bluuebunny/crossref_metadata_2025 huggingface dataset:
SeqLib: a C ++ API for rapid BAM manipulation, sequence alignment and sequence assembly
Authors: Wala Jeremiah , Beroukhim Rameen
Published: November 2016

We present SeqLib, a C ++ API and command line tool that provides a rapid and user-friendly interface to BAM/SAM/CRAM files, global sequence alignment operations and sequence assembly. Four C libraries perform core operations in SeqLib: HTSlib for BAM access, BWA-MEM and BLAT for sequence alignment and Fermi for error correction and sequence assembly. Benchmarking indicates that SeqLib has lower CPU and memory requirements than leading C ++ sequence analysis APIs. We demonstrate an example of how minimal SeqLib code can extract, error-correct and assemble reads from a CRAM file and then align with BWA-MEM. SeqLib also provides additional capabilities, including chromosome-aware interval queries and read plotting. Command line tools are available for performing integrated error correction, micro-assemblies and alignment.

Availability and Implementation: SeqLib is available on Linux and OSX for the C ++98 standard and later at github.com/walaj/SeqLib. SeqLib is released under the Apache2 license. Additional capabilities for BLAT alignment are available under the BLAT license.
Association of Diabetes and Insulin Therapy With Risk of Hospitalization for Infection and 28-Day Mortality Risk
Authors: Donnelly John P. , Nair Sunil , Griffin Russell , Baddley John W. , Safford Monika M. , Wang Henry E. , Shapiro Nathan I.
Published: November 2016

Background.

Epidemiologic and experimental evidence suggests that individuals with diabetes are at increased risk of infection. We sought to examine the association of diabetes and insulin therapy with hospitalization for infection and 28-day mortality.

Methods.

We performed a prospective cohort study using data from 30 239 community-dwelling participants aged ≥45 years enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. We defined diabetes as a fasting glucose level ≥126 mg/L (or ≥200 mg/L for those not fasting), the use of insulin or oral hypoglycemic agents, or self-reported history. We identified infection-related hospitalizations over the years 2003–2012. We fit Cox proportional hazards models to assess the association of diabetes with hazard rates of infection and logistic regression models for 28-day mortality.

Results.

Among 29 683 patients from the REGARDS study with complete follow-up, 7375 had diabetes. Over a median follow-up period of 6.5 years, we identified 2593 first and 3411 total infection hospitalizations. In adjusted analyses, participants with diabetes had an increased hazard of infection (hazard ratio, 1.50; 95% confidence interval [CI], 1.37–1.64) compared with those without diabetes. Participants with diabetes hospitalized for infection did not have an increased odds of death within 28 days (odds ratio, 0.94; 95% CI, .67–1.32). Participants receiving insulin therapy had greater hazard of infection (hazard ratio, 2.18; 95% CI, 1.90–2.51) but no increased odds of mortality (odd ratio, 1.07; 95% CI, .67–1.71).

Conclusions.

Diabetes is associated with increased risk of hospitalization for infection. However, we did not find an association with 28-day mortality. Insulin therapy conferred an even greater risk of hospitalization, without increased mortality.
What Is the More Effective Antibiotic Stewardship Intervention: Preprescription Authorization or Postprescription Review With Feedback?
Authors: Tamma Pranita D. , Avdic Edina , Keenan John F. , Zhao Yuan , Anand Gobind , Cooper James , Dezube Rebecca , Hsu Steven , Cosgrove Sara E.
Published: November 2016

Background.

The optimal approach to conducting antibiotic stewardship interventions has not been defined. We compared days of antibiotic therapy (DOT) using preprescription authorization (PPA) vs postprescription review with feedback (PPRF) strategies.

Methods.

A quasi-experimental, crossover trial comparing PPA and PPRF for adult inpatients prescribed any antibiotic was conducted. For the first 4 months, 2 medicine teams were assigned to the PPA arm and the other 2 teams to the PPRF arm. The teams were then assigned to the alternate arm for an additional 4 months. Appropriateness of antibiotic use was adjudicated by at least 2 infectious diseases–trained clinicians and according to institutional guidelines.

Results. There were 2686 and 2693 patients admitted to the PPA and PPRF groups, with

29% and 27% of patients prescribed antibiotics, respectively. Initially, antibiotic DOTs remained relatively unchanged in the PPA arm. When changed to the PPRF arm, antibiotic use decreased (−2.45 DOT per 1000 patient-days [PD]). In the initial PPRF arm, antibiotic use decreased (slope of −5.73 DOT per 1000 PD) but remained constant when changed to the PPA arm. Median patient DOTs in the PPA and PPRF arms were 8 and 6 DOT per 1000 PD, respectively (P = .03). Antibiotic therapy was guideline-noncompliant in 34% and 41% of patients on days 1 and 3 in the PPA group (P < .01) and in 57% and 36% of patients on days 1 and 3 in the PPRF group (P = .03).

Conclusions.

PPRF may have more of an impact on decreasing antibiotic DOTs compared with PPA. This information may be useful for institutions without sufficient resources to incorporate both stewardship approaches.
Longitudinal Viral Dynamics in Semen During Early HIV Infection
Authors: Morris Sheldon R. , Zhao Mitchell , Smith Davey M. , Vargas Milenka V. , Little Susan J. , Gianella Sara
Published: November 2016

Background.

Multiple viruses coinfect the male genital tract, influencing each other’s replication and perhaps affecting human immunodeficiency virus (HIV) pathogenesis and disease progression.

Methods.

This study included 453 longitudinal seminal samples from 195 HIV-infected men from the San Diego Primary Infection Resource Consortium and 67 seminal samples from HIV-negative healthy controls. Seminal HIV RNA and DNA from 7 human herpesviruses (HHVs) were measured by real-time polymerase chain reaction. Longitudinal shedding rates were determined by Kaplan-Meier survival analysis. Predictors of viral shedding were determined using backwards selection in a multivariable generalized estimating equation model.

Results.

HIV-infected participants presented significantly increased rates of seminal HHV shedding compared with HIV-uninfected controls. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were the most commonly detected HHV in semen of HIV-infected participants. Persistent shedding was more common for CMV and EBV when compared to other HHVs. With exception of HHV-7, HHV shedding was not significantly influenced by HIV RNA levels, CD4+ cell counts, or antiretroviral therapy. Presence of CMV, EBV, and herpes simplex virus (HSV) were independent predictors of genital HIV RNA shedding after adjusting for plasma HIV RNA and longitudinal measurements.

Conclusions.

Seminal replication of multiple HHVs is common in our HIV primary infection cohort. Genital replication of CMV and EBV was the most common and was significantly associated with seminal HIV RNA shedding. Prevalence of HSV shedding was lower and mostly intermittent, but its association with seminal HIV RNA was the strongest. Understanding the complex viral milieu in semen is important for HIV transmission but might also play a role in HIV pathogenesis and disease progression.
Efficacy and Safety of Praziquantel Against Light Infections of Opisthorchis viverrini: A Randomized Parallel Single-Blind Dose-Ranging Trial
Authors: Sayasone Somphou , Meister Isabel , Andrews Jason R. , Odermatt Peter , Vonghachack Youthanavanh , Xayavong Syda , Senggnam Kanpaseuth , Phongluxa Khampheng , Hattendorf Jan , Bogoch Isaac I. , Keiser Jennifer
Published: November 2016

Background.

The liver fluke Opisthorchis viverrini, highly prevalent in Southeast Asia, is an important public health burden, including a risk factor for developing an aggressive bile duct cancer, cholangiocarcinoma, in chronically infected patients. Praziquantel, administered at a single 40 mg/kg dose in preventive chemotherapy programs and 3 × 25 mg/kg for individual treatment, is the drug of choice, yet information on the nature of the dose-response relationship is lacking.

Methods.

We performed a randomized, parallel, single-blind dose-ranging phase 2 trial in the Lao People’s Democratic Republic in O. viverrini–infected adults. Patients were randomly assigned to 30 mg/kg, 40 mg/kg, 50 mg/kg, or 3 × 25 mg/kg praziquantel or placebo. Adverse events were recorded at baseline, 3 hours, and 24 hours posttreatment. Cure rates (CRs) and egg reduction rates (ERRs) were estimated 3 weeks after drug administration using available case analysis. Dose-response curves were predicted using Emax models.

Results.

Two-hundred seventeen O. viverrini–infected patients were assigned to the 5 treatment arms. The majority (94.3%) of patients harbored light infections. The Emax model predicted a high efficacy among the observed dose range. We observed CRs ranging from 92.7% to 95.5% and ERRs >99.5% for all praziquantel treatment groups. Adverse events were mild but higher in the standard treatment group (3 × 25 mg/kg) than in the single-dose treatment arms.

Conclusions.

Single-dose praziquantel appears to be as efficacious as the standard 3 × 25 mg/kg regimen for the treatment of O. viverrini infections, while presenting fewer adverse events. Further studies are necessary in moderate and heavy O. viverrini infections.

Clinical Trials Registration.

Randomized Controlled Trials (ISRCTN77186750).
High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature
Authors: Wang Fulong , Jia Jocelyn , Lal Nathaniel , Zhang Dahai , Chiu Amy Pei-Ling , Wan Andrea , Vlodavsky Israel , Hussein Bahira , Rodrigues Brian
Published: November 2016

Aims

The secretion of enzymatically active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature.

Methods and results

HG promoted both HepL and HepA secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepL reuptake. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition using small interfering RNA (siRNA), receptor-associated protein, or an LRP1 neutralizing antibody significantly reduced uptake. In cardiomyocytes, which have a negligible amount of heparanase gene expression, LRP1 also participated in the uptake of HepL. Exogenous addition of HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2 induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes.

Conclusion

Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy.
Polarized emission from an off-centred dipole
Authors: Pétri J.
Published: November 2016

Radio polarization measurements of pulsed emission from pulsars offer a valuable insight into the basic geometry of the neutron star: inclination angle between the magnetic and rotation axis and inclination of the line of sight. So far, all studies about radio polarization focused on the standard rotating vector model with the underlying assumption of a centred dipole. In this Letter, we extend this model to the most general off-centred dipole configuration and give an exact closed analytic expression for the phase-resolved polarization angle. It is shown that contrary to the rotating vector model, for an off-centred dipole, the polarization angle also depends on the emission altitude. Although the fitting parameter space increases from two to six (position of the dipole, altitude and shift of the zero phase), statistical analysis should remain tractable. Observations revealing an evolution of the polarization angle with frequency would undeniably furnish a strong hint for the presence of a decentred magnetic dipole in neutron stars.
Projected axis ratios of galaxy clusters in the Horizon-AGN simulation: Impact of baryon physics and comparison with observations
Authors: Suto Daichi , Peirani Sébastien , Dubois Yohan , Kitayama Tetsu , Nishimichi Takahiro , Sasaki Shin , Suto Yasushi
Published: November 2016

We characterize the non-sphericity of galaxy clusters by the projected axis ratio of spatial distribution of star, dark matter, and X-ray surface brightness (XSB). We select 40 simulated groups and clusters of galaxies with mass larger than 5 × 1013 M⊙ from the Horizon simulation that fully incorporates the relevant baryon physics, in particular, the active galactic nucleus feedback. We find that the baryonic physics around the central region of galaxy clusters significantly affects the non-sphericity of dark matter distribution even beyond the central region, approximately up to half of the virial radius. Therefore it is very difficult to predict the probability density function (PDF) of the projected axis ratio of XSB from dark-matter-only N-body simulations as attempted in previous studies. Indeed, we find that the PDF derived from our simulated clusters exhibits much better agreement with that from the observed X-ray clusters. This indicates that our present methodology to estimate the non-sphericity directly from the Horizon simulation is useful and promising. Further improvements in both numerical modeling and observational data will establish the non-sphericity of clusters as a cosmological test complementary to more conventional statistics based on spherically averaged quantities.
Understanding the general feature of microvariability in Kepler blazar W2R 1926+42
Authors: Sasada Mahito , Mineshige Shin , Yamada Shinya , Negoro Hitoshi
Published: November 2016

We analyze the Kepler monitoring light curve of a blazar W2R 1926+42 to examine features of microvariability by means of the “shot analysis” technique. We select 195 intra-day, flare-like variations (shots) for the continuous light curve of Quarter 14 with a duration of 100 d. In the application of the shot analysis, an averaged profile of variations is assumed to converge with a universal profile which reflects a physical mechanism generating the microvariability in a blazar jet, although light-variation profiles of selected shots show a variety. A mean profile, which is obtained by aligning the peaks of the 195 shots, is composed of a spiky-shaped shot component at ± 0.1 d (with respect to the time of the peak), and two slow varying components ranging from −0.50 d to −0.15 d and from 0.10 d to 0.45 d of the peak time. The former spiky feature is well represented by an exponential rise of 0.043 ± 0.001 d and an exponential decay of 0.061 ± 0.002 d. These timescales are consistent with that corresponding to a break frequency of a power spectrum density calculated from the obtained light curve. After verification with the Monte Carlo method, the exponential shape, but not the observed asymmetry, of the shot component can be explained by noise variation. The asymmetry is difficult to explain through a geometrical effect (i.e., changes of the geometry of the emitting region), but is more likely to be caused by the production and dissipation of high-energy accelerated particles in the jet. Additionally, the durations of the detected shots show a systematic variation with a dispersion caused by a statistical randomness. A comparison with the variability of Cygnus X-1 is also briefly discussed.
Obscene Humour, Gender, and Sociability in Sixteenth-Century St Gallen*
Authors: Roth Carla
Published: November 2016

Over the last few decades, studies of early modern satires, Shrovetide plays and printed joke collections have gone a long way to establishing humour as a valid subject of historical research. Yet unfortunately these sources rarely shed any light on the role of jokes in everyday life. When writing about the social function of sexual humour, historians have therefore often relied on sociological and psychological studies which depict obscene jokes as a form of aggression, in particular against women. Through a detailed analysis of the obscene jokes recorded by the St. Gallen linen merchant Johannes Rï¿½tiner (1501-1556/7), this article shall propose an alternative perspective on sixteenth-century sexual humour. Based on the premise that in order to get the joke, we need to place it within both its social and cultural context, the analysis of Rï¿½tiner’s joke collection shall be twofold: first, the article will discuss obscene humour as an important element of sociability, in particular among the town’s educated elite. It will also examine how jokes circulated orally and in print, and highlight some of the creative processes and social skills involved in making a successful joke. Subsequently, Rï¿½tiner’s collection of jokes shall be analysed and placed within its broader cultural context. I shall argue that sexual and scatological jokes were closely linked through both medical discourse and a common set of metaphors, and that this type of humour primarily targeted the male body and his fluids. Rather than representing a safety valve for men’s aggressions against women, Rï¿½tiner’s obscene jokes first and foremost offered a platform on which acceptable forms of masculinity could be circumscribed and reaffirmed.
Esomeprazole FDA Approval in Children With GERD
Authors: Earp Justin C. , Mehrotra Nitin , Peters Kristina E. , Fiorentino Robert P. , Griebel Donna , Lee Sue C. , Mulberg Andrew , Röhss Kerstin , Sandström Marie , Taylor Amy , Tornøe Christoffer W. , Wynn Erica L. , Van der Walt Jan‐Stefan , Garnett Christine
Published: November 2016

Objectives:

Food and Drug Administration approval of proton‐pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure‐response and exposure matching analyses were sought to identify approvable pediatric doses.

Methods:

Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady‐state esomeprazole exposures for children at different doses to match the observed exposures in adults.

Results:

Exposure‐response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady‐state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching Cmax values with adults.

Conclusions:

The exposure‐matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure‐response for intragastric pH‐permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.
Plant growth regulators ameliorate or exacerbate abiotic and biotic stress effects on Zea mays kernel weight in a genotype-specific manner
Authors: Stutts Lauren , Wang Yishi , Stapleton Ann E.
Published: November 2016

Plant growth regulators have documented roles in plant responses to single stresses. In combined-stress environments, plants display novel genetic architecture for growth traits and the response to growth regulators is unclear. We investigated the role of plant growth regulators in combined-stress responses in Zea mays. Twelve maize inbreds were exposed to all combinations of the following stressors: drought, nitrogen, and density stress. Chemical treatments were utilized to alter balances of the hormones abscisic acid, gibberellic acid, and brassinosteroids. We found a significant difference between the seed weights of plants given different chemical treatments after accounting for differences in genotype and stress environments. We conclude that plant growth regulators have targets in combined-stress response pathways in Zea mays.

HIGHLIGHT

Plant growth regulators can ameliorate effects of combinations of abiotic and biotic stress in maize, in certain genotypes and under specific stress conditions.
A unified characterization of population structure and relatedness
Authors: Weir Bruce S. , Goudet Jérôme
Published: November 2016

Many population genetic activities, ranging from evolutionary studies to association mapping to forensic identification, rely on appropriate estimates of population structure or relatedness. All applications require recognition that quantities with an underlying meaning of allelic identity by descent are not defined in an absolute sense, but instead are made “relative to” some set of alleles other than the target set. The early Weir and CockerhamFSTestimate made explicit that the reference set of alleles was across independent populations. Standard kinship estimates have an implicit assumption that pairs of individuals in a study sample, other than the target pair, are unrelated, whereas other estimates assume alleles within individuals are not identical by descent. However, populations lose independence when there is migration between them, and when individuals in a study are related it is difficult to see how they can also be non-inbred. We have therefore re-cast our treatments of population structure, relatedness and inbreeding to make explicit that the parameters of interest involve differences of probabilities of identity by descent in the target and the reference sets of alleles and so can be negative. We take the reference set to be for the population from which study individuals have been sampled. We provide simple moment estimates of these parameters, phrased in terms of allele matching within and between individuals for relatedness and inbreeding, or within and between populations for population structure. A multi-level hierarchy of alleles within individuals, alleles between individuals within populations, and alleles between populations allows a unified treatment of relatedness and population structure. Our new estimates appear to be sensitive to rare or private variants, to give indications of the effects of natural selection, and to be appropriate for use in association studies.
GLASS: assisted and standardized assessment of gene variations from Sanger sequence trace data
Authors: Pal Karol , Bystry Vojtech , Reigl Tomas , Demko Martin , Krejci Adam , Touloumenidou Tasoula , Stalika Evangelia , Tichy Boris , Ghia Paolo , Stamatopoulos Kostas , Pospisilova Sarka , Malcikova Jitka , Darzentas Nikos ,   European Research Initiative on CLL (ERIC) – TP53 Network
Published: November 2016

Motivation

Sanger sequencing remains the reference method for sequence variant detection, especially in a clinical setting. However, chromatogram interpretation often requires manual inspection and in some cases considerable expertise. Additionally, variant reporting and nomenclature is typically left to the user, which can lead to inconsistencies.

Results

We introduce GLASS, a tool built to assist with the assessment of gene variations in Sanger sequencing data. Critically, it provides a standardized variant output as recommended by the Human Genome Variation Society.

Availability

The program is freely available online athttp://bat.infspire.org/genomepd/glass/.

Contact

nikos.darzentas@gmail.com,malcikova.jitka@fnbrno.cz

Supplementary information

Supplementary data are available at Bioinformatics online.
Chromatin environment, transcriptional regulation, and splicing distinguish lincRNAs and mRNAs
Authors: Melé Marta , Mattioli Kaia , Mallard William , Shechner David M , Gerhardinger Chiara , Rinn John
Published: November 2016

While long intergenic noncoding RNAs (lincRNAs) and mRNAs share similar biogenesis pathways, these transcript classes differ in many regards. LincRNAs are less evolutionarily conserved, less abundant, and more tissue-specific, suggesting that their pre‐ and post-transcriptional regulation is different from that of mRNAs. Here, we perform an in-depth characterization of the features that contribute to lincRNA regulation in multiple human cell lines. We find that lincRNA promoters are depleted of transcription factor (TF) binding sites, yet enriched for some specific factors such as GATA and FOS relative to mRNA promoters. Surprisingly, we find that H3K9me3—a histone modification typically associated with transcriptional repression—is more enriched at the promoters of active lincRNA loci than at those of active mRNAs. Moreover, H3K9me3-marked lincRNA genes are more tissue-specific. The most discriminant differences between lincRNAs and mRNAs involve splicing. LincRNAs are less efficiently spliced, which cannot be explained by differences in U1 binding or the density of exonic splicing enhancers, but may be partially attributed to lower U2AF65 binding and weaker splicing–related motifs. Conversely, the stability of lincRNAs and mRNAs is similar, differing only with regard to the location of stabilizing protein binding sites. Finally, we find that certain transcriptional properties are correlated with higher evolutionary conservation in both DNA and RNA motifs, and are enriched in lincRNAs that have been functionally characterized.
A SIMPLE pipeline for mapping point mutations
Authors: Wachsman Guy , Modliszewski Jennifer L. , Valdes Manuel , Benfey Philip N.
Published: November 2016

A forward genetic screen is one of the best methods for revealing the regulatory functions of genes. In plants, this technique is highly efficient since it is relatively easy to grow and screen the phenotypes of hundreds or thousands of individuals. The cost-efficiency and ease of data production afforded by next-generation sequencing techniques have created new opportunities for mapping induced mutations. The principles of genetic mapping remain the same. However, the details have changed, which allows for rapid mapping of causal mutations. Current mapping tools are often not user-friendly and complicated or require extensive preparation steps. To simplify the process of mapping new mutations, we developed a pipeline that takes next generation sequencing fastq files as input, calls on several well-established and freely available genome-analysis tools, and outputs the most likely causal DNA change(s). The pipeline has been validated in Arabidopsis and can be readily applied to other species.
Pulse of α-2-macroglobulin and lipocalin-1 in the pregnant uterus of European polecats (Mustela putorius) at the time of implantation
Authors: Lindeberg Heli , Burchmore Richard J.S. , Kennedy Malcolm W.
Published: November 2016

Uterine secretory proteins protect the uterus and conceptuses against infection, facilitate implantation, control cellular damage resulting from implantation, and supply embryos with nutrients. The early conceptus of the European polecat (Mustela putorius) grows and develops free in the uterus until implanting at about 12 days after mating. Using a proteomics approach we found that the proteins appearing in the uterus leading up to and including the time of implantation changed dramatically with time. Several of the proteins identified have been found in pregnant uteri of other placental mammals, such as α1-antitrypsin, serum albumin, lactoferrin, cathepsin L1, uteroferrin, and ectonucleotide pyrophosphatase. The broad-spectrum proteinase inhibitor α2-macroglobulin rose from relatively low abundance initially to dominate the protein profile by the time of implantation. Its functions may be to limit damage caused by the release of proteinases during implantation, and to control other processes around the site of implantation. Lipocalin-1 (also known as tear lipocalin) has not previously been recorded as a uterine secretion in pregnancy, and also increased substantially in concentration. If polecat lipocalin-1 has similar biochemical properties to the human form, then it may have a combined function in transporting or scavenging lipids, and antimicrobial activities. The changes in the uterine secretory proteome of Euroepan polecats may be similar in those species of mustelid that engage in embryonic diapause, but possibly only following reactivation of the embryo.
An icosahedral virus as a fluorescent calibration standard: a method for counting protein molecules in cells by fluorescence microscopy
Authors: Murray John M.
Published: November 2016

The ability to replace genes coding for cellular proteins with DNA that codes for fluorescent protein-tagged versions opens the way to counting the number of molecules of each protein component of macromolecular assembliesin vivoby measuring fluorescence microscopically. Converting fluorescence to absolute numbers of molecules requires a fluorescent standard whose molecular composition is known precisely. In this report the construction, properties, and mode of using a set of fluorescence calibration standards are described. The standards are based on an icosahedral virus engineered to contain exactly 240 copies of one of seven different fluorescent proteins. Two applications of the fluorescent standards to counting molecules in the human parasiteToxoplasma gondiiare described. Methods for improving the preciseness of the measurements and minimizing potential inaccuracies are emphasized.

Lay Abstract

A broad goal of modern biology is to understand how the machines within living cells work. It is nowadays routine to identify the individual protein components of a machine, but not yet straightforward to tell how many copies of each component are needed to build a functional assembly. In many types of cells it is now possible to substitute for the native proteins within cells altered versions that are fluorescent. If one knew how much fluorescence is generated by a single molecule of the altered protein, then one could use a light microscope to count the number of copies of the protein in a cellular machine by simply measuring the total fluorescence coming from that part of the cell. This paper describes the construction and methods for using a set of fluorescent virus particles that can be used to determine how much fluorescence is contributed by one molecule of fluorescent protein. The virus particles were chosen for this role because the particular icosahedral symmetry of their structure guarantees that each particle contains exactly 240 copies of one fluorescent protein.
Detecting differential growth of microbial populations with Gaussian process regression
Authors: Tonner Peter D. , Darnell Cynthia L. , Engelhardt Barbara E. , Schmid Amy K.
Published: November 2016

Microbial growth curves are used to study differential effects of media, genetics, and stress on microbial population growth. Consequently, many modeling frameworks exist to capture microbial population growth measurements. However, current models are designed to quantify growth under conditions for which growth has a specific functional form. Extensions to these models are required to quantify the effects of perturbations, which often exhibit nonstandard growth curves. Rather than assume specific functional forms for experimental perturbations, we developed a general and robust model of microbial population growth curves using Gaussian process (GP) regression. GP regression modeling of high-resolution time-series growth data enables accurate quantification of population growth and allows explicit control of effects from other covariates such as genetic background. This framework substantially outperforms commonly used microbial population growth models, particularly when modeling growth data from environmentally stressed populations. We apply the GP growth model and develop statistical tests to quantify the differential effects of environmental perturbations on microbial growth across a large compendium of genotypes in archaea and yeast. This method accurately identifies known transcriptional regulators and implicates novel regulators of growth under standard and stress conditions in the model archaeal organism Halobacterium salinarum. For yeast, our method correctly identifies known phenotypes for a diversity of genetic backgrounds under cyclohexamide stress and also detects previously unidentified oxidative stress sensitivity across a subset of strains. Together, these results demonstrate that the GP models are interpretable, recapitulating biological knowledge of growth response while providing new insights into the relevant parameters affecting microbial population growth.
Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes
Authors: Lawlor Nathan , George Joshy , Bolisetty Mohan , Kursawe Romy , Sun Lili , Sivakamasundari V. , Kycia Ina , Robson Paul , Stitzel Michael L.
Published: November 2016

Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type–specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.
Pediatric case of anaplastic lymphoma kinase‐positive anaplastic large cell lymphoma forming a solitary skin tumor on the forearm
Authors: Tokuyama Michio , Kurashige Yuta , Ota Tami , Manabe Yasuaki , Yamaoka Hanako , Ikoma Norihiro , Fukumura Akiko , Miyashita Michie , Otsubo Keisuke , Morimoto Tsuyoshi , Mochizuki Hiroyuki , Nakano Natsuko , Nakamura Naoya , Ozawa Akira , Mabuchi Tomotaka
Published: November 2016

A 5‐year‐old girl noticed a rapidly growing reddish nodule on her right forearm. Although oral antibiotics had been administrated for 2 weeks, the tumor enlarged. Skin biopsy revealed excessive infiltration of atypical neoplastic cells expressing CD4, CD30 and anaplastic lymphoma kinase (ALK). These histological and immunohistochemical findings were consistent with anaplastic large cell lymphoma (ALCL). Computed tomography showed multiple lymphadenopathy, but lymph node biopsy and bone marrow examination did not show any evidence of systemic dissemination. However, due to the positive results for ALK and multiple lymphadenopathy, we diagnosed ALK‐positive ALCL forming a solitary skin tumor on the forearm. The patient received chemotherapy and presented marked improvement. This paper discusses the difficulty of diagnosing pediatric ALK‐positive ALCL limited to the skin and reviews the medical published work.
Maternal Na+ intake induces renal function injury in rats prevented by a short‐term angiotensin converting enzyme inhibitor
Authors: Ribeiro Natalie E , Cabral Edjair V , Aires Regina S , Vieira‐Filho Leucio D , Ribeiro Valdilene S , Gonçalves Daianna RM , Borges Luis PNC , Melo Ismaela MF , Ferreira Cintia GM , Wanderley‐Teixeira Valeria , Teixeira Álvaro AC , Soares Anísio F , Paixão Ana D
Published: November 2016

The Na+‐ATPase, a secondary pump in the proximal tubule, is only weakly responsive to angiotensin II in adult offspring exposed perinatally to high Na+ intake. We have investigated whether the offspring from mothers given 0.3 mol/L NaCl show an ineffective angiotensin II action to increase in blood pressure. It was hypothesized that functional alterations at adult life are associated with the number of angiotensin II‐positive cells in the developing kidney, with increased oxidative stress in maternal/foetal organs, or with morphometrical changes in placentas. Wistar female rats were maintained on 0.3 mol/L NaCl in their drinking water from 20 days before conception until weaning. After weaning, some of the male offspring were treated with enalapril for 21 days. Glomerular filtration rate was recorded up to 210 days of age, when mean arterial pressure was measured after infusion of angiotensin II. To investigate the placenta and foetal kidneys, mothers on tap water or NaCl were also treated with alpha‐tocopherol, pregnancy being interrupted on the 20th day. There were no changes in the number of cells positive for angiotensin II in the foetal kidney and unchanged lipid peroxidation in the placenta of offspring exposed to NaCl, but the intermediate trophoblast area in the junctional zone was increased, possibly reducing maternal–foetal exchange. Glomerular filtration rate was reduced and there was an attenuated effect of angiotensin II on elevation of blood pressure, which could be mediated by an elevated angiotensin II during early life, once these disturbances had been prevented by early and short‐term treatment with enalapril.
Reduction of the foreign body response and neuroprotection by apyrase and minocycline in chronic cannula implantation in the rat brain
Authors: Hayn Linda , Deppermann Linda , Koch Michael
Published: November 2016

Implantation of electrodes or cannulae into the brain is accompanied by a tissue response referred to as foreign body response. Adenosine triphosphate (ATP) is one of the signalling molecules released by injured cells which mediate the chemoattraction of microglial cells. The constitutive release of pro‐inflammatory and cytotoxic substances by microglial cells in chronic implants exacerbates neuronal cell death and the immune response. This study aimed to interfere with the initial events of the foreign body response in order to mitigate neurotoxicity and inflammation. For this purpose, the ATP‐hydrolysing enzyme apyrase and the antibiotic minocycline with a broad range of anti‐inflammatory, anti‐apoptotic and glutamate‐antagonist properties were locally infused during cannula implantation in the caudal forelimb area of the motor cortex in Lister Hooded rats. The rats’ motor performance was assessed in a skilled reaching task and the distribution of neurons and glial cells in the vicinity of the implant was examined 2 and 6 weeks post‐implantation. Apyrase as well as minocycline increased the number of surviving neurons and reduced microglial activation. Moreover, minocycline improved the motor performance and, additionally, caused a temporary reduction in astrogliosis, suggesting it as a possible therapeutic candidate to improve the biocompatibility of chronic brain implants.
Delivering Public Services: Locality, Learning and Reciprocity in Place Based Practice
Authors: Marsh Ian , Crowley Kate , Grube Dennis , Eccleston Richard
Published: November 2016

Policymakers across myriad jurisdictions are grappling with the challenge of complex policy problems. Multi‐faceted, complex, and seemingly intractable, ‘wicked’ problems have exhausted the repertoire of the standard policy approaches. In response, governments are increasingly looking for new options, and one approach that has gained significant scholarly interest, along with increasing attention from practitioners, is ‘place‐based’ solutions. This paper surveys conceptual aspects of this approach. It describes practices in comparable jurisdictions – the United Kingdom, the EU, and the United States. And it explores efforts over the past decade to ‘localise’ Indigenous services. It sketches the governance challenge in migrating from top‐down or principal‐agent arrangements towards place‐based practice. The paper concludes that many of the building blocks for this shift already exist but that these need to be re‐oriented around ‘learning’. Funding and other administrative protocols may also ultimately need to be redefined.
Risk of psychiatric disorders, self‐harm behaviour and service use associated with bariatric surgery
Authors: Kovacs Z. , Valentin J. B. , Nielsen R. E.
Published: November 2016

Objective

To investigate psychiatric outcomes after bariatric surgery, including suicide, self‐harm, psychiatric service use and substance misuse.

Method

Retrospective study on a Danish nationwide register‐based cohort of 22 451 patients followed for 1 029 736 person‐years. Data were analysed utilizing single‐ and multi‐event Cox regression with non‐operated controls with obesity and mirror‐image analyses with the operated patient serving as their own controls.

Results

We showed an increased ratio of self‐harm (hazard ratio [HR] 3.23, P < 0.001; incidence rate ratio [IRR] 1.71, P < 0.001), psychiatric service use (admissions IRR 1.52, P < 0.001; emergency room visits IRR 1.70, P < 0.001), psychiatric diagnosis (organic psychiatric disorders HR 1.78, P < 0.001; substance use HR 2.06, P < 0.001; mood disorders HR 2.66, P < 0.001; neurotic, stress‐related and somatoform disorders HR 2.48, P < 0.001; behavioural syndromes HR 3.15, P < 0.001; disorders of personality HR 2.68, P < 0.001; behavioural and emotional disorders HR 6.43, P < 0.001), as well as substance misuse utilizing Cox regression as well as mirror‐image analyses, as compared to non‐operated. We did not find an increased suicide rate (HR 1.35, P = 0.658) among operated as compared to non‐operated.

Conclusion

Our study shows that undergoing bariatric surgery is associated with increases in self‐harm, psychiatric service use and occurrence of mental disorders.
Cannabis use during treatment for alcohol use disorders predicts alcohol treatment outcomes
Authors: Subbaraman Meenakshi Sabina , Metrik Jane , Patterson Deidre , Swift Robert
Published: November 2016

Aims

To compare post‐treatment alcohol use between those who use cannabis and those who abstain during treatment for alcohol use disorders (AUD); and to examine potential cannabis use thresholds by comparing post‐treatment alcohol use between four frequency groups of cannabis users relative to abstainers.

Design

Secondary analyses of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, a randomized control trial of AUD treatments. The current study compares longitudinal drinking data between those who used cannabis versus those who abstained during COMBINE treatment.

Setting

The COMBINE Study treatments were delivered on an out‐patient basis for 16 weeks. The current analyses include 206 cannabis users and 999 cannabis abstainers.

Participants

All participants met diagnosis of primary alcohol dependence (n = 1383).

Measurements

Primary exposures were any cannabis use and quartiles of cannabis use (Q1: 1–4 use days during treatment, Q2: 5–9 days, Q3: 10–44 days, Q4: 45–112 days). Outcomes were percentage of days abstinent from alcohol (PDA), drinks per drinking day (DPDD) and percentage of heavy drinking days (PHD), all measured at treatment end and 1 year post‐treatment.

Findings

Compared with no cannabis use, any cannabis use during treatment was associated with 4.35% [95% confidence interval (CI) = –8.68, −0.02], or approximately 4 fewer alcohol abstinent days at the end of treatment. This association weakened by 1 year post‐treatment (95% CI = –9.78, 0.54). Compared with no cannabis use, only those in the second quartile of cannabis use (those who used once or twice per month during treatment) had 8.81% (95% CI = –17.00, −0.63), or approximately 10 fewer days alcohol abstinent at end of treatment, and 11.82% (95% CI = –21.56, −2.07), or approximately 13 fewer alcohol abstinent days 1 year post‐treatment. Neither any cannabis use nor quartiles were associated with DPDD or PHD at either time‐point.

Conclusions

Among individuals in alcohol treatment, any cannabis use (compared with none) is related to a significantly lower percentage of days abstinent from alcohol post‐treatment, although only among those who used cannabis once or twice per month.
Alcohol consumption during adolescence is associated with reduced grey matter volumes
Authors: Heikkinen Noora , Niskanen Eini , Könönen Mervi , Tolmunen Tommi , Kekkonen Virve , Kivimäki Petri , Tanila Heikki , Laukkanen Eila , Vanninen Ritva
Published: November 2016

Background and aims

Cognitive impairment has been associated with excessive alcohol use, but its neural basis is poorly understood. Chronic excessive alcohol use in adolescence may lead to neuronal loss and volumetric changes in the brain. Our objective was to compare the grey matter volumes of heavy‐ and light‐drinking adolescents.

Design

This was a longitudinal study: heavy‐drinking adolescents without an alcohol use disorder and their light‐drinking controls were followed‐up for 10 years using questionnaires at three time‐points. Magnetic resonance imaging was conducted at the last time‐point.

Setting

The area near Kuopio University Hospital, Finland.

Participants

The 62 participants were aged 22–28 years and included 35 alcohol users and 27 controls who had been followed‐up for approximately 10 years.

Measurements

Alcohol use was measured by the Alcohol Use Disorders Identification Test (AUDIT)‐C at three time‐points during 10 years. Participants were selected based on their AUDIT‐C score. Magnetic resonance imaging was conducted at the last time‐point. Grey matter volume was determined and compared between heavy‐ and light‐drinking groups using voxel‐based morphometry on three‐dimensional T1‐weighted magnetic resonance images using predefined regions of interest and a threshold of P < 0.05, with small volume correction applied on cluster level.

Findings

Grey matter volumes were significantly smaller among heavy‐drinking participants in the bilateral anterior cingulate cortex, right orbitofrontal and frontopolar cortex, right superior temporal gyrus and right insular cortex compared to the control group (P < 0.05, family‐wise error‐corrected cluster level).

Conclusions

Excessive alcohol use during adolescence appears to be associated with an abnormal development of the brain grey matter. Moreover, the structural changes detected in the insula of alcohol users may reflect a reduced sensitivity to alcohol's negative subjective effects.