Search results for: surfactant deficiency

Authors: Ekta Yadav, Sukanta Bhattacharya, Brijesh Yadav, Ariel Hus, Jagjit Yadav

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Background and Significance: Respiratory exposure to toxicants (chemicals or particulates) causes disruption of lung homeostasis leading to lung toxicity/injury manifested as pulmonary inflammation, edema, and/or other effects depending on the type and extent of exposure. This emphasizes the need for investigating toxicant type-specific mechanisms to understand therapeutic targets. Aquaporins, aka water channels, are known to play a role in lung homeostasis. Particularly, the two major lung aquaporins AQP5 and AQP1 expressed in alveolar epithelial and vasculature endothelia respectively allow for movement of the fluid between the alveolar air space and the associated vasculature. In view of this, the current study is focused on understanding the regulation of lung aquaporins and other targets during inhalation exposure to toxic chemicals (Cigarette smoke chemicals) versus toxic particles (Carbon nanoparticles) or co-exposures to understand their relevance as markers of injury and intervention. Methodologies: C57BL/6 mice (5-7 weeks old) were used in this study following an approved protocol by the University of Cincinnati Institutional Animal Care and Use Committee (IACUC). The mice were exposed via oropharyngeal aspiration to multiwall carbon nanotube (MWCNT) particles suspension once (33 ugs/mouse) followed by housing for four weeks or to Cigarette smoke Extract (CSE) using a daily dose of 30µl/mouse for four weeks, or to co-exposure using the combined regime. Control groups received vehicles following the same dosing schedule. Lung toxicity/injury was assessed in terms of homeostasis changes in the lung tissue and lumen. Exposed lungs were analyzed for transcriptional expression of specific targets (AQPs, surfactant protein A, Mucin 5b) in relation to tissue homeostasis. Total RNA from lungs extracted using TRIreagent kit was analyzed using qRT-PCR based on gene-specific primers. Total protein in bronchoalveolar lavage (BAL) fluid was determined by the DC protein estimation kit (BioRad). GraphPad Prism 5.0 (La Jolla, CA, USA) was used for all analyses. Major findings: CNT exposure alone or as co-exposure with CSE increased the total protein content in the BAL fluid (lung lumen rinse), implying compromised membrane integrity and cellular infiltration in the lung alveoli. In contrast, CSE showed no significant effect. AQP1, required for water transport across membranes of endothelial cells in lungs, was significantly upregulated in CNT exposure but downregulated in CSE exposure and showed an intermediate level of expression for the co-exposure group. Both CNT and CSE exposures had significant downregulating effects on Muc5b, and SP-A expression and the co-exposure showed either no significant effect (Muc5b) or significant downregulating effect (SP-A), suggesting an increased propensity for infection in the exposed lungs. Conclusions: The current study based on the lung toxicity mouse model showed that both toxicant types, particles (CNT) versus chemicals (CSE), cause similar downregulation of lung innate defense targets (SP-A, Muc5b) and mostly a summative effect when presented as co-exposure. However, the two toxicant types show differential induction of aquaporin-1 coinciding with the corresponding differential damage to alveolar integrity (vascular permeability). Interestingly, this implies the potential of AQP1 as a differential marker of toxicant type-specific lung injury.

Keywords: aquaporin, gene expression, lung injury, toxicant exposure

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Authors: Charlotte K. Lee, Henrique R. N. Aguiar, Ralph Smith, James Baldock, Sam Botchey

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Background: Femoral neck stress fractures (FNSF) are uncommon, making up 1 to 7.2% of stress fractures in healthy subjects. FNSFs are prevalent in young women, military recruits, endurance athletes, and individuals with energy deficiency syndrome or female athlete triad. Presentation is often non-specific and is often misdiagnosed following the initial examination. There is limited research addressing the return–to–activity time after FNSF. Previous studies have demonstrated prognostic time predictions based on various imaging techniques. Here, (1) OxSport clinic FNSF practice standards are retrospectively reviewed, (2) FNSF cohort demographics are examined, (3) Regression models were used to predict return–to–activity prognosis and consequently determine bone stress risk factors. Methods: Patients with a diagnosis of FNSF attending Oxsport clinic between 01/06/2020 and 01/01/2020 were selected from the Rheumatology Assessment Database Innovation in Oxford (RhADiOn) and OxSport Stress Fracture Database (n = 14). (1) Clinical practice was audited against five criteria based on local and National Institute for Health Care Excellence guidance, with a 100% standard. (2) Demographics of the FNSF cohort were examined with Student’s T-Test. (3) Lastly, linear regression and Random Forest regression models were used on this patient cohort to predict return–to–activity time. Consequently, an analysis of feature importance was conducted after fitting each model. Results: OxSport clinical practice met standard (100%) in 3/5 criteria. The criteria not met were patient waiting times and documentation of all bone stress risk factors. Importantly, analysis of patient demographics showed that of the population with complete bone stress risk factor assessments, 53% were positive for modifiable bone stress risk factors. Lastly, linear regression analysis was utilized to identify demographic factors that predicted return–to–activity time [R2 = 79.172%; average error 0.226]. This analysis identified four key variables that predicted return-to-activity time: vitamin D level, total hip DEXA T value, femoral neck DEXA T value, and history of an eating disorder/disordered eating. Furthermore, random forest regression models were employed for this task [R2 = 97.805%; average error 0.024]. Analysis of the importance of each feature again identified a set of 4 variables, 3 of which matched with the linear regression analysis (vitamin D level, total hip DEXA T value, and femoral neck DEXA T value) and the fourth: age. Conclusion: OxSport clinical practice could be improved by more comprehensively evaluating bone stress risk factors. The importance of this evaluation is demonstrated by the population found positive for these risk factors. Using this cohort, potential bone stress risk factors that significantly impacted return-to-activity prognosis were predicted using regression models.

Keywords: eating disorder, bone stress risk factor, femoral neck stress fracture, vitamin D

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Authors: Zuhal Eltayeb Awad

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Alryad neighborhood is located in Khartoum town– the administrative center of the Capital of Sudan. The neighborhood is one of the high-income residential areas with villa type development of low-density. It was planned and developed in 1972 with large plots (600-875m²), wide crossing roads and balanced environment. Recently the area transformed into more compact urban form of high density, mixed-use integrated development with more intensive use of land; multi-storied apartments. The most important socio-economic process in the neighborhood has been the commercialization and deinitialization of the area in connect with the displacement of the residential function. This transformation affected the quality of the neighborhood and the inter-related features of the built environment. A case study approach was chosen to gather the necessary qualitative and quantitative data. A detailed survey on existing development pattern was carried out over the whole area of Alryad. Data on the built and social environment of the neighborhoods were collected through observations, interviews and secondary data sources. The paper reflected a theoretical and empirical interest in the particular characteristics of compact neighborhood with high density, and mixed land uses and their effect on social wellbeing of the residents all in the context of the sustainable development. The research problem is focused on the challenges of transformation that associated with compact neighborhood that created multiple urban problems, e.g., stress of essential services (water supply, electricity, and drainage), congestion of streets and demand for parking. The main objective of the study is to analyze the transformation of this area from residential use to commercial and administrative use. The study analyzed the current situation of the neighborhood compared to the five principles of sustainable neighborhood prepared by UN Habitat. The study found that the neighborhood is experienced changes that occur to inner-city residential areas and the process of change of the neighborhood was originated by external forces due to the declining economic situation of the whole country. It is evident that non-residential uses have taken place uncontrolled, unregulated and haphazardly that led to damage the residential environment and deficiency in infrastructure. The quality of urban life and in particular on levels of privacy was reduced, the neighborhood changed gradually to be a central business district that provides services to the whole Khartoum town. The change of house type may be attributed to a demand-led housing market and absence of policy. The results showed that Alryad is not fully sustainable and self-contained, street network characteristics and mixed land-uses development are compatible with the principles of sustainability. The area of streets represents 27.4% of the total area of the neighborhood. Residential density is 4,620 people/ km², that is lower than the recommendations, and the limited block land-use specialization is higher than 10% of the blocks. Most inhabitants have a high income so that there is no social mix in the neighborhood. The study recommended revision of the current zoning regulations in order to control and regulate undesirable development in the neighborhood and provide new solutions which allow promoting the neighborhood sustainable development.

Keywords: compact neighborhood, land uses, mixed use, residential area, transformation

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Authors: Sophio Kobauri, Temur Kantaria, Nina Kulikova, David Tugushi, Ramaz Katsarava

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Polymeric nanoparticles-based drug delivery systems and therapeutics have a great potential in the treatment of a numerous diseases, due to they are characterizing the flexible properties which is giving possibility to modify their structures with a complex definition over their structures, compositions and properties. Important characteristics of the polymeric nanoparticles (PNPs) used as drug carriers are high particle’s stability, high carrier capacity, feasibility of encapsulation of both hydrophilic and hydrophobic drugs, and feasibility of variable routes of administration, including oral application and inhalation; NPs are especially effective for intracellular drug delivery since they penetrate into the cells’ interior though endocytosis. A variety of PNPs based drug delivery systems including charged and neutral, degradable and non-degradable polymers of both natural and synthetic origin have been developed. Among these huge varieties the biodegradable PNPs which can be cleared from the body after the fulfillment of their function could be considered as one of the most promising. For intracellular uptake it is highly desirable to have positively charged PNPs since they can penetrate deep into cell membranes. For long-lasting circulation of PNPs in the body it is important they have so called “stealth coatings” to protect them from the attack of immune system of the organism. One of the effective ways to render the PNPs “invisible” for immune system is their PEGylation which represent the process of pretreatment of polyethylene glycol (PEG) on the surface of PNPs. The present work deals with constructing PNPs from amino acid based biodegradable polymers – regular poly(ester amide) (PEA) composed of sebacic acid, leucine and 1,6-hexandiol (labeled as 8L6), cationic PEA composed of sebacic acid, arginine and 1,6-hexandiol (labeled as 8R6), and comb-like co-PEA composed of sebacic acid, malic acid, leucine and 1,6-hexandiol (labeled as PEG-PEA). The PNPs were fabricated using the polymer deposition/solvent displacement (nanoprecipitation) method. The regular PEA 8L6 form stable negatively charged (zeta-potential within 2-12 mV) PNPs of desired size (within 150-200 nm) in the presence of various surfactants (Tween 20, Tween 80, Brij 010, etc.). Blending the PEAs 8L6 and 8R6 gave the 130-140 nm sized positively charged PNPs having zeta-potential within +20 ÷ +28 mV depending 8L6/8R6 ratio. The PEGylating PEA PEG-PEA was synthesized by interaction of epoxy-co-PEA [8L6]0,5-[tES-L6]0,5 with mPEG-amine-2000 The stable and positively charged PNPs were fabricated using pure PEG-PEA as a surfactant. A firm anchoring of the PEG-PEA with 8L6/8R6 based PNPs (owing to a high afinity of the backbones of all three PEAs) provided good stabilization of the NPs. In vitro biocompatibility study of the new PNPs with four different stable cell lines: A549 (human), U-937 (human), RAW264.7 (murine), Hepa 1-6 (murine) showed they are biocompatible. Considering high stability and cell compatibility of the elaborated PNPs one can conclude that they are promising for subsequent therapeutic applications. This work was supported by the joint grant from the Science and Technology Center in Ukraine and Shota Rustaveli National Science Foundation of Georgia #6298 “New biodegradable cationic polymers composed of arginine and spermine-versatile biomaterials for various biomedical applications”.

Keywords: biodegradable poly(ester amide)s, cationic poly(ester amide), pegylating poly(ester amide), nanoparticles

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

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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

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Authors: Hassan Younis

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Purpose: The objective of this study is to review influential papers in the sustainability and supply chain studies domain, leveraging insights from this review to develop a structured framework for academics and researchers. This framework aims to assist scholars in identifying the most impactful publications for their scholarly pursuits. Subsequently, the study will apply and trial the developed framework on selected scholarly articles within the sustainability and supply chain studies domain to evaluate its efficacy, practicality, and reliability. Design/Methodology/Approach: Utilizing the "Publish or Perish" tool, a search was conducted to locate papers incorporating "sustainability" and "supply chain" in their titles. After rigorous filtering steps, a panel of university professors identified five crucial criteria for evaluating research robustness: average yearly citation counts (25%), scholarly contribution (25%), alignment of findings with objectives (15%), methodological rigor (20%), and journal impact factor (15%). These five evaluation criteria are abbreviated as “ACMAJ" framework. Each paper then received a tiered score (1-3) for each criterion, normalized within its category, and summed using weighted averages to calculate a Final Normalized Score (FNS). This systematic approach allows for objective comparison and ranking of the research based on its impact, novelty, rigor, and publication venue. Findings: The study's findings highlight the lack of structured frameworks for assessing influential sustainability research in supply chain management, which often results in a dependence on citation counts. A complete model that incorporates five essential criteria has been suggested as a response. By conducting a methodical trial on specific academic articles in the field of sustainability and supply chain studies, the model demonstrated its effectiveness as a tool for identifying and selecting influential research papers that warrant additional attention. This work aims to fill a significant deficiency in existing techniques by providing a more comprehensive approach to identifying and ranking influential papers in the field. Practical Implications: The developed framework helps scholars identify the most influential sustainability and supply chain publications. Its validation serves the academic community by offering a credible tool and helping researchers, students, and practitioners find and choose influential papers. This approach aids field literature reviews and study suggestions. Analysis of major trends and topics deepens our grasp of this critical study area's changing terrain. Originality/Value: The framework stands as a unique contribution to academia, offering scholars an important and new tool to identify and validate influential publications. Its distinctive capacity to efficiently guide scholars, learners, and professionals in selecting noteworthy publications, coupled with the examination of key patterns and themes, adds depth to our understanding of the evolving landscape in this critical field of study.

Keywords: supply chain management, sustainability, framework, model

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Authors: Nodar Kekelidze, David Kekelidze, Elza Khutsishvili, Bela Kvirkvelia

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The semiconductor devices are irreplaceable elements for investigations in Space (artificial Earth satellite, interplanetary space craft, probes, rockets) and for investigation of elementary particles on accelerators, for atomic power stations, nuclear reactors, robots operating on heavily radiation contaminated territories (Chernobyl, Fukushima). Unfortunately, the most important parameters of semiconductors dramatically worsen under irradiation. So creation of radiation-resistant semiconductor materials for opto and microelectronic devices is actual problem, as well as investigation of complicated processes developed in irradiated solid states. Homogeneous single crystals of InP-InAs solid solutions were grown with zone melting method. There has been studied the dependence of the optical absorption coefficient vs photon energy near fundamental absorption edge. This dependence changes dramatically with irradiation. The experiments were performed on InP, InAs and InP-InAs solid solutions before and after irradiation with electrons and fast neutrons. The investigations of optical properties were carried out on infrared spectrophotometer in temperature range of 10K-300K and 1mkm-50mkm spectral area. Radiation fluencies of fast neutrons was equal to 2·1018neutron/cm2 and electrons with 3MeV, 50MeV up to fluxes of 6·1017electron/cm2. Under irradiation, there has been revealed the exponential type of the dependence of the optical absorption coefficient vs photon energy with energy deficiency. The indicated phenomenon takes place at high and low temperatures as well at impurity different concentration and practically in all cases of irradiation by various energy electrons and fast neutrons. We have developed the common mechanism of this phenomenon for unirradiated materials and implemented the quantitative calculations of distinctive parameter; this is in a satisfactory agreement with experimental data. For the irradiated crystals picture get complicated. In the work, the corresponding analysis is carried out. It has been shown, that in the case of InP, irradiated with electrons (Ф=1·1017el/cm2), the curve of optical absorption is shifted to lower energies. This is caused by appearance of the tails of density of states in forbidden band due to local fluctuations of ionized impurity (defect) concentration. Situation is more complicated in the case of InAs and for solid solutions with composition near to InAs when besides noticeable phenomenon there takes place Burstein effect caused by increase of electrons concentration as a result of irradiation. We have shown, that in certain conditions it is possible the prevalence of Burstein effect. This causes the opposite effect: the shift of the optical absorption edge to higher energies. So in given solid solutions there take place two different opposite directed processes. By selection of solid solutions composition and doping impurity we obtained such InP-InAs, solid solution in which under radiation mutual compensation of optical absorption curves displacement occurs. Obtained result let create on the base of InP-InAs, solid solution radiation-resistant optical materials. Conclusion: It was established the nature of optical absorption near fundamental edge in semiconductor materials and it was created radiation-resistant optical material.

Keywords: InAs-InP, electrons concentration, irradiation, solid solutions

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Authors: Ananya Hazare, Ranjit Kamble

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Introduction: Patients with Cleft lip and palate (CL/P) can present with a maxillary retrution after cleft repair. Anterior Maxillary distraction osteogenesis (AMD) is a technique that provides simultaneous skeletal advancement and expansion of the soft tissues related to an anterior segment of the maxilla. This case presented is a case of AMD. The advantage of this technique is that the occlusion in the posterior segment can be maintained, and only the segment in cross bite is advanced for correction of the midfacial deficiency. The other alternative treatment is anterior movement by a Lefort 1 osteotomy. When a Lefort 1 osteotomy is compared with the Distraction osteogenesis or AMD, the disadvantages of the Le Fort 1 include a higher risk of morbidity, requirement of fixation, relapse tendency and unexpected changes in the nasal form. These complications were eliminated by AMD technique. This was followed by placement of the implant in the bone formed after AMD. Hence complete surgical, orthodontic and prosthodontics rehabilitation of the patient was done by an interdisciplinary approach. Methods: Patient presented with repaired UCL/P of the right side with midfacial retrusion. Intro-oral examination revealed a good occlusion in the posterior arch and anterior Crossbite from canine to canine. Patient's both maxillary lateral incisors were missing. The lower arch was well aligned with all teeth present. The study models when scored according to GOSLON yardstick received a score of 4. After pre-surgical orthodontic phase was completed an intraoral distractor was fabricated by modification of HYRAX expansion screw. After surgery, low subapical osteotomy cuts were placed and the distractor was fixed. The latency period of 5 days was observed after which the distraction was started. Distraction was done at a rate of 1 mm/day with a rhythm of 0.5mm in morning and 0.5mm in the evening. The total distraction of 12 mm was done. After a consolidation period, the distractor was removed, and retention by a removable partial denture was given. Radiographic examination confirmed mature bone formation in the distracted segment. Implants were placed and allowed to osseointegrate for approximately 4 months and were then loaded with abutments. Results: Total distraction done was 12mm and after relapse it was 8mm. After consolidation phase the radiographic examination revealed a B2 quality of bone according to the Misch's classification and sufficient height from the maxillary sinus. These findings were indicative for placement of implants in the distracted bone formed in premolar region. Implants were placed and after radiographic evidence of osseointegration was seen they were loaded with abutments. Thus resulting in a complete rehabilitation of a cleft patient by an interdisciplinary approach. Conclusion: Anterior maxillary distraction can be used as an alternative method instead of complete distraction osteogenesis or Lefort 1 advancement of maxilla in cases where the advancement needed is minimum. Use of HYRAX expansion screw modified as intra-oral distractor can be used in such cases, which significantly reduces the cost of treatment, as expensive distractors are not used. This technique is very useful and efficient in countries like India where the patient cannot afford expensive treatment options.

Keywords: cleft lip and palate, distraction osteogenesis, anterior maxillary distraction, orthodontics and dentofacial orthopaedics, hyrax expansion screw modification

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Authors: Abha Gupta, Deepak K. Mishra

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The focus of food security studies in India has been on the adequacy of calories and its linkage with poverty level. India currently being undergoing a massive demographic and epidemiological transition has demonstrated a decline in average physical activity with improved mechanization and urbanization. Food consumption pattern is also changing with decreasing intake of coarse cereals and a marginal increase in the consumption of fruits, vegetables and meat products resulting into a nutrition transition in the country. However, deficiency of essential micronutrients such as vitamins and minerals is rampant despite their growing importance in fighting back with lifestyle and other modern diseases. The calorie driven studies can hardly tackle the complex problem of malnutrition. This paper fills these research lacuna and analyses mean intake of different major and micro-nutrients among different socio-economic groups and adequacy of these nutrients from recommended dietary allowance. For the purpose, a cross-sectional survey covering 304 households selected through proportional stratified random sampling was conducted in six villages of Aligarh district of the state of Uttar Pradesh, India. Data on quantity consumed of 74 food items grouped into 10 food categories with a recall period of seven days was collected from the households and converted into energy, protein, fat, carbohydrate, calcium, iron, thiamine, riboflavin, niacin and vitamin C using standard guidelines of National Institute of Nutrition. These converted nutrients were compared with recommended norms given by National Nutrition Monitoring Bureau. Per capita nutrient adequacy was calculated by dividing mean nutrient intake by the household size and then by comparing it with recommended norm. Findings demonstrate that source of both macro and micro-nutrients are mainly cereals followed by milk, edible oil and sugar items. Share of meat in providing essential nutrients is very low due to vegetarian diet. Vegetables, pulses, nuts, fruits and dry fruits are a poor source for most of the nutrients. Further analysis evinces that intake of most of the nutrients is higher than the recommended norm. Riboflavin is the only vitamin whose intake is less than the standard norm. Poor group, labour, small farmers, Muslims, scheduled caste demonstrate comparatively lower intake of all nutrients than their counterpart groups, though, they get enough macro and micro-nutrients significantly higher than the norm. One of the major reasons for higher intake of most of the nutrients across all socio-economic groups is higher consumption of monotonous diet based on cereals and milk. Most of the nutrients get their major share from cereals particularly wheat and milk intake. It can be concluded from the analysis that although there is adequate intake of most of the nutrients in the diet of rural population yet their source is mainly cereals and milk products depicting a monotonous diet. Hence, more efforts are needed to diversify the diet by giving more focus to the production of other food items particularly fruits, vegetables and pulse products. Awareness among the population, more accessibility and incorporating food items other than cereals in government social safety programmes are other measures to improve food security in India.

Keywords: hidden hunger, India, nutrients, recommended norm

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Authors: K. C. Apil, Keshab Sharma, Bigul Pokharel

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Kathmandu Valley, capital city of Nepal houses numerous historical monuments as well as religious structures which are as old as from the 4th century A.D. The city alone is home to seven UNESCO’s world heritage sites including various public squares and religious sanctums which are often regarded as living heritages by various historians and archeological explorers. Recently on April 25, 2015, the capital city including other nearby locations was struck with Gorkha earthquake of moment magnitude (Mw) 7.8, followed by the strongest aftershock of moment magnitude (Mw) 7.3 on May 12. This study reports structural failures and collapse of heritage structures in Kathmandu Valley during the earthquake and presents preliminary findings as to the causes of failures and collapses. Field reconnaissance was carried immediately after the main shock and the aftershock, in major heritage sites: UNESCO world heritage sites, a number of temples and historic buildings in Kathmandu Durbar Square, Patan Durbar Square, and Bhaktapur Durbar Square. Despite such catastrophe, a significant number of heritage structures stood high, performing very well during the earthquake. Preliminary reports from archeological department suggest that 721 of such structures were severely affected, whereas numbers within the valley only were 444 including 76 structures which were completely collapsed. This study presents recorded accelerograms and geology of Kathmandu Valley. Structural typology and architecture of the heritage structures in Kathmandu Valley are briefly described. Case histories of damaged heritage structures, the patterns, and the failure mechanisms are also discussed in this paper. It was observed that performance of heritage structures was influenced by the multiple factors such as structural and architecture typology, configuration, and structural deficiency, local ground site effects and ground motion characteristics, age and maintenance level, material quality etc. Most of such heritage structures are of masonry type using bricks and earth-mortar as a bonding agent. The walls' resistance is mainly compressive, thus capable of withstanding vertical static gravitational load but not horizontal dynamic seismic load. There was no definitive pattern of damage to heritage structures as most of them behaved as a composite structure. Some structures were extensively damaged in some locations, while structures with similar configuration at nearby location had little or no damage. Out of major heritage structures, Dome, Pagoda (2, 3 or 5 tiered temples) and Shikhara structures were studied with similar variables. Studying varying degrees of damages in such structures, it was found that Shikhara structures were most vulnerable one where Dome structures were found to be the most stable one, followed by Pagoda structures. The seismic performance of the masonry-timber and stone masonry structures were slightly better than that of the masonry structures. Regular maintenance and periodic seismic retrofitting seems to have played pivotal role in strengthening seismic performance of the structure. The study also recommends some key functions to strengthen the seismic performance of such structures through study based on structural analysis, building material behavior and retrofitting details. The result also recognises the importance of documentation of traditional knowledge and its revised transformation in modern technology.

Keywords: Gorkha earthquake, field observation, heritage structure, seismic performance, masonry building

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Authors: Thaminda Liyanage, Chamila Shamika Kurukulasuriya

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Introduction: Morbid obesity has been successfully treated with bariatric surgery for over 60 years. Although operative procedures have improved and associated complications have reduced substantially, surgery still carries the risk of post-operative malabsorption, malnutrition and a range of gastrointestinal disorders. Overweight by itself can impair libido in both sexes and cause erectile dysfunction in males by inducing a state of hypogonadotropic hypogonadism, proportional to the degree of obesity. Impact of weight reduction on libido and sexual activity remains controversial, however it is broadly accepted that weight loss improves sexual drive. Zinc deficiency, subsequent to malabsorption, may lead to impaired testosterone synthesis in men while excessive and/or rapid weight loss in females may result in reversible amenorrhoea leading to sub-fertility. Methods: We describe a 37 year old male, 6 years post Roux-en-Y gastric bypass surgery, who presented with erectile dysfunction, loss of libido, worsening fatigue and generalized weakness for 4 months. He also complained of constipation and frequent muscle cramps but denied having headache, vomiting or visual disturbances. Patient had lost 38 kg of body weight post gastric bypass surgery over four years {135kg (BMI 42.6 kg/m2) to 97 kg (BMI 30.6 kg/m2)} and the weight had been stable for past two years. He had no recognised co-morbidities at the time of the surgery and noted marked improvement in general wellbeing, physical fitness and psychological confident post surgery, up until four months before presentation. Clinical examination revealed dry pale skin with normal body hair distribution, no thyroid nodules or goitre, normal size testicles and normal neurological examination with no visual field defects or diplopia. He had low serum testosterone, follicular stimulating hormone (FSH), luteinizing hormone (LH), T3, T4, thyroid stimulating hormone (TSH), insulin like growth factor 1 (IGF-1) and 24-hour urine cortisol levels. Serum cortisol demonstrated an appropriate rise to ACTH stimulation test but growth hormone (GH) failed increase on insulin tolerance test. Other biochemical and haematological studies were normal, except for low zinc and folate with minimally raised liver enzymes. MRI scan of the head confirmed a solid pituitary mass with no mass effect on optic chiasm. Results: In this patient clinical, biochemical and radiological findings were consistent with anterior pituitary dysfunction. However, there were no features of raised intracranial pressure or neurological compromise. He was commenced on appropriate home replacement therapy and referred for neurosurgical evaluation. Patient reported marked improvement in his symptoms, specially libido and erectile dysfunction, on subsequent follow up visits. Conclusion: Sexual dysfunction coupled with non specific constitutional symptoms has multiple aetiologies. Clinical symptoms out of proportion to nutritional deficiencies post bariatric surgery should be thoroughly investigated. Close long term follow up is crucial for overall success.

Keywords: obesity, bariatric surgery, erectile dysfunction, loss of libido

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Authors: Azza A. Ali, Toqa M. Elnahhas, Abeer I. Abd El-Fattah, Mona M. Kamal, Karema Abu-Elfotuh

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Background: Environmental pollution with the different aluminium (Al) containing compounds especially those in industrial waste water exposes people to higher than normal levels of Al that represents an environmental risk factor. Cosmetics, Al ware, and containers are also sources of Al besides some foods and food additives. In addition to its known neurotoxicity, Al affects other body structures like skeletal system, blood cells, liver and kidney. Accumulation of Al in kidney and liver induces nephrotoxicity and hepatotoxicity. Coenzyme Q10 (CoQ10) is a pseudo-vitamin substance primarily present in the mitochondria. It is a powerful antioxidant and acts as radical scavenger. Wheat grass is a natural product that contains carbohydrates, proteins, vitamins, minerals, enzymes and has antioxidant, anti-inflammatory, anticancer and cardiovascular protection activities. Cocoa is an excellent source of iron, potent antioxidants and can protect against many diseases. Vinpocetine is an antioxidant and anti inflammatory while zinc is an essential trace element involved in cell division and its deficiency is observed in many types of liver disease. Objective: To evaluate and compare the potency of different drugs (CoQ10, wheatgrass, cocoa, vinpocetine and zinc) against nephro- and hepato-toxicity induced by Al in rats. Methods: Rats were divided to seven groups and received daily for three weeks either saline for control group or AlCl3 (70 mg/kg, IP) for Al-toxicity model groups. Five groups of Al-toxicity model (treated groups) were orally received together with Al each of the following; CoQ10 (200mg/kg), wheat grass (100mg/kg), cocoa powder (24mg/kg), vinpocetine (20mg/kg) or zinc (32mg/kg). Biochemical changes in the serum level of Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate deshydrogenase (LDH) as well as total bilirubin, lipids, cholesterol, triglycerides, glucose, proteins, creatinine and urea were measured. Liver and kidney specimens from all groups were also collected for the assessment of hepatic and nephrotic level of inflammatory mediators (TNF-α, IL-6β, nuclear factor kappa B (NF-κB), Caspase-3, oxidative parameters (MDA, SOD, TAC, NO) and DNA fragmentation. Histopathological changes in liver and kidney were also evaluated. Results: Three weeks of AlCl3 (70 mg/kg, IP) exposure induced nephro- and hepato-toxicity in rats. Treatment by the all used drugs showed protection against hazards of AlCl3. The protective effects were indicated by the significant decrease in ALT, AST, ALP, LDH as well as total bilirubin, lipids, cholesterol, triglycerides, glucose, creatinine and urea levels which were increased by Al. Liver and kidney of the treated groups showed decrease in MDA, NO, TNF-α, IL-6β, NF-κB, caspase-3 and DNA fragmentation which were increased by Al, together with significant increase in total proteins, SOD and TAC which were decreased by Al. The protection against both nephro- and hepato-toxicity was more pronounced especially with CoQ10 and wheat grass than the other used drugs. Histopathological examinations confirmed the biochemical results of toxicity and of protection. Conclusion: Protection from nephrotoxicity, hepatotoxicity and the consequent degenerations induced by Al can be achieved by using different drugs as CoQ10, wheatgrass, cocoa, vinpocetine and zinc, but CoQ10 as well as wheat grass possesses the most superior protection.

Keywords: aluminum, nephrotoxicity, hepatotoxicity, coenzyme Q10, wheatgrass, cocoa, vinpocetine, zinc

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Authors: Roshni Raha, Kavya P., Gayathri M.

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India, with a humongous population, remains the world's poorest developing nation in terms of nutritional status, with iron deficiency anaemia (IDA) affecting the population. Despite efforts over the past decades, India's anaemia prevalence has not been reduced. Researchers are interested in developing therapies that will minimize the typical side effects of oral iron and optimize iron salts-based treatment through delivery methods based on the physiology of hepcidin regulation. However, they need to come up with iron therapies that will prevent making the infection worse. This article explores using bio-nanotechnology as the alternative, promising substitution of providing iron supplements for the treatment of diarrhoea and gut inflammation in kids and pregnant women. This article is an exploratory study using a literature survey and secondary research from review papers. In the realm of biotechnology, nanoparticles have become extremely famous due to unexpected variations in surface characteristics caused by particle size. Particle size distribution and shape exhibit unusual, enhanced characteristics when reduced to nanoscale. The article attempts to develop a model for a nanotechnology based solution in iron fortification to combat the problems of diarrhoea and gut inflammation. Certain dimensions that have been considered in the model include the size, shape, source, and biosynthesis of the iron nanoparticles. Another area of investigation addressed in the article is the cost-effective biocompatible production of these iron nanoparticles. Studies have demonstrated that a substantial reduction of metal ions to form nanoparticles from the bulk metal occurs in plants because of the presence of a wide diversity of biomolecules. Using this concept, the paper investigates the effectiveness and impact of how similar sources can be used for the biological synthesis of iron nanoparticles. Results showed that iron particles, when prepared in nano-metre size, offer potential advantages. When the particle size of the iron compound decreases and attains nano configuration, its surface area increases, which further improves its solubility in the gastric acid, leading to higher absorption, higher bioavailability, and producing the least organoleptic changes in food. It has no negative effects and possesses a safe, effective profile to reduce IDA. Considering all the parameters, it has been concluded that iron particles in nano configuration serve as alternative iron supplements for the complete treatment of IDA. Nanoparticles of ferric phosphate, ferric pyrophosphate, and iron oxide are the choices of iron supplements. From a sourcing perspective, the paper concludes green sources are the primary sources for the biological synthesis of iron nanoparticles. It will also be a cost-effective strategy since our goal is to treat the target population in rural India. Bio-nanotechnology serves as an alternative and promising substitution for iron supplements due to its low cost, excellent bioavailability, and strong organoleptic properties. One area of future research can be to explore the type of size and shape of iron nanoparticles that would be suitable for the different age groups of pregnant women and children and whether it would be influenced based on the topography in certain areas.

Keywords: anemia, bio-nanotechnology, iron-fortification, nanoparticle

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Authors: Mohammadjavad Sotoudeheian, Soroush Nematollahi

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Crohn’s disease (CD) is a chronic gastrointestinal segment inflammation encompassing immune dysregulation in a genetically susceptible individual in response to the environmental triggers and interaction between the microbiome and immune system. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures and enteric fistulae. Increased production of Th1 and Th17-cell cytokines and defects in T-regulatory cells have been associated with CD. Th17-cells are essential for protection against extracellular pathogens, but their atypical activity can cause autoimmunity. Intrinsic defects in the control of programmed cell death in the mucosal T-cell compartment are strongly implicated in the pathogenesis of CD. The apoptosis defect in mucosal T-cells in CD has been endorsed as an imbalance of the Bcl-2 and the Bax. The immune system encounters foreign antigens through microbial colonization of mucosal surfaces or infections. In addition, FOSL downregulated IL-26 expression, a cytokine that marks inflammatory Th17-populations in patients suffering from CD. Furthermore, the expression of IL-23 is associated with the transcription factor primary leucine zipper transcription factor ATF-like (Batf). Batf-deficiency demonstrated the crucial role of Batf in colitis development. Batf and IL-23 mediate their effects by inducing IL-6 production. Strong association of IL-23R, Stat3, and Stat4 with IBD susceptibility point to a critical involvement of T-cells. IL-23R levels in transfer fistula were dependent on the AP-1 transcription factor JunB that additionally controlled levels of RORγt by facilitating DNA binding of Batf. T lymphocytes lacking JunB failed to induce IL-23- and Th17-mediated experimental colitis highlighting the relevance of JunB for the IL-23/ Th17 pathway. The absence of T-bet causes unrestrained Th17-cell differentiation. T-cells are central parts of immune-mediated colon fistula. Especially Th17-cells were highly prevalent in inflamed IBD tissues, as RORγt is effective in preventing colitis. Intraepithelial lymphocytes (IEL) contain unique T-cell subsets, including cells expressing RORγt. Increased activated Th17 and decreased T-regulatory cells in inflamed intestinal tissues had been seen. T-cells differentiate in response to many cytokines, including IL-1β, IL-6, IL-23, and TGF-β, into Th17-cells, a process which is critically dependent on the Batf. IL-23 promotes Th17-cell in the colon. Batf manages the generation of IL-23 induced IL-23R+ Th17-cells. Batf is necessary for TGF-β/IL-6-induced Th17-polarization. Batf-expressing T-cells are the core of T-cell-mediated colitis. The human-specific parts of three AP-1 transcription factors, FOSL1, FOSL2, and BATF, are essential during the early stages of Th17 differentiation. BATF supports the Th17 lineage. FOSL1, FOSL2, and BATF make possession of regulatory loci of genes in the Th17 lineage cascade. The AP1 transcription factor Batf is identified to control intestinal inflammation and seems to regulate pathways within lymphocytes, which could theoretically control the expression of several genes. It shows central regulatory properties over Th17-cell development and is intensely upregulated within IBD-affected tissues. Here, we demonstrated that targeting Batf in IBD appears as a therapeutic approach that reduces colitogenic T-cell activities during fistula formation while aiming to affect inflammation in the gut epithelial cells.

Keywords: immune system, Crohn’s Disease, BATF, T helper cells, Bcl, interleukin, FOSL

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Authors: Yong H Sheng, Beatriz Garcillán, Eden Whitlock, Yukli Freedman, SiLing Yang, M Arifur Rahman, Nicholas Weber, Fabienne Mackay

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Chronic lymphocytic leukemia (CLL) is closely associated with immune dysfunction, yet the mechanisms underlying this immune deficiency remain poorly understood. Transmembrane Activator and CAML Interactor (TACI), a receptor known for its role in IL-10 regulation and autoimmunity, to the best of our knowledge has not been investigated in the context of anti-tumor immunity or its impact on CLL progression. This study addresses the gap by exploring the role of TACI in regulating CLL cells within the tumor microenvironment and its broader effects on disease progression and immune competence. We utilized the Eµ-TCL1 mouse model to generate CLL mice deficient in TACI and examined the consequences of TACI loss in adoptive transfer models over a five-week period. Comprehensive transcriptomic analysis, including RNA sequencing and microarray, was employed to determine TACI’s influence on the CLL gene expression profile. Additionally, we studied TACI’s direct role in CLL cell migration and immune modulation using patient-derived CLL cells in culture and Patient-Derived Xenograph (PDX) models. Our findings demonstrate that TACI signaling plays a pivotal role in promoting CLL progression and immune suppression. Loss of TACI signaling significantly inhibited CLL development and enhanced immune functionality. When TACI+/+ or TACI-/- TCL1 CLL cells were transferred into wild-type recipient mice, those receiving TACI-deficient cells showed reduced disease progression and lower incidence of CLL. Mice with TACI-/- CLL cells exhibited normalized serum levels of pro-inflammatory cytokines IL-6 and IL-10, restored proportions of T-cell subsets, and improved immune compartment function compared to counterparts with TACI+/+ CLL cells. Mechanistically, TACI-deficient CLL cells expressed significantly lower levels of IL-10, TNF, and inhibitory receptors such as PD-L1 and PD-L2. These cells also display restored circulating immunoglobulin levels and responses to T cell-dependent antigens, highlighting a recovery of immune competence. Further mechanistic studies revealed that TACI signaling drives CLL cell migration and homing to the spleen, where these cells actively establish an immunosuppressive microenvironment that supports immune evasion and tumor growth. Patient-derived CLL cells and PDX models confirmed TACI’s direct role in enhancing CLL cell migration and fostering immune suppression, emphasizing its critical function in the tumor microenvironment. By disrupting TACI signaling, we observed a reduction in CLL-associated immune suppression and tumor progression, offering a promising therapeutic avenue. This study establishes, for the first time, that targeting TACI disrupts key mechanisms underlying CLL progression while preserving vital immune functions. Unlike existing treatments that often impair immunity and lead to infection-related complications, TACI inhibition offers the dual benefit of controlling disease and maintaining immune homeostasis. These findings provide a strong rationale for developing therapeutic strategies that inhibit TACI as a means to improve outcomes in CLL patients. Beyond its implications for CLL, this research underscores the broader importance of TACI in regulating immune-tumor interactions, paving the way for future studies into its role in other malignancies.

Keywords: chronic lymphocytic leukemia, TACI, IL-10, immune suppression

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Authors: Jeremy Woods, Fanqing Chen

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Rapid genome testing can provide results in at best hours to days, though there are certain clinical decisions that could be guided by genetic test results that need results in hours to minutes. As such, methods of genetic Point of Care Testing (POCT) are required if genetic data is to guide management in illnesses in a wide variety of critical and emergent medical situations such as neonatal sepsis, chemotherapy administration in endometrial cancer, and glucose-6-phosphate dehydrogenase deficiency (G6PD)-associated neonatal hyperbilirubinemia. As such, we developed a POCT “lab-on-chip” technology capable of identifying up to 144 alleles in under an hour. This test required no specialized training to utilize and is suitable to deployment in clinics and hospitals for use by non-laboratory personnel such as nurses. We developed a multiplexed qPCR-based sample-to-answer system with melting curve analysis capable of detecting up to 144 alleles utilizing the Kelliop RapidSeq126 PCR platform combined with a single-use microfluidic cartridge. The RapidSeq126 is the size of a standard desktop printer and the microfluidic cartridges are smaller than a deck of playing cards. Thus the system was deployable in the outpatient setting for clinical trials of MT-RNR1 genotyping. The sample (buccal swab from volunteers or plasmids in media) used for DNA extraction was placed in the cartridge sample inlet prior to inserting the cartridge into the RapidSeq126. The microfluidic cartridge was composed of heat resistant polymer with a sample inlet, 100um conduits, liquid and solid reagents, valves, extraction chamber, lyophilization chamber, 12 PCR reaction chambers, and a waste chamber. No human effort was required for processing the sample and performing the assay other than placing the sample in the cartridge and placing the cartridge in the RapidSeq126. The RapidSeq126 has demonstrated ex vivo detection in plasmids and in vivo detection from human volunteer samples of up to 144 alleles per microfluidic cartridge used and did not require specialized laboratory training to operate. Efficacy was proven for several applications, such as multiple microsatellite instability (MSI) sites (SULF/RYR3/MRE11/ACVR2A/DIDO1/SEC31A/BTBD7), endometrial cancer POLE exonuclease domain (EMD) mutation status, and G6PD variants such as those commonly associated with hemolysis (c.202G>A, c.376A>G, c.680G>A>T, c.968T>C, 404A>C, c.871G>A). The RapidSeq126 system was also able to identify the three MT-RNR1 variants associated with aminoglycoside-induced sensorineural hearing loss (m.1555A>G, m.1095T>C, m.1494C>T). Results were provided in under an hour in a sample-to-answer fashion requiring no processing other than inserting the cartridge with the sample into the RapidSeq126. Results were provided in a digital, HL7-compliant format suitable for interfacing with Electronic Healthcare Record (EHR). The RapidSeq126 system provides a solution for emergency and critical medical situations requiring results in a matter of minutes to hours. The HL7-compliant data format of results enables the RapidSeq126 to interface directly with EHRs to generate best practice advisories and further reduce errors and time to diagnosis by providing digital results.

Keywords: genetic testing, pharmacogenomics, point of care testing, rapid genetic testing

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Authors: Adewale Tolulope Irewale, Elias Emeka Elemike, Christian O. Dimkpa, Emeka Emmanuel Oguzie

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As the global population steadily approaches the 10billion mark, the world is currently faced with two major challenges among others – accessing sustainable and clean energy, and food security. Accessing cleaner and sustainable energy sources to drive global economy and technological advancement, and feeding the teeming human population require sustainable, innovative, and smart solutions. To solve the food production problem, producers have relied on fertilizers as a way of improving crop productivity. Commercial inorganic fertilizers, which is employed to boost agricultural food production, however, pose significant ecological sustainability and economic problems including soil and water pollution, reduced input efficiency, development of highly resistant weeds, micronutrient deficiency, soil degradation, and increased soil toxicity. These ecological and sustainability concerns have raised uncertainties about the continued effectiveness of conventional fertilizers. With the application of nanotechnology, plant biomass upcycling offers several advantages in greener energy production and sustainable agriculture through reduction of environmental pollution, increasing soil microbial activity, recycling carbon thereby reducing GHG emission, and so forth. This innovative technology has the potential for a circular economy and creating a sustainable agricultural practice. Nanomaterials have the potential to greatly enhance the quality and nutrient composition of organic biomass which in turn, allows for the conversion of biomass into nanofertilizers that are potentially more efficient. Water hyacinth plant harvested from an inland water at Warri, Delta State Nigeria were air-dried and milled into powder form. The dry biomass were used to prepare biochar at a pre-determined temperature in an oxygen deficient atmosphere. Physicochemical analysis of the resulting biochar was carried out to determine its porosity and general morphology using the Scanning Transmission Electron Microscopy (STEM). The functional groups (-COOH, -OH, -NH2, -CN, -C=O) were assessed using the Fourier Transform InfraRed Spectroscopy (FTIR) while the heavy metals (Cr, Cu, Fe, Pb, Mg, Mn) were analyzed using Inductively Coupled Plasma – Optical Emission Spectrometry (ICP-OES). Impregnation of the biochar with nanonutrients were achieved under varied conditions of pH, temperature, nanonutrient concentrations and resident time to achieve optimum adsorption. Adsorption and desorption studies were carried out on the resulting nanofertilizer to determine kinetics for the potential nutrients’ bio-availability to plants when used as green fertilizers. Water hyacinth (Eichhornia crassipes) which is an aggressively invasive aquatic plant known for its rapid growth and profusion is being examined in this research to harness its biomass as a sustainable feedstock to formulate functionalized nano-biochar fertilizers, offering various benefits including water hyacinth biomass upcycling, improved nutrient delivery to crops and aquatic ecosystem remediation. Altogether, this work aims to create output values in the three dimensions of environmental, economic, and social benefits.

Keywords: biochar-based nanofertilizers, eichhornia crassipes, greener agriculture, sustainable ecosystem, water hyacinth

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Authors: Aidan Ryan, Nahima Miah, Sahaj Kaur, Imogen Sutherland, Mohamed Saleh

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Pulmonary symptoms are a common presentation to the emergency department. Due to a lack of understanding of the underlying pathophysiology, chronic liver disease is not often considered a cause of dyspnea. We present three patients who were admitted with significant respiratory distress secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. The first is a 27-year-old male with a 6-month history of progressive dyspnea. The patient developed a severe type 1 respiratory failure with a PaO₂ of 6.3kPa and was escalated to critical care, where he was managed with non-invasive ventilation to maintain oxygen saturation. He had an agitated saline contrast echocardiogram, which showed the presence of a possible shunt. A CT angiogram revealed significant liver cirrhosis, portal hypertension, and large para esophageal varices. Ultrasound of the abdomen showed coarse liver echo patter and enlarged spleen. Along with these imaging findings, his biochemistry demonstrated impaired synthetic liver function with an elevated international normalized ratio (INR) of 1.4 and hypoalbuminaemia of 28g/L. The patient was then transferred to a tertiary center for further management. Further investigations confirmed a shunt of 56%, and liver biopsy confirmed cirrhosis suggestive of alpha-1-antitripsyin deficiency. The findings were consistent with a diagnosis of hepatopulmonary syndrome, and the patient is awaiting a liver transplant. The second patient is a 56-year-old male with a 12-month history of worsening dyspnoea, jaundice, confusion. His medical history included liver cirrhosis, portal hypertension, and grade 1 oesophageal varices secondary to significant alcohol excess. On admission, he developed a type 1 respiratory failure with PaO₂ of 6.8kPa requiring 10L of oxygen. CT pulmonary angiogram was negative for pulmonary embolism but showed evidence of chronic pulmonary hypertension, liver cirrhosis, and portal hypertension. An echocardiogram revealed a grossly dilated right heart with reduced function, pulmonary and tricuspid regurgitation, and pulmonary artery pressures estimated at 78mmHg. His biochemical markers showed impaired synthetic liver function with an INR of 3.2, albumin of 29g/L, along with raised bilirubin of 148mg/dL. During his long admission, he was managed with diuretics with little improvement. After three weeks, he was diagnosed with portopulmonary hypertension and was commenced on terlipressin. This resulted in successfully weaning off oxygen, and he was discharged home. The third patient is a 61-year-old male who presented to the local ambulatory care unit for therapeutic paracentesis on a background of decompensated liver cirrhosis. On presenting, he complained of a 2-day history of worsening dyspnoea and a productive cough. Chest x-ray showed a large pleural effusion, increasing in size over the previous eight months, and his abdomen was visibly distended with ascitic fluid. Unfortunately, the patient deteriorated, developing a larger effusion along with an increase in oxygen demand, and passed away. Without underlying cardiorespiratory disease, in the presence of a persistent pleural effusion with underlying decompensated cirrhosis, he was diagnosed with hepatic hydrothorax. While each presented with dyspnoea, the cause and underlying pathophysiology differ significantly from case to case. By describing these complications, we hope to improve awareness and aid prompt and accurate diagnosis, vital for improving outcomes.

Keywords: dyspnea, hepatic hydrothorax, hepatopulmonary syndrome, portopulmonary syndrome

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Authors: Mohammadjavad Sotoudeheian, Navid Farahmandian

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Cardiac hypertrophy arises in response to persistent increases in hemodynamic loads. In comparison, diabetic cardiomyopathy is defined by an abnormal myocardial changes without other cardiac-related risk factors. Pathological cardiac hypertrophy and myocardial remodeling are hallmarks of cardiovascular diseases and are risk factors for heart failure. The transcription factor forkhead box class O (FOXOs) can protect heart tissue by hostile oxidative stress and stimulating apoptosis and autophagy. FOXO proteins, as sensitive elements and mediators in response to environmental changes, have been revealed to prevent and inverse cardiac hypertrophy. FOXOs are inhibited by insulin and are critical mediators of insulin action. Insulin deficiency and uncontrolled diabetes lead to a catabolic state. FOXO1 acts downstream of the insulin-dependent pathways, which are dysregulated in diabetes. It regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K/Akt activation, which are critical regulators of cardiac hypertrophy. The complex network of signaling pathways comprising insulin/IGF-1 signaling, AMPK, JNK, and Sirtuins regulate the development of cardiovascular dysfunction by modulating the activity of FOXOs. Insulin receptors and IGF1R act via the PI3k/Akt and the MAPK/ERK pathways. Activation of Akt in response to insulin or IGF-1 induces phosphorylation of FOXOs. Increased protein synthesis induced by activation of the IGF-I/Akt/mTOR signaling pathway leads to hypertrophy. This pathway and the myostatin/Smad pathway are potent negative muscle development regulators. In cardiac muscle, insulin receptor substrates (IRS)-1 or IRS-2 activates the Akt signaling pathway and inactivate FOXO1. Under metabolic stress, p38 MAPK promotes degradation of IRS-1 and IRS-2 in cardiac myocytes and activates FOXO1, leading to cardiomyopathy. Sirt1 and FOXO1 interaction play an essential role in starvation-induced autophagy in cardiac metabolism. Inhibition of Angiotensin-II induced cardiomyocyte hypertrophy is associated with reduced FOXO1 acetylation and activation of Sirt1. The NF-κB, ERK, and FOXOs are de-acetylated by SIRT1. De-acetylation of FOXO1 induces the expression of genes involved in autophagy and stimulates autophagy flux. Therefore, under metabolic stress, FOXO1 can cause diabetic cardiomyopathy. The overexpression of FOXO1 leads to decreased cardiomyocyte size and suppresses cardiac hypertrophy through inhibition of the calcineurin–NFAT pathway. Diabetes mellitus is associated with elevation of O-GlcNAcylation. Some of its binding partners regulate the substrate selectivity of O-GlcNAc transferase (OGT). O-GlcNAcylation of essential contractile proteins may inhibit protein-protein interactions, reduce calcium sensitivity, and modulate contractile function. Uridine diphosphate (UDP)-GlcNAc is the obligatory substrate of OGT, which catalyzes a reversible post-translational protein modification. The increase of O-GlcNAcylation is accompanied by impaired cardiac hypertrophy in diabetic hearts. Inhibition of O-GlcNAcylation blocks activation of ERK1/2 and hypertrophic growth. O-GlcNAc modification on NFAT is required for its translocation from the cytosol to the nucleus, where NFAT stimulates the transcription of various hypertrophic genes. Inhibition of O-GlcNAcylation dampens NFAT-induced cardiac hypertrophic growth. Transcriptional activity of FOXO1 is enriched by improved O-GlcNAcylation upon high glucose stimulation or OGT overexpression. In diabetic conditions, the modification of FOXO1 by O-GlcNAc is promoted in cardiac troponin I and myosin light chain 2. Therefore targeting O-GlcNAcylation represents a potential therapeutic option to prevent hypertrophy in the diabetic heart.

Keywords: diabetes, cardiac hypertrophy, O-GlcNAcylation, FOXO1, Akt, PI3K, AMPK, insulin

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Authors: Teesta Dey

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Integrated Transport development with proper traffic management leads to sustainable growth of any urban sphere. Appropriate mass transport planning is essential for the populous cities in third world countries like India. The exponential growth of motor vehicles with unplanned road network is now the common feature of major urban centres in India. Kolkata, the third largest mega city in India, is not an exception of it. The imbalance between demand and supply of unplanned transport services in this city is manifested in the high economic and environmental costs borne by the associated society. With the passage of time, the growth and extent of passenger demand for rapid urban transport has outstripped proper infrastructural planning and causes severe transport problems in the overall urban realm. Hence Kolkata stands out in the world as one of the most crisis-ridden metropolises. The urban transport crisis of this city involves severe traffic congestion, the disparity in mass transport services on changing peripheral land uses, route overlapping, lowering of travel speed and faulty implementation of governmental plans as mostly induced by rapid growth of private vehicles on limited road space with huge carbon footprint. Therefore the paper will critically analyze the extant road network pattern for improving regional connectivity and accessibility, assess the degree of congestion, identify the deviation from demand and supply balance and finally evaluate the emerging alternate transport options as promoted by the government. For this purpose, linear, nodal and spatial transport network have been assessed based on certain selected indices viz. Road Degree, Traffic Volume, Shimbel Index, Direct Bus Connectivity, Average Travel and Waiting Tine Indices, Route Variety, Service Frequency, Bus Intensity, Concentration Analysis, Delay Rate, Quality of Traffic Transmission, Lane Length Duration Index and Modal Mix. Total 20 Traffic Intersection Points (TIPs) have been selected for the measurement of nodal accessibility. Critical Congestion Zones (CCZs) are delineated based on one km buffer zones of each TIP for congestion pattern analysis. A total of 480 bus routes are assessed for identifying the deficiency in network planning. Apart from bus services, the combined effects of other mass and para transit modes, containing metro rail, auto, cab and ferry services, are also analyzed. Based on systematic random sampling method, a total of 1500 daily urban passengers’ perceptions were studied for checking the ground realities. The outcome of this research identifies the spatial disparity among the 15 boroughs of the city with severe route overlapping and congestion problem. North and Central Kolkata-based mass transport services exceed the transport strength of south and peripheral Kolkata. Faulty infrastructural condition, service inadequacy, economic loss and workers’ inefficiency are the most dominant reasons behind the defective mass transport network plan. Hence there is an urgent need to revive the extant road based mass transport system of this city by implementing a holistic management approach by upgrading traffic infrastructure, designing new roads, better cooperation among different mass transport agencies, better coordination of transport and changing land use policies, large increase in funding and finally general passengers’ awareness.

Keywords: carbon footprint, critical congestion zones, direct bus connectivity, integrated transport development

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Authors: Riccardo Fratini, Riccardo Santini, Jacopo Serafini, Massimo Gennaretti, Stefano Panzieri

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This paper presents a nonlinear differential model, for a three-bladed horizontal axis wind turbine (HAWT) suited for control applications. It is based on a 8-dofs, lumped parameters structural dynamics coupled with a quasi-steady sectional aerodynamics. In particular, using the Euler-Lagrange Equation (Energetic Variation approach), the authors derive, and successively validate, such model. For the derivation of the aerodynamic model, the Greenbergs theory, an extension of the theory proposed by Theodorsen to the case of thin airfoils undergoing pulsating flows, is used. Specifically, in this work, the authors restricted that theory under the hypothesis of low perturbation reduced frequency k, which causes the lift deficiency function C(k) to be real and equal to 1. Furthermore, the expressions of the aerodynamic loads are obtained using the quasi-steady strip theory (Hodges and Ormiston), as a function of the chordwise and normal components of relative velocity between flow and airfoil Ut, Up, their derivatives, and section angular velocity ε˙. For the validation of the proposed model, the authors carried out open and closed-loop simulations of a 5 MW HAWT, characterized by radius R =61.5 m and by mean chord c = 3 m, with a nominal angular velocity Ωn = 1.266rad/sec. The first analysis performed is the steady state solution, where a uniform wind Vw = 11.4 m/s is considered and a collective pitch angle θ = 0.88◦ is imposed. During this step, the authors noticed that the proposed model is intrinsically periodic due to the effect of the wind and of the gravitational force. In order to reject this periodic trend in the model dynamics, the authors propose a collective repetitive control algorithm coupled with a PD controller. In particular, when the reference command to be tracked and/or the disturbance to be rejected are periodic signals with a fixed period, the repetitive control strategies can be applied due to their high precision, simple implementation and little performance dependency on system parameters. The functional scheme of a repetitive controller is quite simple and, given a periodic reference command, is composed of a control block Crc(s) usually added to an existing feedback control system. The control block contains and a free time-delay system eτs in a positive feedback loop, and a low-pass filter q(s). It should be noticed that, while the time delay term reduces the stability margin, on the other hand the low pass filter is added to ensure stability. It is worth noting that, in this work, the authors propose a phase shifting for the controller and the delay system has been modified as e^(−(T−γk)), where T is the period of the signal and γk is a phase shifting of k samples of the same periodic signal. It should be noticed that, the phase shifting technique is particularly useful in non-minimum phase systems, such as flexible structures. In fact, using the phase shifting, the iterative algorithm could reach the convergence also at high frequencies. Notice that, in our case study, the shifting of k samples depends both on the rotor angular velocity Ω and on the rotor azimuth angle Ψ: we refer to this controller as a spatial repetitive controller. The collective repetitive controller has also been coupled with a C(s) = PD(s), in order to dampen oscillations of the blades. The performance of the spatial repetitive controller is compared with an industrial PI controller. In particular, starting from wind speed velocity Vw = 11.4 m/s the controller is asked to maintain the nominal angular velocity Ωn = 1.266rad/s after an instantaneous increase of wind speed (Vw = 15 m/s). Then, a purely periodic external disturbance is introduced in order to stress the capabilities of the repetitive controller. The results of the simulations show that, contrary to a simple PI controller, the spatial repetitive-PD controller has the capability to reject both external disturbances and periodic trend in the model dynamics. Finally, the nominal value of the angular velocity is reached, in accordance with results obtained with commercial software for a turbine of the same type.

Keywords: wind turbines, aeroelasticity, repetitive control, periodic systems

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