bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of associations between genotypes and longitudinal phenotypes via temporally-constrained group sparse canonical correlation analysis
Authors: Hao Xiaoke , Li Chanxiu , Yan Jingwen , Yao Xiaohui , Risacher Shannon L , Saykin Andrew J , Shen Li , Zhang Daoqiang ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2017

Motivation

Neuroimaging genetics identifies the relationships between genetic variants (i.e., the single nucleotide polymorphisms) and brain imaging data to reveal the associations from genotypes to phenotypes. So far, most existing machine-learning approaches are widely used to detect the effective associations between genetic variants and brain imaging data at one time-point. However, those associations are based on static phenotypes and ignore the temporal dynamics of the phenotypical changes. The phenotypes across multiple time-points may exhibit temporal patterns that can be used to facilitate the understanding of the degenerative process. In this article, we propose a novel temporally constrained group sparse canonical correlation analysis (TGSCCA) framework to identify genetic associations with longitudinal phenotypic markers.

Results

The proposed TGSCCA method is able to capture the temporal changes in brain from longitudinal phenotypes by incorporating the fused penalty, which requires that the differences between two consecutive canonical weight vectors from adjacent time-points should be small. A new efficient optimization algorithm is designed to solve the objective function. Furthermore, we demonstrate the effectiveness of our algorithm on both synthetic and real data (i.e., the Alzheimer’s Disease Neuroimaging Initiative cohort, including progressive mild cognitive impairment, stable MCI and Normal Control participants). In comparison with conventional SCCA, our proposed method can achieve strong associations and discover phenotypic biomarkers across multiple time-points to guide disease-progressive interpretation.

Availability and implementation

The Matlab code is available at https://sourceforge.net/projects/ibrain-cn/files/.
Direct AUC optimization of regulatory motifs
Authors: Zhu Lin , Zhang Hong-Bo , Huang De-Shuang
Published: April 2017

Motivation

The discovery of transcription factor binding site (TFBS) motifs is essential for untangling the complex mechanism of genetic variation under different developmental and environmental conditions. Among the huge amount of computational approaches for de novo identification of TFBS motifs, discriminative motif learning (DML) methods have been proven to be promising for harnessing the discovery power of accumulated huge amount of high-throughput binding data. However, they have to sacrifice accuracy for speed and could fail to fully utilize the information of the input sequences.

Results

We propose a novel algorithm called CDAUC for optimizing DML-learned motifs based on the area under the receiver-operating characteristic curve (AUC) criterion, which has been widely used in the literature to evaluate the significance of extracted motifs. We show that when the considered AUC loss function is optimized in a coordinate-wise manner, the cost function of each resultant sub-problem is a piece-wise constant function, whose optimal value can be found exactly and efficiently. Further, a key step of each iteration of CDAUC can be efficiently solved as a computational geometry problem. Experimental results on real world high-throughput datasets illustrate that CDAUC outperforms competing methods for refining DML motifs, while being one order of magnitude faster. Meanwhile, preliminary results also show that CDAUC may also be useful for improving the interpretability of convolutional kernels generated by the emerging deep learning approaches for predicting TF sequences specificities.

Availability and Implementation

CDAUC is available at: https://drive.google.com/drive/folders/0BxOW5MtIZbJjNFpCeHlBVWJHeW8.

Supplementary information

Supplementary data are available at Bioinformatics online.
Laboratory x-ray micro-computed tomography: a user guideline for biological samples
Authors: du Plessis Anton , Broeckhoven Chris , Guelpa Anina , le Roux Stephan Gerhard
Published: April 2017

Laboratory x-ray micro–computed tomography (micro-CT) is a fast-growing method in scientific research applications that allows for non-destructive imaging of morphological structures. This paper provides an easily operated “how to” guide for new potential users and describes the various steps required for successful planning of research projects that involve micro-CT. Background information on micro-CT is provided, followed by relevant setup, scanning, reconstructing, and visualization methods and considerations. Throughout the guide, a Jackson's chameleon specimen, which was scanned at different settings, is used as an interactive example. The ultimate aim of this paper is make new users familiar with the concepts and applications of micro-CT in an attempt to promote its use in future scientific studies.
Demixing sines and spikes: Robust spectral super-resolution in the presence of outliers
Authors: Fernandez-Granda Carlos , Tang Gongguo , Wang Xiaodong , Zheng Le
Published: April 2017

We consider the problem of super-resolving the line spectrum of a multisinusoidal signal from a finite number of samples, some of which may be completely corrupted. Measurements of this form can be modeled as an additive mixture of a sinusoidal and a sparse component. We propose to demix the two components and super-resolve the spectrum of the multisinusoidal signal by solving a convex program. Our main theoretical result is that—up to logarithmic factors—this approach is guaranteed to be successful with high probability for a number of spectral lines that is linear in the number of measurements, even if a constant fraction of the data are outliers. The result holds under the assumption that the phases of the sinusoidal and sparse components are random and the line spectrum satisfies a minimum-separation condition. We show that the method can be implemented via semi-definite programming, and explain how to adapt it in the presence of dense perturbations as well as exploring its connection to atomic-norm denoising. In addition, we propose a fast greedy demixing method that provides good empirical results when coupled with a local non-convex-optimization step.
Risk of Acute Liver Injury With Antiretroviral Therapy by Viral Hepatitis Status
Authors: Gowda Charitha , Newcomb Craig W. , Liu Qing , Carbonari Dena M. , Lewis James D. , Forde Kimberly A. , Goldberg David S. , Reddy K. Rajender , Roy Jason A. , Marks Amy R. , Schneider Jennifer L. , Kostman Jay R. , Tate Janet P. , Lim Joseph K. , Justice Amy C. , Goetz Matthew Bidwell , Corley Douglas A. , Lo Re Vincent
Published: April 2017

Background

The risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status.

Methods

We followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status.

Results

Liver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P < .001). No evidence of differential risk was found between initiators of abacavir/lamivudine versus tenofovir/emtricitabine among coinfected (HR, 0.68; 95% CI, .29–1.57) or HIV-monoinfected (HR, 1.19; 95% CI, .47–2.97) groups. Coinfected patients had a higher risk of aminotransferases >200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36–2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P < .001) but was too uncommon to evaluate in adjusted analyses.

Conclusions

Within the year after ART initiation, aminotransferase elevations were infrequently observed and rarely led to severe ALI. Protease inhibitor use was associated with a higher risk of aminotransferase elevations among viral hepatitis-coinfected patients.
Powerful Inference with the D-statistic on Low-Coverage Whole-Genome Data
Authors: Soraggi Samuele , Wiuf Carsten , Albrechtsen Anders
Published: April 2017

The detection of ancient gene flow between human populations is an important issue in population genetics. A common tool for detecting ancient admixture events is the D-statistic. The D-statistic is based on the hypothesis of a genetic relationship that involves four populations, whose correctness is assessed by evaluating specific coincidences of alleles between the groups.

When working with high throughput sequencing data calling genotypes accurately is not always possible, therefore the D-statistic currently samples a single base from the reads of one individual per population. This implies ignoring much of the information in the data, an issue especially striking in the case of ancient genomes.

We provide a significant improvement to overcome the problems of the D-statistic by considering all reads from multiple individuals in each population. We also apply type-specific error correction to combat the problems of sequencing errors and show a way to correct for introgression from an external population that is not part of the supposed genetic relationship, and how this leads to an estimate of the admixture rate.

We prove that the D-statistic is approximated by a standard normal. Furthermore we show that our method outperforms the traditional D-statistic in detecting admixtures. The power gain is most pronounced for low/medium sequencing depth (1-10X) and performances are as good as with perfectly called genotypes at a sequencing depth of 2X. We show the reliability of error correction on scenarios with simulated errors and ancient data, and correct for introgression in known scenarios to estimate the admixture rates.
Chemotaxonomic characterisation of the thaumarchaeal lipidome
Authors: Elling Felix J. , Könneke Martin , Nicol Graeme W. , Stieglmeier Michaela , Bayer Barbara , Spieck Eva , de la Torre José R. , Becker Kevin W. , Thomm Michael , Prosser James I. , Herndl Gerhard J. , Schleper Christa , Hinrichs Kai‐Uwe
Published: April 2017

Thaumarchaeota are globally distributed and abundant microorganisms occurring in diverse habitats and thus represent a major source of archaeal lipids. The scope of lipids as taxonomic markers in microbial ecological studies is limited by the scarcity of comparative data on the membrane lipid composition of cultivated representatives, including the phylum Thaumarchaeota. Here, we comprehensively describe the core and intact polar lipid (IPL) inventory of ten ammonia‐oxidising thaumarchaeal cultures representing all four characterized phylogenetic clades. IPLs of these thaumarchaeal strains are generally similar and consist of membrane‐spanning, glycerol dibiphytanyl glycerol tetraethers with monoglycosyl, diglycosyl, phosphohexose and hexose‐phosphohexose headgroups. However, the relative abundances of these IPLs and their core lipid compositions differ systematically between the phylogenetic subgroups, indicating high potential for chemotaxonomic distinction of thaumarchaeal clades. Comparative lipidomic analyses of 19 euryarchaeal and crenarchaeal strains suggested that the lipid methoxy archaeol is synthesized exclusively by Thaumarchaeota and may thus represent a diagnostic lipid biomarker for this phylum. The unprecedented diversity of the thaumarchaeal lipidome with 118 different lipids suggests that membrane lipid composition and adaptation mechanisms in Thaumarchaeota are more complex than previously thought and include unique lipids with as yet unresolved properties.
Robustness of a model microbial community emerges from population structure among single cells of a clonal population
Authors: Thompson Anne W. , Turkarslan Serdar , Arens Christina E. , López García de Lomana Adrián , Raman Arjun V. , Stahl David A. , Baliga Nitin S.
Published: April 2017

Microbial populations can withstand, overcome and persist in the face of environmental fluctuation. Previously, we demonstrated how conditional gene regulation in a fluctuating environment drives dilution of condition‐specific transcripts, causing a population of Desulfovibrio vulgaris Hildenborough (DvH) to collapse after repeatedly transitioning from sulfate respiration to syntrophic conditions with the methanogen Methanococcus maripaludis. Failure of the DvH to successfully transition contributed to the collapse of this model community. We investigated the mechanistic basis for loss of robustness by examining whether conditional gene regulation altered heterogeneity in gene expression across individual DvH cells. We discovered that robustness of a microbial population across environmental transitions was attributable to the retention of cells in two states that exhibited different condition‐specific gene expression patterns. In our experiments, a population with disrupted conditional regulation successfully alternated between cell states. Meanwhile, a population with intact conditional regulation successfully switched between cell states initially, but collapsed after repeated transitions, possibly due to the high energy requirements of regulation. These results demonstrate that the survival of this entire model microbial community is dependent on the regulatory system's influence on the distribution of distinct cell states among individual cells within a clonal population.
Natural resource landscapes of a marine bacterium reveal distinct fitness‐determining genes across the genome
Authors: Takemura Alison F. , Corzett Christopher H. , Hussain Fatima , Arevalo Philip , Datta Manoshi , Yu Xiaoqian , Le Roux Frederique , Polz Martin F.
Published: April 2017

Heterotrophic bacteria exploit diverse microhabitats in the ocean, from particles to transient gradients. Yet the degree to which genes and pathways can contribute to an organism's fitness on such complex and variable natural resource landscapes remains poorly understood. Here, we determine the gene‐by‐gene fitness of a generalist saprophytic marine bacterium (Vibrio sp. F13 9CS106) on complex resources derived from its natural habitats – copepods (Apocyclops royi) and brown algae (Fucus vesiculosus) – and as reference substrates, glucose and the polysaccharide alginate, derived from brown algal cell walls. We find that resource complexity strongly buffers fitness costs of mutations, and that anabolic rather than catabolic pathways are more stringently required, likely due to functional redundancy in the latter. Moreover, while carbohydrate‐rich algae requires several synthesis pathways, protein‐rich Apocyclops does not, suggesting this ancestral habitat for Vibrios is a replete medium with metabolically redundant substrates. We also identify a candidate fitness trade‐off for algal colonization: deletion of mshA increases mutant fitness. Our results demonstrate that gene fitness depends on habitat composition, and suggest that this generalist uses distinct resources in different natural habitats. The results further indicate that substrate replete conditions may lead to relatively relaxed selection on catabolic genes.
Microbial ecology of mountain glacier ecosystems: biodiversity, ecological connections and implications of a warming climate
Authors: Hotaling Scott , Hood Eran , Hamilton Trinity L.
Published: April 2017

Glacier ecosystems are teeming with life on, beneath, and to a lesser degree, within their icy masses. This conclusion largely stems from polar research, with less attention paid to mountain glaciers that overlap environmentally and ecologically with their polar counterparts in some ways, but diverge in others. One difference lies in the susceptibility of mountain glaciers to the near‐term threat of climate change, as they tend to be much smaller in both area and volume. Moreover, mountain glaciers are typically steeper, more dependent upon basal sliding for movement, and experience higher seasonal precipitation. Here, we provide a modern synthesis of the microbial ecology of mountain glacier ecosystems, and particularly those at low‐ to mid‐latitudes. We focus on five ecological zones: the supraglacial surface, englacial interior, subglacial bedrock–ice interface, proglacial streams and glacier forefields. For each, we discuss the role of microbiota in biogeochemical cycling and outline ecological and hydrological connections among zones, underscoring the interconnected nature of these ecosystems. Collectively, we highlight the need to: better document the biodiversity and functional roles of mountain glacier microbiota; describe the ecological implications of rapid glacial retreat under climate change and resolve the relative contributions of ecological zones to broader ecosystem function.
Do State Continuing Medical Education Requirements for Physicians Improve Clinical Knowledge?
Authors: Vandergrift Jonathan L. , Gray Bradley M. , Weng Weifeng
Published: April 2017

Objective

To evaluate the effect of state continuing medical education (CME) requirements on physician clinical knowledge.

Data Sources

Secondary data for 19,563 general internists who took the Internal Medicine Maintenance of Certification (MOC) examination between 2006 and 2013.

Study Design

We took advantage of a natural experiment resulting from variations in CME requirements across states over time and applied a difference‐in‐differences methodology to measure associations between changes in CME requirements and physician clinical knowledge. We measured changes in clinical knowledge by comparing initial and MOC examination performance 10 years apart. We constructed difference‐in‐differences estimates by regressing examination performance changes against physician demographics, county and year fixed effects, trend–state indicators, and state CME change indicators.

Data Collection

Physician data were compiled by the American Board of Internal Medicine. State CME policies were compiled from American Medical Association reports.

Principal Findings

More rigorous CME credit‐hour requirements (mostly implementing a new requirement) were associated with an increase in examination performance equivalent to a shift in examination score from the 50th to 54th percentile.

Conclusions

Among physicians required to engage in a summative assessment of their clinical knowledge, CME requirements were associated with an improvement in physician clinical knowledge.
Comparison of safety and efficacy of image‐guided enema reduction techniques for paediatric intussusception: A review of the literature
Authors: Chew Renny , Ditchfield Michael , Paul Eldho , Goergen Stacy K
Published: April 2017

There is variable international practice regarding the technique used for image‐guided enema reduction in paediatric intussusception. A recent meta‐analysis found pneumatic reduction to be more effective than hydrostatic techniques. Clinical practice variation may impact on perforation rates, ionizing radiation exposure and requirement for surgery. The aim of this study was to review the literature regarding the efficacy and safety of fluoroscopically guided pneumatic reduction (FGPR) compared to ultrasound (US) guided intussusception reduction (USGIR) techniques for paediatric intussusception treatment. Articles were identified by searching OVID Medline on 21/02/14 and by scanning retrieved articles reference lists. The search was repeated on 30/09/15. Systematic reviews (SR) were appraised with the PRISMA critical appraisal tool. Primary studies underwent a separate critical appraisal process. Successful reductions and perforations per attempt were calculated for each study. Pooled estimates of proportions were calculated for each of these dichotomous outcomes. A SR and 42 primary studies were included in the review. No randomised control trial (RCT) study was included. Non‐randomised comparative studies and non‐comparative studies suggest that hydrostatic reduction under US control has a similar efficacy and safety profile to pneumatic reduction under fluoroscopic control, but USGIR data are dominated by a single large, non‐comparative study performed in China. US‐guided intussusception reduction should be considered an alternative to FGPR as it has similar efficacy and safety, and affords no ionised radiation exposure. However, RCT data are required to inform practice.
Comparison of Emergency Department Patients to Inpatients Receiving a Pulmonary Embolism Response Team (PERT) Activation
Authors: Deadmon Erin K. , Giordano Nicholas J. , Rosenfield Kenneth , Rosovsky Rachel , Parry Blair Alden , Al‐Bawardy Rasha Fahad , Chang Yuchiao , Kabrhel Christopher
Published: April 2017

Objectives

The development of pulmonary embolism response teams (PERTs) has been widely adopted nationally with the goal of providing multidisciplinary care to patients with high‐risk PE. Most PERT activations originate from the emergency department (ED), while others are from the intensive care unit (ICU) or inpatient floors. It is unclear if ED PERT activations differ from non‐ED PERT activation in terms of presentation, management, and outcome.

Methods

We enrolled a consecutive cohort of patients for whom PERT was activated at an urban academic medical center. We compared three groups of PERT activations based on whether the activation originated from the ED, ICU, or a non‐ICU inpatient floor. We compared these groups in terms of the proportion of PERT activations that occurred during day, evening, or weekend hours and the proportion of confirmed PE. We also compared PE severity, treatment, and outcomes across locations. We tested differences using chi‐square tests, with a two‐tailed p‐value of <0.05 considered statistically significant.

Results

We enrolled 561 patients, of whom 449 (79.5%) had confirmed PE. The mean ± SD age of patients with confirmed PE was 61 ± 17 years, and 300 (53.5%) were male. Activations from the ED (n = 283, 88.4%) or floor (n = 100, 74.6%) were more likely to be for confirmed PE than activations from the ICU (n = 63, 58.9%; p < 0.0001). There was a statistical difference in the time of day of PERT activation with the ED having more activations during night hours than the ICU or floors (p = 0.004). Most activations for confirmed, massive PE originated from the ICU (n = 41, 65.1%), followed by the ED (n = 82, 29%) and inpatient floors (n = 22, 22%; p < 0.0001). Most activations from the ED (n = 155, 54.8%) and floors (n = 55, 55%) were for submassive PE. The use of thrombolysis or thrombectomy was more common among ICU patients (n = 18, 33.3%), followed by ED patients (n = 53, 19.6%) and then floor patients (n = 8, 8.2%). Mortality and major bleeding events were most common among ICU patients and similar among ED and floor patients.

Conclusions

Pulmonary embolism response team activations from different clinical locations differ in terms of patient presentation, PE confirmation, treatments, and outcomes. PERTs should be customized to support the different needs of each clinical area.
The involuntary nature of binge drinking: goal directedness and awareness of intention
Authors: Doñamayor Nuria , Strelchuk Daniela , Baek Kwangyeol , Banca Paula , Voon Valerie
Published: April 2017

Binge drinking represents a public health issue and is a known risk factor in the development of alcohol use disorders. Previous studies have shown behavioural as well as neuroanatomical alterations associated with binge drinking. Here, we address the question of the automaticity or involuntary nature of the behaviour by assessing goal‐directed behaviour and intentionality. In this study, we used a computational two‐step task, designed to discern between model‐based/goal‐directed and model‐free/habitual behaviours, and the classic Libet clock task, to study intention awareness, in a sample of 31 severe binge drinkers (BD) and 35 matched healthy volunteers. We observed that BD had impaired goal‐directed behaviour in the two‐step task compared with healthy volunteers. In the Libet clock task, BD showed delayed intention awareness. Further, we demonstrated that alcohol use severity, as reflected by the alcohol use disorders identification test, correlated with decreased conscious awareness of volitional intention in BD, although it was unrelated to performance on the two‐step task. However, the time elapsed since the last drinking binge influenced the model‐free scores, with BD showing less habitual behaviour after longer abstinence. Our findings suggest that the implementation of goal‐directed strategies and the awareness of volitional intention are affected in current heavy alcohol users. However, the modulation of these impairments by alcohol use severity and abstinence suggests a state effect of alcohol use in these measures and that top‐down volitional control might be ameliorated with alcohol use cessation.
Suvorexant, an orexin/hypocretin receptor antagonist, attenuates motivational and hedonic properties of cocaine
Authors: Gentile Taylor A. , Simmons Steven J. , Barker David J. , Shaw Jessica K. , España Rodrigo A. , Muschamp John W.
Published: April 2017

Orexins (‘hypocretins’) are peptides produced by neurons of the hypothalamus that project to structures implicated in reward and emotion processing. Converging evidence demonstrates functional roles of orexin signaling in arousal, sleep/wakefulness and motivated behaviors for natural and drug rewards. Suvorexant, a dual orexin receptor antagonist, recently received approval from the US Food and Drug Administration to treat insomnia. In Experiment 1, rats self‐administered cocaine under a progressive‐ratio schedule of reinforcement and the effects of suvorexant on motivation to self‐administer cocaine were measured. In Experiment 2, the effects of suvorexant on cocaine reward were assessed by using a place conditioning paradigm, and 50‐kHz ultrasonic vocalizations were also recorded to track changes in hedonic reactivity to cocaine. To rule out potentially confounding effects of suvorexant‐induced somnolence, locomotor activity was also measured. In Experiment 3, the effects of suvorexant on cocaine‐evoked elevations in ventral striatal dopamine were examined. Data reveal that suvorexant (i) reduced the number of cocaine infusions earned during progressive‐ratio self‐administration; (ii) attenuated initial positive hedonic reactivity to cocaine and prevented cocaine place preference; (iii) did not affect cocaine‐induced hyperlocomotion and (iv) reduced cocaine‐induced elevations in extracellular ventral striatal dopamine. The present study examined the therapeutic potential of suvorexant in rodent models of cocaine use disorder. These results contribute toward a growing literature supporting therapeutic roles of orexin receptor antagonists in treating substance use disorders.
A paradigm for examining stress effects on alcohol‐motivated behaviors in participants with alcohol use disorder
Authors: McCaul Mary E. , Wand Gary S. , Weerts Elise M. , Xu Xiaoqiang
Published: April 2017

Although epidemiological research has shown an increase in drinking following stressors and trauma, limited paradigms have been validated to study the relationship between stress and drinking in the human laboratory. The current study developed a progressive ratio (PR) operant procedure to examine the effects of psychosocial stress on alcohol craving and several alcohol‐motivated behaviors in persons with alcohol use disorder. Current heavy, nontreatment‐seeking drinkers (N = 30) were media‐recruited and completed a comprehensive assessment of recent drinking, mood and health. Participants were admitted to the clinical research unit and underwent 4‐day, physician‐monitored alcohol abstinence. On days 4 and 5, participants underwent the Trier Social Stress Test or a neutral session in random order followed by the alcohol‐motivated response (AMR) procedure in which subjects worked for money or alcohol under a PR operant procedure. Subjects received earned money vouchers or alcohol at the conclusion of the session. The Trier Social Stress Test increased alcohol craving and rate of responding and decreased the number of changeovers between alcohol versus money reinforcers on the PR schedule. There was a positive relationship between alcohol craving and drinks earned during the stress session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, thereby setting the stage for future studies of alcohol interventions.
Comparative analysis between RQ‐PCR and digital droplet PCR of BCL2/IGH gene rearrangement in the peripheral blood and bone marrow of early stage follicular lymphoma
Authors: Cavalli Marzia , De Novi Lucia Anna , Della Starza Irene , Cappelli Luca Vincenzo , Nunes Vittorio , Pulsoni Alessandro , Del Giudice Ilaria , Guarini Anna , Foà Robin
Published: April 2017

BCL2/IGH rearrangements were analysed by polymerase chain reaction (PCR) at diagnosis in paired peripheral blood (PB) and bone marrow (BM) samples from 67 patients with stage I/II follicular lymphoma (FL). Real time quantitative PCR (RQ‐PCR) and digital droplet PCR (ddPCR) were performed in cases with a major breakpoint region (MBR+) at diagnosis and after localized radiotherapy and rituximab administration in order to investigate the applicability of ddPCR. The overall ddPCR/RQ‐PCR concordance was 81·9% (113/138 samples) and 97·5% in the 40/138 with quantifiable disease (RQ‐PCR≥10−5). At baseline, ddPCR allowed the recovery of a MBR+ marker in 8/18 (44·4%) samples that resulted MBR‐negative/minor cluster region‐negative/minor BCL2‐negative by qualitative PCR. Moreover, the tumour burden at diagnosis significantly predicted progression‐free survival (PSF) only when quantified by ddPCR. Paired PB and BM samples analysis demonstrated a high concordance in the detection of BCL2/IGH+ cells by qualitative and quantitative methods; in particular, 40/62 samples were positive by ddPCR (25 PB+/BM+; 9 PB+/BM−; 6 PB−/BM+), with 34/40 (85%) identified by the study of PB only. In conclusion, in localized FL, ddPCR is a promising tool for monitoring minimal residual disease (MRD) that is at least comparable to RQ‐PCR and potentially more accurate. PB is a suitable source for serial BCL2/IGH MRD assessments, regardless of the methodology utilized.
Eliminating malignant cells from cryopreserved ovarian tissue is possible in leukaemia patients
Authors: Soares Michelle , Saussoy Pascale , Maskens Mathilde , Reul Hélène , Amorim Christiani A. , Donnez Jacques , Dolmans Marie‐Madeleine
Published: April 2017

Reimplantation of cryopreserved ovarian tissue (OT) can successfully restore ovarian function in young cancer patients after gonadotoxic treatment. However, for patients with leukaemia, there is a risk of malignant cell transmission. Our objective was to evaluate minimal disseminated disease in OT from leukaemia patients and test a follicle isolation technique to obtain disease‐free follicle suspensions. Cryopreserved OT from 12 leukaemia patients was thawed and analysed by histology and long‐term xenografting in immunosuppressed mice. In 10 patients, follicles were isolated from OT, and polymerase chain reaction (PCR) was performed on tissue, digested ovarian suspensions and isolated follicle suspensions to investigate leukaemic cell presence. Mean patient age was 17·1 years. An average of 3·2 follicles were isolated per mm² of cortex. Xenografting of OT induced leukaemic masses in 2/12 mice. PCR identified leukaemic cell presence in 66% of OT. Malignant cells were also detected in digested ovarian suspensions. However, none of the follicle samples (>2300 follicles tested) showed any malignant cell presence after washing. This study demonstrates that it is possible to recover large numbers of viable follicles from cryopreserved OT of leukaemia patients. All isolated and washed follicle suspensions tested negative for leukaemic cells, giving leukaemia patients genuine hope of fertility restoration.
How I manage children with neutropenia
Authors: Dale David C.
Published: April 2017

Neutropenia, usually defined as a blood neutrophil count <1·5 × 109/l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony‐stimulating factor to treat childhood neutropenia.
A field‐based disparity analysis of new 1,2,5‐oxadiazole derivatives endowed with antiproliferative activity
Authors: Porta Federica , Gelain Arianna , Barlocco Daniela , Ferri Nicola , Marchianò Silvia , Cappello Valentina , Basile Livia , Guccione Salvatore , Meneghetti Fiorella , Villa Stefania
Published: April 2017

A series of 1,2,5‐oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT‐116 cancer cell line. The field‐based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure–activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization.
Ligand recognition properties of the vasopressin V2 receptor studied under QSAR and molecular modeling strategies
Authors: Martínez‐Archundia Marlet , Colín‐Astudillo Brenda , Moreno‐Vargas Liliana M. , Ramírez‐Galicia Guillermo , Garduño‐Juárez Ramón , Deeb Omar , Contreras‐Romo Martha Citlalli , Quintanar‐Stephano Andres , Abarca‐Rojano Edgar , Correa‐Basurto José
Published: April 2017

The design of new drugs that target vasopressin 2 receptor (V2R) is of vital importance to develop new therapeutic alternatives to treat diseases such as heart failure, polycystic kidney disease. To get structural insights related to V2R‐ligand recognition, we have used a combined approach of docking, molecular dynamics simulations (MD) and quantitative structure–activity relationship (QSAR) to elucidate the detailed interaction of the V2R with 119 of its antagonists. The three‐dimensional model of V2R was built by threading methods refining its structure through MD simulations upon which the 119 ligands were subjected to docking studies. The theoretical results show that binding recognition of these ligands on V2R is diverse, but the main pharmacophore (electronic and π–π interactions) is maintained; thus, this information was validated under QSAR results. QSAR studies were performed using MLR analysis followed by ANN analysis to increase the model quality. The final equation was developed by choosing the optimal combination of descriptors after removing the outliers. The applicability domains of the constructed QSAR models were defined using the leverage and standardization approaches. The results suggest that the proposed QSAR models can reliably predict the reproductive toxicity potential of diverse chemicals, and they can be useful tools for screening new chemicals for safety assessment.
Giant proliferating trichilemmal cyst arising from a nevus sebaceus growing for 30 years
Authors: Lindsey Scott F. , Aickara Divya , Price Alexandra , Pavlis Janelle , Wei Erin X. , Elgart George , Cho‐Vega Jeong Hee
Published: April 2017

Nevus sebaceus of Jadassohn, a congenital cutaneous hamartoma, has the potential to develop into various epidermal adnexal‐origin neoplasms. While the most common neoplasms are trichoblastoma or syringocystadenoma, proliferating trichilemmal cysts are exceptionally rare. We report a case of a 63‐year‐old Cuban male with a giant proliferating trichilemmal cyst arising from a nevus sebaceus on the right shoulder which had been growing for 30 years. Proliferating trichilemmal cysts arising from nevus sebaceus cases are difficult to diagnose clinically and histologically as they are very rare and have not been defined by exact diagnostic criteria. Our case creates awareness of this particular tumor in nevus sebaceus and shares clinical and histological diagnostic information that can be used to make a proper diagnosis.
Sodium‐glucose co‐transporter (SGLT)2 and SGLT1 renal expression in patients with type 2 diabetes
Authors: Solini Anna , Rossi Chiara , Mazzanti Chiara M. , Proietti Agnese , Koepsell Hermann , Ferrannini Ele
Published: April 2017

Aim

To quantify the expression of sodium‐glucose co‐transporter (SGLT)2 and SGLT1, their cognate basolateral transporters, GLUT2 and GLUT1, and the transcriptional regulator of SGLTs in renal tissue obtained from people with T2DM and a group of well‐matched people without diabetes.

Methods

We measured SGLT2 and SGLT1 expression in unaffected renal tissue from 19 people with T2DM and 20 people without diabetes, matched for age and estimated glomerular filtration rate (controls), undergoing unilateral nephrectomy. Expression of SGLT2 and SGLT1, as well as that of GLUT2 and GLUT1, was quantified using real‐time and digital PCR; an affinity‐purified antibody against human SGLT2 was used to localize SGLT2 by immunohistochemistry.

Results

SGLT2 expression was higher in control than T2DM tissue (median [interquartile range] target/β‐actin 1.62 [2.02] vs 0.67 [0.61]; P < .0001), and SGLT1 trended in the same direction (0.98 [1.19] vs 0.44 [0.48]; P = .08). Immunohistochemistry clearly localized SGLT2 to the tubular brush‐border membranes, and was semi‐quantitatively stronger in control than T2DM tissue (5.0 [1.0] vs 4.0 [1.0] score units; P = .043). GLUT2 (control vs T2DM: 1.00 [0.69] vs 0.49 [0.36]) and GLUT1 expression (control vs T2DM: 0.86 [0.73] vs 0.35 [0.30]; P = .0007 for both) were closely correlated with those of the respective SGLT partner. Hypoxia‐inducible factor 1α, more abundant in control than T2DM tissue, might be a transcription factor involved in the modulation of SGLT2 expression.

Conclusions

In whole renal tissue, expressions of SGLT2/GLUT2 and SGLT1/GLUT1 are coupled and slightly lower in typical people with T2DM as compared with well‐matched people without diabetes.
Declining diversity and abundance of High Arctic fly assemblages over two decades of rapid climate warming
Authors: Loboda Sarah , Savage Jade , Buddle Christopher M. , Schmidt Niels M. , Høye Toke T.
Published: April 2017

Insects are particularly vulnerable to rapid environmental changes, which are disproportionally affecting high latitudes. Increased temperature could influence insect species differentially and reshape assemblages over time. We quantified temporal assemblage turnover of Arctic Diptera (flies) in the Muscidae, one of the most diverse and abundant families of Arctic insects, using time series data from Zackenberg, north‐east Greenland. We measured temporal patterns of abundance, diversity, and composition of muscid assemblages in wet fen, mesic and arid heath habitats from yearly collections spanning 1996–2014 and tested their relationship to climate. A total of 18 385 individuals representing 16 species of muscid flies were identified. A significant decrease of 80% of total muscid abundance was observed during the study period. Species richness declined in each habitat type but this trend was not significant across habitats. The number of common and abundant species also decreased significantly over time across habitats revealing a temporal modification of species evenness. Significant temporal changes in composition observed in the wet fen and across habitats were mainly driven by a change in relative abundance of certain species rather than by species replacement. Shift in composition in each habitat and decline in muscid abundance across habitats were associated with summer temperature, which has significantly increased over the study period. However, relationships between temperature and muscid abundance at the species level were noticeable for a few species only. Significant directional change in composition was documented in the wet fen but no biotic homogenization across habitats was observed. As one of the few studies of species‐level changes in abundance, diversity and composition of an insect taxon in the Arctic over the past two decades, our study shows that habitat types may modulate insect species responses to recent climate change and that contrasting species responses can alter species assemblages within a few decades.
Invasion of the Hawaiian Islands by a parasite infecting imperiled stream fishes
Authors: Gagne Roderick B. , Sprehn C. Grace , Alda Fernando , McIntyre Peter B. , Gilliam James F. , Blum Michael J.
Published: April 2017

Points of origin and pathways of spread are often poorly understood for introduced parasites that drive disease emergence in imperiled native species. Co‐introduction of parasites with non‐native hosts is of particular concern in remote areas like the Hawaiian Islands, where the introduced nematode Camallanus cotti has become the most prevalent parasite of at‐risk native stream fishes. In this study, we evaluated the prevailing hypothesis that C. cotti entered the Hawaiian Islands with poeciliid fishes from the Americas, and spread by translocation of poeciliid hosts across the archipelago for mosquito control. We also considered the alternative hypothesis of multiple independent co‐introductions with host fishes originating from Asia. We inferred conduits of introduction and spread of C. cotti across the archipelago from geographic patterns of mtDNA sequence variation and allelic variation across 11 newly developed microsatellite markers. The distribution of haplotypes suggests that C. cotti spread across the archipelago following an initial introduction on O'ahu. Approximate Bayesian Computation modeling and allelic variation also indicate that O'ahu is the most likely location of introduction, from which C. cotti dispersed to Maui followed by spread to the other islands in the archipelago. Evidence of significant genetic structure across islands indicates that contemporary dispersal is limited. Our findings parallel historical records of non‐native poeciliid introductions and suggest that remediating invasion hotspots could reduce the risk of infection in native stream fishes, which illustrates how inferences on parasite co‐introductions can improve conservation efforts by guiding responses to emerging infectious disease in species of concern.
Effect of dehydration and rehydration intervals on fracture resistance of reattached tooth fragments using a multimode adhesive
Authors: Poubel Déborah L. N. , Almeida Júlio César F. , Dias Ribeiro Ana P. , Maia Guilherme B. , Martinez Jesús Maurício G. , Garcia Fernanda Cristina P.
Published: April 2017

Background/Aims

The tooth fragment bonding technique, frequently used to restore traumatized teeth, may be affected by dehydration/rehydration periods. The aim of this study was to evaluate the effects of different dry and wet storage intervals on multimode adhesive bonding between reattached fragments and teeth.

Materials and Methods

Eighty‐four bovine incisors were fractured and randomized into groups (n=12). After teeth fracturing, each specimen was assigned to one of the following groups: G0: control group (sound tooth); GA1 and GA2: 1‐h dehydration and a 15‐min or 24‐hours rewetting period, respectively; GB1 and GB2: 24‐hours dehydration and a 15‐minutes or 24‐hours rewetting period, respectively; and GC: 1‐hour (GC1) or 24‐hours (GC2) dehydration period only. Tooth fragments were then reattached using a multimode adhesive in a self‐mode technique with a flowable resin composite. The fracture resistance was evaluated in a universal testing machine under a compressive load (1 mm/min−1). Data were submitted to two‐way analysis of variance and post hoc Tukey test (5%).

Results

No significant interaction between dehydration and rehydration intervals was observed (P>.05). Only the step of rehydration significantly affected the reattachment strength when compared to the groups submitted only to dehydration, regardless of the interval (15 minutes or 24 hours).

Conclusion

Rehydrating a tooth fragment for 15 minutes before bonding with a multimode adhesive maintained sufficient moisture to increase reattachment strength.
The major miR‐31 target genes STK40 and LATS2 and their implications in the regulation of keratinocyte growth and hair differentiation
Authors: Luan Liming , Shi Jianyun , Yu Zhengquan , Andl Thomas
Published: April 2017

Emerging evidence indicates that even subtle changes in the expression of key genes of signalling pathways can have profound effects. MicroRNAs (miRNAs) are masters of subtlety and generally have only mild effects on their target genes. The microRNA miR‐31 is one of the major microRNAs in many cutaneous conditions associated with activated keratinocytes, such as the hyperproliferative diseases psoriasis, non‐melanoma skin cancer and hair follicle growth. miR‐31 is a marker of the hair growth phase, and in our miR‐31 transgenic mouse model it impairs the function of keratinocytes. This leads to aberrant proliferation, apoptosis, and differentiation that results in altered hair growth, while the loss of miR‐31 leads to increased hair growth. Through in vitro and in vivo studies, we have defined a set of conserved miR‐31 target genes, including LATS2 and STK40, which serve as new players in the regulation of keratinocyte growth and hair follicle biology. LATS2 can regulate growth of keratinocytes and we have identified a function of STK40 that can promote the expression of key hair follicle programme regulators such as HR, DLX3 and HOXC13.