Search results for: pathways

Authors: Gizaw Mamo Gebeyehu, Marianna Pap, Geza Makkai, Tibor Z. Janosi, Shima Rashidian, Tibor A. Rauch

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Sepsis poses a significant global health threat, necessitating extensive exploration of indicators tied to its pathological mechanisms and multi-organ dysfunction. While murine studies have shed light on sepsis, the intricate cellular and molecular landscape in human sepsis remains enigmatic. Exploring the influence of activated monocyte-derived exosomes in sepsis sheds light on a promising pathway for understanding the intricate cellular and molecular mechanisms involved in this condition in humans. In sepsis, exosome-borne mRNA and miRNA orchestrate immune response gene expression in recipient cells. Yet, the specifics of exosome-mediated cell-to-cell communication, especially how mRNA cargoes modulate gene expression in recipient cells, remain poorly understood. This study aims to elucidate the precise molecular pathways through which exosomal mRNA cargo, particularly MAFB, contributes to the developing sepsis-induced molecular aberrations in liver tissues, employing rigorously defined cell culture conditions. THP-1 cells were treated with LPS to induce changes in exosomal RNA profiles. Exosomes were isolated and characterized using microscopy and mass spectrometry. RNA was extracted from exosomes and sequenced. The most abundant exosomal mRNAs were subjected to GO analysis for functional annotation analysis and KEGG database analysis to identify the involved enriched pathways. PCR (Polymerase Chain Reaction), RNA sequencing, and Western blotting were involved to analyze changes in gene expression, protein levels, and signaling pathways within the liver cells( HepG2) after exposure to exosomal MAFB. This study pinpoints exosomal MAFB as a potential key regulator linked to liver cell damage during sepsis, along with associated genes (miR155HG, H3F3A, and possibly JARD2) forming a crucial molecular pathway contributing to liver cell injury, Together, these elements indicate a vital molecular pathway that plays a significant role in the emergence of liver cell injury during sepsis.. These findings suggest the importance of further research on these components for potential therapeutic interventions in managing acute liver damage in sepsis.

Keywords: sepsis, exososome, exosomal MAFB, LPS-induced THP-1 cells, RNA profiles, sepsis-triggered liver injury

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Authors: R. Tariq, R. Lee

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Background: Additional demands placed on senior clinical teams with ongoing COVID-19 management has accelerated the need to harness the wider healthcare professional resources and upskill them to take on greater clinical responsibility safely. The UK NHS Long Term Plan (2019)¹ emphasises the importance of expanding Advanced Practitioners’ (APs) roles to take on more clinical diagnostic responsibilities to cope with increased demand. In acute settings, APs are often the first point of care for patients and require training to take on initial triage responsibilities efficiently and safely. Critically, their roles include determining which onward services the patients may require, and assessing whether they can be treated at home, avoiding unnecessary admissions to the hospital. Dem Dx is a Clinical Reasoning Platform (CRP) that claims to help frontline healthcare professionals independently assess and triage patients. It guides the clinician from presenting complaints through associated symptoms to a running list of differential diagnoses, media, national and institutional guidelines. The objective of this study was to compare the clinical referral rates and guidelines adherence registered by the HMR Urgent Community Care Team (UCCT)² and Dem Dx recommendations using retrospective cases. Methodology: 192 cases seen by the UCCT were anonymised and reassessed using Dem Dx clinical pathways. We compared the UCCT’s performance with Dem Dx regarding the appropriateness of onward referrals. We also compared the clinical assessment regarding adherence to NICE guidelines recorded on the clinical notes and the presence of suitable guidance in each case. The cases were audited by two medical doctors. Results: Dem Dx demonstrated appropriate referrals in 85% of cases, compared to 47% in the UCCT team (p<0.001). Of particular note, Dem Dx demonstrated an almost 65% (p<0.001) improvement in the efficacy and appropriateness of referrals in a highly experienced clinical team. The effectiveness of Dem Dx is in part attributable to the relevant NICE and local guidelines found within the platform's pathways and was found to be suitable in 86% of cases. Conclusion: This study highlights the potential of clinical decision support, as Dem Dx, to improve the quality of onward clinical referrals delivered by a multidisciplinary team in primary care. It demonstrated that it could support healthcare professionals in making appropriate referrals, especially those that may be overlooked by providing suitable clinical guidelines directly embedded into cases and clear referral pathways. Further evaluation in the clinical setting has been planned to confirm those assumptions in a prospective study.

Keywords: advanced practitioner, clinical reasoning, clinical decision-making, management, multidisciplinary team, referrals, triage

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Authors: Ji Won Kim, Moo Yeol Lee, Keon Wook Kang

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GV-1001, 16 amino acid fragment of human telomerase reverse transcriptase catalytic subunit (hTERT), has been developed as an injectable cancer vaccine for many types of solid tumors showing high-level of telomerase activity. In the present study, we evaluated the anti-cancer effect of GV-1001 on androgen-receptor-positive prostate cancer. Two signaling pathways, Gs-adenylate cyclase-cAMP and Gq-IP3-Ca2+ pathways play a central role in GnRH receptor (GnRHR)-mediated activities. We found that leuprolide acetate (LA) mainly acted on Gq-mediated Ca2+ signaling, while GV-1001 preferentially acted on cAMP signaling; and both the effects were counteracted by cetrorelix, a GnRHR antagonist. We further tested whether GV-1001 affects tumor growth of human prostate cancer cells in vivo. Prostate tumor xenografts were established using LNCap, androgen receptor-positive prostate cancer cells, and the nude mice bearing tumors were subcutaneously injected with GV-1001 (0.01, 0.1, 1, 10 microg/kg/day) and LA (0.01 microg/kg/day) for 2 weeks. GV-1001 (1 and 10 microg/kg/day) significantly inhibited tumor growth of LNCap xenografts. Interestingly, mRNA expression of MMP2 and MMP9 was significantly suppressed by GV-1001 injection, but not by LA administration. Boyden chamber assay revealed that GV-1001 potently inhibited cell migration of LNCap. Our finding suggests that GV-1001 as a novel GnRHR ligand, has anti-proliferative and anti-migratory effects on androgen receptor-positive prostate cancer cells.

Keywords: GV-1001, GnRH, hTERT, prostate cancer

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Authors: O. H. Gebril, N. A. Meguid

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Background: Iron had been a focus of interest recently as a main exaggerating factor for oxidative stresses in the central nervous system and a link to various neurological disorders is suspected. Many studies with various techniques showed evidence of disturbed iron-related proteins in the cell in human and animal models of neurodegenerative disorders. Also, linkage to significant pathological changes had been evidenced e.g. apoptosis and cell signaling. On the other hand, the role of iron in neurodevelopmental disorders is still unclear. With increasing prevalence of autism worldwide, some changes in iron parameters and its stores were documented in many studies. This study includes Haemochromatosis HFE gene polymorphisms (p.H63D and p.C282Y) and ferroportin gene (SLC40A1) Q248H polymorphism in autism and control children. Materials and Methods: Whole genome DNA was extracted; p.H63D and p.C282Y genotyping was studied using specific sequence amplification followed by restriction enzyme digestion on a sample of autism patients (25 cases) and twenty controls. Results: The p.H63D is seen more than the C282Y among both autism and control samples, with no significant association of p.H63D or p.C282Y polymorphism and autism was revealed. Also, no association with Q248H polymorphism was evidenced. Conclusion: The study results do not prove the role of cellular iron genes polymorphisms as risk factors for neurodevelopmental disorders, and in turn highlights the specificity of cellular iron related pathways in neurodegeneration. These results demand further gene expression studies to elucidate the main pathophysiological pathways that are disturbed in autism and other neurodevelopmental disorders.

Keywords: iron, neurodevelopmental, oxidative stress, haemohromatosis, ferroportin, genes

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Authors: Mindy A. Brown, Emma E. Reardon, Jennifer Isenhour, Sheila E. Crowell, K. Lee Raby, Elisabeth Conradt

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The positive impact of maternal sensitivity on infant social and emotional development is well-known, as is the notion that stress may impair a mother’s ability to provide sensitive care for her infant. However, individual differences in susceptibility to parenting-related stress are less understood. This study explores how chronic prenatal stress moderates the effect of acute stressors on maternal sensitivity. Data were gathered from 110 mothers and their 7-month-old infants. Mothers were exposed to either an acute stress task or a control task, after which they engaged in the still-face paradigm, a face-to-face interaction where maternal sensitivity was measured. Chronic maternal stress was assessed using the UCLA Life Stress Interview during the third trimester of pregnancy. The results revealed that among mothers exposed to the stress condition, those with higher chronic stress levels in the previous six months displayed significantly lower sensitivity during the still-face paradigm compared to those with lower chronic stress. Notably, past stress levels had no effect on maternal sensitivity in the control condition. These findings suggest a moderating effect of chronic stress on maternal caregiving behavior, with higher prenatal stress diminishing a mother’s ability to cope with acute parenting-related stressors in the present. The mechanisms behind this may involve changes in stress reactivity pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis or altered emotion regulation strategies developed in response to chronic stress. Understanding these pathways could guide targeted interventions for mothers who may be more vulnerable to stress, improving caregiving outcomes.

Keywords: acute stress, maternal stress, prenatal stress, still-face paradigm

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Authors: Fadi Saleh, Çığdem Sezer Zhmurov

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Biopharmaceuticals represent one of the wildest developing fields within biotechnology, and the biological macromolecules being produced inside cells have a variety of applications for therapies. In the past, mammalian cells, especially CHO cells, have been employed in the production of biopharmaceuticals. This is because these cells can achieve human-like completion of PTM. These systems, however, carry apparent disadvantages like high production costs, vulnerability to contamination, and limitations in scalability. This research is focused on the utilization of microalgae as a bioreactor system for the synthesis of biopharmaceutical glycoproteins in relation to PTMs, particularly N-glycosylation. The research points to a growing interest in microalgae as a potential substitute for more conventional expression systems. A number of advantages exist in the use of microalgae, including rapid growth rates, the lack of common human pathogens, controlled scalability in bioreactors, and the ability of some PTMs to take place. Thus, the potential of microalgae to produce recombinant proteins with favorable characteristics makes this a promising platform in order to produce biopharmaceuticals. The study focuses on the examination of the N-glycosylation pathways across different species of microalgae. This investigation is important as N-glycosylation—the process by which carbohydrate groups are linked to proteins—profoundly influences the stability, activity, and general performance of glycoproteins. Additionally, bioinformatics methodologies are employed to explain the genetic pathways implicated in N-glycosylation within microalgae, with the intention of modifying these organisms to produce glycoproteins suitable for human consumption. In this way, the present comparative analysis of the N-glycosylation pathway in humans and microalgae can be used to bridge both systems in order to produce biopharmaceuticals with humanized glycosylation profiles within the microalgal organisms. The results of the research underline microalgae's potential to help improve some of the limitations associated with traditional biopharmaceutical production systems. The study may help in the creation of a cost-effective and scale-up means of producing quality biopharmaceuticals by modifying microalgae genetically to produce glycoproteins with N-glycosylation that is compatible with humans. Improvements in effectiveness will benefit biopharmaceutical production and the biopharmaceutical sector with this novel, green, and efficient expression platform. This thesis, therefore, is thorough research into the viability of microalgae as an efficient platform for producing biopharmaceutical glycoproteins. Based on the in-depth bioinformatic analysis of microalgal N-glycosylation pathways, a platform for their engineering to produce human-compatible glycoproteins is set out in this work. The findings obtained in this research will have significant implications for the biopharmaceutical industry by opening up a new way of developing safer, more efficient, and economically more feasible biopharmaceutical manufacturing platforms.

Keywords: microalgae, glycoproteins, post-translational modification, genome

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Authors: Michelle Blewitt, Scott P. Wilson, Heidi Tait, Juniper Riordan

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Rubber crumb is a physical and chemical pollutant of concern for the environment and human health, warranting immediate investigations into its pathways to the environment and potential impacts. This emerging microplastic is created by shredding end-of-life tyres into ‘rubber crumb’ particles between 1-5mm used on synthetic turf fields and soft-fall playgrounds as a solution to intensifying tyre waste worldwide. Despite having known toxic and carcinogenic properties, studies into the transportation pathways and movement patterns of rubber crumbs from these surfaces remain in their infancy. To address this deficit, AUSMAP, the Australian Microplastic Assessment Project, in partnership with the Tangaroa Blue Foundation, conducted a study to quantify crumb loss from soft-fall surfaces. To our best knowledge, this is the first of its kind, with funding for the audits being provided by the Australian Government’s Reef Trust. Sampling occurred at 12 soft-fall playgrounds within the Great Barrier Reef Catchment Area on Australia’s North-East coast, in close proximity to the United Nations World Heritage Listed Reef. Samples were collected over a 12-month period using randomized sediment cores at 0, 2 and 4 meters away from the playground edge along a 20-meter transect. This approach facilitated two objectives pertaining to particle movement: to establish that crumb loss is occurring and that it decreases with distance from the soft-fall surface. Rubber crumb abundance was expressed as a total value and used to determine an expected average of rubber crumb loss per m2. An Analysis of Variance (ANOVA) was used to compare the differences in crumb abundance at each interval from the playground. Site characteristics, including surrounding sediment type, playground age, degree of ultra-violet exposure and amount of foot traffic, were additionally recorded for the comparison. Preliminary findings indicate that crumb is being lost at considerable rates from soft-fall playgrounds in the region, emphasizing an urgent need to further examine it as a potential source of aquatic pollution, soil contamination and threat to individuals who regularly utilize these surfaces. Additional implications for the future of rubber crumbs as a fit-for-purpose recycling initiative will be discussed with regard to industry, governments and the economic burden of surface maintenance and/ or replacement.

Keywords: microplastics, toxic rubber crumb, litter pathways, marine environment

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Authors: Pramod Somvanshi, Manu Tomar, K. V. Venkatesh

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Insulin and glucagon are responsible for homeostasis of key plasma metabolites like glucose, amino acids and fatty acids in the blood plasma. These hormones act antagonistically to each other during the secretion and signaling stages. In the present work, we analyze the effect of macronutrients on the response from integrated insulin and glucagon signaling pathways. The insulin and glucagon pathways are connected by DAG (a calcium signaling component which is part of the glucagon signaling module) which activates PKC and inhibits IRS (insulin signaling component) constituting a crosstalk. AKT (insulin signaling component) inhibits cAMP (glucagon signaling component) through PDE3 forming the other crosstalk between the two signaling pathways. Physiological level of anabolism and catabolism is captured through a metric quantified by the activity levels of AKT and PKA in their phosphorylated states, which represent the insulin and glucagon signaling endpoints, respectively. Under resting and starving conditions, the phosphorylation metric represents homeostasis indicating a balance between the anabolic and catabolic activities in the tissues. The steady state analysis of the integrated network demonstrates the presence of a bistable response in the phosphorylation metric with respect to input plasma glucose levels. This indicates that two steady state conditions (one in the homeostatic zone and other in the anabolic zone) are possible for a given glucose concentration depending on the ON or OFF path. When glucose levels rise above normal, during post-meal conditions, the bistability is observed in the anabolic space denoting the dominance of the glycogenesis in liver. For glucose concentrations lower than the physiological levels, while exercising, metabolic response lies in the catabolic space denoting the prevalence of glycogenolysis in liver. The non-linear positive feedback of AKT on IRS in insulin signaling module of the network is the main cause of the bistable response. The span of bistability in the phosphorylation metric increases as plasma fatty acid and amino acid levels rise and eventually the response turns monostable and catabolic representing diabetic conditions. In the case of high fat or protein diet, fatty acids and amino acids have an inhibitory effect on the insulin signaling pathway by increasing the serine phosphorylation of IRS protein via the activation of PKC and S6K, respectively. Similar analysis was also performed with respect to input amino acid and fatty acid levels. This emergent property of bistability in the integrated network helps us understand why it becomes extremely difficult to treat obesity and diabetes when blood glucose level rises beyond a certain value.

Keywords: bistability, diabetes, feedback and crosstalk, obesity

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Authors: Hafiz Arbab Sakandar

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Time-restricted intermittent fasting (TRIF) impacts host’s physiology and health. Plenty of health benefits have been reported for TRIF in animal models. However, limited studies have been conducted on humans especially in underdeveloped economies. Here, we designed a study to investigate the impact of TRIF/Ramadan fasting (16:8) on the modulation of gut-microbiome structure, metabolic pathways, and predicted metabolites and explored the correlation among them at different time points (during and after the month of Ramadan) in Pakistani Expats living in China. We observed different trends of Shannon-Wiener index in different subjects; however, all subjects showed substantial change in bacterial diversity with the progression of TRIF. Moreover, the changes in gut microbial structure by the end of TRIF were higher vis-a-vis in the beginning, significant difference was observed among individuals. Additionally, metabolic pathways analysis revealed that amino acid, carbohydrate and energy metabolism, glycan biosynthesis metabolism of cofactors and vitamins were significantly affected by TRIF. Pyridoxamine, glutamate, citrulline, arachidonic acid, and short chain fatty acid showed substantial difference at different time points based on the predicted metabolism. In conclusion, these results contribute to further our understanding about the key relationship among, dietary intervention (TRIF), gut microbiome structure and function. The preliminary results from study demonstrate significant potential for elucidating the mechanisms underlying gut microbiome stability and enhancing the effectiveness of microbiome-tailored interventions among the Pakistani populace. Nonetheless, extensive, and rigorous large-scale research on the Pakistani population is necessary to expound on the association between diet, gut microbiome, and overall health.

Keywords: gut microbiome, health, fasting, functionality

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Authors: Mamdouh Milad Adly Morkos

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Despite having the greatest rates of mortality and morbidity in the world, low- and middle-income (LMIC) nations trail high-income nations in terms of the number of clinical trials, the number of qualified researchers, and the amount of research information specific to their people. Health inequities and the use of precision medicine may be hampered by a lack of local genomic data, clinical pharmacology and pharmacometrics competence, and training opportunities. These issues can be solved by carrying out health care infrastructure development, which includes data gathering and well-designed clinical pharmacology training in LMICs. It will be advantageous if there is international cooperation focused at enhancing education and infrastructure and promoting locally motivated clinical trials and research. This paper outlines various instances where clinical pharmacology knowledge could be put to use, including pharmacogenomic opportunities that could lead to better clinical guideline recommendations. Examples of how clinical pharmacology training can be successfully implemented in LMICs are also provided, including clinical pharmacology and pharmacometrics training programmes in Africa and a Tanzanian researcher's personal experience while on a training sabbatical in the United States. These training initiatives will profit from advocacy for clinical pharmacologists' employment prospects and career development pathways, which are gradually becoming acknowledged and established in LMICs. The advancement of training and research infrastructure to increase clinical pharmacologists' knowledge in LMICs would be extremely beneficial because they have a significant role to play in global health

Keywords: electromagnetic solar system, nano-material, nano pharmacology, pharmacovigilance, quantum theoryclinical simulation, education, pharmacology, simulation, virtual learning low- and middle-income, clinical pharmacology, pharmacometrics, career development pathways

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Authors: A. A. Adebayo, A. O. Ogunkeyede, A. O. Adeigbe

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Digital globalisation and yarn of Nigeria society to overcome the digital divide have resulted in contamination of soil by heavy metals (HMs) from e-waste activities at Alaba international market, Lagos, Nigeria. The aim of this research was to determine the concentration of various metals {Cadmium (Cd), Chromium (Cr), Copper (Cu), and Lead (Pb)} and identify their ecological and health risks for the people within the study area. A total of 60 soil samples were collected at Alaba market study area. Two types of samples were collected from each sampling points: topsoil (0-15 cm), subsoil (15 -30 cm). The metal concentration results showed that the soils were heavily contaminated by HMs at topsoil and subsoil. The geoaccummulation and ecological risk indices revealed high pollution level from all studied site. The health risk assessment results suggested that there is high possibility of carcinogenic risk to humans because the carcinogenic risk via corresponding exposure pathways exceeded the safety limit of 10-6 (the acceptable level of carcinogenic risk for human). Furthermore, inhalation of soil particles is the main exposure pathway for Cr to enter the human body for all ages. Children in the vicinity are exposed more to ingestion of Pb since they tend to eat earth (pica) and repeatedly suck their fingers. This study provides basic information to create awareness for a need to introduce pollution control measures and the need to protect the ecosystem and human health within the study area at Alaba international market.

Keywords: contaminated soil, ecological risk, hazard index, risk factor, exposure pathways, heavy metals

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Authors: Liang Ning, Chung Hau Yin

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Angiogenesis is the process of new blood vessel development. It has been recognized as a therapeutic target for blocking cancer growth four decades ago. Vascular sprouting is initiated by pro-angiogenic factors. Vascular endothelial cell growth factor (VEGF) plays a central role in angiogenic initiation, many patients with cancer or ocular neovascularization have been benefited from anti-VEGF therapy. Emerging approaches impacting in the later stages of vessel remodeling and maturation are expected to improve clinical efficacy. TIE receptor as well as the corresponding angiopoietin ligands, were identified as another endothelial cell specific receptor tyrosine kinase signaling system. Much efforts were made to reduce the activity of angiopoietin-TIE receptor axis. Two eudesmane-type sesquiterpenes from laggera alata, namely, 15-dihydrocostic acid and ilicic acid were found with strong anti-angiogenic properties in zebrafish model. Meanwhile, the mRNA expression levels of VEGFR2 and TIE2 pathway related genes were down-regulated in the sesquiterpenes treated zebrafish embryos. Besides, in human umbilical vein endothelial cells (HUVECs), the sesquiterpenes have the ability to inhibit VEGF-induced HUVECs proliferation and migration at non-toxic concentration. Moreover, angiopoietin-2 induced TIE2 phosphorylation was inhibited by the sesquiterpenes, the inhibitory effect was detected in angiopoietin-1 induced HUVECs proliferation as well. Thus, we hypothesized the anti-angiogenic activity of the compounds may via the inhibition of VEGF and TIE2 related pathways. How the compounds come into play as the pathways inhibitors need to be evaluated in the future.

Keywords: Laggera alata, eudesmane-type sesquiterpene, anti-angiogenesis, VEGF, angiopoietin, TIE2

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Authors: Shabnam Sarwar, Franck Lacoeuille, Nadia Withofs, Roland Hustinx

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After the development of a potential surrogate of MAA, and its successful application for the diagnosis of pulmonary embolism in artificially embolized rats’ lungs, this microparticulate system were radiolabelled with gallium-68 to synthesize 68Ga-SBMP with high radiochemical purity >99%. As a prerequisite step of clinical trials, 68Ga- labelled starch based microparticles (SBMP) were analysed for their in-vivo behavior in small animals. The purpose of the presented work includes the ex-vivo biodistribution studies of 68Ga-SBMP in order to assess the activity uptake in target organs with respect to time, excretion pathways of the radiopharmaceutical, %ID/g in major organs, T/NT ratios, in-vivo stability of the radiotracer and subsequently the microparticles in the target organs. Radiolabelling of starch based microparticles was performed by incubating it with 68Ga generator eluate (430±26 MBq) at room temperature and pressure without using any harsh reaction condition. For Ex-vivo biodistribution studies healthy White Wistar rats weighing between 345-460 g were injected intravenously 68Ga-SBMP 20±8 MBq, containing about 2,00,000-6,00,000 SBMP particles in a volume of 700µL. The rats were euthanized at predefined time intervals (5min, 30min, 60min and 120min) and their organ parts were cut, washed, and put in the pre-weighed tubes and measured for radioactivity counts through automatic Gamma counter. The 68Ga-SBMP produced >99% RCP just after 10-20 min incubation through a simple and robust procedure. Biodistribution of 68Ga-SBMP showed that initially just after 5 min post injection major uptake was observed in the lungs following by blood, heart, liver, kidneys, bladder, urine, spleen, stomach, small intestine, colon, skin and skeleton, thymus and at last the smallest activity was found in brain. Radioactivity counts stayed stable in lungs with gradual decrease with the passage of time, and after 2h post injection, almost half of the activity were seen in lungs. This is a sufficient time to perform PET/CT lungs scanning in humans while activity in the liver, spleen, gut and urinary system decreased with time. The results showed that urinary system is the excretion pathways instead of hepatobiliary excretion. There was a high value of T/NT ratios which suggest fine tune images for PET/CT lung perfusion studies henceforth further pre-clinical studies and then clinical trials should be planned in order to utilize this potential lung perfusion agent.

Keywords: starch based microparticles, gallium-68, biodistribution, target organs, excretion pathways

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Authors: Ronald Villamar-Torres, Michael Staudt, Christopher Viot

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Cotton Gossypium hirsutum L. is one of the most important industrial crops, producing the world leading natural textile fiber, but is very prone to arthropod attacks that reduce crop yield and quality. Cotton cultivation, therefore, makes an outstanding use of chemical pesticides. In reaction to herbivorous arthropods, cotton plants nevertheless show natural defense reactions, in particular through volatile organic compounds (VOCs) emissions. These natural defense mechanisms are nowadays underutilized but have a very high potential for cotton cultivation, and elucidating their genetic bases will help to improve their use. Simulating herbivory attacks by mechanical wounding of cotton plants in greenhouse, we studied by qPCR the changes in gene expression for genes of the terpenoids biosynthesis pathway. Differentially expressed genes corresponded to higher levels of the terpenoids biosynthesis pathway and not to enzymes synthesizing particular terpenoids. The genes were mapped on the G. hirsutum L. reference genome; their global relationships inside the general metabolic pathways and the biosynthesis of secondary metabolites were visualized with iPath2. The chromatographic profiles of VOCs emissions indicated first monoterpenes and sesquiterpenes emissions, dominantly four molecules known to be involved in plant reactions to arthropod attacks. As a result, the study permitted to identify potential key genes for the emission of volatile terpenoids by cotton plants in reaction to an arthropod attack, opening possibilities for molecular-assisted cotton breeding in benefit of smallholder cotton growers.

Keywords: biosynthesis pathways, cotton, mechanisms of plant defense, terpenoids, volatile organic compounds

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Authors: Alireza Monzavi Chaleshtari, Mahnaz Aliakbari Dehkordi, Nazila Esmaeili, Ahmad Alipour, Amin Asadi Hieh

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Headache disorders are one of the most common disorders of the nervous system and are associated with suffering, disability, and financial costs for patients. Mindfulness as a lifestyle, in line with human nature, has the ability to affect the emotional system, i.e. thoughts, body sensations, raw emotions and action impulses of people. The aim of this study was to test the fit of structural model of mindfulness and severity of headache mediated by resilience and perfectionism in patients with migraine. Methods: The statistical population of this study included all patients with migraine referred to neurologists in Tehran in the spring and summer of 1401. The inclusion criteria were diagnosis of migraine by a neurologist, not having mental disorders or other physical diseases, and having at least a diploma. According to the number of research variables, 180 people were selected by convenience sampling method, which online answered the Ahvaz perfectionism questionnaire (AMQ), Connor and Davidson resilience questionnaire (CD-RISC), Ahvaz migraine headache questionnaire (APS) and 5-factor mindfulness questionnaire ((MAAS). Data were analyzed using structural equation modeling and Amos software. Results: The results showed that the direct pathways of mindfulness were not significant for severe headache (P <0.05), but other direct pathways - mindfulness to resilience, mindfulness to perfectionism, resilience to severe headache and perfectionism to severe headache), Was significant (P <0.01). After modifying and removing the non-significant paths, the final model fitted. Mediating variables Resilience and perfectionism mediated all paths of predictor variables to the criterion. Conclusion: According to the findings of the present study, mindfulness in migraine patients reduces the severity of headache by promoting resilience and reducing perfectionism.

Keywords: migraine, headache severity, mindfulness, resilience, perfectionism

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Authors: Nico Fuchs, Fabian Wüllhorst, Laura Maier, Dirk Müller

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The decarbonization of building stocks necessitates the modernization of existing buildings. Key measures for this include reducing energy demands through insulation of the building envelope, replacing heat generators, and installing solar systems. Given limited financial resources, it is impractical to modernize all buildings in a portfolio simultaneously; instead, prioritization of buildings and modernization measures for a given planning horizon is essential. Optimization models for modernization pathways can assist portfolio managers in this prioritization. However, modeling and solving these large-scale optimization problems, often represented as mixed-integer problems (MIP), necessitates simplifying the operation of building energy systems particularly with respect to system dynamics and transient behavior. This raises the question of which level of simplification remains sufficient to accurately account for realistic costs and emissions of building energy systems, ensuring a fair comparison of different modernization measures. This study addresses this issue by comparing a two-stage simulation-based optimization approach with a single-stage mathematical optimization in a mixed-integer linear programming (MILP) formulation. The simulation-based approach serves as a benchmark for realistic energy system operation but requires a restriction of the solution space to discrete choices of modernization measures, such as the sizing of heating systems. After calculating the operation of different energy systems in terms of the resulting final energy demands in simulation models on a first stage, the results serve as input for a second stage MILP optimization, where the design of each building in the portfolio is optimized. In contrast to the simulation-based approach, the MILP-based approach can capture a broader variety of modernization measures due to the efficiency of MILP solvers but necessitates simplifying the building energy system operation. Both approaches are employed to determine the cost-optimal design and dimensioning of several buildings in a portfolio to meet climate targets within limited yearly budgets, resulting in a modernization pathway for the entire portfolio. The comparison reveals that the MILP formulation successfully captures design decisions of building energy systems, such as the selection of heating systems and the modernization of building envelopes. However, the results regarding the optimal dimensioning of heating technologies differ from the results of the two-stage simulation-based approach, as the MILP model tends to overestimate operational efficiency, highlighting the limitations of the MILP approach.

Keywords: building energy system optimization, model accuracy in optimization, modernization pathways, building stock decarbonization

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Authors: Hussain Mustatab Wahedi, Sun You Kim

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Skin acts as a barrier against the harmful environmental factors. Integrity and timely recovery of the skin from injuries and harmful effects of radiations is thus very important. This study aimed to investigate the importance of Sirt1 in the recovery of skin from UVB-induced damage and cutaneous wounds by using natural and synthetic novel Sirt1 activators. Juglone, known as a natural Pin1 inhibitor, and NED416 a novel synthetic Sirt1 activator were checked for their ability to regulate the expression and activity of Sirt1 and hence photo-damage and wound healing in cultured skin cells (NHDF and HaCaT cells) and mouse model by using Sirt1 siRNA knockdown, cell migration assay, GST-Pulldown assay, western blot analysis, tube formation assay, and immunohistochemistry. Interestingly, Sirt1 knockdown inhibited skin cell migration in vitro. Juglone up regulated the expression of Sirt1 in both the cell lines under normal and UVB irradiated conditions, enhanced Sirt1 activity and increased the cell viability by reducing reactive oxygen species synthesis and apoptosis. Juglone promoted wound healing by increasing cell migration and angiogenesis through Cdc42/Rac1/PAK, MAPKs and Smad pathways in skin cells. NED416 upregulated Sirt1 expression in HaCaT and NHDF cells as well as increased Sirt1 activity. NED416 promoted the process of wound healing in early as well as later stages by increasing macrophage recruitment, skin cell migration, and angiogenesis through Cdc42/Rac1 and MAPKs pathways. So, both these compounds activated Sirt1 and promoted the process of wound healing thus pointing towards the possible role of Sirt1 in skin regeneration and wound healing.

Keywords: skin regeneration, wound healing, Sirt1, UVB light

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Authors: Anjan Hazra, Nirjhar Dasgupta, Chandan Sengupta, Sauren Das

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Tea (Camellia sinensis) has received substantial attention from the scientific world time to time, not only for its commercial importance, but also for its demand to the health-conscious people across the world for its extensive use as potential sources of antioxidant supplement. These health-benefit traits primarily rely on some regulatory networks of different metabolic pathways. Development of microsatellite markers from the conserved genomic regions is being worthwhile for studying the genetic diversity of closely related species or self-pollinated species. Although several SSR markers have been reported, in tea the trait-specific Simple Sequence Repeats (SSRs) are yet to be identified, which can be used for marker assisted breeding technique. MicroRNAs are endogenous, noncoding, short RNAs directly involved in regulating gene expressions at the post-transcriptional level. It has been found that diversity in miRNA gene interferes the formation of its characteristic hair pin structure and the subsequent function. In the present study, the precursors of small regulatory RNAs (microRNAs) has been fished out from tea Expressed Sequence Tag (EST) database. Furthermore, the simple sequence repeat motifs within the putative miRNA precursor genes are also identified in order to experimentally validate their existence and function. It is already known that genic-SSR markers are very adept and breeder-friendly source for genetic diversity analysis. So, the potential outcome of this in-silico study would provide some novel clues in understanding the miRNA-triggered polymorphic genic expression controlling specific metabolic pathways, accountable for tea quality.

Keywords: micro RNA, simple sequence repeats, tea quality, trait specific marker

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Authors: Eduardo Kanagushiku Pereira, Frank Gregory Cavalcante da Silva, Barbara Soares Gonçalves, Ana Lúcia Bergamasco Galastri, Ronei Luciano Mamoni

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The inflammatory response initiates after the recognition of pathogens by receptors expressed by innate immune cells. Among these receptors, the NLRP3 was associated with the recognition of pathogenic fungi in experimental models. NLRP3 operates forming a multiproteic complex called inflammasome, which actives caspase-1, responsible for the production of the inflammatory cytokines IL-1beta and IL-18. In this study, we aimed to investigate the involvement of NLRP3 in the inflammatory response elicited in macrophages against Paracoccidioides brasiliensis (Pb), the etiologic agent of PCM. Macrophages were differentiated from THP-1 cells by treatment with phorbol-myristate-acetate. Following differentiation, macrophages were stimulated by Pb yeast cells for 24 hours, after previous treatment with specific NLRP3 (3,4-methylenedioxy-beta-nitrostyrene) and/or caspase-1 (VX-765) inhibitors, or specific inhibitors of pathways involved in NLRP3 activation such as: Reactive Oxigen Species (ROS) production (N-Acetyl-L-cysteine), K+ efflux (Glibenclamide) or phagossome acidification (Bafilomycin). Quantification of IL-1beta and IL-18 in supernatants was performed by ELISA. Our results showed that the production of IL-1beta and IL-18 by THP-1-derived-macrophages stimulated with Pb yeast cells was dependent on NLRP3 and caspase-1 activation, once the presence of their specific inhibitors diminished the production of these cytokines. Furthermore, we found that the major pathways involved in NLRP3 activation, after Pb recognition, were dependent on ROS production and K+ efflux. In conclusion, our results showed that NLRP3 participates in the recognition of Pb yeast cells by macrophages, leading to the activation of the NLRP3-inflammasome and production of IL-1beta and IL-18. Together, these cytokines can induce an inflammatory response against P. brasiliensis, essential for the establishment of the initial inflammatory response and for the development of the subsequent acquired immune response.

Keywords: inflammation, IL-1beta, IL-18, NLRP3, Paracoccidioidomycosis

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Authors: Susan Hall, Gary D. Grant, Catherine McDermott, Devinder Arora

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Introduction /Aim: The kynurenine pathway is thought to play an important role in the pathophysiology of numerous neurodegenerative diseases including depression, Alzheimer’s disease, and Parkinson’s disease. Numerous neuroactive compounds, including the neurotoxic 3-hydroxyanthranilic acid, 3-hydroxykynurenine and quinolinic acid and the neuroprotective kynurenic acid and picolinic acid, are produced through the metabolism of kynurenine and are thought to be the causative agents responsible for neurodegeneration. The toxicity of 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid has been widely evaluated and demonstrated in primary cell cultures but to date only 3-hydroxykynurenine and 3-hydroxyanthranilic acid have been shown to cause toxicity in immortal tumour cells. The aim of this study was to evaluate the toxicity of kynurenine metabolites, both individually and in combination, on SH-SY5Y neuroblastoma cells after 24 and 72 h exposure in order to explore a cost-effective model to study their neurotoxic effects and potential protective agents. Methods: SH-SY5Y neuroblastoma cells were exposed to various concentrations of the neuroactive kynurenine metabolites, both individually and in combination, for 24 and 72 h, and viability was subsequently evaluated using the Resazurin (Alamar blue) proliferation assay. Furthermore, the effects of these compounds, alone and in combination, on specific death pathways including apoptosis, necrosis and free radical production was evaluated using various assays. Results: Consistent with literature, toxicity was shown with short-term 24-hour treatments at 1000 μM concentrations for both 3-hydroxykynurenine and 3-hydroxyanthranilic acid. Combinations of kynurenine metabolites showed modest toxicity towards SH-SY5Y neuroblastoma cells in a concentration-dependent manner. Specific cell death pathways, including apoptosis, necrosis and free radical production were shown to be increased after both 24 and 72 h exposure of SH-SY5Y neuroblastoma cells to 3-hydroxykynurenine and 3-hydroxyanthranilic acid and various combinations of neurotoxic kynurenine metabolites. Conclusion: It is well documented that neurotoxic kynurenine metabolites show toxicity towards primary human neurons in the nanomolar to low micromolar concentration range. Results show that the concentrations required to show significant cell death are in the range of 1000 µM for 3-hydroxykynurenine and 3-hydroxyanthranilic acid and toxicity of quinolinic acid towards SH-SY5Y was unable to be shown. This differs significantly from toxicities observed in primary human neurons. Combinations of the neurotoxic metabolites were shown to have modest toxicity towards these cells with increased toxicity and activation of cell death pathways observed after 72 h exposure. This study suggests that the 24 h model is unsuitable for use in neurotoxicity studies, however, the 72 h model better represents the observations of the studies using primary human neurons and may provide some benefit in providing a cost-effective model to assess possible protective agents against kynurenine metabolite toxicities.

Keywords: kynurenine metabolites, neurotoxicity, quinolinic acid, SH-SY5Y neuroblastoma

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Authors: Neha Bhadauria, Indu Gaur, Shilpi Shilpi, Susmita Goswami, Prabir K. Paul

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The aerial surface of plants colonized by Human Enteric Pathogens ()has been implicated in outbreaks of enteric diseases in humans. Practice of organic farming primarily using animal dung as manure and sewage water for irrigation are the most significant source of enteric pathogens on the surface of leaves, fruits and vegetables. The present work aims to have an insight into the molecular mechanism of interaction of Human Enteric Pathogens or their metabolites with cell wall receptors in plants. Tomato plants grown under aseptic conditions at 12 hours L/D photoperiod, 25±1°C and 75% RH were inoculated individually with S. fonticola and K. pneumonia. The leaves from treated plants were sampled after 24 and 48 hours of incubation. The cell wall and cytoplasmic proteins were extracted and isocratically separated on 1D SDS-PAGE. The sampled leaves were also subjected to formaldehyde treatment prior to isolation of cytoplasmic proteins to study protein-protein interactions induced by Human Enteric Pathogens. Protein bands extracted from the gel were subjected to MALDI-TOF-TOF MS analysis. The foremost interaction of Human Enteric Pathogens on the plant surface was found to be cell wall bound receptors which possibly set ups a wave a critical protein-protein interaction in cytoplasm. The study revealed the expression and suppression of specific cytoplasmic and cell wall-bound proteins, some of them being important components of signaling pathways. The results also demonstrated HEP induced rearrangement of signaling pathways which possibly are crucial for adaptation of these pathogens to plant surface. At the end of the study, it can be concluded that controlling the over-expression or suppression of these specific proteins rearrange the signaling pathway thus reduces the outbreaks of food-borne illness.

Keywords: cytoplasmic protein, cell wall-bound protein, Human Enteric Pathogen (HEP), protein-protein interaction

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Authors: Atena Sadat Hosseini, Mohammadhossein Habibi

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Acute myeloid leukemia (AML) is the most typically diagnosed leukemia. In older adults, AML imposes a dismal outcome. AML originates with a dominant mutation, then adds collaborative, transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Several chemotherapeutic drugs are used for this cancer. These drugs are naturally associated with several side effects, and finding a more accurate molecular mechanism of these drugs can have a significant impact on the selection and better candidate of drugs for treatment. In this study, we evaluated bortezomibin myeloma cells using bioinformatics analysis and evaluation of RNA-Seq data. Then investigated the molecular pathways proteins- proteins interactions associated with this chemotherapy drug. A total of 658upregulated genes and 548 downregulated genes were sorted.AUF1 (hnRNP D0) binds and destabilizes mRNA, degradation of GLI2 by the proteasome, the role of GTSE1 in G2/M progression after G2 checkpoint, TCF dependent signaling in response to WNT demonstrated in upregulated genes. Besides insulin resistance, AKT phosphorylates targets in the nucleus, cytosine methylation, Longevity regulating pathway, and Signal Transduction of S1P Receptor were related to low expression genes. With respect to this results, HIST2H2AA3, RP11-96O20.4, ZED9, PRDX1, and DOK2, according to node degrees and betweenness elements candidates from upregulated genes. in the opposite side, PYURF, NRSN1, FGF23, UPK3BL, and STAG3 were a prominent role in downregulated genes. Sum up, Using in silico analysis in the present study, we conducted a precise study ofbortezomib molecular mechanisms in myeloma cells. so that we could take further evaluation to discovermolecular cancer therapy. Naturally, more additional experimental and clinical procedures are needed in this survey.

Keywords: myeloma cells, acute myeloid leukemia, bioinformatics analysis, bortezomib

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Authors: Sima Saadi, Carolyn Johns

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The concept of a "Smart Water City" is emerging as a framework to address critical urban water challenges, integrating technology, data, and sustainable management practices to enhance water quality, conservation, and accessibility. This paper explores the definition of a Smart Water City, examines the pressing need for such cities in Canada, and proposes policy pathways for their development. Smart Water Cities utilize advanced monitoring systems, data analytics, and integrated water resources management to optimize water usage, anticipate and mitigate environmental impacts, and engage citizens in sustainable practices. Global examples from regions such as Europe, Asia, and Australia illustrate how Smart Water City models can transform urban water systems by enhancing resilience, improving resource efficiency, and driving economic development through job creation in environmental technology sectors. For Canada, adopting Smart Water City principles could address pressing challenges, including climate-induced water stress, aging infrastructure, and the need for equitable water access across diverse urban and rural communities. Building on Canada's existing water policies and technological expertise, it propose strategic investments in digital water infrastructure, data-driven governance, and community partnerships. Through case studies, this paper offers insights into how Canadian cities could benefit from cross-sector collaboration, policy development, and funding for smart water technology. By aligning national policy with smart urban water solutions, Canada has the potential to lead globally in sustainable water management, ensuring long-term water security and environmental stewardship for its cities and communities.

Keywords: smart water city, urban water resilience, water management technology, sustainable water infrastructure, canada water policy, smart city initiatives

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Authors: Yuzhen Hu, Sirui Wang

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As a training base for intellectual talents, universities have a large number of students. Teaching is a primary activity in universities, and during the teaching process, a large number of people gather both inside and outside the teaching buildings, posing a strong risk of close contact. The class schedule is the fundamental basis for teaching activities in universities and plays a crucial role in the management of teaching order. Different class schedules can lead to varying degrees of indoor gatherings and trajectories of class attendees. In recent years, highly contagious diseases have frequently occurred worldwide, and how to reduce the risk of infection has always been a hot issue related to public safety. "Reducing gatherings" is one of the core measures in epidemic prevention and control, and it can be controlled through scientific scheduling in specific environments. Therefore, the scientific prevention and control goal can be achieved by considering the reduction of the risk of excessive gathering of people during the course schedule arrangement. Firstly, we address the issue of personnel gathering in various pathways on campus, with the goal of minimizing congestion and maximizing teaching effectiveness, establishing a nonlinear mathematical model. Next, we design an improved genetic algorithm, incorporating real-time evacuation operations based on tracking search and multidimensional positive gradient cross-mutation operations, considering the characteristics of outdoor crowd evacuation. Finally, we apply undergraduate course data from a university in Harbin to conduct a case study. It compares and analyzes the effects of algorithm improvement and optimization of gathering situations and explores the impact of path blocking on the degree of gathering of individuals on other pathways.

Keywords: the university timetabling problem, risk prevention, genetic algorithm, risk control

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Authors: Ankan Roy, Niharika, Samir Kumar Patra

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Anomalous nexus of complex topological assemblies and spatiotemporal epigenetic choreography at chromosomal territory may forms the most sophisticated regulatory layer of gene expression in cancer. Colon cancer is one of the leading malignant neoplasms of the lower gastrointestinal tract worldwide. There is still a paucity of information about the complex molecular mechanisms of colonic cancerogenesis. Bioinformatics prediction and analysis helps to identify essential genes and significant pathways for monitoring and conquering this deadly disease. The present study investigates and explores potential hub genes as biomarkers and effective therapeutic targets for colon cancer treatment. Colon cancer patient sample containing gene expression profile datasets, such as GSE44076, GSE20916, and GSE37364 were downloaded from Gene Expression Omnibus (GEO) database and thoroughly screened using the GEO2R tool and Funrich software to find out common 2 differentially expressed genes (DEGs). Other approaches, including Gene Ontology (GO) and KEGG pathway analysis, Protein-Protein Interaction (PPI) network construction and hub gene investigation, Overall Survival (OS) analysis, gene correlation analysis, methylation pattern analysis, and hub gene-Transcription factors regulatory network construction, were performed and validated using various bioinformatics tool. Initially, we identified 166 DEGs, including 68 up-regulated and 98 down-regulated genes. Up-regulated genes are mainly associated with the Cytokine-cytokine receptor interaction, IL17 signaling pathway, ECM-receptor interaction, Focal adhesion and PI3K-Akt pathway. Downregulated genes are enriched in metabolic pathways, retinol metabolism, Steroid hormone biosynthesis, and bile secretion. From the protein-protein interaction network, thirty hub genes with high connectivity are selected using the MCODE and cytoHubba plugin. Survival analysis, expression validation, correlation analysis, and methylation pattern analysis were further verified using TCGA data. Finally, we predicted COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2 as potential master regulators in colonic cancerogenesis. Moreover, our experimental data highlights that disruption of lipid raft and RAS/MAPK signaling cascade affects this gene hub at mRNA level. We identified COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2 as determinant hub genes in colon cancer progression. They can be considered as biomarkers for diagnosis and promising therapeutic targets in colon cancer treatment. Additionally, our experimental data advertise that signaling pathway act as connecting link between membrane hub and gene hub.

Keywords: hub genes, colon cancer, DNA methylation, epigenetic engineering, bioinformatic predictions

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Authors: Mohammad Altaf Hossain

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A growing body of literature in urban studies has presented that urban precarity has been a lived experience for low-income groups of people in the cities of the Global South. It does not necessarily mean that cities in the Global North, where advanced capitalist economies exist, avoided the adverse realities of urban precarity. As a multifaceted condition, it creates other associated precariousness in lives -for example, economic deprivation, mental stress, and housing precarity. The interrelations between urbanity and precarity have been ubiquitous regardless of the developed and developing countries. People, mainly manual labourers with low incomes, go through uncertainties in every aspect of life. By analysing qualitative data and embracing structure-agency interaction, this paper intends to present how Bangladeshi migrants experience housing precarity in Dublin. Continued population growth and political economy factors such as labour market inequality, financialisation of the private rental sector, and the impact of cuts to government funding for social housing provision are combined to produce a housing supply crisis, affordability, and access in the city. As a result, low-income people practice informality in securing jobs and housing. The macro-structural components of this analysis include the Irish housing policy, the European labour market, the immigration policy, and the financialised housing market. The micro-structural components of South Asian communities’ experiences include social networks and social class. Access to social networks and practices of informality play a significant role in enabling them to negotiate urban precarity, including housing crises and income insecurity. In some cases, the collective agency of ethnic diaspora communities plays a vital role in negotiating with structural constraints.

Keywords: housing precarity, housing pathways, migration, agency, Dublin

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Authors: Ozlem Oral, Seval Kilic, Ozlem Yedier, Serap Dokmeci, Devrim Gozuacik

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Autophagy is a degradation pathway, activating under stress conditions. It digests macromolecules, such as abnormal proteins and long-lived organelles by engulfing them and by subsequent delivery of the cargo to lysosomes. The members of the phospholipid-dependent serine/threonine kinases, involved in many signaling pathways, which are necessary for the regulation of cellular metabolic activation. Previous studies implicate that, serine/threonine kinases have crucial roles in the mechanism of many diseases depend on the activated and/or inactivated signaling pathway. Data indicates, the signaling pathways activated by serine/threonine kinases are also involved in activation of autophagy mechanism. However, the information about the effect of serine/threonine kinases on autophagy mechanism and the roles of these effects in disease formation is limited. In this study, we investigated the effect of activated serine/threonine kinases on autophagic pathway. We performed a commonly used autophagy technique, GFP-LC3 dot formation and by using microscopy analyses, we evaluated promotion and/or inhibition of autophagy in serine/threonine kinase-overexpressed fibroblasts as well as cancer cells. In addition, we carried out confocal microscopy analyses and examined autophagic flux by utilizing the differential pH sensitivities of RFP and GFP in mRFP-GFP-LC3 probe. Based on the shRNA-library based screening, we identified autophagy-related proteins affected by serine/threonine kinases. We further studied the involvement of serine/threonine kinases on the molecular mechanism of newly identified autophagy proteins and found that, autophagic pathway is indirectly controlled by serine/threonine kinases via specific autophagic proteins. Our data indicate the molecular connection between two critical cellular mechanisms, which have important roles in the formation of many disease pathologies, particularly cancer. This project is supported by TUBITAK-1001-Scientific and Technological Research Projects Funding Program, Project No: 114Z836.

Keywords: autophagy, GFP-LC3 dot formation assay, serine/threonine kinases, shRNA-library screening

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Authors: Tomokazu Shirai, Akihiko Kondo

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Technologies of metabolic engineering or synthetic biology are essential for effective microbial bioproduction. It is especially important to develop an in silico tool for designing a metabolic pathway producing an unnatural and valuable chemical such as fossil materials of fuel or plastics. We here demonstrated two in silico tools for designing novel metabolic pathways: BioProV and HyMeP. Furthermore, we succeeded in creating an artificial metabolic pathway by enzyme engineering.

Keywords: bioinformatics, metabolic engineering, synthetic biology, genome scale model

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Authors: M. Sasajima, M. Watanabe, T. Yamaguchi Y. Kurosawa, Y. Koike

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In very narrow pathways, the speed of sound propagation and the phase of sound waves change due to the air viscosity. We have developed a new Finite Element Method (FEM) that includes the effects of air viscosity for modeling a narrow sound pathway. This method is developed as an extension of the existing FEM for porous sound-absorbing materials. The numerical calculation results for several three-dimensional slit models using the proposed FEM are validated against existing calculation methods.

Keywords: simulation, FEM, air viscosity, slit

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Authors: Afsaneh Mohammadnejad, Marianne Nygaard, Jan Baumbach, Shuxia Li, Weilong Li, Jesper Lund, Jacob v. B. Hjelmborg, Lene Christensen, Qihua Tan

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Cognitive impairment in the elderly is a key issue affecting the quality of life. Despite a strong genetic background in cognition, only a limited number of single nucleotide polymorphisms (SNPs) have been found. These explain a small proportion of the genetic component of cognitive function, thus leaving a large proportion unaccounted for. We hypothesize that one reason for this missing heritability is the misspecified modeling in data analysis concerning phenotype distribution as well as the relationship between SNP dosage and the phenotype of interest. In an attempt to overcome these issues, we introduced a model-free method based on the generalized correlation coefficient (GCC) in a genome-wide association study (GWAS) of cognitive function in twin samples and compared its performance with two popular linear regression models. The GCC-based GWAS identified two genome-wide significant (P-value < 5e-8) SNPs; rs2904650 near ZDHHC2 on chromosome 8 and rs111256489 near CD6 on chromosome 11. The kinship model also detected two genome-wide significant SNPs, rs112169253 on chromosome 4 and rs17417920 on chromosome 7, whereas no genome-wide significant SNPs were found by the linear mixed model (LME). Compared to the linear models, more meaningful biological pathways like GABA receptor activation, ion channel transport, neuroactive ligand-receptor interaction, and the renin-angiotensin system were found to be enriched by SNPs from GCC. The GCC model outperformed the linear regression models by identifying more genome-wide significant genetic variants and more meaningful biological pathways related to cognitive function. Moreover, GCC-based GWAS was robust in handling genetically related twin samples, which is an important feature in handling genetic confounding in association studies.

Keywords: cognition, generalized correlation coefficient, GWAS, twins

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