of adhesively bonded elements during the design phase of new products, the development and verification of an authentic moisture-dependent constitutive model for various species is of great significance. Since up to now, a comprehensive moisture-dependent rheological model comprising all possibly emerging deformation mechanisms was missing, a 3D orthotropic elasto-plastic, visco-elastic, mechano-sorptive material model for wood, with all material constants being defined as a function of moisture content, was developed. Apart from the solid wood adherends, adhesive layer also plays a crucial role in the generation and distribution of the interfacial stresses. Adhesive substance can be treated as a continuum layer constructed from finite elements, represented as a homogeneous and isotropic material. To obtain a realistic assessment on the mechanical performance of the adhesive layer and a detailed look at the interfacial stress distributions, a generic constitutive model including all potentially activated deformation modes, namely elastic, plastic, and visco-elastic creep was developed. We focused our studies on the three most common adhesive systems for structural timber engineering: one-component polyurethane adhesive (PUR), melamine-urea-formaldehyde (MUF), and phenol-resorcinol-formaldehyde (PRF). The corresponding numerical integration approaches, with additive decomposition of the total strain are implemented within the ABAQUS FEM environment by means of user subroutine UMAT. To predict the true stress state, we perform a history dependent sequential moisture-stress analysis using the developed material models for both wood substrate and adhesive layer. Prediction of the delamination process is founded on the fracture mechanical properties of the adhesive bond-line, measured under different levels of moisture content and application of the cohesive interface elements. Finally, we compare the numerical predictions with the experimental observations of de-bonding in glued-laminated samples under changing environmental conditions.

Keywords: engineered wood, adhesive, material model, FEM analysis, fracture mechanics, delamination

Procedia PDF Downloads 407

Authors: Andrew Gennett

Abstract:

Designing for fungal development means embracing the symbiotic relationship between the living system and built environment. The potential of mycelium post-colonization is explored for the fabrication of advanced pure mycelium products, going beyond the conventional methods of aggregating materials. Fruiting induction imparts desired material properties such as enhanced environmental resistance. Production approach allows for simultaneous generation of multiple products while scaling up raw materials supply suitable for architectural applications. The following work explores the integration of fungal environmental perception with computational design of built fruiting chambers. Polyporales, are classified by their porous reproductive tissues supported by a wood-like context tissue covered by a hard waterproofing coat of hydrobpobins. Persisting for years in the wild, these species represent material properties that would be highly desired in moving beyond flat sheets of arial mycelium as with leather or bacon applications. Understanding the inherent environmental perception of fungi has become the basis for working with and inducing desired hyphal differentiation. Working within the native signal interpretation of a mycelium mass during fruiting induction provides the means to apply textures and color to the final finishing coat. A delicate interplay between meeting human-centered goals while designing around natural processes of living systems represents a blend of art and science. Architecturally, physical simulations inform model design for simple modular fruiting chambers that change as fungal growth progresses, while biological life science principles describe the internal computations occurring within the fungal hyphae. First, a form filling phase of growth is controlled by growth chamber environment. Second, an initiation phase of growth forms the final exterior finishing texture. Hyphal densification induces cellular cascades, in turn producing the classical hardened cuticle, UV protective molecule production, as well, as waterproofing finish. Upon fruiting process completion, the fully colonized spent substrate holds considerable value and is not considered waste. Instead, it becomes a valuable resource in the next cycle of production scale-up. However, the acquisition of new substrate resources poses a critical question, particularly as these resources become increasingly scarce. Pursuing a regenerative design paradigm from the environmental perspective, the usage of “agricultural waste” for architectural materials would prove a continuation of the destructive practices established by the previous industrial regime. For these residues from fields and forests serve a vital ecological role protecting the soil surface in combating erosion while reducing evaporation and fostering a biologically diverse food web. Instead, urban centers have been identified as abundant sources of new substrate material. Diverting the waste from secondary locations such as food processing centers, papers mills, and recycling facilities not only reduces landfill burden but leverages the latent value of these waste steams as precious resources for mycelium cultivation. In conclusion, working with living systems through innovative built environments for fungal development, provides the needed gain of function and resilience of mycelium products. The next generation of sustainable fungal products will go beyond the current binding process, with a focus upon reducing landfill burden from urban centers. In final considerations, biophilic material builds to an ecologically regenerative recycling production cycle.

Keywords: regenerative agriculture, mycelium fabrication, growth chamber design, sustainable resource acquisition, fungal morphogenesis, soil fertility

Procedia PDF Downloads 41

Authors: Krishna Raj Regmi

Abstract:

A “Climate change adaptation and disaster risk management for sustainable agriculture” project was implemented in Nepal, a Himalayan country during 2008 to 2013 sponsored jointly by Food and Agriculture Organization (FAO) and United Nations Development Programme (UNDP), Nepal. The paper is based on the results and findings of this joint pilot project. The climate change events such as increased intensity of erratic rains in short spells, trend of prolonged drought, gradual rise in temperature in the higher elevations and occurrence of cold and hot waves in Terai (lower plains) has led to flash floods, massive erosion in the hills particularly in Churia range and drying of water sources. These recurring natural and climate-induced disasters are causing heavy damages through sedimentation and inundation of agricultural lands, crops, livestock, infrastructures and rural settlements in the downstream plains and thus reducing agriculture productivity and food security in the country. About 65% of the cultivated land in Nepal is rainfed with drought-prone characteristics and stabilization of agricultural production and productivity in these tracts will be possible through adoption of rainfed and drought-tolerant technologies as well as efficient soil-water management by the local communities. The adaptation and mitigation technologies and options identified by the project for soil erosion, flash floods and landslide control are on-farm watershed management, sloping land agriculture technologies (SALT), agro-forestry practices, agri-silvi-pastoral management, hedge-row contour planting, bio-engineering along slopes and river banks, plantation of multi-purpose trees and management of degraded waste land including sandy river-bed flood plains. The stress tolerant technologies with respect to drought, floods and temperature stress for efficient utilization of nutrient, soil, water and other resources for increased productivity are adoption of stress tolerant crop varieties and breeds of animals, indigenous proven technologies, mixed and inter-cropping systems, system of rice/wheat intensification (SRI), direct rice seeding, double transplanting of rice, off-season vegetable production and regular management of nurseries, orchards and animal sheds. The alternate energy use options and resource conservation practices for use by local communities are installation of bio-gas plants and clean stoves (Chulla range) for mitigation of green house gas (GHG) emissions, use of organic manures and bio-pesticides, jatropha cultivation, green manuring in rice fields and minimum/zero tillage practices for marshy lands. The efficient water management practices for increasing productivity of crops and livestock are use of micro-irrigation practices, construction of water conservation and water harvesting ponds, use of overhead water tanks and Thai jars for rain water harvesting and rehabilitation of on-farm irrigation systems. Initiation of some works on community-based early warning system, strengthening of met stations and disaster database management has made genuine efforts in providing disaster-tailored early warning, meteorological and insurance services to the local communities. Contingent planning is recommended to develop coping strategies and capacities of local communities to adopt necessary changes in the cropping patterns and practices in relation to adverse climatic and disaster risk conditions. At the end, adoption of awareness raising and capacity development activities (technical and institutional) and networking on climate-induced disaster and risks through training, visits and knowledge sharing workshops, dissemination of technical know-how and technologies, conduct of farmers' field schools, development of extension materials and their displays are being promoted. However, there is still need of strong coordination and linkage between agriculture, environment, forestry, meteorology, irrigation, climate-induced pro-active disaster preparedness and research at the ministry, department and district level for up-scaling, implementation and institutionalization of climate change and disaster risk management activities and adaptation mitigation options in agriculture for sustainable livelihoods of the communities.

Keywords: climate change adaptation, disaster risk management, soil-water management practices, sustainable agriculture

Procedia PDF Downloads 482