Fire activity and deforestation in Remote Oceanian islands caused by anthropogenic and climate interactions.

Remote islands in the Pacific Ocean (Oceania) experienced dramatic environmental transformations after initial human settlement in the past 3,000 yr. Here, human causality of this environmental degradation has been unquestioned and viewed as evidence of the inherent destructive tendencies of human societies in both archaeological and popular discourse. We use charcoal and stable carbon isotopes from deep soil cores to reconstruct the dynamics of fire activity and deforestation across the Sigatoka River valley on the leeward (dry) side of Viti Levu, Fiji.

Characteristics and early clinical outcomes of patients undergoing totally subcutaneous vs. transvenous single chamber implantable cardioverter defibrillator placement.

Aims: In 2012, the first totally Subcutaneous Implantable Cardioverter-Defibrillator (S-ICD) was approved by the Food and Drug Administration (FDA) in the United States. A possible benefit of this device is that it does not involve placing leads 'in' or 'on' the heart, potentially reducing complications.

Methods Amd Results: Ninety-one S-ICD and 182 single chamber TV-ICD implants were performed between 10/22/2012 and 9/22/2015.

Impact of Multi-Night Experimentally Induced Short Sleep on Adolescent Performance in a Simulated Classroom.

Study Objectives: Investigate whether a realistic "dose" of shortened sleep, relative to a well-rested state, causes a decline in adolescents' learning and an increase in inattentive and sleepy behaviors in a simulated classroom setting.

Methods: Eighty-seven healthy 14.0- to 16.

The IGNITE network: a model for genomic medicine implementation and research.

Background: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility.

Methods: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.

Clinician Perspectives on Using Pharmacogenomics in Clinical Practice.

Aim: To describe the knowledge and attitudes of clinicians participating in a large pharmacogenomics implementation program.

Materials & Methods: Semi-structured interviews with 15 physicians and nurse practitioners were conducted.

Results: Three categories of themes were identified: preparation and knowledge, pharmacogenomics usage in practice, and future management of genomic variants.

A prognostic model based on readily available clinical data enriched a pre-emptive pharmacogenetic testing program.

Objectives: We describe the development, implementation, and evaluation of a model to pre-emptively select patients for genotyping based on medication exposure risk.

Study Design And Setting: Using deidentified electronic health records, we derived a prognostic model for the prescription of statins, warfarin, or clopidogrel. The model was implemented into a clinical decision support (CDS) tool to recommend pre-emptive genotyping for patients exceeding a prescription risk threshold.

Impact of experimentally manipulated sleep on adolescent simulated driving.

Objective/background: Sleep restriction (SR) impairs adolescents' attention, which could contribute to high rates of driving crashes. Here, we examine the impact of experimental SR on adolescent drivers, considering whether that impact is moderated by the nature of the drive (urban/suburban vs. rural) or how vulnerable each adolescent is to attentional decline after SR.

Sweet/dessert foods are more appealing to adolescents after sleep restriction.

Study Objective: Examine the effect of experimental sleep restriction (SR) on adolescents' subjective hunger and perceived appeal of sweet/dessert foods versus other foods. A secondary goal was to replicate previous findings on the effects of SR on dietary intake.

Design: Randomized cross-over sleep restriction-extension paradigm.

Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.

Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia.

Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index.

Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip.

Sleep restriction worsens mood and emotion regulation in adolescents.

Background: The relationship between inadequate sleep and mood has been well-established in adults and is supported primarily by correlational data in younger populations. Given that adolescents often experience shortened sleep on school nights, we sought to better understand the effect of experimentally induced chronic sleep restriction on adolescents' mood and mood regulation.

Methods: Fifty healthy adolescents, ages 14-17, completed a 3-week sleep manipulation protocol involving a baseline week, followed by a sleep restriction (SR) condition (6.

Biobanks and electronic medical records: enabling cost-effective research.

The use of electronic medical record data linked to biological specimens in health care settings is expected to enable cost-effective and rapid genomic analyses. Here, we present a model that highlights potential advantages for genomic discovery and describe the operational infrastructure that facilitated multiple simultaneous discovery efforts.

Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data.

Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry.

Stakeholder engagement: a key component of integrating genomic information into electronic health records.

Integrating genomic information into clinical care and the electronic health record can facilitate personalized medicine through genetically guided clinical decision support. Stakeholder involvement is critical to the success of these implementation efforts. Prior work on implementation of clinical information systems provides broad guidance to inform effective engagement strategies.

Electronic health record design and implementation for pharmacogenomics: a local perspective.

Purpose: The design of electronic health records to translate genomic medicine into clinical care is crucial to successful introduction of new genomic services, yet there are few published guides to implementation.

Methods: The design, implemented features, and evolution of a locally developed electronic health record that supports a large pharmacogenomics program at a tertiary-care academic medical center was tracked over a 4-year development period.

Results: Developers and program staff created electronic health record mechanisms for ordering a pharmacogenomics panel in advance of clinical need (preemptive genotyping) and in response to a specific drug indication.

Technical note: The use of geographical information systems software for the spatial analysis of bone microstructure.

Geographic information systems (GIS) software is typically used for analyzing geographically distributed data, allowing users to annotate points or areas on a map and attach data for spatial analyses. While traditional GIS-based research involves geo-referenced data (points tied to geographic locations), the use of this technology has other constructive applications for physical anthropologists. The use of GIS software for the study of bone histology offers a novel opportunity to analyze the distribution of bone nano- and microstructures, relative to macrostructure and in comparison to other variables of interest, such as biomechanical loading history.

Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents.

Targeting glutamate synapses in schizophrenia.

Although early clinical observations implicated dopamine dysfunction in the neuropathology of schizophrenia, accumulating evidence suggests that multiple neurotransmitter pathways are dysregulated. The psychotomimetic actions of NMDA receptor antagonists point to an imbalance of glutamatergic signaling. Encouragingly, numerous preclinical and clinical studies have elucidated several potential targets for increasing NMDA receptor function and equilibrating glutamatergic tone, including the metabotropic glutamate receptors 2, 3 and 5, the muscarinic acetylcholine receptors M(1) and M(4), and the glycine transporter GlyT1.

A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport.

Na(+)- and Cl(-)-dependent uptake of neurotransmitters via transporters of the SLC6 family, including the human serotonin transporter (SLC6A4), is critical for efficient synaptic transmission. Although residues in the human serotonin transporter involved in direct Cl(-) coordination of human serotonin transport have been identified, the role of Cl(-) in the transport mechanism remains unclear. Through a combination of mutagenesis, chemical modification, substrate and charge flux measurements, and molecular modeling studies, we reveal an unexpected role for the highly conserved transmembrane segment 1 residue Asn-101 in coupling Cl(-) binding to concentrative neurotransmitter uptake.

Household expansion linked to agricultural intensification during emergence of Hawaiian archaic states.

The Leeward Kohala Field System (LKFS) covering ∼ 60 km(2) on Hawai'i Island is one of the world's best-studied archaeological examples of preindustrial agricultural intensification. Archaeological correlates for households over a 400-y period of intensification of the LKFS (A.D.

Y95 and E444 interaction required for high-affinity S-citalopram binding in the human serotonin transporter.

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) is responsible for the reuptake of 5-HT following synaptic release, as well as for import of the biogenic amine into several non-5-HT synthesizing cells including platelets. The antidepressant citalopram blocks SERT and thereby inhibits the transport of 5-HT. To identify key residues establishing high-affinity citalopram binding, we have built a comparative model of hSERT and Drosophila melanogaster SERT (dSERT) based on the Aquifex aeolicus leucine transporter (LeuT(Aa)) crystal structure.

Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.

Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects.

Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats.

Herein we report the discovery, synthesis, and evaluation of a series of N-(4-acetamido)-phenylpicolinamides as positive allosteric modulators of mGlu(4). Compounds from the series show submicromolar potency at both human and rat mGlu(4). In addition, pharmacokinetic studies utilizing subcutaneous dosing demonstrated good brain exposure in rats.

Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine.

The plasma membrane serotonin (5-HT) transporter (SERT, SLC6A4) clears 5-HT after release at nerve termini and is targeted by both antidepressant medications and psychostimulants (e.g. MDMA, cocaine).

Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies.

To identify potential determinants of substrate selectivity in serotonin (5-HT) transporters (SERT), models of human and Drosophila serotonin transporters (hSERT, dSERT) were built based on the leucine transporter (LeuT(Aa)) structure reported by Yamashita et al. (Nature 2005;437:215-223), PBDID 2A65. Although the overall amino acid identity between SERTs and the LeuT(Aa) is only 17%, it increases to above 50% in the first shell of the putative 5-HT binding site, allowing de novo computational docking of tryptamine derivatives in atomic detail.