bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch‐up Development
Authors: Platzer Konrad , Cogné Benjamin , Hague Jennifer , Marcelis Carlo L. , Mitter Diana , Oberndorff Katrin , Park Soo‐Mi , Ploos van Amstel Hans K. , Simonic Ingrid , van der Smagt Jasper J. , Stegmann Alexander P.A. , Stevens Servi J.C. , Stumpel Constance T.R.M. , Vincent Marie , Lemke Johannes R. , Jamra Rami 
Published: July 2018

ObjectiveDevelopmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology.MethodsWe clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER.ResultsAll 9 individuals harbored heterozygous null‐allele variants in CUX1, encoding the Cut‐homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age‐related intelligence at ages 4, 6, and 8 years after a previous history of significant DD.InterpretationOur results suggest that null‐allele variants, and thus haploinsufficiency of CUX1, cause an isolated phenotype of DD or ID with possible catch‐up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200–207
A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain
Authors: Fujii Takayuki , Yamasaki Ryo , Iinuma Kyoko , Tsuchimoto Daisuke , Hayashi Yoshinori , Saitoh Ban‐yu , Matsushita Takuya , Kido Mizuho A. , Aishima Shinichi , Nakanishi Hiroshi , Nakabeppu Yusaku , Kira Jun‐ichi 
Published: July 2018

ObjectiveTo identify novel autoantibodies for neuropathic pain (NeP).MethodsWe screened autoantibodies that selectively bind to mouse unmyelinated C‐fiber type dorsal root ganglion (DRG) neurons using tissue‐based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA‐positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC‐MS/MS) to identify target autoantigens.ResultsAntiunmyelinated C‐fiber type DRG neuron antibodies were more frequent in patients with NeP than non‐NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4‐ and P2X3‐positive pain‐conducting small neurons but not with S100β‐positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC‐MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti–small DRG neuron antibody‐positive patients had anti–plexin D1 antibodies. Application of anti–plexin D1 antibody‐positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti–plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C‐fibers. Main comorbidities were atopy and collagen‐vascular disease. Immunotherapies ameliorated NeP in 7 treated cases.InterpretationAnti–plexin D1 antibodies are a novel biomarker for immunotherapy‐responsive NeP. Ann Neurol 2018;84:208–224
Long‐range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy
Authors: Weiss Robert B. , Vieland Veronica J. , Dunn Diane M. , Kaminoh Yuuki , Flanigan Kevin M. ,   for the United Dystrophinopathy Project
Published: July 2018

ObjectiveDuchenne muscular dystrophy (DMD) is a severe X‐linked recessive disease caused by loss‐of‐function dystrophin (DMD) mutations in boys, who typically suffer loss of ambulation by age 12. Previously, we reported that coding variants in latent transforming growth factor beta (TGFβ)‐binding protein 4 (LTBP4) were associated with reduced TGFβ signaling and prolonged ambulation (p = 1.0 × 10−3) in DMD patients; this result was subsequently replicated by other groups. In this study, we evaluated whether additional DMD modifier genes are observed using whole‐genome association in the original cohort.MethodsWe performed a genome‐wide association study (GWAS) for single‐nucleotide polymorphisms (SNPs) influencing loss of ambulation (LOA) in the same cohort of 253 DMD patients used to detect the candidate association with LTBP4 coding variants. Gene expression and chromatin interaction databases were used to fine‐map association signals above the threshold for genome‐wide significance.ResultsDespite the small sample size, two loci associated with prolonged ambulation met genome‐wide significance and were tagged by rs2725797 (chr15, p = 6.6 × 10−9) and rs710160 (chr19, p = 4.7 × 10−8). Gene expression and chromatin interaction data indicated that the latter SNP tags regulatory variants of LTBP4, whereas the former SNP tags regulatory variants of thrombospondin‐1 (THBS1): an activator of TGFβ signaling by direct binding to LTBP4 and an inhibitor of proangiogenic nitric oxide signaling.InterpretationTogether with previous evidence implicating LTBP4, the THBS1 modifier locus emphasizes the role that common regulatory variants in gene interaction networks can play in mitigating disease progression in muscular dystrophy. Ann Neurol 2018;84:234–245
Sustainable method for Alzheimer dementia prediction in mild cognitive impairment: Electroencephalographic connectivity and graph theory combined with apolipoprotein E
Authors: Vecchio Fabrizio , Miraglia Francesca , Iberite Francesco , Lacidogna Giordano , Guglielmi Valeria , Marra Camillo , Pasqualetti Patrizio , Tiziano Francesco Danilo , Rossini Paolo Maria 
Published: July 2018

ObjectiveMild cognitive impairment (MCI) is a condition intermediate between physiological brain aging and dementia. Amnesic‐MCI (aMCI) subjects progress to dementia (typically to Alzheimer‐Dementia = AD) at an annual rate which is 20 times higher than that of cognitively intact elderly. The present study aims to investigate whether EEG network Small World properties (SW) combined with Apo‐E genotyping, could reliably discriminate aMCI subjects who will convert to AD after approximately a year.Methods145 aMCI subjects were divided into two sub‐groups and, according to the clinical follow‐up, were classified as Converted to AD (C‐MCI, 71) or Stable (S‐MCI, 74).ResultsResults showed significant differences in SW in delta, alpha1, alpha2, beta2, gamma bands, with C‐MCI in the baseline similar to AD. Receiver Operating Characteristic(ROC) curve, based on a first‐order polynomial regression of SW, showed 57% sensitivity, 66% specificity and 61% accuracy(area under the curve: AUC=0.64). In 97 out of 145 MCI, Apo‐E allele testing was also available. Combining this genetic risk factor with Small Word EEG, results showed: 96.7% sensitivity, 86% specificity and 91.7% accuracy(AUC=0.97). Moreover, using only the Small World values in these 97 subjects, the ROC showed an AUC of 0.63; the resulting classifier presented 50% sensitivity, 69% specificity and 59.6% accuracy. When different types of EEG analysis (power density spectrum) were tested, the accuracy levels were lower (68.86%).InterpretationConcluding, this innovative EEG analysis, in combination with a genetic test (both low‐cost and widely available), could evaluate on an individual basis with great precision the risk of MCI progression. This evaluation could then be used to screen large populations and quickly identify aMCI in a prodromal stage of dementia. Ann Neurol 2018 Ann Neurol 2018;84:302–314
Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease
Authors: Kia Demis A. , Noyce Alastair J. , White Jon , Speed Doug , Nicolas Aude ,   IPDGC collaborators, Burgess Stephen , Lawlor Debbie A. , Davey Smith George , Singleton Andrew , Nalls Mike A. , Sofat Reecha , Wood Nicholas W. 
Published: July 2018

ObjectiveObservational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two‐sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk.MethodsWe used a genetic instrument consisting of 31 independent loci for plasma urate on a case‐control genome‐wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse‐variance weighted (IVW) method. Two additional methods, MR‐Egger and a penalized weighted median (PWM)‐based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments.ResultsWe found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88–1.20) per 1‐standard‐deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83–1.17] and 0.99 [95% CI, 0.86−1.14], respectively).InterpretationWe did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191–199
Metal‐Free Synthetic Approach to 3‐Monosubstituted Unsymmetrical 1,2,4,5‐Tetrazines Useful for Bioorthogonal Reactions
Authors: Qu Yangyang , Sauvage François‐Xavier , Clavier Gilles , Miomandre Fabien , Audebert Pierre 
Published: July 2018

AbstractA facile, efficient and metal‐free synthetic approach to 3‐monosubstituted unsymmetrical 1,2,4,5‐tetrazines is presented. Dichloromethane (DCM) is for the first time recognized as a novel reagent in the synthetic chemistry of tetrazines. Using this novel approach 11 3‐aryl/alkyl 1,2,4,5‐tetrazines were prepared in excellent yields (up to 75 %). The mechanism of this new reaction, including the role of DCM in the tetrazine ring formation, has been investigated by 13C labeling of DCM, and is also presented and discussed as well as the photophysical and electrochemical properties.
Highly Selective Mitochondrial Targeting by a Ruthenium(II) Peptide Conjugate: Imaging and Photoinduced Damage of Mitochondrial DNA
Authors: Burke Christopher S. , Byrne Aisling , Keyes Tia E. 
Published: July 2018

AbstractMitochondrial DNA (mtDNA) plays a crucial but incompletely understood role in cellular biochemistry and etiology of numerous disease states. Thus, there is an urgent need for targeted probes that can dynamically respond to changes to mtDNA such as copy number in live cells, but it is difficult to permeate the mitochondrial membrane of the living cell. Now, a ruthenium(II) light‐switching probe targeted by peptide vectorization selectively to mitochondrial nucleoids is presented. Evidence for DNA binding by the probe in live cells is derived from confocal fluorescence microscopy, resonance Raman, and luminescence lifetime imaging. While viable under imaging conditions, specific staining of mitochondrial DNA permitted efficient and selective photoinduced toxicity on a cell‐by‐cell basis under higher excitation intensities. This powerful combination of imaging and photocytotoxicity is an important step towards realizing phototheranostic application of such RuII probes.
A quantitative PCR‐based environmental DNA assay for detecting Atlantic salmon (Salmo salar L.)
Authors: Atkinson Siobhán , Carlsson Jeanette E.L. , Ball Bernard , Egan Damian , Kelly‐Quinn Mary , Whelan Ken , Carlsson Jens 
Published: July 2018

Abstract

The Atlantic salmon (Salmo salar L.) has worldwide ecological, cultural, and economic importance. The species has undergone extensive decline across its native range, yet concerns have been raised about its invasive potential in the Pacific. Knowledge on the distribution of this species is vital for addressing conservation goals.
This study presents an environmental DNA assay to detect S. salar in water samples, using quantitative polymerase chain reaction technology. Species‐specific primers and a minor groove binding probe were designed for the assay, based on the mitochondrial cytochrome oxidase I gene.
The results of this study indicate that environmental DNA is a highly effective tool for detecting S. salar in situ, and could provide an alternative, non‐invasive method for determining the distribution of this species.
Migration and feeding habits of juvenile Chinese sturgeon (Acipenser sinensis Gray 1835) in the Yangtze Estuary: Implications for conservation
Authors: Wang Sikai , Zhang Tao , Yang Gang , Wang Yu , Zhao Feng , Zhuang Ping 
Published: July 2018

Abstract

Spatial and temporal variation in migration and feeding ecology of juvenile Chinese sturgeon (Acipenser sinensis Gray 1835) is reported for waters around Chongming Island, Yangtze Estuary, between April and August 2015.
A migration survey showed that juvenile Chinese sturgeon remained within the Yangtze Estuary for a period of time preceding their onward migration to the sea; upper estuarine reaches were an important transition habitat during April and May, while nearshore coastal areas were foraging habitat during June to August.
Stable isotopic analysis revealed (1) significantly lower isotope values in smaller‐sized Chinese sturgeon (≤100 mm) than larger‐ sized fish (>100 mm), which indicated a dietary shift likely occurs at fork lengths greater than 100 mm; (2) the increase in values of δ13C and δ15N from May to August implied an ontogenetic dietary shift from lower to higher trophic‐level prey items; and (3) slight changes in distributional range among different coastal sites implied that individuals fed on similar food items.
Coastal shallows represent major foraging areas for juvenile Chinese sturgeon in the Yangtze Estuary. In addition to the conventional conservation measures at the nature reserve, we suggest additional conservation actions to better protect juvenile Chinese sturgeon residing in the estuary; namely: (1) expanding the protected area and adding a seasonal component, from April to August, to afford better protection of juvenile Chinese sturgeon in the whole estuary, but particularly just upstream of the estuary mouth and in nearshore waters; and (2) banning all fishing activities and extending protection to the food resources (such as zoobenthos and small‐sized fishes) of juvenile Chinese sturgeon in coastal shallows.
Decision making in the prisoner's dilemma game: The effect of exit on cooperation and social welfare
Authors: Haesevoets Tessa , Bostyn Dries H. , Reinders Folmer Chris , Roets Arne , Van Hiel Alain 
Published: July 2018

AbstractThe prisoner's dilemma game is a mixed‐motive game that offers two players the simultaneous choice between a cooperative and a defective alternative. An often neglected aspect of such a binary‐choice game, however, is that in many real‐life encounters, people can choose not only to cooperate or defect, but they also have a third option: to exit the social dilemma. Although in the literature a consensus has emerged that the addition of an exit opportunity benefits cooperation, there is only scant research into its effect on social welfare. In order to allow a direct comparison of cooperation rates and welfare levels across binary‐choice and trinary‐choice games, in this study, we used a design in which the same participants played similar games with and without an exit option (i.e., a within‐subjects design), and this in a range of structural variations. The findings of our study indicated that the aggregated outcome of both players is generally lower in games with an exit option than in games without an exit option. Moreover, our results showed that the efficiency of the exit option strongly depends on the specific outcome structure of the game (in terms of its endowment size, (a)symmetry, and level of noncorrespondence). In the discussion, it is argued that the implementation of an exit option as a strategy to increase social welfare should be critically assessed.
Superior protein titers in half the fermentation time: Promoter and process engineering for the glucose‐regulated GTH1 promoter of Pichia pastoris
Authors: Prielhofer Roland , Reichinger Michaela , Wagner Nina , Claes Katrien , Kiziak Christoph , Gasser Brigitte , Mattanovich Diethard 
Published: July 2018

AbstractProtein production in Pichia pastoris is often based on the methanol‐inducible P
AOX1 promoter which drives the expression of the target gene. The use of methanol has major drawbacks, so there is a demand for alternative promoters with good induction properties such as the glucose‐regulated P
GTH1 promoter which we reported recently. To further increase its potential, we investigated its regulation in more details by the screening of promoter variants harboring deletions and mutations. Thereby we could identify the main regulatory region and important putative transcription factor binding sites of P
GTH1. Concluding from that, yeast metabolic regulators, monomeric Gal4‐class motifs, carbon source‐responsive elements, and yeast GC‐box proteins likely contribute to the regulation of the promoter. We engineered a P
GTH1 variant with greatly enhanced induction properties compared with that of the wild‐type promoter. Based on that, a model‐based bioprocess design for high volumetric productivity in a limited time was developed for the P
GTH1 variant, to employ a glucose fed‐batch strategy that clearly outperformed a classical methanol fed‐batch of a P
AOX1 strain in terms of titer and process performance.
Molecular Probes for Imaging Fibrosis and Fibrogenesis
Authors: Désogère Pauline , Montesi Sydney B. , Caravan Peter 
Published: July 2018

AbstractFibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common result of chronic tissue injury. Advances in the clinical management of fibrotic diseases have been hampered by the low sensitivity and specificity of noninvasive early diagnostic options, lack of surrogate end points for use in clinical trials, and a paucity of noninvasive tools to assess fibrotic disease activity longitudinally. Hence, the development of new methods to image fibrosis and fibrogenesis is a large unmet clinical need. Herein, an overview of recent and selected molecular probes for imaging of fibrosis and fibrogenesis by magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography is provided.
The Dual‐State Luminescent Mechanism of 2,3,4,5‐Tetraphenyl‐1H‐pyrrole
Authors: Lei Yunxiang , Liu Qianwei , Dong Lichao , Cai Zhengxu , Shi Jianbing , Zhi Junge , Tong Bin , Dong Yuping 
Published: July 2018

Abstract2,3,4,5‐Tetraphenyl‐1H‐pyrrole (TePP) was synthesized by a simple one‐step reaction. The compound showed a balanced emission in both the solution and solid state with the absolute quantum yield of ΦF/THF=65.6 % and ΦF/solid=74.3 %, respectively. Temperature and viscosity variation measurements demonstrated that the phenyl group at the 1‐position (N‐position) of the pyrrole core can act as a rotor in pyrrole‐based molecules, which can consume the excited energy and reduce the molecular emission in solution. TePP without the phenyl group at the 1‐position can effectively enhance the emission in solution. Single‐crystal analysis showed that the phenyl groups at the 2,5‐positions of pyrrole extend the molecular conjugation and lock the conformation. The phenyl groups at the 3,4‐positions with a twisted conformation prevent their molecules from close packing and are helpful for aggregated emission. A delicate balance between the twisting conformation and rigid conjugation takes advantage of both ACQ and AIE luminogens. The strategy can tune the AIE, ACQ, or solution and solid dual‐state emission properties of pyrrole‐based molecules by simply altering the position of phenyl groups, which provides a great opportunity to explore the luminescent mechanism in greater detail and to facilitate practical applications.
The distributed circuit within the piriform cortex makes odor discrimination robust
Authors: Srinivasan Shyam , Stevens Charles F. 
Published: July 2018

AbstractDistributed circuits wherein connections between subcircuit components seem randomly distributed are common to the olfactory circuit, hippocampus, and cerebellum. In such circuits, activation patterns seem random too, showing no detectable spatial preference, and contrast with regions that have topographic connections between subcircuits and topographic activation patterns. Quantitative studies of topographic circuits in the neocortex have yielded common principles of organization. Whether distributed circuits share similar principles of organization is unknown because similar quantitative information is missing and understanding the way they encode information remains a challenge. We addressed these needs by providing a quantitative description of the mouse piriform cortex, a paleocortical distributed circuit that subserves olfaction. The quantitative information provided two insights. First, with a nearly parameter‐free model of the olfactory circuit, we show that the piriform cortex robustly maintains odor information and discrimination ability present in the olfactory bulb. Second, the paleocortex is quantitatively different from the neocortex: it has a lower surface area density, which decreases from the anterior to posterior paleocortex contrasting with the uniform neuronal density of the neocortex. These insights might also apply to other distributed circuits.
MHD Boundary Layers Theory in Sobolev Spaces Without Monotonicity I: Well‐Posedness Theory
Authors: Liu Cheng‐Jie , Xie Feng , Yang Tong 
Published: July 2018

AbstractWe study the well‐posedness theory for the MHD boundary layer. The boundary layer equations are governed by the Prandtl‐type equations that are derived from the incompressible MHD system with non‐slip boundary condition on the velocity and perfectly conducting condition on the magnetic field. Under the assumption that the initial tangential magnetic field is not zero, we establish the local‐i‐time existence, uniqueness of solutions for the nonlinear MHD boundary layer equations. Compared with the well‐posedness theory of the classical Prandtl equations for which the monotonicity condition of the tangential velocity plays a crucial role, this monotonicity condition is not needed for the MHD boundary layer. This justifies the physical understanding that the magnetic field has a stabilizing effect on MHD boundary layer in rigorous mathematics. © 2018 Wiley Periodicals, Inc.