bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular basis for the recognition of the human AAUAAA polyadenylation signal
Authors: Sun Yadong , Zhang Yixiao , Hamilton Keith , Manley James L. , Shi Yongsheng , Walz Thomas , Tong Liang 
Published: October 2017

AbstractNearly all eukaryotic messenger RNA precursors must undergo cleavage and polyadenylation at their 3′-end for maturation. A crucial step in this process is the recognition of the AAUAAA polyadenylation signal (PAS), and the molecular mechanism of this recognition has been a long-standing problem. Here we report the cryo-electron microscopy structure of a quaternary complex of human CPSF-160, WDR33, CPSF-30 and an AAUAAA RNA at 3.4 Å resolution. Strikingly, the AAUAAA PAS assumes an unusual conformation that allows this short motif to be bound directly by both CPSF-30 and WDR33. The A1 and A2 bases are recognized specifically by zinc finger 2 (ZF2) of CPSF-30 and the A4 and A5 bases by ZF3. Interestingly, the U3 and A6 bases form an intramolecular Hoogsteen base pair and directly contact WDR33. CPSF-160 functions as an essential scaffold and pre-organizes CPSF-30 and WDR33 for high-affinity binding to AAUAAA. Our findings provide an elegant molecular explanation for how PAS sequences are recognized for mRNA 3′-end formation.
Simultaneous CRISPR/Cas9-mediated editing of cassavaeIF4EisoformsnCBP-1andnCBP-2reduces cassava brown streak disease symptom severity and incidence
Authors: Gomez Michael A. , Lin Z. Daniel , Moll Theodore , Chauhan Raj Deepika , Renninger Kelley , Beyene Getu , Taylor Nigel J. , Carrington J. , Staskawicz B. , Bart R. 
Published: October 2017

SummaryCassavabrownstreakdisease (CBSD) is a major constraint on cassava yields in East and Central Africa and threatens production in West Africa. CBSD is caused by two species of positive sense RNA viruses belonging to the familyPotyviridae, genusIpomovirus:Cassavabrownstreakvirus(CBSV) andUgandancassavabrownstreakvirus(UCBSV). Diseases caused by the familyPotyviridaerequire the interaction of viral genome-linked protein (VPg) and hosteukaryotic translationinitiationfactor4E(eIF4E) isoforms. Cassava encodes five eIF4E proteins: eIF4E, eIF(iso)4E-1, eIF(iso)4E-2,novelcap-bindingprotein-1(nCBP-1), and nCBP-2. Protein-protein interaction experiments consistently found that VPg proteins associate with cassava nCBPs. CRISPR/Cas9-mediated genome editing was employed to generatencbp-1, ncbp-2, andncbp-1/ncbp-2mutants in cassava cultivar 60444. Challenge with CBSV showed thatncbp-1/ncbp-2mutants displayed delayed and attenuated CBSD aerial symptoms, as well as reduced severity and incidence of storage root necrosis. Suppressed disease symptoms were correlated with reduced virus titer in storage roots relative to wild-type controls. Our results demonstrate the ability to modify multiple genes simultaneously in cassava to achieve tolerance to CBSD. Future studies will investigate the contribution of remaining eIF4E isoforms on CBSD and translate this knowledge into an optimized strategy for protecting cassava from disease.
Robustness encoded across essential and accessory replicons in an ecologically versatile bacterium
Authors: diCenzo George C , Benedict Alex B , Fondi Marco , Walker Graham C , Finan Turlough M , Mengoni Alessio , Griffitts Joel S 
Published: October 2017

ABSTRACTBacterial genome evolution is characterized by gains, losses, and rearrangements of functional genetic segments. The extent to which genotype-phenotype relationships are influenced by large-scale genomic alterations has not been investigated in a high-throughput manner. In the symbiotic soil bacteriumSinorhizobium meliloti,the genome is composed of a chromosome and two large extrachromosomal replicons (pSymA and pSymB, which together constitute 45% of the genome). Massively parallel transposon insertion sequencing (Tn-seq) was employed to evaluate contributions of chromosomal genes to fitness in both the presence and absence of these extrachromosomal replicons. Ten percent of chromosomal genes from diverse functional categories are shown to genetically interact with pSymA and pSymB. These results demonstrate the pervasive robustness provided by the extrachromosomal replicons, which is further supported by constraint-based metabolic modelling. A comprehensive picture of coreS. melilotimetabolism was generated through a Tn-seq-guidedin silicometabolic network reconstruction, producing a core network encompassing 726 genes. This integrated approach facilitated functional assignments for previously uncharacterized genes, while also revealing that Tn-seq alone misses over a quarter of wild type metabolism. This work highlights the strong functional dependencies and epistatic relationships that may arise between bacterial replicons and across a genome, while also demonstrating how Tn-seq and metabolic modelling can be used together to yield insights not obtainable by either method alone.
Subsurface Zircons with Presumptive “Biogenic” Inclusions as Potentially Useful Proxies for Studying Precambrian Bygone Biospheres in Goa
Authors: Sujata Dabolkar , Nandkumar Kamat 
Published: October 2017

AbstractThis work was inspired by recent report by Bell et al., 2015 who studied potentially biogenic carbon preserved in a 4.1 billion-year-old Zircon and need to assess the potential of Zircons found in Goa. Zircons (ZrSiO4) are naturally occurring silicate minerals which show radioactivity and high ductility and contain traces of Thorium and Uranium useful in Uranium–Thorium /Thorium −230 dating techniques. Zircons can be found in igneous, metamorphic rocks, sedimentary deposits and occurs as a detrital minerals in river and beach sands. Previous reports show that the Zircons can occur in different shapes such as round, elongated and with surface characteristics (Gartner et al.,2013). U-Pb Zircon dating methods had been used to study the continental growth in the western Dharwar craton of southern India (Jayananda et al., 2015). The present study was aimed at detection of subsurface Zircons with biogenic inclusions and assess their use as proxies for studying bygone Precambrium biospheres in Goa. Deep tubewell drilled Cores (60 and 65 m deep from surface) in island of Tiswadi at Taleigao were analyzed by light microscopy, Phase contrast microscopy and SEM to detect and classify the Zircons. In rapid preliminary sampling, total 50 Zircons were identified and 98% indicated the presence of interesting inclusions. These could be bubbles or kerogens or unidentified biological material. Zircons were classified as elongated, slightly rounded with sharp edges and showed widespread variety of surface characteristics like fracturing, cracks, scratches, striations and impact pits which may occur during transport processes. It is suggested that Zircons with presumptive biogenic inclusions can be further studied using techniques such as Raman Spectroscopy, Carbon Isotopic Measurements, X-Ray Microscopy, Trace Element Measurement consistent with Bell et al., 2015. More exhaustive studies have been undertaken to create a detail image database of Zircons from various other local samples to pinpoint those specifically useful for advanced work based on image analysis of the presumptive bioinclusions. Further attempts would be made to develop specific harvesting techniques to select potentially useful Zircons. International collaborations would be sought for applications of advanced techniques to local Zircons. Such studies would shed light on nature of bygone Precambrian biospheres in Goa and help in understanding evolution of life and the impact of plate tectonics and cataclysmic events shaping life on this planet.
Probabilistic Graphical Models Relate Immune Status with Response to Neoadjuvant Chemo-Therapy in Breast Cancer
Authors: Zapater-Moros Andrea , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , Trilla-Fuertes Lucía , Arevalillo Jorge M , Díaz-Almirón Mariana , Navarro Hilario , Maín Paloma , Feliú Jaime , Zamora Pilar , Espinosa Enrique , Fresno Vara Juan Ángel 
Published: October 2017

ABSTRACTBreast cancer is the most frequent tumor in women and its incidence is increasing. Neoadjuvant chemotherapy has become standard of care as a complement to surgery in locally advanced or poor-prognosis early stage disease. The achievement of a complete response to neoadjuvant chemotherapy correlates with prognosis but it is not possible to predict who will obtain an excellent response. The molecular analysis of the tumor offers a unique opportunity to unveil predictive factors. In this work, gene expression profiling in 279 tumor samples from patients receiving neoadjuvant chemotherapy was performed and probabilistic graphical models were used. This approach enables addressing biological and clinical questions from a Systems Biology perspective, allowing to deal with large gene expression data and their interactions. Tumors presenting complete response to neoadjuvant chemotherapy had a higher activity of immune related functions compared to resistant tumors. Similarly, samples from complete responders presented higher expression of lymphocyte cell lineage markers, immune-activating and immune-suppressive markers, which may correlate with tumor infiltration by lymphocytes (TILs). These results suggest that the patient’s immune system plays a key role in tumor response to neoadjuvant treatment. However, future studies with larger cohorts are necessary to validate these hypotheses.
Prediction and interpretation of deleterious coding variants in terms of protein structural stability
Authors: Ancien F. , Pucci F. , Godfroid M. , Rooman M. 
Published: October 2017

ABSTRACTThe classification of human genetic variants into deleterious and neutral is a challenging issue, whose complexity is rooted in the large variety of biophysical mechanisms that can be responsible for disease conditions. For non-synonymous mutations in structured proteins, one of these is the protein stability change, which can lead to functionality loss. We developed a stability-driven knowledge-based classifier that uses protein structure, artificial neural networks and solvent accessibility-dependent combinations of statistical potentials to predict whether destabilizing or stabilizing mutations are disease-causing. Our predictor yields a balanced accuracy of 71% in cross validation. As expected, it has a very high positive predictive value of 89%: it predicts with high accuracy the subset of mutations that are deleterious because of stability issues, but is by construction unable of classifying variants that are deleterious for other reasons. Its combination with an evolutionary-based predictor increases the balanced accuracy up to 75%, and allowed predicting more than 1/4 of the deleterious variants with 95% positive predictive value. Our method, called SNPMuSiC, can be used with both experimental and structural models and compares favorably with other prediction tools on several independent test sets. It constitutes a step towards interpreting variant effects at the molecular scale.
The self-organization of plant microtubules in three dimensions enable stable cortical localization and sensitivity to external cues
Authors: Mirabet Vincent , Krupinski Pawel , Hamant Olivier , Meyerowitz Elliot M , Jönsson Henrik , Boudaoud Arezki 
Published: October 2017

AbstractMany cell functions rely on the ability of microtubules to self-organize as complex networks. In plants, cortical microtubules are essential to determine cell shape as they guide the deposition of cellulose microfibrils, and thus control mechanical anisotropy in the cell wall. Here we analyze how, in turn, cell shape may influence microtubule behavior. Using a computational model of microtubules enclosed in a three-dimensional space, We show that the microtubule network has spontaneous configurations that could explain many experimental observations without resorting to specific regulation. In particular, we find that the preferred localization of microtubules at the cortex emerges from directional persistence of the microtubules, combined with their growth mode. We identified microtubule parameters that seem relatively insensitive to cell shape, such as length or number. In contrast, microtubule array anisotropy depends strongly on local curvature of the cell surface and global orientation follows robustly the longest axis of the cell. Lastly, we found that the network is capable of reorienting toward weak external directional cues. Altogether our simulations show that the microtubule network is a good transducer of weak external polarity, while at the same time, it easily reaches stable global configurations.Author summaryPlants exhibit an astonishing diversity in architecture and shape. A key to such diversity is the ability of their cells to coordinate and grow to reach a broad spectrum of sizes and shapes. Cell growth in plants is guided by the microtubule cytoskeleton. Here, we seek to understand how microtubules self-organize close to the cell surface. We build upon previous two-dimensional models and we consider microtubules as lines growing in three dimensions, accounting for interactions between microtubules or between microtubules and the cell surface. We show that microtubule arrays are able to adapt to various cell shapes and to reorient in response to factors such as signals or environment. Altogether, our results help to understand how the microtubule cytoskeleton contributes to the diversity of plant shapes and to how these shapes adapt to environment.
Restriction of dietary protein leads to conditioned protein preference and elevated palatability of protein-containing food in rats
Authors: Murphy Michelle , Peters Kate Z. , Denton Bethany S. , Lee Kathryn A. , Chadchankar Heramb , McCutcheon James E. 
Published: October 2017

AbstractThe mechanisms by which intake of dietary protein is regulated are poorly understood despite their potential involvement in determining food choice and appetite. In particular, it is unclear whether protein deficiency results in a specific appetite for protein and whether influences on diet are immediate or develop over time. To determine the effects of protein restriction on consumption, preference, and palatability for protein we assessed patterns of intake for casein (protein) and maltodextrin (carbohydrate) solutions in adult rats. To induce a state of protein restriction, rats were maintained on a low protein diet (5% casein) and compared to control rats on non-restricted diet (20% casein). Under these dietary conditions, relative to control rats, protein-restricted rats exhibited hyperphagia without weight gain. After two weeks, on alternate conditioning days, rats were given access to either isocaloric casein or maltodextrin solutions that were saccharin-sweetened and distinctly flavoured whilst consumption and licking patterns were recorded. This allowed rats to learn about the post-ingestive nutritional consequences of the two different solutions. Subsequently, during a preference test when rats had access to both solutions, we found that protein-restricted rats exhibited a preference for casein over carbohydrate whereas non-restricted rats did not. Analysis of lick microstructure revealed that this preference was associated with an increase in cluster size and number, reflective of an increase in palatability. In conclusion, protein-restriction induced a conditioned preference for protein, relative to carbohydrate, and this was associated with increased palatability.
Deep-RBPPred: Predicting RNA binding proteins in the proteome scale based on deep learning
Authors: Zheng Jinfang , Zhang Xiaoli , Zhao Xunyi , Tong Xiaoxue , Hong Xu , Xie Juan , Liu Shiyong 
Published: October 2017

AbstractRNA binding protein (RBP) plays an important role in cell processes. Identifying RBPs by computation and experiment are both essential. Recently, RBPPred is proposed in our group to predict RBP with a high performance. However, RBPPred is too slow for that it will generate PSSM matrix as its feature. Herein, we develop a deep learning model called Deep-RBPPred. The model has three advantages comparing to previous models. 1. Deep-RBPPred only needs few physicochemical properties. 2. Deep-RBPPred runs much faster. 3. Deep-RBPPred has a good generalization ability. In the meantime, the performance is still as good as the stats-of-the-art method. In the testing in A. thaliana, S. cerevisiae and H. sapiens proteomics, MCC (AUC) are 0.6077 (0.9421), 0.573 (0.9034) and 0.8141(0.9515) respectively when the score cutoff is set to 0.5. In the verifying in Gerstberger-1538, the SN of our model is 90.38%. The running times are 9s, 7s, 8s and 10s, respectively, for H.sapiens, A.thaliana, S.cerevisiae and Gerstberger-1538 when it is tested in GPU. Deep-RBPPred forecasts 94.65% of 299 new RBP and about 8% higher sensitivity than RBPPred. We also apply deep-RBPPred in 19 eukaryotes proteomics and 11 bacteria proteomics downloaded from Uniprot. The result shows that rate of RBPs in eukaryotes proteome are much higher than bacteria proteome. Testing in 6 proteomics shows the many RBPs may be still undiscovered so far.
In vivoRNA targeting of point mutations via suppressor tRNAs and adenosine deaminases
Authors: Katrekar Dhruva , Mali Prashant 
Published: October 2017

ABSTRACTPoint mutations underlie many genetic diseases. In this regard, while programmable DNA nucleases have been used to repair mutations, their use for gene therapy poses multiple challenges: one, efficiency of homologous recombination is typically low in cells; two, an active nuclease presents a risk of introducing permanent off-target mutations; and three, prevalent programmable nucleases typically comprise elements of non-human origin raising the potential ofin vivoimmunogenicity. In light of these, approaches to instead directly target RNA, and use of molecular machinery native to the host would be highly desirable. Towards this, we engineered and optimized two complementary approaches, referred together hereon astRiAD, based on the use oftRNAsin codon suppression andadenosinedeaminases in RNA editing. Specifically, by delivering modified endogenous tRNAs and/or the RNA editing enzyme ADAR2 and an associated guiding RNA (adRNA) via adeno-associated viruses, we enabled premature stop codon read-through and correction in themdxmouse model of muscular dystrophy that harbors a nonsense mutation in the dystrophin gene. We further demonstrated inducible restoration of dystrophin expression by pyrolysyl-tRNA mediated incorporation of unnatural amino acids (UAAs) at the stop codon. Additionally, we also engineered ADAR2 mediated correction of a point mutation in liver RNA of thespfashmouse model of ornithine transcarbamylase (OTC) deficiency. Taken together, our results establish the use of suppressor tRNAs and ADAR2 forin vivoRNA targeting, and this integrated tRiAD approach is robust, genomically scarless, and potentially non-immunogenic as it utilizes effector RNAs and human proteins.
Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke
Authors: Rao Abhiram S. , Lindholm Daniel , Rivas Manuel A. , Knowles Joshua W. , Montgomery Stephen B. , Ingelsson Erik 
Published: October 2017

AbstractPCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.
Accounting for Apparent Deviations between Calorimetric and van’t Hoff Enthalpies
Authors: Kantonen Samuel A. , Henriksen Niel M. , Gilson Michael K. 
Published: October 2017

AbstractBackgroundIn theory, binding enthalpies directly obtained from calorimetry (such as ITC) and the temperature dependence of the binding free energy (van’t Hoff method) should agree. However, previous studies have often found them to be discrepant.MethodsExperimental binding enthalpies (both calorimetric and van’t Hoff) are obtained for two host-guest pairs using ITC, and the discrepancy between the two enthalpies is examined. Modeling of artificial ITC data is also used to examine how different sources of error propagate to both types of binding enthalpies.ResultsFor the host-guest pairs examined here, good agreement, to within about 0.4 kcal/mol, is obtained between the two enthalpies. Additionally, using artificial data, we find that different sources of error propagate to either enthalpy uniquely, with concentration error and heat error propagating primarily to calorimetric and van’t Hoff enthalpies, respectively.ConclusionsWith modern calorimeters, good agreement between van’t Hoff and calorimetric enthalpies should be achievable, barring issues due to non-ideality or unanticipated measurement pathologies. Indeed, disagreement between the two can serve as a flag for error-prone datasets. A review of the underlying theory supports the expectation that these two quantities should be in agreement.General SignificanceWe address and arguably resolve long-standing questions regarding the relationship between calorimetric and van’t Hoff enthalpies. In addition, we show that comparison of these two quantities can be used as an internal consistency check of a calorimetry study.HighlightsAgreement within ~0.4 kcal/mol between calorimetric and van’t Hoff enthalpies can be achieved for systems with typical heat and concentration errors, if solution non-ideality is not an issue.Concentration error chiefly affects calorimetric enthalpies, while error in measured heat chiefly affects van’t Hoff enthalpies.Large discrepancies between calorimetric and van’t Hoff enthalpies can be used to flag experimental error.There is no theoretical basis to expect discrepancies between these two methods of determining the binding enthalpy.