bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activating killer cell immunoglobulin-like receptor 2DS2 binds to HLA-A*11
Authors: Liu Jingxian , Xiao Ziwei , Ko Hui Ling , Shen Meixin , Ren Ee Chee 
Published: February 2014

SignificanceKiller cell immunoglobulin-like receptors (KIRs) function as key recognition elements in innate immunity. Structural information for inhibitory KIRs 2DL2, 2DL1, and 3DL1 in complex with their respective HLA ligands is available, but such data for activating KIRs are lacking. We report here the successful crystallization and solved structure of the activating KIR2DS2 in complex with HLA-A*11:01. The structure clearly explains the role of Tyr45, which has long puzzled KIR researchers because it differentiates KIR2DS2 from all inhibitory KIRs, and is now shown to bind Thr80 of HLA-A*11:01. Using KIR2DS2 tetramers to bind HLA on live cells, we also provide evidence that peptide sequence can affect KIR–HLA binding. Our data thus resolve a long-standing problem in KIR biology.
Evolution and selection of river networks: Statics, dynamics, and complexity
Authors: Rinaldo Andrea , Rigon Riccardo , Banavar Jayanth R. , Maritan Amos , Rodriguez-Iturbe Ignacio 
Published: February 2014

Significance
Our focus is on a rich interdisciplinary problem touching on earth science, hydrology, and statistical mechanics—an understanding of the statics and dynamics of the network structures that we observe in the fluvial landscape, and their relation to evolution and selection of recurrent patterns of self-organization. It is an exemplar of how diverse ideas, numerical simulation, and elementary mathematics can come together to help solve the mystery of understanding a ubiquitous pattern of nature.
Platelets are efficient and protective depots for storage, distribution, and delivery of lysosomal enzyme in mice with Hurler Syndrome
Authors: Dai Mei , Han Jingfen , El-Amouri Salim S. , Brady Roscoe O. , Pan Dao 
Published: February 2014

Significance
The therapeutic potential of hematopoietic stem cell (HSC)-mediated gene therapy has been demonstrated in clinical trials, and yet the dilemma of the need for high transgene frequency to maximize expression while concurrently minimizing the associated increased risk of oncogenesis remains unresolved. Use of megakaryocytes (MKs)/platelets for transgene expression may take advantage of their rapid turnover and protective storage in platelets and reduce the risk of activating oncogenes in HSC. Here, we demonstrate that the MK/platelet lineage is capable of generating/storing a fully functional lysosomal enzyme and leads to highly efficient, continuous, and versatile transport/distribution of enzyme into the circulation and major diseased organs. This study provides proof of concept of MK/platelet as a depot for efficient production, delivery, and effective distribution of lysosomal enzymes.
Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer
Authors: Monk Brian C. , Tomasiak Thomas M. , Keniya Mikhail V. , Huschmann Franziska U. , Tyndall Joel D. A. , O’Connell Joseph D. , Cannon Richard D. , McDonald Jeffrey G. , Rodriguez Andrew , Finer-Moore Janet S. , Stroud Robert M. 
Published: February 2014

Significance
The absence in the Protein Data Bank of full-length structures of bitopic membrane proteins with one transmembrane helix, probably because of difficulties with ordered crystallization, has limited understanding of how single-transmembrane helices orient enzymes and sensors at the bilayer surface. X-ray crystal structures of full-length yeast lanosterol 14α-demethylase, a cytochrome P450, show how a helix spanning a single transmembrane may lead to constraints on the orientation of the putative substrate entry portal from within the bilayer. The crystal structures also locate the substrate lanosterol, identify putative substrate and product channels, and reveal constrained interactions with triazole antifungal drugs that are important for drug design and understanding the drug resistance associated with orthologs of the enzyme found in fungal pathogens.
Light responses of primate and other mammalian cones
Authors: Cao Li-Hui , Luo Dong-Gen , Yau King-Wai 
Published: February 2014

SignificanceWe aimed to solve a longstanding conundrum about the light response of primate cones. Unlike those of lower vertebrates, the primate cones’ response to light has long been reported as being biphasic. This surprise has also raised a yet-unanswered question about the requisite signal processing in the retina. More recently, human paired-flash electroretinographic data have challenged the biphasic waveform of the primate cone response. Our suction-pipette recordings from single primate cones now show directly that the light responses of primate and other mammalian cones are in fact very predominantly monophasic, much like those in invertebrates.
Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging
Authors: Eberlin Livia S. , Tibshirani Robert J. , Zhang Jialing , Longacre Teri A. , Berry Gerald J. , Bingham David B. , Norton Jeffrey A. , Zare Richard N. , Poultsides George A. 
Published: February 2014

SignificanceComplete resection of a tumor is associated with an improved prognosis for most types of solid malignancies. In gastric-cancer surgery, surgical-margin evaluation is commonly performed intraoperatively by histopathologic evaluation of frozen sections. However, frozen-section results are subjective and can be unreliable in up to 30% of patients undergoing resection of gastrointestinal cancers. We used desorption electrospray ionization mass spectrometric imaging (DESI-MSI) and the statistical method of least absolute shrinkage and selection operator (Lasso) to classify tissue as cancer or normal based on molecular information obtained from tissue and also to select those mass-spectra features most indicative of disease state. The results obtained using margin samples from nine gastric-cancer operations suggest that DESI-MSI/Lasso may be a valuable tool for routine intraoperative assessment of surgical margins during gastric-cancer surgery.
Dopamine dependency for acquisition and performance of Pavlovian conditioned response
Authors: Darvas Martin , Wunsch Amanda M. , Gibbs Jeffrey T. , Palmiter Richard D. 
Published: February 2014

SignificanceDopaminergic signaling is critical for many reward-related processes, including learning associations between stimuli and rewards (“Pavlovian learning”). Behavioral responses to reward-associated stimuli have been described as being initially directed either at the stimulus itself (“sign tracking”) or at the location of reward delivery (“goal tracking”). Although other studies have demonstrated that dopaminergic signaling is crucial for sign tracking, its role for goal-tracking behavior is less clear. Our approach uses genetic manipulations that allow determining whether dopamine is required for learning goal tracking and also which dopaminergic projections are most relevant for this behavior. Moreover, we report that instrumental learning can facilitate Pavlovian learning in mice that are impaired in Pavlovian learning but not in instrumental learning.
Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
Authors: Chatzigeorgiou Antonios , Seijkens Tom , Zarzycka Barbara , Engel David , Poggi Marjorie , van den Berg Susan , van den Berg Sjoerd , Soehnlein Oliver , Winkels Holger , Beckers Linda , Lievens Dirk , Driessen Ann , Kusters Pascal , Biessen Erik , Garcia-Martin Ruben , Klotzsche-von Ameln Anne , Gijbels Marion , Noelle Randolph , Boon Louis , Hackeng Tilman , Schulte Klaus-Martin , Xu Aimin , Vriend Gert , Nabuurs Sander , Chung Kyoung-Jin , Willems van Dijk Ko , Rensen Patrick C. N. , Gerdes Norbert , de Winther Menno , Block Norman L. , Schally Andrew V. , Weber Christian , Bornstein Stefan R. , Nicolaes Gerry , Chavakis Triantafyllos , Lutgens Esther 
Published: February 2014

Significance
Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism.
Inducible and titratable silencing ofCaenorhabditis elegansneurons in vivo with histamine-gated chloride channels
Authors: Pokala Navin , Liu Qiang , Gordus Andrew , Bargmann Cornelia I. 
Published: February 2014

SignificanceInducible silencing of neurons is a powerful method for studying the functions of neural circuits. We describe a system for inducible silencing ofCaenorhabditis elegansneurons, based on transgenicC. elegansnematodes engineered to produce the inhibitoryDrosophilahistamine-gated chloride channel (HisCl1) in specific neurons. The activity of HisCl1-expressing neurons is acutely and reversibly silenced by exogenous histamine, whichC. elegansabsorbs from the media. In addition to completely silencing neurons, the histamine-HisCl1 system can be used to titrate neural activity, demonstrating quantitative relationships between neural activity and behavior. The histamine-HisCl1 system is complementary to other methods of monitoring and manipulating neuronal activity, providing opportunities for combinatorial control of circuits.
ARTS: automated randomization of multiple traits for study design
Authors: Maienschein-Cline Mark , Lei Zhengdeng , Gardeux Vincent , Abbasi Taimur , Machado Roberto F. , Gordeuk Victor , Desai Ankit A. , Saraf Santosh , Bahroos Neil , Lussier Yves 
Published: February 2014

Abstract
Summary: Collecting data from large studies on high-throughput platforms, such as microarray or next-generation sequencing, typically requires processing samples in batches. There are often systematic but unpredictable biases from batch-to-batch, so proper randomization of biologically relevant traits across batches is crucial for distinguishing true biological differences from experimental artifacts. When a large number of traits are biologically relevant, as is common for clinical studies of patients with varying sex, age, genotype and medical background, proper randomization can be extremely difficult to prepare by hand, especially because traits may affect biological inferences, such as differential expression, in a combinatorial manner. Here we present ARTS (automated randomization of multiple traits for study design), which aids researchers in study design by automatically optimizing batch assignment for any number of samples, any number of traits and any batch size.
Availability and implementation: ARTS is implemented in Perl and is available at github.com/mmaiensc/ARTS. ARTS is also available in the Galaxy Tool Shed, and can be used at the Galaxy installation hosted by the UIC Center for Research Informatics (CRI) at galaxy.cri.uic.edu.
Contact: mmaiensc@uic.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
PARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage
Authors: Das Benu Brata , Huang Shar-yin N. , Murai Junko , Rehman Ishita , Amé Jean-Christophe , Sengupta Souvik , Das Subhendu K. , Majumdar Papiya , Zhang Hongliang , Biard Denis , Majumder Hemanta K. , Schreiber Valérie , Pommier Yves 
Published: February 2014

AbstractPoly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for trapped Top1cc, hydrolyzes the phosphodiester bond between the DNA 3′-end and the Top1 tyrosyl moiety. Alternative repair pathways for Top1cc involve endonuclease cleavage. However, it is unknown what determines the choice between TDP1 and the endonuclease repair pathways. Here we show that PARP1 plays a critical role in this process. By generating TDP1 and PARP1 double-knockout lymphoma chicken DT40 cells, we demonstrate that TDP1 and PARP1 are epistatic for the repair of Top1cc. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1, and TDP1 is PARylated by PARP1. PARylation stabilizes TDP1 together with SUMOylation of TDP1. TDP1 PARylation enhances its recruitment to DNA damage sites without interfering with TDP1 catalytic activity. TDP1–PARP1 complexes, in turn recruit X-ray repair cross-complementing protein 1 (XRCC1). This work identifies PARP1 as a key component driving the repair of trapped Top1cc by TDP1.
DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues
Authors: DeNizio Jamie E. , Elsässer Simon J. , Black Ben E. 
Published: February 2014

Abstract
Histone chaperones are a diverse class of proteins that facilitate chromatin assembly. Their ability to stabilize highly abundant histone proteins in the cellular environment prevents non-specific interactions and promotes nucleosome formation, but the various mechanisms for doing so are not well understood. We now focus on the dynamic features of the DAXX histone chaperone that have been elusive from previous structural studies. Using hydrogen/deuterium exchange coupled to mass spectrometry (H/DX-MS), we elucidate the concerted binding-folding of DAXX with histone variants H3.3/H4 and H3.2/H4 and find that high local stability at the variant-specific recognition residues rationalizes its known selectivity for H3.3. We show that the DAXX histone binding domain is largely disordered in solution and that formation of the H3.3/H4/DAXX complex induces folding and dramatic global stabilization of both histone and chaperone. Thus, DAXX uses a novel strategy as a molecular chaperone that paradoxically couples its own folding to substrate recognition and binding. Further, we propose a model for the chromatin assembly reaction it mediates, including a stepwise folding pathway that helps explain the fidelity of DAXX in associating with the H3.3 variant, despite an extensive and nearly identical binding surface on its counterparts, H3.1 and H3.2.
Improved search heuristics find 20 000 new alignments between human and mouse genomes
Authors: Frith Martin C. , Noé Laurent 
Published: February 2014

Abstract
Sequence similarity search is a fundamental way of analyzing nucleotide sequences. Despite decades of research, this is not a solved problem because there exist many similarities that are not found by current methods. Search methods are typically based on a seed-and-extend approach, which has many variants (e.g. spaced seeds, transition seeds), and it remains unclear how to optimize this approach. This study designs and tests seeding methods for inter-mammal and inter-insect genome comparison. By considering substitution patterns of real genomes, we design sets of multiple complementary transition seeds, which have better performance (sensitivity per run time) than previous seeding strategies. Often the best seed patterns have more transition positions than those used previously. We also point out that recent computer memory sizes (e.g. 60 GB) make it feasible to use multiple (e.g. eight) seeds for whole mammal genomes. Interestingly, the most sensitive settings achieve diminishing returns for human–dog and melanogaster–pseudoobscura comparisons, but not for human–mouse, which suggests that we still miss many human–mouse alignments. Our optimized heuristics find ∼20 000 new human–mouse alignments that are missing from the standard UCSC alignments. We tabulate seed patterns and parameters that work well so they can be used in future research.
Resuscitation with Lipid Emulsion
Authors: Fettiplace Michael R. , Akpa Belinda S. , Ripper Richard , Zider Brian , Lang Jason , Rubinstein Israel , Weinberg Guy 
Published: February 2014

Abstract

Background:
Recent publications have questioned the validity of the “lipid sink” theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model.

Methods:
Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. After catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of the four treatments: 30% intravenous lipid emulsion, 20% intravenous lipid emulsion, intravenous saline, or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared with the predictions of a pharmacokinetic–pharmacodynamic model parameterized using previously published laboratory data.

Results:
Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment. Intravenous lipid emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous lipid emulsion, saline, and no treatment. An increase in arterial blood pressure underlay the recovery in both lipid emulsion–treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery, and the model that combined volume, sequestration, and inotropy predicted in vivo results most accurately.

Conclusion:
Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect.
Beneficial Effects of Nitric Oxide on Outcomes after Cardiac Arrest and Cardiopulmonary Resuscitation in Hypothermia-treated Mice
Authors: Kida Kotaro , Shirozu Kazuhiro , Yu Binglan , Mandeville Joseph B. , Bloch Kenneth D. , Ichinose Fumito 
Published: February 2014

Abstract

Background:
Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Although nitric oxide prevents organ injury induced by ischemia and reperfusion, role of nitric oxide during TH after CPR remains unclear. In this article, the authors examined the impact of endogenous nitric oxide synthesis on the beneficial effects of hypothermia after CA/CPR. The authors also examined whether or not inhaled nitric oxide during hypothermia further improves outcomes after CA/CPR in mice treated with TH.

Methods:
Wild-type mice and mice deficient for nitric oxide synthase 3 (NOS3−/−) were subjected to CA at 37°C and then resuscitated with chest compression. Body temperature was maintained at 37°C (normothermia) or reduced to 33°C (TH) for 24 h after resuscitation. Mice breathed air or air mixed with nitric oxide at 10, 20, 40, 60, or 80 ppm during hypothermia. To evaluate brain injury and cerebral blood flow, magnetic resonance imaging was performed in wild-type mice after CA/CPR.

Results:
Hypothermia up-regulated the NOS3-dependent signaling in the brain (n = 6 to 7). Deficiency of NOS3 abolished the beneficial effects of hypothermia after CA/CPR (n = 5 to 6). Breathing nitric oxide at 40 ppm improved survival rate in hypothermia-treated NOS3−/− mice (n = 6) after CA/CPR compared with NOS3−/− mice that were treated with hypothermia alone (n = 6; P < 0.05). Breathing nitric oxide at 40 (n = 9) or 60 (n = 9) ppm markedly improved survival rates in TH-treated wild-type mice (n = 51) (both P < 0.05 vs. TH-treated wild-type mice). Inhaled nitric oxide during TH (n = 7) prevented brain injury compared with TH alone (n = 7) without affecting cerebral blood flow after CA/CPR (n = 6).

Conclusions:
NOS3 is required for the beneficial effects of TH. Inhaled nitric oxide during TH remains beneficial and further improves outcomes after CA/CPR. Nitric oxide breathing exerts protective effects after CA/CPR even when TH is ineffective due to impaired endogenous nitric oxide production.
Vegetative and Sperm Cell-Specific Aquaporins of Arabidopsis Highlight the Vacuolar Equipment of Pollen and Contribute to Plant Reproduction
Authors: Wudick Michael M. , Luu Doan-Trung , Tournaire-Roux Colette , Sakamoto Wataru , Maurel Christophe 
Published: February 2014

Abstract
The water and nutrient status of pollen is crucial to plant reproduction. Pollen grains of Arabidopsis (Arabidopsis thaliana) contain a large vegetative cell and two smaller sperm cells. Pollen grains express AtTIP1;3 and AtTIP5;1, two members of the Tonoplast Intrinsic Protein subfamily of aquaporins. To address the spatial and temporal expression pattern of the two homologs, C-terminal fusions of AtTIP1;3 and AtTIP5;1 with green fluorescent protein and mCherry, respectively, were expressed in transgenic Arabidopsis under the control of their native promoter. Confocal laser scanning microscopy revealed that AtTIP1;3 and AtTIP5;1 are specific for the vacuoles of the vegetative and sperm cells, respectively. The tonoplast localization of AtTIP5;1 was established by reference to fluorescent protein markers for the mitochondria and vacuoles of sperm and vegetative cells and is at variance with the claim that AtTIP5;1 is localized in vegetative cell mitochondria. AtTIP1;3-green fluorescent protein and AtTIP5;1-mCherry showed concomitant expression, from first pollen mitosis up to pollen tube penetration in the ovule, thereby revealing the dynamics of vacuole morphology in maturating and germinating pollen. Transfer DNA insertion mutants for either AtTIP1;3 or AtTIP5;1 showed no apparent growth phenotype and had no significant defect in male transmission of the mutated alleles. By contrast, a double knockout displayed an abnormal rate of barren siliques, this phenotype being more pronounced under limited water or nutrient supply. The overall data indicate that vacuoles of vegetative and sperm cells functionally interact and contribute to male fertility in adverse environmental conditions.