bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural insights into the promiscuous DNA binding and broad substrate selectivity of fowlpox virus resolvase
Authors: Li Na , Shi Ke , Rao Timsi , Banerjee Surajit , Aihara Hideki 
Published: January 2020

AbstractFowlpox virus resolvase (Fpr) is an endonuclease that cleaves a broad range of branched DNA structures, including the Holliday junction (HJ), with little sequence-specificity. To better understand the mechanisms underlying its relaxed substrate specificity, we determined the crystal structures of Fpr and that in a novel complex with HJ at 3.1-Å resolution. In the Fpr-HJ complex, two Fpr dimers use several distinct regions to interact with different DNA structural motifs, showing versatility in DNA-binding. Biochemical and solution NMR data support the existence of non-canonical modes of HJ interaction in solution. The binding of Fpr to various DNA motifs are mediated by its flat DNA-binding surface, which is centered on a short loop spanning K61 to I72 and flanked by longer α-helices at the outer edges, and basic side grooves near the dimer interface. Replacing the Fpr loop K61~I72 with a longer loop from Thermus thermophilus RuvC (E71~A87) endows Fpr with an enhanced selectivity toward HJ cleavage but with a target sequence preference distinct from that of RuvC, highlighting a unique role of this loop region in Fpr-HJ interaction. Our work helps explain the broad substrate selectivity of Fpr and suggests a possible mode of its association with poxvirus hairpin telomeres.
Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems
Authors: Dijk Frederike , Veenstra Veronique L. , Soer Eline C. , Dings Mark P. G. , Zhao Lan , Halfwerk Johannes B. , Hooijer Gerrit K. , Damhofer Helene , Marzano Marco , Steins Anne , Waasdorp Cynthia , Busch Olivier R. , Besselink Marc G. , Tol Johanna A. , Welling Lieke , van Rijssen Lennart B. , Klompmaker Sjors , Wilmink Hanneke W. , van Laarhoven Hanneke W. , Medema Jan Paul , Vermeulen Louis , van Hooff Sander R. , Koster Jan , Verheij Joanne , van de Vijver Marc J. , Wang Xin , Bijlsma Maarten F. 
Published: January 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.
SOX9 promotes tumor progression through the axis BMI1-p21CIP
Authors: Aldaz Paula , Otaegi-Ugartemendia Maddalen , Saenz-Antoñanzas Ander , Garcia-Puga Mikel , Moreno-Valladares Manuel , Flores Juana M. , Gerovska Daniela , Arauzo-Bravo Marcos J. , Samprón Nicolas , Matheu Ander , Carrasco-Garcia Estefania 
Published: January 2020

AbstractThe developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the differentiated cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma. SOX9 silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence in vitro and tumor growth in vivo. Gain of-SOX9 function showed that high levels of SOX9 promote tumor cell proliferation in vitro and in vivo. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21CIP in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21CIP in clinical samples of the different cancers. Moreover, BMI1 re-establishment in SOX9-silenced tumor cells restored cell viability and proliferation as well as decreased p21CIPin vitro and tumor growth in vivo. These results indicate that BMI1 is a critical effector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21CIP. Our results highlight the relevance of the SOX9-BMI1-p21CIP axis in tumor progression, shedding novel opportunities for therapeutic development.
Anticipatory Control of Momentum for Bipedal Walking on Uneven Terrain
Authors: Darici Osman , Temeltas Hakan , Kuo Arthur D. 
Published: January 2020

AbstractHumans and other walking bipeds often encounter and compensate for uneven terrain. They might, for example, regulate the body’s momentum when stepping on stones to cross a stream. We examined what to do and how far to look, as a simple optimal control problem, where forward momentum is controlled to compensate for a step change in terrain height, and steady gait regained with no loss of time relative to nominal walking. We modeled planar, human-like walking with pendulum-like legs, and found the most economical control to be quite stereotypical. It starts by gaining momentum several footfalls ahead of an upward step, in anticipation of the momentum lost atop that step, and then ends with another speed-up to regain momentum thereafter. A similar pattern can be scaled to a variety of conditions, including both upward or downward steps, yet allow for considerably reduced overall energy and peak power demands, compared to compensation without anticipation. We define a “persistence time” metric from the transient decay response after a disturbance, to describe how momentum is retained between steps, and how far ahead a disturbance should be planned for. Anticipatory control of momentum can help to economically negotiate uneven terrain.
Choroidal spatial distribution indexes as novel parameters for topographic features of the choroid
Authors: Hwang Sungsoon , Kong Mingui , Song Yun-Mi , Ham Don-Il 
Published: January 2020

AbstractThe purpose of the study is to propose choroidal spatial distribution indexes (CSDIs) to represent choroidal topographic features, establish a normative database for CSDIs, and identify factors associated with CSDIs in healthy eyes. Retrospective data analysis of 363 healthy eyes from a single-center, prospective, cross-sectional, non-interventional study. Subjects were evaluated using spectral domain OCT with enhanced depth imaging. Choroidal volume and average thickness were measured with OCT in nine macular subfields defined by the Early Treatment Diabetic Retinopathy Study. Vertical CSDI was defined as the natural logarithm of superior choroidal volume divided by inferior choroidal volume. Horizontal CSDI was defined as the natural logarithm of temporal choroidal volume divided by nasal choroidal volume. The overall distributions of vertical and horizontal CSDIs was analyzed. Linear regression analyses were used to identify ocular and systemic factors associated with vertical and horizontal CSDIs. The average vertical CSDI was 0.062 ± 0.206, and average horizontal CSDI was 0.138 ± 0.226. Both vertical and horizontal CSDIs followed normal distribution. Increasing age was significantly associated with greater vertical CSDI (choroidal volume distribution tilted toward the superior region), and longer axial length and thinner subfoveal choroidal thickness were significantly associated with greater horizontal CSDI (choroidal volume distribution tilted toward the temporal region).
Infection Prevention Measures for Surgical Procedures during a Middle East Respiratory Syndrome Outbreak in a Tertiary Care Hospital in South Korea
Authors: Park Jiyeon , Yoo Seung Yeon , Ko Jae-Hoon , Lee Sangmin M. , Chung Yoon Joo , Lee Jong-Hwan , Peck Kyong Ran , Min Jeong Jin 
Published: January 2020

AbstractIn 2015, we experienced the largest in-hospital Middle East respiratory syndrome (MERS) outbreak outside the Arabian Peninsula. We share the infection prevention measures for surgical procedures during the unexpected outbreak at our hospital. We reviewed all forms of related documents and collected information through interviews with healthcare workers of our hospital. After the onset of outbreak, a multidisciplinary team devised institutional MERS-control guidelines. Two standard operating rooms were converted to temporary negative-pressure rooms by physically decreasing the inflow air volume (−4.7 Pa in the main room and −1.2 Pa in the anteroom). Healthcare workers were equipped with standard or enhanced personal protective equipment according to the MERS-related patient’s profile and symptoms. Six MERS-related patients underwent emergency surgery, including four MERS-exposed and two MERS-confirmed patients. Negative conversion of MERS-CoV polymerase chain reaction tests was noticed for MERS-confirmed patients before surgery. MERS-exposed patients were also tested twice preoperatively, all of which were negative. All operative procedures in MERS-related patients were performed without specific adverse events or perioperative MERS transmission. Our experience with setting up a temporary negative-pressure operation room and our conservative approach for managing MERS-related patients can be referred in cases of future unexpected MERS outbreaks in non-endemic countries.
Adipophilin and perilipin 3 positively correlate with total lipid content in human breast milk
Authors: Pavlova Tereza , Spacil Zdenek , Vidova Veronika , Zlamal Filip , Cechova Eliska , Hodicka Zuzana , Bienertova-Vasku Julie 
Published: January 2020

AbstractLipids are secreted into milk as bilayer-coated structures: milk fat globules (MFGs). Adipophilin (ADRP) and perilipin 3 (TIP47) are associated with MFGs in human breast milk; however, the role of these proteins in milk lipid secretion is not fully understood. The study aimed to investigate levels of ADRP, TIP47 and total lipid content in human breast milk, their mutual correlations, and dynamics during lactation. Milk samples from 22 healthy lactating women (Caucasian, Central European) were collected at five time points during lactation (1–3, 12–14, 29–30, 88–90 and 178–180 days postpartum). Mass spectrometry-based method was used for quantification of ADRP and TIP47 in the samples. The gravimetric method was used to determine milk total lipid content. We observed distinctive trends in ADRP, TIP47 levels and lipid content in human breast milk during the first six months of lactation. We also found a significant association between lipid content and ADRP, lipid content and TIP47, and ADRP and TIP47 concentrations in breast milk at all sampling points. A mass spectrometry-based method was developed for quantifying ADRP and TIP47 in human breast milk. Strong mutual correlations were found between ADRP, TIP47 and total lipid content in human breast milk.
Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer
Authors: Li Rui , Ong Stephanie L. , Tran Linh M. , Jing Zhe , Liu Bin , Park Stacy J. , Huang Zi Ling , Walser Tonya C. , Heinrich Eileen L. , Lee Gina , Salehi-Rad Ramin , Crosson William P. , Pagano Paul C. , Paul Manash K. , Xu Shili , Herschman Harvey , Krysan Kostyantyn , Dubinett Steven 
Published: January 2020

AbstractChronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in the at-risk for lung cancer pulmonary and the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory. Utilizing a doxycycline-controlled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory. Chromatin immunoprecipitation and methylation-specific PCR further revealed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDH1 (E-cadherin) promoter following the chronic IL-1β exposure. Chemical inhibition of DNA methylation not only restored E-cadherin expression in EMT memory, but also primed cells for chemotherapy-induced apoptosis.
Increased 18F-FDG signal recovery from small physiological structures in digital PET/CT and application to the pituitary gland
Authors: Meyer Marie , Allenbach Gilles , Nicod Lalonde Marie , Schaefer Niklaus , Prior John O. , Gnesin Silvano 
Published: January 2020

AbstractOn conventional PET/CT, and under physiological conditions, the volume of the pituitary gland (PG) is small, and its metabolic activity is commonly comparable to the surrounding background level in 18F-FDG imaging. We compared the physiological 18F-FDG uptake of the PG in patients imaged with digital PET (dPET) and with conventional PET (cPET). Additionally, we performed phantom experiments to characterize signal recovery and detectability of small structures. We retrospectively included 10 dPET and 10 cPET patients and measured PG SUVmax, SUVmean and SUVratio (using cerebellum as reference). We imaged a modified NEMA/IEC phantom with both dPET and cPET (background activity 5 kBq/mL, and 3× and 5× higher concentrations in ∅2–20-mm spherical inserts). Mean recovery coefficients (RCmean) and signal-difference-to-noise-ratio (SDNR) were computed to assess lesion detectability. Patients imaged with dPET presented higher PG SUVmax and SUVratio (SUVR) compared to patients imaged with cPET (4.7 ± 2.05 vs. 2.9 ± 0.64, p = 0.004; and 0.62 ± 0.25 vs 0.39 ± 0.09, p = 0.029, respectively), while there was no difference for SUVmean (2.7 ± 1.32 vs 2.1 ± 0.44, p = 0.39). Thus, with a SUV readout scale of 0–5 g/mL, normal PG appeared abnormally hot with dPET, but not with cPET. Phantom evidenced higher RCmean in dPET compared to cPET. For both 3x and 5x measurements, lesion detectability according to size was systematically superior with dPET. In conclusion, patients imaged with dPET presented higher 18F-FDG physiological uptake of the PG as compared to patients imaged with cPET. These findings were supported by phantom experiments demonstrating superior signal recovery and small region detectability with dPET. Awareness of this new “higher” SUV of the normal 18F-FDG uptake of the PG is important to avoid potential pitfalls in image interpretation, notably in oncologic patients treated with immunotherapy, who are at increased risk to develop hypophysitis.
Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo
Authors: Aggarwal Jasmin A. , Liu Wen-Ying , Montandon Gaspard , Liu Hattie , Hughes Stuart W. , Horner Richard L. 
Published: January 2020

AbstractMotoneurons are the final output pathway for the brain’s influence on behavior. Here we identify properties of hypoglossal motor output to the tongue musculature. Tongue motor control is critical to the pathogenesis of obstructive sleep apnea, a common and serious sleep-related breathing disorder. Studies were performed on mice expressing a light sensitive cation channel exclusively on cholinergic neurons (ChAT-ChR2(H134R)-EYFP). Discrete photostimulations under isoflurane-induced anesthesia from an optical probe positioned above the medullary surface and hypoglossal motor nucleus elicited discrete increases in tongue motor output, with the magnitude of responses dependent on stimulation power (P < 0.001, n = 7) and frequency (P = 0.002, n = 8, with responses to 10 Hz stimulation greater than for 15–25 Hz, P < 0.022). Stimulations during REM sleep elicited significantly reduced responses at powers 3–20 mW compared to non-rapid eye movement (non-REM) sleep and wakefulness (each P < 0.05, n = 7). Response thresholds were also greater in REM sleep (10 mW) compared to non-REM and waking (3 to 5 mW, P < 0.05), and the slopes of the regressions between input photostimulation powers and output motor responses were specifically reduced in REM sleep (P < 0.001). This study identifies that variations in photostimulation input produce tunable changes in hypoglossal motor output in-vivo and identifies REM sleep specific suppression of net motor excitability and responsivity.
Feasibility Study of MRI Muscles Molecular Imaging in Evaluation of Early Post-Mortem Interval
Authors: Sapienza Daniela , Asmundo Alessio , Silipigni Salvatore , Barbaro Ugo , Cinquegrani Antonella , Granata Francesca , Barresi Valeria , Gualniera Patrizia , Bottari Antonio , Gaeta Michele 
Published: January 2020

AbstractEstimating early postmortem interval (EPI) is a difficult task in daily forensic activity due to limitations of accurate and reliable methods. The aim of the present work is to describe a novel approach in the estimation of EPI based on quantitative magnetic resonance molecular imaging (qMRMI) using a pig phantom since post-mortem degradation of pig meat is similar to that of human muscles. On a pig phantom maintained at 20° degree, using a 1.5 T MRI scanner we performed 10 scans (every 4 hours) monitoring apparent diffusion coefficient (ADC), fractional anisotropy (FA) magnetization transfer ration (MTR), tractography and susceptibility weighted changes in muscles until 36 hours after death. Cooling of the phantom during the experiment was recorded. Histology was also obtained. Pearson’s Test was carried out for time correlation between post-mortem interval and MRI data. We found a significative inverse correlation between ADC, FA, MT values and PMI. Our preliminary data shows that post-mortem qMRMI is a potential powerful tool in accurately determining EPI and is worth of further investigation.
HbA1c may contribute to the development of non-alcoholic fatty liver disease even at normal-range levels
Authors: Chen Changxi , Zhu Zhongwei , Mao Yushan , Xu Yimin , Du Juan , Tang Xiaoping , Cao Hongbao 
Published: January 2020

AbstractPrevious clinical studies highlighted nonalcoholic fatty liver disease (NAFLD) as a hepatic facet of metabolic syndrome, which progresses toward Type 2 diabetes along with an elevation of HbA1c in the blood. Longitudinal observations were performed in a cohort of 2811 participants with no liver disease at inception. The rate of the conversion into NAFLD was 15.7% (440/2811), with a steady increase in prevalence observed in sub-cohorts with increasing HbA1c levels. Moreover, regression analysis indicated that HbA1c levels serve as the risk factors for NAFLD after multiple adjustments (odds ratio: 1.58, P-value &lt; 0.004). When HbA1c-related molecular networks were investigated using natural language programming algorithms, multiple genetic/small molecular (SM) pathways were highlighted as connectors between the HbA1c levels and the development of NAFLD, including ones for nitric oxide, hypoxia and receptor for advanced glycation end products (RAGE). Our results suggest that increased levels of HbA1c may contribute to the progression of NAFLD either directly, by stimulating RAGE or indirectly, through the promotion of hypoxia and suppression of the release of NO. Further studies are needed to test the impact of HbA1c on the development of the chronic liver disease.
Recurrences in Sudden Sensorineural Hearing Loss: A Long-Term Observational Study
Authors: Pecorari Giancarlo , Riva Giuseppe , Bruno Gabriele , Naqe Nertila , Nardo Matteo , Albera Andrea , Albera Roberto 
Published: January 2020

PurposeLong-term outcomes of sudden sensorineural hearing loss (SSNHL) are poorly studied. The recurrence rate is heterogeneous, and the prognosis of relapses is uncertain. The aim of this retrospective study was to evaluate the recurrence rate of SSNHL and to analyze the correlation with clinical and audiometric characteristics.MethodSeventy-three patients with idiopatic SSNHL were evaluated. Clinical and audiometric features were recorded. Seventy patients (95.8%) had at least a 2-year follow-up, whereas 50 (68.4%) had a 5-year follow-up.ResultsTwo- and 5-year recurrence rates were 5.60% and 10.34%, respectively. Mean time lapse between 1st episode and recurrence was 29.33 ± 26.60 months. About 70% of patients had a partial recovery at recurrence. The same ear was affected in 42.8% of patients, the contralateral ear was affected in 42.8% of patients, and recurrence was bilateral in 14.4% of cases. Recurrence correlated only with the presence of tinnitus during follow-up. However, the small number of participants with recurrence represented a limiting factor of our study.ConclusionsRecurrences of SSNHL are rare events that can involve ipsilateral or contralateral ear. Further studies are necessary to identify predictors of recurrence.
Gaia-DR2 extended kinematical maps
Authors: López-Corredoira M. , Garzón F. , Wang H.-F. , Sylos Labini F. , Nagy R. , Chrobáková Ž. , Chang J. , Villarroel B. 
Published: January 2020

Context.In our Paper I, by using statistical deconvolution methods, extended kinematics maps ofGaia-DR2 data have been produced in a range of heliocentric distances that are a factor of two to three larger than those analyzed previously by theGaiaCollaboration with the same data. It added the range of Galactocentric distances between 13 kpc and 20 kpc to the previous maps.Aims.Here, we investigate the dynamical effects produced by different mechanisms that can explain the radial and vertical components of these extended kinematic maps, including a decomposition of bending and breathing of the vertical components. This paper as a whole tries to be a compendium of different dynamical mechanisms whose predictions can be compared to the kinematic maps.Methods.Using analytical methods or simulations, we are able to predict the main dynamical factors and compare them to the predictions of the extended kinematic maps ofGaia-DR2.Results.The gravitational influence of Galactic components that are different from the disk, such as the long bar or bulge, the spiral arms, or a tidal interaction with Sagittarius dwarf galaxy, may explain some features of the velocity maps, especially in the inner parts of the disk. However, they are not sufficient in explaining the most conspicuous gradients in the outer disk. Vertical motions might be dominated by external perturbations or mergers, although a minor component may be due to a warp whose amplitude evolves with time. Here, we show with two different methods, which analyze the dispersion of velocities, that the mass distribution of the disk is flared. Despite these partial explanations, the main observed features can only be explained in terms of out-of-equilibrium models, which are either due to external perturbers or to the fact that the disk has not had time to reach equilibrium since its formation.