bluuebunny/crossref_metadata_2025 huggingface dataset:
Peanut Seed Cultivars with Contrasting Resistance to Aspergillus parasiticus Colonization Display Differential Temporal Response of Protease Inhibitors
Authors: Müller Virginia , Bonacci Gustavo , Batthyany Carlos , Amé María V. , Carrari Fernando , Gieco Jorge , Asis Ramón
Published: November 2016

Significant efforts are being made to minimize aflatoxin contamination in peanut seeds and one possible strategy is to understand and exploit the mechanisms of plant defense against fungal infection. In this study we have identified and characterized, at biochemical and molecular levels, plant protease inhibitors (PPIs) produced in peanut seeds of the resistant PI 337394 and the susceptible Forman cultivar during Aspergillus parasiticus colonization. With chromatographic methods and 2D-electrophoresis-mass spectrometry we have isolated and identified four variants of Bowman-Birk trypsin inhibitor (BBTI) and a novel Kunitz-type protease inhibitor (KPI) produced in response to A. parasiticus colonization. KPI was detected only in the resistant cultivar, while BBTI was produced in the resistant cultivar in a higher concentration than susceptible cultivar and with different isoforms. The kinetic expression of KPI and BBTI genes along with trypsin inhibitory activity was analyzed in both cultivars during infection. In the susceptible cultivar an early PPI activity response was associated with BBTI occurrence. Meanwhile, in the resistant cultivar a later response with a larger increase in PPI activity was associated with BBTI and KPI occurrence. The biological significance of PPI in seed defense against fungal infection was analyzed and linked to inhibitory properties on enzymes released by the fungus during infection, and to the antifungal effect of KPI.
Vesivirus 2117 capsids more closely resemble sapovirus and lagovirus particles than other known vesivirus structures
Authors: Conley Michaela , Emmott Edward , Orton Richard , Taylor David , Carneiro Daniel G. , Murata Kazuyoshi , Goodfellow Ian G. , Hansman Grant S. , Bhella David
Published: November 2016

Vesivirus 2117 is an adventitious agent that, in 2009, was identified as a contaminant of Chinese hamster ovary cells propagated in bioreactors at a pharmaceutical manufacturing plant belonging to Genzyme. The consequent interruption in supply of Fabrazyme and Cerezyme (drugs used to treat Fabry and Gaucher diseases, respectively) caused significant economic losses. Vesivirus 2117 is a member of the Caliciviridae, a family of small icosahedral viruses encoding a positive-sense RNA genome. We have used cryo-electron microscopy and three-dimensional image reconstruction to calculate a structure of vesivirus 2117 virus-like particles as well as feline calicivirus and a chimeric sapovirus. We present a structural comparison of several members of the Caliciviridae, showing that the distal P domain of vesivirus 2117 is morphologically distinct from that seen in other known vesivirus structures. Furthermore, at intermediate resolutions, we found a high level of structural similarity between vesivirus 2117 and Caliciviridae from other genera: sapovirus and rabbit hemorrhagic disease virus. Phylogenetic analysis confirms vesivirus 2117 as a vesivirus closely related to canine vesiviruses. We postulate that morphological differences in virion structure seen between vesivirus clades may reflect differences in receptor usage.
Influenza C incidence and herd immunity in Lancaster, UK, in the winter of 2014-2015
Authors: Atkinson Kate V , Bishop Lisa A , Rhodes Glenn , Salez Nico , McEwan Neil R , Hegarty Matthew J , Robey Julie , Harding Nicola , Wetherell Simon , Lauder Robert M , Pickup Roger W , Wilkinson Mark , Gatherer Derek
Published: November 2016

Influenza C is not included in the annual seasonal influenza vaccine, and has historically been regarded as a minor respiratory pathogen. However, recent work has highlighted its potential role as a cause of pneumonia in infants. We performed nasopharyngeal or nasal swabbing and/or serum sampling (n=148) in Lancaster, UK, over the winter of 2014-2015. Using enzyme-linked immunosorbent assay (ELISA), we estimated a seropositivity of 77%. By contrast, only 2 individuals, both asymptomatic adults, were influenza C-positive by polymerase chain reaction (PCR). Deep sequencing of nasopharyngeal samples produced partial sequences for 4 genome segments in one of these patients. Bayesian phylogenetic analysis demonstrated that the influenza C genome from this individual is evolutionarily distant to those sampled in recent years and represents a novel genome constellation, indicating that it is a product of a decades-old reassortment event. Although we find no evidence that influenza C was a significant respiratory pathogen during the winter of 2014-2015 in Lancaster, we confirm previous observations of seropositivity in the majority of the population. We calculate that this level of herd immunity would be sufficient to suppress epidemics of influenza C and restricts the virus to sporadic endemic spread.
Mouse T cell repertoires as statistical ensembles: overall characterization and age dependence
Authors: Sethna Zachary , Elhanati Yuval , Dudgeon Crissy S. , Callan Curtis G. , Levine Arnold , Mora Thierry , Walczak Aleksandra M.
Published: November 2016

The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors (TCRs). This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts each time a new immune cell is created from a stem cell. By analyzing T cell sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the significant changes in this process that occur in development from embryo to young adult. We find a rapid increase with age in the number of random insertions in the VDJ recombination process, leading to a dramatic increase in diversity. Since the blood accumulates thymic output over time, blood repertoires are mixtures of different statistical recombination processes and, by unraveling the mixture statistics, we can obtain a clear picture of the time evolution of the early immune system. Sequence repertoire analysis also allows us to detect the effect of selection on the output of the VDJ recombination process. The effects we find are nearly identical between thymus and blood, suggesting that they mainly reflect selection for proper folding of the TCR receptor protein.
Spatial tuning shifts increase the discriminability and fidelity of population codes in visual cortex
Authors: Vo Vy A. , Sprague Thomas C. , Serences John T.
Published: November 2016

Selective visual attention enables organisms to enhance the representation of behaviorally relevant stimuli by altering the encoding properties of single receptive fields (RFs). Yet we know little about how the attentional modulations of single RFs contribute to the encoding of an entire visual scene. Addressing this issue requires (1) measuring a group of RFs that tile a continuous portion of visual space, (2) constructing a population-level measurement of spatial representations based on these RFs, and (3) linking how different types of RF attentional modulations change the population-level representation. To accomplish these aims, we used fMRI to characterize the responses of thousands of voxels in retinotopically organized human cortex. First, we found that the response modulations of voxel RFs (vRFs) depend on the spatial relationship between the RF center and the visual location of the attended target. Second, we used two analyses to assess the spatial encoding quality of a population of voxels. We found that attention increased fine spatial discriminability and representational fidelity near the attended target. Third, we linked these findings by manipulating the observed vRF attentional modulations and recomputing our measures of the fidelity of population codes. Surprisingly, we discovered that attentional enhancements of population-level representations largely depend on position shifts of vRFs, rather than changes in size or gain. Our data suggest that position shifts of single RFs are a principal mechanism by which attention enhances population-level representations in visual cortex.

SIGNIFICANCE STATEMENT

While changes in the gain and size of RFs have dominated our view of how attention modulates information codes of visual space, such hypotheses have largely relied on the extrapolation of single-cell responses to population responses. Here we use fMRI to relate changes in single voxel receptive fields (vRFs) to changes in the precision of representations based on larger populations of voxels. We find that vRF position shifts contribute more to population-level enhancements of visual information than changes in vRF size or gain. This finding suggests that position shifts are a principal mechanism by which spatial attention enhances population codes for relevant visual information in sensory cortex. This poses challenges for labeled line theories of information processing, suggesting that downstream regions likely rely on distributed inputs rather than single neuron-to-neuron mappings.
Antidepressant-like effects of P2 purinergic antagonist PPADS is dependent on serotonergic and noradrenergic integrity
Authors: Diniz Cassiano R. A. F. , Rodrigues Murilo , Casarotto Plínio C. , Pereira Vítor S. , Crestani Carlos C. , Joca Sâmia R. L.
Published: November 2016

Depression is a common mental disorder affecting around 350 million of individuals globally. The available antidepressant drug monotherapy is far from ideal since it has an efficiency of approximately 60% and takes around 3-4 week to achieve clinical improvement. Attention has been paid to the purinergic signaling regarding neuropathological mechanisms, since it might be involved in psychiatric disorders, such as depression. In fact, blockade of purinergic P2X receptors induces antidepressant-like effects in preclinical models. However, the mechanisms involved in this effect are not yet completely understood. The present work investigated the interplay between a P2X receptor antagonist (PPADS) and clinically used antidepressant drugs on the forced swimming test, an animal model predictive of antidepressant effect. We observed significant synergistic effect of PPADS combined with sub-effective doses of fluoxetine or reboxetine in the FST. Moreover, depletion of serotonergic or noradrenergic systems, with PCPA and DSP-4 treatment, respectively, blocked the antidepressant-like effect of PPADS. No increase in locomotion, a possible source of confusion on FST data, was detected in any of the treated groups. Our results indicate the antidepressant-like effect of PPADS depends on the integrity of serotonergic and noradrenergic transmission.
Recent progress in multi-electrode spike sorting methods
Authors: Lefebvre Baptiste , Yger Pierre , Marre Olivier
Published: November 2016

In recent years, arrays of extracellular electrodes have been developed and manufactured to record simultaneously from hundreds of electrodes packed with a high density. These recordings should allow neuroscientists to reconstruct the individual activity of the neurons spiking in the vicinity of these electrodes, with the help of signal processing algorithms. Algorithms need to solve a source separation problem, also known as spike sorting. However, these new devices challenge the classical way to do spike sorting. Here we review different methods that have been developed to sort spikes from these large-scale recordings. We describe the common properties of these algorithms, as well as their main differences. Finally, we outline the issues that remain to be solved by future spike sorting algorithms.
TheNDE1genomic locus can affect treatment of psychiatric illness through gene expression changes related to MicroRNA-484
Authors: Bradshaw Nicholas J. , Ukkola-Vuoti Liisa , Pankakoski Maiju , Zheutlin Amanda B. , Ortega-Alonso Alfredo , Torniainen-Holm Minna , Sinha Vishal , Therman Sebastian , Paunio Tiina , Suvisaari Jaana , Lönnqvist Jouko , Cannon Tyrone D. , Haukka Jari , Hennah William
Published: November 2016

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes,DISC1, NDE1, NDEL1,PDE4BandPDE4D,the “DISC1 network”. Here, we utilize gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, whilst prescription medication information has been collected over a ten-year period for 931 affected individuals. We demonstrate that theNDE1SNP rs2242549 associates with significant changes in gene expression for 2,908 probes (2,542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p=3.0×10−8), located on a non-coding exon ofNDE1.Variants within theNDE1locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression ofCYP2C19in a cell culture system. Thus, variation at theNDE1locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.
Response variability and population coupling of cortical synaptic inputs are strongly influenced by network properties
Authors: Wright Nathaniel C. , Hoseini Mahmood , Yasar Tansel Baran , Wessel Ralf
Published: November 2016

The highly variable spiking of a cortical neuron is “coupled” to that of other neurons in the network. This has implications for sensory coding, and appears to represent a fundamental property of cortical sensory processing. To date, most studies of population coupling have focused on recorded spiking activity, an approach that suffers from several confounding issues. Moreover, the contributions of various network properties to population coupling are largely unexplored. To this end, we recorded the membrane potential (V) and the nearby LFP in the visual cortex of the turtleex vivowholebrain preparation during ongoing and visually-evoked activity. We used an algorithm to infer the excitatory conductance (g) from V, and calculated the g-LFP coupling. We found that g-LFP coupling was highly variable across neurons, and increased following visual stimulation before relaxing to intermediate values. To investigate the role of the network, we implemented a driven small-world network of leaky integrate-and-fire neurons. This model reproduces the large across-trial response variability and g-LFP coupling dynamic, and suggests crucial roles for anatomical and emergent network properties.
Interpreting deep mutational scanning data resulting from selections on solid media
Authors: Klesmith Justin R. , Thorwall Sarah , Whitehead Timothy A.
Published: November 2016

Deep mutational scanning is now used in directed evolution experiments to quantify the change in frequency of a cellular variant in a mixed population. A key concern is the extent to which the enrichment of a variant in a population corresponds to a fitness metric like relative growth rate or survival percentage. We present here analytical equations converting the enrichment of a variant to fitness metrics for plate-based selections. Using isogenic and mixed cultures we show that growth rates and survival percentages correlate for antibiotic plate-based selections. These results are important for proper interpretation of data resulting from deep sequencing.
Genome-scale transcriptional regulatory network models for the mouse and human striatum predict roles for SMAD3 and other transcription factors in Huntington’s disease
Authors: Ament Seth A. , Pearl Jocelynn R. , Bragg Robert M. , Skene Peter J. , Coffey Sydney R. , Bergey Dani E. , Plaisier Christopher L. , Wheeler Vanessa C. , MacDonald Marcy E. , Baliga Nitin S. , Rosinski Jim , Hood Leroy E. , Carroll Jeffrey B. , Price Nathan D.
Published: November 2016

Transcriptional changes occur presymptomatically and throughout Huntington’s Disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome-scale model for the target genes of 718 TFs in the mouse striatum by integrating a model of the genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age‐ andHttallele-dependent gene expression changes in the mouse striatum, and replicated many of these associations in independent transcriptomic and proteomic datasets. Strikingly, many of these predicted target genes were also differentially expressed in striatal tissue from human disease. We experimentally validated a key model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We foundHttallele-dependent changes in the genomic occupancy of SMAD3 and confirmed our model’s prediction that many SMAD3 target genes are down-regulated early in HD. Importantly, our study provides a mouse and human striatal-specific TRN and prioritizes a hierarchy of transcription factor drivers in HD.
Learning enhances sensory processing in mouse V1 before improving behavior
Authors: Jurjut Ovidiu , Georgieva Petya , Busse Laura , Katzner Steffen
Published: November 2016

A fundamental property of visual cortex is to enhance the representation of those stimuli that are relevant for behavior, but it remains poorly understood how such enhanced representations arise during learning. Using classical conditioning in mice, we show that orientation discrimination is learned in a sequence of distinct behavioral stages, in which animals first rely on stimulus appearance before exploiting its orientation to guide behavior. After confirming that orientation discrimination under classical conditioning requires primary visual cortex (V1), we measured, during learning, response properties of V1 neurons. Learning improved neural discriminability, sharpened orientation tuning and led to higher contrast sensitivity. Remarkably, these learning-related improvements in the V1 representation were fully expressed before successful orientation discrimination was evident in the animals’ behavior. We propose that V1 plays a key role early in discrimination learning to enhance behaviorally relevant sensory information.
Evaluating Methods of Updating Training Data in Long-Term Genomewide Selection
Authors: Neyhart Jeffrey L. , Tiede Tyler , Lorenz Aaron J. , Smith Kevin P.
Published: November 2016

Genomewide selection is hailed for its ability to facilitate greater genetic gains per unit time. Over breeding cycles, the requisite linkage disequilibrium (LD) between quantitative trait loci (QTL) and markers is expected to change as a result of recombination, selection, and drift, leading to a decay in prediction accuracy. Previous research has identified the need to update the training population using data that may capture new LD generated over breeding cycles, however optimal methods of updating have not been explored. In a barley (Hordeum vulgareL.) breeding simulation experiment, we examined prediction accuracy and response to selection when updating the training population each cycle with the best predicted lines, the worst predicted lines, both the best and worst predicted lines, random lines, criterion-selected lines, or no lines. In the short-term, we found that updating with the best predicted lines or the best and worst predicted lines resulted in high prediction accuracy and genetic gain, but in the long-term, all methods (besides not updating) performed similarly. We also examined the impact of including all data in the training population or only the most recent data. Though patterns among update methods were similar, using a smaller, but more recent training population provided a slight advantage in prediction accuracy and genetic gain. In an actual breeding program, a breeder might desire to gather phenotypic data on lines predicted to be the best, perhaps to evaluate possible cultivars. Therefore, our results suggest that an optimal method of updating the training population is also very practical.
A functional genomic meta-analysis of clinical trials in systemic sclerosis: towards precision medicine and combination therapy
Authors: Taroni Jaclyn N. , Martyanov Viktor , Mahoney J. Matthew , Whitfield Michael L.
Published: November 2016

Systemic sclerosis (SSc) is an orphan, systemic autoimmune disease with no FDA-approved treatments. Its heterogeneity and rarity often result in underpowered clinical trials making the analysis and interpretation of associated molecular data challenging. We performed a meta-analysis of gene expression data from skin biopsies of SSc patients treated with five therapies: mycophenolate mofetil (MMF), rituximab, abatacept, nilotinib, and fresolimumab. A common clinical improvement criterion of -20% OR -5 modified Rodnan Skin Score was applied to each study. We developed a machine learning approach that captured features beyond differential expression that was better at identifying targets of therapies than the differential expression alone. Regardless of treatment mechanism, abrogation of inflammatory pathways accompanied clinical improvement in multiple studies suggesting that high expression of immune-related genes indicates active and targetable disease. Our framework allowed us to compare different trials and ask if patients who failed one therapy would likely improve on a different therapy, based on changes in gene expression. Genes with high expression at baseline in fresolimumab non-improvers were downregulated in MMF improvers, suggesting that immunomodulatory or combination therapy may have benefitted these patients. This approach can be broadly applied to increase tissue-specificity and sensitivity of differential expression results.
78Gy with Fiducial Marker Image‐Guided Radiotherapy in Prostate Cancer: Single Center Analysis of 301 Patients
Authors: Choong Ee Siang , Hruby George , Yang Jean , Kwong Carol , Patanjali Nitya
Published: November 2016

Aim

In prostate cancer, fiducial marker image‐guided radiotherapy (FMIGRT) allows correction of setup errors and interfraction physiological motion resulting in improved accuracy of target and sparing of at risk organs. We aim to report outcomes and toxicities observed in patients treated with dose escalation to 78Gy with FMIGRT in our center.

Methods and Materials

Retrospective review of consecutive patients with histologically confirmed T1‐4N0M0 localized prostate cancer treated with dose escalation to 78Gy with FMIGRT in our center. All patients had 3‐D conformal radiotherapy. Duration of androgen deprivation therapy use was tailored to risk group. Toxicity was scored according to CTCAE.v04. Kaplan–Meier analysis was performed for freedom from biochemical failure (FFBF), prostate cancer‐specific survival and overall survival.

Results

Median follow‐up was 48.6 months. Median duration of androgen deprivation therapy was 6 and 23 months in the intermediate‐ and high‐risk group, respectively. FFBF at 5 years was 88.8%. FFBFs when stratified to risk groups were 100% for low risk, 88.9% for low‐intermediate risk, 89.9% for high‐intermediate risk and 85.4% for high risk, respectively. Acute severe toxicity (grade≥3) rate for both genitourinary (GU) and gastrointestinal (GI) was 1%. Late moderate‐to‐severe toxicity (grade≥2) rates for GU and GI were 15% and 17%, respectively, with severe (grade≥3) toxicity rate for GU and GI at 2% and 3%, respectively.

Conclusion

Dose escalation to 78Gy with FMIGRT in our series achieved good FFBF at 5 years with low acute and late toxicity rates. These results provide a good comparator cohort to our current use of image‐guided intensity modulated radiotherapy.
Every three‐hour versus every six‐hour oral feeding in preterm infants: a randomised clinical trial
Authors: Gray Megan M. , Medoff‐Cooper Barbara , Enlow Elizabeth M. , Mukhopadhyay Sagori , DeMauro Sara B.
Published: November 2016

Aim

This trial compares two oral feeding schedules, every three‐hour and every six‐hour oral feeding attempts, to determine which schedule allows for more rapid attainment of full oral feeding in preterm infants.

Methods

Infants born at ≤33‐week gestation were randomly assigned to receive oral feeding every three hours or every six hours if feeding cues were present. The primary outcome was time to full oral feeding; secondary outcomes include respiratory and apnoea rates, growth and length of stay.

Results

A total of 55 infants were recruited. There was no difference between the groups in the primary or secondary outcomes.

Conclusion

For preterm infants fed when oral feeding cues are present, an every six‐hour schedule did not alter the time to full oral feeding and had no effect on rates of tachypnoea, apnoea or length of hospital stay compared to every three‐hour feeding schedule. An every six‐hour oral feeding schedule led to only small reductions in number of oral feeding attempts per day.
Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus
Authors: Hines Delaney , Modi Neena , Lee Shoo K. , Isayama Tetsuya , Sjörs Gunnar , Gagliardi Luigi , Lehtonen Liisa , Vento Maximo , Kusuda Satoshi , Bassler Dirk , Mori Rintaro , Reichman Brian , Håkansson Stellan , Darlow Brian A. , Adams Mark , Rusconi Franca , San Feliciano Laura , Lui Kei , Morisaki Naho , Musrap Natasha , Shah Prakesh S. ,   the International Network for Evaluating Outcomes (iNeo) of Neonates
Published: November 2016

The use of different definitions for bronchopulmonary dysplasia (BPD) has been an ongoing challenge. We searched papers published in English from 2010 and 2015 reporting BPD as an outcome, together with studies that compared BPD definitions between 1978 and 2015. We found that the incidence of BPD ranged from 6% to 57%, depending on the definition chosen, and that studies that investigated correlations with long‐term pulmonary and/or neurosensory outcomes reported moderate‐to‐low predictive values regardless of the BPD criteria.

Conclusion

A comprehensive and evidence‐based definition for BPD needs to be developed for benchmarking and prognostic use.
Reintroduction failure is common among adolescents after double‐blind placebo‐controlled food challenges
Authors: Strinnholm Å , Winberg A , Hedman L , Rönmark E , Lindh V
Published: November 2016

Aim

There has been a lack of research on adolescents who undergo double‐blind placebo‐controlled food challenges. The aim of this study was to investigate food allergic adolescents' experiences and consequences of double‐blind placebo‐controlled food challenges.

Methods

This qualitative, descriptive interview study included 17 adolescents aged 14–15 years with total elimination of cows' milk, hens' eggs or cod due to food allergies. The participants, who were initially identified from a large population‐based cohort study, were interviewed 18 months after completing their challenges.

Results

The double‐blind placebo‐controlled food challenge proved to be a complex experience for the adolescents, involving fear of potential reactions and the hope that the food could be reintroduced. Experiences during the challenge were described in three themes: facing fears in a secure environment, being hesitant but curious about unknown tastes and waiting for unknown food reactions. Experiences after the challenge were described in two themes: gaining control and freedom and continuing old habits. A negative challenge was not consistently associated with the reintroduction of the challenged food.

Conclusion

This study highlighted the importance of considering the adolescents' expectations and experiences of the challenge and the reintroduction process to ensure desirable changes in their dietary habits. Follow‐ups should be performed regardless of the outcome of challenges.
Clinical utility of next‐generation sequencing‐based minimal residual disease in paediatric B‐cell acute lymphoblastic leukaemia
Authors: Sekiya Yuko , Xu Yinyan , Muramatsu Hideki , Okuno Yusuke , Narita Atsushi , Suzuki Kyogo , Wang Xinan , Kawashima Nozomu , Sakaguchi Hirotoshi , Yoshida Nao , Hama Asahito , Takahashi Yoshiyuki , Kato Koji , Kojima Seiji
Published: November 2016

We assessed the clinical utility of next‐generation sequencing (NGS)‐based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B‐cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre‐ (4–5 months) and post‐ (24 months) maintenance therapy time points, and at relapse. We identified leukaemia‐specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4–5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561–21·6), P < 0·001], at 4–5 months [RR (95% CI) = 10·24 (3·374–31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974–74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia‐free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS‐MRD for patients with B‐cell ALL.
Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image‐fusion guided transperineal prostate biopsy in patients with a previous negative biopsy
Authors: Hansen Nienke L. , Kesch Claudia , Barrett Tristan , Koo Brendan , Radtke Jan P. , Bonekamp David , Schlemmer Heinz‐Peter , Warren Anne Y. , Wieczorek Kathrin , Hohenfellner Markus , Kastner Christof , Hadaschik Boris
Published: November 2016

Objectives

To evaluate the detection rates of targeted and systematic biopsies in magnetic resonance imaging (MRI) and ultrasound (US) image‐fusion transperineal prostate biopsy for patients with previous benign transrectal biopsies in two high‐volume centres.

Patients and Methods

A two centre prospective outcome study of 487 patients with previous benign biopsies that underwent transperineal MRI/US fusion‐guided targeted and systematic saturation biopsy from 2012 to 2015. Multiparametric MRI (mpMRI) was reported according to Prostate Imaging Reporting and Data System (PI‐RADS) Version 1. Detection of Gleason score 7–10 prostate cancer on biopsy was the primary outcome. Positive (PPV) and negative (NPV) predictive values including 95% confidence intervals (95% CIs) were calculated. Detection rates of targeted and systematic biopsies were compared using McNemar's test.

Results

The median (interquartile range) PSA level was 9.0 (6.7–13.4) ng/mL. PI‐RADS 3–5 mpMRI lesions were reported in 343 (70%) patients and Gleason score 7–10 prostate cancer was detected in 149 (31%). The PPV (95% CI) for detecting Gleason score 7–10 prostate cancer was 0.20 (±0.07) for PI‐RADS 3, 0.32 (±0.09) for PI‐RADS 4, and 0.70 (±0.08) for PI‐RADS 5. The NPV (95% CI) of PI‐RADS 1–2 was 0.92 (±0.04) for Gleason score 7–10 and 0.99 (±0.02) for Gleason score ≥4 + 3 cancer. Systematic biopsies alone found 125/138 (91%) Gleason score 7–10 cancers. In patients with suspicious lesions (PI‐RADS 4–5) on mpMRI, systematic biopsies would not have detected 12/113 significant prostate cancers (11%), while targeted biopsies alone would have failed to diagnose 10/113 (9%). In equivocal lesions (PI‐RADS 3), targeted biopsy alone would not have diagnosed 14/25 (56%) of Gleason score 7–10 cancers, whereas systematic biopsies alone would have missed 1/25 (4%). Combination with PSA density improved the area under the curve of PI‐RADS from 0.822 to 0.846.

Conclusion

In patients with high probability mpMRI lesions, the highest detection rates of Gleason score 7–10 cancer still required combined targeted and systematic MRI/US image‐fusion; however, systematic biopsy alone may be sufficient in patients with equivocal lesions. Repeated prostate biopsies may not be needed at all for patients with a low PSA density and a negative mpMRI read by experienced radiologists.
Mourning Dr. Alfred G. Knudson: the two‐hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex
Authors: Hino Okio , Kobayashi Toshiyuki
Published: November 2016

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two‐hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor‐predisposing syndromes. To understand the molecular mechanism of two‐hit‐initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor‐predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1‐independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.
Downregulation of MicroRNA‐320d predicts poor overall survival and promotes the growth and invasive abilities in glioma
Authors: Qin Chong‐Zhen , Lv Qiao‐Li , Yang Yan‐Tao , Zhang Jing‐Min , Zhang Xiao‐Jian , Zhou Hong‐Hao
Published: November 2016

Previous studies have demonstrated that miRNAs play an important role in tumor development and progression. The role of miR‐320d has been studied in several cancers except for glioma. The aim of the study was to investigate the expression levels, biological function, and mechanism of miR‐320d in glioma. The expression levels of miR‐320d were detected in glioma tissues and cell lines (U87 and U251) by RT‐qPCR. Cell proliferation, colony formation, apoptosis, cell cycle, and transwell assays were performed in glioma cell lines transfected with miR‐320d mimics or controls to evaluate the effects of miR‐320d in vitro. The expression levels of invasive‐related proteins were determined by Western blot analysis. Results showed that the expression of miR‐320d was significantly decreased in glioma tissues and cell lines. Overexpression of miR‐320d could significantly suppress cell growth, migration and invasion, and induced cell apoptosis as well as cell cycle at G0/G1 arrest in U87 and U251 cell lines. Additionally, expression levels of MMP‐2, MMP‐9, N‐cadherin, and integrin‐β1 reduced, while E‐cadherin increased in miR‐320d mimic group. Overall, this study is the first to demonstrate that miR‐320d may serve as an independent prognostic factor, indicating that miR‐320d is a biomarker for prognosis and therapy in glioma.
Parents' Sexual Orientation and Children's Development
Authors: Patterson Charlotte J.
Published: November 2016

What if any influence does parents' sexual orientation have on children's development? Research suggests that, contrary to concerns voiced by many observers, parents' sexual orientation has little if any direct impact on children's development. Even so, some distinctive qualities of experiences in families of lesbian and gay parents have been noted, and their implications are not fully understood. Moreover, research on individual differences among families headed by lesbian mothers and gay fathers, and their possible impact on children, is still in its early phases. In this article, I provide an overview of research in this area and offer suggestions for further studies.
Promoting Neuroprotective Care in Neonatal Intensive Care Units and Preterm Infant Development: Insights From the Neonatal Adequate Care for Quality of Life Study
Authors: Montirosso Rosario , Tronick Ed , Borgatti Renato
Published: November 2016

During their stay in a neonatal intensive care unit (NICU), preterm infants are exposed to adverse stressful experiences that deplete their resources and often result in problematic functioning and developmental outcomes. The impact of specific developmental care practices (e.g., kangaroo care) on preterm infants has been researched extensively. Moreover, the dissemination of knowledge about developmental care has facilitated broader neuroprotective care (NC) that combines different kinds of developmental care practices in different NICUs. However, little is known about how variation in NC affects infants and their long‐term developmental outcomes. Using the findings from the Neonatal Adequate Care for Quality of Life project, in this article, we discuss how variation in the NC incorporated by NICUs into standard care affects short‐ and long‐term outcomes in children born preterm.
Fair Resource Allocation Among Children and Adolescents: The Role of Group and Developmental Processes
Authors: Rutland Adam , Killen Melanie
Published: November 2016

The fair exchange of resources provides a basis for developing morality, yet research has rarely examined the role of group processes that are central to children's world. In this article, we describe a new perspective as well as research demonstrating that group processes play a key role in the fair allocation of resources among children and adolescents. We contend that when children allocate resources, group processes and moral judgments are relevant, a developmental shift occurs in children's ability to coordinate moral and group concerns, and group processes contribute to intergroup bias regarding allocations but also to efforts to consider the status of disadvantaged groups. Our perspective informs efforts to reduce prejudice as well as increase fairness and equality in situations in which group processes are relevant for allocating resources fairly.
The Social Tasks of Friendship: Do Boys and Girls Excel in Different Tasks?
Authors: Rose Amanda J. , Asher Steven R.
Published: November 2016

Research documents the strengths of girls’ friendships compared to boys’ friendships leading to the inference that boys are not very skilled as friends. In this article, we use a friendship tasks framework to propose that this inference is premature and should be reconciled with evidence that boys are as satisfied as girls with their friendships and that their friendships are as stable over time. We also propose that the inference arises partly because the friendship tasks that girls handle well have been studied extensively, whereas certain friendship tasks boys handle as well as or more successfully than girls are understudied. These tasks include being a fun and enjoyable companion, coping when a friend violates a core expectation of friendship, and sustaining friendships in the broader social context of a friend having other friends. Finally, we suggest that girls and boys who develop skills to respond to a range of friendship tasks will benefit in the long term.
One‐hour postload plasma glucose concentration in people with normal glucose homeostasis predicts future diabetes mellitus: a 12‐year community‐based cohort study
Authors: Oh Tae Jung , Lim Soo , Kim Kyoung Min , Moon Jae Hoon , Choi Sung Hee , Cho Young Min , Park Kyong Soo , Jang HakChul , Cho Nam H.
Published: November 2016

Objective

In Caucasians, plasma glucose concentration at 1 h during an oral glucose tolerance test (OGTT) may be a better predictor of future diabetes mellitus than the fasting or 2‐h postload glucose concentration. We investigated whether the 1‐h glucose concentration could be used to predict future diabetes mellitus in Asian ethnicity.

Measurements

A total of 5703 Koreans with normal glucose tolerance were enrolled from the Korean Genome and Epidemiology Study. Indices of insulin sensitivity and β‐cell function estimated from standard 75‐g OGTTs performed every 2 years for 12 years were used to identify whether the 1‐h glucose concentration could predict future diabetes mellitus.

Results

The mean age and body mass index at baseline were 51·3 ± 8·7 years and 24·2 ± 3·0 kg/m2, respectively. During the 12‐year follow‐up, 593 subjects (10·3%) developed diabetes mellitus. The area under the receiver‐operating characteristic curve for incident diabetes mellitus was higher for the 1‐h postload glucose concentration than for the fasting or postload 2‐h glucose concentration (0·74 vs 0·61 or 0·63). The cut‐off value of ≥8·0 mmol/l identified incident diabetes mellitus with 70% sensitivity and 68% specificity. After adjusting for typical risk factors, subjects with a 1‐h postload glucose concentration ≥8·0 mmol/l had lower β‐cell function and a 2·84‐fold increased risk of incident diabetes mellitus compared with their counterparts.

Conclusions

In this community‐based 12‐year prospective cohort study, 1‐h postload plasma glucose concentration was an independent predictor of future diabetes mellitus and 8·0 mmol/l was suggested as a cut‐off value.
Estimation of the occupancy of butterflies in diverse biogeographic regions
Authors: Fleishman Erica , Scherer Rick D. , Zappalla Angela , Leu Matthias
Published: November 2016

Aim

We explored the extent to which occupancy of butterflies within three biogeographic regions could be explained by vegetation structure and composition, topography and other environmental attributes; whether results were consistent among regions; and whether assumptions of closure were met with assemblage‐level sampling designs.

Location

Chesapeake Bay Lowlands (Virginia), central Great Basin (Nevada) and western Great Basin (Nevada and California) (all USA).

Methods

We applied single‐season occupancy models that either assumed closure or relaxed the closure assumption to data from 2013 and 2014 for 13–15 species in each region.

Results

Maximum single‐year estimates of detection probabilities ranged from 0.14 to 0.99, and single‐year occupancy from 0.28 to 0.98. The assumption of closure was met for a maximum of 54% of the species in a given region and year. Detection probabilities of > 90% of the species in each region increased as the categorical abundance of nectar or mud increased. Measures of the dominance or abundance of deciduous woody species and structural heterogeneity were included in the greatest number of occupancy models for the Chesapeake Bay Lowlands, which may in part reflect the intensity of browsing by white‐tailed deer (Odocoileus virginianus). Elevation and precipitation were prominent covariates in occupancy models for Great Basin butterflies.

Main conclusions

Because occupancy models do not rely on captures or observations of multiple individuals in a population, they potentially can be applied to a relatively high proportion of the species in an assemblage. However, estimation of occupancy is complicated by taxonomic, temporal and spatial variation in phenology. In multiple, widely divergent ecosystems, all or some associations between covariates and detection probability or occupancy for at least one‐third of the species could not be estimated, often because a given species rarely was detected at locations with relatively low or high values of a covariate. Despite their advantages, occupancy models may leave unexplained the environmental associations with the distributions of many species.
Fatigue and its relationship with physical activity, age, and body composition in adults with cerebral palsy
Authors: McPhee Patrick G , Brunton Laura K , Timmons Brian W , Bentley Todd , Gorter Jan Willem
Published: November 2016

Aim

The objectives of this exploratory study were (1) to describe the experience of fatigue in adults with cerebral palsy (CP) inclusive of all levels of the Gross Motor Function Classification System (GMFCS); and (2) to determine if physical activity level, sedentary time, age, or body composition can predict fatigue in adults with CP.

Method

An observational study was conducted in an outpatient setting in Ontario, Canada. Participants included adults with CP (n=41; GMFCS levels I–V; mean age 33.7y, standard deviation [SD] 12.3y). Fatigue was measured using the Fatigue Impact and Severity Self‐Assessment (FISSA) questionnaire. Habitual physical activity and sedentary time were measured using accelerometry. Body mass index (BMI) and waist circumference were reported as measures of body composition.

Results

The mean (SD) FISSA score for all participants was 84.5 (30.6), ranging from 54.0 (18.3) (GMFCS level I) to 93.6 (21.9) (GMFCS level V). Significant positive relationships (regression coefficient β [95% confidence intervals]) were observed between BMI and FISSA scores (1.9 [0.73–3.1]), waist circumference and FISSA scores (0.71 [0.19–1.2]), and age and FISSA scores (0.99 [0.26–1.7]). A significant negative relationship was observed between moderate‐to‐vigorous physical activity (MVPA) per hour and FISSA scores −6.4 [−12 to −0.83]). Backwards stepwise regression analysis revealed BMI (1.8 [0.61–2.9]) and MVPA per hour (−5.4 [−10 to −0.30]) were significant predictors of FISSA scores.

Interpretation

Health care providers should consider the importance of weight management and physical activity to prevent and treat fatigue in this population.
Sleep disorders in cerebral palsy
Authors: Gringras Paul
Published: November 2016

This commentary is on the original article by Jacquier and Newman on pages 420–426 of this issue.
Managing cryptic biodiversity: Fine‐scale intralacustrine speciation along a benthic gradient in Alpine whitefish (Coregonusspp.)
Authors: Hudson Alan G. , Lundsgaard‐Hansen Baenz , Lucek Kay , Vonlanthen Pascal , Seehausen Ole
Published: November 2016

Whitefish (Coregonusspp.) are an important catch for many freshwater fisheries, particularly in Switzerland. In support of this, supplemental stocking of whitefish species is carried out, despite lacking complete knowledge of the extent, distribution and origin of whitefish diversity in these lakes, potentially threatening local endemics via artificial gene flow. Here, we investigate phenotypic and genetic differentiation among coexisting whitefish species spawning along a depth gradient in a subalpine Swiss lake to better delineate intralacustrine whitefish biodiversity. We find depth‐related clines in adaptive morphology and in neutral genetic markers. This individual variation is structured in three distinct clusters with spatial overlap. Individual genetic distances correlate strongly with differences in growth rate and gill‐raker number, consistent with predictions of isolation‐by‐adaptation and ecological speciation. Genetic differentiation between species suggests reproductive isolation, despite demographic admixture on spawning grounds. Our results are consistent with clinal speciation resulting in three species coexisting in close ecological parapatry, one (C. sp. “benthic intermediate”) being previously unknown. A second unknown species spawning in close proximity was found to be of potential allochthonous origin. This study highlights the importance of taxonomically unbiased sampling strategies to both understand evolutionary mechanisms structuring biodiversity and to better inform conservation and fisheries management.