bluuebunny/crossref_metadata_2025 huggingface dataset:
Middle Mesial Canal in Mandibular Molar: Two Case Report
Authors: Vats Shrivastava Anjali , Singh Teja Tanvir , Vats Ankur , Singh Grewal Gurkirat , Aggarwal Suchi , Paul Shashi
Published: September 2018

From the past several years, there have been numerous studies that describe the morphology of teeth, including mandibular first molars. This tooth presents a high rate of intercanals and anastomosis, mainly in the apical 5 mm, which presents a clinical challenge in terms of cleaning and disinfection. A missed canal can lead to failure of endodontic therapy. Therefore every effort must be made to locate additional canals if any. This case report shows a variation in conventional anatomy in mandibular first molars.
Asenapin - Update der klinischen Daten zur bipolaren Störung und Abgleich mit klinischer Erfahrung
Authors: Illy D. , Krüger S.
Published: September 2018

Asenapin ist ein Pharmakon, das mit hoher Affinität und Spezifität an dopaminerge, serotonerge, noradrenerge und histaminerge Rezeptorsubtypen bindet. Es ist für die Behandlung der der bipolaren Manie zugelassen. Der nachfolgende Review fasst die bisher erschienenen Studien zur Therapie der manischen Epsiode bei Bipolar-I-Störungen zusammen. Berücksichtigt werden Studien mit Olanzapin bzw. Placebo in der Akuttherapie sowie Langzeitstudien im Vergleich mit Olanzapin für 12 Wochen, mit Placebo unter Fortführung einer stimmungsstabilisierenden Therapie mit Lithium oder Valproinsäure für 12 Wochen, bzw. Olanzapin und Placebo für 40 Wochen. Zudem wird eine post-hoc-Analyse von zwei der genannten Studien vorgestellt. Schwerpunkt der Studien liegt auf Wirksamkeit und Verträglichkeit der Substanz.
Depression – from remission to functional recovery
Authors: Volker D. , Vlasveld M. , Feltz-Cornelis C. van der
Published: September 2018

Depression occurs frequently in the general population and in the workplace and it leads to significant work absenteeism. Treatments aimed at improvement of depressive symptoms do not automatically lead to functional recovery in terms of return to work, and if they do, there is generally a long time lag. Several approaches have been suggested to improve return to work, that generally imply that the sick-listed employee should not wait for remission before resuming work, but rather try to return gradually. Personal as well as work factors influence the outcome of such a process, so that this approach has interpersonal as well as workplace implications that should be addressed at the same time as personal factors and the depressive symptoms.
Prognosebeurteilung
Authors: Müller J. L.
Published: September 2018

Einschätzungen über den Schweregrad einer psychischen Störung, deren Behandelbarkeit und Verlauf sind Bestandteil einer jeden ärztlichen Behandlung. Im forensisch psychiatrischen Kontext sind prognostische Aussagen zur Stabilität des Therapieverlaufs, zu den Auswirkungen von Belastungsfaktoren und zur störungsbedingten Gefährlichkeit besonders bedeutsam. Beurteilungen der Legalprognose folgen einem strukturierten Vorgehen und analysieren die Persönlichkeit, die störungsbedingte Gefährlichkeit, die Delinquenzgenese, potenzielle Risikofaktoren und Gefährdungssituationen sowie die Bedingungen eines geeigneten Empfangsraums. Prognosebeurteilung hat sich von intuitiv getroffenen Entscheidungen über die Gefährlichkeit eines Probanden fortentwickelt zu einem differenzierten und graduell beurteilbaren Gefährdungsprofil als Voraussetzung eines geeigneten Risikomanagements. Im Folgenden wird eine knappe Einführung in legalprognostische Beurteilungen gegeben.
Begutachtung und Behandlung bei sexueller Delinquenz
Authors: Rettenberger M. , Briken P. , Basdekis-Jozsa R.
Published: September 2018

Der vorliegende Beitrag stellt Aspekte der Schuldfähigkeits- sowie der Kriminalprognosebegutachtung von Sexualstraftätern dar, indem die Besonderheiten bei dieser Straftätergruppe unter den Gesichtspunkten der Mindestanforderungen für Begutachtungen beschrieben werden. In diesem Zusammenhang wird auch auf die Verwendung spezifischer Prognoseinstrumente eingegangen. Des Weiteren wird ein kurzer Überblick über die Behandlung von Sexualstraftätern gegeben, und zwar sowohl über die psychotherapeutische Behandlung und die Entwicklung spezifischer Therapieprogramme für Sexualstraftäter als auch über die Möglichkeiten einer Pharmakotherapie.
Schizophrenie – ethnopsychiatrische und ethnopharmakologische Aspekte
Authors: Weiss A. , Korwischka J. , Assion H.-J.
Published: September 2018

Die ethnische Herkunft und die mit Migrationsprozessen verbundenen psychosozialen Herausforderungen haben Bedeutung bei der Entwicklung von psychischen Erkrankungen und beeinflussen die Behandlung von Migranten. Im klinischen Versorgungsalltag wird ethnopsychiatrisches Wissen bei der Diagnostik und Therapie bisher noch unzureichend berücksichtigt. Migranten sind komplexen Belastungsfaktoren und einem höheren Stressniveau ausgesetzt, was wiederum als Risikofaktor für psychische Erkrankungen wirken kann. Das lässt sich anhand von Studiendaten zur Schizophrenie zeigen. Migranten haben ein höheres Risiko, an einer Schizophrenie zu erkranken als die ansässige Bevölkerung. Es werden Hypothesen erläutert, wie das Zusammenspiel von sozialen Stressoren und neurobiologischen Auslösern erklärt werden kann. Schizophren Erkrankte erfahren in Abhängigkeit von ihrer ethnischen oder rassischen Zugehörigkeit eine unterschiedliche psychopharmakologische Behandlung.
Der irreversible MAO-Hemmer Tranylcypromin
Authors: Heilemann H.
Published: September 2018

Tranylcypromin ist der einzige in Deutschland für die Behandlung depressiver Syndrome zugelassene irreversible MAO-Hemmer. Er verfügt über eine gute antidepressive Wirksamkeit und ist insbesondere bei therapieresistenten und atypischen Depressionen eine wichtige Therapieoption. Der Artikel bietet eine Übersicht über Pharmakologie, Indikationen, praktisches Vorgehen, einzuhaltende Diätvorschriften, Nebenwirkungen, mögliche Wechselwirkungen und Kontraindikationen.
The Extended Purse-String Rhytidectomy
Authors: Obourn Chelsea , Frodel John
Published: September 2018

Facelifts remain a critical part of a facial plastic surgeon's cosmetic practice. Techniques continue to evolve, while at the same time patients demand less invasive procedures with less morbidity. The authors present a facelift plication technique using wide purse-string sutures placed into the superficial musculoaponeurotic system and platysma. This is a retrospective review with a level of evidence 3 set at a medical spa and tertiary referral center designed to assess a purse-string suture technique using an inner followed by an outer purse-string, with refinements being made during the timeframe of the review. One hundred and eighteen patients were reviewed and 95 were included in the study given the inclusion criteria of a minimum of 1-year follow-up. Based on the subjective judgment of the primary surgeon, 37 patients were found to have excellent results, while 43 patients were judged as having good results. The judgment was based on the physical exam improvement of the aging aspects of the patient, and patient satisfaction. Ten patients displayed fair results (the patients were marginally happy), and five patients were noted to have poor results (they were notably unhappy). Complications included eight hematomas, five patients with prominent scars, and one patient with skin loss in the temple region. There were no cases of facial nerve injury. The extended purse-string rhytidectomy is a good alternative to traditional facelift techniques. This offers a plication method that results in the vertical vector that is now considered of paramount importance with all facelifts. The authors feel that it is a valuable tool that can be considered in most patients presenting for aging face surgery.
Medication recommendations in the updated NICE guideline for the treatment and management of schizophrenia
Authors: Paton C. , Barnes T. R. E.
Published: September 2018

The NICE guideline titled, „Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care“, appeared in 2002, and was the first NICE guideline to be published. It was updated in 2009, and this article comments on some of the revised recommendations relating to pharmacotherapy. The accumulating evidence influencing the recommendations relating to informed choice of antipsychotic, the use of high dose and combined antipsychotics and the assessment and monitoring of side effects is reviewed. The impact of such guidelines, and the extent to which clinical practice in the UK complies with some of the key pharmacological recommendations, are also addressed.
Tunneling Nucleation of Kink Pairs on Dislocations in the Peierls Potential Relief with Random Distortions
Authors: Petukhov B. V.
Published: September 2018

In view of the recent increased interest in the mechanical properties of quantum crystals, the study of the low-temperature dynamics of dislocations is necessary. Tunneling through the barriers created by periodic relief of the crystal lattice, which leads to the formation of pairs of kinks, makes an important contribution to this dynamics. Incomplete perfection of crystals often imposes uncontrollable perturbations that modify the features of the process of the tunneling nucleation of kinks. This article presents the modelling of perturbation effect by the random fields of internal stresses such as spatial “Gaussian noise.” The average value of the realizations of the rate of quantum-mechanical tunnel formation of kink pairs in the random fields is calculated. It is shown that even perturbations that are relatively weak in comparison with the crystalline relief lead to a significant modification of the kink formation rate dependence on a driving force.
Determination of the low-temperature self-diffusion coefficient in solid p-H2 from creep experiments
Authors: Alekseeva L. A. , Dobryden I.
Published: September 2018

Dependencies of the relative elongation ε under the constantly applied stress at T = 1.8 K on the endurance time t of polycrystalline parahydrogen (p-H2, ∼ 0.2% of o-H2) of high purity (99.9999 mol.%), with varying deuterium content, were measured. The region of linear dependence between the measured creep rates ε˙ of samples and the applied stress σ was revealed. The conclusion that the low-temperature creep of the studied p-H2 possesses a vacancy-type diffusion character was made on the basis of linear dependence ε˙ ∼ σ. Determination of the low-temperature self-diffusion coefficient of vacancies D in solid p-H2, which characterizes the rate of low-temperature mass transfer, was performed. The cases of migration of vacancies in the crystal bulk, along boundaries separating individual crystallites, as well as between dislocations existing in crystals, are considered. A significant decrease in the ε˙ and D values with an increase in the isotope concentration in the samples was observed, while maintaining the linear relationship between ε˙ and σ for the studied p-H2.
On the proposed martensitic-like structural transformation in V, Nb, and Ta
Authors: Cordero F.
Published: September 2018

The transition metals Nb, Ta and V have been known to be cubic at all temperatures, until recently the existence of a martensitic transformation has been reported, based on anomalies in the thermal expansion at low temperatures. Such a structural transformation would have passed unnoticed, because it would be hindered by small amounts of impurities. This finding is discussed in the light of anelastic measurements on Nb samples whose purities are comparable to those presenting the dilatometric anomalies. It results that the effects of the alleged transformation on the anelastic spectra would be at least three orders of magnitude smaller than in typical mar- tensitic transformations. A possible alternative explanation for the observed anomalies is proposed in terms of precipitation of unnoticed residual H.
Low-temperature relaxation of magnetization in manganite Pr0.4Bi0.3Ca0.3MnO3
Authors: Desnenko V. A. , Sirenko V. A. , Troyanchuk I. O. , Fedorchenko A. V. , Yeremenko A. V.
Published: September 2018

Low-temperature relaxation of magnetization in Pr0.4Bi0.3Ca0.3MnO3 ceramics was measured after cooling in a magnetic field and aging at temperatures from 5 K to 38 K near the transition temperature to the magnetically ordered state. It was found that the relaxation process has a thermoactivation character at the first stage and is described in terms of the Arrhenius equation. Its activation energy Q ≈ 1.1 meV is comparable with the antiferromagnetic interaction energy in this compound. The temperature–time dependence of the relaxation rate at the second stage is described by a power law. The relaxation slows down as the temperature approaches the critical value, which may be associated with the formation of a cluster structure in the studied compound under these conditions.
In vitro characterisation of two Lactobacillus strains and evaluation of their suitability as probiotics for growing-finishing pigs
Authors: Zhang D. Y. , Ji H. F. , Wang S. X. , Liu H. , Wang J. , Wang Y. M.
Published: September 2018

In this study, we evaluated the probiotic properties of two strains Lactobacillus reuteri ZLR003 and Lactobacillus salivarius ZLS006. The two strains displayed tolerance of acid and heat, and demonstrated antimicrobial ability in vitro. Furthermore, their potential functions in vivo were also tested. A total of 120 crossbred (Landrace × Large White) growing pigs were divided into three groups: a control diet, the same diet supplemented with L. reuteri ZLR003 (2.0 × 109 cfu/kg of diet) or L. salivarius ZLS006 (3.50 × 109 cfu/kg of diet). The results showed that the average daily gain and feed conversion ratio were significantly improved in L. reuteri ZLR003- (1–5 weeks and 1–9 weeks) (P < 0.05) and L. salivarius ZLS006-treated pigs (1–5 weeks, 6–9 weeks and 1–9 weeks) (P < 0.05) compared with the control group. Dietary supplementation with L. salivarius ZLS006 increased the apparent digestibility of nitrogen at Week 9 (P < 0.05). The faecal Lactobacillus populations increased at the end of experiment, and the Escherichia coli and Staphylococcus aureus in faeces decreased in the two Lactobacillus treatments compared with the control at Week 5 (P < 0.05) and Week 9 (P < 0.05), respectively. Furthermore, the total cholesterol, alanine transferase, aspartate transferase, blood urea nitrogen and haptoglobin levels in serum were significantly decreased following L. reuteri ZLR003 and L. salivarius ZLS006 treatments (P < 0.05). In conclusion, these data suggest that the two Lactobacillus strains may be promising candidates for probiotic products in growing-finishing pigs.
Genetic differentiation between estuarine and open coast ecotypes of a dominant ecosystem engineer
Authors: Coleman M. A. , Clark J. S. , Doblin M. A. , Bishop M. J. , Kelaher B. P.
Published: September 2018

Temperate intertidal shores globally are often dominated by habitat-forming seaweeds, but our knowledge of these systems is heavily biased towards northern hemisphere species. Rocky intertidal shores throughout Australia and New Zealand are dominated by a single monotypic species, Hormosira banksii. This species plays a key role in facilitating biodiversity on both rocky shores and estuarine habitats, yet we know little about the processes that structure populations. Herein we characterise the genetic diversity and structure of Hormosira and demonstrate strong restrictions to gene flow over small spatial scales, as well as between estuarine and open coast populations. Estuarine ecotypes were often genetically unique from nearby open coast populations, possibly due to extant reduced gene flow between habitats, founder effects and coastal geomorphology. Deviations from random mating in many locations suggest complex demographic processes are at play within shores, including clonality in estuarine populations. Strong isolation by distance in Hormosira suggests that spatial management of intertidal habitats will necessitate a network of broad-scale protection. Understanding patterns of genetic diversity and gene flow in this important ecosystem engineer will enhance the ability to manage, conserve and restore this key species into the future.
Geology is a significant indicator of algal cover and invertebrate species composition on intertidal reefs of Ngari Capes Marine Park, south-western Australia
Authors: Bessey C. , Rule M. J. , Dasey M. , Brearley A. , Huisman J. M. , Wilson S.K. , Kendrick A. J.
Published: September 2018

Effective management of rocky intertidal reefs requires an understanding of spatial variation in species composition and abundance, and the identification of high biodiversity areas. This study identified patterns of invertebrate biodiversity on intertidal reefs of differing underlying structure within Ngari Capes Marine Park, south-west Western Australia. Intertidal reef surveys were conducted at 12 limestone and 9 granite sites throughout the park. Geology was a significant indicator of variation in percentage cover of substrate and invertebrate composition, which covaried with rugosity and complexity. Limestone reefs were characterised by a combination of high and low branching algae and a sand–turf matrix, whereas granite reefs consisted of bare rock. A total of 15772 individual invertebrates representing 10 phyla, 16 classes, 60 families and 121 species was recorded. A high abundance of dove (Family Columbellidae) and jewel top snails (Family Trochidae) characterised limestone reefs, whereas an assortment of limpets and chitons characterised granite reefs. Granite reefs contained more species (92v. 63) and a higher mean (±s.d.) number of individuals (119±58v. 42±79m–2) than did limestone reefs. These findings emphasise the effect of underlying geology on the distribution of intertidal invertebrates and the need for management programs to accommodate different habitat types to effectively conserve biodiversity.
Sperm-mediated DNA lesions alter metabolite levels in spent embryo culture medium
Authors: Souza Fiona D' , Asampille Gitanjali , Uppangala Shubhashree , Kalthur Guruprasad , Atreya Hanudatta S. , Adiga Satish Kumar
Published: September 2018

Paternal genetic alterations may affect embryo viability and reproductive outcomes. Currently it is unknown whether embryo metabolism is affected by sperm-mediated abnormalities. Hence, using a mouse model, this study investigated the response to paternally transmitted DNA lesions on genetic integrity and metabolism in preimplantation embryos. Spent embryo culture media were analysed for metabolites by nuclear magnetic resonance spectroscopy and embryonic genetic integrity was determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay on embryonic Day 4.5 (E4.5). Metabolic signatures were compared between normally derived embryos (control) and embryos derived from spermatozoa carrying induced DNA lesions (SDL). SDL embryos showed a significant reduction in blastocyst formation on E3.5 and E4.5 (P<0.0001) and had an approximately 2-fold increase in TUNEL-positive cells (P<0.01). A cohort of SDL embryos showing delayed development on E4.5 had increased uptake of pyruvate (P<0.05) and released significantly less alanine (P<0.05) to the medium compared with the corresponding control embryos. On the other hand, normally developed SDL embryos had a reduced (P<0.001) pyruvate-to-alanine ratio compared with normally developed embryos from the control group. Hence, the difference in the metabolic behaviour of SDL embryos may be attributed to paternally transmitted DNA lesions in SDL embryos.
Urban biochar improves nitrogen and phosphorus availability in growing media
Authors: Kaudal Bhawana Bhatta , Chen Deli , Weatherley Anthony J.
Published: September 2018

The purpose of this study was to substitute sphagnum peat from plant growing media with urban biochar (UB) and evaluate its impact on nitrogen (N) and phosphorus (P) availability. The UB was produced from the pyrolysis (650°C) of a 2 : 1 ratio of biosolids to green waste. We compared three mixes – 20% sphagnum peat mixed with composted pine bark (B0), 20% UB mixed with composted pine bark (B20) and 60% UB mixed with composted pine bark (B60) – for their ability to promote plant growth and minimise leaching losses in a greenhouse experiment using silverbeet (Beta vulgaris ssp. cicla). Plants were grown in 4.0-L custom-made chambers with the capacity to collect leachate and measure nitrous oxide gas flux. Both biochar mixes increased media pH, air filled porosity, bulk density and nutrient content relative to B0. The B0 had the highest cation exchange capacity and electrical conductivity. The UB-based mixes, B20 and B60, had no significant effect on silverbeet biomass after 11 weeks of growth but had higher N use efficiency and P availability than B0. These results indicate that UB can completely replace sphagnum peat from growing media and can be used at the rate of 60% on volume basis while improving N and P availability. Using a higher rate of biochar in growing media has the additional advantage of sequestering more carbon and reducing urban waste streams and landfill costs.
Reversible photoswitching of encapsulated azobenzenes in water
Authors: Samanta Dipak , Gemen Julius , Chu Zonglin , Diskin-Posner Yael , Shimon Linda J. W. , Klajn Rafal
Published: September 2018

Efficient molecular switching in confined spaces is critical for the successful development of artificial molecular machines. However, molecular switching events often entail large structural changes and therefore require conformational freedom, which is typically limited under confinement conditions. Here, we investigated the behavior of azobenzene—the key building block of light-controlled molecular machines—in a confined environment that is flexible and can adapt its shape to that of the bound guest. To this end, we encapsulated several structurally diverse azobenzenes within the cavity of a flexible, water-soluble coordination cage, and investigated their light-responsive behavior. Using UV/Vis absorption spectroscopy and a combination of NMR methods, we showed that each of the encapsulated azobenzenes exhibited distinct switching properties. An azobenzene forming a 1:1 host–guest inclusion complex could be efficiently photoisomerized in a reversible fashion. In contrast, successful switching in inclusion complexes incorporating two azobenzene guests was dependent on the availability of free cages in the system, and it involved reversible trafficking of azobenzene between the cages. In the absence of extra cages, photoswitching was either suppressed or it involved expulsion of azobenzene from the cage and consequently its precipitation from the solution. This finding was utilized to develop an information storage medium in which messages could be written and erased in a reversible fashion using light.
A clustering linear combination approach to jointly analyze multiple phenotypes for GWAS
Authors: Sha Qiuying , Wang Zhenchuan , Zhang Xiao , Zhang Shuanglin
Published: September 2018

There is an increasing interest in joint analysis of multiple phenotypes for genome-wide association studies (GWASs) based on the following reasons. First, cohorts usually collect multiple phenotypes and complex diseases are usually measured by multiple correlated intermediate phenotypes. Second, jointly analyzing multiple phenotypes may increase statistical power for detecting genetic variants associated with complex diseases. Third, there is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. In this paper, we develop a clustering linear combination (CLC) method to jointly analyze multiple phenotypes for GWASs. In the CLC method, we first cluster individual statistics into positively correlated clusters and then, combine the individual statistics linearly within each cluster and combine the between-cluster terms in a quadratic form. CLC is not only robust to different signs of the means of individual statistics, but also reduce the degrees of freedom of the test statistic. We also theoretically prove that if we can cluster the individual statistics correctly, CLC is the most powerful test among all tests with certain quadratic forms. Our simulation results show that CLC is either the most powerful test or has similar power to the most powerful test among the tests we compared, and CLC is much more powerful than other tests when effect sizes align with inferred clusters. We also evaluate the performance of CLC through a real case study.

Availability and implementation

R code for implementing our method is available at http://www.math.mtu.edu/∼shuzhang/software.html.

Supplementary information

Supplementary data are available at Bioinformatics online.
Gimpute: an efficient genetic data imputation pipeline
Authors: Chen Junfang , Lippold Dietmar , Frank Josef , Rayner William , Meyer-Lindenberg Andreas , Schwarz Emanuel
Published: September 2018

Motivation

Genotype imputation is essential for genome-wide association studies (GWAS) to retrieve information of untyped variants and facilitate comparability across studies. However, there is a lack of automated pipelines that perform all required processing steps prior to and following imputation.

Results

Based on widely used and freely available tools, we have developed Gimpute, an automated processing and imputation pipeline for genome-wide association data. Gimpute includes processing steps for genotype liftOver, quality control, population outlier detection, haplotype pre-phasing, imputation, post imputation, data management and the extension to other existing pipeline.

Availability and implementation

The Gimpute package is an open source R package and is freely available at https://github.com/transbioZI/Gimpute.

Supplementary information

Supplementary data are available at Bioinformatics online.
RNApuzzler: efficient outerplanar drawing of RNA-secondary structures
Authors: Wiegreffe Daniel , Alexander Daniel , Stadler Peter F , Zeckzer Dirk
Published: September 2018

Motivation

RNA secondary structure is a useful representation for studying the function of RNA, which captures most of the free energy of RNA folding. Using empirically determined energy parameters, secondary structures of nucleic acids can be efficiently computed by recursive algorithms. Several software packages supporting this task are readily available. As RNA secondary structures are outerplanar graphs, they can be drawn without intersection in the plane. Interpretation by the practitioner is eased when these drawings conform to a series of additional constraints beyond outerplanarity. These constraints are the reason why RNA drawing is difficult. Many RNA drawing algorithms therefore do not always produce intersection-free (outerplanar) drawings.

Results

To remedy this shortcoming we propose here the RNApuzzler algorithm which is guaranteed to produce intersection-free drawings. It is based on a drawing algorithm respecting constraints based on nucleotide distances (RNAturtle). We investigate relaxations of these constraints allowing for intersection-free drawings. Based on these relaxations, we implemented a fully automated, simple, and robust algorithm that produces aesthetic drawings adhering to previously established guidelines. We tested our algorithm using the RFAM database and found that we can compute intersection-free drawings of all RNAs therein efficiently.

Availability and implementation

The software can be accessed freely at: https://github.com/dwiegreffe/RNApuzzler.

Supplementary information

Supplementary data are available at Bioinformatics online.
Quantitative solid-phase assay to measure deoxynucleoside triphosphate pools
Authors: Landoni Juan Cruz , Wang Liya , Suomalainen Anu
Published: September 2018

deoxynucleoside triphosphate (dNTPs) are the reduced nucleotides used as the building blocks and energy source for deoxyribonucleic acid (DNA) replication and maintenance in all living systems. They are present in highly regulated amounts and ratios in the cell, and their balance has been implicated in the most important cell processes, from determining the fidelity of DNA replication to affecting cell fate. Furthermore, many cancer drugs target biosynthetic enzymes in dNTP metabolism, and mutations in genes directly or indirectly affecting these pathways that are the cause of devastating diseases. The accurate and systematic measurement of these pools is key to understanding the mechanisms behind these diseases and their treatment. We present a new method for measuring dNTP pools from biological samples, utilizing the current state-of-the-art polymerase method, modified to a solid-phase setting and optimized for larger scale measurements.
Towards the third 90: improving viral load testing with a simple quality improvement program in health facilities in Malawi
Authors: Hubbard Julie , Kakwesa Gift , Nyirenda Mike , Mwambene James , Bardon Ashley , Balakasi Kelvin , Dovel Kathryn , Kalua Thokozani , Hoffman Risa M
Published: September 2018

Background

Viral load (VL) scale-up efforts have largely focused on laboratory systems, with less attention on facility-level strengthening of staff who facilitate VL testing. To address this gap we implemented a quality improvement (QI) program at 13 health facilities in central and southern Malawi.

Methods

QI program tools focused on patient and provider VL knowledge and clarification of site-level roles and responsibilities, including the designation of a VL ‘focal person’ to oversee all VL activities. T-tests were used to compare differences in VL testing before (November 2016–April 2017) and after (May 2017–November 2017) the intervention.

Results

The mean number of VL tests performed significantly increased after implementation of the QI program. Overall there was a 164% increase in the mean number of routine VL tests performed per month (p<0.001). Increased VL testing was sustained during the 6 months of follow-up.

Conclusions

A simple QI program focused on improving VL knowledge among patients and providers, and clarifying staff roles at a facility level increased VL testing over a 6-month period. Further investigation is needed on whether this program can be scaled in different settings across sub-Saharan Africa and on the duration of follow-up required for sustained improvements in VL testing.
Monopoiesis in humans and mice
Authors: Kawamura Shunsuke , Ohteki Toshiaki
Published: September 2018

Monocytes are a widely conserved cell population in vertebrates with important roles in both inflammation and homeostasis. Under both settings, monocytes continuously arise from hematopoietic progenitors in the bone marrow and, on demand, migrate into tissues through the bloodstream. Monocytes are classified into three subsets—classical, intermediate and non-classical—based on their cell surface expression of CD14 and CD16 in humans and Ly6C, CX3CR1 and CCR2 in mice. In tissues, monocytes differentiate further into monocyte-derived macrophages and dendritic cells to mediate innate and adaptive immune responses and maintain tissue homeostasis. Recently, the progenitors that strictly give rise to monocytes were identified in both humans and mice, thereby revealing the monocyte differentiation pathways.
Reliability and validity of the Thai Drug Hypersensitivity Quality of Life Questionnaire: a multi-center study
Authors: Chongpison Yuda , Rerknimitr Pawinee , Hurst Cameron , Mongkolpathumrat Pungjai , Palapinyo Sirinoot , Chularojanamontri Leena , Srinoulprasert Yuttana , Rerkpattanapipat Ticha , Chanprapaph Kumutnart , Disphanurat Wareeporn , Chakkavittumrong Panlop , Tovanabutra Napatra , Srisuttiyakorn Chutika , Sukasem Chonlaphat , Tuchinda Papapit , Baiardini Ilaria , Klaewsongkram Jettanong
Published: September 2018

Objective

To adapted the Drug Hypersensitivity Quality of Life (DrHy-Q) Questionnaire from Italian into Thai and assessed its validity and reliability.

Design

Prospectively recruited during January 2012–May 2017.

Setting

Multicenter; six Thai tertiary university hospitals.

Study Participants

Total of 306 patients with physician-diagnosed drug hypersensitivity.

Interventions

Internal consistency and test–retest reliability were evaluated among 68 participants using Cronbach’s ɑ and intra-class correlation coefficient (ICC). The validity of Thai DrHy-Q was assessed among 306 participants who completed World Health Organization Quality of Life-BREF (WHOQOL-BREF-THAI). Construct and divergent validities were assessed for Thai DrHy-Q. Known-groups validity assessing discriminating ability was conducted in Thai DrHy-Q and WHOQOL-BREF-THAI.

Main outcome measures

Validity; reliability; single vs. multiple drug allergy; non-severe cutaneous adverse reactions (SCAR) vs. SCAR.

Results

Thai DrHy-Q showed good reliability (Cronbach’s ɑ = 0.94 and ICC = 0.8). Unidimensional factor structure was established by confirmatory factor analysis (CFI&TLI = 0.999, RMSEA = 0.02). Divergent validity was confirmed by weak correlation between Thai DrHy-Q and WHOQOL-BREF-THAI domains (Pearson’s r = −0.41 to −0.19). Known-groups validity of Thai DrHy-Q was confirmed with significant difference between patients with and without life-threatening SCAR (P = 0.02) and patients with multiple implicated drug classes vs. those with one class (P < 0.01); while WHOQOL-BREF-THAI could differentiate presence of life-threatening SCAR (P < 0.01) but not multiple-drug allergy.

Conclusions

Thai DrHy-Q was reliable and valid in evaluating quality of life among patients with drug hypersensitivity. Thai DrHy-Q was able to discriminate serious drug allergy phenotypes from non-serious manifestations in clinical practice and capture more specific drug-hypersensitivity aspects than WHOQOL-BREF-THAI.
Separation and Identification of Isomeric and Structurally Related Synthetic Cannabinoids Using 2D Liquid Chromatography and High Resolution Mass Spectrometry
Authors: Eckberg Melanie N , Arroyo-Mora Luis E , Stoll Dwight R , DeCaprio Anthony P
Published: September 2018

Novel psychoactive substances (NPS) are emerging drugs of abuse that are variations of existing compounds intended to cause a CNS psychotropic effect. Some NPS are so comparable in structure and physicochemical properties that they co-elute using traditional single column chromatographic techniques and therefore will not be detected as individual compounds. 2D liquid chromatography (2D-LC) has demonstrated applicability in difficult separations of small molecules and compounds in complex mixtures. It was hypothesized that this technique could also be used to separate co-eluting isomeric and structurally related, non-isomeric NPS, including synthetic cannabinoids (SC). Initial studies assessed several parameters, including column type, mobile phase, analysis time, gradient and flow rate, to optimize a 2D-LC method for separation and analysis of SC. The final comprehensive on-line 2D-LC method employed a Bonus-RP column in the first dimension (1D) coupled with UV detection and a biphenyl column in the second dimension (2D) coupled with QTOF-MS detection in full scan positive mode. To test the utility of the method, three SC mixes were created, each containing five compounds that were unresolvable in a traditional, 1D-LC separation; one mix with isomeric compounds and two with structurally related but non-isomeric compounds. Contour plots of UV absorbance in 1D and MS ion intensity in 2D demonstrated that all components in each mixture were successfully resolved using the 2D-LC separation method. This research serves as proof-of-concept for the application of 2D-LC to the separation of isomeric and structurally related SC. With further optimization and validation, 2D-LC may be a generally useful tool for separation of complex mixtures of NPS.
Re-estimating the relationship between inequality and growth
Authors: Scholl Nathalie , Klasen Stephan
Published: September 2018

In this paper, we revisit the inequality–growth relationship using an enhanced panel data set with improved inequality data. We explicitly take into account the special role of transition (post-Soviet) countries and add an instrumental variable (IV) estimation to add a causal interpretation to our findings. Our analysis is based on the specification used by Forbes in her 2000 paper, but we also address functional form concerns raised by Banerjee and Duflo three years later. We arrive at three main findings: First, the significant positive association between inequality and economic growth in the full sample is entirely driven by transition countries. Second, this relationship in transition countries is not robust to the inclusion of separate time effects. Lastly, it appears that this association is not causal but rather driven by the particular timing of the transition. Results from IV estimation confirm our interpretation of the observed positive relationship in the overall sample as non-causal.
Philosophy of Neuroscience
Authors: Roskies Adina L. , Craver Carl F.
Published: September 2018

The experimental study of the brain has exploded in the past several decades, providing rich material for both philosophers of science and philosophers of mind. In this chapter, the authors summarize some central research areas in philosophy of neuroscience. Some of these areas focus on the internal practice of neuroscience, that is, on the assumptions underlying experimental techniques, the accepted structures of explanations, the goals of integrating disciplines, and the possibility of a unified science of the mind-brain. Other areas focus outwards on the potential impact that neuroscience is having on our conception of the mind and its place in nature.
Causation in Science
Authors: Woodward James
Published: September 2018

This article discusses some philosophical theories of causation and their application to several areas of science. Topics addressed include regularity, counterfactual, and causal process theories of causation; the causal interpretation of structural equation models and directed graphs; independence assumptions in causal reasoning; and the role of causal concepts in physics. In connection with this last topic, this article focuses on the relationship between causal asymmetries, the time-reversal invariance of most fundamental physical laws, and the significance of differences among varieties of differential equations (e.g., hyperbolic versus nonhyperbolic) in causal interpretation. It concludes with some remarks about “grounding” special science causal generalizations in physics.
Molecular Characterization and Detection of 16SrIII Group Phytoplasma Associated with Huanglongbing Symptoms
Authors: Wulff Nelson Arno , Fassini Camila Giacomo , Marques Viviani Vieira , Martins Elaine Cristina , Coletti Daniela Aparecida Bononi , Teixeira Diva do Carmo , Sanches Marcio Martinello , Bové Joseph Marie
Published: September 2018

When huanglongbing (HLB) was found in Brazil in 2004, ‘Candidatus Liberibacter americanus’ was infecting most of the trees while ‘Ca. L. asiaticus’ was present in a minor proportion. Currently, ‘Ca. L. asiaticus’ is the predominant bacterium associated with HLB in citrus trees in São Paulo (SP) and Minas Gerais (MG) States, the major citrus-growing regions in Brazil. A phytoplasma from the 16SrIX group was associated with HLB symptoms in Brazil in 2007, in plants free of Liberibacter spp. In this report, HLB samples testing negative for ‘Ca. L. asiaticus’, ‘Ca. L. americanus’, and 16SrIX phytoplasma were infected with 16SrIII phytoplasmas. Coinfection with ‘Ca. L. asiaticus’ and 16SrIII was also found. The 16S ribosomal RNA (rRNA) gene sequences from 22 samples were obtained and sequenced, confirming that the 16SrIII group phytoplasma is associated with HLB symptoms in SP and MG States. Ten single-nucleotide polymorphisms (SNPs) were found in the 1,427-bp 16S rRNA gene sequences from 16SrIII phytoplasmas from citrus, whereas none was detected in 16S rRNA gene sequences among 16SrIX phytoplasma from citrus. Ribosomal protein (rp) rpsSrplVrpsC gene sequences were amplified with 16SrIII group-specific primers, sequenced from a subset of nine samples, and assembled into three groups based on eight SNPs. SNPs in 16S rRNA gene and rp gene sequences are common in 16SrIII phytoplasmas from other hosts and this phytoplasma group is widespread in South America. 16SrIII phytoplasmas highly related are commonly found in Melia azedarach, a widespread tree in Brazil and Argentina. The finding of a new phytoplasma associated with HLB symptoms belonging to the 16SrIII group reinforces the need to develop diagnostic tools to assess HLB-associated microbiomes.
Functional heterogeneity of lymphocytic patterns in primary melanoma dissected through single-cell multiplexing
Authors: Maria Bosisio Francesca , Antoranz Asier , van Herck Yannick , Maria Bolognesi Maddalena , Marcelis Lukas , Chinello Clizia , Wouters Jasper , Magni Fulvio , Alexopoulos Leonidas , Stas Marguerite , Boecxstaens Veerle , Bechter Oliver , Cattoretti Giorgio , van den Oord Joost
Published: September 2018

In melanoma, the lymphocytic infiltrate is a prognostic parameter classified morphologically into “brisk”, “non-brisk” and “absent” entailing a functional association that has never been proved. Recently, it has been shown that lymphocytic populations can be very heterogeneous, and that anti-PD-1 immunotherapy supports activated T cells. Here, we characterize the immune landscape in primary melanoma by high-dimensional single cell multiplex analysis in tissue sections (MILAN technique) followed by image analysis, RT-PCR and shotgun proteomics. We observed that the brisk and non-brisk patterns are heterogeneous functional categories that can be further sub-classified into active, transitional or exhausted. The classification of primary melanomas based on the functional paradigm also shows correlation with spontaneous regression, and an improved prognostic value than that of the brisk classification. Finally, the main inflammatory cell subpopulations that are present in the microenvironment associated with activation and exhaustion and their spatial relationships are described using neighbourhood analysis.
Thermal selection drives biodiversity origination across the Atlantic/Indian Ocean boundary
Authors: Teske Peter R. , Sandoval-Castillo Jonathan , Golla Tirupathi Rao , Emami-Khoyi Arsalan , Tine Mbaye , Heyden Sophie von der , Beheregaray Luciano B.
Published: September 2018

Intraspecific genetic structure in widely distributed marine species often mirrors the boundaries between temperature-defined bioregions. This suggests that the same thermal gradients that maintain distinct species assemblages also drive the evolution of new biodiversity. Ecological speciation scenarios are often invoked to explain such patterns, but the fact that adaptation is usually only identified when phylogenetic splits are already evident makes it impossible to rule out the alternative scenario of allopatric speciation with subsequent adaptation. We integrated large-scale genomic and environmental datasets along one of the world’s best defined marine thermal gradients (the South African coastline) to test the hypothesis that incipient speciation in the sea is due to divergence linked to the thermal environment. We identified temperature-associated gene regions in a coastal fish species that is spatially homogeneous throughout several temperature-defined biogeographical regions on the basis of selectively neutral markers. Based on these gene regions, the species is divided into geographically distinct regional populations. Importantly, the ranges of these populations are delimited by the same ecological boundaries that define distinct infraspecific genetic lineages in co-distributed marine the species, and biogeographical disjunctions in species assemblages. Our results indicate that ecologically-mediated selection represents an early stage of marine speciation in coastal regions that lack physical dispersal barriers.
Haemophilus, Antibiotic Therapy and the Airway Microbiome in Chronic Obstructive Pulmonarydisease
Authors: Brill Simon E , James Phillip L , Cuthbertson Leah , Zhu Ana , Lawley Trevor , Cookson William OCM , Cox Michael J , Wedzicha Jadwiga A , Moffatt Miriam F
Published: September 2018

Chronic obstructive pulmonary disease (COPD) is a smoking-related illness affecting 64 million people worldwide. Airway infection drives recurrent exacerbations and lung function decline. Prophylactic antibiotics may prevent exacerbations but their use is a significant cause of population antimicrobial resistance.

We characterised the sputum microbiome by 16S rRNA gene analysis using 138 samples collected during a randomised controlled trial of prophylactic antibiotics in 71 patients with stable COPD. On comparing the profile of the microbiome obtained by sequencing to the isolates grown from samples using standard culture, there were similarities overall, although with a much narrower spectrum of genera on culture with under-representation of certain genera includingVeillonellaandPrevotella.There was concordance in the most abundant genera within samples and the number of isolates cultured reflected the measured bacterial diversity.

We found that at baseline the microbiota of 17 (24%) patients were dominated byHaemophilus influenzae, accompanied by narrowed microbial diversity and higher levels of sputum inflammatory cytokines. DifferentH. influenzaestrains co-existed within individuals. Opportunistic whole genome sequencing of sixH. influenzaeisolates obtained during the study revealed that all were non-typeableH. influenzae(NTHI), with a range of different antibiotic resistance gene profiles, but an identical complement of virulence genes.

Administration of 13 weeks prophylaxis with moxifloxacin, azithromycin or doxycycline revealed distinctive changes in microbial communities for each group.Haemophilusnumbers reduced by 90% compared to placebo only after moxifloxacin, and significant reduction in sputum cytokines occurred in patients dominated byHaemophilusat baseline.Haemophilus influenzaedominance defines COPD patients with active disease who may particularly benefit from antibiotics or vaccination.
Deciphering the enigmatic role of the amidotransferase LipL inBacillus subtilislipoic acid utilization
Authors: Rasetto Natalí B. , Lavatelli Antonela , Martin Natalia , Mansilla María Cecilia
Published: September 2018

Lipoate is an essential cofactor for key enzymes of oxidative and one-carbon metabolism. It is covalently attached to E2 subunits of dehydrogenase (DH) complexes and the GcvH subunit of the glycine cleavage system.Bacillus subtilispossess two protein lipoylation pathways: biosynthesis and scavenging. The former requires octanoylation of GcvH, amidotransfer of the octanoate to E2s, and insertion of sulfur atoms. Lipoate scavenging is mediated by a lipoate ligase (LplJ), that catalizes a classical two-step ATP-dependent reaction. Although these pathways were thought to be redundant, a ΔlipLmutant, unable to transfer the octanoyl group from GcvH to the E2s during lipoate synthesis, showed growth defects in minimal media even when supplemented with this cofactor, despite the presence of a functional LplJ. In this study we demonstrated that LipL is essential to modify E2 subunits of branched chain ketoacid and pyruvate DH during lipoate scavenging. LipL must be functional and it is not forming a complex with LplJ, which suggests that these enzymes might be acting sequentially. We also show that the E2 subunit of oxoglutarate DH is a good donor for LipL amidotransfer reaction. The essential role of LipL during lipoate utilization relies on the strict substrate specificity of LplJ, determined by charge complementarity between the ligase and the lipoylable subunits. LplJ does not recognize E2 subunits without a negatively charged residue in key positions of the target protein, and thus LipL is required to transfer the lipoate to them. This model of lipoate scavenging seems widespread among Gram-positive bacteria.