bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycobacterial dynamin-like protein IniA mediates membrane fission
Authors: Wang Manfu , Guo Xiangyang , Yang Xiuna , Zhang Bing , Ren Jie , Liu Aijun , Ran Yajun , Yan Bing , Chen Fang , Guddat Luke W. , Hu Junjie , Li Jun , Rao Zihe 
Published: August 2019

AbstractMycobacterium tuberculosis infection remains a major threat to human health worldwide. Drug treatments against tuberculosis (TB) induce expression of several mycobacterial proteins, including IniA, but its structure and function remain poorly understood. Here, we report the structures of Mycobacterium smegmatis IniA in both the nucleotide-free and GTP-bound states. The structures reveal that IniA folds as a bacterial dynamin-like protein (BDLP) with a canonical GTPase domain followed by two helix-bundles (HBs), named Neck and Trunk. The distal end of its Trunk domain exists as a lipid-interacting (LI) loop, which binds to negatively charged lipids for membrane attachment. IniA does not form detectable nucleotide-dependent dimers in solution. However, lipid tethering indicates nucleotide-independent association of IniA on the membrane. IniA also deforms membranes and exhibits GTP-hydrolyzing dependent membrane fission. These results confirm the membrane remodeling activity of BDLP and suggest that IniA mediates TB drug-resistance through fission activity to maintain plasma membrane integrity.
In vitro fusion of single synaptic and dense core vesicles reproduces key physiological properties
Authors: Kreutzberger Alex J. B. , Kiessling Volker , Stroupe Christopher , Liang Binyong , Preobraschenski Julia , Ganzella Marcelo , Kreutzberger Mark A. B. , Nakamoto Robert , Jahn Reinhard , Castle J. David , Tamm Lukas K. 
Published: August 2019

AbstractRegulated exocytosis of synaptic vesicles is substantially faster than of endocrine dense core vesicles despite similar molecular machineries. The reasons for this difference are unknown and could be due to different regulatory proteins, different spatial arrangements, different vesicle sizes, or other factors. To address these questions, we take a reconstitution approach and compare regulated SNARE-mediated fusion of purified synaptic and dense core chromaffin and insulin vesicles using a single vesicle-supported membrane fusion assay. In all cases, Munc18 and complexin are required to restrict fusion in the absence of calcium. Calcium triggers fusion of all docked vesicles. Munc13 (C1C2MUN domain) is required for synaptic and enhanced insulin vesicle fusion, but not for chromaffin vesicles, correlating inversely with the presence of CAPS protein on purified vesicles. Striking disparities in calcium-triggered fusion rates are observed, increasing with curvature with time constants 0.23 s (synaptic vesicles), 3.3 s (chromaffin vesicles), and 9.1 s (insulin vesicles) and correlating with rate differences in cells.
Molecular ground-state dissociation in the condensed phase employing plasmonic field enhancement of chirped mid-infrared pulses
Authors: Morichika Ikki , Murata Kei , Sakurai Atsunori , Ishii Kazuyuki , Ashihara Satoshi 
Published: August 2019

AbstractSelective bond cleavage via vibrational excitation is the key to active control over molecular reactions. Despite its great potential, the practical implementation in condensed phases have been hampered to date by poor excitation efficiency due to fast vibrational relaxation. Here we demonstrate vibrationally mediated, condensed-phase molecular dissociation by employing intense plasmonic near-fields of temporally-shaped mid-infrared (mid-IR) pulses. Both down-chirping and substantial field enhancement contribute to efficient ladder climbing of the carbonyl stretch vibration of W(CO)6 in n-hexane solution and to the resulting CO dissociation. We observe an absorption band emerging with laser irradiation at the excitation beam area, which indicates that the dissociation is followed by adsorption onto metal surfaces. This successful demonstration proves that the combination of ultrafast optics and nano-plasmonics in the mid-IR range is useful for mode-selective vibrational ladder climbing, paving the way toward controlled ground-state chemistry.
EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
Authors: Sun Zhixiong , Xu Xiguang , He Jianlin , Murray Alexander , Sun Ming-an , Wei Xiaoran , Wang Xia , McCoig Emmarose , Xie Evan , Jiang Xi , Li Liwu , Zhu Jinsong , Chen Jianjun , Morozov Alexei , Pickrell Alicia M. , Theus Michelle H. , Xie Hehuang 
Published: August 2019

AbstractLife experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
Metabolomic analysis of serum may refine 21-gene expression assay risk recurrence stratification
Authors: McCartney Amelia , Vignoli Alessia , Tenori Leonardo , Fornier Monica , Rossi Lorenzo , Risi Emanuela , Luchinat Claudio , Biganzoli Laura , Di Leo Angelo 
Published: August 2019

AbstractDespite recent refinements to the 21-gene g score, allowing a better identification of patients who may derive no benefit from the addition of adjuvant chemotherapy to that of endocrine therapy, patients with early breast cancer still stand to be over-treated in the setting of clinical and/or genomic uncertainty or discordance. Here we describe and demonstrate a potential approach of further refining the OncotypeDX risk score by metabolomic analysis of serum. In a clinical dataset (N = 87), the risk of recurrence was further sub-stratified by metabolomic signature, with an effective splitting of each Oncotype risk classification. A total of seven recurrences were recorded, with metabolomic analysis accurately predicting six of these. Contrastingly, the genomic risk score of the seven recurrences ranged across all three Oncotype classifications (one recurrence occurred in the “low”-risk group, three in the “intermediate” group and three in the “high”-risk group).
A dataset describing a suite of novel antibody reagents for the RAS signaling network
Authors: Schoenherr Regine M. , Huang Dongqing , Voytovich Uliana J. , Ivey Richard G. , Kennedy Jacob J. , Saul Richard G. , Colantonio Simona , Roberts Rhonda R. , Knotts Joseph G. , Kaczmarczyk Jan A. , Perry Candice , Hewitt Stephen M. , Bocik William , Whiteley Gordon R. , Hiltke Tara , Boja Emily S. , Rodriguez Henry , Whiteaker Jeffrey R. , Paulovich Amanda G. 
Published: August 2019

AbstractRAS genes are frequently mutated in cancer and have for decades eluded effective therapeutic attack. The National Cancer Institute’s RAS Initiative has a focus on understanding pathways and discovering therapies for RAS-driven cancers. Part of these efforts is the generation of novel reagents to enable the quantification of RAS network proteins. Here we present a dataset describing the development, validation (following consensus principles developed by the broader research community), and distribution of 104 monoclonal antibodies (mAbs) enabling detection of 27 phosphopeptides and 69 unmodified peptides from 20 proteins in the RAS network. The dataset characterizes the utility of the antibodies in a variety of applications, including Western blotting, immunoprecipitation, protein array, immunohistochemistry, and targeted mass spectrometry. All antibodies and characterization data are publicly available through the CPTAC Antibody Portal, Panorama Public Repository, and/or PRIDE databases. These reagents will aid researchers in discerning pathways and measuring expression changes in the RAS signaling network.
The prognostic significance of MRI-detected extramural venous invasion, mesorectal extension, and lymph node status in clinical T3 mid-low rectal cancer
Authors: Gu Chaoyang , Yang Xuyang , Zhang Xubing , Zheng Erliang , Deng Xiangbing , Hu Tao , Wu Qingbin , Bi Liang , Wu Bing , Su Minggang , Wang Ziqiang 
Published: August 2019

AbstractThe purpose of this study was to evaluate the prognostic significance of the magnetic resonance imaging-detected extramural venous invasion (MR-EMVI), the depth of mesorectal extension (MR-DME), and lymph node status (MR-LN) in clinical T3 mid-low rectal cancer. One hundred and forty-six patients with clinical T3 mid-low rectal cancer underwent curative surgery were identified. Pretreatment high-resolution MRI was independently reviewed by two experienced radiologists to evaluate MR-EMVI score (0–4), MR-DME (≤4 mm or >4 mm), and MR-LN (positive or negative). The Cox-multivariate regression analysis revealed that the MR-EMVI was the only independent prognostic factor that correlated with overall 3-year disease-free survival (DFS) (p = 0.01). The survival analysis showed that patients with positive MR-EMVI, MR-DME > 4 mm, and positive MR-LN had a poorer prognosis in the overall 3-year DFS (HR 3.557, 95% CI 2.028 to 13.32, p < 0.01; HR 3.744, 95% CI:1.165 to 5.992, p = 0.002; HR 2.946, 95% CI: 1.386 to 6.699, p < 0.01). By combining MR-EMVI with MR-DME or MR-LN, the prognostic significance was more remarkable. Our study suggested that the MR-EMVI, MR-DME, and MR-LN were the important prognostic factors for patients with clinical T3 mid-low rectal cancer and the MR-EMVI was an independent prognostic factor.
Collaboration in Complex Systems: Multilevel Network Analysis for Community-Based Obesity Prevention Interventions
Authors: McGlashan Jaimie , de la Haye Kayla , Wang Peng , Allender Steven 
Published: August 2019

AbstractCommunity-based systems interventions represent a promising, but complex approach to the prevention of childhood obesity. Existing studies suggest that the implementation of multiple actions by engaged community leaders (steering committees) is of critical importance to influence a complex system. This study explores two key components of systems interventions: (1) steering committees; and (2) causal loop diagrams (CLDs), used to map the complex community-level drivers of obesity. The interactions between two components create an entangled, complex process difficult to measure, and methods to analyse the dependencies between these two components in community-based systems interventions are limited. This study employs multilevel statistical models from social network analysis to explore the complex interdependencies between steering committee collaboration and their actions in the CLD. Steering committee members from two communities engaged in obesity prevention interventions reported on their collaborative relationships with each other, and where their actions are situated in a locally developed CLD. A multilevel exponential random graph model (MERGM) was developed for each community to explore the structural configurations of the collaboration network, actions in the CLD, and cross-level interactions. The models showed the tendency for reciprocated and transitive collaboration among committee members, as well as some evidence of more complex multilevel configurations that may indicate integrated solutions and collective action. The use of multilevel network analysis represents a step toward unpacking the complexities inherent in community-based systems interventions for obesity prevention.
No single, stable 3D representation can explain pointing biases in a spatial updating task
Authors: Vuong Jenny , Fitzgibbon Andrew W. , Glennerster Andrew 
Published: August 2019

AbstractPeople are able to keep track of objects as they navigate through space, even when objects are out of sight. This requires some kind of representation of the scene and of the observer’s location but the form this might take is debated. We tested the accuracy and reliability of observers’ estimates of the visual direction of previously-viewed targets. Participants viewed four objects from one location, with binocular vision and small head movements then, without any further sight of the targets, they walked to another location and pointed towards them. All conditions were tested in an immersive virtual environment and some were also carried out in a real scene. Participants made large, consistent pointing errors that are poorly explained by any stable 3D representation. Any explanation based on a 3D representation would have to posit a different layout of the remembered scene depending on the orientation of the obscuring wall at the moment the participant points. Our data show that the mechanisms for updating visual direction of unseen targets are not based on a stable 3D model of the scene, even a distorted one.
Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity
Authors: Gonçalves Ana Cláudia , Towers Emily R. , Haq Naila , Porco John A. , Pelletier Jerry , Dawson Sally J. , Gale Jonathan E. 
Published: August 2019

AbstractStress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases.
Probing the solution structure of the E. coli multidrug transporter MdfA using DEER distance measurements with nitroxide and Gd(III) spin labels
Authors: Yardeni Eliane H. , Bahrenberg Thorsten , Stein Richard A. , Mishra Smriti , Zomot Elia , Graham Bim , Tuck Kellie L. , Huber Thomas , Bibi Eitan , Mchaourab Hassane S. , Goldfarb Daniella 
Published: August 2019

AbstractMethodological and technological advances in EPR spectroscopy have enabled novel insight into the structural and dynamic aspects of integral membrane proteins. In addition to an extensive toolkit of EPR methods, multiple spin labels have been developed and utilized, among them Gd(III)-chelates which offer high sensitivity at high magnetic fields. Here, we applied a dual labeling approach, employing nitroxide and Gd(III) spin labels, in conjunction with Q-band and W-band double electron-electron resonance (DEER) measurements to characterize the solution structure of the detergent-solubilized multidrug transporter MdfA from E. coli. Our results identify highly flexible regions of MdfA, which may play an important role in its functional dynamics. Comparison of distance distribution of spin label pairs on the periplasm with those calculated using inward- and outward-facing crystal structures of MdfA, show that in detergent micelles, the protein adopts a predominantly outward-facing conformation, although more closed than the crystal structure. The cytoplasmic pairs suggest a small preference to the outward-facing crystal structure, with a somewhat more open conformation than the crystal structure. Parallel DEER measurements with the two types of labels led to similar distance distributions, demonstrating the feasibility of using W-band spectroscopy with a Gd(III) label for investigation of the structural dynamics of membrane proteins.
Image-based Classification of Tumor Type and Growth Rate using Machine Learning: a preclinical study
Authors: Tang Tien T. , Zawaski Janice A. , Francis Kathleen N. , Qutub Amina A. , Gaber M. Waleed 
Published: August 2019

AbstractMedical images such as magnetic resonance (MR) imaging provide valuable information for cancer detection, diagnosis, and prognosis. In addition to the anatomical information these images provide, machine learning can identify texture features from these images to further personalize treatment. This study aims to evaluate the use of texture features derived from T1-weighted post contrast scans to classify different types of brain tumors and predict tumor growth rate in a preclinical mouse model. To optimize prediction models this study uses varying gray-level co-occurrence matrix (GLCM) sizes, tumor region selection and different machine learning models. Using a random forest classification model with a GLCM of size 512 resulted in 92%, 91%, and 92% specificity, and 89%, 85%, and 73% sensitivity for GL261 (mouse glioma), U87 (human glioma) and Daoy (human medulloblastoma), respectively. A tenfold cross-validation of the classifier resulted in 84% accuracy when using the entire tumor volume for feature extraction and 74% accuracy for the central tumor region. A two-layer feedforward neural network using the same features is able to predict tumor growth with 16% mean squared error. Broadly applicable, these predictive models can use standard medical images to classify tumor type and predict tumor growth, with model performance, varying as a function of GLCM size, tumor region, and tumor type.
Survival of HIV/HCV co-infected patients before introduction of HCV direct acting antivirals (DAA)
Authors: Dold L. , Schwarze-Zander C. , Boesecke C. , Mohr R. , Langhans B. , Wasmuth J.-C. , Strassburg C. P. , Rockstroh J. K. , Spengler U. 
Published: August 2019

AbstractHIV/HCV infection is supposed to substantially reduce survival as compared to HIV mono-infection. Here, we compared longtime-survival and causes of death in a cohort of HIV- and HIV/HCV-co-infected patients on combined antiretroviral therapy (cART), before introduction of HCV direct acting antivirals (DAA). 322 Caucasian patients with HIV (n = 176) and HIV/HCV-infection (n = 146) were enrolled into this study. All patients were recruited between 2003 and 2004 and followed until 01.01.2014. We compared overall survival between the two groups by the Kaplan-Meyer method and identified independent factors associated with long-time survival by conditional Cox regression analysis. In total 46 (14.3%) patients died during the observation period (HIV infection: n = 23 (13.1%), HIV/HCV infection: n = 23 (15.8%) but overall-survival did not differ significantly between HIV/HCV-infected and HIV mono-infected patients (p = 0.619). Survival was substantially better in patients with complete suppression of HIV replication below the level of detection than in those with residual viremia (p = 0.001). Age (p = 0.008), γ-glutamyltranspeptidase (p < 0.0001) and bilirubin (p = 0.008) were significant predictors of survival irrespective from HCV co-infection. Complete repression of HIV replication on cART is the key factor determining survival both in HIV- and HIV/HCV-co-infected patients, while HCV co-infection and therapy without DAAs seem to affect survival to a lesser extent. Thus, patients with HIV/HCV co-infection require particularly intensive cART.
Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans
Authors: Müller Mattea , Hernández Manuel A. González , Goossens Gijs H. , Reijnders Dorien , Holst Jens J. , Jocken Johan W. E. , van Eijk Hans , Canfora Emanuel E. , Blaak Ellen E. 
Published: August 2019

AbstractMicrobial-derived short-chain fatty acids (SCFA) acetate, propionate and butyrate may provide a link between gut microbiota and whole-body insulin sensitivity (IS). In this cross-sectional study (160 participants, 64% male, BMI: 19.2–41.0 kg/m2, normal or impaired glucose metabolism), associations between SCFA (faecal and fasting circulating) and circulating metabolites, substrate oxidation and IS were investigated. In a subgroup (n = 93), IS was determined using a hyperinsulinemic-euglycemic clamp. Data were analyzed using multiple linear regression analysis adjusted for sex, age and BMI. Fasting circulating acetate, propionate and butyrate concentrations were positively associated with fasting GLP-1 concentrations. Additionally, circulating SCFA were negatively related to whole-body lipolysis (glycerol), triacylglycerols and free fatty acids levels (standardized (std) β adjusted (adj) −0.190, P = 0.023; std β adj −0.202, P = 0.010; std β adj −0.306, P = 0.001, respectively). Circulating acetate and propionate were, respectively, negatively and positively correlated with IS (M-value: std β adj −0.294, P < 0.001; std β adj 0.161, P = 0.033, respectively). We show that circulating rather than faecal SCFA were associated with GLP-1 concentrations, whole-body lipolysis and peripheral IS in humans. Therefore, circulating SCFA are more directly linked to metabolic health, which indicates the need to measure circulating SCFA in human prebiotic/probiotic intervention studies as a biomarker/mediator of effects on host metabolism.
Diamond-inclusion system recording old deep lithosphere conditions at Udachnaya (Siberia)
Authors: Nestola Fabrizio , Zaffiro Gabriele , Mazzucchelli Mattia L. , Nimis Paolo , Andreozzi Giovanni B. , Periotto Benedetta , Princivalle Francesco , Lenaz Davide , Secco Luciano , Pasqualetto Leonardo , Logvinova Alla M. , Sobolev Nikolay V. , Lorenzetti Alessandra , Harris Jeffrey W. 
Published: August 2019

AbstractDiamonds and their inclusions are unique fragments of deep Earth, which provide rare samples from inaccessible portions of our planet. Inclusion-free diamonds cannot provide information on depth of formation, which could be crucial to understand how the carbon cycle operated in the past. Inclusions in diamonds, which remain uncorrupted over geological times, may instead provide direct records of deep Earth’s evolution. Here, we applied elastic geothermobarometry to a diamond-magnesiochromite (mchr) host-inclusion pair from the Udachnaya kimberlite (Siberia, Russia), one of the most important sources of natural diamonds. By combining X-ray diffraction and Fourier-transform infrared spectroscopy data with a new elastic model, we obtained entrapment conditions,Ptrap = 6.5(2) GPa andTtrap = 1125(32)–1140(33) °C, for the mchr inclusion. These conditions fall on a ca. 35 mW/m2geotherm and are colder than the great majority of mantle xenoliths from similar depth in the same kimberlite. Our results indicate that cold cratonic conditions persisted for billions of years to at least 200 km in the local lithosphere. The composition of the mchr also indicates that at this depth the lithosphere was, at least locally, ultra-depleted at the time of diamond formation, as opposed to the melt-metasomatized, enriched composition of most xenoliths.