bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colistin heteroresistance in Enterobacter cloacae is mediated by PmrAB-independent 4-amino-4-deoxy-L-arabinose addition to lipid A
Authors: Kang Katie N. , Klein Dustin R. , Kazi Misha I. , Guérin François , Cattoir Vincent , Brodbelt Jennifer S. , Boll Joseph M. 
Published: January 2019

AbstractThe Enterobacter cloacae complex (ECC) consists of closely-related, but genetically distinct bacteria commonly associated with the human microbiota. ECC have been increasingly isolated from healthcare-associated infections, demonstrating that these Enterobacteriaceae are emerging nosocomial pathogens. ECC strains can rapidly acquire multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the highly conserved lipid A component of the Gram-negative outer membrane to lyse the bacterial cell. Many Gram-negative Enterobacteriaceae fortify their outer membrane with cationic amine-containing moieties to protect from CAMP-inflicted lysis. The PmrAB two-component system (TCS) transcriptionally activates 4-amino-4-deoxy-L-arabinose (L-Ara4N) biosynthesis to result in amine moiety addition to lipid A in many Enterobacteriaceae such as E. coli and Salmonella. In contrast, PmrAB in E. cloacae is dispensable for CAMP resistance. Instead, fitness against CAMPs presents as heteroresistance, or a subpopulation of cells that exhibit clinically significant increases in resistance levels compared to the majority population. We demonstrate that E. cloacae lipid A is modified with L-Ara4N to induce CAMP heteroresistance and that the regulatory mechanism is independent of the PmrABEcl TCS. We show that the response regulator, PhoPEcl, directly binds to the arnBEcl promoter to induce expression of L-Ara4N biosynthesis and PmrAB-independent addition to the lipid A disaccharolipid. Therefore, we have identified a mechanism of ECC colistin heteroresistance that directly involves the PhoPQ system.ImportanceMembers of the Enterobacter cloacae complex (ECC) are Gram-negative nosocomial pathogens that have emerged within healthcare facilities around the world. ECC infections are associated with immunocompromised patients and infections are often life threatening. The cationic antimicrobial peptide, colistin (polymyxin E), is a last-line treatment option to combat Gram-negative multidrug resistant infections. However, many ECC intrinsically encode a colistin heteroresistance mechanism. Our analysis to characterize colistin heteroresistance in E. cloacae revealed that 4-amino-4-deoxy-L-arabinose is conjugated to the lipid A disaccharolipid to protect from colistin-mediated lysis. Additionally, this mechanism is directly regulated by the PhoPQEcl two-component system. Elucidation of outer membrane antimicrobial resistance modifications and their regulatory pathways in E. cloacae isolates will advance our understanding of CAMP heteroresistance.
Control of Staphylococcus aureus quorum sensing by a membrane-embedded peptidase
Authors: Cosgriff Chance J. , White Chelsea R. , Ping Teoh Wei , Grayczyk James P. , Alonzo Francis 
Published: January 2019

AbstractGram-positive bacteria process and release small peptides or “pheromones” that act as signals for the induction of adaptive traits including those involved in pathogenesis. One class of small signaling pheromones is the cyclic auto-inducing peptides (AIPs), which regulate expression of genes that orchestrate virulence and persistence in a range of microbes including Staphylococci, Listeria, Clostridia, and Enterococci. In a genetic screen for Staphylococcus aureus secreted virulence factors, we identified a S. aureus mutant containing an insertion in gene SAUSA300_1984 (mroQ), which encodes a putative membrane-embedded metalloprotease. A ΔmroQ mutant exhibits impaired induction of TLR2-dependent inflammatory responses from macrophages, but elicits greater production of the inflammatory cytokine IL-1β and is attenuated in a murine skin and soft tissue infection model. The ΔmroQ mutant phenocopies a S. aureus mutant containing a deletion of the accessory gene regulatory system (Agr), wherein both strains have significantly reduced production of secreted toxins and virulence factors, but increased surface Protein A abundance. The Agr system controls virulence factor gene expression in S. aureus through sensing accumulation of AIP via the histidine kinase AgrC and response regulator AgrA. We provide evidence to suggest that MroQ acts within the Agr pathway to facilitate optimal processing or export of AIP for signal amplification through AgrC/A and induction of virulence factor gene expression. Mutation of MroQ active site residues significantly reduces AIP signaling and attenuates virulence. Altogether, this work identifies a new component of the Agr quorum sensing circuit that is critical for the production of S. aureus virulence factors.
Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer
Authors: Song Mengjia , Ping Yu , Zhang Kai , Yang Li , Li Feng , Cheng Shaoyan , Yue Dongli , Maimela Nomathamsanqa Resegofetse , Qu Jiao , Liu Shasha , Sun Ting , Li Zihai , Xia Jianchuan , Zhang Bin , Wang Liping , Zhang Yi 
Published: January 2019

AbstractInterferon-γ (IFN-γ) is conventionally recognized as an inflammatory cytokine that play a central role in antitumor immunity. Clinically, although has been used clinically to treat a variety of malignancies, low-level IFN-γ in the tumor microenvironment (TME) increases the risk of tumor metastasis during immunotherapy. Accumulating evidence has suggested that IFN-γ can induce cancer progression. The mechanisms underlying the controversial role of IFN-γ regulating tumor development remain unclear. Herein, we firstly revealed a dose-dependent effect of IFN-γ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Mechanically, low-level IFN-γ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high-level IFN-γ activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFN-γ bothin vitroandin vivo. Our study first defines the role of low-level IFN-γ in conferring tumor stemness and clearly elucidate the distinct signaling pathways activated by IFN-γ in a dose-dependent manner, providing new insights into cancer treatment, particularly patients with low-level IFN-γ expression in the TME.
Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses
Authors: Banks Susan M. L. , Medeiros Audrey T. , McQuillan Molly , Busch David J. , Ibarraran-Viniegra Ana Sofia , Roy Subhojit , Sousa Rui , Lafer Eileen M. , Morgan Jennifer R. 
Published: January 2019

ABSTRACTα-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey γ-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein to lamprey axons, Hsc70 availability was reduced at the synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 together with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the toxic impacts of excess α-synuclein at synapses, which may be of value for ameliorating synaptic defects in PD and other synuclein-linked diseases.SIGNIFICANCE STATEMENTSynaptic defects caused by α-synuclein overexpression are linked to cognitive deficits in PD and other diseases. However, the mechanisms by which excess α-synuclein impairs synaptic vesicle trafficking are unknown. Data presented here demonstrate that acute introduction of excess α-synuclein at a classical vertebrate synapse selectively inhibits CCV uncoating, leading to impaired vesicle recycling. Furthermore, increasing α-synuclein reduced synaptic levels of Hsc70, the clathrin uncoating ATPase. Subsequently increasing Hsc70 restored CCV uncoating and improved vesicle recycling. This study identifies a novel molecular mechanism underlying the α-synuclein-induced synaptic defects and presents one viable strategy for reversing them.
Lactate and glycerol-3-phosphate metabolism cooperatively regulate growth and redox balance during Drosophila melanogaster larval development
Authors: Li Hongde , Buddika Kasun , Sterrett Maria C. , Julick Cole R. , Pletcher Rose C. , Gosney Chelsea J. , Burton Anna K. , Karty Jonathan A. , Montooth Kristi L. , Sokol Nicholas S. , Tennessen Jason M. 
Published: January 2019

ABSTRACTThe dramatic growth that occurs during Drosophila larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands by increasing carbohydrate metabolism and lactate dehydrogenase (dLDH) activity. The resulting metabolic program is ideally suited to synthesize macromolecules and mimics the manner by which cancer cells rely on aerobic glycolysis. To explore the potential role of Drosophila dLDH in promoting biosynthesis, we examined how dLdh mutations influence larval development. Our studies unexpectantly found that dLdh mutants grow at a normal rate, indicating that dLDH is dispensable for larval biomass production. However, subsequent metabolomic analyses suggested that dLdh mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P), the production of which also influences larval redox balance. Consistent with this possibility, larvae lacking both dLDH and G3P dehydrogenase (GPDH1) exhibit developmental delays, synthetic lethality, and aberrant carbohydrate metabolism. Considering that human cells also generate G3P upon Lactate Dehydrogenase A (LDHA) inhibition, our findings hint at a conserved mechanism in which the coordinate regulation of lactate and G3P synthesis imparts metabolic robustness upon growing animal tissues.
Seasonal and directional dispersal behavior in an ongoing dove invasion
Authors: Slager David L. 
Published: January 2019

AbstractThe dispersal behavior that underlies range expansions can be difficult to study. Eurasian Collared-Doves have staged independent northwestward invasions across both Europe and North America, reaching carrying capacity in Europe but continuing to increase exponentially in the Americas, where their dispersal behavior remains enigmatic. I used citizen science observations to investigate Eurasian Collared-Dove dispersal behavior along the North American Pacific coast, a natural barrier to land-bird dispersal. Using coastal and pelagic observations, I assessed the seasonality and directionality of dispersal and its prevalence across years. Dispersal flights peaked in spring, like in Europe, and were north-biased, consistent with northwestward initial colonization. A non-significant trend of increasing dispersal across years may reflect evolution of dispersal via spatial sorting and selection. These results inform management of this invasive dove, raise new questions about evolutionary mechanisms behind the invasion, and exemplify using citizen science to study dispersal behavior, a longstanding challenge in ecology.
A Domain-general Cognitive Core defined in Multimodally Parcellated Human Cortex
Authors: Assem Moataz , Glasser Matthew F. , Van Essen David C. , Duncan John 
Published: January 2019

AbstractNumerous brain imaging studies identified a domain-general or “multiple-demand” (MD) activation pattern accompanying many tasks and may play a core role in cognitive control. Though this finding is well established, the limited spatial localization provided by traditional imaging methods precluded a consensus regarding the precise anatomy, functional differentiation and connectivity of the MD system. To address these limitations, we used data from 449 subjects from the Human Connectome Project, with cortex of each individual parcellated using neurobiologically grounded multi-modal MRI features. The conjunction of three cognitive contrasts reveals a core of 10 widely distributed MD parcels per hemisphere that are most strongly activated and functionally interconnected, surrounded by a penumbra of 17 additional areas. Outside cerebral cortex, MD activation is most prominent in the caudate and cerebellum. Comparison with canonical resting state networks shows MD regions concentrated in the fronto-parietal network but also engaging three other networks. MD activations show modest relative task preferences accompanying strong co-recruitment. With distributed anatomical organization, mosaic functional preferences, and strong interconnectivity, we suggest MD regions are well positioned to integrate and assemble the diverse components of cognitive operations. Our precise delineation of MD regions provides a basis for refined analyses of their functions.
Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS
Authors: Manzo Ernesto , Lorenzini Ileana , Barrameda Dianne , O’Conner Abigail G. , Barrows Jordan M. , Starr Alexander , Kovalik Tina , Rabichow Benjamin E. , Lehmkuhl Erik M. , Shreiner Dakotah D. , Joardar Archi , Liévens Jean-Charles , Bowser Robert , Sattler Rita , Zarnescu Daniela C. 
Published: January 2019

AbstractAmyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.
CIC-DUX4 expression drives the development of small round cell sarcoma in transgenic zebrafish: a new model revealing a role for ETV4 in CIC-mediated sarcomagenesis
Authors: Watson Sarah , Kendall Genevieve C. , Rakheja Dinesh , McFaul Matthew E. , Draper Bruce W. , Tirode Franck , Delattre Olivier , Amatruda James F 
Published: January 2019

AbstractCIC-DUX4 sarcoma is a rare subtype of sarcoma characterized by a devastating prognosis and resistance to conventional therapeutic strategies. So far, only few models of the disease have been reported, and its biological mechanisms remain to be elucidated. We established mosaic transgenic zebrafish expressing the human CIC-DUX4 fusion under the control of the β-actin promoter. CIC-DUX4 transgenic fish rapidly developed aggressive soft tissue tumors with a high penetrance. RNAseq profiling revealed that fish tumors shared major common targets with human tumors and cell lines, including the overexpression of the Pea3 transcription factors, etv4 and etv5. Tumor development was strongly impaired in etv4-deficient zebrafish, implicating Etv4 as a critical effector of CIC-DUX4-mediated oncogenesis. Altogether, we report here the first in vivo model of CIC-DUX4 sarcoma in zebrafish, which will represent a major tool for future preclinical research.
Economic Burden of Hypoglycaemia among Type II Diabetes Mellitus Patients in Malaysia
Authors: Aljunid Syed Mohamed , Aung Yin New , Ismail Aniza , Abdul Rashid Siti Athirah Zafirah , Nur Amrizal M , Cheah Julius , Matzen Priya 
Published: January 2019

AbstractObjectiveThe main aim of this study is to identify the direct cost and economic burden of hypoglycaemia among patients with Type II diabetes mellitus in Malaysia.MethodsThe incurred cost for hypoglycaemia among patients admitted to University Kebangsaan Malaysia Medical Centre (UKMMC) was explored from a cross sectional study. 20-79 year patients discharged between Jan 2010 to Sept 2015 and having an ICD-10 code of hypoglycaemia as a primary diagnosis in the casemix database were included in the study. Costing analysis from the perspective of health providers was completed using step-down approach. Data related to hospital cost were collected using hospital-costing template, based on three levels of cost centres. The costing data from UKMMC was used to estimate the national burden of hypoglycaemia among type II diabetics for the whole country.ResultsOf 244 diabetes patients admitted primarily for hypoglycaemia to UKMMC, 52% were female and 88% were over 50 years old. The cost increased with severity. Managing a hypoglycaemic case requires 5 days (median) of inpatient stay with a range of 2-26 days; and costs RM 9,083 (USD 2,323). 30% of the cost came from the ward services cost (final cost centre), 16% of the cost came from ICU services and 15% from pharmacy services(secondarylevel cost centres). Based on the prevalence of hypoglycaemia-related admissions of 3.2%, the total cost of care for hypoglycaemia among adult diabetes in Malaysia is estimated to be RM 117.4 (USD 30.0) million, which is translated as 0.5% of Ministry of Health budget.ConclusionHypoglycaemia imposes substantial economic impact even without the direct and indirect cost incurred by patients and other cost of complications. Proper diabetic care and health education is needed in diabetic management to reduce episodes of hypoglycaemia.
Exploring the experiences of birth mothers whose children have been diagnosed with fetal alcohol spectrum disorders: a qualitative study
Authors: Thomas Robyn , Mukherjee Raja 
Published: January 2019

Purpose
Fetal alcohol spectrum disorder (FASD) is an umbrella term for a range of conditions that may occur in an individual whose mother drank alcohol during pregnancy. There has been little research into the experience of birth mothers of children with FASD and no published work of this kind in the UK. This is in contrast to a number of studies that have been conducted on foster/adoptive parents. In light of the recent publication in the UK of a mixed methods study on adoptive carers, it is timely to conduct research on birth mothers in the UK. The purpose of this paper is to explore the experiences of birth mothers following a diagnosis of FASD in their children.

Design/methodology/approach
An interpretive phenomenological analytical approach was used to generate themes from individual semi-structured interviews of five women who are birth mothers of children with FASD.

Findings
Four superordinate main themes and various subthemes were identified. To blame or not to blame captures the tension the mothers experience when considering the cause of their child’s condition. Life is a series of battles which describes the struggles the women experience on a crusade with a renewed sense of purpose that captures the process of transformation that occurs, which helps describe the internal and external factors that help the mothers cope.

Originality/value
FASD is often described in the literature as being completely preventable with the implication that it is the mother’s fault because they drank alcohol during pregnancy. However, a statement like this fails to portray the complexities of the phenomenon of women drinking during pregnancy. Life is difficult for the women for a number of different reasons, yet a sense of hope is present. The mothers have a renewed sense of purpose to do the best they can for their child and to raise awareness of FASD. Understanding their experiences can help service providers better meet the needs of parents and children affected by FASD.
Heuristic-based user interface evaluation of the mobile centralized doctor appointment system
Authors: Inal Yavuz 
Published: January 2019

Purpose
This study aims to evaluate the interface of the mobile Centralized Doctor Appointment System (CDAS), the largest mobile e-government health application developed in Turkey to allow citizens to make medical appointments at public hospitals.

Design/methodology/approach
A total of 40 information systems engineers took part in the study. The evaluation process was mainly based on Nielsen’s heuristics. The data obtained in the evaluation process were enriched using system usability scale to conduct a more detailed analysis.

Findings
Based on the findings, problems related to the usability of the evaluated mobile health application were identified. The most violated heuristic items were found to be “error prevention” and “user control and freedom”, whereas the least violated heuristic item was “consistency and standards”. The participants generally categorized the usability problems they identified as “minor” or “major” according to their severity.

Originality/value
As a developing country, Turkey has made considerable investment in mobile e-government applications in recent years. It is equally important that mobile e-government services provided by public institutions have features that make these applications effective, efficient and satisfying for citizens. Therefore, the usability of mobile health applications in government services needs to be researched to improve their effectiveness and guide authorities, practitioners and designers.