Genetic algorithms as a tool for dosing guideline optimisation : application to intermittent infusion dosing for vancomycin in adults

This paper demonstrates the use of a genetic algorithm (GA) for the optimization of a dosing guideline. GAs are well-suited to derive combinations of doses and dosing intervals that go into a dosing guideline when the number of possible combinations rule out the calculation of all possible outcomes. GAs also allow for different constraints to be imposed on the optimization process to safeguard the clinical feasibility of the dosing guideline. In this work, we demonstrate the use of a GA for the optimization of intermittent vancomycin administration in adult patients. Constraints were placed on the dose strengths, the length of the dosing intervals, and the maximum infusion rate. In addition, flexibility with respect to the timing of the first maintenance dose was included in the optimization process. The GA-based optimal solution is compared with the Scottish Antimicrobial Prescribing Group vancomycin guideline

The challenges of intersectionality: Researching difference in physical education

Researching the intersection of class, race, gender, sexuality and disability raises many issues for educational research. Indeed, Maynard (2002, 33) has recently argued that ‘difference is one of the most significant, yet unresolved, issues for feminist and social thinking at the beginning of the twentieth century’. This paper reviews some of the key imperatives of working with ‘intersectional theory’ and explores the extent to these debates are informing research around difference in education and Physical Education (PE). The first part of the paper highlights some key issues in theorising and researching intersectionality before moving on to consider how difference has been addressed within PE. The paper then considers three ongoing challenges of intersectionality – bodies and embodiment, politics and practice and empirical research. The paper argues for a continued focus on the specific context of PE within education for its contribution to these questions

Pregnancy Rates, Metabolites and Metabolic Hormones in Bighorn Sheep During and After the Breeding Season

Wildlife managers routinely draw blood and harvest serum when bighorn sheep (Ovis canadensis) and other ungulates are captured for management and research purposes.  Serum samples are routinely submitted to state livestock labs that perform a panel of assays to access exposure to a variety of important pathogens that cause disease, providing managers important insights.  Wildlife managers would also benefit from similar procedures that could provide assessments of reproduction, nutrition, and physiological status.  The objectives of this preliminary study were to evaluate pregnancy rates, energy-related metabolites and hormones among herds of Montana and Wyoming bighorn sheep during and after the breeding season in order to assess the general ‘health’ of herds. Metabolites and metabolic hormones are frequently used in domestic animals to evaluate nutrition, reproduction and energy balance, and potentially may provide the same insights in wildlife for managers. A total of 240 bighorn ewes were sampled from 13 herds between December 2014 and March 2015.  Samples were assayed for progesterone (P4) and pregnancy specific protein B (PSPBs) to assess reproductive cycling and pregnancy. Assays were also performed for non-esterified fatty acid, insulin, triiodothyronine and thyroxine which are metabolites and metabolic hormones that indicate nutritional and energy states of animals. We will be presenting the results of this preliminary study and discussing the relationship between pregnancy rates, energy-related metabolites and hormones and how they might be used to inform wildlife management

Taxonomy Based on Science Is Necessary for Global Conservation [Formal comment]

Taxonomy is a scientific discipline that has provided the universal naming and classification system of biodiversity for centuries and continues effectively to accommodate new knowledge. A recent publication by Garnett and Christidis expressed concerns regarding the difficulty that taxonomic changes represent for conservation efforts and proposed the establishment of a system to govern taxonomic changes. Their proposal to “restrict the freedom of taxonomic action” through governing subcommittees that would “review taxonomic papers for compliance” and their assertion that “the scientific community\u27s failure to govern taxonomy threatens the effectiveness of global efforts to halt biodiversity loss, damages the credibility of science, and is expensive to society” are flawed in many respects. They also assert that the lack of governance of taxonomy damages conservation efforts, harms the credibility of science, and is costly to society. Despite its fairly recent release, Garnett and Christidis\u27 proposition has already been rejected by a number of colleagues. Herein, we contribute to the conversation between taxonomists and conservation biologists aiming to clarify some misunderstandings and issues in the proposition by Garnett and Christidis. Placing governance over the science of taxonomy blurs the distinction between taxonomy and nomenclature. Garnett and Christidis\u27s proposal is far-reaching but represents a narrow perspective of taxonomy, as utilized by conservation, and reflects an increasingly broad misunderstanding throughout biology of the scientific basis of taxonomy, formalized nomenclature, and the relationship between them. This trend may have resulted from the attenuation of instruction in taxonomic principles and, in particular, nomenclature at many universities, in part because of a shift in research priorities away from taxonomy

Developing Physiological Profiles using Nuclear Magnetic Resonance Spectroscopy to Inform Bighorn Sheep Management

This study employs new techniques using nuclear magnetic resonance (NMR) to assess the relative health, physiological condition, and reproductive function of wild bighorn sheep (Ovis canadensis)  in Montana and Wyoming. Ongoing bighorn studies in Montana and the Greater Yellowstone Ecosystem are focused on herd attributes and the population dynamics which are affected by disease, climate, habitat and physiology. Indices of herd health and physiological status are typically obtained through expensive and time consuming lab assays and field measurements. Recently, NMR spectroscopy has been used to revolutionize the assessment of human metabolic health, and we expect that there is similar potential for studies of wildlife populations. Using NMR spectroscopy to assess metabolites associated with disease, nutrition and stress may eliminate the need for many traditional assays and techniques used today. NMR can be used to evaluate a large suite of metabolites associated with a variety of physiological functions from as little as 500 ?L of serum or plasma. Blood samples from 242 sheep from 13 different herds were collected during the winters of 2013-14 and 2014-15 to develop a comprehensive metabolite panel for bighorn sheep. We have used a recently developed statistical program known as MetaboAnalyst™ to begin to analyze and evaluate differences in NMR metabolic profiles among herds and across the fall-winter season when nutritional and physiological stress is expected to be acute. We will be presenting the results of this preliminary study and discussing the potential for application in wildlife management

An ALMA survey of CO in submillimetre galaxies: companions, triggering, and the environment in blended sources

We present ALMA observations of the mid-J 12CO emission from six single-dish selected 870-μm sources in the Extended Chandra Deep Field-South and UKIDSS Ultra-Deep Survey fields. These six single-dish submillimetre sources were selected based on previous ALMA continuum observations, which showed that each comprised a blend of emission from two or more individual submillimetre galaxies (SMGs), separated on 5–10 arcsec scales. The six single-dish submillimetre sources targeted correspond to a total of 14 individual SMGs, of which seven have previously measured robust optical/near-infrared spectroscopic redshifts, which were used to tune our ALMA observations. We detect CO(3–2) or CO(4–3) at z = 2.3–3.7 in 7 of the 14 SMGs, and in addition serendipitously detect line emission from three gas-rich companion galaxies, as well as identify four new 3.3 mm selected continuum sources in the six fields. Joint analysis of our CO spectroscopy and existing data suggests that 64(±18)percent of the SMGs in blended submillimetre sources are unlikely to be physically associated. However, three of the SMG fields (50 per cent) contain new, serendipitously detected CO-emitting (but submillimetre-faint) sources at similar redshifts to the 870 μm selected SMGs we targeted. These data suggest that the SMGs inhabit overdense regions, but that these are not sufficiently overdense on ∼100 kpc scales to influence the source blending given the short lifetimes of SMGs. We find that 21±12percent of SMGs have spatially distinct and kinematically close companion galaxies (∼8–150 kpc and ≲ 300 km s−1), which may have enhanced their star formation via gravitational interactions

Electrophysiological Heterogeneity of Fast-Spiking Interneurons: Chandelier versus Basket Cells

In the prefrontal cortex, parvalbumin-positive inhibitory neurons play a prominent role in the neural circuitry that subserves working memory, and alterations in these neurons contribute to the pathophysiology of schizophrenia. Two morphologically distinct classes of parvalbumin neurons that target the perisomatic region of pyramidal neurons, chandelier cells (ChCs) and basket cells (BCs), are generally thought to have the same "fast-spiking" phenotype, which is characterized by a short action potential and high frequency firing without adaptation. However, findings from studies in different species suggest that certain electrophysiological membrane properties might differ between these two cell classes. In this study, we assessed the physiological heterogeneity of fast-spiking interneurons as a function of two factors: species (macaque monkey vs. rat) and morphology (chandelier vs. basket). We showed previously that electrophysiological membrane properties of BCs differ between these two species. Here, for the first time, we report differences in ChCs membrane properties between monkey and rat. We also found that a number of membrane properties differentiate ChCs from BCs. Some of these differences were species-independent (e.g., fast and medium afterhyperpolarization, firing frequency, and depolarizing sag), whereas the differences in the first spike latency between ChCs and BCs were species-specific. Our findings indicate that different combinations of electrophysiological membrane properties distinguish ChCs from BCs in rodents and primates. Such electrophysiological differences between ChCs and BCs likely contribute to their distinctive roles in cortical circuitry in each species. © 2013 Povysheva et al

MARIS: Method for Analyzing RNA following Intracellular Sorting

Transcriptional profiling is a key technique in the study of cell biology that is limited by the availability of reagents to uniquely identify specific cell types and isolate high quality RNA from them. We report a Method for Analyzing RNA following Intracellular Sorting (MARIS) that generates high quality RNA for transcriptome profiling following cellular fixation, intracellular immunofluorescent staining and FACS. MARIS can therefore be used to isolate high quality RNA from many otherwise inaccessible cell types simply based on immunofluorescent tagging of unique intracellular proteins. As proof of principle, we isolate RNA from sorted human embryonic stem cell-derived insulin-expressing cells as well as adult human β cells. MARIS is a basic molecular biology technique that could be used across several biological disciplines.Howard Hughes Medical InstituteHarvard Stem Cell InstituteNational Institutes of Health (U.S.) (grant 2U01DK07247307)National Institutes of Health (U.S.) (grant RL1DK081184)National Institutes of Health (U.S.) (grant 1U01HL10040804

DNA sequence level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes