bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flexible-to-rigid transition is central for substrate transport in the ABC transporter BmrA from Bacillus subtilis
Authors: Lacabanne Denis , Orelle Cédric , Lecoq Lauriane , Kunert Britta , Chuilon Claire , Wiegand Thomas , Ravaud Stéphanie , Jault Jean-Michel , Meier Beat H. , Böckmann Anja 
Published: April 2019

AbstractATP-binding-cassette (ABC) transporters are molecular pumps that translocate molecules across the cell membrane by switching between inward-facing and outward-facing states. To obtain a detailed understanding of their mechanism remains a challenge to structural biology, as these proteins are notoriously difficult to study at the molecular level in their active, membrane-inserted form. Here we use solid-state NMR to investigate the multidrug ABC transporter BmrA reconstituted in lipids. We identify the chemical-shift differences between the inward-facing, and outward-facing state induced by ATP:Mg2+:Vi addition. Analysis of an X-loop mutant, for which we show that ATPase and transport activities are uncoupled, reveals an incomplete transition to the outward-facing state upon ATP:Mg2+:Vi addition, notably lacking the decrease in dynamics of a defined set of residues observed in wild-type BmrA. This suggests that this stiffening is required for an efficient transmission of the conformational changes to allow proper transport of substrate by the pump.
A c-di-AMP riboswitch controlling kdpFABC operon transcription regulates the potassium transporter system in Bacillus thuringiensis
Authors: Wang Xun , Cai Xia , Ma Hongdan , Yin Wen , Zhu Li , Li Xinfeng , Lim Heon M. , Chou Shan-Ho , He Jin 
Published: April 2019

AbstractThe intracellular K+ level in bacteria is strictly controlled by K+ uptake and efflux systems. Among these, KdpFABC is a high-affinity K+ transporter system that is generally activated by the KdpDE two-component system in response to K+ limitation stress. However, the regulatory mechanism remains obscure in bacteria lacking the kdpDE genes. Here we report that the transcription of a kdpFABC operon is distinctively regulated by a cyclic diadenylate monophosphate (c-di-AMP) riboswitch located at the 5′-untranslated region of kdp transcript, and binding of c-di-AMP to the riboswitch promotes its intrinsic termination that blocks the kdpFABC transcription. Further, the intracellular c-di-AMP concentration was found to decrease under the K+ limitation stress, leading to transcriptional read-through over the terminator to allow kdpFABC expression. This regulatory element is found predominantly in the Bacillus cereus group and correlate well with the K+ and c-di-AMP homeostasis that affects a variety of crucial cellular functions.
Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers
Authors: Katoh Masaru 
Published: April 2019

Abstract
Hedgehog signals are transduced through Patched receptors to the Smoothened (SMO)-SUFU-GLI and SMO-Gi-RhoA signaling cascades. MTOR-S6K1 and MEK-ERK signals are also transduced to GLI activators through post-translational modifications. The GLI transcription network up-regulates target genes, such as BCL2, FOXA2, FOXE1, FOXF1, FOXL1, FOXM1, GLI1, HHIP, PTCH1 and WNT2B, in a cellular context-dependent manner. Aberrant Hedgehog signaling in tumor cells leads to self-renewal, survival, proliferation and invasion. Paracrine Hedgehog signaling in the tumor microenvironment (TME), which harbors cancer-associated fibroblasts, leads to angiogenesis, fibrosis, immune evasion and neuropathic pain. Hedgehog-related genetic alterations occur frequently in basal cell carcinoma (BCC) (85%) and Sonic Hedgehog (SHH)-subgroup medulloblastoma (87%) and less frequently in breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, non-small-cell lung cancer (NSCLC) and ovarian cancer. Among investigational SMO inhibitors, vismodegib and sonidegib are approved for the treatment of patients with BCC, and glasdegib is approved for the treatment of patients with acute myeloid leukemia (AML). Resistance to SMO inhibitors is caused by acquired SMO mutations, SUFU deletions, GLI2 amplification, other by-passing mechanisms of GLI activation and WNT/β-catenin signaling activation. GLI–DNA-interaction inhibitors (glabrescione B and GANT61), GLI2 destabilizers (arsenic trioxide and pirfenidone) and a GLI-deacetylation inhibitor (4SC-202) were shown to block GLI-dependent transcription and tumorigenesis in preclinical studies. By contrast, SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the immune checkpoint inhibitor pembrolizumab with or without vismodegib in BCC patients is ongoing.
Stellar activity and rotation of the planet host Kepler-17 from long-term space-borne photometry
Authors: Lanza A. F. , Netto Y. , Bonomo A. S. , Parviainen H. , Valio A. , Aigrain S. 
Published: April 2019

Context. The study of young Sun-like stars is fundamental to understanding the magnetic activity and rotational evolution of the Sun. Space-borne photometry by the Kepler telescope provides unprecedented datasets to investigate these phenomena in Sun-like stars.
Aims. We present a new analysis of the entire Kepler photometric time series of the moderately young Sun-like star Kepler-17 accompanied by a transiting hot Jupiter.
Methods. We applied a maximum-entropy spot model to the long-cadence out-of-transit photometry of the target to derive maps of the starspot filling factor versus the longitude and the time. These maps are compared to the spots occulted during transits to validate our reconstruction and derive information on the latitudes of the starspots.
Results. We find two main active longitudes on the photosphere of Kepler-17, one of which has a lifetime of at least ∼1400 days although with a varying level of activity. The latitudinal differential rotation is of solar type, that is, with the equator rotating faster than the poles. We estimate a minimum relative amplitude ΔΩ/Ω between ∼0.08 ± 0.05 and 0.14 ± 0.05, our determination being affected by the finite lifetime of individual starspots and depending on the adopted spot model parameters. We find marginal evidence of a short-term intermittent activity cycle of ∼48 days and an indication of a longer cycle of 400−600 days characterized by an equatorward migration of the mean latitude of the spots as in the Sun. The rotation of Kepler-17 is likely to be significantly affected by the tides raised by its massive close-by planet.
Conclusion. We confirm the reliability of maximum-entropy spot models to map starspots in young active stars and characterize the activity and differential rotation of this young Sun-like planetary host.
Phase-curve analysis of comet 67P/Churyumov-Gerasimenko at small phase angles
Authors: Masoumzadeh N , Kolokolova L , Tubiana C , El-Maarry M. R. , Mottola S , Güttler C. , Snodgrass C , Sierks H. , Naletto G. , Lamy P. L. , Rodrigo R. , Koschny D , Davidsson B , Barucci M. A. , Bertaux J.-L. , Bertini I , Bodewits D. , Cremonese G , Da Deppo V. , Debei S. , De Cecco M. , Deller J. , Fornasier S. , Fulle M , Gutiérrez P. J. , Hasselmann P. H. , Ip W.-H. , Keller H. U. , Lara L. M. , Lazzarin M , López-Moreno J. J. , Marzari F , Shi X , Toth I 
Published: April 2019

Aims. The Rosetta-OSIRIS images acquired at small phase angles in three wavelengths during the fly-by of the spacecraft on 9–10 April 2016 provided a unique opportunity to study the opposition effect on the surface of comet 67P/Churyumov-Gerasimenko (67P). Our goal is to study phase curves of the nucleus at small phase angles for a variety of surface structures to show the differences in their opposition effect and to determine which surface properties cause the differences.
Methods. We used OSIRIS NAC images that cover the Ash-Khepry-Imhotep region to extract the phase curve, that is, the reflectance of the surface as a function of phase angle. We selected six regions of interest (ROIs) and derived the phase curves for each ROI. We fit a linear-exponential function to the phase curves. The resulting model parameters were then interpreted by spectrophotometric, geomorphological, and phase-ratio analyses, and by investigating the influence of structural and textural properties of the surface.
Results. We find evidence for the opposition effect (deviation of the phase curve from linear behavior) in phase curves for all areas. We found an anticorrelation between the phase ratio and reflectance in a small phase angle range. This provides evidence for the shadow-hiding effect. We conclude that the decrease in the slope of the phase ratio versus reflectance indicates a decrease in the proportion of shadowed regions and reduces the contribution of the shadow-hiding effect. Large uncertainties in the determination of the opposition effect parameters with respect to wavelength do not allow us to conclusively claim coherent backscattering in the opposition effect phenomenon. Based on the two analyses, we conclude that the opposition effect of comet 67P in the Ash-Khepry-Imhotep region is mainly affected by shadow-hiding.
Physical and chemical fingerprint of protostellar disc formation
Authors: Artur de la Villarmois E. , Jørgensen J. K. , Kristensen L. E. , Bergin E. A. , Harsono D. , Sakai N. , van Dishoeck E. F. , Yamamoto S. 
Published: April 2019

Context. The structure and composition of emerging planetary systems are likely strongly influenced by their natal environment within the protoplanetary disc at the time when the star is still gaining mass. It is therefore essential to identify and study the physical processes at play in the gas and dust close to young protostars and investigate the chemical composition of the material that is inherited from the parental cloud.
Aims. The purpose of this paper is to explore and compare the physical and chemical structure of Class I low-mass protostellar sources on protoplanetary disc scales.
Methods. We present a study of the dust and gas emission towards a representative sample of 12 Class I protostars from the Ophiuchus molecular cloud with the Atacama Large Millimeter/submillimeter Array (ALMA). The continuum at 0.87 mm and molecular transitions from C17O, C34S, H13CO+, CH3OH, SO2, and C2H were observed at high angular resolution (0.′′4, ~60 au diameter) towards each source. The spectrally and spatially resolved maps reveal the kinematics and the spatial distribution of each species. Moreover, disc and stellar masses are estimated from the continuum flux and position-velocity diagrams, respectively.
Results. Six of the sources show disc-like structures in C17O, C34S, or H13CO+ emission. Towards the more luminous sources, compact emission and large line widths are seen for transitions of SO2 that probe warm gas (Eu ~ 200 K). In contrast, C17O emission is detected towards the least evolved and less luminous systems. No emission of CH3OH is detected towards any of the continuum peaks, indicating an absence of warm CH3OH gas towards these sources.
Conclusions. A trend of increasing stellar mass is observed as the envelope mass decreases. In addition, a power-law relation is seen between the stellar mass and the bolometric luminosity, corresponding to a mass accretion rate of (2.4 ± 0.6) × 10−7 M⊙ yr−1 for the Class I sources, with a minimum and maximum value of 7.5 × 10−8 and 7.6 × 10−7 M⊙ yr−1, respectively. This mass accretion rate is lower than the expected value if the accretion is constant in time and rather points to a scenario of accretion occurring in bursts. The differentiation between C17O and SO2 suggests that they trace different physical components: C17O traces the densest and colder regions of the disc-envelope system, while SO2 may be associated with regions of higher temperature, such as accretion shocks. The lack of warm CH3OH emission suggests that there is no hot-core-like region around any of the sources and that the CH3OH column density averaged over the disc is low. Finally, the combination of bolometric temperature and luminosity may indicate an evolutionarytrend of chemical composition during these early stages.
Variations in the Detection of Anorectal Anomalies at Birth among European Cities
Authors: Aldeiri Bashar , Davidson Joseph R. , Eaton Simon , Coletta Riccardo , Cardoso Almeida Andre , Long Anna-May , Knight Marian , Cross Kate M. , Chouikh Taieb , Iacobelli Barbara Daniela , Sarnacki Sabine , Bagolan Pietro , Cretolle Celia , Siminas Sotirios , Curry Joe I. , Morabito Antonino , De Coppi Paolo 
Published: April 2019

Introduction The diagnosis of anorectal malformations (ARMs) is made at birth by perineal examination of the newborn, yet small series reported late diagnosis in almost 13%. No large series to date have looked into the magnitude of missed ARM cases in the neonatal period across Europe. This study aimed to define the rate of missed ARM at birth across four United Kingdom and European Union centers.
Materials and Methods All ARM cases treated at two United Kingdom tertiary centers in the past 15 years were compared with two tertiary European centers. Demographic and relevant clinical data were collected. Late diagnosis was defined as any diagnosis made after discharge from the birth unit. Factors associated with late diagnosis were explored with descriptive statistics.
Results Across the four centers, 117/1,350, 8.7% were sent home from the birth unit without recognizing the anorectal anomaly. Missed cases showed a slight female predominance (1.3:1), and the majority (113/117, 96.5%) were of the low anomaly with a fistula to the perineum. The rate of missed ARM cases was significantly higher in the United Kingdom centers combined (74/415, 17.8%) compared with those in the European Union (43/935, 4.6%) (p < 0.00001), and this was independent of individual center and year of birth.
Conclusion Significant variation exists between the United Kingdom and other European countries in the detection of ARM at birth. We recommend raising the awareness of accurate perineal examination at the time of newborn physical examination. We feel this highlights an urgent need for a national initiative to assess and address the timely diagnosis of ARM in the United Kingdom.
Elastic Wrapping of Lower Extremity Free Flaps during Dangling Improves Microcirculation and Reduces Pain as well as Edema
Authors: Kolbenschlag Jonas , Ruikis Alexandra , Faulhaber Lisa , Daigeler Adrien , Held Manuel , Rothenberger Jens , Lehnhardt Marcus , Sogorski Alexander , Goertz Ole 
Published: April 2019

Background Free tissue transfer has become a common and safe reconstructive procedure. However, total or partial flap losses remain a looming threat, especially for lower extremity free flaps due to the gravitational challenge associated with dependency. Thus, the majority of microsurgical centers apply some kind of structured flap training. However, due to the lack of evidence, these differ greatly, for example, in the application of an elastic wrapping during dangling. Therefore, the aim of this study was to assess the impact of an elastic wrapping on free flap microcirculation, edema, and pain during dangling.
Methods Standardized dangling was performed from postoperative day (POD) 6 to 9 in 30 patients with microvascular reconstruction of the lower extremity. The first dangling per day was performed without elastic wrapping, followed by another session with 30 mm Hg of elastic wrapping. Tissue oxygen saturation (StO2), regional hemoglobin content (rHb), and blood flow (BF) were continuously measured in the free flap; the circumference of the flap as well as pain was assessed.
Results During wrapped dangling, BF as well as StO2 was significantly increased, while rHb was significantly lower on all PODs. Wrapped dangling was rated significantly more comfortable and the girth of the free flaps was significantly less after wrapped dependency when compared with unwrapped dangling.
Conclusion Dangling with an elastic wrapping with 30 mm Hg pressure improved flap microcirculation and reduced pain and edema formation.
Outcomes of Elective Induction of Labor versus Expectant Management among Obese Women at ≥39 Weeks
Authors: Palatnik Anna , Kominiarek Michelle A. 
Published: April 2019

Objective Maternal obesity is associated with many adverse obstetric outcomes including cesarean delivery. It is unclear whether induction of labor can reduce these risks. Previous studies report conflicting results on the outcomes of elective induction of labor among obese women. This study aimed to compare maternal and neonatal outcomes between obese women undergoing elective induction of labor and those undergoing expectant management at ≥39 weeks.
Study Design This was a retrospective cohort study from the Consortium on Safe Labor of obese women (defined by prepregnancy body mass index≥ 30kg/m2) with singleton gestations at ≥39 weeks without medical comorbidities from 2002 through 2008. Women scheduled for medically indicated induction of labor were excluded. The primary outcome of cesarean delivery was compared between obese women undergoing elective induction of labor and expectant management during 39th, 40th, and 41st weeks using univariable and multivariable analyses, stratifying by parity.
Results In all, 7,298 nulliparous and 9,789 parous women were eligible for analysis. After controlling for potential confounders, elective induction of labor during 39th week in nulliparous and parous women was associated with lower odds of cesarean delivery (39.1 vs. 41.6%, adjusted odds ratio [OR]: 0.47, 95% confidence interval [CI]: 0.30–0.74 for nulliparous and 5.5 vs. 10.1%, adjusted OR: 0.34, 95% CI: 0.20–0.61 for parous women) compared with expectant management. Elective induction of labor during 40th and 41st weeks was not associated with lower odds of cesarean delivery. In addition, macrosomia was reduced in nulliparous women undergoing elective induction of labor during the 40th week (12.1 vs. 18.5%, adjusted OR: 0.56, 95% CI: 0.35–0.87) and in parous women undergoing elective induction of labor during 39th (11.6 vs. 17.6%, adjusted OR: 0.50, 95% CI: 0.38–0.66) and 40th weeks (16.4 vs. 22.2%, adjusted OR: 0.53, 95% CI: 0.36–0.78).
Conclusion Elective induction of labor at 39 weeks, when compared with expectant management, was associated with lower cesarean deliveries in obese nulliparous and parous women.
Using the ‘journey metaphor’ to restructure philosophy of religion
Authors: Knepper Timothy 
Published: April 2019

AbstractThis essay forwards a new orientation and point of origin for philosophy of religion—an orientation that does not privilege theism, and a point of origin that does not begin with the attributes and proofs of God (and thereby privilege theism). To do so, it turns to the metaphor theory of George Lakoff and Mark Johnson, specifically their analysis of the metaphorlife is a journey. It draws on the internal structure of the journey metaphor to identify its core, constituent parts: journeys have a point of origin and destination, a route that is planned, obstacles and sights that are encountered along the way, and a traveler who is accompanied by and encounters other travelers. It then uses these core, constituent parts to generate five philosophical questions about the “journey” of the self and five philosophical questions about the “journey” of the cosmos: (1) Who am I (as traveler)?; (2) Where do I come from?; (3) Where am I going?; (4) How do I get there?; (5) What obstacles lie in my way?; (6) What is the cosmos?; (7) Where does the cosmos come from?; (8) Where is the cosmos going?; (9) How does the cosmos get there?; (10) What obstacles lie in the cosmos’ way? The majority of the essay then shows how each of these questions generates topics for global philosophy of religion and embraces content from a diversity of religious philosophies. Thus, this essay concludes that the journey metaphor is able to offer a new orientation and point of origin for philosophy of religion that is inclusive of a global diversity of religious traditions.
Long-term declines in bird populations in tropical agricultural countryside
Authors: Şekercioğlu Çağan H. , Mendenhall Chase D. , Oviedo-Brenes Federico , Horns Joshua J. , Ehrlich Paul R. , Daily Gretchen C. 
Published: April 2019

Significance
As agricultural lands rapidly expand in the tropics, they become critical for the future of tropical biodiversity, but little is known about their long-term conservation value. Over 12 years in Costa Rica, we measured the abundance and diversity of birds in agricultural areas and embedded forest remnants. We recorded 185 bird species in coffee plantations and 230 species at forest sites, but 69 out of 112 populations showed declines—mostly among more specialized, sedentary, and/or insectivorous species. Nevertheless, coffee plantations with modestly higher tree cover had higher bird diversity and capture rates. With limited opportunities to expand protected areas worldwide, even small improvements in farming practices can increase the long-term sustainability of tropical wildlife and its benefits to people.
Responses in area hMT+ reflect tuning for both auditory frequency and motion after blindness early in life
Authors: Huber Elizabeth , Jiang Fang , Fine Ione 
Published: April 2019

Significance
When individuals lose a sense early in life, widespread neural reorganization occurs. This extraordinary plasticity plays a critical role in allowing blind and deaf individuals to make better use of their remaining senses. Here, we show that area hMT+, selective for visual motion in sighted individuals, responds to auditory frequency as well as auditory motion after early blindness. Remarkably, auditory frequency tuning persisted in two adult sight-recovery subjects, despite their recovered ability to see visual motion. Thus, auditory frequency selectivity coexists with the neural architecture required for visual motion processing. In blind individuals, selectivity for auditory motion and frequency seems to exist within a conserved neural architecture capable of supporting analogous computations in the visual domain should vision be restored.
Assembly of modern mammal community structure driven by Late Cretaceous dental evolution, rise of flowering plants, and dinosaur demise
Authors: Chen Meng , Strömberg Caroline A. E. , Wilson Gregory P. 
Published: April 2019

SignificanceAmazing fossil discoveries over the last 30 years have led to the paleontological consensus that some Mesozoic mammaliaforms underwent ecomorphological diversification in the midst of dinosaurs. However, the ecological structure of Mesozoic mammaliaform communities remains unclear. Here, we quantify the ecological structure of extinct and extant small-bodied mammaliaform communities aiming to identify evolutionary and ecological drivers that have influenced those communities through time. We used body size, diet, and locomotion of constituent species to plot ecospace occupation and calculate ecological richness and disparity of those communities. We propose that the interplay of Late Cretaceous dental evolution, the rise of angiosperms, and competition with other vertebrates were critical in shaping the ecological structure of small-bodied mammaliaform communities through time.