bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolving Environmental and Geometric Controls on Columbia Glacier's Continued Retreat
Authors: Enderlin Ellyn M. , O'Neel Shad , Bartholomaus Timothy C. , Joughin Ian 
Published: June 2018

AbstractGeometry strongly controls the dynamic behavior of marine‐terminating (tidewater) glaciers, significantly influencing advance and retreat cycles independent of climate. Yet the recent, nearly ubiquitous retreat of tidewater glaciers suggests that changes in atmospheric and oceanic forcing may also drive dynamic change. To isolate the influence of geometry on tidewater glacier dynamics, we analyzed detailed observational time series from 2012 to 2016 for two tidewater glaciers with shared dynamic histories and environmental forcing: Columbia Glacier and its former tributary (Post Glacier) in southcentral Alaska. We find that although terminus retreat has driven decadal‐scale changes in dynamics of the Columbia‐Post system, environmental factors contribute to short‐term (i.e., seasonal) dynamic variability. In particular, analysis of force balance time series indicates that observed variations in speed result from seasonal changes to the subglacial hydrologic system and associated changes in basal drag. Variations in terminus position only drive noticeable speed change when the terminus retreats from regions of relatively high basal drag. In agreement with long‐term analyses of Columbia Glacier, we find that terminus geometry can perturb the timing of seasonal ice flow patterns. Specifically, our data support the idea that retreat of a glacier terminus into deeper water is accompanied by a shift in the primary control on frontal ablation. Although our analysis focuses on two Alaskan glaciers, our data suggest that changes in the relative importance of surface meltwater and buoyancy effects on submarine melting and/or calving may manifest as a shift in terminus change seasonality and offer a mechanism to identify frontal ablation controls.
Dependence of Present and Future European Temperature Extremes on the Location of Atmospheric Blocking
Authors: Brunner Lukas , Schaller Nathalie , Anstey James , Sillmann Jana , Steiner Andrea K. 
Published: June 2018

AbstractThe impact of atmospheric blocking on European heat waves (HWs) and cold spells (CSs) is investigated for present and future conditions . A 50‐member ensemble of the second generation Canadian Earth System Model is used to quantify the role of internal variability in the response to blocking. We find that the present blocking‐extreme temperature link is well represented compared to ERA‐Interim, despite a significant underestimation of blocking frequency in most ensemble members. Our results show a strong correlation of blocking with northern European HWs in summer, spring, and fall. However, we also find a strong anticorrelation between blocking and HW occurrence in southern Europe in all seasons. Blocking increases the CS frequency particularly in southern Europe in fall, winter, and spring but reduces it in summer. For the future we find that blocking will continue to play an important role in the development of both CSs and HWs in all seasons.
Genetics of attention deficit hyperactivity disorder
Authors: Faraone Stephen V. , Larsson Henrik 
Published: June 2018

AbstractDecades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD’s high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD’s heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD’s heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
Update in myopia and treatment strategy of atropine use in myopia control
Authors: Wu Pei-Chang , Chuang Meng-Ni , Choi Jessy , Chen Huan , Wu Grace , Ohno-Matsui Kyoko , Jonas Jost B , Cheung Chui Ming Gemmy 
Published: June 2018

AbstractThe prevalence of myopia is increasing globally. Complications of myopia are associated with huge economic and social costs. It is believed that high myopia in adulthood can be traced back to school age onset myopia. Therefore, it is crucial and urgent to implement effective measures of myopia control, which may include preventing myopia onset as well as retarding myopia progression in school age children. The mechanism of myopia is still poorly understood. There are some evidences to suggest excessive expansion of Bruch’s membrane, possibly in response to peripheral hyperopic defocus, and it may be one of the mechanisms leading to the uncontrolled axial elongation of the globe. Atropine is currently the most effective therapy for myopia control. Recent clinical trials demonstrated low-dose atropine eye drops such as 0.01% resulted in retardation of myopia progression, with significantly less side effects compared to higher concentration preparation. However, there remain a proportion of patients who are poor responders, in whom the optimal management remains unclear. Proposed strategies include stepwise increase of atropine dosing, and a combination of low-dose atropine with increase outdoor time. This review will focus on the current understanding of epidemiology, pathophysiology in myopia and highlight recent clinical trials using atropine in the school-aged children, as well as the treatment strategy in clinical implementation in hyperopic, pre-myopic and myopic children.
Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy
Authors: Ni Kaiyuan , Lan Guangxu , Chan Christina , Quigley Bryan , Lu Kuangda , Aung Theint , Guo Nining , La Riviere Patrick , Weichselbaum Ralph R. , Lin Wenbin 
Published: June 2018

AbstractCheckpoint blockade immunotherapy enhances systemic antitumor immune response by targeting T cell inhibitory pathways; however, inadequate T cell infiltration has limited its anticancer efficacy. Radiotherapy (RT) has local immunomodulatory effects that can alter the microenvironment of irradiated tumors to synergize with immune checkpoint blockade. However, even with high doses of radiation, RT has rarely elicited systemic immune responses. Herein, we report the design of two porous Hf-based nanoscale metal-organic frameworks (nMOFs) as highly effective radioenhancers that significantly outperform HfO2, a clinically investigated radioenhancer in vitro and in vivo. Importantly, the combination of nMOF-mediated low-dose RT with an anti-programmed death-ligand 1 antibody effectively extends the local therapeutic effects of RT to distant tumors via abscopal effects. Our work establishes the feasibility of combining nMOF-mediated RT with immune checkpoint blockade to elicit systemic antitumor immunity in non-T cell-inflamed tumor phenotypes without normal tissue toxicity, promising to broaden the application of checkpoint blockade immunotherapy.
When optimization for governing human-environment tipping elements is neither sustainable nor safe
Authors: Barfuss Wolfram , Donges Jonathan F. , Lade Steven J. , Kurths Jürgen 
Published: June 2018

AbstractOptimizing economic welfare in environmental governance has been criticized for delivering short-term gains at the expense of long-term environmental degradation. Different from economic optimization, the concepts of sustainability and the more recent safe operating space have been used to derive policies in environmental governance. However, a formal comparison between these three policy paradigms is still missing, leaving policy makers uncertain which paradigm to apply. Here, we develop a better understanding of their interrelationships, using a stylized model of human-environment tipping elements. We find that no paradigm guarantees fulfilling requirements imposed by another paradigm and derive simple heuristics for the conditions under which these trade-offs occur. We show that the absence of such a master paradigm is of special relevance for governing real-world tipping systems such as climate, fisheries, and farming, which may reside in a parameter regime where economic optimization is neither sustainable nor safe.
Efficient RNA drug delivery using red blood cell extracellular vesicles
Authors: Usman Waqas Muhammad , Pham Tin Chanh , Kwok Yuk Yan , Vu Luyen Tien , Ma Victor , Peng Boya , Chan Yuen San , Wei Likun , Chin Siew Mei , Azad Ajijur , He Alex Bai-Liang , Leung Anskar Y. H. , Yang Mengsu , Shyh-Chang Ng , Cho William C. , Shi Jiahai , Le Minh T. N. 
Published: June 2018

AbstractMost of the current methods for programmable RNA drug therapies are unsuitable for the clinic due to low uptake efficiency and high cytotoxicity. Extracellular vesicles (EVs) could solve these problems because they represent a natural mode of intercellular communication. However, current cellular sources for EV production are limited in availability and safety in terms of horizontal gene transfer. One potentially ideal source could be human red blood cells (RBCs). Group O-RBCs can be used as universal donors for large-scale EV production since they are readily available in blood banks and they are devoid of DNA. Here, we describe and validate a new strategy to generate large-scale amounts of RBC-derived EVs for the delivery of RNA drugs, including antisense oligonucleotides, Cas9 mRNA, and guide RNAs. RNA drug delivery with RBCEVs shows highly robust microRNA inhibition and CRISPR–Cas9 genome editing in both human cells and xenograft mouse models, with no observable cytotoxicity.
Serum Proteomic Profiling to Identify Biomarkers of Premature Carotid Atherosclerosis
Authors: Bhosale Santosh D. , Moulder Robert , Venäläinen Mikko S. , Koskinen Juhani S. , Pitkänen Niina , Juonala Markus T. , Kähönen Mika A. P. , Lehtimäki Terho J. , Viikari Jorma S. A. , Elo Laura L. , Goodlett David R. , Lahesmaa Riitta , Raitakari Olli T. 
Published: June 2018

AbstractTo evaluate the presence of serum protein biomarkers associated with the early phases of formation of carotid atherosclerotic plaques, label-free quantitative proteomics analyses were made for serum samples collected as part of The Cardiovascular Risk in Young Finns Study. Samples from subjects who had an asymptomatic carotid artery plaque detected by ultrasound examination (N = 43, Age = 30–45 years) were compared with plaque free controls (N = 43) (matched for age, sex, body weight and systolic blood pressure). Seven proteins (p < 0.05) that have been previously linked with atherosclerotic phenotypes were differentially abundant. Fibulin 1 proteoform C (FBLN1C), Beta-ala-his-dipeptidase (CNDP1), Cadherin-13 (CDH13), Gelsolin (GSN) and 72 kDa type IV collagenase (MMP2) were less abundant in cases, whereas Apolipoproteins C-III (APOC3) and apolipoprotein E (APOE) were more abundant. Using machine learning analysis, a biomarker panel of FBLN1C, APOE and CDH13 was identified, which classified cases from controls with an area under receiver-operating characteristic curve (AUROC) value of 0.79. Furthermore, using selected reaction monitoring mass spectrometry (SRM-MS) the decreased abundance of FBLN1C was verified. In relation to previous associations of FBLN1C with atherosclerotic lesions, the observation could reflect its involvement in the initiation of the plaque formation, or represent a particular risk phenotype.
The germline mutational landscape of BRCA1 and BRCA2 in Brazil
Authors: Palmero Edenir Inêz , Carraro Dirce Maria , Alemar Barbara , Moreira Miguel Angelo Martins , Ribeiro-dos-Santos Ândrea , Abe-Sandes Kiyoko , Galvão Henrique Campos Reis , Reis Rui Manuel , de Pádua Souza Cristiano , Campacci Natalia , Achatz Maria Isabel , Brianese Rafael Canfield , da Cruz Formiga Maria Nirvana , Makdissi Fabiana Baroni , Vargas Fernando Regla , Evangelista dos Santos Anna Cláudia , Seuanez Hector N. , Lobo de Souza Kelly Rose , Netto Cristina B. O. , Santos-Silva Patrícia , da Silva Gustavo Stumpf , Burbano Rommel M. R. , Santos Sidney , Assumpção Paulo Pimentel , Bernardes Izabel Maria Monteiro , Machado-Lopes Taisa Manuela Bonfim , Bomfim Thais Ferreira , Toralles Maria Betânia Pereira , Nascimento Ivana , Garicochea Bernardo , Simon Sergio D. , Noronha Simone , de Lima Fernanda Teresa , Chami Anisse Marques , Bittar Camila Matzenbacher , Bines Jose , Artigalas Osvaldo , Esteves-Diz Maria Del Pilar , Lajus Tirzah Braz Petta , Gifoni Ana Carolina Leite Vieira Costa , Guindalini Rodrigo S. C. , Cintra Terezinha Sarquis , Schwartz Ida V. D. , Bernardi Pricila , Miguel Diego , Nogueira Sonia Tereza dos Santos , Herzog Josef , Weitzel Jeffrey N. , Ashton-Prolla Patricia 
Published: June 2018

AbstractThe detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.
Predictive Modeling of the Progression of Alzheimer’s Disease with Recurrent Neural Networks
Authors: Wang Tingyan , Qiu Robin G. , Yu Ming 
Published: June 2018

AbstractThe number of service visits of Alzheimer’s disease (AD) patients is different from each other and their visit time intervals are non-uniform. Although the literature has revealed many approaches in disease progression modeling, they fail to leverage these time-relevant part of patients’ medical records in predicting disease’s future status. This paper investigates how to predict the AD progression for a patient’s next medical visit through leveraging heterogeneous medical data. Data provided by the National Alzheimer’s Coordinating Center includes 5432 patients with probable AD from August 31, 2005 to May 25, 2017. Long short-term memory recurrent neural networks (RNN) are adopted. The approach relies on an enhanced “many-to-one” RNN architecture to support the shift of time steps. Hence, the approach can deal with patients’ various numbers of visits and uneven time intervals. The results show that the proposed approach can be utilized to predict patients’ AD progressions on their next visits with over 99% accuracy, significantly outperforming classic baseline methods. This study confirms that RNN can effectively solve the AD progression prediction problem by fully leveraging the inherent temporal and medical patterns derived from patients’ historical visits. More promisingly, the approach can be customarily applied to other chronic disease progression problems.
Deletion of DDB1- and CUL4- associated factor-17 (Dcaf17) gene causes spermatogenesis defects and male infertility in mice
Authors: Ali Asmaa , Mistry Bhavesh V. , Ahmed Hala A. , Abdulla Razan , Amer Hassan A. , Prince Abdelbary , Alazami Anas M. , Alkuraya Fowzan S. , Assiri Abdullah 
Published: June 2018

AbstractDDB1– and CUL4–associated factor 17 (Dcaf17) is a member of DCAF family genes that encode substrate receptor proteins for Cullin-RING E3 ubiquitin ligases, which play critical roles in many cellular processes. To unravel the function of DCAF17, we performed expression profiling of Dcaf17 in different tissues of wild type mouse by qRT-PCR and generated Dcaf17 knockout mice by gene targeting. Expression profiling of Dcaf17 showed highest expression in testis. Analyses of Dcaf17 transcripts during post-natal development of testis at different ages displayed gradual increase in Dcaf17 mRNA levels with the age. Although Dcaf17 disruption did not have any effect on female fertility, Dcaf17 deletion led to male infertility due to abnormal sperm development. The Dcaf17−/− mice produced low number of sperm with abnormal shape and significantly low motility. Histological examination of the Dcaf17−/− testis revealed impaired spermatogenesis with presence of vacuoles and sloughed cells in the seminiferous tubules. Disruption of Dcaf17 caused asymmetric acrosome capping, impaired nuclear compaction and abnormal round spermatid to elongated spermatid transition. For the first time, these data indicate that DCAF17 is essential for spermiogenesis.
Duplication of a germline promoter downstream of the IgH 3′ regulatory region impairs class switch recombination
Authors: Santos Joana M. , Braikia Fatima-Zohra , Oudinet Chloé , Haddad Dania , Conte Caroline , Dauba Audrey , Khamlichi Ahmed Amine 
Published: June 2018

AbstractDuring an adaptive immune response, B cells can change their surface immunoglobulins from IgM to IgG, IgE or IgA through a process called class switch recombination (CSR). Switching is preceded by inducible non-coding germline transcription (GLT) of the selected constant gene(s), which is largely controlled by a super-enhancer called the 3′ regulatory region (3′RR). Despite intense efforts, the precise mechanisms that regulate GLT are still elusive. In order to gain additional insights into these mechanisms, we analyzed GLT and CSR in mutant B cells carrying a duplication of the promoter of the α constant gene (Iα) downstream of 3′RR. Duplication of the Iα promoter affected differently GLT and CSR. While for most isotypes a drop in GLT was accompanied by a decrease in CSR, that was not the case for switching to IgA, which diminished despite unchanged GLT. Unexpectedly, there was no obvious effect on GLT and CSR to IgG3. Remarkably, specific stimuli that normally induce switching to IgG2b had contrasting effects in mutant B cells; Iγ2b was now preferentially responsive to the stimulus that induced Iα promoter. We propose that one mechanism underlying the induced 3′RR-mediated activation of GL promoters involves, at least in part, specific transcription factories.
Place Cell-Like Activity in the Primary Sensorimotor and Premotor Cortex During Monkey Whole-Body Navigation
Authors: Yin A. , Tseng P. H. , Rajangam S. , Lebedev M. A. , Nicolelis M. A. L. 
Published: June 2018

AbstractPrimary motor (M1), primary somatosensory (S1) and dorsal premotor (PMd) cortical areas of rhesus monkeys previously have been associated only with sensorimotor control of limb movements. Here we show that a significant number of neurons in these areas also represent body position and orientation in space. Two rhesus monkeys (K and M) used a wheelchair controlled by a brain-machine interface (BMI) to navigate in a room. During this whole-body navigation, the discharge rates of M1, S1, and PMd neurons correlated with the two-dimensional (2D) room position and the direction of the wheelchair and the monkey head. This place cell-like activity was observed in both monkeys, with 44.6% and 33.3% of neurons encoding room position in monkeys K and M, respectively, and the overlapping populations of 41.0% and 16.0% neurons encoding head direction. These observations suggest that primary sensorimotor and premotor cortical areas in primates are likely involved in allocentrically representing body position in space during whole-body navigation, which is an unexpected finding given the classical hierarchical model of cortical processing that attributes functional specialization for spatial processing to the hippocampal formation.
Foveal Crowding Resolved
Authors: Coates Daniel R. , Levi Dennis M. , Touch Phanith , Sabesan Ramkumar 
Published: June 2018

AbstractCrowding is the substantial interference of neighboring items on target identification. Crowding with letter stimuli has been studied primarily in the visual periphery, with conflicting results for foveal stimuli. While a cortical locus for peripheral crowding is well established (with a large spatial extent up to half of the target eccentricity), disentangling the contributing factors in the fovea is more challenging due to optical limitations. Here, we used adaptive optics (AO) to overcome ocular aberrations and employed high-resolution stimuli to precisely characterize foveal lateral interactions with high-contrast letters flanked by letters. Crowding was present, with a maximal edge-to-edge interference zone of 0.75-1.3 minutes at typical unflanked performance levels. In agreement with earlier foveal contour interaction studies, performance was non-monotonic, revealing a recovery effect with proximal flankers. Modeling revealed that the deleterious effects of flankers can be described by a single function across stimulus sizes when the degradation is expressed as a reduction in sensitivity (expressed in Z-score units). The recovery, however, did not follow this pattern, likely reflecting a separate mechanism. Additional analysis reconciles multiple results from the literature, including the observed scale invariance of center-to-center spacing, as well as the size independence of edge-to-edge spacing.
Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets
Authors: Nagy Ádám , Lánczky András , Menyhárt Otília , Győrffy Balázs 
Published: June 2018

AbstractMultiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and hsa-miR-3677 in the RNA-seq and hsa-miR-146b-3p, hsa-miR-584, and hsa-miR-31 in the microarray dataset. Of the 223 miRNAs studied, the expression was significantly altered in 102 miRNAs in tumors compared to normal liver tissues. In summary, we set up an integrated miRNA expression database and validated prognostic miRNAs in HCC.