bluuebunny/crossref_metadata_2025 huggingface dataset:
A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction
Authors: Watterson Steven , Guerriero Maria Luisa , Blanc Mathieu , Mazein Alexander , Loewe Laurence , Robertson Kevin A , Gibbs Holly , Shui Guanghou , Wenk Markus R , Hillston Jane , Ghazal Peter
Published: November 2013

Graphical Abstract

Highlights

We model the cholesterol biosynthesis pathway and its regulation

The innate immune response leads to a suppression of flux through the pathway

Statin inhibitors show a different mode of suppression to the immune response

Statin inhibitor suppression is less robust and less specific than immune suppression

Asbtract

The cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalyzing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus infection or treated with IFNγ, we show that, under these assumptions, coordinate down regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses.
Universality and predictability in molecular quantitative genetics
Authors: Nourmohammad Armita , Held Torsten , Lässig Michael
Published: November 2013

Molecular traits, such as gene expression levels or protein binding affinities, are increasingly accessible to quantitative measurement by modern high-throughput techniques. Such traits measure molecular functions and, from an evolutionary point of view, are important as targets of natural selection. We review recent developments in evolutionary theory and experiments that are expected to become building blocks of a quantitative genetics of molecular traits. We focus onuniversalevolutionary characteristics: these are largely independent of a trait’s genetic basis, which is often at least partially unknown. We show that universal measurements can be used to infer selection on a quantitative trait, which determines its evolutionary mode of conservation or adaptation. Furthermore, universality is closely linked to predictability of trait evolution across lineages. We argue that universal trait statistics extends over a range of cellular scales and opens new avenues of quantitative evolutionary systems biology.
Negative autoregulation matches production and demand in synthetic transcriptional networks
Authors: Franco Elisa , Giordano Giulia , Forsberg Per-Ola , Murray Richard M.
Published: November 2013

We propose a negative feedback architecture that regulates activity of artificial genes, or “genelets”, to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the “error” between the circuit output concentration and its actual demand. This two-device system is experimentally implemented usingin vitrotranscriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system, and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times.
Gappy TotalReCaller for RNASeq Base-Calling and Mapping
Authors: Mishra Bud
Published: November 2013

Understanding complex mammalian biology depends crucially on our ability to define a precise map of all the transcripts encoded in a genome, and to measure their relative abundances. A promising assay depends on RNASeq approaches, which builds on next generation sequencing pipelines capable of interrogating cDNAs extracted from a cell. The underlying pipeline starts with base-calling, collect the sequence reads and interpret the raw-read in terms of transcripts that are grouped with respect to different splice-variant isoforms of a messenger RNA. We address a very basic problem involved in all of these pipeline, namely accurate Bayesian base-calling, which could combine the analog intensity data with suitable underlying priors on base-composition in the transcripts. In the context of sequencing genomic DNA, a powerful approach for base-calling has been developed in the TotalReCaller pipeline. For these purposes, it uses a suitable reference whole-genome sequence in a compressed self-indexed format to derive its priors. However, TotalReCaller faces many new challenges in the transcriptomic domain, especially since we still lack a fully annotated library of all possible transcripts, and hence a sufficiently good prior. There are many possible solutions, similar to the ones developed for TotalReCaller, in applications addressing de novo sequencing and assembly, where partial contigs or string-graphs could be used to boot-strap the Bayesian priors on base-composition. A similar approach would be applicable here too, partial assembly of transcripts can be used to characterize the splicing junctions or organize them in incompatibility graphs and then used as priors for TotalReCaller. The key algorithmic techniques for this purpose have been addressed in a forthcoming paper on Stringomics. Here, we address a related but fundamental problem, by assuming that we only have a reference genome, with certain intervals marked as candidate regions for ORF (Open Reading Frames), but not necessarily complete annotations regarding the 5’ or 3’ termini of a gene or its exon-intron structure. The algorithms we describe find the most accurate base-calls of a cDNA with the best possible segmentation, all mapped to the genome appropriately.
A structural classification of candidate oscillators and multistationary systems
Authors: Blanchini Franco , Franco Elisa , Giordano Giulia
Published: November 2013

Molecular systems are uncertain: the variability of reaction parameters and the presence of unknown interactions can weaken the predictive capacity of solid mathematical models. However, strong conclusions on the admissible dynamic behaviors of a model can often be achieved without detailed knowledge of its specific parameters. In particular, starting with Thomas' conjectures, loop–based criteria have been largely used to characterize oscillatory and multistationary dynamic outcomes in systems with a sign definite Jacobian.

We build on the rich literature focused on the identification of potential oscillatory and multistationary behaviors based on parameter–free criteria. We propose a classification for sign–definite non autocatalytic biological networks which summarize several existing results in the literature, adding new results when necessary. We define candidate oscillators and multistationary systems based on their admissible transitions to instability. We introduce four categories: strong/weak candidate oscillatory/multistationary systems, which correspond to networks in which all/some of the existing feedback loops are negative/positive. We provide necessary and sufficient conditions characterizing strong and weak candidate oscillators and multistationary systems based on the exclusive or simultaneous presence of positive and negative loops in their linearized dynamics. We also consider the case in which the overall system is the connection of several stable aggregate monotone components, providing conditions in terms of positive/negative loops in a suitable network with aggregate monotone systems as nodes.

Most realistic examples of biological networks fall in the gray area of systems in which both positive and negative cycles are present: therefore, both oscillatory and bistable behavior are in principle possible. Native systems with a large number of components are often interconnections of monotone modules, where negative/positive loops among modules characterize oscillatory and bistable behaviors, in agreement with our results. Finally, we note that many canonical example circuits exhibiting oscillations or bistability fall in the categories of strong candidate oscillators/multistationary systems.
Effects of metsulfuron-methyl on aquatic plant (Lemna gibba L.) and recovery from after prolonged exposure under rice cropping conditions
Authors: Rajeswari Raja , Ramesh Atmakuru
Published: November 2013

The effects and potential recovery of aquatic plant Lemna gibba exposed to a sulfonyl urea herbicide metsulfuron-methyl (MSM) for 120 days under rice cropping condition was investigated. The frond number was decreased by day 15 at the concentration 11 µg/L and 100% inhibition on growth rate of Lemna was observed. Continuous decrease of frond number by day 50 at below the detectable level of residues exhibited symptoms (chlorosis) of MSM toxicity. Toxicity was assessed on the basis of toxicity index (TI) value, growth rate, yield and pigment contents (chlorophyll, carotene, total carotenoid and xanthophyll) of treated samples compared with untreated control. The observed value of 0.698 µg/g chlorophyll a, 0.263 µg/g chlorophyll b, 0.147 µg/g carotene, 1.620 µg/g total carotenoid and 1.473 µg/g xanthophyll contents in treated samples was statistically significantly different from control value of 4.366 µg/g chlorophyll a, 3.132 µg/g chlorophyll b, 0.796 µg/g carotene, 17.755 µg/g total carotenoid and 16.937 µg/g xanthophyll contents by day 50 samples. After prolonged exposure, growth rate, yield and pigment content for the treated samples recovered to control levels on day 120. The obtained data indicate the application of aquatic plant Lemna gibba as sensitive biomarker of water quality as well as the significance of selected biological parameters in the reliable assessment of toxic potential of MSM under rice cropping condition.
ROS accumulation in cotton ovule epidermal cells is necessary for fiber initiation
Authors: Pang Mingxiong , Sanford Nicholas , Wilkins Thea A
Published: November 2013

Cotton (Gossypium hirsutum) fiber, an extremely elongated and thickened single cell of the seed epidermis, is the world’s most important natural and economical textile fiber. UnlikeArabidopsisleaf trichomes, fiber initials are randomly developed and frequently form in adjacent seed epidermal cells and follow no apparent pattern. Numerous publications suggested cotton fiber development shares a similar mechanism withArabidopsisleaf trichome development. Here we show that H2O2 accumulation in cotton ovule epidermal cells by NBT staining ovules at different development stages between TM1 and N1n2, a lintless-fuzzless doubled mutant originated from TM1. In contrast,Arabidopsisand cotton leaf trichomes do not show H2O2 content. By adding DPI (H2O2 inhibitor) and SHAM (H2O2 activator) in vitro ovule cultures, we show fiber initiation directly involves with H2O2 accumulation. We propose that the directional accumulation of H2O2 in cotton ovule epidermal cell is the drive for fiber initiation, elongation.
Journey to the Center of the Mitochondria Guided by the Tail Anchor of Protein Tyrosine Phosphatase 1B
Authors: Fueller Julia , Egorov Mikhail , Walther Kirstin A. , Sabet Ola , Mallah Jana , Grabenbauer Markus , Kinkhabwala Ali
Published: November 2013

The canonical protein tyrosine phosphatase PTP1B has traditionally been considered to exclusively reside on the endoplasmic reticulum (ER). Using confocal microscopy, we show that endogenous PTP1B actually exhibits a higher local concentration at the mitochondria in all mammalian cell lines that we tested. Fluorescently labeled chimeras containing full-length PTP1B or only its 35 amino acid tail anchor localized identically, demonstrating the complete dependence of PTP1B’s subcellular partitioning on its tail anchor. Correlative light and electron microscopy using GFP-driven photo-oxidation of DAB revealed that PTP1B’s tail anchor localizes it to the mitochondrial interior and to mitochondrial-associated membrane (MAM) sites along the ER. Heterologous expression of the tail anchor of PTP1B in the yeastS. cerevisiaesurprisingly led to its exclusive localization to the ER/vacuole with no presence at the mitochondria. Studies with various yeast mutants of conserved membrane insertion pathways revealed a role for the GET/TRC40 pathway in ER insertion, but also emphasized the likely dominant role of spontaneous insertion. Further studies of modified tail isoforms in both yeast and mammalian cells revealed a remarkable sensitivity of subcellular partitioning to slight changes in transmembrane domain (TMD) length, C-terminal charge, and hydropathy. For example, addition of a single positive charge to the tail anchor was sufficient to completely shift the tail anchor to the mitochondria in mammalian cells and to largely shift it there in yeast cells, and a point mutation that increased TMD hydropathy was sufficient to localize the tail anchor exclusively to the ER in mammalian cells. Striking differences in the subcellular partitioning of a given tail anchor isoform in mammalian versus yeast cells most likely point to fundamental differences in the lipid composition of specific organelles (e.g. affecting membrane charge or thickness) in higher versus lower eukaryotes. Fluorescence lifetime imaging microscopy (FLIM) detection of the Förster Resonance Energy Transfer (FRET)-based interaction of the catalytic domain of PTP1B with the epidermal growth factor receptor (EGFR/ErbB1) at the mitochondria revealed a strong interaction on the cytosolic face of the outer mitochondrial membrane (OMM), suggesting the presence of a significant pool of PTP1B there and a novel role for PTP1B in the regulation of mitochondrial ErbB1 activity. In summary, in addition to its well-established general localization along the ER, our results reveal that PTP1B specifically accumulates at MAM sites along the ER and localizes as well to the OMM and mitochondrial matrix. Further elucidation of PTP1B’s roles in these different locations (including the identification of its targets) will likely be critical for understanding its complex regulation of general cellular responses, cell proliferation, and diseased states.
Genomics via Optical Mapping (I): 0-1 Laws for Mapping with Single Molecules
Authors: Anantharaman Thomas , Mishra Bud
Published: November 2013

The genomic data that can be collected from a single DNA molecule by the best chemical and optical methods (e.g., using technologies from OpGen, BioNanoGenomics, NABSys, PacBio, etc.) are badly corrupted by many poorly understood noise processes. Thus, single molecule technology derives its utility through powerful probabilistic modeling, which can provide precise lower and upper bounds on various experimental parameters to create the correct map or validate sequence assembly. As an example, this analysis shows how as the number of “imaged” single molecules (i.e., coverage) is increased in the optical mapping data, the probability of successful computation of the map jumps from 0 to 1 for fairly small number of molecules.
Inferring tree causal models of cancer progression with probability raising
Authors: Olde Loohuis Loes , Caravagna Giulio , Graudenzi Alex , Ramazzotti Daniele , Mauri Giancarlo , Antoniotti Marco , Mishra Bud
Published: November 2013

Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges) to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models.
Repurposing CRISPR/Cas9 for in situ functional assays
Authors: Malina Abba , Mills John R. , Cencic Regina , Yan Yifei , Fraser James , Schippers Laura M. , Paquet Marilène , Dostie Josée , Pelletier Jerry
Published: December 2013

RNAi combined with next-generation sequencing has proven to be a powerful and cost-effective genetic screening platform in mammalian cells. Still, this technology has its limitations and is incompatible with in situ mutagenesis screens on a genome-wide scale. Using p53 as a proof-of-principle target, we readapted the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR associated 9) genome-editing system to demonstrate the feasibility of this methodology for targeted gene disruption positive selection assays. By using novel “all-in-one” lentiviral and retroviral delivery vectors heterologously expressing both a codon-optimized Cas9 and its synthetic guide RNA (sgRNA), we show robust selection for the CRISPR-modified Trp53 locus following drug treatment. Furthermore, by linking Cas9 expression to GFP fluorescence, we use an “all-in-one” system to track disrupted Trp53 in chemoresistant lymphomas in the Eμ-myc mouse model. Deep sequencing analysis of the tumor-derived endogenous Cas9-modified Trp53 locus revealed a wide spectrum of mutants that were enriched with seemingly limited off-target effects. Taken together, these results establish Cas9 genome editing as a powerful and practical approach for positive in situ genetic screens.
Labeling Second-Order Sensory Neurons in the Posterior Lateral-Line System of Zebrafish
Authors: Schuster Kevin , Ghysen Alain
Published: December 2013

The lateral line is a mechanosensory system that comprises a set of discrete sense organs called neuromasts, which are arranged in reproducible patterns on the surface of fish and amphibians. The posterior component of the system, the posterior lateral line (PLL), comprises the neuromasts on the body and tail and has its ganglion just posterior to the otic vesicle. The peripheral location of the PLL system makes it accessible and easily visualized by imaging methods. Neuromasts are innervated by a few afferent neurons (usually two, but sometimes more), which have their cell bodies clustered in cranial ganglia and project their central axons to the hindbrain, where they extend longitudinally along all rhombomeres. Positively charged lipophilic carbocyanine dyes, such as DiI, have traditionally been used to label neurons, as described here. This method is especially useful for the analysis of PLL innervation because injection of the dye into a neuromast leads to specific labeling of the afferent neurons. The method can also be used to follow the flow of PLL information to higher central nervous system levels by first labeling the central projection of chosen afferent neurons and then making a second injection of DiI within the synaptic field to label the second-order neurons that extend dendrites to this field.
Optically Induced Occlusion of Single Blood Vessels in Rodent Neocortex
Authors: Shih Andy Y. , Nishimura Nozomi , Nguyen John , Friedman Beth , Lyden Patrick D. , Schaffer Chris B. , Kleinfeld David
Published: December 2013

The ability to form targeted vascular occlusions in small vessels of the brain is an important technique for studying the microscopic basis of cerebral ischemia. We describe two complementary methods that enable targeted occlusion of any single blood vessel within the upper 500 µm of adult rodent neocortex. Our goal is to generate highly localized regions of ischemia by blocking penetrating arterioles and ascending venules, which are bottlenecks of flow in the cortical angioarchitecture. One method, termed photothrombosis, makes use of linear optical absorption by a photosensitizer, transiently circulated in the blood stream, to induce a clot in a surface or near-surface segment of a vessel. The second method, termed plasma-mediated ablation, makes use of nonlinear optical interactions, without the need to introduce an exogenous absorber, to induce clots in subsurface segments of penetrating vessels, as well as subsurface microvessels and capillaries. The choice of the method for occlusion of individual vessels depends on the location of the vessels being studied and the objectives of the study. Here we describe concurrent high resolution in vivo imaging and auxiliary laser setups, occlusion protocols, and post hoc histological procedures.
Infrastructure Needs for Translational Integration of Mouse and Human Trials
Authors: Clohessy John G. , de Stanchina Elisa
Published: December 2013

Advances in the treatment of human cancer are frequently limited by the inability to test novel drugs and drug combinations in patients in a rapid and streamlined manner. Increasing data from the application of clinically relevant mouse models has highlighted the ability of preclinical trials in mice to address this problem, and has paved the way for what is now termed the “Co-Clinical Trial Project,” in which mouse trials are performed concurrently with human trials. This in turn enables efficient patient stratification and therapy optimization based on molecular determinants for effective treatment of cancer. To fully realize the potential of preclinical, coclinical, and postclinical trials in mice, there is a need to establish key principles for carrying out therapeutic mouse trials, to standardize practices for performing such trials, and to establish mouse hospitals where trials can be integrated with corresponding clinical trial efforts in humans. Here we describe critical infrastructural components that are required for effective implementation of such efforts and suggest a model for how mouse hospitals for clinical trials should be established.
Developmental plasticity of growth and digestive efficiency in dependence of early‐life food availability
Authors: Kotrschal Alexander , Szidat Sönke , Taborsky Barbara
Published: December 2013

Nutrition is a potent mediator of developmental plasticity. If food is scarce, developing organisms may invest into growth to outgrow size‐dependent mortality (short‐term benefit) and/or into an efficient digestion system (long‐term benefit).

We investigated this potential trade‐off, by determining the influence of food availability on juvenile body and organ growth, and on adult digestive efficiency in the cichlid fish Simochromis pleurospilus.

We reared two groups of fish at constant high or low food rations, and we switched four other groups between these two rations at an early and late juvenile period. We measured juvenile growth and organ sizes at different developmental stages and determined adult digestive efficiency.

Fish kept at constant, high rations grew considerably faster than low‐food fish. Nevertheless, S. pleurospilus partly buffered the negative effects of low food availability by developing heavier digestive organs, and they were therefore more efficient in digesting their food as adults.

Results of fish exposed to a ration switch during either the early or late juvenile period suggest (i) that the ability to show compensatory growth after early exposure to low food availability persists during the juvenile period, (ii) that digestive efficiency is influenced by varying juvenile food availability during the late juvenile phase and (iii) that the efficiency of the adult digestive system is correlated with the growth rate during a narrow time window of juvenile period.
3D simultaneous joint PP‐PS prestack seismic inversion at Schiehallion field, United Kingdom Continental Shelf
Authors: Barnola Anne‐Sophie , Ibram Mark
Published: December 2013

A workflow for simultaneous joint PP‐PS prestack inversion of data from the Schiehallion field on the United Kingdom Continental Shelf is presented and discussed. The main challenge, describing reasonable PS to PP data registration before any prestack or joint PP‐PS inversion, was overcome thanks to a two‐stage process addressing the signal envelope, then working directly on the seismic data to estimate appropriate time‐variant time‐shift volumes. We evaluated the benefits of including PS along with PP prestack seismic data in a joint inversion process to improve the estimated elastic property quality and also to enable estimation of density compared with other prestack and post‐stack inversion approaches. While the estimated acoustic impedance exhibited a similar quality independent of the inversion used (PP post‐stack, PP prestack or joint PP‐PS prestack inversion) the shear impedance estimation was noticeably improved by the joint PP‐PS prestack inversion when compared to the PP prestack inversion. Finally, the density estimated from joint PP and PS prestack data demonstrated an overall good quality, even where not well‐controlled. The main outcome of this study was that despite several data‐related limitations, inverting jointly correctly processed PP and PS data sets brought extra value for reservoir delineation as opposed to PP‐only or post‐stack inversion.
Evaluation of the impact of fetal fibronectin test implementation on hospital admissions for preterm labour inOntario: a multiple baseline time‐series design
Authors: Fell DB , Sprague AE , Grimshaw JM , Yasseen AS , Coyle D , Dunn SI , Perkins SL , Peterson WE , Johnson M , Bunting PS , Walker MC
Published: December 2013

Objective

To determine the impact of a health system‐wide fetal fibronectin (fFN) testing programme on the rates of hospital admission for preterm labour (PTL).

Design

Multiple baseline time‐series design.

Setting

Canadian province ofOntario.

Population

A retrospective population‐based cohort of antepartum and delivered obstetrical admissions in allOntario hospitals between 1April 2002 and 31March 2010.

Methods

International Classification of Diseases codes in a health system‐wide hospital administrative database were used to identify the study population and define the outcome measure. An aggregate time series of monthly rates of hospital admissions forPTLwas analysed using segmented regression models after aligning the fFNtest implementation date for each institution.

Main outcome measure

Rate of obstetrical hospital admission forPTL.

Results

Estimated rates of hospital admission forPTLfollowing fFNimplementation were lower than predicted had pre‐implementation trends prevailed. The reduction in the rate was modest, but statistically significant, when estimated at 12 months following fFNimplementation (−0.96 hospital admissions for PTL per 100 preterm births; 95% confidence interval [CI], −1.02 to −0.90,P = 0.04). The statistically significant reduction was sustained at 24 and 36 months following implementation.

Conclusions

Using a robust quasi‐experimental study design to overcome confounding as a result of underlying secular trends or concurrent interventions, we found evidence of a small but statistically significant reduction in the health system‐level rate of hospital admissions forPTLfollowing implementation of fFNtesting in a largeCanadian province.
A comparison of intramuscular diamorphine and intramuscular pethidine for labour analgesia: a two‐centre randomised blinded controlled trial
Authors: Wee MYK , Tuckey JP , Thomas PW , Burnard S
Published: December 2013

Objective

Intramuscular (i.m.) pethidine is used worldwide for labour analgesia and i.m. diamorphine usage has increased in the UK in the last 15 years. This trial aims to ascertain the relative efficacy and adverse effects of diamorphine and pethidine for labour pain.

Design

Prospective, parallel‐arm randomised controlled trial with blinding of participants, care‐givers and outcome assessors.

Setting

Maternity units in two District General Hospitals in the UK.

Population

After written informed consent, 484 women were randomised and recruited (244 diamorphine, 240 pethidine). Inclusion criteria included women 16 years or older, established labour, singleton pregnancy, 37–42 weeks of gestation and weight 60–120 kg.

Methods

On request of i.m. analgesia, participants received either 150 mg pethidine or 7.5 mg diamorphine based on computer‐generated block randomisation.

Main outcome measures

Maternal—reduction in pain intensity from baseline (10‐cm visual analogue scale) at 60 minutes and over the 3‐hour period after drug administration. Neonatal—requirement for resuscitation and Apgar score at 1 minute.

Results

Diamorphine provided modestly improved pain relief at 60 minutes, mean difference 1 cm (95% confidence interval [CI] 0.5–1.5), and over the 3 hours, mean difference 0.7 cm (95% CI 0.3–1.1). However, average length of labour in women receiving diamorphine was 82 minutes longer (95% CI 39–124) and therefore they experienced more pain overall. There were no statistically significant differences in primary neonatal outcomes.

Conclusions

There is a modest difference between the analgesia provided by diamorphine or pethidine for labour analgesia but diamorphine is associated with significantly longer labours.
Overview of: “Translating Causal Claims: Principles and Strategies for Policy‐Relevant Criminology”
Authors: Sampson Robert J. , Winship Christopher , Knight Carly
Published: December 2013

Research Summary

This article reviews the causal turn in the social sciences and accompanying efforts by criminologists to make policy claims more credible. Although there has been much progress in techniques for the estimation of causal effects, we find that the link between evidence and valid policy implications remains elusive. Drawing on criminological theory and research insights from disciplines such as sociology, economics, and statistics, we assess principles and strategies for informing policy in a causally uncertain world. We identify three distinct domains of inquiry that form a part of the translational process from evidence to policy and that complicate the straightforward exportation of causal effects to policy recommendations: (a) mechanisms and causal pathways, (b) effect heterogeneity, and (c) contextualization. We elaborate these three concepts by examining research on broken windows theory, policing, video games and violence, the Moving to Opportunity voucher experiment, incarceration, and especially the rich set of experimental studies on domestic violence that originated in Minneapolis, MN in the early 1980s. We also articulate a set of conceptual tools for advancing the goal of policy translation and offer recommendations for how what we call “policy graphs”—causal graphs used to analyze the policy implications of a system of causal relations—can potentially integrate the theoretical and policy arms of criminology.

Policy Implications

Evidence, even if causal, does not necessarily inform policy. In fact, the question of “what works,” the focus of the growing evidence‐based movement in criminology, turns out to be a different question than, “what will work?” Evidence‐based policy research must therefore be concerned with much more than providing policy makers with research on causal effects, however precisely measured. The implication is that we must separate criminology's increasing focus on causality from its policy turn and formally recognize that the latter requires a different standard of theory and evidence than does the former. In particular, criminologists interested in making policy claims must ask hard questions about the potential mechanisms through which a treatment influences an outcome, heterogeneous effects across people and time, contextual variations, and all of the real‐world phenomena to which these challenges give rise—such as unintended consequences, policies that change incentive and opportunity structures, and the scale at which policies change in meaning. Theoretically guided causal graphs enhance this goal and help inform policy in a causally uncertain world. Translational criminology is ultimately a process that entails the constant interplay of theory, research, and practice.
Evaluation of health‐related physical fitness parameters and association analysis with depression, anxiety, and quality of life in patients with fibromyalgia
Authors: Sener Umit , Ucok Kagan , Ulasli Alper M. , Genc Abdurrahman , Karabacak Hatice , Coban Necip F. , Simsek Hasan , Cevik Halime
Published: November 2013

Aim

The purpose of this study was to investigate the physical fitness parameters (maximal aerobic capacity, muscle strength and flexibility), daily physical activity, resting metabolic rate (RMR), pulmonary function tests (PFTs), body composition, depression, anxiety and health‐related quality of life (HRQoL) changes as well as the associations among these parameters in patients with fibromyalgia and to compare them with healthy controls.

Methods

Thirty‐nine women with fibromyalgia and 40 controls were included in this study. Physical measurements, HRQoL questionnaire, Beck Depression Inventory (BDI) score and Beck Anxiety Inventory (BAI) score were applied to all participants.

Results

Maximal aerobic capacity, trunk flexibility, daily step numbers, total energy expenditure, RMR and PFT values were not significantly different between the patients and the controls. Fibromyalgia patients had higher daily moderate activity times, active energy expenditure values, and BDI and BAI scores, while their lower handgrip strength and back‐leg strength values and Short‐form health survey (SF)‐36 scores were comparable to controls. Handgrip strength and back‐leg strength values showed moderately positive correlations with SF‐36 scores (total, physical health, mental health) and moderately negative correlations with BDI and BAI scores in patients with fibromyalgia.

Conclusion

Our results suggested that muscle strength, HRQoL, depression and anxiety symptomatology were impaired in fibromyalgia patients compared to healthy controls. Low muscle strength is related to reduced HRQoL and increased depression and anxiety symptomatology in patients with fibromyalgia. Also we suggest that performing daily exercises, including aerobic and strength training, as part of one's lifestyle may have beneficial effects in fibromyalgia patients.
Investigating the relationship between biodiversity and ecosystem multifunctionality: challenges and solutions
Authors: Byrnes Jarrett E. K. , Gamfeldt Lars , Isbell Forest , Lefcheck Jonathan S. , Griffin John N. , Hector Andy , Cardinale Bradley J. , Hooper David U. , Dee Laura E. , Emmett Duffy J.
Published: December 2013

Extensive research shows that more species‐rich assemblages are generally more productive and efficient in resource use than comparable assemblages with fewer species. But the question of how diversity simultaneously affects the wide variety of ecological functions that ecosystems perform remains relatively understudied. It presents several analytical and empirical challenges that remain unresolved. In particular, researchers have developed several disparate metrics to quantify multifunctionality, each characterizing different aspects of the concept and each with pros and cons.

We compare four approaches to characterizing multifunctionality and its dependence on biodiversity, quantifying (i) magnitudes of multiple individual functions separately, (ii) the extent to which different species promote different functions, (iii) the average level of a suite of functions and (iv) the number of functions that simultaneously exceeds a critical threshold.

We illustrate each approach using data from the pan‐European BIODEPTH experiment and the R multifunc package developed for this purpose, evaluate the strengths and weaknesses of each approach and implement several methodological improvements.

We conclude that an extension of the fourth approach that systematically explores all possible threshold values provides the most comprehensive description of multifunctionality to date. We outline this method and recommend its use in future research.
Penile size in healthy Nigerian newborns: country‐based reference values and international comparisons
Authors: Jarrett OO , Ayoola OO , Jonsson B , Albertsson‐Wikland K , Ritzen EM
Published: December 2013

Aim

To establish normal reference values for penile size in Nigerian newborn boys and to compare those values with standards from other populations.

Methods

A total number of 261 healthy newborn boys delivered at gestational ages of 28 weeks or more were enrolled in the study. Penile lengths and widths were measured within 72 h of birth.

Results

The mean (±SD) penile length in the 261 Nigerian males studied was 3.4 ± 0.48 cm, while the mean mid‐shaft diameter was 1.2 ± 0.14 cm. Compared with data from other populations, Nigerian newborn boys had similar penile sizes to those reported for US Caucasian boys (mean 3.4 cm), but significantly greater penile sizes than those reported for boys from China and Hong Kong (mean 3.0 and 3.1 cm, respectively; both p < 0.001). There was a slight, but significant, difference in size between Nigerian and Malaysian boys, with Malaysian boys having greater penile sizes (mean 3.5 cm; p < 0.05).

Conclusion

A Nigerian newborn with a penile length of <2.39 cm can be considered to have a micropenis.
Empirical Analysis of Fiscal Soundness and Public Social Expenditure: A Lesson for the Future Direction of the Korean Welfare State
Authors: Ko Hyejin
Published: December 2013

The aim of this paper is to investigate the relations between fiscal soundness and public social expenditure in advanced welfare states so as to reconsider the conventional wisdom that welfare expenditure aggravates national finances. Through this, I propose the clues of building the sustainable Korean welfare state. I focus on the interdependent relationship between fiscal soundness and public social expenditure based on fiscal sociology. Considering this interaction, I form two sets of simultaneous equations models and employ a special statistical method, three‐stage least squares (3SLS). The results regarding the causal relationship between fiscal soundness and public social spending indicate that, if public welfare spending is increased, fiscal health is damaged. However, as many comparative social policy researchers have pointed out, outcomes of welfare states differ from country to country according to the composition of public welfare spending. Specifically, some welfare states with priority given to social services such as vocational training or childcare services have maintained the stability of public finance. By extension, we can say that public social expenditures have a positive influence on fiscal soundness based on the composition of social expenditures. Finally, it is possible to create financially sustainable welfare states.
In vitro precision of fit of computer‐aided designed and computer‐aided manufactured titanium screw‐retained fixed dental prostheses before and after ceramic veneering
Authors: Katsoulis Joannis , Mericske‐Stern Regina , Enkling Norbert , Katsoulis Konstantinos , Blatz Markus B.
Published: December 2013

Objective

To compare the precision of fit of full‐arch implant‐supported screw‐retained computer‐aided designed and computer‐aided manufactured (CAD/CAM) titanium‐fixed dental prostheses (FDP) before and after veneering. The null‐hypothesis was that there is no difference in vertical microgap values between pure titanium frameworks and FDPs after porcelain firing.

Materials and methods

Five CAD/CAM titanium grade IV frameworks for a screw‐retained 10‐unit implant‐supported reconstruction on six implants (FDI tooth positions 15, 13, 11, 21, 23, 25) were fabricated after digitizing the implant platforms and the cuspid‐supporting framework resin pattern with a laser scanner (CARES® Scan CS2; Institut Straumann AG, Basel, Switzerland). A bonder, an opaquer, three layers of porcelain, and one layer of glaze were applied (Vita Titankeramik) and fired according to the manufacturer's preheating and fire cycle instructions at 400–800°C. The one‐screw test (implant 25 screw‐retained) was applied before and after veneering of the FDPs to assess the vertical microgap between implant and framework platform with a scanning electron microscope. The mean microgap was calculated from interproximal and buccal values. Statistical comparison was performed with non‐parametric tests.

Results

All vertical microgaps were clinically acceptable with values <90 μm. No statistically significant pairwise difference (P = 0.98) was observed between the relative effects of vertical microgap of unveneered (median 19 μm; 95% CI 13–35 μm) and veneered FDPs (20 μm; 13–31 μm), providing support for the null‐hypothesis. Analysis within the groups showed significantly different values between the five implants of the FDPs before (P = 0.044) and after veneering (P = 0.020), while a monotonous trend of increasing values from implant 23 (closest position to screw‐retained implant 25) to 15 (most distant implant) could not be observed (P = 0.169, P = 0.270).

Conclusions

Full‐arch CAD/CAM titanium screw‐retained frameworks have a high accuracy. Porcelain firing procedure had no impact on the precision of fit of the final FDPs. All implant microgap measurements of each FDP showed clinically acceptable vertical misfit values before and after veneering. Thus, the results do not only show accurate performance of the milling and firing but show also a reproducible scanning and designing process.
Simvastatin Exerts Antiamnesic Effect in Aβ25‐35‐Injected Mice
Authors: Zhi Wen‐Hong , Zeng Yan‐Ying , Lu Zi‐Hong , Qu Wei‐Jun , Chen Wei‐Xian , Chen Lei , Chen Ling
Published: December 2013

Aim and Methods

Simvastatin (SV) is reported to improve cognition and slow the progression of Alzheimer's disease (AD). This study explored the mechanisms underlying the antiamnesic effect ofSVinADusing behavior tests, histological examination, western blot analysis, and electrophysiological recording technique inADmodel mice created by intracerebroventricular injection (i.c.v.) of Aβ25‐35.

Results

Chronic administration ofSV(40 mg/kg/day) for 11 days after Aβ25‐35‐injection ameliorated the impairment of acquisition performance and probe trail test in Morris water maze task and alternation behavior in Y maze task in Aβ25‐35‐mice. Aβ25‐35‐induced apoptosis of hippocampalCA1 pyramidal cells and Aβ25‐35‐impaired high‐frequency stimulation (HFS)‐dependent long‐term potentiation (LTP) induction in hippocampal Schaffer collaterale‐CA1 synapse were rescued bySV‐treatment.SVprevented Aβ25‐35‐inhibited protein kinase B (Akt) and extracellular signal‐related kinase‐2 (ERK2) phosphorylation, which was sensitive to α7 nicotinic acetylcholine receptor (α7nAChR) antagonistMLA.SV‐induced neuroprotection was attenuated byMLAor phosphatidylinositol‐3‐kinase (PI3K) antagonistLY294002.SV‐rescuedLTPinduction was blocked by α7nAChR,PI3K orMAPK/ERKkinase (MEK) antagonist. Finally, the antiamnesia ofSVin Aβ25‐35‐mice was attenuated by blockage ofSV‐induced neuroprotection orSV‐rescuedLTPinduction.

Conclusion

The antiamnesia ofSVin Aβ25‐35‐mice depends on its neuroprotection and synaptic plasticity improvement.
Choosing and Using Climate‐Change Scenarios for Ecological‐Impact Assessments and Conservation Decisions
Authors: SNOVER AMY K. , MANTUA NATHAN J. , LITTELL JEREMY S. , ALEXANDER MICHAEL A. , MCCLURE MICHELLE M. , NYE JANET
Published: December 2013

Increased concern over climate change is demonstrated by the many efforts to assess climate effects and develop adaptation strategies. Scientists, resource managers, and decision makers are increasingly expected to use climate information, but they struggle with its uncertainty. With the current proliferation of climate simulations and downscaling methods, scientifically credible strategies for selecting a subset for analysis and decision making are needed. Drawing on a rich literature in climate science and impact assessment and on experience working with natural resource scientists and decision makers, we devised guidelines for choosing climate‐change scenarios for ecological impact assessment that recognize irreducible uncertainty in climate projections and address common misconceptions about this uncertainty. This approach involves identifying primary local climate drivers by climate sensitivity of the biological system of interest; determining appropriate sources of information for future changes in those drivers; considering how well processes controlling local climate are spatially resolved; and selecting scenarios based on considering observed emission trends, relative importance of natural climate variability, and risk tolerance and time horizon of the associated decision. The most appropriate scenarios for a particular analysis will not necessarily be the most appropriate for another due to differences in local climate drivers, biophysical linkages to climate, decision characteristics, and how well a model simulates the climate parameters and processes of interest. Given these complexities, we recommend interaction among climate scientists, natural and physical scientists, and decision makers throughout the process of choosing and using climate‐change scenarios for ecological impact assessment.

Selección y Uso de Escenarios de Cambio Climático para Estudios de Impacto Ecológico y Decisiones de Conservación