bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations
Authors: Li Mingkun , Schröder Roland , Ni Shengyu , Madea Burkhard , Stoneking Mark 
Published: February 2015

Significance
Heteroplasmy is the existence of different mtDNA sequences within an individual due to somatic or inherited mutations, and it has been implicated in many mtDNA-related diseases, other diseases, cancer, and aging. However, little is known about how heteroplasmy varies across different tissues from the same individual; here, we analyzed heteroplasmy variation across the entire mtDNA genome in 12 tissues obtained at autopsy from each of 152 individuals. Our results suggest that in addition to neutral processes and negative selection, positive selection has an important influence on heteroplasmy: As individuals get older, specific alleles are selected for at specific nucleotide positions in specific tissues. The functional consequences of these positively selected somatic mutations may play a role in human health and disease.
Localizing a gate in CFTR
Authors: Gao Xiaolong , Hwang Tzyh-Chang 
Published: February 2015

Significance
Cystic fibrosis transmembrane conductance regulator (CFTR), albeit a bona fide member of the ATP-binding cassette (ABC) transporter superfamily, is an ATP-gated chloride channel. However, phylogenetic analysis has led to a popular conjecture that CFTR evolves from a primordial ABC exporter by simply degenerating the cytoplasmic gate. This degraded transporter hypothesis predicts that CFTR’s gate is located at the external end of the substrate translocation pathway as the one documented in the crystal structures of ABC exporters. Here we provide experimental data supporting the presence of a gate in CFTR at a segment that may also serve as the selectivity filter. This functional duality of a restrictive segment close to the middle of the pore axis distinguishes CFTR from its myriad brethren in the ABC protein family.
Arabidopsis
OR proteins are the major posttranscriptional regulators of phytoene synthase in controlling carotenoid biosynthesis
Authors: Zhou Xiangjun , Welsch Ralf , Yang Yong , Álvarez Daniel , Riediger Matthias , Yuan Hui , Fish Tara , Liu Jiping , Thannhauser Theodore W. , Li Li 
Published: February 2015

Significance
Carotenoids are indispensable to plants and humans. Despite significant achievements in carotenoid research, we still lack the fundamental knowledge of the regulatory mechanisms underlying carotenogenesis in plants. Phytoene synthase (PSY) and ORANGE (OR) are the two key proteins for carotenoid biosynthesis and accumulation in plastids. This study shows that OR family proteins interact directly with PSY and function as the major regulators of active PSY protein abundance in mediating carotenoid biosynthesis. The findings establish posttranscriptional regulation of PSY as a novel way to control carotenoid biosynthesis in plants and provide strategies for crop nutritional quality improvement.
Toward link predictability of complex networks
Authors: Lü Linyuan , Pan Liming , Zhou Tao , Zhang Yi-Cheng , Stanley H. Eugene 
Published: February 2015

SignificanceQuantifying a network's link predictability allows us to (i) evaluate predictive algorithms associated with the network, (ii) estimate the extent to which the organization of the network is explicable, and (iii) monitor sudden mechanistic changes during the network's evolution. The hypothesis of this paper is that a group of links is predictable if removing them has only a small effect on the network's structural features. We introduce a quantitative index for measuring link predictability and an algorithm that outperforms state-of-the-art link prediction methods in both accuracy and universality. This study provides fundamental insights into important scientific problems and will aid in the development of information filtering technologies.
Lack of exercise leads to significant and reversible loss of scale invariance in both aged and young mice
Authors: Gu Changgui , Coomans Claudia P. , Hu Kun , Scheer Frank A. J. L. , Stanley H. Eugene , Meijer Johanna H. 
Published: February 2015

Significance
Healthy systems are characterized by scale invariance across multiple timescales. We investigated whether loss of scale invariance that occurs with aging and disease can be counteracted by exercise, in four age groups of mice. Surprisingly, we observed that lack of exercise was detrimental not only in old but also in young mice, raising the possibility of an unforeseen role of behavioral activity for health in aged and young subjects alike. Moreover, we show that scale invariance could be restored by high levels of exercise, even in old animals. The World Health Organization has pinpointed lack of exercise and a sedentary lifestyle as a major risk factor for various diseases. Our measures may guide health programs.
Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway
Authors: Wang May-Yun , Yan Hai , Shi Zhiqing , Evans Matthew R. , Yu Xinxin , Lee Young , Chen Shiuhwei , Williams Annie , Philippe Jacques , Roth Michael G. , Unger Roger H. 
Published: February 2015

Significance
Subcutaneous injections of insulin sustain life in mammals unable to produce insulin (type 1 diabetes) but do not prevent hyperglycemic and hypoglycemic swings or decrease hemoglobin A1c levels to normal amounts. In mice treated with insulin alone, repeated episodes of transient elevated blood glucose cause long-term damage. We show that in mice with type 1 diabetes treated with insulin, the transient high blood glucose levels require production of glucagon, a hormone that will cause the liver to produce more glucose. Blocking the action of glucagon with an antibody to the glucagon receptor completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy. Suppressing glucagon action in combination with low-dose insulin would be a superior treatment for type 1 diabetes.
Calorimetric glass transition in a mean-field theory approach
Authors: Mariani Manuel Sebastian , Parisi Giorgio , Rainone Corrado 
Published: February 2015

Significance
Understanding the properties of glasses is one of the major open challenges of theoretical physics. Making analytical predictions is usually very difficult for the known glassy models. Moreover, in experiments and numerical simulations thermalization of glasses cannot be achieved without sophisticated procedures, such as the vapor deposition technique. In this work we study a glassy model that is simple enough to be analytically solved and that can be thermalized in the glassy phase with a simple numerical method, opening the door to an intensive comparison between replica theory predictions and numerical outcomes.
Transplantation of bovine adrenocortical cells encapsulated in alginate
Authors: Balyura Mariya , Gelfgat Evgeny , Ehrhart-Bornstein Monika , Ludwig Barbara , Gendler Zohar , Barkai Uriel , Zimerman Baruch , Rotem Avi , Block Norman L. , Schally Andrew V. , Bornstein Stefan R. 
Published: February 2015

Significance
Adrenal insufficiency is a life-threatening disorder that requires a complex and permanent hormone replacement strategy. All current replacement schemes suffer from numerous problems, as they fail to restore circadian variations in hormone secretion. Therefore, adrenal cell transplantation could be a preferable therapeutic alternative for patients suffering from primary adrenal dysfunction. This strategy is critically limited, however, by the lack of suitable donors of human organs and the requirement of chronic immunosuppression. Transplantation of immunoisolated xenogeneic adrenal cells could and would be a promising alternative for these patients. The most significant accomplishment of this study is the creation of long-term functional and immunoisolated artificial adrenals and their transplantation into animal models of adrenal insufficiency.
Mechanism of initiation of aggregation of p53 revealed by Φ-value analysis
Authors: Wang GuoZhen , Fersht Alan R. 
Published: February 2015

Significance
The tumor suppressor p53 is inactivated by aggregation in a substantial number of tumors, and those oncogenic mutants coaggregate with WT protein and other tumor suppressors. Inhibition of aggregation by small molecules is a possible drug therapy. p53 aggregation appears to have much simpler kinetics than commonly encountered in fibrillation, with two rate-determining sequential, apparently first-order, steps. We showed by combining mutagenesis and kinetics that the rate determining steps involve two molecules of p53 extensively unfolding and reacting in a bimolecular process that can appear first order. The mechanism provides a basis for understanding the progress of aggregation and coaggregation and points to the most effective drug targeting sites.
Propagation of aggregated p53: Cross-reaction and coaggregation vs. seeding
Authors: Wang GuoZhen , Fersht Alan R. 
Published: February 2015

Significance
Aggregation of tumor suppressor p53 oncogenic mutants not only loses their activity but may also lead to gain of oncogenic function, possibly by coaggregation with other proteins. We explored how a destabilized p53 mutant may coaggregate with WT p53 and its homologs p63 and p73. The results are explained by the simple two-step initiation mechanism we proposed. Rather than the oncogenic mutant seeding coaggregation by a prion-like process, coaggregation results from the simultaneous unfolding and cross-reaction of WT and mutant molecules. Consequently, preformed p53 aggregate displays little seeding of aggregation of p53, and high concentrations of p53 mutants are required to trap WT p53 into aggregate. Coaggregation is predominantly by trapping rather than seeding and induced propagation.
Dysregulation ofEscherichia coliα-hemolysin expression alters the course of acute and persistent urinary tract infection
Authors: Nagamatsu Kanna , Hannan Thomas J. , Guest Randi L. , Kostakioti Maria , Hadjifrangiskou Maria , Binkley Jana , Dodson Karen , Raivio Tracy L. , Hultgren Scott J. 
Published: February 2015

SignificanceThe majority of urinary tract infections (UTIs) are caused by uropathogenicEscherichia coli(UPEC). Upon UPEC infection, exfoliation of host bladder epithelial (urothelial) cells leads to sloughing of bacteria-laden cells into the urine for expulsion. However, it can also facilitate bacterial dissemination into deeper tissues. Thus, the balance and timing of exfoliation are important in determining disease outcomes. Here, we investigate host–pathogen dynamics in human urothelial cells in vitro and in murine model of acute cystitis. We discovered that the CpxR response regulator-CpxA sensor kinase two-component system regulates the expression of the pore-forming toxin α-hemolysin (HlyA) in response to environmental conditions. HlyA, in turn, is critical for fine-tuning the dynamics of host cell exfoliation and enhancing UPEC fitness during acute UTI.
Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs
Authors: Bayrer James R. , Mukkamala Sridevi , Sablin Elena P. , Webb Paul , Fletterick Robert J. 
Published: February 2015

Significance
This work addresses a key question in the field of liver receptor homolog-1 (LRH-1) pathophysiology in colorectal cancer (CRC)—namely, does LRH-1 contribute exclusively to tumorigenesis, or does LRH-1 also drive established CRC tumor growth? These two models have widely different implications for pharmaceutical targeting in CRC. To our knowledge, our work is the first to demonstrate that silencing of LRH-1 in established human CRC cell lines impairs proliferation though G0/G1 phase prolongation. Our microarray gene expression analysis shows that loss of LRH-1 expression yields alterations in diverse cellular pathways consistent with the critical role of LRH-1 in CRC. Taken together, our study suggests that a subset of CRC patients could benefit from selective antagonism of LRH-1.
Convergence of ion channel genome content in early animal evolution
Authors: Liebeskind Benjamin J. , Hillis David M. , Zakon Harold H. 
Published: February 2015

Significance
The early evolution of animal nervous systems is poorly understood, but comparative genomics provides a new window into the past. One important controversy is about whether nervous systems evolved just once or independently in different animal lineages. In this work, we explore the history of the gene families most central to nervous system function: ion channels. We track when these gene families expanded in animal evolution and find that these gene families radiated on several occasions and, in some cases, underwent periods of contraction. The multiple origins of these gene families may signify large-scale convergent evolution of nervous system complexity.
β-Thujaplicin modulates estrogen receptor signaling and inhibits proliferation of human breast cancer cells
Authors: Ko Jiwon , Bao Cheng , Park Hyun-Chang , Kim Minchae , Choi Hyung-Kyoon , Kim Young-Suk , Lee Hong Jin 
Published: February 2015

Abstract
β-Thujaplicin, one of the major constituents in Chamaecyparis obtusa, has been demonstrated to exert different health beneficial efficacy, but the role of β-thujaplicin in regulating mammary tumorigenesis has not been investigated. In this study, we found that β-thujaplicin significantly suppressed the proliferation through arresting the cell cycle transition from G1 to S phase as well as inhibited the expression of cell cycle-related proteins, cyclin D1, and cyclin-dependent kinase 4 (CDK4) in MCF-7 and T47D luminal subtype breast cancer cells. In addition, estrogen receptor α (ER-α) was down-regulated by β-thujaplicin via enhanced proteolysis by ubiquitination, which led to cell growth inhibition. These results suggest that β-thujaplicin may be considered as a potent agent regulating the hormone sensitive mammary tumorigenesis.
Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction: Acute Hemodynamic Effects of Inhaled Iloprost
Authors: Grossman Nicole L. , Fiack Christopher A. , Weinberg Janice M. , Rybin Denis V. , Farber Harrison W. 
Published: February 2015

Iloprost, an inhaled synthetic prostacyclin analogue, improves hemodynamic and clinical status with minimal systemic adversity in patients with pulmonary arterial hypertension. Our single‐site, prospective case series aimed to determine the effects of iloprost in subjects with group 2 pulmonary hypertension and heart failure with preserved ejection fraction. Patients referred to Boston Medical Center for initial evaluation of suspected pulmonary hypertension received a test dose of 2.5 μg inhaled iloprost, followed by two subsequent doses of 5 μg. Hemodynamic measurements were recorded for each inhalation after 15, 30, 60, and 90 minutes. Results were analyzed via paired t test and signed‐rank test. Eight subjects fulfilled criteria and elected to enter the study. There was a reduction of pulmonary arterial pressure (by an average of 7.0 mmHg [P = 0.005] and 4.7 mmHg [P = 0.021] with the first and second 5‐μg inhalations, respectively) and pulmonary vascular resistance (by an average of 161.9 dyn· s/cm5 [P = 0.019] and 95.0 dyn · s/cm5 [P = 0.014] with the first and second 5‐μg inhalations, respectively). There were trends for increased cardiac output and decreased oxygen saturation. There were no changes in other vital or hemodynamic parameters, including pulmonary capillary wedge pressure. All patients completed each cycle of iloprost administration without preestablished termination criteria. In patients with pulmonary hypertension and heart failure with preserved ejection fraction, inhaled iloprost resulted in acute reduction of pulmonary arterial pressure and pulmonary vascular resistance. Further evaluation of iloprost in this subset of patients is warranted.
A multiobjective memetic algorithm for PPI network alignment
Authors: Clark Connor , Kalita Jugal 
Published: February 2015

Abstract
Motivation: There recently has been great interest in aligning protein–protein interaction (PPI) networks to identify potentially orthologous proteins between species. It is thought that the topological information contained in these networks will yield better orthology predictions than sequence similarity alone. Recent work has found that existing aligners have difficulty making use of both topological and sequence similarity when aligning, with either one or the other being better matched. This can be at least partially attributed to the fact that existing aligners try to combine these two potentially conflicting objectives into a single objective.
Results: We present Optnetalign, a multiobjective memetic algorithm for the problem of PPI network alignment that uses extremely efficient swap-based local search, mutation and crossover operations to create a population of alignments. This algorithm optimizes the conflicting goals of topological and sequence similarity using the concept of Pareto dominance, exploring the tradeoff between the two objectives as it runs. This allows us to produce many high-quality candidate alignments in a single run. Our algorithm produces alignments that are much better compromises between topological and biological match quality than previous work, while better characterizing the diversity of possible good alignments between two networks. Our aligner’s results have several interesting implications for future research on alignment evaluation, the design of network alignment objectives and the interpretation of alignment results.
Availability and Implementation: The C++ source code to our program, along with compilation and usage instructions, is available at https://github.com/crclark/optnetaligncpp/
Contact: connor.r.clark@gmail.com
Supplementary information: Supplementary data are available at Bioinformatics online.
An Intemperate Map: Orientation and Disorientation in the Old French Fabliau ‘Les Trois Dames de Paris’
Authors: Goyette Stefanie A. 
Published: February 2015

Abstract
This article argues that the early fourteenth-century fabliau ‘Les Trois Dames de Paris’ invites the reader to map its temporal moment and topographical locations in historical space and time, but also that this invitation is frustrated by the events and displacements represented in the story. The subversion of potentially mappable urban topography mirrors the moral straying of the three eponymous women, who set out over the course of the narrative to have a private feast, which descends into an orgy of drunken excess. As the women become increasingly inebriated, their subjective disorientation allows further social and spatial transgression, briefly interrupted by unconsciousness and burial, but finally culminating in their resurgence, seemingly as possessed corpses, into public space. Each of these events represents the women's resistance to social norms, yet in the end their illusory freedom dissolves along with their intoxication, and the fabliau makes their transgression a subject of ridicule.
Commercial fishers' perceptions of jellyfish interference in the Northern California Current
Authors: Conley Keats R. , Sutherland Kelly R. 
Published: February 2015

Abstract
Jellyfish disruption of fisheries has been described in some coastal systems, but few thorough investigations have been conducted. To ascertain the economic impact and trend of jellyfish blooms in the Northern California Current (NCC), we mailed surveys to resident commercial shrimpers, salmon trollers, rockfish (blue, black), and groundfish fishers (n = 872). We asked fishers to estimate the damages caused by jellyfish—including costs of relocating to avoid blooms, lost fishing time, time lost to bycatch sorting, fish depreciation, and gear damage. Of the total respondents (n = 111), 67% reported that jellyfish reduce their seasonal revenue, but the degree of impact ranged considerably by fishery and location. Highest jellyfish nuisance corresponded to regions with the most salmon trolling effort. Using the mean revenue losses provided by respondents, we estimate that the combined economic impact of jellyfish on Oregon's salmon and pink shrimp fishers was over $650 000 in peak jellyfish season (June–September) in 2012. Fishers reported that jellyfish biomass varies annually, but most respondents (51%) reported observing no appreciable change in jellyfish populations in the last 5 years. Since economic impact analyses have been conducted primarily in areas with anomalous, high-density blooms, data from the NCC, which is not known to be experiencing increases in jellyfish abundance, provides baseline information on the socio-economic impact of jellyfish blooms in this region. In addition, the finding that jellyfish impact hook and line fisheries—not solely net fisheries—has implications for many other regions where fishers employ this gear type.
A combination of new screening assays for prioritization of transmission-blocking antimalarials reveals distinct dynamics of marketed and experimental drugs
Authors: Bolscher J. M. , Koolen K. M. J. , van Gemert G. J. , van de Vegte-Bolmer M. G. , Bousema T. , Leroy D. , Sauerwein R. W. , Dechering K. J. 
Published: February 2015

Abstract

Objectives
The development of drugs to reduce malaria transmission is an important part of malaria eradication plans. We set out to develop and validate a combination of new screening assays for prioritization of transmission-blocking molecules.

Methods
We developed high-throughput assays for screening compounds against gametocytes, the parasite stages responsible for onward transmission to mosquitoes. An existing gametocyte parasitic lactate dehydrogenase (pLDH) assay was adapted for use in 384-well plates, and a novel homogeneous immunoassay to monitor the functional transition of female gametocytes into gametes was developed. A collection of 48 marketed and experimental antimalarials was screened and subsequently tested for impact on sporogony in Anopheles mosquitoes, to directly quantify the transmission-blocking properties of antimalarials in relation to their effects on gametocyte pLDH activity or gametogenesis.

Results and Conclusions
The novel screening assays revealed distinct stage-specific kinetics and dynamics of drug effects. Peroxides showed the most potent transmission-blocking effects, with an intermediate speed of action and IC50 values that were 20–40-fold higher than the IC50s against the asexual stages causing clinical malaria. Finally, the novel synthetic peroxide OZ439 appeared to be a promising drug candidate as it exerted gametocytocidal and transmission-blocking effects at clinically relevant concentrations.