bluuebunny/crossref_metadata_2025_split huggingface dataset:
KCNQ2 mutations in childhood nonlesional epilepsy: Variable phenotypes and a novel mutation in a case series
Authors: Lee Inn‐Chi , Chang Tung‐Ming , Liang Jao‐Shwann , Li Shuan‐Yow 
Published: June 2019

AbstractBackgroundEpilepsy caused by a KCNQ2 gene mutation usually manifests as neonatal seizures during the first week of life. The genotypes and phenotypes of KCNQ2 mutations are noteworthy.MethodsThe KCNQ2 sequencings done were selected from 131 nonconsanguineous pediatric epileptic patients (age range: 2 days to 18 years) with nonlesional epilepsy.ResultsSeven (5%) index patients had verified KCNQ2 mutations: c.387+1 G>T (splicing), c.1741 C>T (p.Arg581*), c.740 C>T p.(Ser247Leu), c.853 C>A p.(Pro285Thr), c.860 C>T p.(Thr287Ile), c.1294 C>T p.(Arg432Cys), and c.1627 G>A p.(Val543Met). We found, after their paternity had been confirmed, that three patients had de novo p.(Ser247Leu), p.(Pro285Thr), and p.(Thr287Ile) mutations and neonatal‐onset epileptic encephalopathy; however, their frequent seizures remitted after they turned 6 months old. Those with the c.387+1G>T (splicing), (p.Arg581*), and p.(Val543Met) mutations presented with benign familial neonatal convulsions. In addition to their relatives, 14 patients had documented KCNQ2 mutations, and 12 (86%) had neonatal seizures. The seizures of all five patients treated with oxcarbazepine remitted.ConclusionKCNQ2‐related epilepsy led to varied outcomes (from benign to severe) in our patients. KCNQ2 mutations accounted for 13% of patients with seizure onset before 2 months old in our study. KCNQ2 mutations can cause different phenotypes in children. p.(Pro 285Thr) is a novel mutation, and the p.(Pro 285Thr), p.(Ser247Leu), and p.(Thr287Ile) variants can cause neonatal‐onset epileptic encephalopathy.
Mitochondria‐Mediated Pathogenesis and Therapeutics for Non‐Alcoholic Fatty Liver Disease
Authors: Li Zheng , Li Yan , Zhang Hui‐Xia , Guo Jian‐Ru , Lam Christopher Wai Kei , Wang Cai‐Yun , Zhang Wei 
Published: June 2019

AbstractNon‐alcoholic fatty liver disease (NAFLD) has become a worldwide epidemic over the last decade. Remarkable progress has been made in understanding the pathogenesis of NAFLD and, subsequently, in developing medications to treat this disease. Although the mechanisms of NAFLD are complex and multifactorial, accumulating and emerging evidence indicates that mitochondria play a critical role in the pathogenesis and progression of NAFLD. Pharmacologic therapies acting on mitochondria may therefore pave the way to novel strategies for the prevention and protection against NAFLD. This review focuses on new insights into the role of hepatic mitochondrial dysfunction in NAFLD, and summarizes recent studies on mitochondria‐centric therapies for NAFLD utilizing new medications or repurposing of currently available drugs. Although some studies presented may feature controversial results or are still in lack of clinical verification, it is undoubted that medications that may spare the mitochondria from multiple levels of damage are highly promising, and have begun to be used with some degree of success.
Two‐dimensional EPID dosimetry for an MR‐linac: Proof of concept
Authors: Torres‐Xirau Iban , Olaciregui‐Ruiz Igor , van der Heide Uulke A. , Mans Anton 
Published: June 2019

PurposeAt our institute, in vivo patient dose distributions are reconstructed for all treatments delivered using conventional linacs from electronic portal imaging device (EPID) transit images acquired during treatment using a simple back‐projection model. Currently, the clinical implementation of MRI‐guided radiotherapy systems, which aims for online and real‐time adaptation of the treatment plan, is progressing. In our department, the MR‐linac (Unity, Elekta AB, Stockholm, Sweden) is now in clinical use. The aim of this work is to demonstrate the feasibility of two‐dimensional (2D) EPID dosimetric verification for the magnetic resonance (MR)‐linac by comparing back‐projected EPID doses to ionization chamber (IC) array dose distributions.Materials and methodsOur conventional back‐projection algorithm was adapted for the MR‐linac. The most important changes involve modeling of the attenuation by and scatter from the cryostat. The commissioning process involved the acquisition of square field EPID measurements using various phantom setups (varying SSD, phantom thickness, and field size). Commissioning models were created for gantry 0°, 90°, and 180° and verified by comparing EPID‐reconstructed 2D dose distributions to measurements made with the OCTAVIUS 1500 IC array (PTW, Freiburg, Germany) for two prostate and one rectum IMRT plans (25 beams total). The average of the γ parameters (y‐mean and y‐pass rate) and the dose difference at a reference point were reported. Due to their construction, the attenuation of couch, bridge, and cryostat shows a much stronger dependence on gantry angle in the MR‐linac compared to conventional linacs. We present a method to correct for these effects. This method is validated by dose reconstruction of the 25 intensity‐modulated radiation therapy beams recorded at a certain gantry angle using the model of another gantry angle, combined with the correction method.ResultsFor dose verification performed at a gantry angle identical to the commissioned model, the average y‐mean and y‐pass rate values (3% global dose, 2 mm, 10% isodose) were 0.37 ± 0.07 and 98.1, 95% CI [98.1 ± 2.4], respectively. The average dose difference at the reference point was −0.5% ± 1.8%. Verification at gantry angles different from the commissioned model (i.e., using the gantry angle dependent correction) reported 0.39 ± 0.08 and 97.6, 95% CI [96.9, 98.3] average y‐mean and y‐pass rate values. The average dose difference at the reference point was −0.1% ± 1.8%.ConclusionThe EPID dosimetry back‐projection model was successfully adapted for the MR‐linac at gantry 0°, 90°, and 180°, accounting for the presence of the MRI housing between phantom (or patient) and the EPID. A method to account for the gantry angle dependence was also tested reporting similar results.
Methods to generate and validate a Pregnancy Register in the UK Clinical Practice Research Datalink primary care database
Authors: Minassian Caroline , Williams Rachael , Meeraus Wilhelmine H. , Smeeth Liam , Campbell Oona M.R. , Thomas Sara L. 
Published: June 2019

AbstractPurposePrimary care databases are increasingly used for researching pregnancy, eg, the effects of maternal drug exposures. However, ascertaining pregnancies, their timing, and outcomes in these data is challenging. While individual studies have adopted different methods, no systematic approach to characterise all pregnancies in a primary care database has yet been published. Therefore, we developed a new algorithm to establish a Pregnancy Register in the UK Clinical Practice Research Datalink (CPRD) GOLD primary care database.MethodsWe compiled over 4000 read and entity codes to identify pregnancy‐related records among women aged 11 to 49 years in CPRD GOLD. Codes were categorised by the stage or outcome of pregnancy to facilitate delineation of pregnancy episodes. We constructed hierarchical rule systems to handle information from multiple sources. We assessed the validity of the Register to identify pregnancy outcomes by comparing our results to linked hospitalisation records and Office for National Statistics population rates.ResultsOur algorithm identified 5.8 million pregnancies among 2.4 million women (January 1987‐February 2018). We observed close agreement with hospitalisation data regarding completeness of pregnancy outcomes (91% sensitivity for deliveries and 77% for pregnancy losses) and their timing (median 0 days difference, interquartile range 0‐2 days). Miscarriage and prematurity rates were consistent with population figures, although termination and, to a lesser extent, live birth rates were underestimated in the Register.ConclusionsThe Pregnancy Register offers huge research potential because of its large size, high completeness, and availability. Further validation work is underway to enhance this data resource and identify optimal approaches for its use.
On the presence of short‐range periodicities in protein structures that are not related to established secondary structure elements
Authors: Riziotis Ioannis G. , Glykos Nicholas M. 
Published: June 2019

AbstractStandard secondary structure elements such as α‐helices or β‐sheets, are characterized by repeating backbone torsion angles (φ,ψ) at the single residue level. Two‐residue motifs of the type (φ,ψ)2 are also observed in nonlinear conformations, mainly turns. Taking these observations a step further, it can be argued that there is no a priori reason why the presence of higher order periodicities can not be envisioned in protein structures, such as, for example, periodic transitions between successive residues of the type (…‐α‐β‐α‐β‐α‐…), or (…‐β‐αL‐β‐αL‐β‐…), or (…‐α‐β‐αL‐α‐β‐αL‐…), and so forth, where the symbols (α,β,αL) refer to the established Ramachandran‐based residue conformations. From all such possible higher order periodicities, here we examine the deposited (with the PDB) protein structures for the presence of short‐range periodical conformations comprising five consecutive residues alternating between two (and only two) distinct Ramachandran regions, for example, conformations of the type (α‐β‐α‐β‐α) or (β‐αL‐β‐αL‐β), and so forth. Using a probabilistic approach, we have located several thousands of such peptapeptides, and these were clustered and analyzed in terms of their structural characteristics, their sequences, and their putative functional correlations using a gene ontology‐based approach. We show that such nonstandard short‐range periodicities are present in a large and functionally diverse sample of proteins, and can be grouped into two structurally conserved major types. Examination of the structural context in which these peptapeptides are observed gave no conclusive evidence for the presence of a persistent structural or functional role of these higher order periodic conformations.
Driven to near‐experimental accuracy by refinement via molecular dynamics simulations
Authors: Heo Lim , Arbour Collin F. , Feig Michael 
Published: June 2019

AbstractProtein model refinement has been an essential part of successful protein structure prediction. Molecular dynamics simulation‐based refinement methods have shown consistent improvement of protein models. There had been progress in the extent of refinement for a few years since the idea of ensemble averaging of sampled conformations emerged. There was little progress in CASP12 because conformational sampling was not sufficiently diverse due to harmonic restraints. During CASP13, a new refinement method was tested that achieved significant improvements over CASP12. The new method intended to address previous bottlenecks in the refinement problem by introducing new features. Flat‐bottom harmonic restraints replaced harmonic restraints, sampling was performed iteratively, and a new scoring function and selection criteria were used. The new protocol expanded conformational sampling at reduced computational costs. In addition to overall improvements, some models were refined significantly to near‐experimental accuracy.
Fast quantum crystallography
Authors: Polkosnik Walter , Matta Chérif F. , Huang Lulu , Massa Lou 
Published: June 2019

AbstractTypical contemporary X‐ray crystallography delivers the geometries and, at best, the electron densities of molecules or periodic systems in the crystalline phase. Energies, electron momentum densities, and information relating to the pair density such as electron delocalization measures—all crucial to chemistry—are simply missed. Quantum crystallography (QCr) is an emerging line of research aimed at filling this gap by solving the crystallographic problem under the constraints of quantum mechanics. In this way, not only geometries and electron densities become experimentally accessible but also the entire panoply of quantum mechanical properties that are in the output of any quantum chemical software package. However, QCr remains limited to smaller systems (small molecules or small unit cells) due to the exponential bottleneck that plagues quantum mechanical calculations. When combined with a fragmentation technique, termed the “kernel energy method (KEM)”, QCr's reach to larger molecules is extended considerably to almost “any size”, that is, systems of up to many hundreds of thousands of atoms. KEM has made this doable with any chemical model and is capable of providing the entire quantum mechanics of large molecular systems. The smallness of theR‐factor adjudicates the accuracy of the quantum mechanics extracted from the crystallography.
Nonadiabatic coupling and diabatic electronic population dynamics on 11A2 and 11B1 states of ozone molecule
Authors: Mirzaie‐Khalilabadi Elahe , Dehestani Maryam 
Published: June 2019

AbstractIn this work, we examine nonadiabatic population dynamics for 11B1 and 11A2 states of ozone molecule (O3). In O3, two lowest singlet excited states, 1A2 and 1B1, can be coupled. Thus, population transfer between them occurs through the seam involving these two states. At any point of the seam (conical intersection), the Born‐Oppenheimer approximation breaks down, and it is necessary to investigate nonadiabatic dynamics. We consider a linear vibronic coupling Hamiltonian model and evaluate vibronic coupling constant, diabatic frequencies for three modes of O3, bilinear and quadratic coupling constants for diabatic potentials, displacements, and Huang‐Rhys coupling constants using ab initio calculations. The electronic structure calculations have been performed at the multireference configuration interaction and complete active space with second‐order perturbation theory with a full‐valence complete active space self‐consistent field methods and augmented Dunning's standard correlation‐consistent‐polarized quadruple zeta basis set to determine ab initio potential energy surfaces for the ground state and first two excited states of O3, respectively. We have chosen active space comprising 18 electrons distributed over 12 active orbitals. Our calculations predict the linear vibronic coupling constant 0.123 eV. We have obtained the population on the 11B1 and 11A2 excited electronic states for the first 500 fs after photoexcitation.
A counterexample to the DeMarco‐Kahn upper tail conjecture
Authors: Šileikis Matas , Warnke Lutz 
Published: June 2019

Given a fixed graph H, what is the (exponentially small) probability that the number XH of copies of H in the binomial random graph Gn,p is at least twice its mean? Studied intensively since the mid 1990s, this so‐called infamous upper tail problem remains a challenging testbed for concentration inequalities. In 2011 DeMarco and Kahn formulated an intriguing conjecture about the exponential rate of decay of for fixed ε > 0. We show that this upper tail conjecture is false, by exhibiting an infinite family of graphs violating the conjectured bound.
PM2.5 upregulates rat mesenteric arteries 5‐HT2A receptor via inflammatory‐mediated mitogen‐activated protein kinases signaling pathway
Authors: Wang Rong , Cao Lei , Shen Zhen‐Xing , Cao Yong‐Xiao , Yu Jun 
Published: June 2019

AbstractFine particulate matter (PM2.5) is an important environmental risk factor for cardiovascular diseases. However, little is known about the effects of PM2.5 on arteries. The present study investigated whether PM2.5 alters 5‐hydroxytryptamine (5‐HT) receptor expression and inflammatory mediators on rat mesenteric arteries, and examined the underlying mechanisms. Isolated rat mesenteric arteries segments were cultured with PM2.5 in the presence or absence of ERK1/2, JNK, and p38 pathway inhibitors. Contractile reactivity was monitored by a sensitive myograph. The expression of 5‐HT2A/1B receptors and inflammatory mediators were studied by a real‐time polymerase chain reaction and/or by immunohistochemistry. The phosphorylation of mitogen‐activated protein kinases (MAPK) pathway was detected by Western blot. Compared with the fresh or culture alone groups, 1.0 μg/mL PM2.5 cultured for 16 hours significantly enhanced contractile response induced by 5‐HT and increased 5‐HT2A receptor mRNA and protein expressions, indicating PM2.5 upregulates 5‐HT2A receptor. SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly decreased PM2.5‐induced elevated contraction and mRNA and protein expression of 5‐HT2A receptor. Cultured with PM2.5 significantly increased the mRNA expression of inflammatory mediators (NOS2, IL‐1β, and TNF‐α), while SB203580 decreased mRNA expression level of NOS2, IL‐1β, and TNF‐α. SP600125 (JNK inhibitor) decreased mRNA expression level of TNF‐α and IL‐1β. After PM2.5 exposure, the phosphorylation of p38 and ERK1/2 protein were increased. SB203580 and U0126 inhibited the PM2.5 caused increased phosphorylation protein of p38 and ERK1/2. In conclusion, PM2.5 induces inflammatory‐mediated MAPK pathway in artery which subsequently results in enhanced vascular contraction responding to 5‐HT via the upregulated 5‐HT2A receptors.
Cover Image, Volume 10, Issue 4
Authors: Peck Sarah A. , Hughes Katlyn D. , Victorino Jose F. , Mosley Amber L. 
Published: June 2019

The cover image is based on the Advanced Review Writing a Wrong: Coupled RNA Polymerase II Transcription and RNA Quality Control by Amber Mosley, Jose Victorino, Sarah Peck, and Katlyn Burriss. https://doi.org/10.1002/wrna.1529
image
From bean collection to seed bank: transformations in heirloom vegetable conservation, 1970–1985
Authors: CURRY HELEN ANNE 
Published: June 2019

AbstractIn 1975, the Missouri homesteaders Kent and Diane Ott Whealy launched True Seed Exchange (later Seed Savers Exchange), a network of ‘serious gardeners’ interested in growing and conserving heirloom and other hard-to-find plant varieties, especially vegetables. In its earliest years, the organization pursued its conservation mission through member-led exchange and cultivation, seeing members’ gardens and seed collections as the best means of ensuring that heirloom varieties remained both extant and available to growers. Beginning in 1981, however, Kent Whealy began to develop a central seed repository. As I discuss in this paper, the development of this central collection was motivated in part by concerns about the precariousness of very large individual collections, the maintenance of which was too demanding to entrust to most growers. Although state-run institutions were better positioned to take on large collections, they were nonetheless unsuitable stewards because they placed limits on access. For seed savers, loss of access to varieties via their accession into a state collection could be as much an ending for treasured collections as total physical loss, as it did not necessarily enable continued cultivation. As I show here, these imagined endings inspired the adoption of a new set of conservation practices that replicated those seen in the formal genetic conservation sector, including seed banking, cold storage and safety duplication.
Attributable mortality due to fluoroquinolone and extended-spectrum cephalosporin resistance in hospital-onset Escherichia coli and Klebsiella spp bacteremia: A matched cohort study in 129 Veterans Health Administration medical centers
Authors: Suzuki Hiroyuki , Perencevich Eli N. , Livorsi Daniel J. , Alexander Bruce , Beck Brice F. , Richardson Kelly K. , Goto Michihiko 
Published: June 2019

AbstractIn this cohort of Escherichia coli and Klebsiella spp hospital-onset bacteremia, isolated fluoroquinolone resistance had a larger relative impact on mortality than other phenotypic resistance patterns. This finding may support stewardship efforts targeting unnecessary fluoroquinolone use and increased attention from infection prevention and control departments.
Multi-Substrate Radiocarbon Data Constrain Detrital and Reservoir Effects in Holocene Sediments of the Great Salt Lake, Utah
Authors: Bowen Gabriel J , Nielson Kristine E , Eglinton Timothy I 
Published: June 2019

ABSTRACTThe radiocarbon (14C) content of simultaneously deposited substrates in lacustrine archives may differ due to reservoir and detrital effects, complicating the development of age models and interpretation of proxy records. Multi-substrate14C studies quantifying these effects remain rare, however, particularly for large, terminal lake systems, which are excellent recorders of regional hydroclimate change. We report14C ages of carbonates, brine shrimp cysts, algal mat biomass, total organic carbon (TOC), terrestrial macrofossils, andn-alkane biomarkers from Holocene sediments of the Great Salt Lake (GSL), Utah.14C ages for co-deposited aquatic organic substrates are generally consistent, with small offsets that may reflect variable terrestrial organic matter inputs to the system. Carbonates and long-chainn-alkanes derived from vascular plants, however, are ∼1000–400014C years older than other substrates, reflecting deposition of pre-aged detrital materials. All lacustrine substrates are14C-depleted compared to terrestrial macrofossils, suggesting that the reservoir age of the GSL was > 1200 years throughout most of the Holocene, far greater than the modern reservoir age of the lake (∼300 years). These results suggest good potential for multi-substrate paleoenvironmental reconstruction from Holocene GSL sediments but point to limitations including reservoir-induced uncertainty in14C chronologies and attenuation and time-shifting of some proxy signals due to detrital effects.
Oligosaccharides in goats’ milk-based infant formula and their prebiotic and anti-infection properties
Authors: Leong Andrea , Liu Zhiqian , Almshawit Hala , Zisu Bogdan , Pillidge Christopher , Rochfort Simone , Gill Harsharn 
Published: June 2019

AbstractHuman milk contains an abundant supply and diverse array of oligosaccharides that are known to impart significant health benefits to the nursing infant including establishment and maintenance of a healthy gut microflora, immune development and protection against gastrointestinal infections. When breastfeeding is not possible or insufficient, infant formulas are commonly used as an alternative. However, limited information is available about the presence of naturally occurring oligosaccharides in these infant formulas and their likely health benefits. The present study examined the presence of naturally occurring oligosaccharides in commercial goats’ milk-based stage 1 and stage 2 infant formulas and their prebiotic and anti-infection properties. LC/MS was used to detect and quantify oligosaccharides and their prebiotic potential was assessed by their ability, at concentrations present in reconstituted ready-to-use infant formula, to promote the growth of Bifidobacterium animalis subsp. lactis BB12, B. longum BB536, Lactobacillus acidophilus 4461 and L. casei 2607 in vitro. For anti-infection properties, the ability of goat milk oligosaccharides to prevent the adhesion of Escherichia coli NCTC 10418 and a Salmonella typhimurium isolate to Caco-2 cells was investigated. The results showed the presence of fourteen quantifiable oligosaccharides in stage 1 and stage 2 goats’ milk-based infant formula. This was similar to the number of oligosaccharides detected in the fresh goats’ milk. Of these, five were structurally similar to those found in human milk. These oligosaccharides were shown to significantly enhance the growth of bifidobacteria and lactobacilli and reduce the adhesion of E. coli NCTC 10418 and S. typhimurium to Caco-2 cells. Together, these results suggest that oligosaccharides naturally present in goats’ milk-based infant formula exhibit strong prebiotic and anti-pathogen adhesion properties and may confer gut health benefits to infants.