One possible mechanism to explain the observed variability of the short- lived ¹⁴⁶Sm → ¹⁴²Nd and ¹⁸²Hf → ¹⁸²W systems recorded in some early Earth rocks is crystal-liquid fractionation and overturn in an early magma ocean. This process could also potentially explain the deviation between the ¹⁴²Nd isotopic composition of the accessible Earth and the chondritic average. To examine these effects, the magma ocean solidification code of Elkins-Tanton (2008) and a modified Monte Carlo algorithm, designed to randomly choose physically reasonable trace element partition coefficients in crystallizing mantle phases, are used to model the isotopic evolution of early Earth reservoirs. This model, also constrained by the ¹⁴³Nd composition of the accessible Earth, explores the effects of changing the amount of interstitial liquid trapped in cumulates, the half-life of ¹⁴⁶Sm, the magnitude of late accretion, and the simplified model of post-overturn reservoir mixing. Regardless of the parameters used, our results indicate the generation of early mantle reservoirs with isotopic characteristics consistent with observed anomalies is a likely outcome of magma ocean crystallization and overturn of shallow, enriched, and dense (i.e., gravitationally unstable) cumulates. The high-iron composition and density of a hypothesized, early-formed enriched mantle reservoir is compatible with seismic observations indicating large, low-shear velocity provinces (LLSVPs) (e.g., Trampert et al., 2004) present in the mantle today. Later melts of an enriched reservoir are likely to have remained isolated deep within the mantle (e.g., Thomas et al., 2012), consistent with the possibility that the presently observed LLSVPs could be partially or fully composed of remnants of an early enriched reservoir.

Background: 3′untranslated regions (3′UTRs) are poorly understood portions of eukaryotic mRNAs essential for post-transcriptional gene regulation. Sequence elements in 3′UTRs can be target sites for regulatory molecules such as RNA binding proteins and microRNAs (miRNAs), and these interactions can exert significant control on gene networks. However, many such interactions remain uncharacterized due to a lack of high-throughput (HT) tools to study 3′UTR biology. HT cloning efforts such as the human ORFeome exemplify the potential benefits of genomic repositories for studying human disease, especially in relation to the discovery of biomarkers and targets for therapeutic agents. Currently there are no publicly available human 3′UTR libraries. To address this we have prepared the first version of the human 3′UTRome (h3′UTRome v1) library. The h3′UTRome is produced to a single high quality standard using the same recombinational cloning technology used for the human ORFeome, enabling universal operating methods and high throughput experimentation. The library is thoroughly sequenced and annotated with simple online access to information, and made publicly available through gene repositories at low cost to all scientists with minimal restriction.

Results: The first release of the h3′UTRome library comprises 1,461 human 3′UTRs cloned into Gateway® entry vectors, ready for downstream analyses. It contains 3′UTRs for 985 transcription factors, 156 kinases, 171 RNA binding proteins, and 186 other genes involved in gene regulation and in disease. We demonstrate the feasibility of the h3′UTRome library by screening a panel of 87 3′UTRs for targeting by two miRNAs: let-7c, which is implicated in tumorigenesis, and miR-221, which is implicated in atherosclerosis and heart disease. The panel is enriched with genes involved in the RAS signaling pathway, putative novel targets for the two miRNAs, as well as genes implicated in tumorigenesis and heart disease.

Conclusions: The h3′UTRome v1 library is a modular resource that can be utilized for high-throughput screens to identify regulatory interactions between trans-acting factors and 3′UTRs, Importantly, the library can be customized based on the specifications of the researcher, allowing the systematic study of human 3′UTR biology.

Background: Continuous monitoring technologies such as accelerometers and pedometers are the gold standard for physical activity (PA) measurement. However, inconsistencies in use, analysis, and reporting limit the understanding of dose–response relationships involving PA and the ability to make comparisons across studies and population subgroups. These issues are particularly detrimental to the study of PA across different ethnicities with different PA habits. This systematic review examined the inclusion of published guidelines involving data collection, processing, and reporting among articles using accelerometers or pedometers in Hispanic or Latino populations.

Methods: English (PubMed; EbscoHost) and Spanish (SCIELO; Biblioteca Virtual en Salud) articles published between 2000 and 2013 using accelerometers or pedometers to measure PA among Hispanics or Latinos were identified through systematic literature searches. Of the 253 abstracts which were initially reviewed, 57 met eligibility criteria (44 accelerometer, 13 pedometer). Articles were coded and reviewed to evaluate compliance with recommended guidelines (N = 20), and the percentage of accelerometer and pedometer articles following each guideline were computed and reported.

Results: On average, 57.1 % of accelerometer and 62.2 % of pedometer articles reported each recommended guideline for data collection. Device manufacturer and model were reported most frequently, and provision of instructions for device wear in Spanish was reported least frequently. On average, 29.6 % of accelerometer articles reported each guideline for data processing. Definitions of an acceptable day for inclusion in analyses were reported most frequently, and definitions of an acceptable hour for inclusion in analyses were reported least frequently. On average, 18.8 % of accelerometer and 85.7 % of pedometer articles included each guideline for data reporting. Accelerometer articles most frequently included average number of valid days and least frequently included percentage of wear time.

Discussion: Inclusion of standard collection and reporting procedures in studies using continuous monitoring devices in Hispanic or Latino population is generally low.

Background:
Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX.

Results:
We report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis.

Conclusion:
We have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.

Background: With Pennsylvania currently considering a move away from an Alcohol Beverage Control state to a privatized alcohol distribution system, this study uses a spatial analytical approach to examine potential impacts of privatization on the number and spatial distribution of alcohol outlets in the city of Philadelphia over a long time horizon.

Methods: A suite of geospatial data were acquired for Philadelphia, including 1,964 alcohol outlet locations, 569,928 land parcels, and school, church, hospital, park and playground locations. These data were used as inputs for exploratory spatial analysis to estimate the expected number of outlets that would eventually operate in Philadelphia. Constraints included proximity restrictions (based on current ordinances regulating outlet distribution) of at least 200 feet between alcohol outlets and at least 300 feet between outlets and schools, churches, hospitals, parks and playgrounds.

Results: Findings suggest that current state policies on alcohol outlet distributions in Philadelphia are loosely enforced, with many areas exhibiting extremely high spatial densities of outlets that violate existing proximity restrictions. The spatial model indicates that an additional 1,115 outlets could open in Philadelphia if privatization was to occur and current proximity ordinances were maintained.

Conclusions: The study reveals that spatial analytical approaches can function as an excellent tool for contingency-based “what-if” analysis, providing an objective snapshot of potential policy outcomes prior to implementation. In this case, the likely outcome is a tremendous increase in alcohol outlets in Philadelphia, with concomitant negative health, crime and quality of life outcomes that accompany such an increase.

Background: Antenatal Care (ANC) during pregnancy can play an important role in the uptake of evidence-based services vital to the health of women and their infants. Studies report positive effects of ANC on use of facility-based delivery and perinatal mortality. However, most existing studies are limited to cross-sectional surveys with long recall periods, and generally do not include population-based samples.

Methods: This study was conducted within the Health and Demographic Surveillance System (HDSS) of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) in Matlab, Bangladesh. The HDSS area is divided into an icddr,b service area (SA) where women and children receive care from icddr,b health facilities, and a government SA where people receive care from government facilities. In 2007, a new Maternal, Neonatal, and Child Health (MNCH) program was initiated in the icddr,b SA that strengthened the ongoing maternal and child health services including ANC. We estimated the association of ANC with facility delivery and perinatal mortality using prospectively collected data from 2005 to 2009. Using a before-after study design, we also determined the role of ANC services on reduction of perinatal mortality between the periods before (2005 – 2006) and after (2008–2009) implementation of the MNCH program.

Results: Antenatal care visits were associated with increased facility-based delivery in the icddr,b and government SAs. In the icddr,b SA, the adjusted odds of perinatal mortality was about 2-times higher (odds ratio (OR) 1.91; 95% confidence intervals (CI): 1.50, 2.42) among women who received ≤1 ANC compared to women who received ≥3 ANC visits. No such association was observed in the government SA. Controlling for ANC visits substantially reduced the observed effect of the intervention on perinatal mortality (OR 0.64; 95% CI: 0.52, 0.78) to non-significance (OR 0.81; 95% CI: 0.65, 1.01), when comparing cohorts before and after the MNCH program initiation (Sobel test of mediation P < 0.001).

Conclusions: ANC visits are associated with increased uptake of facility-based delivery and improved perinatal survival in the icddr,b SA. Further testing of the icddr,b approach to simultaneously improving quality of ANC and facility delivery care is needed in the existing health system in Bangladesh and in other low-income countries to maximize health benefits to mothers and newborns.

Background: Model selection is a vital part of most phylogenetic analyses, and accounting for the heterogeneity in evolutionary patterns across sites is particularly important. Mixture models and partitioning are commonly used to account for this variation, and partitioning is the most popular approach. Most current partitioning methods require some a priori partitioning scheme to be defined, typically guided by known structural features of the sequences, such as gene boundaries or codon positions. Recent evidence suggests that these a priori boundaries often fail to adequately account for variation in rates and patterns of evolution among sites. Furthermore, new phylogenomic datasets such as those assembled from ultra-conserved elements lack obvious structural features on which to define a priori partitioning schemes. The upshot is that, for many phylogenetic datasets, partitioned models of molecular evolution may be inadequate, thus limiting the accuracy of downstream phylogenetic analyses.

Results: We present a new algorithm that automatically selects a partitioning scheme via the iterative division of the alignment into subsets of similar sites based on their rates of evolution. We compare this method to existing approaches using a wide range of empirical datasets, and show that it consistently leads to large increases in the fit of partitioned models of molecular evolution when measured using AICc and BIC scores. In doing so, we demonstrate that some related approaches to solving this problem may have been associated with a small but important bias.

Conclusions: Our method provides an alternative to traditional approaches to partitioning, such as dividing alignments by gene and codon position. Because our method is data-driven, it can be used to estimate partitioned models for all types of alignments, including those that are not amenable to traditional approaches to partitioning.

Background: Glycosylated proteins and lipids are important regulatory factors whose functions can be altered by addition or removal of sugars to the glycan structure. The glycans are recognized by sugar-binding lectins that serve as receptors on the surface of many cells and facilitate initiation of an intracellular signal that changes the properties of the cells. We identified a peptide that mimics the ligand of an N-acetylgalactosamine (GalNAc)-specific lectin and asked whether the peptide would express specific biological activity.

Findings: A 12-mer phage display library was screened with a GalNAc-specific lectin to identify an amino acid sequence that binds to the lectin. Phage particles that were eluted from the lectin with free GalNAc were considered to have been bound to a GalNAc-binding site. Peptides were synthesized with the selected sequence as a quadravalent structure to facilitate receptor crosslinking. Treatment of human peripheral blood mononuclear cells for 24 h with the peptide stimulated secretion of interleukin-8 (IL-8) but not of IL-1β, IL-6, IL-10, or tumor necrosis factor-α (TNF-α). The secretion of IL-21 was stimulated as strongly with the peptide as with interferon-γ.

Conclusion: The data indicate that the quadravalent peptide has biological activity with a degree of specificity. These effects occurred at concentrations in the nanomolar range, in contrast to free sugars that generally bind to proteins in the micro- to millimolar range.

Background: Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scalec linical trials are daunting, this targeted genomic approach offers a new perspective and hope for improved treatments. Cancers of the ampulla of Vater are rare tumors that comprise only about 0.2% of gastrointestinal cancers. Consequently, they are often treated as either distal common bile duct or pancreatic cancers.

Methods: We analyzed DNA from a resected cancer of the ampulla of Vater and whole blood DNAfrom a 63 year-old man who underwent a pancreaticoduodenectomy by whole genomesequencing, achieving 37× and 40× coverage, respectively. We determined somatic mutations and structural alterations.

Results: We identified relevant aberrations, including deleterious mutations of KRAS and SMAD4 as well as a homozygous focal deletion of the PTEN tumor suppressor gene. These findings suggest that these tumors have a distinct oncogenesis from either common bile duct cancer or pancreatic cancer. Furthermore, this combination of genomic aberrations suggests a therapeutic context for dual mTOR/PI3K inhibition.

Conclusions: Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.

Background: Operant hyperactivity, the emission of reinforced responses at an inordinately high rate, has been reported in children with ADHD and in the Spontaneously Hypertensive Rat (SHR), the most widely studied animal model of ADHD. The SHR emits behavior at hyperactive levels, relative to a normoactive strain, only when such behavior is seldom reinforced. Because of its dependence on rate of reinforcement, operant hyperactivity appears to be driven primarily by incentive motivation, not motoric capacity. This claim was evaluated in the present study using a novel strategy, based on the organization of behavior in bouts of reinforced responses separated by pauses.

Method: Male SHR, Wistar-Kyoto (WKY) and Wistar rats (WIS) were exposed each to a multiple variable-interval schedule of sucrose reinforcement (12, 24, 48, 96, and 192 s) between post-natal days (PND) 48 and 93. Responding in each schedule was examined in two epochs, PND 58-62 and 89-93. Parameters of response-reinforcement functions (Herrnstein's hyperbola) and bout-organized behavior were estimated in each epoch.

Results: SHR emitted higher response rates than WKY and WIS, but only when rate of reinforcement was low (fewer than 2 reinforcers per minute), and particularly in the second epoch. Estimates of Herrnstein's hyperbola parameters suggested the primacy of motivational over motoric factors driving the response-rate differential. Across epochs and schedules, a more detailed analysis of response bouts by SHR revealed that these were shorter than those by WKY, but more frequent than those by WKY and WIS. Differences in bout length subsided between epochs, but differences in bout-initiation rate were exacerbated. These results were interpreted in light of robust evidence linking changes in bout-organization parameters and experimental manipulations of motivation and response-reinforcement contingency.

Conclusions: Operant hyperactivity in SHR was confirmed. Although incentive motivation appears to play an important role in operant hyperactivity and motoric capacity cannot be ruled out as a factor, response-bout patterns suggest that operant hyperactivity is primarily driven by steeper delay-of-reinforcement gradients. Convergence of this conclusion with theoretical accounts of ADHD and with free-operant performance in children with ADHD supports the use of SHR as an animal model of ADHD.