bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational design of a pH-sensitive IgG binding protein
Authors: Strauch Eva-Maria , Fleishman Sarel J. , Baker David 
Published: January 2014

Significance
Protein–protein interactions are part of almost every biological process; hence, the ability to manipulate and design protein binding has widespread applications. Here, we describe an approach to designing pH-dependent protein interfaces and use it to design a protein that binds antibodies at high pH but poorly at low pH. The designed protein should be useful for antibody affinity purification and diagnostic devices.
Analysis and modeling of mitotic spindle orientations in three dimensions
Authors: Jüschke Christoph , Xie Yunli , Postiglione Maria Pia , Knoblich Juergen A. 
Published: January 2014

Significance
During development, three-dimensional tissues with defined architecture are generated from one single cell. To achieve this, cells divide with specific orientations to ensure correct placement of their daughter cells. Because the direction of cell division is determined by the orientation of the mitotic spindle apparatus, precise methodology for determining spindle orientation in three-dimensional tissues is crucial to understanding developmental processes. Here, we describe a method for the analysis of spindle orientation in three dimensions. We use mathematical modeling to demonstrate that our method can avoid systematic errors that are intrinsic to conventional 2D analysis of the process. Using experimental data from the developing mouse brain, we show that our method can distinguish between mechanistically different models for spindle orientation.
Harnessing evolutionary fitness in
Plasmodium falciparum
for drug discovery and suppressing resistance
Authors: Lukens Amanda K. , Ross Leila Saxby , Heidebrecht Richard , Javier Gamo Francisco , Lafuente-Monasterio Maria J. , Booker Michael L. , Hartl Daniel L. , Wiegand Roger C. , Wirth Dyann F. 
Published: January 2014

Significance
Drug resistance is a major problem in treating malaria infections. Resistance pathways are limited by evolutionary fitness constraints, and these pathways can be anticipated and preemptively blocked. We identified compounds selective for mutant malaria parasites that are resistant to either clinically used (chloroquine) or in-development dihydroorotate dehydrogenase (DHODH) inhibitor therapies. In both cases, resistance selections of mutant parasites with the matching mutant-selective drug led to a reversion to the wild-type phenotype. Additionally, combination selection of wild-type parasites with paired wild-type and mutant-type DHODH inhibitors failed to produce resistant parasites. These findings indicate that pairing inhibitors that target the bulk wild-type population and the small, emerging resistant population can suppress the rise and spread of drug resistance.
Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes
Authors: Hayashi Toshio , Kotani Hitoshi , Yamaguchi Tomoe , Taguchi Kumiko , Iida Mayu , Ina Koichiro , Maeda Morihiko , Kuzuya Masafumi , Hattori Yuichi , Ignarro Louis J. 
Published: January 2014

Significance
Our studies demonstrate that the regulation of endothelial cellular senescence emerges as an additional mechanism underlying the antiatherogenic properties of liver X receptor (LXR) agents. Furthermore, our data suggest that combination therapy with LXR agents and metformin may provide a clinically useful therapeutic strategy to alleviate an LXR activation-mediated adverse effect on liver triglyceride metabolism. The beneficial effects of LXR activation appear to be reduced reactive oxygen species levels and increased endothelial NO synthase activity, both of which will lead to increased NO actions. Among the elderly population, atherosclerosis is a growing problem, leading to an increased risk of mortality by cardiovascular events. Adoption of combination therapy with LXR agents and widely prescribed metformin may be of clinical significance.
Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells
Authors: Brenner Dirk , Brüstle Anne , Lin Gloria H. Y. , Lang Philipp A. , Duncan Gordon S. , Knobbe-Thomsen Christiane B. , St. Paul Michael , Reardon Colin , Tusche Michael W. , Snow Bryan , Hamilton Sara R. , Pfefferle Aline , Gilani Syed O. , Ohashi Pamela S. , Lang Karl S. , Mak Tak W. 
Published: January 2014

Significance
More than 1 million people worldwide suffer from the debilitating neurological disorder multiple sclerosis (MS). The initiation of MS is associated with sustained inflammation and an autoimmune T-cell response targeting the central nervous system. The activities of Th1 and Th17 effector T cells, which are the main pathogenic drivers of MS, are balanced by regulatory T cells, which dampen inflammation and mitigate disease. Our study describes an important role for the surface receptor Toso in balancing these T-cell subsets and controlling inflammation. Using an animal model of MS, we have developed a preclinical treatment strategy in which Toso-Fc fusion protein ameliorates the inflammatory symptoms of experimental autoimmune encephalomyelitis, an MS-like disease.
School sports and identity formation: Socialisation or selection?
Authors: Pot Niek , Schenk Niels , van Hilvoorde Ivo 
Published: January 2014

AbstractIt seems common knowledge that school sport participation leads to all kinds of social, educational and health outcomes. However, it may also be that students with a certain predisposition, sometimes referred to as sporting habitus, are more inclined to participate in school sports and that the ‘outcomes’ were already present before participation. Several studies indicated that identity formation mediates between sport participation and the outcomes described. Therefore, a longitudinal survey study was used to investigate whether participation in an elementary school sport competition brought about changes in the formation of sport identity and student identity of students. The results of the study showed that participation in the competition was not related to changes in the sport identity and student identity of the children. In contrast to commonplace assumptions about the socialising effects of school sport participation, the results indicate that participating in this school sport competition did not influence the student identity and sport identity of children. It may be that a selected, predisposed group of children with a strong sport identity participates in school sports, although future research is necessary to test this hypothesis.
The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane
Authors: Tanimura Natsuko , Saitoh Shin-ichiroh , Ohto Umeharu , Akashi-Takamura Sachiko , Fujimoto Yukari , Fukase Koichi , Shimizu Toshiyuki , Miyake Kensuke 
Published: January 2014

AbstractTLR4/MD-2 senses lipid A, activating the MyD88-signaling pathway on the plasma membrane and the TRIF-signaling pathway after CD14-mediated TLR4/MD-2 internalization into endosomes. Monophosphoryl lipid A (MPL), a detoxified derivative of lipid A, is weaker than lipid A in activating the MyD88-dependent pathway. Little is known, however, about mechanisms underlying the attenuated activation of MyD88-dependent pathways. We here show that MPL was impaired in induction of CD14-dependent TLR4/MD-2 dimerization compared with lipid A. Impaired TLR4/MD-2 dimerization decreased CD14-mediated TNFα production. In contrast, MPL was comparable to lipid A in CD14-independent MyD88-dependent TNFα production and TRIF-dependent responses including cell surface CD86 up-regulation and IFNβ induction. Although CD86 up-regulation is dependent on TRIF signaling, it was induced by TLR4/MD-2 at the plasma membrane. These results revealed that the attenuated MPL responses were due to CD14-initiated responses at the plasma membrane, but not just to responses initiated by MyD88, that is, MPL was specifically unable to induce CD14-dependent TLR4/MD-2 dimerization that selectively enhances MyD88-mediated responses at the plasma membrane.
Sufficient observables for large-scale structure in galaxy surveys
Authors: Carron J. , Szapudi I. 
Published: January 2014

Abstract
Beyond the linear regime, the power spectrum and higher order moments of the matter field no longer capture all cosmological information encoded in density fluctuations. While non-linear transforms have been proposed to extract this information lost to traditional methods, up to now, the way to generalize these techniques to discrete processes was unclear; ad hoc extensions had some success. We pointed out in Carron and Szapudi's paper that the logarithmic transform approximates extremely well the optimal ‘sufficient statistics’, observables that extract all information from the (continuous) matter field. Building on these results, we generalize optimal transforms to discrete galaxy fields. We focus our calculations on the Poisson sampling of an underlying lognormal density field. We solve and test the one-point case in detail, and sketch out the sufficient observables for the multipoint case. Moreover, we present an accurate approximation to the sufficient observables in terms of the mean and spectrum of a non-linearly transformed field. We find that the corresponding optimal non-linear transformation is directly related to the maximum a posteriori Bayesian reconstruction of the underlying continuous field with a lognormal prior as put forward in the paper of Kitaura et al.. Thus, simple recipes for realizing the sufficient observables can be built on previously proposed algorithms that have been successfully implemented and tested in simulations.
An online bioinformatics tool predicts zinc finger and TALE nuclease off-target cleavage
Authors: Fine Eli J. , Cradick Thomas J. , Zhao Charles L. , Lin Yanni , Bao Gang 
Published: January 2014

Abstract
Although engineered nucleases can efficiently cleave intracellular DNA at desired target sites, major concerns remain on potential ‘off-target’ cleavage that may occur throughout the genome. We developed an online tool: predicted report of genome-wide nuclease off-target sites (PROGNOS) that effectively identifies off-target sites. The initial bioinformatics algorithms in PROGNOS were validated by predicting 44 of 65 previously confirmed off-target sites, and by uncovering a new off-target site for the extensively studied zinc finger nucleases (ZFNs) targeting C-C chemokine receptor type 5. Using PROGNOS, we rapidly interrogated 128 potential off-target sites for newly designed transcription activator-like effector nucleases containing either Asn-Asn (NN) or Asn-Lys (NK) repeat variable di-residues (RVDs) and 3- and 4-finger ZFNs, and validated 13 bona fide off-target sites for these nucleases by DNA sequencing. The PROGNOS algorithms were further refined by incorporating additional features of nuclease–DNA interactions and the newly confirmed off-target sites into the training set, which increased the percentage of bona fide off-target sites found within the top PROGNOS rankings. By identifying potential off-target sites in silico, PROGNOS allows the selection of more specific target sites and aids the identification of bona fide off-target sites, significantly facilitating the design of engineered nucleases for genome editing applications.
Long-term cycles in the carbon reservoir of the Quaternary ocean: a perspective from the South China Sea
Authors: Wang PinXian , Li QianYu , Tian Jun , Jian ZhiMin , Liu ChuanLian , Li Li , Ma WenTao 
Published: January 2014

AbstractIn recent years, long-term, high-resolution records from the deep sea and ice-cores have offered new research opportunities for Quaternary science. Paleoclimate studies are no longer restricted to individual glacial cycles, but extend to long-term (≥105 yr) processes across those cycles. Ocean Drilling Program Leg 184 of the South China Sea in 1999 uncovered well-preserved sediment sections, in which three long-term cycles in Pleistocene carbon isotope (δ13C) sequence have been found and demonstrated to be common in the global ocean. Subsequent discoveries confirm the existence of long-term processes of 105 yr in both the hydrologic (ice-sheet changes) and carbon (biogeochemical changes) cycles, posing the question whether the two processes are related. The present review shows that the long-eccentricity cycles prevail throughout the δ13C and other biogeochemical records in geologic history, and 400-kyr cycles in the oceanic δ13C sequence before the Quaternary can be hypothetically explained by changes in ratio between particulate and dissolved organic carbon (POC/DOC) in the ocean, depending on the monsoon-controlled nutrient supply. This is a ‘DOC hypothesis’. However, ocean restructuring at 1.6 Ma marked by the isolation of a sluggish abyss under the Southern Ocean has obscured the long-eccentricity 400-kyr signal in oceanic δ13C. The last million-year period has experienced two major changes in the climate regime, namely the mid-Pleistocene transition (MPT) centered at 0.9 Ma and the mid-Brunhes event (MBE) around 0.4 Ma. The MPT and MBE were preluded by δ13C maxima-III (δ13Cmax-III) ∼ 1.0 Ma and δ13Cmax-II ∼ 0.5 Ma, respectively. Together with similar hydroclimatic phenomena over corresponding glacial cycles, the two groups of hydrologic and biogeochemical events appear to have been driven largely by oceanographic changes in the Southern Ocean. Therefore, we interpret that the long-term biogeochemical processes originating from the Southern Ocean must have played a crucial role in Quaternary ice-sheet waxing and waning.
Pathogenesis Implication for Necrotizing Enterocolitis Prevention in Preterm Very‐Low‐Birth‐Weight Infants
Authors: Chen An‐Chyi , Chung Mei‐Yung , Chang Jui Hsing , Lin Hung‐Chih 
Published: January 2014

ABSTRACTRecent reports show that the incidence of and deaths caused by necrotizing enterocolitis (NEC) in preterm very‐low‐birth‐weight (PVLBW) infants are on the rise. Unfortunately, NEC often rapidly progresses from early signs of intestinal inflammation to extensive necrosis within a matter of hours, making treatment and secondary prevention extremely difficult to achieve. Primary prevention should thus be the priority. Recent studies provide information that enhances our understanding of the pathophysiology and provides more practical options for the prevention of NEC. The most accepted hypothesis at present is that enteral feeding (providing substrate) in the presence of abnormal intestinal colonization by pathogens provokes an inappropriately heightened inflammatory response in immature intestinal epithelial cells of PVLBW infants. Seventy‐four relevant articles were reviewed. Our focus was on the present understanding of the pathophysiology of NEC in the context of developing optimal strategies to prevent NEC in PVLBW infants. Strategies such as antenatal glucocorticoids, postnatal breast milk feeding, and cautious approach to enteral feeding failed to eliminate NEC in PVLBW infants because these strategies did not address the complexity of the pathogenesis. Probiotics seem to be the most significant advance in NEC prevention at present because of the significant range of beneficial effects at various levels of gut function and defense mechanism and the present evidence based on 19 randomized controlled trials.
Functions of Multiple Genes Encoding ADP-Glucose Pyrophosphorylase Subunits in Maize Endosperm, Embryo, and Leaf
Authors: Huang Binquan , Hennen-Bierwagen Tracie A. , Myers Alan M. 
Published: January 2014

Abstract
ADP-glucose pyrophosphorylase (AGPase) provides the nucleotide sugar ADP-glucose and thus constitutes the first step in starch biosynthesis. The majority of cereal endosperm AGPase is located in the cytosol with a minor portion in amyloplasts, in contrast to its strictly plastidial location in other species and tissues. To investigate the potential functions of plastidial AGPase in maize (Zea mays) endosperm, six genes encoding AGPase large or small subunits were characterized for gene expression as well as subcellular location and biochemical activity of the encoded proteins. Seven transcripts from these genes accumulate in endosperm, including those from shrunken2 and brittle2 that encode cytosolic AGPase and five candidates that could encode subunits of the plastidial enzyme. The amino termini of these five polypeptides directed the transport of a reporter protein into chloroplasts of leaf protoplasts. All seven proteins exhibited AGPase activity when coexpressed in Escherichia coli with partner subunits. Null mutations were identified in the genes agpsemzm and agpllzm and shown to cause reduced AGPase activity in specific tissues. The functioning of these two genes was necessary for the accumulation of normal starch levels in embryo and leaf, respectively. Remnant starch was observed in both instances, indicating that additional genes encode AGPase large and small subunits in embryo and leaf. Endosperm starch was decreased by approximately 7% in agpsemzm- or agpllzm- mutants, demonstrating that plastidial AGPase activity contributes to starch production in this tissue even when the major cytosolic activity is present.
SWEET17, a Facilitative Transporter, Mediates Fructose Transport across the Tonoplast of Arabidopsis Roots and Leaves
Authors: Guo Woei-Jiun , Nagy Reka , Chen Hsin-Yi , Pfrunder Stefanie , Yu Ya-Chi , Santelia Diana , Frommer Wolf B. , Martinoia Enrico 
Published: January 2014

Abstract
Fructose (Fru) is a major storage form of sugars found in vacuoles, yet the molecular regulation of vacuolar Fru transport is poorly studied. Although SWEET17 (for SUGARS WILL EVENTUALLY BE EXPORTED TRANSPORTERS17) has been characterized as a vacuolar Fru exporter in leaves, its expression in leaves is low. Here, RNA analysis and SWEET17-β-glucuronidase/-GREEN FLUORESCENT PROTEIN fusions expressed in Arabidopsis (Arabidopsis thaliana) reveal that SWEET17 is highly expressed in the cortex of roots and localizes to the tonoplast of root cells. Expression of SWEET17 in roots was inducible by Fru and darkness, treatments that activate accumulation and release of vacuolar Fru, respectively. Mutation and ectopic expression of SWEET17 led to increased and decreased root growth in the presence of Fru, respectively. Overexpression of SWEET17 specifically reduced the Fru content in leaves by 80% during cold stress. These results intimate that SWEET17 functions as a Fru-specific uniporter on the root tonoplast. Vacuoles overexpressing SWEET17 showed increased [14C]Fru uptake compared with the wild type. SWEET17-mediated Fru uptake was insensitive to ATP or treatment with NH4Cl or carbonyl cyanide m-chlorophenyl hydrazone, indicating that SWEET17 functions as an energy-independent facilitative carrier. The Arabidopsis genome contains a close paralog of SWEET17 in clade IV, SWEET16. The predominant expression of SWEET16 in root vacuoles and reduced root growth of mutants under Fru excess indicate that SWEET16 also functions as a vacuolar transporter in roots. We propose that in addition to a role in leaves, SWEET17 plays a key role in facilitating bidirectional Fru transport across the tonoplast of roots in response to metabolic demand to maintain cytosolic Fru homeostasis.
Prolapse surgery with or without stress incontinence surgery for pelvic organ prolapse: a systematic review and meta‐analysis of randomised trials
Authors: van der Ploeg JM , van der Steen A , Oude Rengerink K , van der Vaart CH , Roovers JP 
Published: January 2014

ObjectivesThe combination of prolapse surgery with an incontinence procedure can reduce the incidence of stress urinary incontinence (SUI) after surgery, but may increase adverse events. We compared the effectiveness and safety of prolapse surgery versus combined prolapse and incontinence surgery in women with pelvic organ prolapse.Design and settingPubmed, EMBASE, DARE, the Cochrane Library and the register of Current Controlled Trials were searched for randomised trials (restricted to Burch colposuspension and midurethral sling as incontinence procedure) from 1995 to 2013 limited to the English literature.MethodsTwo reviewers selected eligible articles and extracted the data. Pooling for SUI was based on three patient groups: (1) women with coexisting SUI; (2) women asymptomatic for SUI; and (3) women with occult SUI. For adverse events, pooling was based on incontinence procedure.Main outcome measuresThe primary outcome was SUI. The secondary outcomes were treatment for SUI, bladder storage symptoms, obstructive voiding and adverse events.ResultsSeven trials were included. Pooling for women with coexisting SUI was possible for objective SUI with two studies and showed no difference. Statistical (I2 = 95%) and clinical heterogeneity was, however, high. The largest study showed a lower incidence of persisting SUI (5% versus 23%) and treatment for this (0% versus 57%) in women who underwent prolapse repair with a midurethral sling. The second study did not find a difference in women undergoing a sacrocolpopexy with or without Burch colposuspension. In asymptomatic women, combination surgery resulted in a lower incidence of de novo subjective SUI (two studies; 24% versus 41%; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; I2 = 36%) and the need for subsequent anti‐incontinence surgery (three studies; 2% versus 7%; RR, 0.4; 95% CI, 0.2–0.8; I2 = 13%). For the outcome objective SUI, pooling was possible for five studies, but statistical heterogeneity was high (I2 = 82%) and the difference was not statistically significant. In the subgroup of women with occult stress incontinence, we found a lower incidence of objective SUI after combination surgery (two studies; 22% versus 52%; RR, 0.4; 95% CI, 0.3–0.8; I2 = 32%). There were no differences in bladder storage symptoms, urgency incontinence or long‐term obstructive voiding symptoms. Adverse events (two studies; 15% versus 10%; RR, 1.6; 95% CI, 1.0–2.5; I2 = 0%) and prolonged catheterisation (three studies; 6% versus 1%; RR, 4.5; 95% CI, 1.5–13.3; I2 = 0%) were more frequent after vaginal prolapse repair with a midurethral sling.ConclusionsCombination surgery reduces the risk of postoperative stress incontinence, but short‐term voiding difficulties and adverse events were more frequent after combination surgery with a midurethral sling.