bluuebunny/crossref_metadata_2025_split huggingface dataset:
Healthcare use and cost trajectories during the last year of life: A national population administrative secondary care data linkage study
Authors: Diernberger Katharina , Luta Xhyljeta , Bowden Joanna , Fallon Marie , Droney Joanne , Lemmon Elizabeth , Gray Ewan , Marti Joachim , Hall Peter S 
Published: September 2020

AbstractBackgroundPeople who are nearing the end of life are high users of healthcare. The cost to providers is high and the value of care is uncertain.ObjectivesTo describe the pattern, trajectory and drivers of secondary care use and cost by people in Scotland in their last year of life.MethodsRetrospective whole-population secondary care administrative data linkage study of Scottish decedents of 60 years and over between 2012 and 2017 (N=274,048).ResultsSecondary care use was high in the last year of life with a sharp rise in inpatient admissions in the last three months. The mean cost was £10,000. Cause of death was associated with differing patterns of healthcare use: dying of cancer was preceded by the greatest number of hospital admissions and dementia the least. Greater age was associated with lower admission rates and cost. There was higher resource use in the urban areas. No difference was observed by deprivation.ConclusionsHospitalisation near the end of life was least frequent for older people and those living rurally, although length of stay for both groups, when they were admitted, was longer. Research is required to understand if variation in hospitalisation is due to variation in the quantity or quality of end of life care available, varying community support, patient preferences or an inevitable consequence of disease-specific needs.
A common model for the breathlessness experience
Authors: Finnegan Sarah L. , Pattinson Kyle T.S. , Sundh Josefin , Sköld Magnus , Janson Christer , Blomberg Anders , Sandberg Jacob , Ekström Magnus 
Published: September 2020

AbstractIntroductionChronic breathlessness occurs across many different diseases, independently of severity. Yet, despite being strongly linked to adverse outcomes, chronic breathlessness is generally not considered a stand-alone treatment target. Here we move focus from identifying the “best” measurement tool and use data-driven techniques to identify and confirm the stability of underlying features (factors) driving breathlessness across different cardiorespiratory diseases. Such frameworks could provide an opportunity to address the underlying mechanisms of breathlessness and over-come issues with co-morbidities, particularly when medical therapies have been optimised.MethodsLongitudinal study of questionnaire data on 182 participants with main diagnoses of asthma (21.4%), COPD (24.7%), heart failure (19.2%), idiopathic pulmonary fibrosis (18.7%), other interstitial lung disease (5.5%), and “other diagnoses” (8.8%) were entered into an exploratory factor analysis (EFA). Participants were stratified based on their EFA factor scores, allowing us to examine whether the breathlessness experience differed across disease diagnosis. We then examined model stability after six months and established through an iterative process the most compact, and therefore least burdensome assessment tool.ResultsFrom the 25 input measures, 16 measures were retained for model validation. The resulting model contained four factors to which we assigned the following descriptive labels: body burden, 2) affect/mood, 3) breathing burden and 4) anger/frustration. Stratifying patients by their scores across the four factors revealed two groups corresponding to high and low burden. These were not found to be predictive of primary disease diagnosis and did remain stable after six months.ConclusionsWe have identified four stable and disease-independent factors that seem to underlie the experience of breathlessness. We suggest that interventions may target factors within this framework to answer the question of whether they are also driving the experience itself.
Population structure, biogeography and transmissibility ofMycobacterium tuberculosis
Authors: Freschi Luca , Vargas Roger , Hussain Ashek , Kamal S M Mostofa , Skrahina Alena , Tahseen Sabira , Ismail Nazir , Barbova Anna , Niemann Stefan , Cirillo Daniela Maria , Dean Anna S , Zignol Matteo , Farhat Maha Reda 
Published: September 2020

AbstractMycobacterium tuberculosisis a clonal pathogen proposed to have co-evolved with its human host for millennia, yet our understanding of its genomic diversity and biogeography remains incomplete. Here we use a combination of phylogenetics and dimensionality reduction to reevaluate the population structure ofM. tuberculosis, providing the first in-depth analysis of the ancient East African Indian Lineage 1 and the modern Central Asian Lineage 3 and expanding our understanding of Lineages 2 and 4. We assess sub-lineages using genomic sequences from 4,939 pan-susceptible strains and find 30 new genetically distinct clades that we validate in a dataset of 4,645 independent isolates. We characterize sub-lineage geographic distributions and demonstrate a consistent geographically restricted and unrestricted pattern for 20 groups, including three groups of Lineage 1. We assess the transmissibility of the four major lineages by examining the distribution of terminal branch lengths across theM. tuberculosisphylogeny and identify evidence supporting higher transmissibility in Lineages 2 and 4 than 3 and 1 on a global scale. We define a robust expanded barcode of 95 single nucleotide substitutions (SNS) that allows for the rapid identification of 69Mtbsub-lineages and 26 additional internal groups. Our results paint a higher resolution picture of theMtbphylogeny and biogeography.
The Abl-interactor Abi suppresses the function of the BRAG2 GEF family member Schizo
Authors: Lübke Stefanie , Braukmann Carina , Rexer Karl-Heinz , Cigoja Lubjinka , Önel Susanne F. 
Published: September 2020

AbstractGuanine nucleotide exchange factors (GEF) of the BRAG subfamily activate small Arf GTPases, which are pivotal regulators of intracellular membrane traffic and actin dynamics. Here, we demonstrate a novel interaction between the Abl-interactor (Abi) and the BRAG family member Schizo. We mapped the SH3 domain of Abi to interact with the N-terminal region of Schizo. This region is additionally involved in the binding of the cytodomain of the cell adhesion molecule N-cadherin. Inschizoloss of function mutants, we detected increased amounts of N-cadherin. In contrast, the expression of the GEF (Sec7) and the membrane-binding (pleckstrin homology) domains decreased amounts of N-cadherin, indicating a crucial role of the Sec7-PH module in regulating N-cadherin levels. Unlike other Sec7 GEFs, where the catalytic Sec7 domain is autoinhibited, the Sec7 and PH domain of BRAG2 are constitutively accessible, raising the question how GEF activity is controlled in a spatial and temporal manner. Our genetic analyzes demonstrate that the nature of the Abi Schizo interaction is to antagonize Schizo function and to restore wild-type amounts of N-cadherin.
CDK-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity
Authors: Cantres-Velez Juan A. , Blaize Justin L. , Vierra David A. , Boisvert Rebecca A. , Garzon Jada M. , Piraino Benjamin , Tan Winnie , Deans Andrew J. , Howlett Niall G. 
Published: September 2020

AbstractFanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins under conditions of cellular stress and during S-phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a CDK regulatory phospho-site (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by LC-MS/MS and by immunoblotting with a S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during S-phase. Furthermore, FA-D2 (FANCD2-/-) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including micronuclei and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein that promotes mitotic fidelity.Author SummaryFanconi anemia (FA) is a rare genetic disease characterized by high risk for bone marrow failure and cancer. FA has strong genetic and biochemical links to hereditary breast and ovarian cancer. The FA proteins function to repair DNA damage and to maintain genome stability. The FANCD2 protein functions at a critical stage of the FA pathway and its posttranslational modification is defective in >90% of FA patients. However, the function, and regulation of FANCD2, particularly under unperturbed cellular conditions, remains remarkably poorly characterized. In this study, we describe a novel mechanism of regulation of the FANCD2 protein during S-phase of the cell cycle. CDK-mediated phosphorylation of FANCD2 on S592 promotes the ubiquitination of FANCD2 during S-phase. Disruption of this phospho-regulatory mechanism results in compromised mitotic fidelity and an increase in mitotic chromosome instability.
Sniffing the Human Body-Volatile Hexadecanal Blocks Aggression in Men but Triggers Aggression in Women
Authors: Mishor Eva , Amir Daniel , Weiss Tali , Honigstein Danielle , Weissbrod Aharon , Livne Ethan , Gorodisky Lior , Karagach Shiri , Ravia Aharon , Snitz Kobi , Karawani Diyala , Zirler Rotem , Weissgross Reut , Soroka Timna , Endevelt-Shapira Yaara , Agron Shani , Rozenkrantz Liron , Reshef Netta , Furman-Haran Edna , Breer Heinz , Strotmann Joerg , Sobel Noam 
Published: September 2020

AbstractBody-volatiles can effectively trigger or block conspecific aggression in terrestrial mammals. Here we tested whether hexadecanal (HEX), a human body-volatile implicated as a mammalian-wide social cue, impacts human aggression. Using validated behavioural paradigms, we observed a remarkable dissociation: sniffing HEX blocked aggression in men, but triggered aggression in women. Next, using functional brain imaging, we uncovered a pattern of brain activity mirroring behaviour: In both men and women, HEX increased activity in the left angular gyrus, an area implicated in perception of social cues. Hex then modulated functional connectivity between the angular gyrus and a brain network implicated in social appraisal (temporal pole) and aggressive execution (amygdala and orbitofrontal cortex) in a sex-dependent manner consistent with behaviour: increasing connectivity in men, but decreasing connectivity in women. These findings implicate sex-specific social chemosignaling at the mechanistic heart of human aggressive behaviour.
The Positive Switching RSFP Padron2 Enables Live-Cell RESOLFT Nanoscopy Without Sequential Irradiation Steps
Authors: Konen Timo , Grotjohann Tim , Jansen Isabelle , Jensen Nickels , Hell Stefan W. , Jakobs Stefan 
Published: September 2020

AbstractReversibly switchable fluorescent proteins (RSFPs) can be repeatedly transferred between a fluorescent on- and a non-fluorescent off-state in response to irradiation with light of different wavelengths. Negative switching RSFPs are switched from the on- to the off-state with the same wavelength which also excites fluorescence. Positive switching RSFPs have a reversed light response where the fluorescence excitation wavelength induces the transition from the off- to the on-state. Reversible saturable optical linear (fluorescence) transitions (RESOLFT) nanoscopy utilizes these switching states to achieve diffraction-unlimited resolution, but so far has primarily relied on negative switching RSFPs by using time sequential switching schemes.Based on the green fluorescent RSFP Padron, we engineered the positive switching RSFP Padron2. Compared to its predecessor, it can undergo 50-fold more switching cycles while displaying a contrast ratio between the on- and the off-state of more than 100:1. Because of its robust switching behavior, Padron2 supports a RESOLFT imaging scheme that entirely refrains from sequential switching as it only requires beam scanning of two spatially overlaid light distributions. Using Padron2, we demonstrate live-cell RESOLFT nanoscopy without sequential irradiation steps.
Studies on CRMP2 SUMOylation-deficient transgenic mice reveal novel insights into the trafficking of NaV1.7 channels
Authors: Gomez Kimberly , Ran Dongzhi , Madura Cynthia L. , Moutal Aubin , Khanna Rajesh 
Published: September 2020

AbstractVoltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel NaV1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). If not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2K374A/K374A) female mice have reduced NaV1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2K374A/K374Afemale mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male and female CRMP2K374A/K374Amice, increased pain sensitivity in allodynia-resistant animals. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2K374A/K374Amice. Finally, silencing these proteins in DRG neurons from female CRMP2K374A/K374Amice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non SUMOylated CRMP2-mediated internalization of sodium channelsin vivo.
APEX-based proximity labeling inPlasmodiumidentifies a membrane protein with dual functions during mosquito infection
Authors: Kehrer Jessica , Ricken Dominik , Strauss Leanne , Pietsch Emma , Heinze Julia M. , Frischknecht Friedrich 
Published: September 2020

AbstractTransmission of the malaria parasitePlasmodiumto mosquitoes necessitates gamete egress from red blood cells to allow zygote formation and ookinete motility to enable penetration of the midgut epithelium. Both processes are dependent on the secretion of proteins from distinct sets of specialized vesicles. Inhibiting some of these proteins has shown potential for blocking parasite transmission to the mosquito. To identify new transmission blocking vaccine candidates, we defined the microneme content from ookinetes of the rodent model organismPlasmodium bergheiusing APEX2-mediated rapid proximity-dependent biotinylation. Besides known proteins of ookinete micronemes, this identified over 50 novel candidates and sharpened the list of a previous survey based on subcellular fractionation. Functional analysis of a first candidate uncovered a dual role for this membrane protein in male gametogenesis and ookinete midgut traversal. Mutation of a putative trafficking motif in the C-terminus led to its mis-localization in ookinetes and affected ookinete to oocyst transition but not gamete formation. This suggests the existence of distinct functional and transport requirements for Plasmodium proteins in different parasite stages.SignificanceThe genome of the malaria parasitePlasmodiumcontains over 5500 genes, of which over 30% have no assigned function. Transmission ofPlasmodium spp. to the mosquito contains several essential steps that can be inhibited by antibodies or chemical compounds. Yet few proteins involved in these processes are characterized, thus limiting our capacity to generate transmission interfering tools. Here, we establish a method to rapidly identify proteins in a specific compartment within the parasite that is essential for establishment of an infection within the mosquito, and identify over 50 novel candidate proteins. Functional analysis of the top candidate identifies a protein with two independent essential functions in subsequent steps along thePlasmodiumlife cycle within the mosquito.Highlightsfirst use of APEX based proximity ligation in Apicomplexaidentification of >50 putative ookinete surface proteinsnovel membrane protein essential for microgamete egress and ookinete migrationputative trafficking motif essential in ookinetes but not gametes
An adipocyte-specific lncRAP2 – Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs
Authors: Alvarez-Dominguez Juan R. , Winther Sally , Hansen Jacob B. , Lodish Harvey F. , Knoll Marko 
Published: September 2020

AbstractlncRAP2 is a conserved cytoplasmic adipocyte-specific lncRNA required for adipogenesis. Using hybridization-based purification combined within vivointeractome analyses, we show that lncRAP2 forms ribonucleoprotein complexes with several mRNA stability and translation modulators, among them Igf2bp2. Transcriptome-wide identification of Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic effectors and regulators. Depleting either lncRAP2 or Igf2bp coordinately downregulates these same target proteins. Ribosome profiling and quantitative proteomics show that this occurs predominantly at the level of mRNA, as binding of the lncRAP2-Igf2bp complex does not affect mRNA translation. Suppressing lncRAP2 or Igf2bp2 selectively destabilizes many mRNAs encoding proteins essential for energy expenditure, including Adiponectin, reducing adipocyte lipolytic capacity. Genome-wide association studies reveal specific association of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and we find that adipose lncRAP2 and Igf2bp2 are suppressed during obesity and diabetes progression. Thus, the lncRAP2-Igf2bp complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.
Generated randomly and selected functionally? The nature of enterovirus recombination
Authors: Alnaji Fadi G. , Bentley Kirsten , Pearson Ashley , Woodman Andrew , Moore Jonathan , Fox Helen , MacAdam Andrew , Evans David J. 
Published: September 2020

AbstractGenetic recombination in RNA viruses is an important evolutionary mechanism. It contributes to population diversity, host/tissue adaptation and compromises vaccine efficacy. Both the molecular mechanism and initial products of recombination are relatively poorly understood. We used an established poliovirus-basedin vitrorecombination assay to investigate the roles of sequence identity and RNA structure, both implicated or inferred from analysis of circulating recombinant viruses, in the process. In addition, we used next generation sequencing to investigate the early products of recombination after cellular co-infection with different poliovirus serotypes. In independent studies we find no evidence for a role for RNA identity or structure in determining recombination junctions location. Instead, genome function and fitness are of greater importance in determining the identity of recombinant progeny. These studies provide further insights into this important evolutionary mechanism and emphasise the critical nature of the selection process on a mixed virus population.
Effects of petrophysical parameters on attenuation and dispersion of seismic waves in the simplified poroelastic theory: Comparison between the Biot's theory and viscosity‐extended theory
Authors: Zhao Haixia , Wu Bangyu , Gao Jinghuai 
Published: September 2020

ABSTRACTThe simplified macro‐equations of porous elastic media are presented based on Hickey's theory upon ignoring effects of thermomechanical coupling and fluctuations of porosity and density induced by passing waves. The macro‐equations with definite physical parameters predict two types of compressional waves (P wave) and two types of shear waves (S wave). The first types of P and S waves, similar to the fast P wave and S wave in Biot's theory, propagate with fast velocity and have relatively weak dispersion and attenuation, while the second types of waves behave as diffusive modes due to their distinct dispersion and strong attenuation. The second S wave resulting from the bulk and shear viscous loss within pore fluid is slower than the second P wave but with strong attenuation at lower frequencies. Based on the simplified porous elastic equations, the effects of petrophysical parameters (permeability, porosity, coupling density and fluid viscosity) on the velocity dispersion and attenuation of P and S waves are studied in brine‐saturated sandstone compared with the results of Biot's theory. The results show that the dispersion and attenuation of P waves in simplified theory are stronger than those of Biot's theory and appear at slightly lower frequencies because of the existence of bulk and shear viscous loss within pore fluid. The properties of the first S wave are almost consistent with the S wave in Biot's theory, while the second S wave not included in Biot's theory even dies off around its source due to its extremely strong attenuation. The permeability and porosity have an obvious impact on the velocity dispersion and attenuation of both P and S waves. Higher permeabilities make the peaks of attenuation shift towards lower frequencies. Higher porosities correspond to higher dispersion and attenuation. Moreover, the inertial coupling between fluid and solid induces weak velocity dispersion and attenuation of both P and S waves at higher frequencies, whereas the fluid viscosity dominates the dispersion and attenuation in a macroscopic porous medium. Besides, the heavy oil sand is used to investigate the influence of high viscous fluid on the dispersion and attenuation of both P and S waves. The dispersion and attenuation in heavy oil sand are stronger than those in brine‐saturated sandstone due to the considerable shear viscosity of heavy oil. Seismic properties are strongly influenced by the fluid viscosity; thus, viscosity should be included in fluid properties to explain solid–fluid combination behaviour properly.
Implementation of point‐of‐care ROTEM® into a trauma major haemorrhage protocol: A before and after study
Authors: Campbell Don , Wake Elizabeth , Walters Kerin , Ho Debbie , Keijzers Gerben , Wullschleger Martin , Winearls James 
Published: September 2020

AbstractObjectiveThe aim of the present study was to assess transfusion practices with the implementation of a targeted viscoelastic haemostatic assay (VHA) (ROTEM®) guided coagulation management programme into a major haemorrhage protocol for trauma patients requiring ICU admission, starting from time of arrival in the ED.MethodsThis retrospective observational study was conducted in a major trauma centre in Australia. One hundred and sixty‐two trauma patients admitted to the ICU between January 2013 and December 2015 with an Injury Severity Score ≥12 and who received blood products were included: 37 in the pre‐group, 48 during implementation and 77 in post‐group. The primary outcome was blood and blood product administration amounts.ResultsPacked red blood cell transfusion amounts did not significantly change post introduction of the ROTEM®. There was a significant increase in fibrinogen replacement between the pre‐ and post‐groups (P < 0.001), accompanied by a reduction in the use of fresh frozen plasma (P < 0.001) and prothrombinex (P < 0.001). Platelet usage in the post‐group was higher but not reaching statistical significance (P  = 0.051). Post‐implementation point‐of‐care ROTEM® testing was able to be performed in the ED in 94.8% of cases.ConclusionAlthough there was no overall reduction of packed red blood cell usage, a change in the pattern of administration of other blood products was observed with the implementation of a targeted VHA (ROTEM®) guided coagulation management programme. Larger studies are needed to further define the role of early VHA testing to guide correction of trauma‐induced coagulopathy and the effect on clinical outcomes.