bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing complex variants in family trios
Authors: Toptaş Berke Ç , Rakocevic Goran , Kómár Péter , Kural Deniz 
Published: May 2018

AbstractMotivationSeveral tools exist to count Mendelian violations in family trios by comparing variants at the same genomic positions. This naive variant comparison, however, fails to assess regions where multiple variants need to be examined together, resulting in reduced accuracy of existing Mendelian violation checking tools.ResultsWe introduce VBT, a trio concordance analysis tool, which identifies Mendelian violations by approximately solving the 3-way variant matching problem to resolve variant representation differences in family trios. We show that VBT outperforms previous trio comparison methods by accuracy.Availability and implementationVBT is implemented in C++ and source code is available under GNU GPLv3 license at the following URL: https://github.com/sbg/VBT-TrioAnalysis.git.Supplementary informationSupplementary data are available at Bioinformatics online.
Accelerating flux balance calculations in genome-scale metabolic models by localizing the application of loopless constraints
Authors: Chan Siu H J , Wang Lin , Dash Satyakam , Maranas Costas D 
Published: May 2018

Abstract

Background
Genome-scale metabolic network models and constraint-based modeling techniques have become important tools for analyzing cellular metabolism. Thermodynamically infeasible cycles (TICs) causing unbounded metabolic flux ranges are often encountered. TICs satisfy the mass balance and directionality constraints but violate the second law of thermodynamics. Current practices involve implementing additional constraints to ensure not only optimal but also loopless flux distributions. However, the mixed integer linear programming problems required to solve become computationally intractable for genome-scale metabolic models.

Results
We aimed to identify the fewest needed constraints sufficient for optimality under the loopless requirement. We found that loopless constraints are required only for the reactions that share elementary flux modes representing TICs with reactions that are part of the objective function. We put forth the concept of localized loopless constraints (LLCs) to enforce this minimal required set of loopless constraints. By combining with a novel procedure for minimal null-space calculation, the computational time for loopless flux variability analysis (ll-FVA) is reduced by a factor of 10–150 compared to the original loopless constraints and by 4–20 times compared to the current fastest method Fast-SNP with the percent improvement increasing with model size. Importantly, LLCs offer a scalable strategy for loopless flux calculations for multi-compartment/multi-organism models of large sizes, for example, shortening the CPU time for ll-FVA from 35 h to less than 2 h for a model with more than104 reactions.

Availability and implementation
Matlab functions are available in the Supplementary Material or at https://github.com/maranasgroup/lll-FVA

Supplementary information
Supplementary data are available at Bioinformatics online.
Misdiagnosis of Bordetella bronchiseptica Respiratory Infection as Bordetella pertussis by Multiplex Molecular Assay
Authors: McNulty Moira C , Shibib Dena R , Steinbeck Jennifer L , Mullane Kathleen , Pisano Jennifer , Matushek Scott , Beavis Kathleen G , Tesic Vera , Pitrak David 
Published: May 2018

Abstract
Multiplex polymerase chain reaction (PCR) tests are useful for the rapid detection of pathogens, though diagnostic challenges may arise. We report 2 immunocompromised patients with Bordetella bronchiseptica respiratory infection misdiagnosed as Bordetella pertussis using PCR, including discussion of transmission, diagnostic testing, clinical implications, and infection control considerations.
Flow-related right ventricular to pulmonary arterial pressure gradients during exercise
Authors: Wright Stephen P , Opotowsky Alexander R , Buchan Tayler A , Esfandiari Sam , Granton John T , Goodman Jack M , Mak Susanna 
Published: May 2018

AbstractAimsThe assumption of equivalence between right ventricular (RV) and pulmonary arterial systolic pressure is fundamental to several assessments of RV or pulmonary vascular haemodynamic function. Our aims were to (i) determine whether systolic pressure gradients develop across the RV outflow tract in healthy adults during exercise, (ii) examine the potential correlates of such gradients, and (iii) consider the effect of such gradients on calculated indices of RV function.Methods and resultsHealthy untrained and endurance-trained adult volunteers were studied using right-heart catheterization at rest and during submaximal cycle ergometry. RV and pulmonary artery (PA) pressures were simultaneously transduced, and the cardiac output was determined by thermodilution. Systolic pressures, peak and mean gradients, and indices of chamber, vascular, and valve function were analysed offline. Summary data are reported as mean ± standard deviation or median (interquartile range). No significant RV outflow tract gradients were observed at rest [mean gradient = 4 (3–5) mmHg], and the calculated effective orifice area was 3.6 ± 1.0 cm2. The increase in right ventricular systolic pressure during exercise was greater than the PA systolic pressure. Accordingly, mean gradients were developed during light exercise [8 (7–9) mmHg] and increased during moderate exercise [12 (9–14) mmHg, P < 0.001]. The magnitude of the mean gradient was linearly related to the cardiac output (r2 = 0.70, P < 0.001).ConclusionsIn healthy adults without pulmonic stenosis, systolic pressure gradients develop during exercise, and the magnitude is related to the blood flow rate.
Pulsatile arterial haemodynamics in heart failure
Authors: Weber Thomas , Chirinos Julio A 
Published: May 2018

Abstract
Due to the cyclic function of the human heart, pressure and flow in the circulation are pulsatile rather than continuous. Addressing pulsatile haemodynamics starts with the most convenient measurement, brachial pulse pressure, which is widely available, related to development and treatment of heart failure (HF), but often confounded in patients with established HF. The next level of analysis consists of central (rather than brachial) pressures and, more importantly, of wave reflections. The latter are closely related to left ventricular late systolic afterload, ventricular remodelling, diastolic dysfunction, exercise capacity, and, in the long-term, the risk of new-onset HF. Wave reflection may also represent a suitable therapeutic target. Treatments for HF with preserved and reduced ejection fraction, based on a reduction of wave reflection, are emerging. A full understanding of ventricular-arterial coupling, however, requires dedicated analysis of time-resolved pressure and flow signals, which can be readily accomplished with contemporary non-invasive imaging and modelling techniques. This review provides a summary of our current understanding of pulsatile haemodynamics in HF.
Modeling structure, stability and flexibility of double-stranded RNAs in salt solutions
Authors: Jin L. , Shi Y.Z. , Feng C.J. , Tan Y.L. , Tan Z.J. 
Published: May 2018

AbstractDouble-stranded (ds) RNAs play essential roles in many processes of cell metabolism. The knowledge of three-dimensional (3D) structure, stability and flexibility of dsRNAs in salt solutions is important for understanding their biological functions. In this work, we further developed our previously proposed coarse-grained model to predict 3D structure, stability and flexibility for dsRNAs in monovalent and divalent ion solutions through involving an implicit structure-based electrostatic potential. The model can make reliable predictions for 3D structures of extensive dsRNAs with/without bulge/internal loops from their sequences, and the involvement of the structure-based electrostatic potential and corresponding ion condition can improve the predictions on 3D structures of dsRNAs in ion solutions. Furthermore, the model can make good predictions on thermal stability for extensive dsRNAs over the wide range of monovalent/divalent ion concentrations, and our analyses show that thermally unfolding pathway of a dsRNA is generally dependent on its length as well as its sequence. In addition, the model was employed to examine the salt-dependent flexibility of a dsRNA helix and the calculated salt-dependent persistence lengths are in good accordance with experiments.
Body size-dependent energy storage causes Kleiber’s law scaling of the metabolic rate in planarians
Authors: Rink Jochen C. , Thommen Albert , Werner Steffen , Frank Olga , Philipp Jenny , Knittelfelder Oskar , Quek Yihui , Fahmy Karim , Shevchenko Andrej , Friedrich Benjamin M. , Jülicher Frank 
Published: May 2018

AbstractKleiber’s law, or the ¾-power law scaling of the metabolic rate with body mass, is considered one of the few quantitative laws in biology, yet its physiological basis remains unknown. Here, we report Kleiber’s law scaling in the planarian Schmidtea mediterranea. Its reversible and life history-independent changes in adult body size over 2 orders of magnitude reveal that Kleiber’s law does not emerge from the size-dependent decrease in cellular metabolic rate, but from a size-dependent increase in mass per cell. Through a combination of experiment and theoretical analysis of the organismal energy balance, we further show that the mass allometry is caused by body size dependent energy storage. Our results reveal the physiological origins of Kleiber’s law in planarians and thus have general implications for understanding a fundamental scaling law in biology.
Extended regions of suspected mis-assembly in the rat reference genome
Authors: Ramdas Shweta , Ozel Ayse Bilge , Treutelaar Mary K. , Holl Katie , Mandel Myrna , Woods Leah Solberg , Li Jun Z. 
Published: May 2018

AbstractWe performed whole-genome sequencing for eight inbred rat strains commonly used in genetic mapping studies. They are the founders of the NIH heterogeneous stock (HS) outbred colony. We provide their sequences and variant calls to the rat genomics community. When analyzing the variant calls we identified regions with unusually high levels of heterozygosity. These regions are consistent across the eight inbred strains, including Brown Norway, which is the basis of the rat reference genome. These regions show higher read depths than other regions in the genome and contain higher rates of apparent tri-allelic variant sites. The evidence suggests that these regions may correspond to duplicated segments that were incorrectly overlaid as a single segment in the reference genome. We provide masks for these regions of suspected mis-assembly as a resource for the community to flag potentially false interpretations of mapping or functional results.
Rapid Therapeutic Recommendations in the Context of a Global Public Health Crisis using Translational Bioinformatics Approaches: A proof-of-concept study using Nipah Virus Infection
Authors: Shameer Khader , Johnson Kipp W. , Readhead Ben , Glicksberg Benjamin S. , McCallum Claire , Revikumar Amjesh , Hirsch Jamie S. , Bock Kevin , Chelico John , Hajizadeh Negin , Oppenheim Michael , Dudley Joel T. 
Published: May 2018

AbstractWe live in a world of emerging new diseases and old diseases resurging in more aggressive forms. Drug development by pharmaceutical companies is a market-driven and costly endeavor, and thus it is often a challenge when drugs are needed for diseases endemic only to certain regions or which affect only a few patients. However, biomedical open data is accessible and reusable for reanalysis and generation of a new hypotheses and discovery. In this study, we leverage biomedical data and tools to analyze available data on Nipah Virus (NiV) infection. NiV infection is an emerging zoonosis that is transmissible to humans and is associated with high mortality rates. In this study, explored the application of computational drug repositioning and chemogenomic enrichment analyses using host transcriptome data to match drugs that could reverse the virus-induced gene signature. We performed analyses using two gene signatures: i) A previously published gene signature (n=34), and ii) a gene signature generated using the characteristic direction method (n= 5,533). Our predictive framework suggests that several drugs including FDA approved therapies like beclometasone, trihexyphenidyl, S-propranolol etc. could modulate the NiV infection induced gene signatures in endothelial cells. A target specific analysis of CXCL10 also suggests the potential application of Eldelumab, an investigative therapy for Crohn’s disease and ulcerative colitis, as a putative candidate for drug repositioning. To conclude, we also discuss challenges and opportunities in clinical trials (n-of-1 and adaptive trials) for repositioned drugs. Further follow-up studies including biochemical assays and clinical trials are required to identify effective therapies for clinical use. Our proof-of-concept study highlights that translational bioinformatics methods including gene expression analyses and computational drug repositioning could augment epidemiological investigations in the context of an emerging disease with no effective treatment.
The structure of the Pro-domain of mouse proNGF in contact with the NGF domain
Authors: Yan Robert , Yalinca Havva , Paoletti Francesca , Gobbo Francesco , Marchetti Laura , Kuzmanic Antonija , Lamba Doriano , Gervasio Francesco Luigi , Konarev Petr V. , Cattaneo Antonino , Pastore Annalisa 
Published: May 2018

AbstractNerve Growth Factor (NGF) is an important neurotrophic factor involved in the regulation of cell differentiation, maintenance, growth and survival of target neurons. Expressed as a proNGF precursor, NGF is then matured by furin-mediated protease cleavage. Increasing evidence suggests that NGF and proNGF have distinct cellular partners which account for different functional roles. While the structure of mature NGF is available, little is known about the structure of the pro-domain within the context of proNGF because the dynamical and structural features of the protein have so far prevented its structure determination. We have exploited a new hybrid strategy based on nuclear magnetic resonance and modelling validated by small angle X-ray scattering to gain novel insights on the pro-domain, both in isolation and in the context of proNGF. We show that the isolated pro-domain is intrinsically unstructured but has a clear tertiary structure propensity and forms transient tertiary intramolecular contacts. It is also able to interact, albeit weakly, with mature NGF and has per se the ability to induce growth cone collapse, indicating functional independence. Based on paramagnetic relaxation enhancement data and advanced molecular modelling, we have then reconstructed the overall properties of the pro-domain in the context of proNGF and showed that it has a compact structure. Our data represent an important step towards the structural and functional characterization of the properties of proNGF and its pro-domain.
Dynamic expression of risk genes for schizophrenia and bipolar disorder across development
Authors: Clifton Nicholas E , Hannon Eilís , Florio Arianna Di , Thomas Kerrie L , Holmans Peter A , Walters James TR , O’Donovan Michael C , Owen Michael J , Pocklington Andrew J , Hall Jeremy 
Published: May 2018

ABSTRACTCommon genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between schizophrenia and bipolar disorder. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genes associated with schizophrenia have a strong bias towards increased expression in the prefrontal cortex during early midfetal development and early infancy, and decreased expression during late childhood which normalises in adolescence. Risk-associated genes for bipolar disorder shared this postnatal expression profile but did not exhibit a bias towards expression at any prenatal stage. These results emphasise the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the view that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.
The maternal hormone in the male brain: sexually dimorphic distribution of prolactin signalling in the mouse brain
Authors: Salais-López Hugo , Agustín-Pavón Carmen , Lanuza Enrique , Martínez-García Fernando 
Published: May 2018

ABSTRACTResearch of the central actions of prolactin is virtually restricted to females, but this hormone has also documented roles in male physiology and behaviour. Here, we provide the first description of the pattern of prolactin-derived signalling in the male mouse brain, employing the immunostaining of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) after exogenous prolactin administration. Next, we explore possible sexually dimorphic differences by comparing pSTAT5 immunoreactivity in prolactin-supplemented males and females. We also assess the role of testosterone in the regulation of central prolactin signalling in males by comparing intact with castrated prolactin-supplemented males.Prolactin-supplemented males displayed a widespread pattern of pSTAT5 immunoreactivity, restricted to brain centres showing expression of the prolactin receptor. Immunoreactivity for pSTAT5 was present in several nuclei of the preoptic, anterior and tuberal hypothalamus, as well as in the septofimbrial nucleus or posterodorsal medial amygdala of the telencephalon. Conversely, non-supplemented control males were virtually devoid of pSTAT5-immunoreactivity, suggesting that central prolactin actions in males are limited to situations concurrent with substantial hypophyseal prolactin release (e.g. stress or mating). Furthermore, comparison of prolactin-supplemented males and females revealed a significant, female-biased sexual dimorphism, supporting the view that prolactin has a preeminent role in female physiology and behaviour. Finally, in males, castration significantly reduced pSTAT5 immunoreactivity in some structures, including the paraventricular and ventromedial hypothalamic nuclei and the septofimbrial region, thus indicating a region-specific regulatory role of testosterone over central prolactin signalling.
Identifying individual risk rare variants using protein structure-guided local tests (POINT)
Authors: West Rachel Marceau , Lu Wenbin , Rotroff Daniel M. , Kuenemann Melaine , Chang Sheng-Mao , Wagner Michael J. , Buse John B. , Motsinger-Reif Alison , Fourches Denis , Tzeng Jung-Ying 
Published: May 2018

AbstractRare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9 associated with low-density lipoprotein in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.Author summaryWhile it is known that rare variants play an important role in understanding associations between genotype and complex diseases, pinpointing individual rare variants likely to be responsible for association is still a daunting task. Due to their low frequency in the population and reduced signal, localizing causal rare variants often requires additional information, such as type of DNA change or location of variant along the sequence, to be incorporated in a biologically meaningful fashion that does not overpower the genotype data. In this paper, we use the observation that important variants tend to cluster together on functional domains to propose a new approach for prioritizing rare variants: the protein structure guided local test (POINT). POINT uses a gene’s 3-dimensional protein folding structure to guide aggregation of information from neighboring variants in the protein in a robust manner. We show how POINT improves selection performance over single variant tests and sliding window approaches. We further illustrate how it can be used to prioritize individual rare variants using the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data, finding five promising variants within PCSK9 in association with low-density lipoprotein, including three new mutations near the PCSK9-LDLR binding domain.
Prolonged culture of primary human keratinocytes isolated from suction blisters
Authors: Anderson Erik D. , Sastalla Inka , Earland Noah J. , Mahnaz Minai , Moore Ian N. , Otaizo-Carrasquero Francisco , Myers Timothy G. , Myles Christopher A. , Datta Sandip K. , Myles Ian A. 
Published: May 2018

AbstractKeratinocytes are the most abundant cell type in the epidermis. They prevent desiccation and provide immunological and barrier defense against potential pathogens such as Staphylococcus aureus and Candida albicans. The study of this first line of immune defense is hindered by invasive isolation methods and insufficient techniques for long-term passage of primary keratinocytes in vitro. Primary keratinocytes have been successfully isolated from blister roofs induced by negative pressure, which separates the epidermis from the dermis in vivo in human subjects. This method allows collection of pure epidermal cells without dermal contamination in a minimally invasive manner. However, the isolated keratinocytes differentiate and senesce when cultured in vitro beyond five passages. Here, we present evidence that the Rho kinase (ROCK) inhibitor Y-27632 can be used to effectively increase the proliferative capabilities of keratinocytes isolated using the suction blister method, similar to what has been previously reported for primary keratinocytes isolated using alternative methods. We show that the increase in passage number is directly correlated to delayed differentiation, and that cells passaged long term with the inhibitor retain their ability to stratify in organotypic raft cultures and respond to cytokine treatment; additionally, the late passage cells have a heterogeneous mix of differentiated and non-differentiated cells which may be predicted by a ratio of select differentiation markers. The described method presents a minimally invasive procedure for keratinocyte isolation and prolonged culture that allows analysis of keratinocyte function in both healthy volunteers and patients with dermatologic diseases.