bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic fish detection in underwater videos by a deep neural network-based hybrid motion learning system
Authors: Salman Ahmad , Siddiqui Shoaib Ahmad , Shafait Faisal , Mian Ajmal , Shortis Mark R , Khurshid Khawar , Ulges Adrian , Schwanecke Ulrich
Published: February 2019

It is interesting to develop effective fish sampling techniques using underwater videos and image processing to automatically estimate and consequently monitor the fish biomass and assemblage in water bodies. Such approaches should be robust against substantial variations in scenes due to poor luminosity, orientation of fish, seabed structures, movement of aquatic plants in the background and image diversity in the shape and texture among fish of different species. Keeping this challenge in mind, we propose a unified approach to detect freely moving fish in unconstrained underwater environments using a Region-Based Convolutional Neural Network, a state-of-the-art machine learning technique used to solve generic object detection and localization problems. To train the neural network, we employ a novel approach to utilize motion information of fish in videos via background subtraction and optical flow, and subsequently combine the outcomes with the raw image to generate fish-dependent candidate regions. We use two benchmark datasets extracted from a large Fish4Knowledge underwater video repository, Complex Scenes dataset and the LifeCLEF 2015 fish dataset to validate the effectiveness of our hybrid approach. We achieve a detection accuracy (F-Score) of 87.44% and 80.02% respectively on these datasets, which advocate the utilization of our approach for fish detection task.
Symplectic Fillings, Contact Surgeries, and Lagrangian Disks
Authors: Conway James , Etnyre John B , Tosun Bülent
Published: February 2019

This paper completely answers the question of when contact $(r)$–surgery on a Legendrian knot in the standard contact structure on $S^3$ yields a symplectically fillable contact manifold for $r\in (0,1]$. We also give obstructions for other positive $r$ and investigate Lagrangian fillings of Legendrian knots.
Testing and improving the acceptability of a web-based platform for collective intelligence to improve diagnostic accuracy in primary care clinics
Authors: Fontil Valy , Radcliffe Kate , Lyson Helena C , Ratanawongsa Neda , Lyles Courtney , Tuot Delphine , Yuen Kaeli , Sarkar Urmimala
Published: February 2019

Objectives

Usable tools to support individual primary care clinicians in their diagnostic processes could help to reduce preventable harm from diagnostic errors. We conducted a formative study with primary care providers to identify key requisites to optimize the acceptability of 1 online collective intelligence platform (Human Diagnosis Project; Human Dx).

Materials and Methods

We conducted semistructured interviews with practicing primary care clinicians in a sample of the US community-based clinics to examine the acceptability and early usability of the collective intelligence online platform using standardized clinical cases and real-world clinical cases from the participants’ own practice. We used an integrated inductive-deductive qualitative analysis approach to analyze the interview transcripts.

Results and Discussion

Perceived usefulness, perceived accuracy, quality assurance, trust, and ease of use emerged as essential domains of acceptability required for providers to use a collective intelligence tool in clinical practice. Participants conveyed that the collective opinion should: (1) contribute to their clinical reasoning, (2) boost their confidence, (3) be generated in a timely manner, and (4) be relevant to their clinical settings and use cases. Trust in the technology platform and the clinical accuracy of its collective intelligence output emerged as an incontrovertible requirement for user acceptance and engagement.

Conclusion

We documented key requisites to building a collective intelligence technology platform that is trustworthy, useful, and acceptable to target end users for assistance in the diagnostic process. These key lessons may be applicable to other provider-facing decision support platforms.
Economic Causes of Female Suicide Terrorism: Perceived Versus Actual
Authors: Choi Seung-Whan
Published: February 2019

Common belief holds that economic misery motivates more people to commit acts of suicide terrorism. The existing literature, however, fails to find an empirical linkage between these two phenomena. This study offers a novel theoretical perspective and statistical evidence on the economy and terrorism connection. I argue that Muslim women decide to engage in acts of suicide terrorism because of their perception of the national economy, rather than actual economic conditions such as gross domestic product per capita or the Gini index. Based upon a statistical analysis of 4,495 incidents of suicide terrorism during the period from 1981 to 2015, the study shows that, when Muslim women perceive their national economy to be unfavorable, they are more likely to commit acts of suicide terrorism.
Who Should We Blame for Healthcare Failings? Lessons from the French Tainted Blood Scandal
Authors: Kazarian MéLinée
Published: February 2019

Many well-known cases of ‘medical manslaughter’ have shown that systemic issues play a significant role in contributing to fatal errors in healthcare institutions. The most prominent NHS scandal, Mid Staffordshire, demonstrated that wrongful prioritization of resources and staff shortages had contributed to the deaths of between 400 and 1200 patients due to appalling care by nursing staff and doctors between 2005 and 2009. Following the scandal, the Trust was prosecuted and convicted of a criminal offence under the Health and Safety at Work Act 1974 in 2014 and 2015. In contrast, in a scandal of comparable scale across the Channel, ‘the HIV-contaminated blood scandal’, individual decision-makers were subject to criminal convictions. Learning from features of the French criminal process, and the aftermath of the 1980s French tainted blood scandal, this article argues that the criminal process can only be a useful response to healthcare systemic failings if higher-level decision-makers are also included in the scope of criminal liability when they have recklessly endangered patients. When no individual reckless fault is found on the part of decision-makers, corporate criminal liability is a suitable alternative to individual criminal liability, if it is focused on ensuring safety and offering justice to patients who have been harmed as a result of healthcare systemic failings.
The Potential Impact of “Take the Volume Pledge” on Outcomes After Carotid Artery Stenting
Authors: Lopez Ramos Christian , Brandel Michael G , Rennert Robert C , Hirshman Brian R , Wali Arvin R , Steinberg Jeffrey A , Santiago-Dieppa David R , Flagg Mitchell , Olson Scott E , Pannell J Scott , Khalessi Alexander A
Published: February 2019

BACKGROUND

The “Volume Pledge” aims to centralize carotid artery stenting (CAS) to hospitals and surgeons performing ≥10 and ≥5 procedures annually, respectively.

OBJECTIVE

To compare outcomes after CAS between hospitals and surgeons meeting or not meeting the Volume Pledge thresholds.

METHODS

We queried the Nationwide Inpatient Sample for CAS admissions. Hospitals and surgeons were categorized as low volume and high volume (HV) based on the Volume Pledge. Multivariable hierarchical regression models were used to examine the impact of hospital volume (2005-2011) and surgeon volume (2005-2009) on perioperative outcomes.

RESULTS

Between 2005 and 2011, 22 215 patients were identified. Most patients underwent CAS by HV hospitals (86.4%). No differences in poor outcome (composite endpoint of in-hospital mortality, postoperative neurological or cardiac complications) were observed by hospital volume but HV hospitals did decrease the likelihood of other complications, nonroutine discharge, and prolonged hospitalization. From 2005 to 2009, 9454 CAS admissions were associated with physician identifiers. Most patients received CAS by HV surgeons (79.2%). On multivariable analysis, hospital volume was not associated with improved outcomes but HV surgeons decreased odds of poor outcome (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.59-0.97; P = .028), complications (OR 0.56, 95% CI 0.46-0.71, P < .001), nonroutine discharge (OR 0.70, 95% CI 0.57-0.87; P = .001), and prolonged hospitalization (OR 0.52, 95% 0.44-0.61, P < .001).

CONCLUSION

Most patients receive CAS by hospitals and providers meeting the Volume Pledge threshold for CAS. Surgeons but not hospitals who met the policy's volume standards were associated with superior outcomes across all measured outcomes.
(Mis)Measuring Sensitive Attitudes with the List Experiment
Authors: Kramon Eric , Weghorst Keith
Published: February 2019

List experiments (LEs) are an increasingly popular survey research tool for measuring sensitive attitudes and behaviors. However, there is evidence that list experiments sometimes produce unreasonable estimates. Why do list experiments “fail,” and how can the performance of the list experiment be improved? Using evidence from Kenya, we hypothesize that the length and complexity of the LE format make them costlier for respondents to complete and thus prone to comprehension and reporting errors. First, we show that list experiments encounter difficulties with simple, nonsensitive lists about food consumption and daily activities: over 40 percent of respondents provide inconsistent responses between list experiment and direct question formats. These errors are concentrated among less numerate and less educated respondents, offering evidence that the errors are driven by the complexity and difficulty of list experiments. Second, we examine list experiments measuring attitudes about political violence. The standard list experiment reveals lower rates of support for political violence compared to simply asking directly about this sensitive attitude, which we interpret as list experiment breakdown. We evaluate two modifications to the list experiment designed to reduce its complexity: private tabulation and cartoon visual aids. Both modifications greatly enhance list experiment performance, especially among respondent subgroups where the standard procedure is most problematic. The paper makes two key contributions: (1) showing that techniques such as the list experiment, which have promise for reducing response bias, can introduce different forms of error associated with question complexity and difficulty; and (2) demonstrating the effectiveness of easy-to-implement solutions to the problem.
‘Problems of Today and Tomorrow’: Prevention and the National Health Service in the 1970s
Authors: Clark Peder
Published: February 2019

A consensus developed around prevention in the early 1970s as a response to epidemiological studies that had highlighted smoking, diet and physical inactivity as risk factors for chronic disease, especially heart disease. This reaction was catalysed by the financial pressures the National Health Service (NHS) was experiencing, the 1974 reorganisation of the service and international awareness of the Lalonde report. Such widespread interest resulted in three different but contemporaneous reports on prevention in 1976 and 1977. All three emphasised, to varying degrees, personal responsibility and lifestyle as important tenets of prevention. This article focuses on Prevention and Health: Everybody’s Business, a 1976 discussion paper published by the four governments of the UK, to explore this preoccupation with disease prevention throughout the decade, and what it reveals about public health in Britain, political attitudes to the NHS and the changing relationship between citizenship and the welfare state.
Oliguria and Acute Kidney Injury in Critically Ill Children: Implications for Diagnosis and Outcomes*
Authors: Kaddourah Ahmad , Basu Rajit K. , Goldstein Stuart L. , Sutherland Scott M.
Published: February 2019

Objectives:

Consensus definitions for acute kidney injury are based on changes in serum creatinine and urine output. Although the creatinine criteria have been widely applied, the contribution of the urine output criteria remains poorly understood. We evaluated these criteria individually and collectively to determine their impact on the diagnosis and outcome of severe acute kidney injury.

Design and Setting:

Post hoc analysis of Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology study—a prospective international observational multicenter study.

Patients:

Critically ill children enrolled in Assessment of Worldwide Acute Kidney Injury, Renal Angina and, Epidemiology database.

Measurement:

To assess the differential impact of creatinine and urine output criteria on severe acute kidney injury (Kidney Disease: Improving Global Outcomes stage ≥ 2). Patients were divided into four cohorts: no-severe acute kidney injury, severe acute kidney injury by creatinine criteria only, severe acute kidney injury by urine output criteria only, and severe acute kidney injury by both creatinine and urine output criteria.

Results:

Severe acute kidney injury occurred in 496 of 3,318 children (14.9%); 343 (69.2%) were creatinine criteria only, 90 (18.1%) were urine output criteria only, and 63 (12.7%) were both creatinine and urine output criteria. Twenty-eight–day mortality for creatinine criteria only and urine output criteria only patients was similar (6.7% vs 7.8%) and higher than those without severe acute kidney injury (2.9%; p < 0.01). Both creatinine and urine output criteria patients had higher mortality than creatinine criteria only and urine output criteria only patients (38.1%; p < 0.001). Compared with patients without severe acute kidney injury, the relative risk of receiving dialysis increased from 9.1 (95% CI, 3.9–21.2) in creatinine criteria only, to 28.2 (95% CI, 11.8–67.7) in urine output criteria only, to 165.7 (95% CI, 86.3–318.2) in both creatinine and urine output criteria (p < 0.01).

Conclusions:

Nearly one in five critically ill children with acute kidney injury do not experience increase in serum creatinine. These acute kidney injury events, which are only identified by urine output criteria, are associated with comparably poor outcomes as those diagnosed by changes in creatinine. Children meeting both criteria had worse outcomes than those meeting only one. We suggest oliguria represents a risk factor for poorer outcomes among children who develop acute kidney injury. Application of both the creatinine and urine output criteria leads to a more comprehensive epidemiologic assessment of acute kidney injury and identifies a subset of children with acute kidney injury who are at higher risk for morbidity and mortality.
Characteristics and Outcomes of Critical Illness in Children With Feeding and Respiratory Technology Dependence
Authors: Heneghan Julia A. , Reeder Ron W. , Dean J. Michael , Meert Kathleen L. , Berg Robert A. , Carcillo Joseph , Newth Christopher J. L. , Dalton Heidi , Tamburro Robert , Pollack Murray M.
Published: February 2019

Objectives:

Children with dependence on respiratory or feeding technologies are frequently admitted to the PICU, but little is known about their characteristics or outcomes. We hypothesized that they are at increased risk of critical illness–related morbidity and mortality compared with children without technology dependence.

Design:

Secondary analysis of prospective, probability-sampled cohort study of children from birth to 18 years old. Demographic and clinical characteristics were assessed. Outcomes included death, survival with new morbidity, intact survival, and survival with functional status improvement.

Setting:

General and cardiovascular PICUs at seven participating children’s hospitals as part of the Trichotomous Outcome Prediction in Critical Care study.

Subjects:

Children from birth to 18 years of age as part of the Trichotomous Outcome Prediction in Critical Care study.

Interventions:

None.

Measurements and Main Results:

Children with technology dependence composed 19.7% (1,989/10,078) of PICU admissions. Compared with those without these forms of technology dependence, these children were younger, received more ICU-specific therapeutics, and were more frequently readmitted to the ICU. Death occurred in 3.7% of technology-dependent patients (n = 74), and new morbidities developed in 4.5% (n = 89). Technology-dependent children who developed new morbidities had higher Pediatric Risk of Mortality scores and received more ICU therapies than those who did not. A total of 3.0% of technology-dependent survivors (n = 57) showed improved functional status at hospital discharge.

Conclusions:

Children with feeding and respiratory technology dependence composed approximately 20% of PICU admissions. Their new morbidity rates are similar to those without technology dependence, which contradicts our hypothesis that children with technology dependence would demonstrate worse outcomes. These comparable outcomes, however, were achieved with additional resources, including the use of more ICU therapies and longer lengths of stay. Improvement in functional status was seen in some technology-dependent survivors of critical illness.
A real-time multiplexed microbial growth intervalometer for capturing high resolution growth curves
Authors: Vuono David C. , Lipp Bruce , Staub Carl , Loney Evan , Grzymski Joseph J.
Published: February 2019

Batch cultures are a low maintenance and routine culturing method used in anaerobic microbiology. Automated tools that measure growth curves from anaerobic microorganisms grown in traditional laboratory glassware, such as Balch-type tubes, are not commercially available. Here we present a new MicrobiAl Growth Intervalometer (MAGI) that captures microbial growth curves through photo conductivity of the medium using a diffused light pattern of specified frequency, rather than photo-attenuation of collimated light used in traditional systems, and is configured with an offset photodetector/emitter to minimize direct impingement of light from the source to improve the resolution of the solution’s density. MAGI is operated by software-driven automation and offers investigators a low noise/high gain instrument with capabilities for remote visualization and data acquisition. MAGI is a low maintenance, low cost, and robust platform primarily for anaerobic cultivation and growth monitoring. We demonstrate the utility of this device by first showing that growth rates and generation times inEscherichia coliK-12 are reproducible to previously published results. We then tested MAGI to measure growth curves of an environmental organism,Intrasporangium calvum, under various media compositions. Our results demonstrate that MAGI is a versatile platform to measure growth curves in media under various redox conditions (microaerobic and anaerobic), complex mediums such as Luria-Bertani (LB) broth and minimal media, and for resolving diauxic growth curves whenI. calvumis grown on a disaccharide. Lastly, we demonstrate that the device can resolve growth curves for μM concentrations of resources that yield low biomass. This research advances the tools available to microbiologist aiming to monitor growth curves in a variety of disciplines, such as environmental microbiology, clinical microbiology, and food sciences.
GIFT – A Global Inventory of Floras and Traits for macroecology and biogeography
Authors: Weigelt Patrick , König Christian , Kreft Holger
Published: February 2019

To understand how traits and evolutionary history shape the geographic distribution of plant life on Earth, we need to integrate high-quality and global-scale distribution data with functional and phylogenetic information. Large-scale distribution data for plants are, however, often restricted to either certain taxonomic groups or geographic regions. For example, range maps only exist for a small subset of all plant species and digitally available point-occurrence information is strongly biased both geographically and taxonomically. An alternative, currently rarely used resource for macroecological and botanical research are regional Floras and checklists, which contain highly curated information about the species composition of a clearly defined area, and which together virtually cover the entire global land surface. Here we report on our recent efforts to mobilize this information for macroecological and biogeographical analyses in the GIFT database, the Global Inventory of Floras and Traits. GIFT integrates plant distributions, functional traits, phylogenetic information, and region-level geographic, environmental and socioeconomic data. GIFT currently holds species lists for 2,893 regions across the whole globe including ~315,000 taxonomically standardized species names (i.e. c. 80% of all known land plant species) and ~3 million species-by-region occurrences. In addition, GIFT contains information about the floristic status (native, endemic, alien and naturalized) and takes advantage of the wealth of trait information in the regional Floras, complemented by data from global trait databases. Based on a hierarchical and taxonomical derivation scheme, GIFT holds information for 83 functional traits and more than 2.3 million trait-by-species combinations and achieves unprecedented coverage in categorical traits such as woodiness (~233,000 spp.) or growth form (~213,000 spp.). Here we present the structure, content and automated workflows of GIFT and a corresponding web-interface (http://gift.uni-goettingen.de) as proof of concept for the feasibility and potential of mobilizing aggregated biodiversity data for global macroecological and biogeographical research.
Escherichia coliO157:H7 responds to phosphate starvation by modifying LPS involved in biofilm formation
Authors: Vogeleer Philippe , Vincent Antony T. , Chekabab Samuel M. , Charette Steve J. , Novikov Alexey , Caroff Martine , Beaudry Francis , Jacques Mario , Harel Josée
Published: February 2019

In open environments such as water, enterohemorrhagicEscherichia coliO157:H7 responds to inorganic phosphate (Pi) starvation by inducing the Pho regulon controlled by PhoB. The phosphate-specific transport (Pst) system is the high-affinity Pi transporter. In the Δpstmutant, PhoB is constitutively activated and regulates the expression of genes from the Pho regulon. InE. coliO157:H7, the Δpstmutant, biofilm, and autoagglutination were increased. In the double-deletion mutant ΔpstΔphoB, biofilm and autoagglutination were similar to the wild-type strain, suggesting that PhoB is involved. We investigated the relationship between PhoB activation and enhanced biofilm formation by screening a transposon mutant library derived from Δpstmutant for decreased autoagglutination and biofilms mutants. Lipopolysaccharide (LPS) genes involved in the synthesis of the LPS core were identified. Transcriptomic studies indicate the influence of Pi-starvation andpstmutation on LPS biosynthetic gene expression. LPS analysis indicated that the O-antigen was deficient in the Δpstmutant. Interestingly,waaH, encoding a glycosyltransferase associated with LPS modifications inE. coliK-12, was highly expressed in the Δpstmutant ofE. coliO157:H7. Deletion ofwaaHfrom the Δpstmutant and from the wild-type strain grown in Pi-starvation conditions decreased the biofilm formation but without affecting LPS. Our findings suggest that LPS core is involved in the autoagglutination and biofilm phenotypes of the Δpstmutant and that WaaH plays a role in biofilm in response to Pi-starvation. This study highlights the importance of Pi-starvation in biofilm formation of E. coli O157:H7, which may affect its transmission and persistence.

IMPORTANCE

EnterohemorrhagicEscherichia coliO157:H7 is a human pathogen responsible for bloody diarrhea and renal failures. In the environment, O157:H7 can survive for prolonged periods of time under nutrient-deprived conditions. Biofilms are thought to participate in this environmental lifestyle. Previous reports have shown that the availability of extracellular inorganic phosphate (Pi) affected bacterial biofilm formation; however, nothing was known about O157:H7 biofilm formation. Our results show that O157:H7 membrane undergoes modifications upon PhoB activation leading to increased biofilm formation. A mutation in the Pst system results in reduced amount of the smooth type LPS and that this could influence the biofilm composition. This demonstrates how theE. coliO157:H7 adapts to Pi starvation increasing its ability to occupy different ecological niches.
Spontaneous retrotranspositions in normal tissues are rare and associated with cell-type-specific differentiation
Authors: Dong Xiao , Zhang Lei , Brazhnik Kristina , Lee Moonsook , Hao Xiaoxiao , Maslov Alexander Y. , Zhang Zhengdong , Wang Tao , Vijg Jan
Published: February 2019

Activation of retrotransposons and their insertions into new genomic locations, i.e., retrotranspositions (RTs), have been identified in about 50% of tumors. However, the landscape of RTs in different, normal somatic cell types in humans remains largely unknown. Using single-cell whole-genome sequencing we identified 528 RT events, including LINE-1 (L1), and Alu, in 164 single cells and clones of fibroblasts, neurons, B lymphocytes, hepatocytes and liver stem cells, of 29 healthy human subjects aged from 0 to 106 years. The frequency of RTs was found to vary from <1 on average per cell in primary fibroblasts to 7.8 per cell in hepatocytes. Somewhat surprisingly, RT frequency does not increase with age, which is in contrast to other types of spontaneous mutation. RTs were found significantly more likely to insert in or close to target genes of the Polycomb Repressive Complex 2 (PRC2), which represses most of the genes encoding developmental regulators through H3K27me3 histone modification in embryonic stem cells. Indeed, when directly comparing RT frequency between differentiated liver hepatocytes with liver stem cells, the latter were almost devoid of RTs. These results indicate that spontaneous RTs are associated with cellular differentiation and occur, possibly, as a consequence of the transient chromatin transition of differentiation-specific genes from a transcriptionally repressed to activated state during the differentiation process.
Semi-synthetic Cinnamodial Analogues: Structural Insights into the Insecticidal and Antifeedant Activities of Drimane Sesquiterpenes Against the Mosquito Aedes aegypti
Authors: Manwill Preston K. , Kalsi Megha , Wu Sijin , Cheng Xiaolin , Piermarini Peter M. , Rakotondraibe Harinantenaina L.
Published: February 2019

The Aedes aegypti mosquito serves as a major vector for viral diseases, such as dengue, chikungunya, and Zika, which are spreading across the globe and threatening public health. In addition to increased vector transmission, the prevalence of insecticide-resistant mosquitoes is also on the rise, thus solidifying the need for new, safe and effective insecticides to control mosquito populations. We recently discovered that cinnamodial, a unique drimane sesquiterpene dialdehyde of the Malagasy medicinal plant Cinnamosma fragrans, exhibited significant larval and adult toxicity to Ae. aegypti and was more efficacious than DEET – the gold standard for insect repellents – at repelling adult female Ae. aegypti from blood feeding. In this study several semisynthetic analogues of cinnamodial were prepared to probe the structure-activity relationship (SAR) for larvicidal, adulticidal and antifeedant activity against Ae. aegypti. Initial efforts were focused on modification of the dialdehyde functionality to produce more stable active analogues and to understand the importance of the 1,4-dialdehyde and the α,ß-unsaturated carbonyl in the observed bioactivity of cinnamodial against mosquitoes. This study represents the first investigation into the SAR of cinnamodial as an insecticide and repellent against the medically important Ae. aegypti mosquito.
Bayesian active learning for optimization and uncertainty quantification in protein docking
Authors: Cao Yue , Shen Yang
Published: February 2019

Motivation

Ab initio protein docking represents a major challenge for optimizing a noisy and costly “black box”-like function in a high-dimensional space. Despite progress in this field, there is no docking method available for rigorous uncertainty quantification (UQ) of its solution quality (e.g. interface RMSD or iRMSD).

Results

We introduce a novel algorithm, Bayesian Active Learning (BAL), for optimization and UQof such black-box functions and flexible protein docking. BAL directly models the posterior distribution of the global optimum (or native structures for protein docking) with active sampling and posterior estimation iteratively feeding each other. Furthermore, we use complex normal modes to represent a homogeneous Euclidean conformation space suitable for high-dimension optimization and construct funnel-like energy models for encounter complexes. Over a protein docking benchmark set and a CAPRI set including homology docking, we establish that BAL significantly improve against both starting points by rigid docking and refinements by particle swarm optimization, providing for one third targets a top-3 near-native prediction. BAL also generates tight confidence intervals with half range around 25% of iRMSD and confidence level at 85%. Its estimated probability of a prediction being native or not achieves binary classification AUROC at 0.93 and AUPRC over 0.60 (compared to 0.14 by chance); and also found to help ranking predictions. To the best of knowledge, this study represents the first uncertainty quantification solution for protein docking, with theoretical rigor and comprehensive assessment.

Availability

Source codes are available at https://github.com/Shen-Lab/BAL.

Contact

yshen@tamu.edu

Supplementary information

https://github.com/Shen-Lab/BAL/tree/master/Paper_SI/
SPDI: Data Model for Variants and Applications at NCBI
Authors: Holmes J. Bradley , Moyer Eric , Phan Lon , Maglott Donna , Kattman Brandi L.
Published: February 2019

Motivation

Normalizing diverse representations of sequence variants is critical to the elucidation of the genetic basis of disease and biological function. NCBI has long wrestled with integrating data from multiple submitters to build databases such as dbSNP and ClinVar. Inconsistent representation of variants among variant callers, local databases, and tools results in discrepancies and duplications that complicate analysis. Current tools are not robust enough to manage variants in different formats and different reference sequence coordinates.

Results

The SPDI (pronounced “speedy”) data model defines variants as a sequence of 4 operations: start at the boundary before the first position in the sequence S, advance P positions, delete D positions, then insert the sequence in the string I, giving the data model its name, SPDI. The SPDI model can thus be applied to both nucleotide and protein variants, but the services discussed here are limited to nucleotide. Current services convert representations between HGVS, VCF, and SPDI and provide two forms of normalization. The first, based on the NCBI Variant Overprecision Correction Algorithm, returns a unique, normalized representation termed the “Contextual Allele” for any input. The SPDI name, with its four operations, defines exactly the reference subsequence potentially affected by the variant, even in low complexity regions such as homopolymer and dinucleotide sequence repeats. The second level of normalization depends on an alignment dataset (ADS). SPDI services perform remapping (AKA lift-over) of variants from the input reference sequence to return a list of all equivalent Contextual Alleles based on the transcript or genomic sequences that were aligned. One of these contextual alleles is selected to represent all, usually that based on the latest genomic assembly such as GRCh38 and is designated as the unique “Canonical Allele”. ADS includes alignments between non-assembly RefSeq sequences (prefixed NM, NR, NG), as well inter- and intra-assembly-associated genomic sequences (NCs, NTs and NWs) and this allow for robust remapping and normalization of variants across sequences and assembly versions.

Availability and implementation

The SPDI services are available for open access at: https://api.ncbi.nlm.nih.gov/variation/v0/

Contact

holmesbr@ncbi.nlm.nih.gov
Deep Brain Stimulation of the Ventromedial Prefrontal Cortex Disrupts Consolidation of Fear Memories
Authors: Tan Shawn Zheng Kai , Poon Chi Him , Chan Ying-Shing , Lim Lee Wei
Published: February 2019

Anxiety disorders pose one of the biggest threats to mental health worldwide, yet current therapeutics have been mostly ineffective due to issues with relapse, efficacy, and toxicit. Deep brain stimulation (DBS) is a promising therapy for treatment-resistant psychiatric disorders including anxiety, but very little is known about the effects of DBS on fear memories. In this study, we used a modified plus-maze discriminative and showed that DBS of the ventromedial prefrontal cortex (vmPFC) was able to disrupt consolidation, but not acquisition or retrieval of fear memories. We validated these results using a standard tone-footshock fear conditioning paradigm. We further demonstrated short-term changes in dopaminergic receptor and c-Fos expression in the ventral hippocampus (vHPC) and established a partial casual role of dopamine 2 receptors in this effect. Lastly, we showed changes in neurotransmitter levels in the vHPC. This study highlights the potential therapeutic effect of vmPFC DBS to treat anxiety disorders.
Time Series Experiment Design Under One-Shot Sampling: The Importance of Condition Diversity
Authors: Kang Xiaohan , Hajek Bruce , Wu Faqiang , Hanzawa Yoshie
Published: February 2019

Many biological data sets are prepared using one-shot sampling, in which each individual organism provides only one sample. Time series therefore do not follow trajectories of individuals over time. However, samples collected at different times from individuals grown/raised under the same conditions share the same perturbations of the biological processes, and hence behave as surrogates for multiple samples from a single individual at different times. This implies the importance of growing/raising individuals under multiple conditions if one-shot sampling is used. This paper models the condition effect explicitly by correlated perturbations in the variations driving the expression dynamics, quantifies the performance of the generalized likelihood-ratio test for network structure, and illustrates the difficulty in network reconstruction under one-shot sampling when the condition effect is absent.
Neuronal activity and learning in local cortical networks are modulated by the action-perception state
Authors: Engelhard Ben , Darshan Ran , Ozeri-Engelhard Nofar , Israel Zvi , Werner-Reiss Uri , Hansel David , Bergman Hagai , Vaadia Eilon
Published: February 2019

During sensorimotor learning, neuronal networks change to optimize the associations between action and perception. In this study, we examine how the brain harnesses neuronal patterns that correspond to the current action-perception state during learning. To this end, we recorded activity from motor cortex while monkeys either performed a familiar motor task (movement-state) or learned to control the firing rate of a target neuron using a brain-machine interface (BMI-state). Before learning, monkeys were placed in an observation-state, where no action was required. We found that neuronal patterns during the BMI-state were markedly different from the movement-state patterns. BMI-state patterns were initially similar to those in the observation-state and evolved to produce an increase in the firing rate of the target neuron. The overall activity of the non-target neurons remained similar after learning, suggesting that excitatory-inhibitory balance was maintained. Indeed, a novel neural-level reinforcement-learning network model operating in a chaotic regime of balanced excitation and inhibition predicts our results in detail. We conclude that during BMI learning, the brain can adapt patterns corresponding to the current action-perception state to gain rewards. Moreover, our results show that we can predict activity changes that occur during learning based on the pre-learning activity. This new finding may serve as a key step toward clinical brain-machine interface applications to modify impaired brain activity.
Transposon-mediated, cell type-specific transcription factor recording in the mouse brain
Authors: Cammack Alexander J. , Moudgil Arnav , Lagunas Tomas , Vasek Michael J. , Shabsovich Mark , He June , Chen Xuhua , Wilkinson Michael N. , Miller Timothy M. , Mitra Robi D. , Dougherty Joseph D.
Published: February 2019

Transcription factors (TFs) play a central role in the regulation of gene expression, controlling everything from cell fate decisions to activity dependent gene expression. However, widely-used methods for TF profiling in vivo (e.g. ChIP-seq) yield only an aggregated picture of TF binding across all cell types present within the harvested tissue; thus, it is challenging or impossible to determine how the same TF might bind different portions of the genome in different cell types, or even to identify its binding events at all in rare cell types in a complex tissue such as the brain. Here we present a versatile methodology, FLEX Calling Cards, for the mapping of TF occupancy in specific cell types from heterogenous tissues. In this method, the TF of interest is fused to a hyperactive piggyBac transposase (hypPB), and this bipartite gene is delivered, along with donor transposons, to mouse tissue via a Cre-dependent adeno-associated virus (AAV). The fusion protein is expressed in Cre-expressing cells where it inserts transposon “Calling Cards” near to TF binding sites. These transposons permanently mark TF binding events and can be mapped using high-throughput sequencing. Alternatively, unfused hypPB interacts with and records the binding of the super enhancer (SE)-associated bromodomain protein, Brd4. To demonstrate the FLEX Calling Card method, we first show that donor transposon and transposase constructs can be efficiently delivered to the postnatal day 1 (P1) mouse brain with AAV and that insertion profiles report TF occupancy. Then, using a Cre-dependent hypPB virus, we show utility of this tool in defining cell type-specific TF profiles in multiple cell types of the brain. This approach will enable important cell type-specific studies of TF-mediated gene regulation in the brain and will provide valuable insights into brain development, homeostasis, and disease.
Refractory and metastatic infantile fibrosarcoma harboring LMNA–NTRK1 fusion shows complete and durable response to crizotinib
Authors: Bender Jonathan , Anderson Bailey , Bloom David A. , Rabah Raja , McDougall Rhonda , Vats Pankaj , Mody Rajen
Published: February 2019

Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life. The presence of ETV6 and NTRK3 gene rearrangement is characteristic of IFS, which can be detected on routine fluorescence in situ hybridization (FISH) testing. Patients with IFS typically respond well to surgical resection and chemotherapy and have an overall survival of ∼90%. In this report, we outline the use of integrative clinical sequencing (ICS) including RNA-seq in a patient with refractory, metastatic IFS to reveal an unusual fusion (LMNA–NTRK1), not detected by routine FISH testing, which was treated with oral crizotinib and resulted in a complete and durable long-term response. This study highlights the utility of ICS in identifying cryptic gene fusions, especially in refractory malignancies, and demonstrates how such information can be used to select targeted therapies in patients with actionable molecular alterations.
Cross-Linking Antibodies to Beads Using Dimethyl Pimelimidate (DMP)
Authors: DeCaprio James , Kohl Thomas O.
Published: February 2019

This protocol describes the cross-linking of antibodies to either Protein A or G agarose beads using dimethyl pimelimidate (DMP). DMP contains an imidoester at each end of a 7-carbon spacer arm and forms an amidine bond with amino groups at alkaline pH; however, cross-linking is more efficient when performed at pH >8. DMP will react with primary amines; thus, it is important that the cross-linking procedure is conducted using nonamine-containing buffers. Following the antibody–bead incubation, beads are washed in Borate buffer to remove residual amines from the Tris buffer. After completion of the cross-linking process in the presence of DMP, unreacted DMP is quenched with ethanolamine, and beads are washed extensively to remove residual noncross-linked antibody before immediate use or storage at 4°C.
D+: software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures
Authors: Ginsburg Avi , Ben-Nun Tal , Asor Roi , Shemesh Asaf , Fink Lea , Tekoah Roee , Levartovsky Yehonatan , Khaykelson Daniel , Dharan Raviv , Fellig Amos , Raviv Uri
Published: February 2019

This paper presents the computer programD+(https://scholars.huji.ac.il/uriraviv/book/d-0), where the reciprocal-grid (RG) algorithm is implemented.D+efficiently computes, at high-resolution, the X-ray scattering curves from complex structures that are isotropically distributed in random orientations in solution. Structures are defined in hierarchical trees in which subunits can be represented by geometric or atomic models. Repeating subunits can be docked into their assembly symmetries, describing their locations and orientations in space. The scattering amplitude of the entire structure can be calculated by computing the amplitudes of the basic subunits on 3D reciprocal-space grids, moving up in the hierarchy, calculating the RGs of the larger structures, and repeating this process for all the leaves and nodes of the tree. For very large structures (containing over 100 protein subunits), a hybrid method can be used to avoid numerical artifacts. In the hybrid method, only grids of smaller subunits are summed and used as subunits in a direct computation of the scattering amplitude.D+can accurately analyze both small- and wide-angle solution X-ray scattering data. This article describes howD+applies the RG algorithm, accounts for rotations and translations of subunits, processes atomic models, accounts for the contribution of the solvent as well as the solvation layer of complex structures in a scalable manner, writes and accesses RGs, interpolates between grid points, computes numerical integrals, enables the use of scripts to define complicated structures, applies fitting algorithms, accounts for several coexisting uncorrelated populations, and accelerates computations using GPUs.D+may also account for different X-ray energies to analyze anomalous solution X-ray scattering data. An accessory tool that can identify repeating subunits in a Protein Data Bank file of a complex structure is provided. The tool can compute the orientation and translation of repeating subunits needed for exploiting the advantages of the RG algorithm inD+. A Python wrapper (https://scholars.huji.ac.il/uriraviv/book/python-api) is also available, enabling more advanced computations and integration ofD+with other computational tools. Finally, a large number of tests are presented. The results ofD+are compared with those of other programs when possible, and the use ofD+to analyze solution scattering data from dynamic microtubule structures with different protofilament number is demonstrated.D+and its source code are freely available for academic users and developers (https://bitbucket.org/uriraviv/public-dplus/src/master/).
Use of TEM-EDX for structural formula identification of clay minerals: a case study of Di Linh bentonite, Vietnam
Authors: Hoang-Minh Thao , Kasbohm Jörn , Nguyen-Thanh Lan , Nga Pham Thi , Lai Le Thi , Duong Nguyen Thuy , Thanh Nguyen Duc , Thuyet Nguyen Thi Minh , Anh Dao Duy , Pusch Roland , Knutsson Sven , Ferreiro Mählmann Rafael
Published: February 2019

Transmission electron microscopy linked with energy-dispersive X-ray spectroscopy (TEM-EDX) was applied to characterize mineralogical signals of weathering processes in the Di Linh bentonite deposit (Vietnam) and to visualize the effects of Na activation on the smectitic phases. Modelling of X-ray diffraction patterns (oriented mount) was applied in order to refine the computed structural formula. X-ray diffraction, X-ray fluorescence and Fourier-transform infrared spectroscopy (FT-IR) methods were also applied to verify the TEM-EDX results. AnExcel-based routine has been developed in this research to allow fast computation of structural formulae and classification of the investigated clay particles. This routine supports the acquirement of 100–300 TEM-EDX analyses as a representative set of individual particles for each sample. TheExcel-based routine involves end members of different clay-mineral groups and interstratifications with two or three members (e.g.illite–smectite interstratifications – IS-ml; dioctahedral vermiculite–smectite interstratifications – diVS-ml; and kaolinite–montmorillonite–dioctahedral vermiculite interstratifications – KSV-ml). The routine is now freely available. According to the identification procedure, the <2 µm fraction of the Di Linh bentonite (Vietnam) is composed mainly of K- and charge-deficient illite–smectite interstratifications (or diVS-ml): montmorillonite-rich randomly ordered (R0) type and illite-rich regularly ordered (R1) type. Additionally, Fe-poor KSV-ml was identified. Industrial Na activation of the Di Linh bentonite resulted in an increase of the R1 diVS-ml portion and dissolution of a large part of the smectite-rich phases. The TEM-EDX approach also gave analytical proof of a sedimentary process for Di Linh smectite. The parent muscovite was altered in two different environments: (i) K-leaching and layer-wise alteration into kaolinite (weathering), and (ii) further edge-controlled alteration of mica into lath-like montmorillonite particles associated with a dissolution of kaolinite layers from the former kaolinite–mica intergrowths by heat impact (basalt flow).
REFLEX: a program for the analysis of specular X-ray and neutron reflectivity data
Authors: Vignaud Guillaume , Gibaud Alain
Published: February 2019

The use of X-ray and neutron reflectivity has been generalized worldwide for scientists who want to determine specific physical properties (such as electron-density profile, scattering-length density, roughness and thickness) of films less than 200 nm thick deposited on a substrate. This paper describes a freeware program namedREFLEX, which is a standalone program dedicated to the simulation and analysis of X-ray and neutron reflectivity from multilayers. This program was first written two decades ago and has been constantly improved since, but never published until now. The latest version ofREFLEXcovers generalized types of calculation of reflectivity curves including both neutron and X-ray reflectivity. In the case of X-rays, the program can deal with both s and p polarization, which is quite important in the soft X-ray region where the two polarizations can yield different results. Neutron reflectivity is calculated within the framework of non-spin-polarized neutrons.REFLEXhas also been designed to include any type of fluid (such as supercritical CO2) on top of the analysed film and includes corrections of the footprint effect for analysis on an absolute scale.