bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Predictors of Overweight and Obesity Among a Multiethnic Population of Pediatric Acute Lymphoblastic Leukemia Survivors: A Cross-Sectional Assessment
Authors: Brown Austin L. , Lupo Philip J. , Danysh Heather E. , Okcu Mehmet F. , Scheurer Michael E. , Kamdar Kala Y.
Published: March 2016

As previous studies of obesity in survivors of pediatric acute lymphoblastic leukemia (ALL) have primarily been conducted among non-Hispanic white survivors or children treated on older protocols, our objective was to describe the prevalence and correlates of overweight status among an ethnically diverse population of pediatric ALL survivors, largely treated with more contemporary therapies. We evaluated the overweight/obesity status of pediatric ALL survivors (n=406) followed in the Texas Children’s Cancer Center between 2004 and 2014. Survivors were classified as underweight, normal weight, overweight, or obese on the basis of their body mass index at their most current follow-up visit. Our results showed that Hispanic ethnicity (39% of the subjects) was associated with being overweight (adjusted odds ratio=1.88; 95% confidence interval, 1.13-3.14) or obese (adjusted odds ratio=2.84; 95% confidence interval, 1.59-5.06) at follow-up, even after adjusting for cranial radiotherapy (CRT) exposure. Body mass index z-score at diagnosis was also associated with overweight/obesity at follow-up. In addition, there was a statistically significant interaction between younger age at diagnosis and CRT, indicating that younger age at diagnosis was associated with obesity among patients who received CRT. These findings may help identify pediatric ALL patients that are at increased risk of being overweight or obese after treatment.
End-Stage Renal Disease From Cast Nephropathy in a Teenager With Neuroendocrine Carcinoma
Authors: Butani Lavjay , Ducore Jonathan
Published: March 2016

Cast nephropathy is the most common manifestation of renal injury in patients with multiple myeloma but is rarely reported in other conditions. We are reporting our experience in caring for a teenager with a metastatic neuroendocrine carcinoma who developed rapidly progressive kidney injury that advanced to end-stage renal disease. On renal biopsy extensive tubular necrosis and intratubular eosinophilic casts were noted. This previously unreported finding should prompt oncologists to closely monitor for such a complication in patients with secretory tumors. Whether early plasmapheresis could be of benefit, as has been tried in multiple myeloma, remains to be determined.
Renal Late Effects After the Treatment of Unilateral Nonsyndromic Wilms Tumor
Authors: Kostel Bal Ayse Sevgi , Yalcin Bilgehan , Susam-Şen Hilal , Aydin Burça , Varan Ali , Kutluk Tezer , Akyüz Canan
Published: March 2016

Wilms tumor is the most common renal malignancy of childhood. Because of the improvement in prognosis and the increase in survival rates, long-term consequences of the treatment for Wilms tumor are of greater concern. We investigated late renal effects of the treatment on 50 survivors of nonsyndromic unilateral Wilms tumor. After the second year since the cessation of treatment, the glomerular filtration rate (GFR), urinary protein excretion, urinary β2 microglobulin levels, and blood pressure as well as the general health status were assessed. Results were analyzed for correlation with clinical variables, chemotherapy, and radiotherapy as possible risk factors. At a median follow-up time of 8.8 years (mean=10.9; range, 2.3 to 35.4 y), none of the patients developed end-stage renal disease. Compensatory hypertrophy was observed in 68% of the cases. The median maximum bipolar length was significantly higher in patients diagnosed after the age of 36 months. Eleven (22%) and 2 (4%) of the 50 patients were hypertensive at the time of the diagnosis and the study, respectively. Similarly, median GFR values were significantly lower at the time of diagnosis, although at the time of the study, all patients had normal GFR values. With longer follow-up intervals, especially after 10 years, a significant decreasing trend in the GFR was observed (P=0.002).
Inflammatory Myofibroblastic Tumor of the Heart in the Infant: Review of the Literature
Authors: Mizia-Malarz Agnieszka , Sobol-Milejska Grażyna , Buchwald Joachim , Woś Halina
Published: March 2016

Primary heart tumors are extremely rare, constituting approximately 0.02% of all malignancies. Inflammatory myofibroblastic tumor (IMT) constitutes <5% of primary heart tumors. Until now, IMT of the heart has been described in 21 infants below 1 year of age. Its etiology remains unknown. IMT usually develops within the right atrial and ventricular endocardium. The main clinical symptoms reported in the affected infants involved increasing respiratory failure, cyanosis, and heart murmurs. Histopathologically, IMT is characterized by the myofibroblast proliferation with inflammatory infiltrates composed of plasmocytes, lymphocytes, and histiocytes. Tumor resection is the treatment of choice in IMT. Such tumor location is associated with the high risk of perioperative failure. Steroid therapy and chemotherapy is reported in the literature as a nonsurgical treatment alternative. Here, we present a review of clinical symptoms, diagnostic and treatment options, based on published case reports of IMT in infants, including our 11-month-old patient with IMT located within the pericardium.
The Effects of Hospital Length of Stay on Readmissions for Children With Newly Diagnosed Acute Lymphoblastic Leukemia
Authors: Wedekind Mary F. , Dennis Robyn , Sturm Mollie , Koch Terah , Stanek Joseph , O’Brien Sarah H.
Published: March 2016

Although regimens for induction therapy in children with acute lymphoblastic leukemia (ALL) are similar across the United States, typical practice with regard to inpatient length of stay (LOS) varies by institution. US children’s hospitals were categorized by typical induction LOS; and readmissions, pediatric intensive care unit (PICU) admissions, and average adjusted charges were compared for the first 30 days from initial admission. Using Pediatric Health Information System data, we extracted ALL induction admissions from 2007 to 2013. We categorized hospitals into 3 categories based on median LOS: short (≤7 d), medium (8 to 15 d), or long (≥16 d). Median LOS varied from 5 to 31 days across hospitals. Thirty-day median inpatient costs per patient ranged from $32 K for short LOS, $40 K for medium LOS, and $47 K for long LOS. Compared with short LOS hospitals (n=14), medium LOS (n=8) and long LOS hospitals (n=8) had lower odds of PICU readmissions (odds ratio [OR], 0.68; P=0.0124 and OR, 0.31; P<0.001, respectively), and long LOS hospitals had lower odds of any readmission (OR, 0.44; P<0.0001). Average LOS for children with newly diagnosed ALL varies widely by institution. Children’s hospitals that typically admit new ALL patients for >7 days have fewer PICU readmissions but substantial increase in total induction inpatient costs.
Three Rwandan Children With Massive Splenomegaly and Epstein-Barr Virus–associated Lymphoproliferative Disorders: Case Presentations and the Literature Review
Authors: Friedman-Klabanoff DeAnna , Ball Allison , Rutare Samuel , McCall Natalie , Blackall Douglas P.
Published: March 2016

This report describes 3 Rwandan children with massive splenomegaly and pancytopenia who underwent splenectomy. Each was diagnosed with Epstein-Barr virus–associated lymphoproliferative disorder (EBV LPD) based on lymphocyte morphology, lymphocyte immunophenotype, and the results of EBV in situ hybridization studies. The differential diagnosis of splenomegaly, with a special emphasis on the sub-Saharan African context, is discussed along with EBV and associated disorders. These cases serve as a call to consider EBV LPD in the differential diagnosis of splenomegaly in children in whom common causes have been ruled out.
Bacteriocins synthesized by Bacillus thuringiensis: generalities and potential applications
Authors: Salazar-Marroquín Elma Laura , Galán-Wong Luis J. , Moreno-Medina Víctor Ricardo , Reyes-López Miguel Ángel , Pereyra-Alférez Benito
Published: March 2016

The members of the Bacillus thuringiensis group, commonly known as Bt, produce a huge number of metabolites, which show biocidal and antagonistic activity. B. thuringiensis is widely known for synthesizing Cry, Vip and Cyt proteins, active against insects and other parasporins with biocidal activity against certain types of cancerous cells. Nevertheless, B. thuringiensis also synthesizes compounds with antimicrobial activity, especially bacteriocins. Some B. thuringiensis bacteriocins resemble lantibiotics and other small linear peptides (class IIa) from the lactic acid bacteria bacteriocins classification system. Although many bacteriocins produced by Bt have been reported, there is no proper classification for them. In this work, we have grouped these based on molecular weight and functionality. Bacteriocins are small peptides synthesized by bacteria, presenting inhibitory activity against Gram-positive and Gram-negative bacteria and to a lesser extent against fungi. These molecules represent a good study model in the search for microbial control alternatives. Lactic acid bacteria produces a huge number of these types of molecules with great potential. Nonetheless, members of the Bacillus, cereus group, especially B. thuringiensis, emerge as an attractive alternative for obtaining bacteriocins showing novel activities. This review describes the potential applications of B. thuringiensis bacteriocins in the control of foodborne pathogens, environment and medical area.
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma
Authors: Wei Xiaona , Choudhury Yukti , Lim Weng Khong , Anema John , Kahnoski Richard J. , Lane Brian , Ludlow John , Takahashi Masayuki , Kanayama Hiro-omi , Belldegrun Arie , Kim Hyung L. , Rogers Craig , Nicol David , Teh Bin Tean , Tan Min-Han
Published: March 2016

PURPOSE

Evaluation of 12 ccRCC publicly-available ccRCC gene expression datasets showed that previously proposed discrete molecular subtypes are unstable. To reflect the continuous nature of gene expression observed, we developed a quantitative score (Continuous Linear Enhanced Assessment of Renal cell carcinoma, or CLEAR) using expression analysis founded on pathologic parameters.

MATERIALS AND METHODS

265 ccRCC gene expression profiles were used to develop the CLEAR score, representing a genetic correlate of the continuum of morphological tumor grade. A signature derivation method based on correlation of CLEAR score with gene expression ranking was used to derive an 18-transcript signature. External validation was conducted in multiple public expression datasets.

Results

As a measure of intertumoral gene expression heterogeneity, the CLEAR score demonstrated both superior prognostic estimates (94% vs 83% adequacy index in TCGA dataset) and inverse correlation with anti-angiogenic tyrosine-kinase inhibition (65% vs 55% adequacy index) in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score (p=0.05). Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated its ability to reflect intratumoral expression heterogeneity and further analysis showed average intertumoral heterogeneity exceeded intratumoral heterogeneity.

Conclusions

The CLEAR score, a gene expression signature developed on histopathology, outperformed discrete subtype-classification in prognostic estimates and correlated better with treatment outcomes. Recognizing cancer as a continuum has important implications for laboratory and clinical research.
Genome-wide association study identifies 17 new loci influencing concentrations of circulating cytokines and growth factors
Authors: Ahola-Olli AV , Würtz P , Havulinna AS , Aalto K , Pitkänen N , Lehtimäki T , Kähönen M , Lyytikäinen LP , Raitoharju E , Seppälä I , Sarin AP , Ripatti S , Palotie A , Perola M , Viikari JS , Jalkanen S , Maksimow M , Salomaa V , Salmi M , Kettunen J , Raitakari OT
Published: March 2016

Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) up to n=8,293 Finns we identified 27 loci with genome-wide association (P-value<1.2×10-9) for one or more cytokines, including 17 unidentified in previous GWASes. Fifteen of the associated SNPs had expression quantitative trait loci in whole blood. We provide strong genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link known autoimmune disease variants including Crohn's disease, multiple sclerosis and ulcerative colitis with new inflammatory markers, which elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.
Genomic evidence for population-specific responses to coevolving parasites in a New Zealand freshwater snail
Authors: Bankers Laura , Fields Peter , McElroy Kyle E. , Boore Jeffrey L. , Logsdon John M. , Neiman Maurine
Published: March 2016

Reciprocal coevolving interactions between hosts and parasites are a primary source of strong selection that can promote rapid and often population- or genotype-specific evolutionary change. These host-parasite interactions are also a major source of disease. Despite their importance, very little is known about the genomic basis of coevolving host-parasite interactions in natural populations, especially in animals. Here, we use gene expression and sequence evolution approaches to take critical steps towards characterizing the genomic basis of interactions between the freshwatersnail Potamopyrgus antipodarumand its coevolving sterilizing trematode parasite,Microphallussp., a textbook example of natural coevolution. We found thatMicrophallus-infectedP. antipodarumexhibit systematic downregulation of genes relative to uninfectedP. antipodarum. The specific genes involved in parasite response differ markedly across lakes, consistent with a scenario where population-level coevolution is leading to population-specific host-parasite interactions and evolutionary trajectories. We also used anFST-based approach to identify a set of loci that represent promising candidates for targets of parasite-mediated selection across lakes as well as within each lake population. These results constitute the first genomic evidence for population-specific responses to coevolving infection in theP. antipodarum-Microphallusinteraction and provide new insights into the genomic basis of coevolutionary interactions in nature.
Glycerol is the actuator of integral feedback control in yeast osmotic stress signaling
Authors: Rutherford Suzannah
Published: March 2016

In a 2009 article in Cell van Oudenaarden and colleagues employed elegant experiments and control theory to model perfect adaptation of the yeast osmotic stress response – precise return of turgor pressure to its optimal, steady-state value despite variation in system parameters and the continued presence of osmotic stress. Their data convincingly showed that nuclear signaling and cell volume undergo “robust perfect adaptation” implying that integral feedback must restore their steady state values. However, the authors incorrectly mapped the integrator onto a minimal network that violates assumptions implicit in conventional block diagrams. Using known features of osmotic stress signaling and results presented by the authors, I argue that glycerol concentration – the integral of the rate of glycerol accumulation (synthesis minus leakage) – transforms metabolic energy into an increased osmolarity that drives water influx and restoration of turgor pressure. I show how integral feedback control actuated through glycerol synthesis is logically positioned to provide perfect adaptation and robustness in hyperosmotic stress responses.
Absence of Genome Reduction In Diverse, Facultative Endohyphal Bacteria
Authors: Baltrus David A. , Dougherty Kevin , Arendt Kayla R. , Huntemann Marcel , Clum Alicia , Pillay Manoj , Palaniappan Krishnaveni , Varghese Neha , Mikhailova Natalia , Stamatis Dimitrios , Reddy T. B. K. , Ngan Chew Yee , Daum Chris , Shapiro Nicole , Markowitz Victor , Ivanova Natalia , Kyrpides Nikos , Woyke Tanja , Arnold A. Elizabeth
Published: March 2016

Fungi interact closely with bacteria both on the surfaces of hyphae, and within their living tissues (i.e., endohyphal bacteria, EHB). These EHB can be obligate or facultative symbionts, and can mediate a diverse phenotypic traits in their hosts. Although EHB have been observed in many major lineages of fungi, it remains unclear how widespread and general these associations are, and whether there are unifying ecological and genomic features found across all EHB strains. We cultured 11 bacterial strains after they emerged from the hyphae of diverse Ascomycota that were isolated as foliar endophytes of cupressaceous trees, and generated nearly complete genome sequences for all. Unlike the genomes of largely obligate EHB, genomes of these facultative EHB resemble those of closely related strains isolated from environmental sources. Although all analyzed genomes encode structures that can be used to interact with eukaryotic hosts, we find no known pathways that facilitate intimate EHB-fungal interactions in all strains. We isolated two strains with nearly identical genomes from different classes of fungi, consistent with previous suggestions of horizontal transfer of EHB across endophytic hosts. Because bacteria are differentially present during the fungal life cycle, these genomes could shed light on the mechanisms of plant growth promotion by fungal endophytes during the symbiotic phase as well as degradation of plant material during saprotrophic and reproductive phases. Given the capacity of EHB to influence fungal phenotypes, these findings illuminate a new dimension of fungal biodiversity.
Experimental evidence for sexual selection against inbred males when it truly counts
Authors: Vega-Trejo Regina , Head Megan L. , Keogh J. Scott , Jennions Michael D.
Published: March 2016

Although there are many correlational studies, unbiased estimates of inbreeding depression only come from experimental studies that create inbred and outbred individuals. Few such studies determine the extent to which inbreeding depression in males is due to natural or sexual selection. Importantly, traits that are closely related to fitness are predicted to be most strongly affected by inbreeding depression, so measuring fitness or key fitness components, rather than phenotypic traits, is necessary to estimate inbreeding depression accurately. Here, we experimentally created inbred and outbred male mosquitofish (Gambusia holbrooki) by mating full-sibs (f=0.25). We show this led to a 23% reduction in genome-wide heterozygosity. Males were then raised on different diets early in life. We then allowed adult males to compete freely for females to test if inbreeding, early diet, and their interaction affect a male’s share of paternity. Early diet had no effect on paternity, but outbred males sired almost twice as many offspring as inbred males. We also found that males with a relatively long gonopodium (intromittent organ) had greater reproductive success. We demonstrate that inbreeding has important consequences because it negatively affects a key component of male fitness. Given there was no difference in adult mortality this finding can only be due to inbreeding negatively affecting sexually selected traits.
Sexual selection on body size, genitals and heterozygosity:effects of demography and habitat complexity
Authors: Head Megan L. , Kahn Andrew T. , Keogh J. Scott , Jennions Michael D.
Published: March 2016

Environmental variation can maintain genetic variation in sexually selected traits if it affects the strength of directional selection. Specifically, environmental variation in sex-specific mortality will change the operational sex ratio (OSR), which predicts the intensity of mating competition. How the OSR affects selection for specific male traits is poorly understood; and it is unknown how often sexual selection is affected by interactions between the OSR and environmental factors that alter social variables such as mate encounter rates. Here, we experimentally manipulated the OSR and habitat complexity and quantified sexual selection on male mosquitofish (Gambusia holbrooki). InG. holbrookithere is high within-population variation in male size, which may exist because of a tradeoff between the ability to sneak copulate (favouring small males) and monopolize females (favouring large males). The success of each tactic is predicted to depend on the OSR, encounter rates and the ability to stealthily approach conspecifics. We show that, despite greater sharing of paternity under a male-biased OSR, neither the opportunity for selection, nor selection on male traits was affected by the OSR or habitat complexity. Instead, sexual selection consistently favored smaller males with high genetic heterozygosity (using >3000 SNP markers), and a relatively long gonopodium (intromittent organ).
Are sexually selected traits affected by a poor environment early in life?
Authors: Vega-Trejo Regina , Jennions Michael D. , Head Megan L.
Published: March 2016

Conditions experienced early in life can affect key life-history traits. Individuals that experience a poor nutritional environment early in life can reduce potential costs by delaying sexual maturation. The direct costs of delaying maturation are well known (i.e. delayed onset of breeding), but individuals can also face additional costs as adults. Some of these ‘hidden costs’ accrue due to cryptic morphological and physiological changes. In mosquitofish (Gambusia holbrooki), males with limited food intake early in life delay maturation to eventually reach a similar adult body size to their well-fed counterparts (‘catch-up growth’). Here we tested whether a poor diet early in life incurs hidden costs due to reduced expression of sexually selected male traits (genital size and ejaculate traits). We found that diet early in life significantly influenced sperm reserves and replenishment rate due to age and development-rate dependent effects. Although catching-up in body size ameliorates some of the costs of a poor start in life for males, our findings suggest that long-term fitness costs might arise because of sexually selection against these males. Our results highlight that fitness costs of a poor start in life can extend into adulthood.
GDP to GTP exchange on the microtubule end can contribute to the frequency of catastrophe
Authors: Piedra Felipe-Andrés , Kim Tae , Garza Emily S. , Geyer Elisabeth A. , Burns Alexander , Ye Xuecheng , Rice Luke M.
Published: March 2016

Microtubules are dynamic polymers of αβ-tubulin that have essential roles in chromosome segregation and organizing the cytoplasm. Catastrophe – the switch from growing to shrinking – occurs when a microtubule loses its stabilizing GTP cap. Recent evidence indicates that the nucleotide on the microtubule end controls how tightly an incoming subunit will be bound (trans-acting GTP), but most current models do not incorporate this information. We implemented transacting GTP into a computational model for microtubule dynamics. In simulations, growing microtubules often exposed terminal GDP-bound subunits without undergoing catastrophe. Transient GDP exposure on the growing plus end slowed elongation by reducing the number of favorable binding sites on the microtubule end. Slower elongation led to erosion of the GTP cap and an increase in the frequency of catastrophe. Allowing GDP to GTP exchange on terminal subunits in simulations mitigated these effects. Using mutant αβ-tubulin or modified GTP, we showed experimentally that a more readily exchangeable nucleotide led to less frequent catastrophe. Current models for microtubule dynamics do not account for GDP to GTP exchange on the growing microtubule end, so our findings provide a new way of thinking about the molecular events that initiate catastrophe.
Clusterflock: A Flocking Algorithm for Isolating Congruent Phylogenomic Datasets
Authors: Narechania Apurva , Baker Richard , DeSalle Rob , Mathema Barun , Kolokotronis Sergios-Orestis , Kreiswirth Barry , Planet Paul J.
Published: March 2016

Background

Collective animal behavior such as the flocking of birds or the shoaling of fish has inspired a class of algorithms designed to optimize distance-based clusters in various applications including document analysis and DNA microarrays. In the flocking model, individual agents respond only to their immediate environment and move according to a few simple rules. After several iterations the agents self-organize and clusters emerge without the need for partitional seeds. In addition to their unsupervised nature, flocking offers several computational advantages including the potential to decrease the number of required comparisons.

Findings

In Clusterflock, we implement a flocking algorithm designed to find groups (flocks) of orthologous gene families (OGFs) that share a common evolutionary history. Pairwise distances that measure the phylogenetic incongruence between OGFs guide flock formation. We test this approach on several simulated datasets varying the number of underlying topologies, the proportion of missing data, and evolutionary rates, and show that in datasets containing high levels of missing data and rate heterogeneity, clusterflock outperforms other well-established clustering techniques. We also demonstrate its utility on a known, large-scale recombination event inStaphylococcus aureus. By isolating sets of OGFs with divergent phylogenetic signal, we can pinpoint the recombined region without forcing a pre-determined number of groupings or defining a pre-determined incongruence threshold.

Conclusions

Clusterflock is an open source tool that can be used to discover horizontally transferred genes, recombining areas of chromosomes, and the phylogenetic “core” of a genome. Though we use it in an evolutionary context, it is generalizable to any clustering problem. Users can write extensions to calculate any distance metric on the unit interval and use these distances to flock any type of data.
Distinct Responses to Reduplicated Chromosomes Require Distinct Mad2 Responses
Authors: Stormo Benjamin M. , Fox Donald T.
Published: March 2016

Duplicating chromosomes once each cell cycle produces sister chromatid pairs, which separate accurately at anaphase. In contrast, reduplicating chromosomes without separation frequently produces polytene chromosomes, a barrier to accurate mitosis. Chromosome reduplication occurs in many contexts, including: polytene tissue development, polytene tumors, and following treatment with mitosis-blocking chemotherapeutics. However, mechanisms responding to or resolving polyteny during mitosis are poorly understood. Here, usingDrosophila, we uncover two distinct reduplicated chromosome responses. First, when reduplicated polytene chromosomes persist into metaphase, an anaphase delay prevents tissue malformation and apoptosis. Second, reduplicated polytene chromosomes can also separate prior to metaphase through a spindlePindependent mechanism termed Separation-Into-Recent-Sisters (SIRS). Both reduplication responses require the spindle assembly checkpoint protein Mad2. While Mad2 delays anaphase separation of metaphase polytene chromosomes, Mad2’s control of overall mitotic timing ensures efficient SIRS. Our results pinpoint mechanisms enabling continued proliferation after genome reduplication, a finding with implications for cancer progression and prevention.
Case-control association mapping without cases
Authors: Liu Jimmy Z , Erlich Yaniv , Pickrell Joseph K
Published: March 2016

The case-control association study is a powerful method for identifying genetic variants that influence disease risk. However, the collection of cases can be time-consuming and expensive; if a disease occurs late in life or is rapidly lethal, it may be more practical to identify family members of cases. Here, we show that replacing cases with their first-degree relatives enables genome-wide association studies by proxy (GWAX). In randomly-ascertained cohorts, this approach enables previously infeasible studies of diseases that are absent (or nearly absent) in the cohort. As an illustration, we performed GWAX of 12 common diseases in 116,196 individuals from the UK Biobank. By combining these results with published GWAS summary statistics in a meta-analysis, we replicated established risk loci and identified 17 newly associated risk loci: four in Alzheimer’s disease, eight in coronary artery disease, and five in type 2 diabetes. In addition to informing disease biology, our results demonstrate the utility of association mapping using family history of disease as a phenotype to be mapped. We anticipate that this approach will prove useful in future genetic studies of complex traits in large population cohorts.
Connecting Source with Sink: The Role of Arabidopsis AAP8 in Phloem Loading of Amino Acids
Authors: Santiago James P. , Tegeder Mechthild
Published: March 2016

Allocation of large amounts of nitrogen to developing organs occurs in the phloem and is essential for plant growth and seed development. In Arabidopsis (Arabidopsis thaliana) and many other plant species, amino acids represent the dominant nitrogen transport forms in the phloem, and they are mainly synthesized in photosynthetically active source leaves. Following their synthesis, a broad spectrum of the amino nitrogen is actively loaded into the phloem of leaf minor veins and transported within the phloem sap to sinks such as developing leaves, fruits, or seeds. Controlled regulation of the source-to-sink transport of amino acids has long been postulated; however, the molecular mechanism of amino acid phloem loading was still unknown. In this study, Arabidopsis AMINO ACID PERMEASE8 (AAP8) was shown to be expressed in the source leaf phloem and localized to the plasma membrane, suggesting its function in phloem loading. This was further supported by transport studies with aap8 mutants fed with radiolabeled amino acids and by leaf exudate analyses. In addition, biochemical and molecular analyses revealed alterations in leaf nitrogen pools and metabolism dependent on the developmental stage of the mutants. Decreased amino acid phloem loading and partitioning to sinks led to decreased silique and seed numbers, but seed protein levels were unchanged, demonstrating the importance of AAP8 function for sink development rather than seed quality. Overall, these results show that AAP8 plays an important role in source-to-sink partitioning of nitrogen and that its function affects source leaf physiology and seed yield.
Liberal Interventionism
Authors: Lipsey David
Published: March 2016

David Lipsey analyses the arguments made by former Labour prime minister Tony Blair in his Chicago speeches for armed liberal intervention in states which are abusing the human rights of their citizens. He traces these arguments back to previous advocates of such intervention such as W. E. Gladstone and Woodrow Wilson. The arguments of Blair and advocates are often compelling in principle. However, in most cases—Iraq and Libya are examples—the practical consequences of military action turn out to be disastrous. Though opposing pacifism, and the ill‐thought‐out hostility to all things military of Labour's current leader Jeremy Corbyn, Lipsey's advice to those thinking of intervening is: don't.
Planning Makes (Closer to) Perfect: Exploring United States’ Local Government Officials’ Evaluations of Crisis Management
Authors: Avery Elizabeth Johnson , Graham Melissa , Park Sejin
Published: March 2016

How a government responds to, manages, and communicates about crisis has direct implications for public well‐being and ultimately shapes public opinion about local governments and government officials. Yet, little is known about crisis preparation, especially that of local governments. Local governments are involved in managing any crisis situation that affects their communities, regardless of the responsible organization or nature of the crisis. This study surveys local government officials (N = 307) in 44 states across the United States who manage crisis communication to reveal unique considerations of planning, magnitude and citizen satisfaction on crisis management. Novel findings are revealed with respect to each variable to direct future crisis research, particularly that informing the precrisis stage.
A Bayesian approach for detecting the impact of mass‐extinction events on molecular phylogenies when rates of lineage diversification may vary
Authors: May Michael R. , Höhna Sebastian , Moore Brian R.
Published: March 2016

The paleontological record chronicles numerous episodes of mass extinction that severely culled the Tree of Life. Biologists have long sought to assess the extent to which these events may have impacted particular groups. We present a novel method for detecting the impact of mass‐extinction events on molecular phylogenies, even in the presence of tree‐wide diversification‐rate variation and in the absence of additional information from the fossil record.

Our approach is based on an episodic stochastic‐branching process model in which rates of speciation and extinction are constant between events. We model three types of events: (i) instantaneous tree‐wide shifts in speciation rate; (ii) instantaneous tree‐wide shifts in extinction rate and (iii) instantaneous tree‐wide mass‐extinction events. Each type of event is modelled as an independent compound Poisson process (CPP), where the waiting times between events are exponentially distributed with event‐specific rate parameters. The magnitude of each event is drawn from an event‐specific prior distribution. Parameters of the model are then estimated in a Bayesian statistical framework using a reversible‐jump Markov chain Monte Carlo algorithm. This Bayesian approach enables us to distinguish between tree‐wide diversification‐rate variation and mass‐extinction events by specifying a biologically informed prior on the magnitude of mass‐extinction events and empirical hyperpriors on the diversification‐rate parameters.

We demonstrate via simulation that this method has substantial power to detect the number of mass‐extinction events and provides unbiased estimates of the timing of mass‐extinction events, while exhibiting an appropriate (i.e. <5%) false‐discovery rate, even when background diversification rates vary. Finally, we provide an empirical demonstration of this approach, which reveals that conifers experienced a major episode of mass extinction ≈23 Ma.

This new approach – the CPP on Mass‐Extinction Times (CoMET) model – provides an effective tool for detecting the impact of mass‐extinction events on molecular phylogenies, even when the history of those groups includes temporal variation in diversification rates and when the fossil history of those groups is poorly known.
Dentists' restorative decision‐making and implications for an ‘amalgamless’ profession. Part 3: Dentists' attitudes
Authors: Alexander G , Hopcraft MS , Tyas MJ , Wong RHK
Published: March 2016

Background

The Minamata Convention has agreed to a worldwide reduction in the production and use of mercury‐containing products and processes. This will change the approach to use of direct restorative materials in the future. There is little research exploring the attitudes of dentists to any change.

Methods

A survey relating to the use of direct restorative materials was distributed to dentists who were members of the Australian Dental Association or Members and Fellows of the Royal Australasian College of Dental Surgeons. Data were statistically analysed.

Results

There were 408 respondents. Responses to statements concerning attitudes toward a phase‐down of amalgam depended on whether the respondent used amalgam, year of primary dental qualification and association with academia. Thirty per cent of respondents indicated they do not use amalgam. The mean use of amalgam for all direct restorative procedures was 18%.

Conclusions

Dentists are concerned over potential implications of a phase‐down of amalgam and much should be done to address these concerns. Many dentists are undecided as to what are the implications, which may reflect a lack of understanding of the issues. It is incumbent on policy‐makers to produce and disseminate information relating to the issues identified by this research.
The symptom trajectories to clinical remission in Chinese patients with unipolar major depressive disorder
Authors: Cao Yuping , Shen Jingjin , Li Wen , Zhang Yu , Guo Xiaoyun , Li Chiang‐shan , Zhang Yalin , Luo Xingguang
Published: March 2016

There is little understanding of how unipolar major depressive disorder (UMDD) symptoms evolve in response to antidepressant treatment. The present research examined the associations between symptom trajectories and clinical remission in Chinese patients with UMDD. A total of 165 outpatients with UMDD received treatment of fluoxetine (20 mg/day) for 6 weeks and were assessed for symptom severity at weeks 1, 2, 4, and 6. We found that patients with UMDD show heterogeneity in treatment response to fluoxetine. Psychomotor retardation is a prominent symptom during the 6 weeks of assessment, and its severity at baseline is negatively associated with clinical remission.
Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti‐hyperalgesic effects, in patients with sciatica
Authors: Okkerse Pieter , Hay Justin L. , Versage Eve , Tang Yongqiang , Galluppi Gerald , Ravina Bernard , Verma Ajay , Williams Leslie , Aycardi Ernesto , Groeneveld Geert Jan
Published: March 2016

AIMS

BG00010 is a protein in the glial cell line‐derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha‐3 (GFRα3) co‐receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica.

Methods

This was a randomized, blinded, placebo‐controlled multiple‐dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg−1) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg−1). Safety and efficacy assessments were used as endpoints.

Results

The BG00010 concentration–time data indicated relatively low inter‐patient variability and there was a dose‐dependent (not dose‐proportional) increase in serum exposure from 150 to 1200 μg kg−1. The effective half‐life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67–83%), feeling hot (50–100%), and pruritus (42–67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose–response relationship was not seen.

Conclusions

The pharmacokinetic profile of BG00010 was characterized by low intra‐patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica.
Dietary anthocyanins and health: data from FLORA and ATHENA EU projects
Authors: Cerletti Chiara , De Curtis Amalia , Bracone Francesca , Digesù Cinzia , Morganti Alessio G. , Iacoviello Licia , de Gaetano Giovanni , Donati Maria Benedetta
Published: March 2016

Adherence to a ‘Mediterranean diet’ has been shown to be beneficial to human health. Fruit and vegetables represent some of the main components of the Mediterranean diet and their role has been increasingly considered in the process of preventing or reducing the risk of chronic degenerative diseases, such as cerebrovascular or coronary heart disorders, cancer and neurodegenerative diseases. To investigate the beneficial effect of these dietary compounds, two EU‐funded projects were conducted during the last 10 years. Their results from experimental models suggest that dietary anthocyanin enrichment is beneficial against a number of ischemic and degenerative conditions. On the other hand, human studies demonstrated that anthocyanin supplementation can counteract the inflammatory response to stress conditions, such as a fatty meal. Moreover, an intervention trial in patients with breast cancer undergoing radiotherapy is presently testing the possible beneficial effect of the administration of a product enriched in anthocyanins on the inflammatory response to radiation and on its consequent skin toxicity, as well as on systemic low‐grade inflammation reaction.
Extracellular matrix proteins matrix metallopeptidase 9 (MMP9) and soluble intercellular adhesion molecule 1 (sICAM‐1) and correlations with clinical staging in euthymic bipolar disorder
Authors: Reininghaus Eva Z , Lackner Nina , Birner Armin , Bengesser Susanne , Fellendorf Frederike T , Platzer Martina , Rieger Alexandra , Queissner Robert , Kainzbauer Nora , Reininghaus Bernd , McIntyre Roger S , Mangge Harald , Zelzer Sieglinde , Fuchs Dietmar , Dejonge Silvia , Müller Norbert
Published: March 2016

Objectives

Matrix metallopeptidase 9 (MMP9) and soluble intercellular adhesion molecule 1 (sICAM‐1) are both involved in the restructuring of connective tissues. Evidence also implicates MMP9 and sICAM in cardiovascular and neoplastic diseases, where blood levels may be a marker of disease severity or prognosis. In individuals with bipolar disorder (BD), higher risk for cardiovascular illness has been extensively reported.

Methods

The aim of this investigation was to measure and compare peripheral levels of serum MMP9 and sICAM in adults with euthymic BD and healthy controls (HC). Furthermore, we focussed on correlations with illness severity and metabolic parameters.

Results

MMP9 levels among the BD sample (n = 112) were significantly higher than among the HC (n = 80) (MMP9: F = 9.885, p = 0.002, η2 = 0.058) after controlling for confounding factors. Patients with BD in a later, progressive stage of disease showed significantly higher MMP9 as well as sICAM‐1 levels compared to patients with BD in an earlier stage of disease (MMP9: F = 5.8, p = 0.018, η2 = 0.054; sICAM‐1: F = 5.6, p = 0.020, η2 = 0.052). Correlation analyses of cognitive measures revealed a negative association between performance on the d2 Test of Attention and MMP9 (r = −0.287, p = 0.018) in the BD sample. Despite the sample being euthymic (i.e., according to conventional criteria) at the time of analysis, we found significant correlations between MMP9 as well as sICAM‐1 and subthreshold depressive/hypomanic symptoms.

Conclusions

A collection of disparate findings herein point to a role of MMP9 and cICAM‐1 in the patho‐progressive process of BD: the increased levels of serum MMP9 and sICAM‐1, the correlation between higher levels of these parameters, progressive stage, and cognitive dysfunction in BD, and the positive correlation with subthreshold symptoms. As sICAM‐1 and MMP9 are reliable biomarkers of inflammatory and early atherosclerotic disease, these markers may provide indications of the presence of occult cardiovascular disease in this highly at‐risk population.
The effect of one‐time abutment placement on interproximal bone levels and peri‐implant soft tissues: a prospective randomized clinical trial
Authors: Molina Ana , Sanz‐Sánchez Ignacio , Martín Conchita , Blanco Juan , Sanz Mariano
Published: March 2016

Objective

To compare the effect of placing the definitive abutment at the time of implant placement versus at a later stage, on the soft and hard tissue changes around dental implants.

Material and methods

Platform‐switched implants were placed in the posterior maxilla or mandible of partial edentulous patients and they were randomized to receive the definitive abutment at the moment of implant placement, or 6–12 weeks later. Final prostheses were delivered 2–4 weeks later. Radiographic assessment of vertical bone level changes (primary outcome), clinical status of peri‐implant tissues, changes in soft tissues margin, papilla filling, patient‐related outcomes and adverse events were assessed 6 and 12 months after loading.

Results

60 implants were placed in 40 patients, replacing single or multiple absent teeth. One implant was lost 1 week after insertion (overall survival rate: 98.3%). A statistically significant greater bone resorption from surgery to 6 months post‐loading was observed for those implants subjected to abutment change (control group: −1.24 ± 0.79 mm; test group: −0.61 ± 0.40 mm; P = 0.028). Periodontal clinical parameters and patient‐related outcomes, however, did not demonstrate significant differences between groups at any time point. A significant increase in papilla height was observed from loading to 12 months in all implants (control group: 1.17 ± 1.47 mm; test group: 0.98 ± 0.89 mm) and a slight but not significant coronal migration of the gingival margin.

Conclusions

The connection and disconnection of healing abutments is associated with significantly increased bone loss during the healing period between implant placement and 6 months post‐loading, when compared to one‐time abutment placement.
Multiple Sensory‐Motor Pathways Lead to Coordinated Visual Attention
Authors: Yu Chen , Smith Linda B.
Published: March 2016

Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of this study was to understand the complex system of sensory‐motor behaviors that may underlie the establishment of joint attention between parents and toddlers. In an experimental task, parents and toddlers played together with multiple toys. We objectively measured joint attention—and the sensory‐motor behaviors that underlie it—using a dual head‐mounted eye‐tracking system and frame‐by‐frame coding of manual actions. By tracking the momentary visual fixations and hand actions of each participant, we precisely determined just how often they fixated on the same object at the same time, the visual behaviors that preceded joint attention and manual behaviors that preceded and co‐occurred with joint attention. We found that multiple sequential sensory‐motor patterns lead to joint attention. In addition, there are developmental changes in this multi‐pathway system evidenced as variations in strength among multiple routes. We propose that coordinated visual attention between parents and toddlers is primarily a sensory‐motor behavior. Skill in achieving coordinated visual attention in social settings—like skills in other sensory‐motor domains—emerges from multiple pathways to the same functional end.
Compatibilism and Incompatibilism in Social Cognition
Authors: Turri John
Published: March 2016

Compatibilism is the view that determinism is compatible with acting freely and being morally responsible. Incompatibilism is the opposite view. It is often claimed that compatibilism or incompatibilism is a natural part of ordinary social cognition. That is, it is often claimed that patterns in our everyday social judgments reveal an implicit commitment to either compatibilism or incompatibilism. This paper reports five experiments designed to identify such patterns. The results support a nuanced hybrid account: The central tendencies in ordinary social cognition are compatibilism about moral responsibility, compatibilism about positive moral accountability (i.e., about deserving credit for good outcomes), neither compatibilism nor incompatibilism about negative moral accountability (i.e., about deserving blame for bad outcomes), compatibilism about choice for actions with positive outcomes, and incompatibilism about choice for actions with negative or neutral outcomes.