bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of Refractive Error, Presbyopia, and Spectacle Coverage in Bogotá, Colombia: A Rapid Assessment of Refractive Error
Authors: Casas Luque Luisa , Naidoo Kovin , Chan Ving Fai , Silva Juan Carlos , Naduvilath Thomas John , Peña Fernando , Mayorga Myriam , Ramírez Leonardo 
Published: July 2019

SIGNIFICANCE
Uncorrected refractive error is the leading cause of visual impairment; therefore, reducing its prevalence is important worldwide. For two decades, there has not been a comprehensive assessment of refractive error in Latin America.

PURPOSE
The purpose of this study was to determine the current prevalence of refractive error, presbyopia, spectacle coverage, barriers to uptake refractive services, and spectacle correction in people 15 years and older in Bogotá, Colombia.

METHODS
A cross-sectional community-based survey was conducted using 50 randomly selected clusters from 10 districts of Bogotá reflecting the socioeconomic status of the city. Respondents 15 years and older were interviewed and underwent standardized clinical eye examinations. Prevalence of uncorrected refractive error, spectacle coverage, and visual impairment were standardized to 2015 age-sex population distribution of Bogotá and further analyzed.

RESULTS
A total of 2886 subjects (90% of 3206 eligible subjects) participated in the study; 39.1% were male and 60.9% were female in the age range of 15 to 96 years, with a median age of 46 years (interquartile range, 45 to 54 years). Age- and sex-standardized prevalence of visual impairment was 19.3% (95% confidence interval [CI], 17.8 to 20.8%). Prevalence of uncorrected refractive error was 12.5% (95% CI, 11.3 to 13.7%). Prevalence of presbyopia among participants 35 years and older was 55.2% (95% CI, 52.9 to 57.4%). Spectacle coverage was 50.9% for distance vision, and it was 33.9% for presbyopia. Main barrier to spectacle uptake was a limitation in affording spectacles because of economic factors (29.5%).

CONCLUSIONS
This study provides a current estimate of refractive error using the Rapid Assessment of Refractive Error for Colombia and the Latin American region. The prevalence of uncorrected refractive error and presbyopia was high, and the barriers to spectacle uptake were higher in the lowest socioeconomic strata. The results obtained in the present study will help in making evidence-based decisions related to eye care service delivery in Colombia.
Ultrasound-Guided Posterior Tibial Nerve Block for Plantar Foot Foreign Body Removal
Authors: Moake Matthew M. , Presley Bradley C. , Barnes Ryan M. 
Published: July 2019

AbstractUltrasound-guided regional anesthesia is a growing modality within the pediatric emergency department. Here we present a case where a posterior tibial nerve block was used for anesthesia during foreign body removal from the plantar foot. We further review the technique and literature regarding this straightforward and highly effective procedure.
Can We Predict Incisional Hernia?
Authors: Basta Marten N. , Kozak Geoffrey M. , Broach Robyn B. , Messa Charles A. , Rhemtulla Irfan , DeMatteo Ron P. , Serletti Joseph M. , Fischer John P. 
Published: July 2019

Objective:
The aim of this study was to identify procedure-specific risk factors independently associated with incisional hernia (IH) and demonstrate the feasibility of preoperative risk stratification through the use of an IH risk calculator app and decision–support interface.

Summary Background Data:
IH occurs after 10% to 15% of all abdominal surgeries (AS) and remains among the most challenging, seemingly unavoidable complications. However, there is a paucity of readily available, actionable tools capable of predicting IH occurrence at the point-of-care.

Methods:
Patients (n = 29,739) undergoing AS from 2005 to 2016 were retrospectively identified within inpatient and ambulatory databases at our institution. Surgically treated IH, complications, and costs were assessed. Predictive models were generated using regression analysis and corroborated using a validation group.

Results:
The incidence of operative IH was 3.8% (N = 1127) at an average follow-up of 57.9 months. All variables were weighted according to β-coefficients generating 8 surgery-specific predictive models for IH occurrence, all of which demonstrated excellent risk discrimination (C-statistic = 0.76–0.89). IH occurred most frequently after colorectal (7.7%) and vascular (5.2%) surgery. The most common occurring risk factors that increased the likelihood of developing IH were history of AS (87.5%) and smoking history (75%). An integrated, surgeon-facing, point-of-care risk prediction instrument was created in an app for preoperative estimation of hernia after AS.

Conclusions:
Operative IH occurred in 3.8% of patients after nearly 5 years of follow-up in a predictable manner. Using a bioinformatics approach, risk models were transformed into 8 unique surgery-specific models. A risk calculator app was developed which stakeholders can access to identify high-risk IH patients at the point-of-care.
Adventures with instruments: science and seafaring in the precarious career of Christopher Middleton
Authors: Bennett Jim 
Published: July 2019

Christopher Middleton (d. 1770) was a sea captain, first with the Hudson's Bay Company, then in the Royal Navy, who was awarded the Royal Society's Copley Medal in 1742. His early work on magnetic variation in northern latitudes was encouraged by Edmond Halley, as he published a series of tables of variation in the
Philosophical Transactions
. These tables illustrate Middleton's transition from the priorities characteristic of the seaman's interest in variation to the wider, natural philosophical agenda of the Society. They illustrate also his enthusiasm for novel instrumentation, in particular altitude instruments for use at sea, such as Hadley's quadrant. Middleton was persuaded by Arthur Dobbs to resign from the Hudson's Bay Company and accept a commission in the Royal Navy so as to command an expedition to search for a Northwest Passage to the East Indies from Hudson's Bay. It was his report on this voyage that won him the Copley Medal but which also led to a bitter and, for Middleton, ruinous public dispute with Dobbs. Middleton emerges as an outstanding seaman and a worthy, if relatively unknown, medallist.
An antibody-tumor necrosis factor fusion protein that synergizes with oxaliplatin for treatment of colorectal cancer
Authors: Bajic Davor , Chester Kerry A. , Neri Dario 
Published: July 2019

ABSTRACTWe have cloned and characterized a novel fusion protein (Sm3E-TNF), consisting of the monoclonal antibody Sm3E in single-chain Fv fragment format, fused to murine tumor necrosis factor. The protein, which was expressed in mammalian cells and purified as a non-covalent stable homotrimer, bound to the cognate carcinoembryonic antigen (CEA) and retained tumor necrosis factor activity. A quantitative biodistribution experiment, performed in immunocompetent mice with CT26 colon carcinomas transfected with human CEA, revealed that Sm3E-TNF was able to preferentially accumulate in the tumors with excellent selectivity (tumor:blood ratio = 56:1, twenty-four hours after intravenous administration). The fusion protein mediated a rapid hemorrhagic necrosis of a large portion of the tumor mass, but a rim survived and eventually regrew. Surprisingly, the combination of Sm3E-TNF with 5-fluorouracil led to a reduction of therapeutic activity, while a combination with oxaliplatin led to a prolonged stabilization, with complete tumor eradication in 40% of treated mice. These therapy results were confirmed in a second immunocompetent mouse model of colorectal cancer (CEA-transfected C51 tumors) and provide a rationale for the possible clinical use of oxaliplatin in combination with fully-human antibody-TNF fusions.
Structural Basis of Enhanced Facilitated Diffusion of DNA Binding Proteins in Crowded Cellular Milieu
Authors: Dey P. , Bhattacherjee A. 
Published: July 2019

ABSTRACTDNA binding proteins (DBPs) rapidly recognize and specifically associate with their target DNA sites inside cell nucleus that contains up to 400 g/L macromolecules, most of which are proteins. While the fast association between DBPs and DNA is explained by a facilitated diffusion mechanism, where DBPs adopt a weighted combination of 3D diffusion and 1D sliding and hopping modes of transportation, the role of cellular environment that contains many nonspecifically interacting proteins and other biomolecules is mostly overlooked. By performing large scale computational simulations with an appropriately tuned model of protein and DNA in the presence of nonspecifically interacting bulk and DNA bound crowders (genomic crowders), we demonstrate the structural basis of the enhanced facilitated diffusion of DBPs inside a crowded cellular milieu through novel 1D scanning mechanisms. In the presence of bulk crowders, we identify the protein to float along the DNA under the influence of protein-crowder nonspecific interactions. The search mode is distinctly different compared to usual 1D sliding and hopping dynamics where protein diffusion is regulated by the DNA electrostatics. In contrast, the presence of genomic crowders expedite the target search process by transporting the protein over DNA segments through the formation of a transient protein-crowder bridged complex. By analyzing the ruggedness of the associated potential energy landscape, we underpin the molecular origin of the kinetic advantages of these search modes and show that they successfully explain the experimentally observed acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowder concentration dependent enzymatic activity of transcription factors. Our findings provide crucial insights into gene regulation kinetics inside the crowded cellular milieu.SIGNIFICANCE10-40% of the intracellular volume is occupied by proteins, and other biomolecules, collectively known as macromolecular crowders. Their presence has been found to promote faster translocation of DNA binding proteins (DBPs) during the search of their target DNA sites for crucial cellular processes. Using molecular simulations, we probe the underlying structural basis and underscore the existence of novel DNA scanning mechanisms actuated by protein-crowder nonspecific interactions. We show that the observed search modes are kinetically beneficial and can successfully explain the acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowderconcentration dependent enzymatic activity of transcription factors.Our study sheds new light on the long-standing facilitated diffusion problem of DBPs in the crowded cellular environment for regulating gene expression.
DeepPrime2Sec: Deep Learning for Protein Secondary Structure Prediction from the Primary Sequences
Authors: Asgari Ehsaneddin , Poerner Nina , McHardy Alice C. , Mofrad Mohammad R.K. 
Published: July 2019

AbstractMotivationHere we investigate deep learning-based prediction of protein secondary structure from the protein primary sequence. We study the function of different features in this task, including one-hot vectors, biophysical features, protein sequence embedding (ProtVec), deep contextualized embedding (known as ELMo), and the Position Specific Scoring Matrix (PSSM). In addition to the role of features, we evaluate various deep learning architectures including the following models/mechanisms and certain combinations: Bidirectional Long Short-Term Memory (BiLSTM), convolutional neural network (CNN), highway connections, attention mechanism, recurrent neural random fields, and gated multi-scale CNN. Our results suggest that PSSM concatenated to one-hot vectors are the most important features for the task of secondary structure prediction.ResultsUtilizing the CNN-BiLSTM network, we achieved an accuracy of 69.9% and 70.4% using ensemble top-k models, for 8-class of protein secondary structure on the CB513 dataset, the most challenging dataset for protein secondary structure prediction. Through error analysis on the best performing model, we showed that the misclassification is significantly more common at positions that undergo secondary structure transitions, which is most likely due to the inaccurate assignments of the secondary structure at the boundary regions. Notably, when ignoring amino acids at secondary structure transitions in the evaluation, the accuracy increases to 90.3%. Furthermore, the best performing model mostly mistook similar structures for one another, indicating that the deep learning model inferred high-level information on the secondary structure.AvailabilityThe developed software called DeepPrime2Sec and the used datasets are available athttp://llp.berkeley.edu/DeepPrime2Sec.Contactmofrad@berkeley.edu
A Multistage Sequencing Strategy Pinpoints Many Novel and Candidate Disease Alleles for Orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism
Authors: Meinke Peter , Kerr Alastair R. W. , Czapiewski Rafal , de las Heras Jose I. , Harris Elizabeth , Kölbel Heike , Muntoni Francesco , Schara Ulrike , Straub Volker , Schoser Benedikt , Wehnert Manfred , Schirmer Eric C. 
Published: July 2019

AbstractLimitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.
Genetic architecture influences when and how hybridization contributes to colonization
Authors: Reatini Bryan , Vision Todd J. 
Published: July 2019

AbstractThe role of genetic architecture in adaptation to novel environments has received considerable attention when the source of adaptation variation isde novomutation. Relatively less is known when the source of adaptive variation is inter- or intraspecific hybridization. We model hybridization between divergent source populations and subsequent colonization of an unoccupied novel environment using individual-based simulations in order to understand the influence of genetic architecture on the timing of colonization and the mode of adaptation. We find that two distinct categories of genetic architecture facilitate rapid colonization but that they do so in qualitatively different ways. For few and/or tightly linked loci, the mode of adaptation is via the recovery of adaptive parental genotypes. With many unlinked loci, the mode of adaptation is via the generation of novel hybrid genotypes. The first category results in the shortest colonization lag phases across the widest range of parameter space, but further adaptation is mutation limited. The second category takes longer and is more sensitive to genetic variance and dispersal rate, but can facilitate adaptation to environmental conditions which exceed the tolerance of parental populations. These findings have implications for understanding the origins of biological invasions and the success of hybrid populations.
Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system
Authors: Halpin-Healy Tyler S. , Klompe Sanne E. , Sternberg Samuel H. , Fernández Israel S. 
Published: July 2019

AbstractBacteria have evolved adaptive immune systems encoded by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and the CRISPR-associated (Cas) genes to maintain genomic integrity in the face of relentless assault from pathogens and mobile genetic elements [1–3]. Type I CRISPR-Cas systems canonically target foreign DNA for degradation via the joint action of the ribonucleoprotein complex Cascade and the helicase-nuclease Cas3 [4,5] but nuclease-deficient Type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons [6,7]. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion has remained elusive. Here we determined structures of a novel TniQ-Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using single particle electron cryo-microscopy (cryo-EM), revealing the mechanistic basis of this functional coupling. The quality of the cryo-EM maps allowed for de novo modeling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3’ end of the crRNA. The natural Cas8-Cas5 fusion protein binds the 5’ crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer adjacent motif (PAM) recognition and R-loop formation. The present work lays the foundation for a structural understanding of how DNA targeting by TniQ-Cascade leads to downstream recruitment of additional transposon-associated proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome engineering applications.
Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making
Authors: Chakroun Karima , Mathar David , Wiehler Antonius , Ganzer Florian , Peters Jan 
Published: July 2019

SummaryA central issue in reinforcement learning and decision-making is whether to exploit knowledge of reward values, or to explore novel options. Although it is widely hypothesized that dopamine neurotransmission plays a key role in regulating this balance, causal evidence for a role of dopamine in human exploration is still lacking. Here, we use a combination of computational modeling, pharmacological intervention and functional magnetic resonance imaging (fMRI) to test for a causal effect of dopamine transmission on the exploration-exploitation trade-off in humans. 31 healthy male subjects performed a restless four-armed bandit task in a within-subjects design under three drug conditions: 150mg of the dopamine precursor L-dopa, 2mg of the D2 receptor antagonist haloperidol, and placebo. In all conditions, choice behavior was best explained by an extension of an established Bayesian learning model accounting for perseveration, uncertainty-based exploration and random exploration. Uncertainty-based exploration was attenuated under L-dopa compared to placebo and haloperidol. There was no evidence for a modulation of prediction error signaling or categorical effects of exploration/exploitation under L-dopa, whereas model-based fMRI revealed that L-dopa attenuated neural representations of overall uncertainty in insula and dorsal anterior cingulate cortex. Our results highlight the computational role of these regions in exploration and suggest that dopamine modulates exploration by modulating how this circuit tracks accumulating uncertainty during decision-making.
Understanding interactions between risk factors, and assessing the utility of the additive and multiplicative models through simulations
Authors: Diaz-Gallo Lina-Marcela , Brynedal Boel , Westerlind Helga , Sandberg Rickard , Ramsköld Daniel 
Published: July 2019

ABSTRACTInteraction analysis is used to investigate the magnitude of an effect which two risk factors have on disease risk, and on each other. To study interactions, both additive and multiplicative models have been used, although their interpretations are not universally understood. In this study, we set out to investigate the resulting interactions of several risk factors relationships in additive or multiplicative scenarios using simulations, in the context of case-control studies. Our simulation set up showed that independent risk factors approach additive relative risk at low disease prevalence. However, risk factors that contribute to the same chain of events (i.e. have synergy) lead to multiplicative relative risk. Additionally, thresholds on the number of required risk factors for a disease (the multifactorial threshold model) lead to intermediaries between additive and multiplicative risks. We proposed a novel measure of interaction consistent with additive, multiplicative and multifactorial threshold models. Finally, we demonstrate the utility of the simulation strategy and discovered relationships on real data by analyzing and interpreting gene-gene odds ratios from a case-control rheumatoid arthritis study.
Towards the application of Tc toxins as a universal protein translocation system
Authors: Roderer Daniel , Schubert Evelyn , Sitsel Oleg , Raunser Stefan 
Published: July 2019

AbstractTc toxins are large bacterial protein complexes that inject cytotoxic enzymes into target cells using a sophisticated syringe-like mechanism. Tc toxins are composed of a membrane translocator and a cocoon that encapsulates a toxic enzyme. The toxic enzyme varies between Tc toxins from different species and is not conserved. Here, we investigated whether the toxic enzyme can be replaced by other small proteins of different origin and properties, namely human Cdc42, herpes simplex virus ICP47, Arabidopsis thaliana iLOV, Escherichia coli DHFR, human Ras-binding domain of CRAF kinase, and tobacco etch virus protease. Using a combination of electron microscopy, X-ray crystallography and in vitro translocation assays, we demonstrate that it is possible to turn Tc toxins into customizable molecular syringes for delivering proteins of interest across membranes. We also infer the guidelines that protein cargos must obey in terms of size, charge, and fold in order to successfully take advantage of this new universal protein translocation system.
Retinal morphology inAstyanax mexicanusduring degeneration
Authors: Emam Amany , Yoffe Marina , Cardona Henry , Soares Daphne 
Published: July 2019

AbstractThe teleostAstyanax mexicanusis extant in two readily available forms. One that lives in Mexican rivers and various convergent forms that live in nearby caves. These fish are born with eyes but in the cavefish they degenerate during development. It is known that the lens of cavefish undergoes apoptosis and that some cells in the neuroretina also die. It has not been described, however, if glia and various components of the neuroretina form before complete eye degeneration. Here we examined the development of the retina of the closest living ancestor that lives in the rivers and members of two lineages of cavefish. We report that although the neuroretina is smaller and more compact, it has all cell types and layers including amacrine cells and Muller glia. While various makers for photoreceptors are present in the cavefish inner segments, the outer segments of the photoreceptors in cavefish are missing from the earliest stages examined. This shows that the machinery for visual transducing discs might still be present but not organized in one part of the cell. It is interesting to note that the deficiencies in Astyanax cavefish resemble retinal diseases, such as retinitis pigmentosa.