bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Binding Configurations of Fis Protein Pairs on DNA: Facilitated Dissociation versus Cooperative Dissociation
Authors: Tsai Min-Yeh , Zheng Weihua , Chen Mingchen , Wolynes Peter G. 
Published: July 2019

AbstractAs a master transcription regulator, Fis protein influences over two hundred genes of E-coli. Fis protein’s non-specific binding to DNA is widely acknowledged, and its kinetics of dissociation from DNA is strongly influenced by its surroundings: the dissociation rate increases as the concentration of Fis protein in the solution-phase increases. In this study, we use computational methods to explore the global binding energy landscape of the Fis1:Fis2:DNA ternary complex. The complex contains a binary-Fis molecular dyad whose formation relies on complex structural rearrangements. The simulations allow us to distinguish several different pathways for the dissociation of the protein from DNA with different functional outcomes, and involving different protein stoichiometries: 1. Simple exchange of proteins and 2. Cooperative unbinding of two Fis proteins to yield bare DNA. In the case of exchange, the protein on the DNA is replaced by solution-phase protein through competition for DNA binding sites. This process seen in fluorescence imaging experiments has been called facilitated dissociation. In the latter case of cooperative unbinding of pairs, two neighboring Fis proteins on DNA form a unique binary-Fis configuration via protein-protein interactions, which in turn leads to the co-dissociation of both molecules simultaneously, a process akin to the “molecular stripping” seen in the NFκB/IκB genetic broadcasting system. This simulation shows that the existence of multiple binding configurations of transcription factors can have a significant impact on the kinetics and outcome of transcription factor dissociation from DNA, with important implications for the systems biology of gene regulation by Fis.
Interaction of a sarcolipin pentamer and monomer with the sarcoplasmic reticulum calcium pump, SERCA
Authors: Glaves J. P. , Primeau J. O. , Gorski P. A. , Espinoza-Fonseca L. M. , Lemieux M. J. , Young H. S. 
Published: July 2019

ABSTRACTThe sequential rise and fall of cytosolic calcium underlies the contraction-relaxation cycle of muscle cells. While contraction is initiated by the release of calcium from the sarcoplasmic reticulum, muscle relaxation involves the active transport of calcium back into the sarcoplasmic reticulum. This re-uptake of calcium is catalysed by the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), which plays a lead role in muscle contractility. The activity of SERCA is regulated by small membrane protein subunits, most well-known being phospholamban (PLN) and sarcolipin (SLN). SLN physically interacts with SERCA and differentially regulates contractility in skeletal and atrial muscle. SLN has also been implicated in skeletal muscle thermogenesis. Despite these important roles, the structural mechanisms by which SLN modulates SERCA-dependent contractility and thermogenesis remain unclear. Here, we functionally characterized wild-type SLN and a pair of mutants, Asn4-Ala and Thr5-Ala, which yielded gain-of-function behavior comparable to what has been found for PLN. Next, we analyzed twodimensional crystals of SERCA in the presence of wild-type SLN by electron cryo-microscopy. The fundamental units of the crystals are anti-parallel dimer ribbons of SERCA, known for decades as an assembly of calcium-free SERCA molecules induced by the addition of decavanadate. A projection map of the SERCA-SLN complex was determined to a resolution of 8.5 Å, which allowed the direct visualization of a SLN pentamer. The SLN pentamer was found to interact with transmembrane segment M3 of SERCA, though the interaction appeared to be indirect and mediated by an additional density consistent with a SLN monomer. This SERCA-SLN complex correlated with the ability of SLN to decrease the maximal activity of SERCA, which is distinct from the ability of PLN to increase the maximal activity of SLN. Protein-protein docking and molecular dynamics simulations provided models for the SLN pentamer and the novel interaction between SERCA and a SLN monomer.STATEMENT OF SIGNIFICANCEThis research article describes a novel complex of the sarcoplasmic reticulum calcium pump SERCA and its regulatory subunit sarcolipin. Given the potential role of sarcolipin in skeletal muscle non-shivering thermogenesis, the interactions between SERCA and sarcolipin are of critical importance. Using complementary approaches of functional analysis, electron crystallography, and molecular dynamics simulations, we demonstrate an inherent interaction between SERCA, a sarcolipin monomer, and a sarcolipin pentamer. The interaction involves transmembrane segment M3 of SERCA, which allows sarcolipin to decrease the maximal activity or turnover rate of SERCA. Protein-protein docking and molecular dynamics simulations provided models for the SLN pentamer and the novel interaction between SERCA and a SLN monomer.
GCA: An R package for genetic connectedness analysis using pedigree and genomic data
Authors: Yu Haipeng , Morota Gota 
Published: July 2019

AbstractBackgroundGenetic connectedness is a critical component of genetic evaluation as it assesses the comparability of predicted genetic values across units. Genetic connectedness also plays an essential role in quantifying the linkage between reference and validation sets in whole-genome prediction. Despite its importance, there is no user-friendly software tool available to calculate connectedness statistics.ResultsWe developed the GCA R package to perform genetic connectedness analysis for pedigree and genomic data. The software implements a large collection of various connectedness statistics as a function of prediction error variance or variance of unit effect estimates. The GCA R package is available at GitHub and the source code is provided as open source.ConclusionsThe GCA R package allows users to easily assess the connectedness of their data. It is also useful to determine the potential risk of comparing predicted genetic values of individuals across units or measure the connectedness level between training and testing sets in genomic prediction.
ProTECT – Prediction of T-cell Epitopes for Cancer Therapy
Authors: Rao Arjun A. , Madejska Ada A. , Pfeil Jacob , Paten Benedict , Salama Sofie R. , Haussler David 
Published: July 2019

AbstractSomatic mutations in cancers affecting protein coding genes can give rise to potentially therapeutic neoepitopes. These neoepitopes can guide Adoptive Cell Therapies (ACTs) and Peptide Vaccines (PVs) to selectively target tumor cells using autologous patient cytotoxic T-cells. Currently, researchers have to independently align their data, call somatic mutations and haplotype the patient’s HLA to use existing neoepitope prediction tools. We present ProTECT, a fully automated, reproducible, scalable, and efficient end-to-end analysis pipeline to identify and rank therapeutically relevant tumor neoepitopes in terms of immunogenicity starting directly from raw patient sequencing data, or from pre-processed data. The ProTECT pipeline encompasses alignment, HLA haplotyping, mutation calling (single nucleotide variants, short insertions and deletions, and gene fusions), peptide:MHC (pMHC) binding prediction, and ranking of final candidates. We demonstrate ProTECT on 326 samples from the TCGA Prostate Adenocarcinoma cohort, and compare it with published tools. ProTECT can be run on a standalone computer, a local cluster, or on a compute cloud using a Mesos backend. ProTECT is highly scalable and can process TCGA data in under 30 minutes per sample when run in large batches. ProTECT is freely available athttps://www.github.com/BD2KGenomics/protect.
Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species
Authors: Eldesouky Hassan E. , Salama Ehab A. , Li Xiaoyan , Hazbun Tony R. , Mayhoub Abdelrahman S. , Seleem Mohamed N. 
Published: July 2019

AbstractThe limited number of systemic antifungals and the emergence of azole-resistant Candida species constitute a growing challenge to human medicine. Combinatorial drug therapy represents an appealing approach to enhance the activity of, or restore the susceptibility to current antifungals. Here, we evaluated the fluconazole chemosensitization activity of the Pharmakon 1600 drug library against azole-resistant Candida albicans. We identified 33 non-antifungal drugs that were able to restore susceptibility to fluconazole in an azole-resistant C. albicans. Structural investigation of identified hits revealed phenylpentanol scaffold as a valuable pharmacophore for re-sensitizing azole-resistant Candida species to the effect of current azole antifungal drugs. All phenylpentanol derivatives displayed potent fluconazole chemosensitizing activities (ΣFICI 0.13-0.28) and were able to reduce fluconazole’s MIC by 15-31 fold against the tested strain. Particularly pitavastatin displayed the most potent fluconazole chemosensitizing activity (ΣFICI 0.06-0.50). The pitavastatin-fluconazole combination displayed a broad-spectrum synergistic relationship against 90% of the tested strains, including strains of C. albicans, C. glabrata, and C. auris. Moreover, pitavastatin restored the susceptibility of the multidrug-resistant C. auris to the antifungal activities of itraconazole and voriconazole. Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model. Both pitavastatin and the plain phenylpentanol scaffold were able to interfere significantly with Candida’s efflux activities as demonstrated by Nile Red efflux assays and flow cytometry. This study presents phenylpentanol derivatives as potent azole chemosensitizers that warrant further investigation.
A framework for spatial normalization and voxelwise analysis of diffusion propagators in multiple MAP-MRI data sets
Authors: Avram Alexandru V. , Bernstein Adam S. , Irfanoglu M. Okan , Weinkauf Craig C. , Cota Martin , Gai Neville , Simmons Amber , Moses Anita , Turtzo L. Christine , Jikaria Neekita , Latour Lawrence , Pham Dzung L. , Butman John A. , Basser Peter J. 
Published: July 2019

AbstractWe describe a pipeline for constructing a study-specific template of diffusion propagators measured with mean apparent propagator (MAP) MRI that supports direct voxelwise analysis of differences between propagators across multiple data sets. The pipeline leverages the fact that MAP-MRI is a generalization of diffusion tensor imaging (DTI) and combines simple and robust processing steps from existing tensor-based image registration methods. First, we compute a DTI study template which provides the reference frame and scaling parameters needed to construct a standardized set of MAP-MRI basis functions at each voxel in template space. Next, we transform each subjects diffusion data, including diffusion weighted images (DWIs) and gradient directions, from native to template space using the corresponding tensor-based deformation fields. Finally, we fit MAP coefficients in template space to the transformed DWIs of each subject using the standardized template of MAP basis functions. The consistency of MAP basis functions across all data sets in template space allows us to: 1. compute a template of propagators by directly averaging MAP coefficients and 2. quantify voxelwise differences between co-registered propagators using the angular dissimilarity, or a probability distance metric, such as the Jensen-Shannon Divergence. We illustrate the application of this method by generating a template of MAP propagators for a cohort of healthy volunteers and show a proof-of-principle example of how this pipeline may be used to detect subtle differences between propagators in a single-subject longitudinal clinical data set. The ability to standardize and analyze multiple clinical MAP-MRI data sets could improve assessments in cross-sectional and single-subject longitudinal clinical studies seeking to detect subtle microstructural changes, such as those occurring in mild traumatic brain injury (mTBI), or during the early stages of neurodegenerative diseases, or cancer.
Vocal information and the navigation of social decisions in bats: Is social complexity linked to vocal complexity?
Authors: Knörnschild Mirjam , Fernandez Ahana Aurora , Nagy Martina 
Published: July 2019

AbstractTo make adaptive behavioural decisions, animals must acquire and process information from their natural and social environment. Reducing uncertainty regarding the actions and goals of conspecifics is especially important for group‐living animals.Bats are often highly gregarious and use versatile social vocalizations to mediate social interactions. These social vocalizations encode a substantial amount of ecologically relevant information, such as individual identity, sex and kin. Decoding this information enables receivers to make informed decisions on resource allocation, mate choice, territorial defence and cooperation. Erroneous decisions on such crucial aspects of bats’ social behaviour can be costly due to reduced reproductive success or survival.Increasingly complex social interactions require social vocalizations encoding more information which, in turn, could facilitate the evolution of even more complex social interactions. Evidence for the positive correlation of social and vocal complexity is available for several taxa but is currently very limited for bats.We conducted a phylogenetic comparative analysis to link the information content encoded in bats’ social vocalizations to the complexity of their social lives, that is the level of uncertainty associated with assessing individual identity. We focused on three different vocalization types encoding individual signatures (pup isolation calls, adult contact calls and male‐specific vocalizations). Information content in bit (i.e. the number of binary decisions necessary to discriminate among N individuals) was used as an estimate of vocal complexity; relevant social group size (i.e. the number of conspecifics whose identity a receiver could confuse) was used as an estimate of social complexity.Our phylogenetic comparative analysis detected a positive relationship between the information content of vocalizations and the respective relevant social group size. This relationship suggests a positive feedback loop between social and vocal complexity for bat vocalizations and highlights the importance of vocal information for negotiating fitness‐relevant social decisions of bats.In conclusion, our work suggests that social complexity drives vocal complexity in bats. Future studies on other hitherto understudied taxa are necessary to establish a comprehensive theory on the multi‐faceted co‐evolution of sociality and communication in the animal kingdom.A freePlain Language Summarycan be found within the Supporting Information of this article.
Defence versus defence: Are crucian carp trading off immune function against predator‐induced morphology?
Authors: Vinterstare Jerker , Hegemann Arne , Nilsson Per. Anders , Hulthén Kaj , Brönmark Christer 
Published: July 2019

Abstract

Numerous species adopt inducible defence strategies; that is, they have phenotypically plastic traits that decrease the risk of capture and consumption by potential predators. The benefits of expressing alternative phenotypes in high‐ vs. low‐risk environments are well documented. However, inducible anti‐predator traits are also expected to incur costs, as they are not expressed when predators are absent, yet empirical evidence of such costs remains scarce.

Virtually, all animals in nature are simultaneously under strong selection to evade both capture by predators and infection by parasites or pathogens and, hence, display a diverse arsenal of defences to combat these threats, raising the possibility of trade‐offs between defences. A classic example of a predator‐induced morphological defence is the deep‐bodied shape of crucian carp that reduces risk of predation from gape‐size‐limited predators. The goal of this study was to examine whether predator exposure affects also immune function in crucian carp, and whether the degree of expressed morphological defence is traded off against immune function in individuals.

Following exposure to manipulations of perceived risk (predator presence/absence) in a long‐term experiment (8 months), key aspects of innate immune function and individual differences in the expression of inducible morphological defence were quantified.

Predator‐exposed individuals showed lower haptoglobin levels and complement activity, but higher natural antibody titres than fish from predator‐free conditions. When experimentally challenged with a mimicked bacterial infection (LPS injection), fish reared in the presence of a natural predator showed a weaker immune response. Moreover, among predator‐exposed individuals, the magnitude of morphological defence expression correlated with both baseline immune function and the ability to mount an immune response. However, these relationships were not consistently supportive of a general trade‐off among defences.

Our results suggest that fish exposed to predators on average reduce investment in immune function, and, further, the observed relationships among defences in predator‐exposed individuals can best be explained from individual fitness and pace‐of‐life perspectives.
Microbial communities across nearshore to offshore coastal transects are primarily shaped by distance and temperature
Authors: Wang Zhao , Juarez Doris L. , Pan Jin‐Fen , Blinebry Sara K. , Gronniger Jessica , Clark James S. , Johnson Zackary I. , Hunt Dana E. 
Published: July 2019

SummaryRecent studies have focused on linking marine microbial communities with environmental factors, yet, relatively little is known about the drivers of microbial community patterns across the complex gradients from the nearshore to open ocean. Here, we examine microbial dynamics in 15 five‐station transects beginning at the estuarine Piver's Island Coastal Observatory (PICO) time‐series site and continuing 87 km across the continental shelf to the oligotrophic waters of the Sargasso Sea. 16S rRNA gene libraries reveal strong clustering by sampling site with distinct nearshore, continental shelf and offshore oceanic communities. Water temperature and distance from shore (which serves as a proxy for gradients in factors such as productivity, terrestrial input and nutrients) both most influence community composition. However, at the phylotype level, modelling shows the distribution of some taxa is linked to temperature, others to distance from shore and some by both factors, highlighting that taxa with distinct environmental preferences underlie apparent clustering by station. Thus, continental margins contain microbial communities that are distinct from those of either the nearshore or the offshore environments and contain mixtures of phylotypes with nearshore or offshore preferences rather than those unique to the shelf environment.
A panel of recombinant proteins for the serodiagnosis of caseous lymphadenitis in goats and sheep
Authors: Barral Thiago Doria , Mariutti Ricardo Barros , Arni Raghuvir Krishnaswamy , Santos Anderson Jesus , Loureiro Dan , Sokolonski Ana Rita , Azevedo Vasco , Borsuk Sibele , Meyer Roberto , Portela Ricardo Dias 
Published: July 2019

SummaryCaseous lymphadenitis (CLA) is a small ruminant disease characterized by the development of granulomatous lesions in superficial and internal lymph nodes, as well as in some organs, and causes significant economic losses worldwide. The aetiological agent of CLA is the bacterium Corynebacterium pseudotuberculosis; however, the commercially available diagnostic tools present problems with regard to specificity, which can lead to false‐negative results. This study aimed to develop an indirect enzyme‐linked immunosorbent assay (ELISA) for the detection of specific immunoglobulins in goats and sheep using recombinant C. pseudotuberculosis PLD, CP40, PknG, DtxR and Grx proteins. For validation of the ELISAs, 130 goat serum samples and 160 sheep serum samples were used. The best ELISA for goats was developed using a combination of PLD and CP40 as antigens at a 1:1 ratio, which presented 96.9% sensitivity and 98.4% specificity. The most effective ELISA for sheep presented 91% sensitivity and 98.7% specificity when recombinant PLD alone was used as the antigen. These ELISAs can be used as highly accurate tools in epidemiological surveys and for the serodiagnosis of C. pseudotuberculosis infection in goats and sheep.
Continuous time resource selection analysis for moving animals
Authors: Wang Yi‐Shan , Blackwell Paul G. , Merkle Jerod A. , Potts Jonathan R. 
Published: July 2019

Abstract

Resource selection analysis (RSA) seeks to understand how spatial abundance covaries with environmental features. By combining RSA with movement, step selection analysis (SSA) has helped uncover the mechanisms behind animal relocations, thereby giving insight into the movement decisions underlying spatial patterns. However, SSA typically assumes that at each observed location, an animal makes a ‘selection’ of the next observed location. This conflates observation with behavioural mechanism and does not account for decisions occurring at any other time along the animal’s path.

To address this, we introduce a continuous time framework for resource selection. It is based on a switching Ornstein–Uhlenbeck (OU) model, parameterized by Bayesian Monte Carlo techniques. Such OU models have been used successfully to identify switches in movement behaviour, but hitherto not combined with resource selection. We test our inference procedure on simulated paths, representing both migratory movement (where landscape quality varies according to season) and foraging with depletion and renewal of resources (where the variation is due to past locations of the animals). We apply our framework to location data of migrating mule deer (Odocoileus hemionus) to shed light on the drivers of migratory decisions.

In a wide variety of simulated situations, our inference procedure returns reliable estimations of the parameter values, including the extent to which animals trade‐off resource quality and travel distance (within 95% posterior intervals for the vast majority of cases). When applied to the mule deer data, our model reveals some individual variation in parameter values. Nevertheless, the migratory decisions of most individuals are well‐described by a model that accounts for the cost of moving and the difference between instantaneous change of vegetation quality at source and target patches.

We have introduced a technique for inferring the resource‐driven decisions behind animal movement that accounts for the fact that these decisions may take place at any point along a path, not just when the animal’s location is known. This removes an oft‐acknowledged but hitherto little‐addressed shortcoming of stepwise movement models. Our work is of key importance in understanding how environmental features drive movement decisions and, as a consequence, space use patterns.