bluuebunny/crossref_metadata_2025_split huggingface dataset:
BPscore: an effective metric for meaningful comparisons of structural chromosome segmentations
Authors: Zaborowski Rafal , Wilczyński Bartek 
Published: April 2018

AbstractStudying the 3D structure of chromosomes is an emerging field flourishing in recent years because of rapid development of experimental approaches for studying chromosomal contacts. This has led to numerous studies providing results of segmentation of chromosome sequences of different species into so called Topologically Associating Domains (TADs). As the number of such studies grows steadily and many of them make claims about the perceived differences between TAD structures observed in different conditions, there is a growing need for good measures of similarity (or dissimilarity) between such segmentations. We provide here a BP score, which is a relatively simple distance metric based on the bipartite matching between two segmentations. In this paper, we provide the rationale behind choosing specifically this function and show its results on several different datasets, both simulated and experimental. We show that not only the BP score is a proper metric satisfying the triangle inequality, but that it is providing good granularity of scores for typical situations occuring between different TAD segmentations. We also introduce local variant of the BP metric and show that in actual comparisons between experimental datasets, the local BP score is correlating with the observed changes in gene expression and genome methylation. In summary, we consider the BP score a good foundation for analysing the dynamics of chromosome structures. The methodology we present in this work could be used by many researchers in their ongoing analyses making it a popular and useful tool.Author summaryMany researchers are interested in the chromosomal structure, its function and dynamics. Over the recent years, chromosome conformation capture (3C) methods have become the main source of experimental data on the subject and the Topologically Associating Domains (TADs) have become the de-facto standard unit of chromosomal structure. Many methods have been developed for TAD calling and the 3C experiments have been done in multiple conditions giving us a multitude of chromosomal segmentations describing the most atomic differences in chromosomal structure between conditions. Until now, such segmentations were compared mostly by very rough measures, such as the Jaccard coefficient or TAD overlaps or very general metrics like the variation of information coefficient. This has limited the researchers in the analysis of differential TAD segmentations, and practically prevented any proper analysis of TAD dynamics between conditions. Our approach has the potential to facilitate such analyses by providing researchers with mathematically sound metric that is designed specifically for the purpose and tested on both simulated and experimental data. Additionally, we provide a local variant of our measure that is a natural derivative of the BP score that can indicate which parts of the chromosomes are undergoing the most significant structural reorganizations.
Limb- and tendon-specificAdamtsl2deletion identifies a soft tissue mechanism modulating bone length
Authors: Hubmacher Dirk , Thacker Stetson , Adams Sheila M. , Birk David E. , Schweitzer Ronen , Apte Suneel S. 
Published: April 2018

AbstractDisproportionate distal limb shortening is the hallmark of acromelic dysplasias. Among them, geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature, musculoskeletal, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 (FBN1) or recessiveADAMTSL2mutations, suggesting a functional link between ADAMTSL2 and FBN1. Mice lacking ADAMTSL2 die at birth, precluding analysis of postnatal skeletal growth and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. We show thatAdamtsl2is expressed in limb soft tissues, predominantly in tendon. Expression in developing bones is limited to their terminal cell layers that are destined to become articular cartilage and is absent in growth plate cartilage.Adamtsl2conditional deletion in limb mesenchyme usingPrxl-Cre led to an acromelic dysplasia, providing a suitable model for investigation of geleophysic dysplasia. Unexpectedly, conditionalAdamtsl2deletion usingScx-Cre, a tendon-specific deleter, also impaired skeletal growth. Specific morphogenetic anomalies were seen in Achilles tendon, along with FBN1 accumulation. Thus, ADAMTSL2, shown here to bind fibrillin microfibrils in vitro, limits fibrillin microfibril formation in tendons and promotes tendon growth. The findings suggest that reduced bone growth in geleophysic dysplasia results from external tethering by short tendons rather than intrinsic growth plate anomalies.
A generic normalization method for proper quantification in untargeted proteomics screening
Authors: Anjo Sandra Isabel , Simões Isaura , Castanheira Pedro , Grãos Mário , Manadas Bruno 
Published: April 2018

ABSTRACTThe label-free quantitative mass spectrometry methods, in particular, the SWATH-MS approach, have gained popularity and became a powerful technique for comparison of large datasets. In the present work, it is introduced the use of recombinant proteins as internal standards for untargeted label-free methods. The proposed internal standard strategy reveals a similar intragroup normalization capacity when compared with the most common normalization methods, with the additional advantage of maintaining the overall proteome changes between groups (which are lost using other methods). Therefore, the proposed strategy is able to maintain a good performance even when large qualitative and quantitative differences in sample composition are observed, such as the ones induced by biological regulation (as observed in secretome and other biofluids’ analyses) or by enrichment approaches (such as immunopurifications). Moreover, this approach corresponds to a cost-effective alternative, easier to implement than the current stable-isotope labeling internal standards, therefore being an appealing strategy for large quantitative screening, as clinical cohorts for biomarker discovery.
Bisulfite-free, Base-resolution, and Quantitative Sequencing of Cytosine Modifications
Authors: Liu Yibin , Siejka Paulina , Velikova Gergana , Yuan Fang , Tomkova Marketa , Bai Chunsen , Chen Lei , Bi Ying , Schuster-Boeckler Benjamin , Song Chun-Xiao 
Published: April 2018

AbstractThe deamination of unmodified cytosine to uracil by treatment with bisulfite has for decades been the gold standard for sequencing epigenetic DNA modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). However, this harsh chemical reaction degrades the majority of the DNA and generates sequencing libraries with low complexity. Here, we present a novel bisulfite-free and base-resolution sequencing method, TET Assisted Pic-borane Sequencing (TAPS), for detection of 5mC and 5hmC. TAPS relies on mild reactions, detects modifications directly without affecting unmodified cytosines and can be adopted to detect other cytosine modifications. Compared with bisulfite sequencing, TAPS results in higher mapping rates, more even coverage and lower sequencing costs, enabling higher quality, more comprehensive and cheaper methylome analyses.One Sentence SummaryA bisulfite-free and base-resolution method to directly sequence epigenetically modified cytosine.
Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV
Authors: Dingens Adam S. , Acharya Priyamvada , Haddox Hugh K. , Rawi Reda , Xu Kai , Chuang Gwo-Yu , Wei Hui , Mascola John R. , Carragher Bridget , Potter Clinton S. , Overbaugh Julie , Kwong Peter D. , Bloom Jesse D. 
Published: April 2018

AbstractEliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape provide a template to improve the breadth or potency of future vaccine-induced antibodies against Env’s fusion peptide.Author summaryA major goal of HIV-1 vaccine design is to elicit antibodies that neutralize diverse strains of HIV-1. Recently, some of us elicited such antibodies in animal models using immunogens based on the epitope of a broad antibody (VRC34.01) isolated from an infected individual. Further improving these vaccine-elicited antibody responses will require a detailed understanding of how the resulting antibodies target HIV’s envelope protein (Env). Here, we used mutational antigenic profiling to precisely map the epitope of two vaccine-elicited antibodies and the template VRC34.01 antibody. We did this by quantifying the effect of all possible amino acid mutations to Env on antibody neutralization. Although all antibodies target a similar region of Env, we found clear differences in the functional interaction of Env with the vaccine- and infection-elicited antibodies. We combined these functional data with structural analyses to identify antibody–Env interactions that could improve the breadth of vaccine-elicited antibodies, and thereby help to refine vaccination schemes to achieve broader responses.
Novel anionic cecropins from the spruce budworm feature a poly-L-aspartic acid C-terminus
Authors: Maaroufi Halim , Cusson Michel , Levesque Roger C. 
Published: April 2018

AbstractCecropins form a family of amphipathic α-helical cationic peptides with broad-spectrum antibacterial properties and potent anticancer activity. The emergence of bacteria and cancer cells showing resistance to cationic antimicrobial peptides (CAMPs) has fostered a search for new, more selective and more effective alternatives to CAMPs. With this goal in mind, we looked for cecropin homologs in the genome and transcriptome of the spruce budworm,Choristoneura fumiferana. Not only did we find paralogs of the conventional cationic cecropins (Cfcec+), our screening also led to the identification of previously uncharacterized anionic cecropins (Cfcec−), featuring a poly-L-aspartic acid C-terminus. Comparative peptide analysis indicated that the C-terminal helix of Cfcec−is amphipathic, unlike that of Cfcec+, which is hydrophobic. Interestingly, molecular dynamics simulations pointed to the lower conformational flexibility of Cfcec−peptides, relative to that of Cfcec+. Phylogenetic analysis suggests that the evolution of distinct Cfcec+and Cfcec−peptides may have resulted from an ancient duplication event within the Lepidoptera. Our analyses also indicated that Cfcec−shares characteristics with entericidins, which are involved in bacterial programmed cell death, lunasin, a peptide of plant origins with antimitotic effects, and APC15, a subunit of the anaphase-promoting complex. Finally, we found that both anionic and cationic cecropins contain a BH3-like motif (G-[KQR]-[HKQNR]-[IV]-[KQR]) that could interact with Bcl-2, a protein involved in apoptosis; this observation is congruent with previous reports indicating that cecropins induce apoptosis. Altogether, our observations suggest that cecropins may provide templates for the development of new anticancer drugs.Graphical abstractHighlightsGenes encoding novel anionic cecropins (Cfcec−), featuring a C-terminal poly-L-aspartic acid, were found in the genome of the spruce budworm,Choristoneura fumiferana.Divergence between Cfcec+and Cfcec−could be the result of an ancient duplication event within the Lepidoptera.There is an apparent relationship between motifs observed in cecropin peptides and apoptosis.Anionic cecropins from the spruce budworm display characteristics suggesting they could have anticancer activity
Benchmarking tree and ancestral sequence inference for B cell receptor sequences
Authors: Davidsen Kristian , Matsen Frederick A. 
Published: April 2018

AbstractB cell receptor sequences evolve during affinity maturation according to a Darwinian process of mutation and selection. Phylogenetic tools are used extensively to reconstruct ancestral sequences and phylogenetic trees from affinity-matured sequences. In addition to using general-purpose phylogenetic methods, researchers have developed new tools to accommodate the special features of B cell sequence evolution. However, the performance of classical phylogenetic techniques in the presence of B cell-specific features is not well understood, nor how much the newer generation of B cell specific tools represent an improvement over classical methods. In this paper we benchmark the performance of classical phylogenetic and new B cell-specific tools when applied to B cell receptor sequences simulated from a forward-time model of B cell receptor affinity maturation towards a mature receptor. We show that the currently used tools vary substantially in terms of tree structure and ancestral sequence inference accuracy. Furthermore, we show that there are still large performance gains to be achieved by modeling the special mutation process of B cell receptors. These conclusions are further strengthened with real data using the rules of isotype switching to count possible violations within each inferred phylogeny.
Computational Disease Subtyping based on Joint Analysis of Clinical and Genomic Data
Authors: Diaz Diana , Bollig-Fischer Aliccia , Kotov Alexander 
Published: April 2018

ABSTRACTObjectiveTo investigate application of non-negative tensor decomposition for disease subtype discovery based on joint analysis of clinical and genomic data.Data and MethodsSomatic mutation profiles including 11,996 genes of 503 breast cancer patients from the Cancer Genome Atlas (TCGA) along with 11 clinical variables and markers of these patients were used to construct a binary third-order tensor. CANDECOMP/PARAFAC method was applied to decompose the constructed tensor into rank-one component tensors. Definitions of breast cancer verotypes were constructed from the patient, gene and clinical vectors corresponding to each component tensor. Patient membership proportions in the identified verotypes were utilized in a Cox proportional hazards model to predict their survival.ResultsQualitative evaluation of the verotypes obtained by tensor factorization indicates that they correspond to clinically meaningful breast cancer subtypes. While some components correspond to the known HER2- or ER-positive breast cancer subtypes, other components correspond to a variant of triple negative subtype and a cohort of patients with high mutation load of tumor suppressor genes. Quantitative evaluation indicates that the Cox model utilizing computationally discovered breast cancer verotypes is more accurate (AUC=0.5796) at predicting patient survival than the Cox models utilizing random patient membership proportions in cancer subtypes (AUC=0.4056) as well as patient membership proportions in genotypes (AUC=0.4731) and phenotypes (AUC=0.5047) obtained by non-negative factorization of the somatic mutation and clinical matrices.ConclusionNon-negative factorization of a binary tensor constructed from clinical and genomic data enables high-throughput discovery of breast cancer verotypes that are effective at predicting patient survival.
Shared Data Science Infrastructure for Genomics Data
Authors: Bagher Hamid , Muppiral Usha , Severin Andrew J , Rajan Hridesh 
Published: April 2018

AbstractBackgroundCreating a computational infrastructure to analyze the wealth of information contained in data repositories that scales well is difficult due to significant barriers in organizing, extracting and analyzing relevant data. Shared Data Science Infrastructures like Boa can be used to more efficiently process and parse data contained in large data repositories. The main features of Boa are inspired from existing languages for data intensive computing and can easily integrate data from biological data repositories.ResultsHere, we present an implementation of Boa for Genomic research (BoaG) on a relatively small data repository: RefSeq’s 97,716 annotation (GFF) and assembly (FASTA) files and metadata. We used BoaG to query the entire RefSeq dataset and gain insight into the RefSeq genome assemblies and gene model annotations and show that assembly quality using the same assembler varies depending on species.ConclusionsIn order to keep pace with our ability to produce biological data, innovative methods are required. The Shared Data Science Infrastructure, BoaG, can provide greater access to researchers to efficiently explore data in ways previously not possible for anyone but the most well funded research groups. We demonstrate the efficiency of BoaG to explore the RefSeq database of genome assemblies and annotations to identify interesting features of gene annotation as a proof of concept for much larger datasets.
Enrichment of rare protein truncating variants in amyotrophic lateral sclerosis patients
Authors: Farhan Sali M.K. , Howrigan Daniel P. , Abbott Liam E. , Byrnes Andrea E. , Churchhouse Claire , Phatnani Hemali , Smith Bradley N. , Topp Simon D. , Rampersaud Evadnie , Wu Gang , Wuu Joanne , Gubitz Amelie , Klim Joseph R. , Mordes Daniel A. , Ghosh Sulagna ,   CReATe Consortium, FALS Consortium, ALSGENS Consortium, Eggan Kevin , Rademakers Rosa , McCauley Jacob L. , Schüle Rebecca , Züchner Stephan , Benatar Michael , Taylor J. Paul , Nalls Mike A. , Traynor Bryan , Shaw Christopher E. , Goldstein David B. , Harms Matthew B. , Daly Mark J. , Neale Benjamin M. 
Published: April 2018

SUMMARYTo discover novel genetic risk factors underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry matched controls. We observed a significant excess of ultra-rare and rare protein-truncating variants (PTV) among ALS cases, which was primarily concentrated in constrained genes; however, a significant enrichment in PTVs does persist in the remaining exome. Through gene level analyses, known ALS genes, SOD1, NEK1, and FUS, were the most strongly associated with disease status. We also observed suggestive statistical evidence for multiple novel genes including DNAJC7, which is a highly constrained gene and a member of the heat shock protein family (HSP40). HSP40 proteins, along with HSP70 proteins, facilitate protein homeostasis, such as folding of newly synthesized polypeptides, and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of degraded proteins can occur leading to aberrant protein aggregation, one of the pathological hallmarks of neurodegeneration.
Permanent neuroglial remodeling of the retina following infiltration of CSF1R-inhibition resistant peripheral monocytes
Authors: Paschalis Eleftherios I , Lei Fengyang , Zhou Chengxin , Kapoulea Vassiliki , Dana Reza , Chodosh James , Vavvas Demetrios G. , Dohlman Claes H. 
Published: April 2018

AbstractPrevious studies have demonstrated that ocular injury can lead to prompt infiltration of bone marrow-derived peripheral monocytes into the retina. However, the ability of these cells to integrate into the tissue and become microglia has not been studied. Here we show that such peripheral monocytes not only infiltrate into the retina after ocular injury, but that they engraft permanently, migrate to the three distinct microglia strata, and adopt a microglia-like morphology. However, contrary to the original microglia, after injury the engrafted peripheral monocytes are resistant to depletion by colony stimulating factor 1 receptor (CSF1R) inhibitor and remain pro-inflammatory, expressing high levels of major histocompatibility complex II (MHC-II) for the long-term. In the absence of ocular injury, on the other hand, the peripheral monocytes that repopulate the retina after CSF1R inhibition remain sensitive to CSF1R inhibition and can be re-depleted. The observed permanent neuroglia remodeling after injury constitutes a major potential immunological change that may contribute to progressive retinal degeneration. These findings may be relevant also to other degenerative conditions of the retina and central nervous system.Significance statement: Ocular injury causes permanent neuroglia remodeling that promotes neuroinflammation.
Comparison between three concentration techniques for diagnosing intestinal parasites
Authors: Trabelsi Sonia , Hanachi Majdi , Cheikhrouhou Sarra , Aloui Dorsaf , Bouchekoua Meriam , Khaled Samira 
Published: April 2018

ABSTRACTBackgroundIntestinal parasitoses still are a noticeable threat to public health. The direct diagnosis of such parasites requires the use of concentration techniques, whose sensitivities for protozoan cysts and helminth eggs are far from equal.AimTo compare the Willis, Ritchie and Bailenger concentration techniques in terms of parasite recovery, cost, time, and biosafety.MethodsThis prospective study analysed 236 stool specimens for intestinal parasites using the direct wet smear and the above-mentioned concentration techniques applied separately.ResultsBiphasic techniques identified significantly more positive specimens for intestinal parasites than the Willis technique, the latter leading to less concentrated and more altered parasitic elements on microscopy. No statistically significant difference emerged from comparing Ritchie’s and Bailenger’s methods. The Willis technique was the safest, yet the costliest and the most time-consuming of the studied methods.ConclusionsEven though the hazardous reagents employed may raise legitimate concerns over their health implications, biphasic techniques prove to be uncostly, quick to perform, and highly sensitive for detecting faecal parasites, therefore ensuring a safe diagnosis for routine stool examinations.
Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9Å resolution
Authors: Thonghin Nopnithi , Collins Richard F. , Barbieri Alessandro , Shafi Talha , Siebert Alistair , Ford. Robert C. 
Published: April 2018

AbstractP-glycoprotein (ABCB1) is a ATP-binding cassette transporter that plays an important role in the removal of drugs and xenobiotic compounds from the cell. It is also associated with multi-drug resistance in cancer. Here we report novel features of the cryo-EM-derived structure of P-glycoprotein in the post-hydrolytic state: The cytosolic nucleotide-binding domains (NBDs) are separated despite ADP remaining bound to the NBDs. Gaps in the TMDs that connect to the inner hydrophilic cavity are back-filled by detergent head-groups from the annular detergent micelle and are close to two regions predicted to delineate two pseudo-symmetry-related drug-binding sites. In this conformation, the (newly-resolved) N-terminal extension, NBD-TMD linker region and gap-filling detergents all appear to impede NBD dimerisation. We propose a model for the mechanism of action of the exporter where ATP will be bound to the protein for most of the time, consistent with the high physiological ATP concentrationsin vivo.