bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Impacts of Dietary Modification on Individual Metabolic Phenotypes and their Relationship to Blood Pressure: Evidence of Latent Dietary Responder Sub-phenotypes
Authors: Loo Ruey Leng , Zou Xin , Appel Lawrence J , Nicholson Jeremy K. , Holmes Elaine 
Published: September 2017

ABSTRACTBackgroundHypertension is a worldwide public health issue with significant comorbidity and mortality. We aimed to identify urinary metabolic phenotypes associated with three healthy diets and to establish their relationship to blood pressure (BP).Methods and Results—24-h urine samples from 158 participants, with pre-hypertension and hypertension, consumed a carbohydrate-rich, a protein-rich and a monounsaturated fat-rich healthy diet (6-week per diet) in randomized order, were analyzed by nuclear magnetic resonance spectroscopy. Combinations of metabolites significantly associated with each diet were identified, and associations between these metabolites and cardiovascular disease risk were established. We found coherent responses to all three diets including increased excretion of metabolites originating from vegetables/fruits, protein, tryptophan metabolism and gut microbial-mammalian co-metabolism. Proline betaine (marker of citrus fruit) was significantly inversely associated with systolic BP; 4-cresyl sulfate (gut microbial metabolite) inversely correlated with both systolic and diastolic BP; and hippurate (gut microbial metabolite) - directly associated with reduced systolic BP.ConclusionsVariation in metabolic phenotypes in response to specific diets may hold clues as to the mechanisms underlying inter-individual differences in dietary response. Stratification of individuals based on diet-specific urinary phenotypes highlights the feasibility for individualized approaches to dietary therapy for lowering BP.Clinical Trial RegistrationThis intervention study is registered athttp://www.clinicaltrials.govasNCT00051350
An automated model test system for systematic development and improvement of gene expression models
Authors: Reis Alexander C. , Salis Howard M. 
Published: September 2017

ABSTRACTGene expression models greatly accelerate the engineering of synthetic metabolic pathways and genetic circuits by predicting sequence-function relationships and reducing trial-and-error experimentation. However, developing models with more accurate predictions is a significant challenge, even though they are essential to engineering complex genetic systems. Here we present a model test system that combines advanced statistics, machine learning, and a database of 9862 characterized genetic systems to automatically quantify model accuracies, accept or reject mechanistic hypotheses, and identify areas for model improvement. We also introduce Model Capacity, a new information theoretic metric that enables correct model comparisons across datasets. We demonstrate the model test system by comparing six models of translation initiation rate, evaluating 100 mechanistic hypotheses, and uncovering new sequence determinants that control protein expression levels. We applied these results to develop a biophysical model of translation initiation rate with significant improvements in accuracy. Automated model test systems will dramatically accelerate the development of gene expression models, and thereby transition synthetic biology into a mature engineering discipline.
An experimental test of the mutation-selection balance model for the maintenance of genetic variance in fitness components
Authors: Sharp Nathaniel P. , Agrawal Aneil F. 
Published: September 2017

ABSTRACTDespite decades of research, the factors that maintain genetic variation for fitness are poorly understood. Mutation selection balance will always contribute to standing variance, but it is unclear what fraction of the variance in a typical fitness component can be explained by mutation-selection balance and whether fitness components differ in this respect. In theory, the level of standing variance in fitness due to mutation-selection balance can be predicted using the rate of fitness decline under mutation accumulation, and this prediction can be directly compared to the actual standing variance observed. This approach allows for controlled statistical tests of the sufficiency of the mutation-selection balance model, and could be used to identify traits or populations where genetic variance is maintained by factors beyond mutation-selection balance. For example, some traits may be influenced by sexually antagonistic balancing selection, resulting in an excess of standing variance beyond that generated by deleterious mutations. To encourage the application of this approach, we describe the underlying theory and use it to test the mutation selection balance model for three traits inDrosophila melanogaster. We find some evidence for non-mutational variance in male mating success and female fecundity relative to larval viability, which is consistent with balancing selection on sexual fitness components. Finally, we discuss the theoretical and practical limitations to this approach, and discuss how to apply it successfully.
High concentrations of boric acid induce autophagy in cancer cell lines
Authors: Al-Ali Ruslan , Gonzalez-Sarmiento Rogelio 
Published: September 2017

AbstractBackground/AimBoric acid (BA) is thought to have anticancer effects, but only a handful of studies tackled this subject. Though a very common compound, little is known about its therapeutic value, mechanisms and effective doses. This study investigates into its therapeutic value and autophagy as a possible mechanism.Materials and MethodsWe evaluated the potency of BA treatment in seven different cell lines. We hypothesized that autophagy is involved in the mechanism of BA toxicity in tumor cells based on observations in plants, insects and cancer cell lines. Changes in autophagy-related proteins were measured after BA treatment. Finally, we suspected that blockage of autophagy would increase the effectiveness of BA treatment and enable the use of smaller doses.ResultsOur results demonstrate that all studied cell lines did not suffer mortality in low to medium doses of BA (up to 5mM). However, a high dose (over 25mM) could inflict significant death in all cell lines. Those high doses caused P62/SQSTM1 consumption and LC3II-B accumulation after 3 days of treatment. Using small doses of BA in combination with autophagy blockage did not improve cytotoxicity in lung cancer cell lines.ConclusionWe conclude that high concentrations of BA affect autophagy in short-term treatments. Not enough data is available about BA toxicity, so BA use as cancer treatment can be possible if new toxicity studies are performed.
CRISPR/Cas9 cleavages in budding yeast reveal templated insertions and strand-specific insertion/deletion profiles
Authors: Lemos Brenda R. , Kaplan Adam C. , Bae Ji Eun , Ferazzoli Alex , Kuo James , Anand Ranjith P. , Waterman David P. , Haber James E. 
Published: September 2017

AbstractHarnessing CRISPR-Cas9 technology has provided an unprecedented ability to modify genomic loci via DNA double-strand break (DSB) induction and repair. We have analyzed nonhomologous end-joining (NHEJ) repair induced by Cas9 in the budding yeastSaccharomyces cerevisiaeand find that the orientation of binding of Cas9 and its guide RNA (gRNA) profoundly influences the pattern of insertion/deletions (indels) at the site of cleavage. A common indel created by Cas9 is a one base pair (+1) insertion that appears to result from Cas9 creating a 1-bp 5’ overhang that is filled in by a DNA polymerase and ligated. The origin of +1 insertions was investigated by using two gRNAs with PAM sequences located on opposite DNA strands but designed to cleave the same sequence. These templated +1 insertions are dependent on the X-family DNA polymerase, Pol4. Deleting Pol4 also eliminated +2 and +3 insertions, which were biased toward homonucleotide insertions. Using inverted PAM (iPAM) sequences, we also found significant differences in overall NHEJ efficiency and repair profiles, suggesting that the binding of the Cas9::gRNA complex influences subsequent NHEJ processing. As with well-studied events induced by the site-specific HO endonuclease, CRISPR-Cas9 mediated NHEJ repair depends on the Ku heterodimer and DNA ligase 4. Cas9 events, however, are highly dependent on the Mre11-Rad50-Xrs2 complex, independent of Mre11’s nuclease activity. Inspection of the outcomes of a large number of Cas9 cleavage events in mammalian cells (van Overbeek et al., 2016) reveals a similar templated origin of +1 insertions in human cells, but also a significant frequency of similarly templated +2 insertions.
Architecture of mammalian centriole distal appendages accommodates distinct blade and matrix functional elements
Authors: Yang T. Tony , Chong Weng Man , Wang Won-Jing , Mazo Gregory , Tanos Barbara , Chen Zhengmin , Nguyet Tran Thi Minh , Chen Yi-De , Weng Rueyhung Roc , Huang Chia-En , Jane Wann-Neng , Tsou Meng-Fu Bryan , Liao Jung-Chi 
Published: September 2017

AbstractDistal appendages (DAPs) are nanoscale, pinwheel-like structures protruding from the distal end of the centriole that mediate membrane docking during ciliogenesis, marking the cilia base around the ciliary gate. Here, we determined a superresolved multiplex of 16 centriole-distal-end components. Surprisingly, rather than pinwheels, intact DAPs exhibit a cone-shaped architecture with components filling the space between each pinwheel blade, a new structural element we termed the distal appendage matrix (DAM). Specifically, CEP83, CEP89, SCLT1, and CEP164 form the backbone of pinwheel blades, with CEP83 confined at the root and CEP164 extending to the tip near the membrane-docking site. By contrast, FBF1 marks the distal end of the DAM near the ciliary membrane. Strikingly, unlike CEP164 which is essential for ciliogenesis, FBF1 is required for ciliary gating of transmembrane proteins, revealing DAPs as an essential component of the ciliary gate. Our findings redefine both the structure and function of DAPs.
Antibodies set boundaries limiting microbial metabolite penetration and the resultant mammalian host response
Authors: Uchimura Yasuhiro , Fuhrer Tobias , Li Hai , Lawson Melissa A. , Zimmermann Michael , Gomez de Agüero Mercedes , Yilmaz Bahtiyar , Ronchi Francesca , Sorribas Marcel , Hapfelmeier Siegfried , Ganal-Vonarburg Stephanie C. , McCoy Kathy D. , Sauer Uwe , Macpherson Andrew J. 
Published: September 2017

SUMMARYAlthough the mammalian microbiota is well-contained within the intestine and on other body surfaces, it profoundly shapes development and metabolism of almost every host organ, presumably through pervasive microbial metabolite penetration. The challenge is that most metabolites can be of both host and microbial origin. We developed a model to distinguish between microbial and host metabolites by stable isotope tracing using fully13C-labelled live non-replicatingEscherichia coli, differentiating12C and13C isotopes with high-resolution mass spectrometry. Hundreds of microbial compounds penetrated across 23 host tissues and fluids after intestinal exposure: subsequent12C host metabolome signatures included lipidemia, reduced glycolysis and inflammation. Mucosal barrier maturation with transient microbial exposure increased early clearance of penetrant bacterial metabolites from the small intestine into the urine, independently of antibody induction. Induced antibodies curtailed microbial metabolite exposure at the intestinal surface, by accelerating intestinal bacterial transit into the colon where metabolite transport mechanisms are limiting.
Development of noninvasive biomarkers of response to proteasome inhibitor therapy (ixazomib) by imaging disrupted protein homeostasis in mouse models of solid tumors
Authors: Zhu Yanan , Ramasawmy Rajiv , Johnson Sean Peter , Taylor Valerie , Gibb Alasdair , Pedley R Barbara , Chattopadhyay Nibedita , Lythgoe Mark F , Golay Xavier , Bradley Daniel , Walker-Samuel Simon 
Published: September 2017

AbstractWith clinically-approved proteasome inhibitors now a standard of care for multiple myeloma, and increasing interest in their use in solid tumors, methods for monitoring therapeutic response in vivo are critically required. Here, we show that tumor protein homeostasis can be noninvasively monitored, using chemical exchange (CEST) magnetic resonance imaging (MRI) as a surrogate marker for proteasome inhibition, alongside diffusion MRI and relaxometry. We show that the in vivo CEST signal associated with amides and amines increases in proportion to proteasome inhibitor dose (ixazomib) and the magnitude of therapeutic effect in colorectal cancer xenografts. Moreover, we show that SW1222 and LS174T human colorectal cancer cell lines demonstrate differing sensitivities to ixazomib, which was reflected in our MRI measurements. We also found evidence of a mild stimulation in tumor growth at low ixazomib doses. Our results therefore identify CEST MRI as a promising method for safely and noninvasively monitoring changes in tumor protein homeostasis.
Continuous rearrangement of the postsynaptic gephyrin scaffolding domain: a super-resolution quantified and energetic approach
Authors: Rodriguez Pamela C. , Almeida Leandro G. , Triller Antoine 
Published: September 2017

AbstractSynaptic function and plasticity requires a delicate balance between overall structural stability and the continuous rearrangement of the components that make up the presynaptic active zone and the postsynaptic density (PSD). Photoactivated localization microscopy (PALM) has provided a detailed view of the nanoscopic structure and organization of some of these synaptic elements. Still lacking, are tools to address the morphing and stability of such complexes at super-resolution. We describe an approach to quantify morphological changes and energetic states of multimolecular assemblies over time. With this method, we studied the scaffold protein gephyrin, which forms postsynaptic clusters that play a key role in the stabilization of receptors at inhibitory synapses. Postsynaptic gephyrin clusters exhibit an internal microstructure composed of nanodomains. We found, that within the PSD, gephyrin molecules continuously undergo spatial reorganization. This dynamic behavior depends on neuronal activity and cytoskeleton integrity. The proposed approach also allowed access to the effective energy responsible for the tenacity of the PSD despite molecular instability.Significant statementSuper-resolution microscopy has become an important tool for the study of biological systems, allowing detailed, nano-scale structural reconstruction, single molecule tracking, particle counting, and interaction studies. However, quantification tools that take full advantage of the information provided by this technology are still lacking. We describe a novel quantification method to obtain information related to the size, directionality, dynamics, and stability of clustered structures from super-resolution microscopy. With this method, we studied the stability of gephyrin clusters, the main inhibitory scaffold protein. We found that gephyrin molecules continuously undergo reorganization based on neuronal activity and changes in the cytoskeleton.
PSGfinder: fast identification of genes under divergent positive selection using the dynamic windows method
Authors: Tuberosa Joël , Montoya-Burgos Juan I. 
Published: September 2017

AbstractSummaryOrthologous genes evolving under divergent positive selection are those involved in divergent adaptive trajectories between related species. Current methods to identify such genes are complex and conservative or present some imperfections, limiting genome-wide searches. We present a simple method, Dynamic Windows, to detect regions of protein-coding genes evolving under divergent positive selection. This method is implemented inPSGfinder, a user-friendly and flexible software, allowing rapid genome-wide screenings of regions with a dN/dS >1.PSGfinderadditionally includes an alignment cleaning procedure and an adapted multiple comparison correction to identify significant signals of positive selection.Availability and ImplementationPSGfinderis a software that implements the DWin method, is written in Python and is freely available with its documentation at:https://genev.unige.ch/research/laboratory/Juan-Montoyaor at:https://github.com/joel-tuberosa/psgfinderContactjuan.montoya@unige.ch;joel.tuberosa@unige.ch
Copy number heterogeneity, large origin tandem repeats, and interspecies recombination in HHV-6A and HHV-6B reference strains
Authors: Greninger Alexander L. , Roychoudhury Pavitra , Makhsous Negar , Hanson Derek , Chase Jill , Krueger Gerhard , Xie Hong , Huang Meei-Li , Saunders Lindsay , Ablashi Dharam , Koelle David M. , Cook Linda , Jerome Keith R. 
Published: September 2017

AbstractQuantitative PCR is the diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of HHV-6 is important for detection of viral reactivation and inherited chromosomally integrated HHV-6 in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process. We performed next-generation sequencing to make relative copy number measurements at single nucleotide resolution of eight candidate HHV-6A and seven HHV-6B reference strains and DNA materials from the HHV-6 Foundation and Advanced Biotechnologies. 11 of 17 (65%) HHV6 candidate reference materials showed multiple copies of the origin of replication upstream of the U41 gene by next-generation sequencing. These large tandem repeats arose independently in culture-adapted HHV-6A and HHV-6B strains, measuring 1254 bp and 983 bp, respectively. Copy number measured between 4-10X copies relative to the rest of the genome. We also report the first interspecies recombinant HHV-6 strain with a HHV-6A GS backbone and >5.5kb region from HHV-6B Z29 from U41-U43 that covered the origin tandem repeat. Specific HHV-6A reference strains demonstrated duplication of regions at UL1/UL2, U87, and U89, as well as deletion in the U12-U24 region and U94/95 genes. HHV-6 strains derived from cord blood mononuclear cells from different labs on different continents revealed no copy number differences throughout the viral genome. These data indicate large origin tandem duplications are an adaptation of both HHV-6A and HHV-6B in culture and show interspecies recombination is possible within theBetaherpesvirinae.ImportanceAnything in science that needs to be quantitated requires a standard unit of measurement. This includes viruses, for which quantitation increasingly determines definitions of pathology and guidelines for treatment. However, the act of making standard or reference material in virology can alter its very usefulness through genomic duplications, insertions, and rearrangements. We used deep sequencing to examine candidate reference strains for HHV-6, a ubiquitous human virus that can reactivate in the immunocompromised population and is integrated into the human genome in every cell of the body for 1% of people worldwide. We found large tandem repeats in the origin of replication for both HHV-6A and HHV-6B that are selected for in culture. We also found the first interspecies recombinant between HHV-6A and HHV-6B, a phenomenon that is well-known in alphaherpesviruses but to date has not been seen in betaherpesviruses. These data critically inform HHV-6 biology and the standard selection process.
Demography and Selection Shape Transcriptomic Divergence in Field Crickets
Authors: Blankers Thomas , Vilaça Sibelle T. , Waurick Isabelle , Gray David A. , Matthias Hennig R. , Mazzoni Camila J. , Mayer Frieder , Berdan Emma L. 
Published: September 2017

ABSTRACTGene flow, demography, and selection can result in similar patterns of genomic variation and disentangling their effects is key to understanding speciation. Here, we assess transcriptomic variation to unravel the evolutionary history ofGryllus rubensandGryllus texensis, cryptic field cricket species with highly divergent mating behavior. We infer their demographic history and screen their transcriptomes for footprints of selection in the context of the inferred demography. We find strong support for a long history of bidirectional gene flow, which ceased during the late Pleistocene, and a bottleneck inG. rubensconsistent with a peripatric origin of this species. Importantly, the demographic history has likely strongly shaped patterns of neutral genetic differentiation (empiricalFSTdistribution). Concordantly,FSTbased selection detection uncovers a large number of outliers, likely comprising many false positives, echoing recent theoretical insights. Alternative genetic signatures of positive selection, informed by the demographic history of the sibling species, highlighted a smaller set of loci; many of these are candidates for controlling variation in mating behavior. Our results underscore the importance of demography in shaping overall patterns of genetic divergence and highlight that examining both demography and selection facilitates a more complete understanding of genetic divergence during speciation.
SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells
Authors: Deniz Özgen , de la Rica Lorenzo , Cheng Kevin C. L. , Spensberger Dominik , Branco Miguel R. 
Published: September 2017

BackgroundEndogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET- dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos.ResultsWe used naïve ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming.ConclusionsOur results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.