bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway
Authors: Demirkol Canlı Seçil , Seza Esin Gülce , Sheraj Ilir , Gömçeli Ismail , Turhan Nesrin , Carberry Steven , Prehn Jochen H M , Güre Ali Osmay , Banerjee Sreeparna 
Published: July 2020

Abstract
AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1HIGH) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our previous in silico finding that AKR1B1HIGH was associated with worse overall survival (OS) compared with patients with low expression of AKR1B1 (AKR1B1LOW) samples. A combined signature of AKR1B1HIGH and AKR1B10LOW was significantly associated with worse recurrence-free survival (RFS) in microsatellite stable (MSS) patients and in patients with distal colon tumors as well as a higher mesenchymal signature when compared with AKR1B1LOW/AKR1B10HIGH tumors. When the patients were stratified according to consensus molecular subtypes (CMS), AKR1B1HIGH/AKR1B10LOW samples were primarily classified as CMS4 with predominantly mesenchymal characteristics while AKR1B1LOW/AKR1B10HIGH samples were primarily classified as CMS3 which is associated with metabolic deregulation. Reverse Phase Protein Array carried out using protein samples from the Ankara cohort indicated that AKR1B1HIGH/AKR1B10LOW tumors showed aberrant activation of metabolic pathways. Western blot analysis of AKR1B1HIGH/AKR1B10LOW colon cancer cell lines also suggested aberrant activation of nutrient-sensing pathways. Collectively, our data suggest that the AKR1B1HIGH/AKR1B10LOW signature may be predictive of poor prognosis, aberrant activation of metabolic pathways, and can be considered as a novel biomarker for colon cancer prognostication.
Contextual and Spatial Associations Between Objects Interactively Modulate Visual Processing
Authors: Quek Genevieve L , Peelen Marius V 
Published: July 2020

Abstract
Much of what we know about object recognition arises from the study of isolated objects. In the real world, however, we commonly encounter groups of contextually associated objects (e.g., teacup and saucer), often in stereotypical spatial configurations (e.g., teacup above saucer). Here we used electroencephalography to test whether identity-based associations between objects (e.g., teacup–saucer vs. teacup–stapler) are encoded jointly with their typical relative positioning (e.g., teacup above saucer vs. below saucer). Observers viewed a 2.5-Hz image stream of contextually associated object pairs intermixed with nonassociated pairs as every fourth image. The differential response to nonassociated pairs (measurable at 0.625 Hz in 28/37 participants) served as an index of contextual integration, reflecting the association of object identities in each pair. Over right occipitotemporal sites, this signal was larger for typically positioned object streams, indicating that spatial configuration facilitated the extraction of the objects’ contextual association. This high-level influence of spatial configuration on object identity integration arose ~ 320 ms post-stimulus onset, with lower-level perceptual grouping (shared with inverted displays) present at ~ 130 ms. These results demonstrate that contextual and spatial associations between objects interactively influence object processing. We interpret these findings as reflecting the high-level perceptual grouping of objects that frequently co-occur in highly stereotyped relative positions.
Optimizing Benefits of Testing Key Workers for Infection with SARS-CoV-2: A Mathematical Modeling Analysis
Authors: Sandmann Frank G , White Peter J , Ramsay Mary , Jit Mark 
Published: July 2020

Abstract

Background
Internationally, key workers such as healthcare staff are advised to stay at home if they or household members experience coronavirus disease 2019 (COVID-19)–like symptoms. This potentially isolates/quarantines many staff without SARS-CoV-2, while not preventing transmission from staff with asymptomatic infection. We explored the impact of testing staff on absence durations from work and transmission risks to others.

Methods
We used a decision-analytic model for 1000 key workers to compare the baseline strategy of (S0) no RT-PCR testing of workers to testing workers (S1) with COVID-19–like symptoms in isolation, (S2) without COVID-19–like symptoms but in household quarantine, and (S3) all staff. We explored confirmatory re-testing scenarios of repeating all initial tests, initially positive tests, initially negative tests, or no re-testing. We varied all parameters, including the infection rate (0.1–20%), proportion asymptomatic (10–80%), sensitivity (60–95%), and specificity (90–100%).

Results
Testing all staff (S3) changes the risk of workplace transmission by −56.9 to +1.0 workers/1000 tests (with reductions throughout at RT-PCR sensitivity ≥65%), and absences by −0.5 to +3.6 days/test but at heightened testing needs of 989.6–1995.9 tests/1000 workers. Testing workers in household quarantine (S2) reduces absences the most by 3.0–6.9 days/test (at 47.0–210.4 tests/1000 workers), while increasing risk of workplace transmission by 0.02–49.5 infected workers/1000 tests (which can be minimized when re-testing initially negative tests).

Conclusions
Based on optimizing absence durations or transmission risk, our modeling suggests testing staff in household quarantine or all staff, depending on infection levels and testing capacities.
Development of an Electronic Definition for De-escalation of Antibiotics in Hospitalized Patients
Authors: Moehring Rebekah W , Ashley Elizabeth S Dodds , Davis Angelina E , Dyer April Pridgen , Parish Alice , Ren Xinru , Lokhnygina Yuliya , Hicks Lauri A , Srinivasan Arjun , Anderson Deverick J 
Published: July 2020

Abstract

Background
Antimicrobial stewardship programs (ASPs) promote the principle of de-escalation: moving from broad- to narrow-spectrum agents and stopping antibiotics when no longer indicated. A standard, objective definition of de-escalation applied to electronic data could be useful for ASP assessments.

Methods
We derived an electronic definition of antibiotic de-escalation and performed a retrospective study among 5 hospitals. Antibiotics were ranked into 4 categories: narrow-spectrum, broad-spectrum, extended-spectrum, and agents targeted for protection. Eligible adult patients were cared for on inpatient units, had antibiotic therapy for at least 2 days, and were hospitalized for at least 3 days after starting antibiotics. Number of antibiotics and rank were assessed at 2 time points: day of antibiotic initiation and either day of discharge or day 5. De-escalation was defined as reduction in either the number of antibiotics or rank. Escalation was an increase in either number or rank. Unchanged was either no change or discordant directions of change. We summarized outcomes among hospitals, units, and diagnoses.

Results
Among 39 226 eligible admissions, de-escalation occurred in 14 138 (36%), escalation in 5129 (13%), and antibiotics were unchanged in 19 959 (51%). De-escalation varied among hospitals (median, 37%; range, 31–39%, P &lt; .001). Diagnoses with lower de-escalation rates included intra-abdominal (23%) and skin and soft tissue (28%) infections. Critical care had higher rates of both de-escalation and escalation compared with wards.

Conclusions
Our electronic de-escalation metric demonstrated variation among hospitals, units, and diagnoses. This metric may be useful for assessing stewardship opportunities and impact.
Interleukin-7 and interleukin-15 drive CD4+CD28null T lymphocyte expansion and function in patients with acute coronary syndrome
Authors: Bullenkamp Jessica , Mengoni Veronica , Kaur Satdip , Chhetri Ismita , Dimou Paraskevi , Astroulakis Zoë M J , Kaski Juan Carlos , Dumitriu Ingrid E 
Published: July 2020

AbstractAimsInflammation has important roles in atherosclerosis. CD4+CD28null (CD28null) T cells are a specialized T lymphocyte subset that produce inflammatory cytokines and cytotoxic molecules. CD28null T cells expand preferentially in patients with acute coronary syndrome (ACS) rather than stable angina and are barely detectable in healthy subjects. Importantly, ACS patients with CD28null T-cell expansion have increased risk for recurrent acute coronary events and poor prognosis, compared to ACS patients in whom this cell subset does not expand. The mechanisms regulating CD28null T-cell expansion in ACS remain elusive. We therefore investigated the role of cytokines in CD28null T-cell expansion in ACS.Methods and resultsHigh-purity sorted CD4+ T cells from ACS patients were treated with a panel of cytokines (TNF-α, IL-1β, IL-6, IL-7, and IL-15), and effects on the number, phenotype, and function of CD28null T cells were analysed and compared to the control counterpart CD28+ T-cell subset. IL-7- and IL-15-induced expansion of CD28null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1β, and IL-6 did not. The mechanisms underlying CD28null T-cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28null T cells compared to control CD28+ T cells. Additionally, IL-7/IL-15 markedly augmented CD28null T-cell cytotoxic function and interferon-γ production. Further mechanistic analyses revealed differences in baseline expression of component chains of IL-7/IL-15 receptors (CD127 and CD122) and increased baseline STAT5 phosphorylation in CD28null T cells from ACS patients compared to the control CD28+ T-cell subset. Notably, we demonstrate that CD28null T-cell expansion was significantly inhibited by Tofacitinib, a selective JAK1/JAK3 inhibitor that blocks IL-7/IL-15 signalling.ConclusionOur novel data show that IL-7 and IL-15 drive the expansion and function of CD28null T cells from ACS patients suggesting that IL-7/IL-15 blockade may prevent expansion of these cells and improve patient outcomes.
The impact of aircraft noise on vascular and cardiac function in relation to noise event number: a randomized trial
Authors: Schmidt Frank P , Herzog Johannes , Schnorbus Boris , Ostad Mir Abolfazl , Lasetzki Larissa , Hahad Omar , Schäfers Gianna , Gori Tommaso , Sørensen Mette , Daiber Andreas , Münzel Thomas 
Published: July 2020

Abstract

Aims
Nighttime aircraft noise exposure has been associated with increased risk of hypertension and myocardial infarction, mechanistically linked to sleep disturbance, stress, and endothelial dysfunction. It is unclear, whether the most widely used metric to determine noise exposure, equivalent continuous sound level (Leq), is an adequate indicator of the cardiovascular impact induced by different noise patterns.

Methods and results
In a randomized crossover study, we exposed 70 individuals with established cardiovascular disease or increased cardiovascular risk to two aircraft noise scenarios and one control scenario. Polygraphic recordings, echocardiography, and flow-mediated dilation (FMD) were determined for three study nights. The noise patterns consisted of 60 (Noise60) and 120 (Noise120) noise events, respectively, but with comparable Leq, corresponding to a mean value of 45 dB. Mean value of noise during control nights was 37 dB. During the control night, FMD was 10.02 ± 3.75%, compared to 7.27 ± 3.21% for Noise60 nights and 7.21 ± 3.58% for Noise120 nights (P &lt; 0.001). Sleep quality was impaired after noise exposure in both noise scenario nights (P &lt; 0.001). Serial echocardiographic assessment demonstrated an increase in the E/E′ ratio, a measure of diastolic function, within the three exposure nights, with a ratio of 6.83 ± 2.26 for the control night, 7.21 ± 2.33 for Noise60 and 7.83 ± 3.07 for Noise120 (P = 0.043).

Conclusions
Nighttime exposure to aircraft noise with similar Leq, but different number of noise events, results in a comparable worsening of vascular function. Adverse effects of nighttime aircraft noise exposure on cardiac function (diastolic dysfunction) seemed stronger the higher number of noise events.
Assessing left ventricular systolic function: from ejection fraction to strain analysis
Authors: Halliday Brian P , Senior Roxy , Pennell Dudley J 
Published: July 2020

Abstract
The measurement of left ventricular ejection fraction (LVEF) is a ubiquitous component of imaging studies used to evaluate patients with cardiac conditions and acts as an arbiter for many management decisions. This follows early trials investigating heart failure therapies which used a binary LVEF cut-off to select patients with the worst prognosis, who may gain the most benefit. Forty years on, the cardiac disease landscape has changed. Left ventricular ejection fraction is now a poor indicator of prognosis for many heart failure patients; specifically, for the half of patients with heart failure and truly preserved ejection fraction (HF-PEF). It is also recognized that LVEF may remain normal amongst patients with valvular heart disease who have significant myocardial dysfunction. This emphasizes the importance of the interaction between LVEF and left ventricular geometry. Guidelines based on LVEF may therefore miss a proportion of patients who would benefit from early intervention to prevent further myocardial decompensation and future adverse outcomes. The assessment of myocardial strain, or intrinsic deformation, holds promise to improve these issues. The measurement of global longitudinal strain (GLS) has consistently been shown to improve the risk stratification of patients with heart failure and identify patients with valvular heart disease who have myocardial decompensation despite preserved LVEF and an increased risk of adverse outcomes. To complete the integration of GLS into routine clinical practice, further studies are required to confirm that such approaches improve therapy selection and accordingly, the outcome for patients.
Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4
Authors: Hess Annika , Derlin Thorsten , Koenig Tobias , Diekmann Johanna , Wittneben Alexander , Wang Yong , Wester Hans-Juergen , Ross Tobias L , Wollert Kai C , Bauersachs Johann , Bengel Frank M , Thackeray James T 
Published: July 2020

Abstract

Aims
Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction.

Methods and results
Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P &lt; 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P &lt; 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (r partial = −0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up.

Conclusion
Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.
Interactions of microorganisms with host mucins: a focus on Candida albicans
Authors: Valle Arevalo Ashley , Nobile Clarissa J 
Published: July 2020

ABSTRACT
Mucus is an important host innate defense factor that lines most epithelial cell layers of the body and provides crucial physical and biological protection against pathogenic microorganisms. Mucins are the main glycoproteins of mucus that are responsible for interacting with microorganisms and are critical for the antimicrobial properties of mucus. The mechanisms by which microorganisms interact with mucins are poorly understood, especially in terms of fungi, and these interactions are continually evolving. Work in bacterial pathogens has shown that mucins inhibit bacterial virulence traits, including quorum sensing, toxin secretion and biofilm formation. Among the fungal clade, the common opportunistic human fungal pathogen and commensal Candida albicans engages in constant battle with the host innate immune system. This battle creates strong selective pressures for C. albicans to evolve in response to the host. Recent work in C. albicans found that mucins inhibit specific virulence traits, such as surface adherence, filamentation, biofilm formation and the production of secreted proteases. Here we review the current knowledge of microbial interactions with mucins, with a special emphasis on the interactions between C. albicans and mucins.
External Resistance Is Imperative for Training-Induced Efferent Neural Drive Enhancement in Older Adults
Authors: Unhjem Runar , Tøien Tiril , Kvellestad Ann Charlotte Gjertsen , Øren Thomas Storehaug , Wang Eivind 
Published: July 2020

Abstract
Strength training performed with heavy loads and maximal intended velocity is documented to enhance efferent neural drive to maximally contracting musculature in older adults. However, it remains unclear whether the neural plasticity following training result from motor skill learning or if external resistance is a prerequisite. To investigate this, we assessed electrically evoked potentials (H-reflex and V-waves normalized to maximal M-wave) and voluntary activation (VA) in 36 older adults (73 ± 4 years) randomized to 3 weeks of plantar flexion strength training, with (maximal strength training [MST]) or without (unloaded ballistic training [UBT]) heavy external loading (90% of one repetition maximum), or a control group. Both training groups aimed to execute the concentric phase of movement as fast and forcefully as possible. The MST group improved maximal voluntary contraction (MVC) and rate of force development (RFD) by 18% ± 13% (p = .001; Hedges g = 0.66) and 35% ± 17% (p &lt; .001; g = 0.94), respectively, and this was different (MVC: p = .013; RFD: p = .001) from the UBT group which exhibited a 7% ± 8% (p = .033; g = 0.32) increase in MVC and a tendency to increase RFD (p = .119; g = 0.22). Concomitant improvements in efferent neural drive (Vmax/Msup ratio: 0.14 ± 0.08 to 0.24 ± 0.20; p = .010) and a tendency towards increased VA (79% ± 9% to 84% ± 5%; p = .098), were only apparent after MST. No changes were observed in Hmax/Mmax ratio for the groups. In conclusion, external loading during exercise training appears to be a prerequisite for efferent neural drive enhancement in older adults. Thus, strength training with heavy loads should be recommended to counteract the typically observed age-related decline in motoneuron firing frequency and recruitment.
The Associations of Activity Fragmentation With Physical and Mental Fatigability Among Community-Dwelling 75-, 80-, and 85-Year-Old People
Authors: Palmberg Lotta , Rantalainen Timo , Rantakokko Merja , Karavirta Laura , Siltanen Sini , Skantz Heidi , Saajanaho Milla , Portegijs Erja , Rantanen Taina 
Published: July 2020

Abstract

Background
Fatigue related to task standardized by duration and intensity, termed fatigability, could manifest as shortening of activity bouts throughout the day causing daily activity to accumulate in a more fragmented pattern. Our purpose was to study the association of activity fragmentation with physical and mental dimensions of fatigability.

Methods
A cross-sectional study of 485 community-dwelling 75-, 80-, and 85-year-old people using a thigh-worn accelerometer for 3–7 days. Activity fragmentation was studied as Active-to-Sedentary Transition Probability for 2 operational definitions of physical activity: accelerations equivalent to at least light physical activity and for upright posture. Physical fatigability was assessed as perceived exertion fatigability, performance fatigability severity, and with the Physical Fatigue Subscale of the Situational Fatigue Scale. Mental fatigability was assessed with the Mental Fatigue Subscale of the Situational Fatigue Scale and as a decrease in perceived mental alertness after a 6-minute walk test.

Results
Higher activity fragmentation was associated with higher self-reported physical fatigability, perceived exertion fatigability, and performance fatigability severity, independent of total activity minutes (β = 0.13–0.33, p &lt; .05 for all). Higher activity fragmentation was not associated with mental fatigability in the fully adjusted models. The associations with fatigability indices were similar for both activity fragmentation indicators. Associations of activity fragmentation and performance fatigability severity were similar also among those with the highest intensity-based physical activity volume.

Conclusions
The findings provide support that studying fragmented activity patterns can be useful in identifying those at risk for high fatigability, even among those with relatively high physical activity level.
Targeted chromatin conformation analysis identifies novel distal neural enhancers of ZEB2 in pluripotent stem cell differentiation
Authors: Birkhoff Judith C , Brouwer Rutger W W , Kolovos Petros , Korporaal Anne L , Bermejo-Santos Ana , Boltsis Ilias , Nowosad Karol , van den Hout Mirjam C G N , Grosveld Frank G , van IJcken Wilfred F J , Huylebroeck Danny , Conidi Andrea 
Published: July 2020

Abstract
The transcription factor zinc finger E-box binding protein 2 (ZEB2) controls embryonic and adult cell fate decisions and cellular maturation in many stem/progenitor cell types. Defects in these processes in specific cell types underlie several aspects of Mowat–Wilson syndrome (MOWS), which is caused by ZEB2 haplo-insufficiency. Human ZEB2, like mouse Zeb2, is located on chromosome 2 downstream of a ±3.5 Mb-long gene-desert, lacking any protein-coding gene. Using temporal targeted chromatin capture (T2C), we show major chromatin structural changes based on mapping in-cis proximities between the ZEB2 promoter and this gene desert during neural differentiation of human-induced pluripotent stem cells, including at early neuroprogenitor cell (NPC)/rosette state, where ZEB2 mRNA levels increase significantly. Combining T2C with histone-3 acetylation mapping, we identified three novel candidate enhancers about 500 kb upstream of the ZEB2 transcription start site. Functional luciferase-based assays in heterologous cells and NPCs reveal co-operation between these three enhancers. This study is the first to document in-cis Regulatory Elements located in ZEB2’s gene desert. The results further show the usability of T2C for future studies of ZEB2 REs in differentiation and maturation of multiple cell types and the molecular characterization of newly identified MOWS patients that lack mutations in ZEB2 protein-coding exons.