bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α
Authors: Faubert Brandon , Vincent Emma E. , Griss Takla , Samborska Bozena , Izreig Said , Svensson Robert U. , Mamer Orval A. , Avizonis Daina , Shackelford David B. , Shaw Reuben J. , Jones Russell G. 
Published: February 2014

Significance
Liver kinase B1 (LKB1) is a serine/threonine kinase often inactivated in human cancer. We demonstrate here that loss of LKB1 expression in cancer cells promotes a progrowth metabolic profile that enables increased cell growth and proliferation. Loss of LKB1 promotes increased tumor cell metabolism through mammalian target of rapamycin complex 1- and reactive oxygen species-dependent increases in hypoxia-inducible factor-1α (HIF-1α). LKB1-null cells are dependent on HIF-1α to maintain cellular ATP and viability under poor nutrient conditions, raising the possibility of targeting HIF-1α for synthetic lethality in LKB1-deficient tumors. Together, our data reveal that regulation of cellular metabolism is a key function of LKB1 that may contribute to its tumor-suppressor function in human cancer.
Quasicrystalline tilings with nematic colloidal platelets
Authors: Dontabhaktuni Jayasri , Ravnik Miha , Žumer Slobodan 
Published: February 2014

Significance
Complex nematic fluids have the remarkable capability to organize microparticles and nanoparticles into regular structures of various symmetries and dimensionality, according to their micromolecular orientational order. Structures of particles such as chains, clusters, and crystals are found, but no quasicrystals. In this paper, we demonstrate that quasicrystalline structures can be achieved in the form of Penrose tiling by assembling microplatelets in the shape of pentagons within a thin layer of nematic fluid. The tiling is energetically stabilized with binding energies of typically several orders of magnitude higher than thermal energy and further allows for hierarchical substitution of individual pentagonal tiles with smaller tiles, which is interesting for the design of photonics at multiple frequency ranges.
Predicting the spatiotemporal dynamics of hair follicle patterns in the developing mouse
Authors: Cheng Chi Wa , Niu Ben , Warren Mya , Pevny Larysa Halyna , Lovell-Badge Robin , Hwa Terence , Cheah Kathryn S. E. 
Published: February 2014

Significance
The establishment of orderly patterns in living systems is fascinating. While the Turing class of reaction–diffusion models defines a paradigm for the emergence of primary patterns, we propose here a much simpler expansion–induction (EI) model for the formation of secondary patterns. The EI model is derived from a simple geometric rule revealed by quantitative analysis of the patterns of secondary hair follicles in the developing mouse. It is driven by the physical growth of the embryo and is able to predict the formation of secondary follicles spatially and temporally, given only the locations of primary follicles. The robustness of the EI model provides an important advance by allowing comparison to real biological patterns beyond the qualitative, visual level.
Ancient west Eurasian ancestry in southern and eastern Africa
Authors: Pickrell Joseph K. , Patterson Nick , Loh Po-Ru , Lipson Mark , Berger Bonnie , Stoneking Mark , Pakendorf Brigitte , Reich David 
Published: February 2014

Significance
The hunter–gatherer and pastoralist populations of southern Africa are among the culturally, linguistically, and genetically most diverse human populations. However, little is known about their history. We show that all of these populations have some ancestry most closely related to Europeans and Middle Easterners and use this to reconstruct the history of population movements between Eurasia, eastern Africa, and southern Africa.
ATP turnover by individual myosin molecules hints at two conformers of the myosin active site
Authors: Amrute-Nayak Mamta , Lambeck Katharina-Antonia , Radocaj Ante , Huhnt Helen Elisabeth , Scholz Tim , Hahn Nils , Tsiavaliaris Georgios , Walter Wilhelm J. , Brenner Bernhard 
Published: February 2014

Significance
Myosins use adenosine-5′-triphosphate (ATP) hydrolysis to drive motile functions, including muscle contraction. The main steps of ATP hydrolysis were previously identified by solution studies. Observing individual myosin molecules, one by one, interacting with fluorescently-labeled ATP, we found for one and the same myosin molecule two residence times for fluorescent ATP, a long lived, consistent with solution studies, and an unexpected short lived. Kinetic modeling suggests that this results from two active site conformers. In ensemble studies, generation of both dwell times from one myosin molecule had been indistinguishable from generation by a heterogeneous population of myosin molecules, demonstrating the power of molecule-by-molecule analysis to uncover previously undetected kinetic features and to distinguish, for example, different isoforms or mutant from wild-type molecules even in mixed populations.
In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain
Authors: Xie Hong , Liu Yu , Zhu Youzhi , Ding Xinlu , Yang Yuhao , Guan Ji-Song 
Published: February 2014

Significance
This study demonstrates how sensory information is represented and stored in cortical circuits during complex behavior in the mammalian brain. Using a newly established automatic algorithm for cell detection, we tracked the expression of immediate early genes from more than 20,000 neurons in each living mouse for 2 mo, revealing quantitative signal changes in each neuron within a local cortical circuit. A natural behavioral task induced sparse and task-specific neuronal activation in cortical layer II. The gradually formed sparse activation of neurons was observed in multiple cortical areas. Our results support the concept of consolidation for long-term memory storage in cortical circuits and demonstrate the representation of natural events as sparse coding in the mammalian brain.
PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair
Authors: Khoury-Haddad Hanan , Guttmann-Raviv Noga , Ipenberg Inbal , Huggins David , Jeyasekharan Anand D. , Ayoub Nabieh 
Published: February 2014

Significance
Sophisticated DNA damage repair mechanisms are required to fix DNA lesions and preserve the integrity of the genome. This manuscript provides characterization of KDM4D role in promoting the repair of double-strand breaks (DSBs). Our findings show that KDM4D lysine demethylase is swiftly recruited to DNA breakage sites via its C-terminal region in a PARP1-dependent manner. Further, we have uncovered an exciting function of KDM4D in regulating the association of the DNA damage response master kinase, ATM, with chromatin, thus explaining the defective phosphorylation of ATM substrates found in KDM4D-depleted cells. Altogether, this study advances our understanding of the molecular mechanisms that regulate the repair of DSBs, a critical pathway that is essential for maintaining genome integrity.
Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors
Authors: Laayouni Hafid , Oosting Marije , Luisi Pierre , Ioana Mihai , Alonso Santos , Ricaño-Ponce Isis , Trynka Gosia , Zhernakova Alexandra , Plantinga Theo S. , Cheng Shih-Chin , van der Meer Jos W. M. , Popp Radu , Sood Ajit , Thelma B. K. , Wijmenga Cisca , Joosten Leo A. B. , Bertranpetit Jaume , Netea Mihai G. 
Published: February 2014

Significance
This article gives a unique perspective on the impact of evolution on the immune system under pressure by infections, using the special demographic history of Europe in which two populations with different genetic ancestry, Europeans and Rroma (Gypsies), have lived in the same geographic area and have been exposed to similar environmental hazards, including infections. We identified convergent evolution signals in genes from different human populations. Reconstruction of evolutionary history of European populations has identified Toll-like receptor 1 (TLR1)/TLR6/TLR10 as a pattern recognition pathway shaped by convergent evolution by infections, among which plague is a likely cause, influencing the survival of these populations during the infection.
Mapping the diatom redox-sensitive proteome provides insight into response to nitrogen stress in the marine environment
Authors: Rosenwasser Shilo , Graff van Creveld Shiri , Schatz Daniella , Malitsky Sergey , Tzfadia Oren , Aharoni Asaph , Levin Yishai , Gabashvili Alexandra , Feldmesser Ester , Vardi Assaf 
Published: February 2014

Significance
Phytoplankton form massive blooms in the oceans that are controlled by nutrients, light availability, and biotic interactions with grazers and viruses. Although phytoplankton were traditionally considered passive drifters with currents here we demonstrate how diatom cells sense and respond to oxidative stress through a redox-sensitive protein network. We further demonstrate the redox sensitivity of nitrogen assimilation, which is essential for diatom blooms in the ocean, and provide compelling evidence for organelle-specific oxidation patterns under nitrogen stress conditions using a genetically encoded redox sensor. We propose that redox regulation of metabolic rates in the response to stress provides a mechanism of acclimation to rapid fluctuations in the chemophysical gradients in the marine environment.
Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes
Authors: Zhang Li , Crawford Frances , Yu Liping , Michels Aaron , Nakayama Maki , Davidson Howard W. , Kappler John W. , Eisenbarth George S. 
Published: February 2014

SignificanceAntigen-specific therapies are lacking for autoimmunity diseases. The recent discovery of the nature of the IAg7–insulin complex that drives type 1 diabetes in nonobese diabetic (NOD) mice has allowed us to create a monoclonal antibody specific for this complex. This antibody delays diabetes development in NOD mice. Given the similarities between IAg7and the human diabetes risk alleles, HLA-DQ2 and HLA-DQ8, this work encourages the development of similar monoclonal antibodies for the treatment of the human disease.
Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission
Authors: Corces-Zimmerman M. Ryan , Hong Wan-Jen , Weissman Irving L. , Medeiros Bruno C. , Majeti Ravindra 
Published: February 2014

Significance
A growing body of evidence has determined that somatic mutations in acute myeloid leukemia (AML) accumulate in self-renewing hematopoietic stem cells (HSCs). Thus, at the time of diagnosis, AML patients harbor preleukemic HSCs containing some, but not all, of the mutations in the downstream leukemia. Despite these findings, common patterns of preleukemic clonal evolution have not been determined, nor has the response of preleukemic HSCs to standard therapy been identified. This report addresses both of these questions determining that there are common patterns of preleukemic clonal evolution in AML, and that these preleukemic HSCs often survive standard induction chemotherapy. This study is of interest to the AML field, and broadly in cancer genomics as the principle that stem cells acquire initial cancer-initiating mutations is likely to extend beyond AML.
Functional architecture of MFSd-glucose transporters
Authors: Madej M. Gregor , Sun Linfeng , Yan Nieng , Kaback H. Ronald 
Published: February 2014

SignificanceThe crystallographic model of the Major Facilitator Superfamily (MFS) member,d-xylose permease XylE fromEscherichia coli, a homologue of humand-glucose transporters, the GLUTs (SLC2), provides a structural framework for the identification and physical localization of crucial residues in transporters with medical relevance (i.e. the GLUTs). The mechanism and substrate specificity of human and prokaryotic sugar transporters are discussed by using homology modeling, molecular docking, and experimentation. Substrate-specificity determinants for XylE, GLUT1, and GLUT5 are proposed. Furthermore, concepts derived from other bacterial MFS transporters are examined for their relevance to the GLUTs by comparing conservation of critical residues. XylE mutants that mimic the characteristics of GLUT1 are tested, revealing that uniport and symport are mechanistically related.
Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation
Authors: Staal Ben , Williams Bart O. , Beier Frank , Vande Woude George F. , Zhang Yu-Wen 
Published: February 2014

Significance
Mitogen-inducible gene 6 (Mig-6) was found to be an important factor in maintaining joint homeostasis, and its loss in mice results in the development of an osteoarthritis (OA)-like disorder in multiple synovial joints. However, it was unclear in what cells Mig-6 was expressed and what cells were causal for developing the OA-like phenotype. Here we report that Mig-6 is uniquely expressed in the cells surrounding entire surface of the synovial joint, including chondrocytes in the superficial zone of the articular cartilage and in the meniscus, and synovial lining cells. We found that although chondrocytes play a critical role in developing the OA-like disorder in the knees, other cell types are likely required for full development of the Mig-6–deficient joint phenotype.
SegAnnDB: interactive Web-based genomic segmentation
Authors: Hocking Toby D. , Boeva Valentina , Rigaill Guillem , Schleiermacher Gudrun , Janoueix-Lerosey Isabelle , Delattre Olivier , Richer Wilfrid , Bourdeaut Franck , Suguro Miyuki , Seto Masao , Bach Francis , Vert Jean-Philippe 
Published: February 2014

Abstract
Motivation: DNA copy number profiles characterize regions of chromosome gains, losses and breakpoints in tumor genomes. Although many models have been proposed to detect these alterations, it is not clear which model is appropriate before visual inspection the signal, noise and models for a particular profile.
Results: We propose SegAnnDB, a Web-based computer vision system for genomic segmentation: first, visually inspect the profiles and manually annotate altered regions, then SegAnnDB determines the precise alteration locations using a mathematical model of the data and annotations. SegAnnDB facilitates collaboration between biologists and bioinformaticians, and uses the University of California, Santa Cruz genome browser to visualize copy number alterations alongside known genes.
Availability and implementation: The breakpoints project on INRIA GForge hosts the source code, an Amazon Machine Image can be launched and a demonstration Web site is http://bioviz.rocq.inria.fr.
Contact: toby@sg.cs.titech.ac.jp
Supplementary information: Supplementary data are available at Bioinformatics online.
An antisense promoter in mouse L1 retrotransposon open reading frame-1 initiates expression of diverse fusion transcripts and limits retrotransposition
Authors: Li Jingfeng , Kannan Manoj , Trivett Anna L. , Liao Hongling , Wu Xiaolin , Akagi Keiko , Symer David E. 
Published: February 2014

Abstract
Between 6 and 30% of human and mouse transcripts are initiated from transposable elements. However, the promoters driving such transcriptional activity are mostly unknown. We experimentally characterized an antisense (AS) promoter in mouse L1 retrotransposons for the first time, oriented antiparallel to the coding strand of L1 open reading frame-1. We found that AS transcription is mediated by RNA polymerase II. Rapid amplification of cDNA ends cloning mapped transcription start sites adjacent to the AS promoter. We identified &gt;100 novel fusion transcripts, of which many were conserved across divergent mouse lineages, suggesting conservation of potential functions. To evaluate whether AS L1 transcription could regulate L1 retrotransposition, we replaced portions of native open reading frame-1 in donor elements by synonymously recoded sequences. The resulting L1 elements lacked AS promoter activity and retrotransposed more frequently than endogenous L1s. Overexpression of AS L1 transcripts also reduced L1 retrotransposition. This suppression of retrotransposition was largely independent of Dicer. Our experiments shed new light on how AS fusion transcripts are initiated from endogenous L1 elements across the mouse genome. Such AS transcription can contribute substantially both to natural transcriptional variation and to endogenous regulation of L1 retrotransposition.
Anesthesia-related Cardiac Arrest
Authors: Ellis Sheila J. , Newland Myrna C. , Simonson Jean A. , Peters K. Reed , Romberger Debra J. , Mercer David W. , Tinker John H. , Harter Ronald L. , Kindscher James D. , Qiu Fang , Lisco Steven J. 
Published: February 2014

Abstract

Background:
Much is still unknown about the actual incidence of anesthesia-related cardiac arrest in the United States.

Methods:
The authors identified all of the cases of cardiac arrest from their quality improvement database from 1999 to 2009 and submitted them for review by an independent study commission to give them the best estimate of anesthesia-related cardiac arrest at their institution. One hundred sixty perioperative cardiac arrests within 24 h of surgery were identified from an anesthesia database of 217,365 anesthetics. An independent study commission reviewed all case abstracts to determine which cardiac arrests were anesthesia-attributable or anesthesia-contributory. Anesthesia-attributable cardiac arrests were those cases in which anesthesia was determined to be the primary cause of cardiac arrest. Anesthesia-contributory cardiac arrests were those cases where anesthesia was determined to have contributed to the cardiac arrest.

Results:
Fourteen cardiac arrests were anesthesia-attributable, resulting in an incidence of 0.6 per 10,000 anesthetics (95% CI, 0.4 to 1.1). Twenty-three cardiac arrests were found to be anesthesia-contributory resulting in an incidence of 1.1 per 10,000 anesthetics (95% CI, 0.7 to 1.6). Sixty-four percent of anesthesia-attributable cardiac arrests were caused by airway complications that occurred primarily with induction, emergence, or in the postanesthesia care unit, and mortality was 29%. Anesthesia-contributory cardiac arrest occurred during all phases of the anesthesia, and mortality was 70%.

Conclusion:
As judged by an independent study commission, anesthesia-related cardiac arrest occurred in 37 of 160 cardiac arrests within the 24-h perioperative period.
Modeling bi-modality improves characterization of cell cycle on gene expression in single cells
Authors: McDavid Andrew , Dennis Lucas , Danaher Patrick , Finak Greg , Krouse Michael , Wang Alice , Webster Philippa , Beechem Joseph , Gottardo Raphael 
Published: February 2014

AbstractAdvances in high-throughput, single cell gene expression are allowing interrogation of cell heterogeneity. However, there is concern that the cell cycle phase of a cell might bias characterizations of gene expression at the single-cell level. We assess the effect of cell cycle phase on gene expression in single cells by measuring 333 genes in 930 cells across three phases and three cell lines. We determine each cell’s phase non-invasively without chemical arrest and use it as a covariate in tests of differential expression. We observe bi-modal gene expression, a previously-described phenomenon, wherein the expression of otherwise abundant genes is either strongly positive, or undetectable within individual cells. This bi-modality is likely both biologically and technically driven. Irrespective of its source, we show that it should be modeled to draw accurate inferences from single cell expression experiments. To this end, we propose a semi-continuous modeling framework based on the generalized linear model, and use it to characterize genes with consistent cell cycle effects across three cell lines. Our new computational framework improves the detection of previously characterized cell-cycle genes compared to approaches that do not account for the bi-modality of single-cell data. We use our semi-continuous modelling framework to estimate single cell gene co-expression networks. These networks suggest that in addition to having phase-dependent shifts in expression (when averaged over many cells), some, but not all, canonical cell cycle genes tend to be co-expressed in groups in single cells. We estimate the amount of single cell expression variability attributable to the cell cycle. We find that the cell cycle explains only 5%-17% of expression variability, suggesting that the cell cycle will not tend to be a large nuisance factor in analysis of the single cell transcriptome.
Improving Protein Docking with Constraint Programming and Coevolution Data
Authors: Krippahl Ludwig , Madeira Fábio 
Published: February 2014

BackgroundConstraint programming (CP) is usually seen as a rigid approach, focusing on crisp, precise, distinctions between what is allowed as a solution and what is not. At first sight, this makes it seem inadequate for bioinformatics applications that rely mostly on statistical parameters and optimization. The prediction of protein interactions, or protein docking, is one such application. And this apparent problem with CP is particularly evident when constraints are provided by noisy data, as it is the case when using the statistical analysis of Multiple Sequence Alignments (MSA) to extract coevolution information. The goal of this paper is to show that this first impression is misleading and that CP is a useful technique for improving protein docking even with data as vague and noisy as the coevolution indicators that can be inferred from MSA.ResultsHere we focus on the study of two protein complexes. In one case we used a simplified estimator of interaction propensity to infer a set of five candidate residues for the interface and used that set to constrain the docking models. Even with this simplified approach and considering only the interface of one of the partners, there is a visible focusing of the models around the correct configuration. Considering a set of 400 models with the best geometric contacts, this constraint increases the number of models close to the target (RMSD ¡5Å) from 2 to 5 and decreases the RMSD of all retained models from 26Å to 17.5Å. For the other example we used a more standard estimate of coevolving residues, from the Co-Evolution Analysis using Protein Sequences (CAPS) software. Using a group of three residues identified from the sequence alignment as potentially co-evolving to constrain the search, the number of complexes similar to the target among the 50 highest scoring docking models increased from 3 in the unconstrained docking to 30 in the constrained docking.ConclusionsAlthough only a proof-of-concept application, our results show that, with suitably designed constraints, CP allows us to integrate coevolution data, which can be inferred from databases of protein sequences, even though the data is noisy and often “fuzzy”, with no well-defined discontinuities. This also shows, more generally, that CP in bioinformatics needs not be limited to the more crisp cases of finite domains and explicit rules but can also be applied to a broader range of problems that depend on statistical measurements and continuous data.