30 research outputs found
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Translational Approaches and Preclinical Modeling to Address the Unmet Needs of Ards/Vili
No full textAcute Respiratory Distress Syndrome (ARDS) is a serious critical care illness that occurs as a complication of predisposing conditions such as sepsis, trauma, acid aspiration, and bacteria- and virus-induced pneumonias. ARDS has high mortality rate of 30-40% (pre-COVID 19 pandemic). As the unprecedented pandemic of COVID-19 has increased the need to find effective FDA-approved ARDS therapies, the goal of the current study is to address three key unmet needs in ARDS/ventilation-induced lung injury (VILI). The first unmet need is to find novel FDA-approved ARDS therapeutics that reduce the severity and mortality of ARDS/VILI. The second unmet need is to develop large animal models of ARDS/VILI that recapitulate features of human ARDS/VILI and allow for effective validation of potential biomarkers and testing of novel therapeutics. The third unmet need is to obtain novel phenotypic tools to fully assess preclinical lung fluid imbalance and multi-organ dysfunction. Numerous potential ARDS therapeutics, based upon preclinical rodent studies that utilized lipopolysaccharide (LPS) as the insult without further lung injury related to mechanical ventilation (MV), have failed in human clinical trials. Previously, we utilized preclinical multispecies ARDS models coupled with genomic-intensive approaches to identify novel ARDS biomarkers and targetable pathways. We identified nicotinamide phosphoribosyltransferase (NAMPT) as a novel damage-associated molecular pattern (DAMP) protein and attractive ARDS target. Our data demonstrated that the intravenous administration of an eNAMPT-neutralizing polyclonal antibody (pAb) significantly attenuated the severity of murine VILI. In the current study, we examine humanized eNAMPT-neutralizing monoclonal antibodies (mAbs) for potential therapeutic efficacy in rodent LPS/VILI models and apply the lead mAb, ALT-100 mAb, in an innovative ARDS/VILI porcine model that we have developed. In addition, we evaluate phenotypic tools, such as chest ultrasound and radiograph, to fully assess the lung fluid imbalance in the preclinical models and evaluate the eNAMPT ALT-100 mAb efficacy on ARDS-induced acute kidney injury (AKI), as part of the ARDS multi-organ dysfunction. Methods. Sprague Dawley (SD) rats were challenged with intratracheal (IT) LPS. Eighteen hours (18 hr) later, animals were either harvested “one-hit model” or connected to high tidal volume (Vt) mechanical ventilation (MV) for 4 hr before harvesting “two-hit model”. Animals received eNAMPT ALT-100 mAb concurrently with LPS instillation and prior to exposure to MV. In the porcine ARDS model, we utilized Yucatan minipigs receiving either IV LPS to induce septic shock, or both IT- and IV-delivered LPS to induce the pneumonia/septic shock/ARDS. Animals were intubated and connected to high Vt mechanical ventilation for 12 hr. Animals received the eNAMPT ALT-100 mAb IV at either 2 hr or 6 hr after initiation of septic shock and VILI. Animals were monitored continuously for 12 hr. Chest ultrasound and chest X-ray images were captured at time zero, 2 hr, and 12 hr after the start of LPS/MV exposure. BAL fluid, blood, urine, lung, and kidney tissues were collected at the end of study.
Results. Compared to sepsis/ARDS-exposed, PBS-treated animals, - rats and pigs treated with the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg, 2 hr or 6 hr after injury initiation) demonstrated significantly diminished severity of lung injury (histology, BAL PMNs, plasma cytokines), and reduced biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance in pigs reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue weight ratios, ultrasound-derived B lines, and chest radiograph opacities. ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats and pigs when delivered 2 hr or 6 hr after injury initiation.
Conclusions. These studies indicate that delivery of the eNAMPT-neutralizing ALT-100 mAb, even at a delayed time point after initial injury, directly mitigates the serious unmet need for novel ARDS therapeutics. The ALT-100 mAb reduced inflammatory lung injury, preserved lung fluid balance, and reduced multi-organ dysfunction. Moreover, the porcine preclinical ARDS model proved to be a robust tool to assess ALT-100 mAb efficacy and the therapeutic potential of other ARDS therapeutic candidates. Chest ultrasound and chest X-ray images may provide simple and inexpensive methods to longitudinally assess lung fluid imbalance and surrogate responses to ARDS therapeutics.
Release after 05/10/202
Variations in access to domestic water supply in EN Nahud district, Sudan
No full textThe central aim of this thesis is to develop an understanding of variation in access to domestic water supply in a semi-arid, non-riverain area of Sudan. En Nahud District, in North Kordofan Province, was selected for study because it has existing water supply problems and contains distinct spatial variations in geology, which affects the potential for development of underground water resources. Fieldwork in Sudan was carried out between July and December 1988, and information was collected from a range of sources using a variety of methods. The latter included: semi-structured household interviews conducted with women; key informant interviews; observation; and various published and unpublished articles and data sets. In the thesis, the first chapter introduces the national and international context of this study. Past and present water supply development policies and projects in the Sudan are outlined, and set against the goals of the International Drinking Water Supply and Sanitation Decade. In the second chapter, the research methodology is discussed. Attempt was made to overcome the several spatial, temporal social and economic biases which have occurred in other studies. In the third chapter, the thesis is placed in the physical and socio-economic context of the Province, and the dynamic relationship between water supply and demand is outlined. The following three chapters focus upon the primary constraints which limit access to domestic water supply: water availability; at-source costs; and transportation costs. The components of each, and the way in which they operate to restrict access, are investigated in relation to varying family resources and requirements. The borrowing of carriage resources and the purchase of transportation services are examined as strategies for overcoming families' internal collection-capacity constraints. Finally, seasonal outmigration is discussed as an important response to inadequate access to water supply. In its conclusion, this thesis shows clearly the importance of examining access to water at the family scale: inter-household variations, such as the ownership of carriage animals and varying labour resources, are shown to be influential in affecting household water supply strategies
Biopolymer foams from Novatein thermoplastic protein and poly(lactic acid)
No full textNovatein is the only commercial thermoplastic protein made from bloodmeal, a highly denatured protein and a readily available by-product of the meat processing industry. One of the major limitations of Novatein is its hydrophilic nature and loss of plasticizer during processing which leads to poor mechanical properties. To address these issues, Novatein has been blended with another biodegradable polymer with good mechanical properties, polylactic acid (PLA).
Blending two components can lead to poor mechanical properties of the blend due to weak interfacial adhesion and thermodynamic incompatibility. These problems can be overcome with the use of a compatibilizer which helps to stabilize the interface by coalescence suppression of the dispersed domains. In this work, itaconic anhydride grafted PLA (PLA-g-IA) was chosen as a compatibilizer for Novatein-PLA blends because IA is extremely stable when reacted with proteins and less harmful compared to maleic anhydride.
Reactive extrusion was used to blend different proportions of Novatein and PLA and the compatibilizing effects of itaconic anhydride was examined. Results showed that fewer agglomerated Novatein particles and less phase separation was visible in the presence of compatibilizer. At 50-50 Novatein/PLA, the absence of compatibilizer produced a dispersed morphology which caused the material to disintegrate in chloroform. Upon the addition of itaconic anhydride, the 50-50 blend stayed intact which was thought to be a result of co-continuous morphology. Incorporating 50 wt.% of PLA-g-IA improved the tensile strength of Novatein by 42% and impact strength by 36%. The effect of compatibilizer was evident in wide-angle x-ray scattering. Three phases were detected in the absence of compatibilizer: crystalline Novatein, amorphous Novatein, and amorphous PLA phases. With compatibilizer, the blend was moving toward two phases: crystalline Novatein, and an amorphous blend of Novatein and PLA. Itaconic anhydride grafted PLA improved miscibility between Novatein and PLA, which lead to the fabrication of Novatein-PLA foams.
Foaming Novatein is a new area of study which has never been investigated before. The foamability of a material depends on the ability of the material to withstand the stretching forces during bubble growth and hold the newly formed cellular structure. The low melt strength of Novatein, however, make it difficult to induce a cellular structure in the proteinous bioplastic. Therefore, the foaming ability of Novatein can be improved by blending with PLA, which can successfully be foamed using a batch process with carbon dioxide as the blowing agent.
Various compositions of Novatein/PLA were batch foamed with and without compatibilizer. Results showed that pure Novatein cannot form a cellular structure at a foaming temperature of 80°C, however, in a blend with 50 wt.% PLA, micro cells formed with a higher cell density (8.44x1021 cells cm-3) and smaller cell sizes (3.36 µm) compared to pure PLA and blends with higher amounts of PLA. A further reduction in cell size and increase in cell density was observed upon the addition of compatibilizer due to the higher crystallinity of grafted PLA. The co-continuous morphology obtained upon the addition of compatibilizer led to the development of foams with more uniform cell sizes, which was stable for cell nucleation even at high temperatures
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Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress
No full textRATIONALE: The myosin light chain kinase gene, MYLK, encodes three proteins via unique promoters, including the non-muscle isoform of myosin light chain kinase (nmMLCK), a cytoskeletal protein centrally involved in regulation of vascular integrity. As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation. METHODS: Full-length or serially deleted MYLK luciferase reporter promoter activities were measured in human lung endothelial cells (ECs). SNP-containing non-muscle MYLK (nmMYLK) DNA fragments were generated and nmMYLK promoter binding by transcription factors (TFs) detected by protein-DNA electrophoretic mobility shift assay (EMSA). Promoter demethylation was evaluated by 5-aza-2'-deoxycytidine (5-Aza). A preclinical mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) was utilized for nmMLCK validation. RESULTS: Lung EC levels of nmMLCK were significantly increased in LPS-challenged mice and LPS, tumor necrosis factor-α (TNF-α), 18% cyclic stretch (CS) and 5-Aza each significantly up-regulated EC nmMYLK promoter activities. EC exposure to FG-4592, a prolyl hydroxylase inhibitor that increases hypoxia-inducible factor (HIF) expression, increased nmMYLK promoter activity, confirmed by HIF1α/HIF2α silencing. nmMYLK promoter deletion studies identified distal inhibitory and proximal enhancing promoter regions as well as mechanical stretch-, LPS- and TNFα-inducible regions. Insertion of ARDS-associated SNPs (rs2700408, rs11714297) significantly increased nmMYLK promoter activity via increased transcription binding (glial cells missing homolog 1 (GCM1) and intestine-specific homeobox (ISX), respectively). Finally, the MYLK rs78755744 SNP (-261G/A), residing within a nmMYLK CpG island, significantly attenuated 5-Aza-induced promoter activity. CONCLUSION: These findings indicate nmMYLK transcriptional regulation by clinically relevant inflammatory factors and ARDS-associated nmMYLK promoter variants are consistent with nmMLCK as a therapeutic target in severe inflammatory disorders. © 2021 The Author(s).Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Asymptotic Weak Gravity Conjecture in M-theory on K3 K3
No full textThe Asymptotic WGC has been proposed as a special case of the tower WGC that probes infinite distances in the moduli space corresponding to weakly coupled gauge regimes. The conjecture has been studied in M-theory on Calabi-Yau threefold (CY3) with finite volume inducing a 5D effective QFT. In this paper, we extend the scope of the previous study to encompass lower dimensions, particularly we generalise the obtained 5D asymptotic WGC to the effective field theory coupled to 3D gravity that descends from M-theory compactified on Calabi-Yau fourfold with an emphasis on K3 x K3. We find that the CY4 has three fibration structures labelled as line Type-, surface Type- and bulk Type-. The emergent is shown to have 2+2 towers of states occupied by light and heavy BPS as well as non BPS particles. To ensure the viability of the 3D Asymptotic WGC, we give explicit calculations to thoroughly test the swampland constraint for both the weakly and strongly gauge coupled regimes. Additional aspects, including the gauge symmetry breaking and duality symmetry are also investigated
Rural poverty, migration, and the environment in developing countries : three case studies
No full textThe author presents three case studies (of the links between highlands and lowlands in Latin America; transmigration in Indonesia; and migration and desertification in the Sudan) to illustrate the relationship between poverty, internal migration, and environmental change in rural areas of developing countries. Policies to deal with the problems of environmental degradation in areas that are destinations for migrants would usually include: preparation of a detailed national inventory of land and water resources, and a land-use plan to protect biologically important or fragile areas and direct new agricultural settlements elsewhere; coordination of this plan with the construction of roads; better coordination across government agencies in the development and implementation of policies related to land use; reduction of population growth, a driving force behind decisions to migrate; improving land use in traditional areas of settlement, to reduce both overuse and underuse of land; development of a system of land tenure that provides land users with incentives to maintain productivity; environmental education programs (in schools and for farmers) to create a national environmental consciousness and more appreciation for the country's natural assets and beauty; new, appropriate systems of data collection and analysis, to help clarify underlying processes and develop more refined, appropriate; and broad-based macroeconomic policies. These policies will be aimed at improving incomes in rural areas, relative to urban areas - aimed at reduced poverty, environmental degradation, and rural outmigration.Banks&Banking Reform,Health Monitoring&Evaluation,Municipal Financial Management,Environmental Economics&Policies,Drylands&Desertification
Green synthesis of graphitic nanobiochar for the removal of emerging contaminants in aqueous media
No full textThis study reports the preparation of nanobiochar (NBC) via top-down approach of bioenergy waste-derived dendro biochar through mechanised grinding in order to assess its capacity to remove emerging contaminants, such as antibiotics, agrochemicals, and potentially toxic elements from aqueous media. Preconditioned biochar was disc milled in ethanol media, and the resulting colloidal biochar was dispersed in water to obtain the NBC fraction by centrifugation. Adsorption edge and isotherm experiments were carried out at pH 3 to 8 and NBC dosages of 0.5 g/L for oxytetracycline (OTC), glyphosate (GL), hexavalent chromium (CrVI), and cadmium (CdII). NBC was characterised by scanning electron microscopy, X-ray photoelectron spectroscopy, Brunauer–Emmett–Teller surface area, and Fourier transform infrared spectroscopy, which demonstrated the flakey and graphitic nature of the NBC particles with a surface area of 28 m2/g and the presence of different functional groups, such as [sbnd]OH, C[dbnd]O, [sbnd]NH, and CH3. The best pH for OTC and Cd(II) was 9, whereas the best pH levels for GL and Cr(VI) were 7 and 4, respectively. Isotherms depicted a positive cooperative adsorption mechanism by providing the best fit to the Hills equation, with high removal capacities for four contaminants. Dendro NBC showed the best performance, demonstrated by the high partition coefficient for the removal of OTC, GL, Cr(VI), and Cd(II) over various types of adsorbents. The overall results indicated that graphitic NBC produced by mechanical grinding of dendro biochar is a promising material for the removal of OTC, GL, Cr(VI), and Cd(II) from aqueous media.</p
Synthetic analogues of FTY720 differentially regulate pulmonary vascular permeability in vivo and in vitro JPET #153544 2 RUNNING TITLE PAGE Running title: FTY720 analogues alter vascular permeability *Corresponding Author
No full textMental fatigue does not affect static balance under both single and dual task conditions in young adults
No full textThe ability to control balance and prevent falls while carrying out daily life activities may require a predominantly controlled (cognitive) or automatic processing depending on the balance challenge, age, or other factors. Consequently, this process may be affected by mental fatigue which has been shown to impair cognitive abilities. Controlling static balance in young adults is a relatively easy task that may proceed automatically with minimal cognitive input making it insusceptible to mental fatigue. To investigate this hypothesis, static single and dual task (while concurrently counting backward by seven) balance was assessed in 60 young adults (25.2 ± 2.4 years) before and after 45 min of Stroop task (mental fatigue condition) and watching documentary (control), presented in a randomized counterbalanced order on separate days. Moreover, because mental fatigue can occur due to task underload or overload, participants carried out two different Stroop tasks (i.e., all congruent, and mainly incongruent trials) on separate days in the mental fatigue condition. Results of the study revealed a significantly higher feeling of mental fatigue after the mental fatigue conditions compared to control (p 0.05) indicating lack of effect of mental fatigue on static balance in this population. Therefore, future studies investigating this phenomenon in occupational or sport settings in similar population should consider using more challenging balance tasks. © 2023, The Author(s)
