bluuebunny/crossref_metadata_2025_split huggingface dataset:
A ribosomal protein variant that confers macrolide resistance differentially regulates acid resistance, catabolism, and biofilm formation related genes inEscherichia coli
Authors: Franklin Elizabeth A. , Worthan Sarah B. , Pham Chi , Yap Mee-Ngan F. , Cruz-Vera Luis R. 
Published: April 2021

ABSTRACTMutational changes in bacterial ribosomes that confer antibiotic resistance decrease cell fitness. Determining the genetic factors that interconnect antibiotic resistance and cell fitness is critical in the fight against bacterial infections. Here, we describe gene expression and phenotypic changes presented inEscherichia colicells carrying an uL22(K90D) mutant ribosomal protein, which showed growth defects and resistance to macrolide antibiotics. Ribosome profiling analyses revealed reduced expression of operons involved in catabolism, electron transportation, indole production, and lysine-decarboxylase acid resistance. In general, ribosome occupancy was increased at rare codons while translation initiation of proximal genes in several of the affected operons was substantially reduced. Decline of the activity of these genes was accompanied by increased expression of macrolide multidrug efflux pumps, the glutamate-decarboxylase regulon, and the autoinducer-2 metabolic regulon. In concordance with these changes, uL22(K90D) mutant cells grew better in acidic conditions and generated more biofilm in static cultures than their parental strain. Our work provides new insights on how mutations in ribosomal proteins induce the acquisition of macrolide and pH resistance, and increase the ability to generate biofilms.
An Engineered Contact Lens for Passive and Sustained Release of Lifitegrast, an Anti-Dry Eye Syndrome Drug
Authors: Mu Changhua , Lee Victoria , Liu Yiran , Han Ying , Marriott Gerard 
Published: April 2021

ABSTRACTLifitegrast is an FDA-approved drug that inhibits T-cell mediated inflammation associated with dry eye syndrome (DES). Lifitegrast is a potent inhibitor of the interaction between LFA-1 on T-cells and ICAM-1 on endothelial cells at the ocular surface. While effective in treating DES, 5% (81.2 mM) lifitegrast has low drug utilization and elicits off-target effects. Here we engineer contact lenses to release therapeutically-relevant doses of lifitegrast to every tear film for up to 10-hours. Lifitegrast is coupled to the polymer of the soft hydrogel lens via a photolabile (caged) crosslinker. Exposures of the lens to the 400-430 nm wavelengths of indoor daylight excite the caged crosslinker molecules and trigger a bond-cleavage reaction that releases authentic lifitegrast passively to the tear film. The photoproduct of the reaction remains chemically-linked to the polymer of the single-use lens. Our studies show that passive exposures of the lens to indoor light would generate an average of 990 nM lifitegrast to every tear film in a zero-order reaction for up to 10-hours. This concentration exceeds theKdfor the interaction between ICAM-1 and LFA-1 by ∼330-fold and would sustain inhibition of inflammatory responses at the ocular surface. The amount of lifitegrast released from the lens increases during exposures to outdoor sunlight. Over a 10-hour exposure to indoor light, a single lens would release 0.44% of the lifitegrast present in two drops of commercial 5% lifitegrast. Compared to tear-drop approaches, our engineered lenses would sustain the passive delivery of therapeutically-relevant doses of lifitegrast over a longer period, and exhibit improved drug utilization at a lower cost. Our technology could easily be integrated into daily-use contact lenses in order to prevent inflammation at the ocular surface, dry-eye and contact lens-mediated discomfort.Graphical Abstract
Latitudinal cline in hypoxia tolerance does not result in correlated acid tolerance inTigriopus californicus
Authors: Deconinck Aimee , Willett Christopher 
Published: April 2021

AbstractIntertidal organisms must tolerate a wide range of environmental parameters each day which may result in tolerance to multiple stressors correlating. The intertidal copepodTigriopus californicusexperiences diurnal variation in dissolved oxygen levels and pH as the opposing processes of photosynthesis and cellular respiration lead to coordinated highs during the day and lows at night. While environmental parameters with overlapping spatial gradients frequently result in correlated traits, less attention has been given to exploring temporally correlated stressors. We investigated whether hypoxia tolerance correlated with acid tolerance by testing the hypoxia and low pH stress tolerance of 6 genetically differentiated populations ofT. californicus. We checked for similarities in tolerance for the two stressors by latitude, sex, size, and time since collection as predictors. We found that although hypoxia tolerance correlated with latitude, acid tolerance did not, and no predictor was significant for both stressors. We concluded that temporally coordinated exposure to low pH and low oxygen did not result in populations developing equivalent tolerance for both.
Quarantine, relaxation and mutation explaining the CoViD-19 epidemic in São Paulo State (Brazil)
Authors: Yang Hyun Mo , Lombardi Junior Luis Pedro , Castro Fabio Fernandes Morato , Yang Ariana Campos 
Published: April 2021

AbstractBackgroundThe continuous SARS-CoV-2 transmission in several countries could contribute to the mutations’ appearance. The circulation of more virulent variants may increase the number of severe CoViD-19 needing hospital care and fatalities hugely.MethodsThe partial quarantine in São Paulo State and further relaxation associated with the mutations are explained by a mathematical model based on the CoViD-19 natural history encompassing the age-dependent fatality. The model parameters were fitted considering the observed data from São Paulo State.ResultsThe partial quarantine was explained by the less virulent SARS-CoV-2 transmission, but the relaxation alone could not explain the epidemic observed in São Paulo State. However, more virulent variants plus the transmission among isolated individuals explained the increased CoViD-19 fatalities.ConclusionsThe model described the CoViD-19 epidemic in São Paulo State by considering the partial quarantine, relaxation and mutations. The model provided a potential epidemiological scenario in the absence of mass vaccination.
Transcriptional Control of Brain Tumour Stem Cells by a Carbohydrate Binding Protein
Authors: Sharanek Ahmad , Burban Audrey , Hernandez-Corchado Aldo , Madrigal Ariel , Fatakdawala Idris , Najafabadi Hamed S , Soleimani Vahab D , Jahani-Asl Arezu 
Published: April 2021

SummaryBrain tumour stem cells (BTSCs) and intratumoural heterogeneity represent major challenges in glioblastoma therapy. Here, we report that theLGALS1gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy. Genetic deletion ofLGALS1alters BTSC gene expression profiles and results in downregulation of gene sets associated with mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition ofLGALS1signalling in BTSCs impairs self-renewal, suppresses tumourigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models. Mechanistically, we show thatLGALS1is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram BTSC transcriptional landscape. Our data unravel an oncogenic signalling pathway by which galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.
A measurement model of project control systems success for engineering and construction projects case study: contractor companies in Saudi's petroleum and chemical industry
Authors: Jawad Sahar , Ledwith Ann 
Published: April 2021

Purpose
The purpose of this paper is to presents a new modeling approach that provides a measurement tool for evaluating the effectiveness of Project Control Systems (PCS) and the improvement of the project control capability as a part of an organization's project management processes.

Design/methodology/approach
This study used a project management maturity approach to develop a measurement model of PCS success. The key elements in this model have been identified using the Fuzzy Analytic Hierarchy Process (FAHP) method to analyze data from a case study involving contractor companies in Saudi's petroleum and chemical industry.

Findings
The results identified six critical elements for PCS success: (1) Change Management, (2) Earned Value, (3) Baselined Plan, (4) Resource Loaded, (5) Progress Method and (6) Governance Program. In addition, Project Forecasting and Corrective Action Verification were identified as the main areas where clients and contractors need to focus for the effective deployment of a PCS.

Practical implications
The results of this study were used to create a PCS Maturity Model (PCSMM) and a PCS Success Index (PCSSI). The value of this index can help project managers to identify the maturity level of their PCS and improvement areas that lead to enhanced project performance.

Originality/value
This research presents an alternative maturity model for PCS assessment that provides a practical tool to identify areas for improving the critical elements of PCS success. The study draws a clear distinction between overall project success and the success of the PCS.
Inhibition of skin fibrosis in systemic sclerosis by botulinum toxin B via the suppression of oxidative stress
Authors: Baral Hritu , Sekiguchi Akiko , Uchiyama Akihiko , Nisaa Amalia Syahla , Yamazaki Sahori , Inoue Yuta , Yokoyama Yoko , Ogino Sachiko , Torii Ryoko , Hosoi Mari , Akai Ryoko , Iwawaki Takao , Ishikawa Osamu , Motegi Sei‐ichiro 
Published: April 2021

AbstractOxidative stress has been reported to play an important role in the pathogenesis of skin fibrosis in systemic sclerosis (SSc). We previously identified that botulinum toxin (BTX) injection suppresses pressure ulcer formation in a cutaneous ischemia–reperfusion injury mouse model by regulation of oxidative stress. However, the therapeutic possibility of BTX administration for preventing skin fibrosis in SSc is unclear. The objective of this study was to investigate the effect of BTX‐B on skin fibrosis in a murine model of SSc and determine the underlying mechanism. We found that BTX‐B injection significantly reduced dermal thickness and inflammatory cell infiltration in bleomycin‐induced skin fibrosis lesion in mice. We also identified that the oxidative stress signal detected through bioluminescence in OKD48 mice after bleomycin injection in the skin was significantly decreased by BTX‐B. Additionally, mRNA levels of oxidative stress associated factors (NOX2, HO‐1, Trx2) were significantly decreased by BTX‐B. Apoptotic cells in the lesional skin of bleomycin‐treated mice were significantly reduced by BTX‐B. Oxidant‐induced intracellular accumulation of reactive oxygen species in SSc fibroblasts was also inhibited by BTX‐B. In conclusion, BTX‐B might improve bleomycin‐induced skin fibrosis via the suppression of oxidative stress and inflammatory cells in the skin. BTX‐B injection may have a therapeutic effect on skin fibrosis in SSc.
Debt by design: The anatomy of a social policy fiasco – Or was it something worse?
Authors: Whiteford Peter 
Published: April 2021

Abstract‘Robodebt’ is the label applied to an Australian government initiative designed to increase recoveries of ‘overpayments’ made to social security recipients. Following complaints from many of those affected, there have been multiple investigations and inquiries, and a Federal Court Case which ruled the policy unlawful. The government is in the process of paying back more than $1000 million to more than 400,000 people after conceding the largest class action settlement in Australian history, and faces calls for a Royal Commission. Robodebt resembles a ‘policy fiasco’, as the outcomes could have been foreseen at the inception of the initiative. But it differs from other examples of policy failures in that it was intentional, and not the result of mistakes in design or implementation. The initiative not only failed to achieve the Budgetary savings anticipated, it has undermined rather than protected the integrity of the social security system. It poses serious questions about the quality of Australian public administration. The objective of this article is to clarify exactly how this fiasco occurred and identify the similarities and differences between this case study and other policy failures.
Use of continuous positive airway pressure and non‐invasive ventilation for respiratory failure in an Australian aeromedical retrieval service: A retrospective case series
Authors: Weller Martin , Gibbs Clinton , Pellatt Richard , MacKillop Allan 
Published: April 2021

AbstractObjectiveThe purpose of the present study was to investigate the use of respiratory support via continuous positive airway pressure (CPAP) and non‐invasive ventilation (NIV) in a medical retrieval service in Queensland, Australia, with reference to transport considerations and patient safety.MethodsIn this unblinded retrospective case series over a 13‐month period, a clinical database was reviewed for the use of CPAP/NIV. Retrieval metrics as well as clinical data were recorded.ResultsA total of 128 patients were transferred either by rotary (80%) or fixed wing (20%). The median transport time was 65 min. The median total mission time was 3.7 h. Fifty‐two percent of patients were female. The median age was 69 years and 93% had a background of cardiorespiratory disease. Sixty‐five percent of patients were receiving CPAP/NIV before arrival of the retrieval team. The main diagnoses were respiratory failure (29.7%), acute pulmonary oedema (26.6%) and chronic obstructive pulmonary disease (25.8%). There were no incidences of pneumothorax, intubation in transit, vomiting, desaturation, hypotension, cardiac arrest or death. In two cases NIV was abandoned due to mask intolerance and in one case there was a decrease in Glasgow Coma Scale by 2. In no cases was there a detrimental outcome for the patient.ConclusionThe use of NIV and CPAP appears to have a low‐risk profile in aeromedical retrieval even for prolonged periods of time in an adult population.
Waterfront regeneration in Australia: Local responses to global trends in reimagining disused city docklands
Authors: Oakley Susan 
Published: April 2021

AbstractThis article applies ideas about critical urban assemblages to understand the planning processes, politics, and delivery of waterfront regeneration from an Australian perspective, drawing on the Port Adelaide waterfront in South Australia as a case study. Waterfront regeneration is associated with global economic deregulation, market‐led development, changes to planning regulatory requirements, and “streamlined” governance arrangements. The global spread of waterfront regeneration is an outcome of such processes, with individual waterfronts being “remade” and reimagined to reflect priorities emphasised by those forging urban policies linked to inter‐urban competitiveness and neoliberal urbanism. Waterfront developments may be categorised as “models” of success or failure that limit deeper analysis that can advance theory and practice. How such projects reflect interactions across local and global scales rather than just being expressions of global forces is a question often ignored; so, too, are those considering how policy and politics mediate those relationships. Ideas, strategies, capital, people, policy, and politics are dynamic, provisional, and contested, and are produced and assembled in particular ways to suit specific spatiotemporal contexts. On that understanding, the aim of this article is to highlight how the Port Adelaide waterfront is undergoing assembly and reassembly to reflect socioeconomic priorities and metropolitan planning agendas.
Acidosis‐induced activation of distal nephron principal cells triggers Gdf15 secretion and adaptive proliferation of intercalated cells
Authors: Cheval Lydie , Viollet Benoit , Klein Christophe , Rafael Chloé , Figueres Lucile , Devevre Estelle , Zadigue Georges , Azroyan Anie , Crambert Gilles , Vogt Bruno , Doucet Alain 
Published: April 2021

AbstractAimType A intercalated cells of the renal collecting duct participate in the maintenance of the acid/base balance through their capacity to adapt proton secretion to homeostatic requirements. We previously showed that increased proton secretion stems in part from the enlargement of the population of proton secreting cells in the outer medullary collecting duct through division of fully differentiated cells, and that this response is triggered by growth/differentiation factor 15. This study aimed at deciphering the mechanism of acid load‐induced secretion of Gdf15 and its mechanism of action.MethodsWe developed an original method to evaluate the proliferation of intercalated cells and applied it to genetically modified or pharmacologically treated mice under basal and acid‐loaded conditions.ResultsGdf15 is secreted by principal cells of the collecting duct in response to the stimulation of vasopressin receptors. Vasopressin‐induced production of cAMP triggers activation of AMP‐stimulated kinases and of Na,K‐ATPase, and induction of p53 and Gdf15. Gdf15 action on intercalated cells is mediated by ErbB2 receptors, the activation of which triggers the expression of cyclin d1, of p53 and anti‐proliferative genes, and of Egr1.ConclusionAcidosis‐induced proliferation of intercalated cells results from a cross talk with principal cells which secrete Gdf15 in response to their stimulation by vasopressin. Thus, vasopressin is a major determinant of the collecting duct cellular homeostasis as it promotes proliferation of intercalated cells under acidosis conditions and of principal cells under normal acid‐base status.
Drug metabolism in severe chronic obstructive pulmonary disease: A phenotyping cocktail study
Authors: McNeill Richard P. , Zhang Mei , Epton Michael J. , Doogue Matthew P. 
Published: April 2021

AimsTo evaluate the effect of severe chronic obstructive pulmonary disease (COPD) on drug metabolism by comparing the pharmacokinetics of patients with severe COPD with healthy volunteers and using the modified Inje drug cocktail.MethodsThis was a single‐centre pharmacokinetic study with 12 healthy participants and 7 participants with GOLD D COPD. Midazolam 1 mg, dextromethorphan 30 mg, losartan 25 mg, omeprazole 20 mg, caffeine 130 mg and paracetamol 1000 mg were simultaneously administered and intensive pharmacokinetic sampling was conducted over 8 hours. Drug metabolism by CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, UGT1A6 and UGT1A9 in participants with COPD were compared with phenotypes in healthy controls.ResultsThe oral clearance (95% confidence interval) in participants with COPD relative to controls was: midazolam 63% (60–67%); dextromethorphan 72% (40–103%); losartan 53% (52–55%); omeprazole 35% (31–39%); caffeine 52% (50–53%); and paracetamol 73% (72–74%). There was a 5‐fold increase in AUC for omeprazole and approximately 2‐fold increases for caffeine, losartan, dextromethorphan, and midazolam. The AUC of paracetamol, which is mostly glucuronidated, was increased by about 60%.ConclusionSevere COPD is associated with a clinically significant reduction in oral drug clearance. This may be greater for cytochrome P450 substrates than for glucuronidated drugs. This supports reduced starting doses when prescribing for patients with severe COPD.
Children, language and access to schools in the global South: The case of migrants in Ghana
Authors: Kyereko Daniel Owusu , Faas Daniel 
Published: April 2021

AbstractResearch on migrant children and young people has often focused on the global North and less on South–South migration. This article discusses language and its effect on how young migrants access Ghanaian schools. Through interviews with 68 pupils, 21 parents and 40 teachers and principals from 30 schools across Accra, we found that children and young people from francophone countries were placed in lower than age‐appropriate grades due to their lower command of English. Our study highlights the complex linguistic barriers facing migrant youth in an anglocentric educational system. The article discusses the relevance of our results in other postcolonial multilingual nations in the global South.
Congenital erythrocytosis
Authors: Mallik Nabhajit , Das Reena , Malhotra Pankaj , Sharma Prashant 
Published: April 2021

AbstractErythrocytosis, or increased red cell mass, may be labeled as primary or secondary, depending on whether the molecular defect is intrinsic to the red blood cells/their precursors or extrinsic to them, the latter being typically associated with elevated erythropoietin (EPO) levels. Inherited/congenital erythrocytosis (CE) of both primary and secondary types is increasingly recognized as the cause in many patients in whom acquired, especially neoplastic causes have been excluded. During the past two decades, the underlying molecular mechanisms of CE are increasingly getting unraveled. Gain‐in‐function mutations in the erythropoietin receptor gene were among the first to be characterized in a disorder termed primary familial and congenital polycythemia. Another set of mutations affect the components of the oxygen‐sensing pathway. Under normoxic conditions, the hypoxia‐inducible factor (HIF), upon hydroxylation by the prolyl‐4‐hydroxylase domain protein 2 (PHD2) enzyme, is degraded by the von Hippel‐Lindau protein. In hypoxic conditions, failure of prolyl hydroxylation leads to stabilization of HIF and activation of the EPO gene. CE has been found to be caused by loss‐of‐function mutations in VHL and PHD2/EGLN1 as well as gain‐of‐function mutations in HIF‐2α (EPAS1), all resulting in constitutive activation of EPO signaling. Apart from these, globin gene mutations leading to formation of high oxygen affinity hemoglobins also cause CE. Rarely, bisphosphoglycerate mutate mutations, affecting the 2,3‐bisphosphoglycerate levels, can increase the oxygen affinity of hemoglobin and cause CE. This narrative review examines the current mutational spectrum of CE and the distinctive pathogenetic mechanisms that give rise to this increasingly recognized condition in various parts of the world.