bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial DNA has strong selective effects across the nuclear genome
Authors: Healy Timothy M. , Burton Ronald S. 
Published: May 2019

AbstractOxidative phosphorylation requires gene products encoded in both the nuclear and mitochondrial genomes, and is the primary source of cellular energy in eukaryotes. As a result, functional integration between the genomes is essential for efficient ATP generation in these organisms. Although within populations this integration is presumably maintained by coevolution, both the importance of coevolution in speciation and mitochondrial disease, and the strength of selection for maintenance of coevolved genotypes are widely questioned. In this study, we crossed populations of the intertidal copepod,Tigriopus californicus, to disrupt putatively coevolved mitonuclear genotypes in reciprocal F2hybrids. We utilized inter-individual variation in developmental rate, a proxy for fitness, among these hybrids to assess the strength of selection imposed on the nuclear genome by alternate mitochondrial genotypes. There was substantial variation in developmental rate among hybrid individuals, andin vitroATP synthesis rates of mitochondria isolated from high fitness hybrids were approximately twice those of mitochondria isolated from low fitness individuals. Furthermore, we used Pool-seq to reveal large deviations in nuclear allele frequencies in hybrids, which favored maternal alleles in only high fitness individuals of each reciprocal cross. Therefore, our most fit hybrids had partial recovery of coevolved genotypes, indicating that mitonuclear effects underlie individual-level variation in developmental rate and that inter-genomic compatibility is critical for high fitness. These results demonstrate that mitonuclear interactions have profound impacts on both physiological performance and the evolutionary trajectory of the nuclear genome.
Comparison of odor responses of homologous medial and lateral glomeruli mapped in the olfactory bulb of the mouse
Authors: Sato Tokiharu , Homma Ryota , Nagayama Shin 
Published: May 2019

AbstractOlfactory sensory neurons expressing same-type odorant receptors typically project to a pair of glomeruli in the medial and lateral sides of the olfactory bulbs (OBs) in rodents. However, their functional properties remain unclear, because the majority of medial glomeruli are hidden in the septal OB. Recently, trace amine-associated odorant receptors were identified that project to a pair of glomeruli uniquely located in the dorsal OB. We measured the odorant-induced calcium responses of these glomeruli simultaneously and found that they exhibited similar temporal response patterns. However, the medial glomeruli had significantly larger respiration-locked calcium fluctuations than the lateral glomeruli. This trend was observed with/without odorant stimulation in postsynaptic neurons but not in presynaptic sensory axon terminals. This indicates that the medial rather than the lateral OB map enhances the respiration-locked rhythm and transfers this information to higher brain centers.Impact StatementThis study used in vivo calcium imaging to document the odor-evoked responses in paired glomeruli, demonstrating that activation in medial glomeruli more strongly impacts respiratory-linked odor processing.
Genome-wide association study of appendicular lean mass in UK Biobank cohort
Authors: Pei Yu-Fang , Liu Yao-Zhong , Yang Xiao-Lin , Zhang Hong , Feng Gui-Juan , Zhang Lei 
Published: May 2019

AbstractLean body mass (LBM), an important physiological measure, has a strong genetic determination. To clarify its genetic basis, a large-scale genome-wide association study (GWAS) of appendicular lean mass (ALM) was conducted in 450,580 UK Biobank subjects. A total of 717 variants (p<5×10−9) from 561 loci were identified, which were replicated across genders (achieving p<5×10−5 in both genders). The identified variants explained ~11% phenotypic variance, accounting for one quarter of the total ~40% GWAS-attributable heritability. The identified variants were enriched in gene sets related to musculoskeletal and connective tissue development. Of interest are several genes, including ADAMTS3, PAM, SMAD3 and MEF2C, that either contain multiple significant variants or serve as the hub genes of the associated gene sets. Polygenic score prediction based on the associated variants was able to distinguish subjects of high from low ALM. Overall, our results offered significant findings on the genetic basis of lean mass through an extraordinarily large sample GWAS. The findings are important to not only lean mass per se but also other complex diseases, such as type 2 diabetes and fracture, as our Mendelian randomization analysis showed that ALM is a protective factor for these two diseases.
The effect of APOE genotype and streamline density volume, on hippocampal CA1 down-regulation: a real-time fMRI virtual reality neurofeedback study
Authors: Skouras Stavros , Torner Jordi , Anderson Patrik , Koush Yury , Falcon Carles , Minguillon Carolina , Fauria Karine , Alpiste Francesc , Gispert Juan D. , Molinuevo José L. ,   the ALFA Study
Published: May 2019

AbstractHippocampal hyperactivity is a precursor of Alzheimer’s disease and more prominent in APOE-ε4 carriers. It is therefore important to investigate the processes of hippocampal self-regulation, to monitor therapeutic efficacy of preclinical interventions. We have developed a closed-loop, virtual reality neurofeedback paradigm for real-time fMRI, that provides a standardized method for quantifying processes of hippocampal self-regulation. We acquired multi-modal neuroimaging data from a sample of 53 cognitively unimpaired subjects at risk for AD and applied standard methods of structural and functional connectomics. The analyses reveal significant negative associations between hippocampal CA1 down-regulation performance and APOE-ε4 alleles, as well as hippocampal streamline density volume. Better memory performance was associated with increased, bilateral hippocampal functional connectivity during the neurofeedback task. These are the first results to link neurofeedback performance to a genetic risk factor and structural connectivity. Further, these are the first evidence that functional cohesion between the hippocampi can reflect subtle differences in memory function, in cognitively unimpaired individuals at risk for AD. We provide a novel method to assess hippocampal function in preclinical AD, and propose it can be used to derive proxies for neural reserve.HighlightsAPOE-ε4 alleles impact hippocampal down-regulation neurofeedback performance.Hippocampal streamline density volume is associated with decreased hippocampal down-regulation performance.Bilaterally cohesive hippocampal activity is associated with better memory performance.We provide a novel paradigm to investigate self-regulation and brain function.
Mutators drive evolution of multi-resistance to antibiotics
Authors: Gifford Danna R. , Berríos-Caro Ernesto , Joerres Christine , Suñé Marc , Forsyth Jessica H. , Bhattacharyya Anish , Galla Tobias , Knight Christopher G. 
Published: May 2019

AbstractAntibiotic combination therapies are an approach used to counter the evolution of resistance; their purported benefit is they can stop the successive emergence of independent resistance mutations in the same genome. Here, we show that bacterial populations with ‘mutators’, organisms with defects in DNA repair, readily evolve resistance to combination antibiotic treatment when there is a delay in reaching inhibitory concentrations of antibiotic—under conditions where purely wild-type populations cannot. In populations subjected to combination treatment, we detected a remarkable amount of genomic diversity in resistance-determining mutations, multi-drug efflux pumps, and mutation-rate altering genes. However, using eco-evolutionary simulations, we demonstrate that only the initial mutator allele is required to explain multi-resistance evolution. Unexpectedly, mutators not only allowed multi-resistance to evolve under combination treatment where it was favoured, but also under single-drug treatments. Under both conditions, the mutator allele swept to fixation through hitch-hiking with single-drug resistance, enabling subsequent resistance mutations to emerge. Ultimately, our results suggest that mutators may hinder the utility of combination therapy when mutators are present. Additionally, by raising the rates of population mutation, selection for multi-resistance may have the unwanted side-effect of increasing the potential to evolve resistance to future antibiotic treatments.Significance statementThe global rise in antimicrobial resistance means that we urgently need new approaches to halt its spread. Antibiotic combination therapy, treatment involving more than one antibiotic, is a strategy proposed to do just that. Evolving resistance to combinations is thought to be exceedingly rare, as it would require two independent mutations to occur in the same genetic background before microbial growth is inhibited. We find that wild-type populations cannot achieve this, even when antibiotic concentrations increase gradually. However, populations with ‘mutators’, organisms with elevated mutation rates through DNA repair defects, can readily evolve multi-drug resistance under both single-drug and combination treatments. Further, hitch-hiking of mutator alleles alongside resistance increases the evolutionary potential for acquiring further resistance mutations. As mutators are commonly found in natural populations, including infection, our results suggest that combination therapy may not be as resilient a strategy against resistance evolution as was once thought.
Loss of multiple enzyme activities due to the human genetic variation P284T in NADPH cytochrome P450 oxidoreductase
Authors: Parween Shaheena , Velazquez Maria Natalia Rojas , Udhane Sameer S. , Kagawa Norio , Pandey Amit V. 
Published: May 2019

AbstractCytochromes P450 located in the endoplasmic reticulum require NADPH cytochrome P450 oxidoreductase (POR) for their catalytic activities. Mutations in POR cause multiple disorders in humans related to the biosynthesis of steroid hormones and also affect drug-metabolizing cytochrome P450 activities. Here we are reporting the effects of a POR genetic variant P284T which is located in the hinge region of POR that is necessary for the flexibility of domain movements. Human wild-type and P284T mutant of POR, as well as cytochrome P450 proteins, were expressed in bacteria, purified and then reconstituted in liposomes for enzyme kinetic assays. Quality of POR proteins was checked by cytochrome c, ferricyanide and tetrazolium dye reduction assay and measurements flavin content. We found that for the P284T variant of POR the cytochrome c reduction activity was reduced to 47% of the WT and MTT reduction was reduced to only 15% of the WT. No impact on ferricyanide reduction activity was observed, but a severe loss of CYP19A1 (aromatase) activity was observed (9% of WT). In the assays of drug metabolizing cytochrome P450 enzymes, the P284T variant of POR showed 26% activity for CYP2C9, 44% activity for CYP2C19, 23% activity for CYP3A4 and 44% activity in CYP3A5 assays compared to the WT POR. These results indicate a severe effect on several cytochrome P450 activities due to the P284T variation in POR which suggests a negative impact on both the steroid as well as drug metabolism in the individuals carrying this variation.
Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization
Authors: Greco Alessandro , Valle Jon Sanchez , Pancaldi Vera , Baudot Anaïs , Barillot Emmanuel , Caselle Michele , Valencia Alfonso , Zinovyev Andrei , Cantini Laura 
Published: May 2019

AbstractMatrix Factorization (MF) is an established paradigm for large-scale biological data analysis with tremendous potential in computational biology.We here challenge MF in depicting the molecular bases of epidemiologically described Disease-Disease (DD) relationships. As use case, we focus on the inverse comorbidity association between Alzheimer’s disease (AD) and lung cancer (LC), described as a lower than expected probability of developing LC in AD patients. To the day, the molecular mechanisms underlying DD relationships remain poorly explained and their better characterization might offer unprecedented clinical opportunities.To this goal, we extend our previously designed MF-based framework for the molecular characterization of DD relationships. Considering AD-LC inverse comorbidity as a case study, we highlight multiple molecular mechanisms, among which the previously identified immune system and mitochondrial metabolism. We then discriminate mechanisms specific to LC from those shared with other cancers through a pancancer analysis. Additionally, new candidate molecular players, such as Estrogen Receptor (ER), CDH1 and HDAC, are pinpointed as factors that might underlie the inverse relationship, opening the way to new investigations. Finally, some lung cancer subtype-specific factors are also detected, suggesting the existence of heterogeneity across patients also in the context of inverse comorbidity.
Cellular and Molecular Probing of Intact Transparent Human Organs
Authors: Zhao Shan , Todorov Mihail Ivilinov , Cai Ruiyao , Steinke Hanno , Kemter Elisabeth , Wolf Eckhard , Lipfert Jan , Bechmann Ingo , Ertürk Ali 
Published: May 2019

SUMMARYOptical tissue transparency permits cellular and molecular investigation of complex tissues in 3D, a fundamental need in biomedical sciences. Adult human organs are particularly challenging for this approach, owing to the accumulation of dense and sturdy molecules in decades-aged human tissues. Here, we introduce SHANEL method utilizing a new tissue permeabilization approach to clear and label stiff human organs. We used SHANEL to generate the first intact transparent adult human brain and kidney, and perform 3D histology using antibodies and dyes in centimeters depth. Thereby, we revealed structural details of sclera, iris and suspensory ligament in the human eye, and the vessels and glomeruli in the human kidney. We also applied SHANEL on transgenic pig organs to map complex structures of EGFP expressing beta cells in >10 cm size pancreas. Overall, SHANEL is a robust and unbiased technology to chart the cellular and molecular architecture of intact large mammalian organs.Graphical AbstractSupplementary Movies of SHANEL are available athttp://discotechnologies.org/SHANEL/
Brain-to-brain synchrony between students and teachers predicts learning outcomes
Authors: Davidesco Ido , Laurent Emma , Valk Henry , West Tessa , Dikker Suzanne , Milne Catherine , Poeppel David 
Published: May 2019

SummaryLittle is known about the brain mechanisms that underpin how humans learn while interacting with one another in ecologically-valid environments (1-3). This is because cognitive neuroscientists typically measure one participant at a time in a highly constrained environment (e.g., inside a brain scanner). In the past few years, researchers have begun comparing brain responses across individuals (4-6) demonstrating that brain-to-brain synchrony can predict subsequent memory retention (7-9). Yet previous research has been constrained to non-interacting individuals. Surprisingly, the one study that was conducted in a group setting found that brain synchrony between students in a classroom predicted how engaged the students were, but not how much information they retained (10). This is unexpected because brain-to-brain synchrony is hypothesized to be driven, at least partially, by shared attention (11, 12), and shared attention has been shown to affect subsequent memory (13). Here we used EEG to simultaneously record brain activity from groups of four students and a teacher in a simulated classroom to investigate whether brain-to-brain synchrony, both between students and between the students and the teacher, can predict learning outcomes (Fig. 1A). We found that brain-to-brain synchrony in the Alpha band (8-12Hz) predicted students’ delayed memory retention. Further, moment-to-moment variation in alpha-band brain-to-brain synchrony discriminated between content that was retained or forgotten. Whereas student-to-student brain synchrony best predicted delayed memory retention at a zero time lag, student-to-teacher brain synchrony best predicted memory retention when adjusting for a ∼200 millisecond lag in the students’ brain activity relative to the teacher’s brain activity. These findings provide key new evidence for the importance of brain data collected simultaneously from groups of individuals in ecologically-valid settings.HighlightsElectroencephalogram (EEG) was concurrently recorded in a simulated classroom from groups of four students and a teacher.Alpha-band (8-12Hz) brain-to-brain synchrony predicted students’ performance in a delayed post-test.Moment-to-moment variation in alpha-band brain-to-brain synchrony indicated what specific information was retained by students.Whereas student-to-student brain synchrony best predicted learning at a zero time lag, student-to-teacher brain synchrony best predicted learning when adjusting for a ∼200 millisecond lag in the students’ brain activity relative to the teacher’s brain activity.
Blind exploration of the unreferenced transcriptome reveals novel RNAs for prostate cancer diagnosis
Authors: Pinskaya M. , Saci Z. , Gallopin M. , Nguyen N. H. , Gabriel M. , Firlej V. , Descrimes M. , de la Taille A. , Londoño-Vallejo A. , Allory Y. , Gautheret D. , Morillon A. 
Published: May 2019

AbstractThe broad use of RNA-sequencing technologies held a promise of improved diagnostic tools based on comprehensive transcript sets. However, mining human transcriptome data for disease biomarkers in clinical specimens is restricted by the limited power of conventional reference-based protocols relying on uniquely mapped reads and transcript annotations. Here, we implemented a blind reference-free computational protocol, DE-kupl, to directly infer RNA variations of any origin, including yet unreferenced RNAs, from high coverage total stranded RNA-sequencing datasets of tissue origin. As a bench test, this protocol was powered for detection of RNA subsequences embedded into unannotated putative long noncoding (lnc)RNAs expressed in prostate cancer tissues. Through filtering and visual inspection of 1,179 candidates, we defined 21 lncRNA probes that were further validated for robust tumor-specific expression by NanoString single molecule-based RNA measurements in 144 tissue specimens. Predictive modeling yielded a restricted probe panel enabling over 90% of true positive detection of cancer in an independent dataset from The Cancer Genome Atlas. Remarkably, this clinical signature made of only 9 unannotated lncRNAs largely outperformed PCA3, the only RNA biomarker approved by the Food and Drug Administration agency, specifically, in detection of high-risk prostate tumors. The proposed reference-free computational workflow is modular, highly sensitive and robust and can be applied to any pathology and any clinical application.
A bacterial resolvase first exploits, then constrains intrinsic dynamics of the Holliday junction to direct recombination
Authors: Ray Sujay , Pal Nibedita , Walter Nils G. 
Published: May 2019

AbstractHomologous recombination forms and resolves an entangled DNA Holliday Junction (HJ) critical for achieving genome repair. We use single-molecule observation and cluster analysis to probe how prototypic bacterial resolvase RuvC selects two of four possible HJ strands for cleavage. RuvC first exploits, then constrains intrinsic HJ isomer exchange and branch migration dynamics to direct cleavage toward only a desired, catalytically competent HJ conformation, thus controlling recombination products.
Temperature-induced molecule assembly effects on the near-edge X-ray absorption fine-structure spectra of Zn-phthalocyanine layers on Si substrates
Authors: Fostiropoulos Konstantinos , Mete Tayfun , Li Zheshen , Lauermann Iver 
Published: May 2019

The molecular arrangement of vacuum thermally deposited polycrystalline Zn-phthalocyanine (ZnPc) layers on Si substrates is investigated using near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy in the proximity of the carbon edge at E
0 = 287.33 eV. The data were collected as a function of the deposition substrate temperature T
S (30, 90, 150°C) and the incidence angle θ (20°, 45°, 70°, 90°) of the synchrotron beam with respect to the sample plane. Each spectrum was analysed by mathematical simulation applying an error function for the carbon edge and a set of Voigt and (asymmetric) Gaussian functions for C1s → π* and C1s → σ* transitions of ZnPc, respectively. It turned out that part of the organic layer consists of adventitious carbon, which does not contribute to the molecular transitions of ZnPc, whereas all molecular features exhibit polarization-dependent peak areas pointing to a reasonable fraction of well-assembled molecules at any T
S. The highest adventitious carbon fraction was found at T
S = 30°C, whereas the highest polarization dependence was found at T
S = 90°C. The calculated average molecular tilt angles for the three temperatures (30, 90, 150°C) were γ = 60.6°, 68.7° and 66.7°, respectively. If only the polarization-dependent fractions are considered, then the three samples can be mathematically described using a shared molecular tilt angle of γ = 68.7°, which corresponds to the average tilt angle of the T
S = 90°C sample.
“If not, why not” form of governance
Authors: Lama Tek , Anderson Warwick Wyndham 
Published: May 2019

Purpose
Are the explanations that companies provide when deviating from two board structure-related best practices under the Australian Stock Exchange’s “If not, why not” regulatory regime systematically influenced by company characteristics?

Design/methodology/approach
Multinomial logistic regressions are performed on a sample of 258 ASX-listed firms in the period 2004-2007. The dependent variable is the level of response to the “why not” pillar of the regime which requires companies to provide an explanation where they deviate from the recommended governance practice or practices. The variable is categorised into three levels: zero response, inadequate explanation and adequate explanation. This variable takes on a fourth possible level (full compliance) if both pillars of the regime are considered jointly. The independent variables are company size, ownership concentration, profitability, liquidity, age and the market-to-book ratio.

Findings
The regime appears to be well specified, but size is positively correlated to the quality of explanations given for the deviation. Other company characteristics have no important systematic effect.

Practical implications
Small firms, while availing of the regulatory flexibility that enables them to adopt governance systems that suit their corporate governance requirements, tend not to meet the reporting requirements that go with that flexibility.

Originality/value
To the best of the authors’ knowledge, this paper is one of the first to explore the justifications given for deviations from full compliance in the “if not why not” regime and covers new ground with respect to explanations given for non-adoption of board structure recommendations.