bluuebunny/crossref_metadata_2025_split huggingface dataset:
ΔNp73/ETS2 complex drives glioblastoma pathogenesis— targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma
Authors: Cam Maren , Charan Manish , Welker Alessandra M , Dravid Piyush , Studebaker Adam W , Leonard Jeffrey R , Pierson Christopher R , Nakano Ichiro , Beattie Christine E , Hwang Eugene I , Kambhampati Madhuri , Nazarian Javad , Finlay Jonathan L , Cam Hakan 
Published: November 2019

Abstract

Background
Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM.

Methods
ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model.

Results
ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma.

Conclusion
Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.
The state of nutrition in medical education in the United States
Authors: Bassin Sandhya R , Al-Nimr Rima I , Allen Kathleen , Ogrinc Greg 
Published: November 2019

AbstractDespite the significant impact diet has on health, there is minimal nutrition training for medical students. This review summarizes published nutrition learning experiences in US medical schools and makes recommendations accordingly. Of 902 articles, 29 met inclusion criteria, describing 30 learning experiences. Nutrition learning experiences were described as integrated curricula or courses (n = 10, 33%), sessions (n = 17, 57%), or electives (n = 3, 10%). There was heterogeneity in the teaching and assessment methods utilized. The most common was lecture (n = 21, 70%), often assessed through pre- and/or postsurveys (n = 19, 79%). Six studies (26%) provided experience outcomes through objective measures, such as exam or standardized patient experience scores, after the nutrition learning experience. This review revealed sparse and inconsistent data on nutrition learning experiences. However, based on the extant literature, medical schools should build formal nutrition objectives, identify faculty and physician leadership in nutrition education, utilize preexisting resources, and create nutrition learning experiences that can be applied to clinical practice.
Changes in the Fungal Marker β-D-Glucan After Antiretroviral Therapy and Association With Adiposity
Authors: Dirajlal-Fargo Sahera , Moser Carlee , Rodriguez Katherine , El-Kamari Vanessa , Funderburg Nicholas T , Bowman Emily , Brown Todd T , Hunt Peter W , Currier Judith , McComsey Grace A 
Published: November 2019

Abstract

Background
Bacterial translocation in HIV is associated with inflammation and metabolic complications; few data exist on the role of fungal translocation.

Methods
A5260s was a substudy of A5257, a prospective open label randomized trial in which treatment-naïve people with HIV (PWH) were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) over 96 weeks. Baseline was assessed, and changes in β-D-glucan (BDG) were assessed at weeks 4, 24, and 96. Wilcoxon rank-sum tests were used to compare distribution shifts in the changes from baseline between treatment arms and linear regression models to assess associations between BDG and measures of inflammation, body composition, and insulin resistance.

Results
Two hundred thirty-one participants were randomized; 90% were male, the median age was 36 years, HIV-1 RNA was 4.56 log10c/mL, and CD4 cell count was 338 cells/mm3. There was an overall increase in BDG over 96 weeks (1.57 mean fold-change; 95% confidence interval, 1.39 to 1.77) with no differences between arms. Twofold higher BDG levels at week 96 were associated with increases in trunk fat (8%) and total fat (7%) over 96 weeks (P ≤ .035). At week 4, BDG correlated with I-FABP, a marker of enterocyte damage, and zonulin, a marker of intestinal permeability (r = .19–.20; P < .01).

Conclusions
In treatment-naïve participants initiating antiretroviral therapy (ART) with TDF/FTC and either RAL or ATV/r, DRV/r, BDG, a marker of fungal translocation, increased similarly in all arms over 96 weeks. This may represent continued intestinal damage during ART and resulting fungal translocation. Higher BDG was associated with larger fat gains on ART.
X-ray emissions from magnetic polar regions of neutron stars
Authors: Inoue Hajime 
Published: November 2019

Abstract
Structures of X-ray emitting magnetic polar regions on neutron stars in X-ray pulsars are studied in the accretion rate range 1017 g s−1–1018 g s−1. It is shown that a thin but tall, radiation-energy-dominated, X-ray emitting polar cone appears at each of the polar regions. The height of the polar cone is several times as large as the neutron star radius. The energy gain due to the gravity of the neutron star in the polar cone exceeds the energy loss due to photon diffusion in the azimuthal direction of the cone, and a significant amount of energy is advected to the neutron star surface. Then, the radiation energy carried with the flow should become large enough for the radiation pressure to overcome the magnetic pressure at the bottom of the cone. As a result, the matter should expand in the tangential direction along the neutron star surface, dragging the magnetic lines of force, and form a mound-like structure. The advected energy to the bottom of the cone should finally be radiated away from the surface of the polar mound and the matter should be settled on the neutron star surface there. From such configurations, we can expect an X-ray spectrum composed of a multi-color blackbody spectrum from the polar cone region and a quasi-single blackbody spectrum from the polar mound region. These spectral properties agree with observations. A combination of a fairly sharp pencil beam and a broad fan beam is expected from the polar cone region, while a broad pencil beam is expected from the polar mound region. With these X-ray beam properties, basic patterns of pulse profiles of X-ray pulsars can be explained too.
Cow–calf performance, forage utilization, and economics of warm-season annual baleage in beef cattle winter feeding systems1
Authors: Panhans Mekenzie H , Mason Katie M , Mullenix Mary K , Prevatt Chris G , Moisá Sonia J , Muntifering Russell B 
Published: November 2019

AbstractA 52-d winter feeding trial was conducted to determine animal performance, utilization, and economics of pearl millet (PM) baleage, sorghum × sudangrass (SS) baleage, and “Tifton 85” bermudagrass (B) hay for lactating beef cow–calf pairs. Cone (C) and open-shaped (O) rings were evaluated for potential to minimize forage wastage. The experiment was a completely randomized design with a 3 × 2 factorial arrangement of treatments for each forage type × hay ring (3 cow–calf pairs per treatment; 2 replications per treatment). Animal response measures included cow body weight (BW) change and body condition score (BCS) over the 52-d trial, initial and final calf BW, and cow milk production at the midpoint and end of the study. Forage nutritive value parameters evaluated for each forage type included ash, crude protein (CP), in vitro true digestibility (IVTD), neutral detergent fiber (NDF), acid detergent fiber, and acid detergent lignin (ADL). Forage wastage was estimated for each forage × ring treatment as the percentage of the bale weight remaining in feeding rings at the time of bale replacement. An economic evaluation of the relative costs associated with production and utilization of each forage type was calculated. There were no differences (P ≥ 0.10) in cow BW change or BCS change among forage types, between ring shapes, or an interaction observed for these response variables. Proportion of waste from PM and SS baleage was greater (P &lt; 0.10) than for B hay, although there was no forage type × hay ring interaction or differences between O and C hay ring treatments for forage waste (P ≥ 0.10, respectively). Cow milk production and calf BW gain did not differ among forage type (P ≥ 0.10, respectively); however, beef calves in pens containing the O ring feeder weighed 6 kg more (P ≤ 0.05) than calves whose dams were fed using C rings. The economic analysis implies that it is more costly to feed warm-season annual forage baleage to cow–calf pairs than dry hay, largely due to greater costs of production, lack of difference in animal performance responses, and less utilization of baleage compared with feeding bermudagrass hay in this trial.
Road-safety recognition and network equilibrium with perceived route-choice sets
Authors: Li Mao-sheng , Huang He-lai 
Published: November 2019

Abstract
Safety is regarded as the second basic need in Maslow’s hierarchy of needs (1943), and safety recognition and circumvention behaviour in the route-choice decision-making process should therefore be accommodated in network-traffic equilibrium analysis frameworks. This paper proposes a framework by which crash frequency, forecasted using the safety-analysis method or compiled from historical data for intersections, is used to measure the safety consciousness of drivers. Drivers are then classified into different groups according to their acceptable-risk thresholds, and each group has its own route-choice set. Decision behaviour whereby drivers are willing to bear additional costs in order to circumvent travel risk is incorporated into the variational inequality model based on the user equilibrium in the perceived route-choice set (UE-PRCS), which is an extension of Wardrop’s first principle. The Frank–Wolfe algorithm, based on the convex combination method, is employed to obtain the solution. A small road network is used as a case study to illustrate the proposed framework, incorporating risk recognition and circumvention behaviour under different combinations of traffic demand and risk-sensitivity group ratio. The results show that the standard user equilibrium is a special case of the UE-PRCS, but that the UE traffic state is more common than the UE-PRCS under different parameters.
Cosmological evolution of semilocal string networks
Authors: Achúcarro A. , Avgoustidis A. , López-Eiguren A. , Martins C. J. A. P. , Urrestilla J. 
Published: November 2019

Semilocal strings—a particular limit of electroweak strings—are an interesting example of a stable non-topological defect whose properties resemble those of their topological cousins, the Abrikosov–Nielsen–Olesen vortices. There is, however, one important difference: a network of semilocal strings will contain segments. These are ‘dumbbells’ whose ends behave almost like global monopoles that are strongly attracted to one another. While closed loops of string will eventually shrink and disappear, the segments can either shrink or grow, and a cosmological network of semilocal strings will reach a scaling regime. We discuss attempts to find a ‘thermodynamic’ description of the cosmological evolution and scaling of a network of semilocal strings, by analogy with well-known descriptions for cosmic strings and for monopoles. We propose a model for the time evolution of an overall length scale and typical velocity for the network as well as for its segments, and some supporting (preliminary) numerical evidence.
This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Primordial black holes and the origin of the matter–antimatter asymmetry
Authors: García-Bellido Juan 
Published: November 2019

We review here a new scenario of
hot spot
electroweak baryogenesis where the local energy released in the gravitational collapse to form primordial black holes (PBHs) at the quark-hadron (QCD) epoch drives over-the-barrier sphaleron transitions in a far from equilibrium environment with just the standard model CP violation. Baryons are efficiently produced in relativistic collisions around the black holes and soon redistribute to the rest of the universe, generating the observed matter–antimatter asymmetry well before primordial nucleosynthesis. Therefore, in this scenario there is a common origin of both the dark matter to baryon ratio and the photon to baryon ratio. Moreover, the sudden drop in radiation pressure of relativistic matter at
H
0
/
W
±
/
Z
0
decoupling, the QCD transition and
e
+
e
−
annihilation enhances the probability of PBH formation, inducing a multi-modal broad mass distribution with characteristic peaks at 10
−6
, 1, 30 and 10
6

M
⊙
, rapidly falling at smaller and larger masses, which may explain the LIGO–Virgo black hole mergers as well as the OGLE-GAIA microlensing events, while constituting all of the cold dark matter today. We predict the future detection of binary black hole (BBH) mergers in LIGO with masses between 1 and 5
M
⊙
, as well as above 80
M
⊙
, with very large mass ratios. Next generation gravitational wave and microlensing experiments will be able to test this scenario thoroughly.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Excavating New Facts from Ancient Hepatitis B Virus Sequences
Authors: Datta Sibnarayan 
Published: November 2019

AbstractRecently, Muhlemann et al. (2018) and Krause-Kyora et al. (2018) discovered 15 ancient Hepatitis B virus (aHBV) sequences dating back to the Neolithic age (NA) and the Bronze age (BA). Being published simultaneously, neither of these studies could include sequences from the other for analyses. In the present research, aHBV sequences from these studies were collective re-analysed with reference to a comprehensive database comprising extant HBV diversity to understand their relatedness and role in the evolution of extant HBV diversity. Present analyses revealed several interesting findings on distribution, dispersal, phylogenetic and recombinational relatedness of ancient HBV to extant genotypes, which were not recognized previously. Several interesting recombination patterns were observed, which corroborated well with ancient human migration, shown by the human genetic studies. Present analyses suggest that comparable to the replacement of the Neolithic European farmer associated Y chromosome haplogroups by haplogroups associated with the steppe people during Steppe migration, HBV genotype associated with the early Neolithic European farming cultures was also replaced by the ancestral HBV genotype A probably carried by the migrating steppe people, and a variant of this genotype is the prevalent HBV genotype in contemporary European populations. Additionally, based on recent literature, this research also indicates that HBV genotype divergence estimates proposed by Muhlemann et al., and others cannot sufficiently explain distribution of certain extant HBV genotypes. Hence, an alternative possibility to explain long distance and trans-oceanic distribution of phylogenetically related HBV genotypes was reviewed and discussed in the light of currently available knowledge. Through this manuscript, novel and important findings of the present analyses are communicated.
Inter-hemispheric inhibition in stroke survivors is related to fatigue and cortical excitability
Authors: Ondobaka Sasha , Ward Nick , Kuppuswamy Annapoorna 
Published: November 2019

ABSTRACTObjectivePersistent post-stroke fatigue is a major debilitating condition that has been linked to low corticomotor excitability and aberrant attention, both phenomena that are associated with the inter-hemispheric inhibition balance in the brain. In this study, we examined the relationship between inter-hemispheric inhibitory effective connectivity, motor cortex excitability and chronic persistence of post-stroke fatigue.MethodsWe tested eighteen non-depressed stroke survivors with minimal motoric and cognitive impairments using spectral dynamic causal modelling (spDCM) of ‘resting state’ magnetic resonance imaging (rs-fMRI) and transcranial magnetic stimulation (TMS) measures of cortical excitability. We also assessed the levels of non-exercise induced, persistent fatigue using Fatigue Severity Scale (FSS) - a self-report questionnaire which has been widely applied and validated across different conditions. To understand neural effective connectivity mechanisms involved in fatigue and corticomotor excitability we examined the balance in inhibitory connectivity between homologue regions in M1, anterior insula, caudate and thalamus of the resting brain.ResultsInter-hemispheric inhibition balance between left and right M1 accounted for 67% of variability in the reported fatigue (R=.82, p<0.001). Inter-hemispheric inhibition balance in M1 also accounted for 54% of variability in the corticomotor excitability characterised by individual resting motor thresholds (R=.74, p<0.001), a measure that has been associated with subjective fatigue reports. Other examined inter-hemispheric connections did not show significant relationships with either fatigue or cortical excitability measures.ConclusionOur findings suggest that the balance in inter-hemispheric effective connectivity between primary motor regions is involved in regulation of corticomotor excitability and could explain subjective post-stroke fatigue.
Synthetic gene regulatory networks in the opportunistic human pathogenStreptococcus pneumoniae
Authors: Sorg Robin A. , Gallay Clement , Veening Jan-Willem 
Published: November 2019

AbstractStreptococcus pneumoniaecan cause disease in various human tissues and organs, including the ear, the brain, the blood and the lung, and thus in highly diverse and dynamic environments. It is challenging to study how pneumococci control virulence factor expression, because cues of natural environments and the presence of an immune system are difficult to simulatein vitro. Here, we apply synthetic biology methods to reverse-engineer gene expression control inS. pneumoniae. A selection platform is described that allows for straightforward identification of transcriptional regulatory elements out of combinatorial libraries. We present TetR- and LacI-regulated promoters that show expression ranges of four orders of magnitude. Based on these promoters, regulatory networks of higher complexity are assembled, such as logic AND and IMPLY gates. Finally, we demonstrate single-copy genome-integrated toggle switches that give rise to bimodal population distributions. The tools described here can be used to mimic complex expression patterns, such as the ones found for pneumococcal virulence factors, paving the way forin vivoinvestigations of the importance of gene expression control on the pathogenicity ofS. pneumoniae.
BceAB-type antibiotic resistance transporters appear to act by target protection of cell wall synthesis
Authors: Kobras Carolin M , Piepenbreier Hannah , Emenegger Jennifer , Sim Andre , Fritz Georg , Gebhard Susanne 
Published: November 2019

ABSTRACTResistance against cell wall-active antimicrobial peptides in bacteria is often mediated by transporters. In low GC-content Gram-positive bacteria, a wide-spread type of such transporters are the BceAB-like systems, which frequently provide a high level of resistance against peptide antibiotics that target intermediates of the lipid II cycle of cell wall synthesis. How a transporter can offer protection from drugs that are active on the cell surface, however, has presented researchers with a conundrum. Multiple theories have been discussed, ranging from removal of the peptides from the membrane, internalisation of the drug for degradation, to removal of the cellular target rather than the drug itself. To resolve this much-debated question, we here investigated the mode of action of the transporter BceAB ofBacillus subtilis. We show that it does not inactivate or import its substrate antibiotic bacitracin. Moreover, we present evidence that the critical factor driving transport activity is not the drug itself, but instead the concentration of drug-target complexes in the cell. Our results, together with previously reported findings, lead us to propose that BceAB-type transporters act by transiently freeing lipid II cycle intermediates from the inhibitory grip of antimicrobial peptides, and thus provide resistance through target protection of cell wall synthesis. Target protection has so far only been reported for resistance against antibiotics with intracellular targets, such as the ribosome. However, this mechanism offers a plausible explanation for the use of transporters as resistance determinants against cell wall-active antibiotics in Gram-positive bacteria where cell wall synthesis lacks the additional protection of an outer membrane.
Machine learning reveals adaptive maternal responses to infant distress calls in wild chimpanzees
Authors: Dezecache Guillaume , Zuberbühler Klaus , Davila-Ross Marina , Dahl Christoph D. 
Published: November 2019

AbstractDistress calls are an acoustically variable group of vocalizations ubiquitous in mammals and other animals. Their presumed function is to recruit help, but it is uncertain whether this is mediated by listeners extracting the nature of the disturbance from calls. To address this, we used machine learning to analyse distress calls produced by wild infant chimpanzees. It enabled us to classify calls and examine them in relation to the external event triggering them and the distance to the intended receiver, the mother. In further steps, we tested whether the acoustic variants produced by infants predicted maternal responses. Our results demonstrated that, although infant chimpanzee distress calls were highly graded, they conveyed information about discrete events, which in turn guided maternal parenting decisions. We discuss these findings in light of one the most vexing problems in communication theory, the evolution of vocal flexibility in the human lineage.