Target DNA Structure Plays a Critical Role in RAG Transposition

Antigen receptor gene rearrangements are initiated by the RAG1/2 protein complex, which recognizes specific DNA sequences termed RSS (recombination signal sequences). The RAG recombinase can also catalyze transposition: integration of a DNA segment bounded by RSS into an unrelated DNA target. For reasons that remain poorly understood, such events occur readily in vitro, but are rarely detected in vivo. Previous work showed that non-B DNA structures, particularly hairpins, stimulate transposition. Here we show that the sequence of the four nucleotides at a hairpin tip modulates transposition efficiency over a surprisingly wide (>100-fold) range. Some hairpin targets stimulate extraordinarily efficient transposition (up to 15%); one serves as a potent and specific transposition inhibitor, blocking capture of targets and destabilizing preformed target capture complexes. These findings suggest novel regulatory possibilities and may provide insight into the activities of other transposases

A novel COMP mutation in a pseudoachondroplasia family of Chinese origin

<p>Abstract</p> <p>Background</p> <p>Pseudoachondroplasia (PSACH) is caused exclusively by mutations in the gene for cartilage oligomeric matrix protein (<it>COMP</it>). Only a small number of studies have documented the clinical phenotype and genetic basis in Chinese PSACH patients.</p> <p>Case presentation</p> <p>We investigated a four-generation PSACH pedigree of Chinese Han origin. Two patients and two unaffected individuals were recruited for clinical evaluation and molecular genetic analysis. The genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction (PCR) was adopted to amplify the 8-19 exons of <it>COMP </it>gene. Then the products were sequenced bi-directionally for screening mutation. Clinical evaluation revealed that PSACH patients in this pedigree had a severe disproportionate short stature (-10SD). A heterozygous TGTCCCTGG insertion in exon 13, between nucleotide 1352T and 1353G, were identified in the patients except the unaffected individuals, which resulted in a three-amino-acid insertion (451V_452P ins VPG) in the sixth calmodulin-like repeat of the <it>COMP </it>protein.</p> <p>Conclusion</p> <p>This c. 1352_1353ins TGTCCCTGG is a novel mutation responsible for severe familial PSACH.</p

Characterizing College Science Assessments: The Three-Dimensional Learning Assessment Protocol

Citation: Laverty, J. T., Underwood, S. M., Matz, R. L., Posey, L. A., Carmel, J. H., Caballero, M. D., . . . Cooper, M. M. (2016). Characterizing College Science Assessments: The Three-Dimensional Learning Assessment Protocol. Plos One, 11(9), 21. doi:10.1371/journal.pone.0162333Many calls to improve science education in college and university settings have focused on improving instructor pedagogy. Meanwhile, science education at the K-12 level is undergoing significant changes as a result of the emphasis on scientific and engineering practices, crosscutting concepts, and disciplinary core ideas. This framework of "three-dimensional learning" is based on the literature about how people learn science and how we can help students put their knowledge to use. Recently, similar changes are underway in higher education by incorporating three-dimensional learning into college science courses. As these transformations move forward, it will become important to assess three-dimensional learning both to align assessments with the learning environment, and to assess the extent of the transformations. In this paper we introduce the Three-Dimensional Learning Assessment Protocol (3D-LAP), which is designed to characterize and support the development of assessment tasks in biology, chemistry, and physics that align with transformation efforts. We describe the development process used by our interdisciplinary team, discuss the validity and reliability of the protocol, and provide evidence that the protocol can distinguish between assessments that have the potential to elicit evidence of three-dimensional learning and those that do not

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

The traditional knowledge on stingless bees (Apidae: Meliponina) used by the Enawene-Nawe tribe in western Brazil

<p>Abstract</p> <p>Background</p> <p>This paper presents the Enawene-Nawe Society's traditional knowledge about stingless bees. The Enawene-Nawe are an Aruak speaking people, indigenous to the Meridian Amazon. Specifically, they live in the Jurema River hydrological basin, located in the northwestern region of the Mato Grosso state.</p> <p>Methods</p> <p>The stingless bees were sampled from two ecologically similar regions in the interior of Enawene-Nawe Land. The first sampling took place around the village, i.e., adjacent to houses, by the edge of the Iquê River, next to food leftovers, around human excrement, and simply when the insects were found flying or reposing on a human body. The second round of sampling happened from 29/10 to 02/11/94, during an expedition for honey collection that took place throughout the ciliar bushes of the Papagaio River, an important tributary of Juruena River. We sampled bees adjacent to their nests following the beehive inspection or during the honey extraction.</p> <p>In this work, the main bee species of the sub tribe Meliponina, which were handled by the Enawene-Nawe, was identified, and a brief ethnographic description of the honey collection expeditions and its social-cosmologic meaning for the group was done.</p> <p>Results and Discussion</p> <p>Similar to other indigenous people in Brazil, the Enawene-Nawe recognized 48 stingless bee species. They identified each bee species by name and specified each one's ecological niche. A brief ethnographic description of the honey collection expeditions and bees' social-cosmologic meaning for the group is included.</p> <p>Conclusion</p> <p>We concluded that, as an example of other indigenous people, the Enawene-Nawe classify and identify the bees based not only on their structure and morphological aspects but also on the ecological, etiological, and social characteristics of the species.</p

Medication Therapy Management Interventions in Outpatient Settings: A Systematic Review and Meta-analysis

IMPORTANCE: Medication therapy management (MTM) services (also called clinical pharmacy services) aim to reduce medication-related problems and their downstream outcomes. OBJECTIVE: To assess the effect of MTM interventions among outpatients with chronic illnesses. DATA SOURCES: MEDLINE, Cochrane Library, and International Pharmaceutical Abstracts through January 9, 2014. STUDY SELECTION: Two reviewers selected studies with comparators and eligible outcomes of ambulatory adults. DATA EXTRACTION AND SYNTHESIS: Dual review of titles, abstracts, full-text, extractions, risk of bias, and strength of evidence grading. We conducted meta-analyses using random-effects models. MAIN OUTCOMES AND MEASURES: Medication-related problems, morbidity, mortality, quality of life, health care use, costs, and harms. RESULTS: Forty-four studies met the inclusion criteria. The evidence was insufficient to determine the effect of MTM interventions on most evaluated outcomes (eg, drug therapy problems, adverse drug events, disease-specific morbidity, disease-specific or all-cause mortality, and harms). The interventions improved a few measures of medication-related problems and health care use and costs (low strength of evidence) when compared with usual care. Specifically, MTM interventions improved medication appropriateness (4.9 vs 0.9 points on the medication appropriateness index, P < .001), adherence (approximately 4.6%), and percentage of patients achieving a threshold adherence level (odds ratios [ORs] ranged from 0.99 to 5.98) and reduced medication dosing (mean difference, -2.2 doses; 95% CI, -3.738 to -0.662). Medication therapy management interventions reduced health plan expenditures on medication costs, although the studies reported wide CIs. For patients with diabetes mellitus or heart failure, MTM interventions lowered the odds of hospitalization (diabetes: OR, 0.91 to 0.93 based on type of insurance; adjusted hazard rate for heart failure: 0.55; 95% CI, 0.39 to 0.77) and hospitalization costs (mean differences ranged from -$363.45 to -$398.98). The interventions conferred no benefit for patient satisfaction and most measures of health-related quality of life (low strength). CONCLUSIONS AND RELEVANCE: We graded the evidence as insufficient for most outcomes because of inconsistency and imprecision that stem in part from underlying heterogeneity in populations and interventions. Medication therapy management interventions may reduce the frequency of some medication-related problems, including nonadherence, and lower some health care use and costs, but the evidence is insufficient with respect to improvement in health outcomes

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

A relocatable ocean model in support of environmental emergencies

During the Costa Concordia emergency case, regional, subregional, and relocatable ocean models have been used together with the oil spill model, MEDSLIK-II, to provide ocean currents forecasts, possible oil spill scenarios, and drifters trajectories simulations. The models results together with the evaluation of their performances are presented in this paper. In particular, we focused this work on the implementation of the Interactive Relocatable Nested Ocean Model (IRENOM), based on the Harvard Ocean Prediction System (HOPS), for the Costa Concordia emergency and on its validation using drifters released in the area of the accident. It is shown that thanks to the capability of improving easily and quickly its configuration, the IRENOM results are of greater accuracy than the results achieved using regional or subregional model products. The model topography, and to the initialization procedures, and the horizontal resolution are the key model settings to be configured. Furthermore, the IRENOM currents and the MEDSLIK-II simulated trajectories showed to be sensitive to the spatial resolution of the meteorological fields used, providing higher prediction skills with higher resolution wind forcing.MEDESS4MS Project; TESSA Project; MyOcean2 Projectinfo:eu-repo/semantics/publishedVersio

Bird-spiders (Arachnida, Mygalomorphae) as perceived by the inhabitants of the village of Pedra Branca, Bahia State, Brazil

This paper deals with the conceptions, knowledge and attitudes of the inhabitants of the county of Pedra Branca, Bahia State, on mygalomorph spiders locally known as 'caranguejeiras' (bird-spiders). It is launched here a new filed within ethnozoology: ethnoarachnology, which is defined as the transdisciplinary study of the relationships between human beings and bird-spiders. Data were collected from February to June 2005 by means of open-ended interviews carried out with 30 individuals, which ages ranged from 13 to 86 years old. It was recorded some traditional knowledge regarding the following items: taxonomy, biology, habitat, ecology, seasonality, and behavior. Results show that bird-spiders are classified as "insects". The most commented aspect of the interaction between bird-spiders and inhabitants of Pedra Branca is related to their dangerousness, since they said these spiders are very venomous and can cause health problems. In general, the traditional zoological knowledge of Pedra Branca's inhabitants concerning these spiders is coherent with the academic knowledge