bluuebunny/crossref_metadata_2025 huggingface dataset:
Can early oral prolonged-release oxycodone with or without naloxone reduce the duration of epidural analgesia after cystectomy? A 3-arm, randomized, double-blind, placebo-controlled trial
Authors: Schneider Marc P. , Löffel Lukas M. , Furrer Marc A. , Burkhard Fiona C. , Kleeb Bettina , Curatolo Michele , Wuethrich Patrick Y.
Published: November 2017

Thoracic epidural analgesia (TEA) enhances recovery after bowel surgery. Early postoperative prolonged-release oral formulation of oxycodone or oxycodone/naloxone is potentially useful as a second analgesic step to reduce the duration of TEA. We hypothesized that oxycodone would decrease the duration of TEA and combined with naloxone preserve gastrointestinal function. Ninety patients undergoing open cystectomy and urinary diversion were enrolled in this randomized double-blind, three-arm, parallel-group, placebo-controlled single-center trial between September 2015 and February 2017. Exclusion criteria were known allergy to oxycodone/naloxone, pulmonary diseases, hepatopathy, and analgesics nonnaïve patients. From postoperative day 3, patients received batches with oxycodone, oxycodone/naloxone, or placebo every 12 hours (n = 30 in each arm). Reduction of the epidural drug infusion rate was attempted with the goal to maintain a pain intensity <3 at rest and <5 (numeric rating score) at mobilization during 6 hours. Primary endpoint was duration of TEA and secondary endpoint return of gastrointestinal function. The median duration of TEA did not differ between patients treated with oxycodone/naloxone (6.7 [range 3.1-10.3] days), oxycodone (7.0 [3.0-9.1]), or placebo (6.4 [3.1-8.4]); P = 0.88. Time to the first defecation was prolonged in the oxycodone group compared to the placebo group (difference 22.48 hours ±8.95; P = 0.037). In the oxycodone group, we found 8/30 patients with ileus (27%) compared to 2/28 (7%) in the oxycodone/naloxone group and to 2/30 (7%) in the placebo group; (P = 0.031). Oxycodone, with or without naloxone, did not reduce the duration of TEA. Oxycodone alone led to a delayed return of bowel function, whereas the combination was not different from placebo.
Hypoglycemia and Sudden Death During Treatment With Methadone for Opiate Detoxification
Authors: Plescia Christopher J. , Manu Peter
Published: November 2017

Clinical Features:

We present a case of a middle-aged man admitted to an inpatient detoxification facility for withdrawal of intranasal heroin, alprazolam, and ethanol. The patient was placed on methadone and chlordiazepoxide tapers. Ondansetron and trazodone were prescribed as needed for symptom control. On the third hospital day, the patient was found unresponsive with blood glucose of 40 mg/dL. He had no history of glucose dysregulation. The patient was pronounced dead shortly thereafter. Methadone overdose was ruled the cause of death.

Therapeutic Challenges:

There have been studies linking methadone with glucose dysregulation. Hypoglycemia can induce changes in the electrical system in the heart, including lengthening QT interval, lengthening repolarization, and causing ST wave changes. In addition, there have been studies linking methadone treatment to QT interval prolongation and torsade de pointes. Ondansetron and trazodone have both been associated with cardiac conduction abnormalities.

Solution:

We recommend initial blood glucose and cardiac monitoring in patients taking methadone 40 mg daily or higher.
B7-H4 is Inversely Correlated With T-Cell Infiltration in Clear Cell but Not Serous or Endometrioid Ovarian Cancer
Authors: Pagnotti Gabriel M. , Atkinson Richard M. , Romeiser Jamie , Akalin Ali , Korman Mallory B. , Shroyer Kenneth R.
Published: November 2017

B7-H4, a tumor-associated cell surface protein, is expressed in endometrioid (EM), serous (SE), and clear cell (CC) ovarian carcinomas. Prior in vitro studies from other groups indicated that elevated B7-H4 expression by tumor cells blocks T-cell activation; therefore, it had been postulated to play a role in shielding cancer cells from immune surveillance and averting apoptotic programs. To test the validity of these hypotheses, the present study was designed to compare the immunohistochemical staining intensity of B7-H4 in tumor cells of ovarian cancers with the number of tumor-infiltrating T cells and macrophages and with the levels of caspase-3 staining in apoptotic debris. Serial tissue sections from EM, SE, and CC carcinomas were analyzed across representative cross-sections of tumor resection specimens, demonstrating different levels of B7-H4 expression, highest in CC cancers. B7-H4 staining in CC tissue sections was significantly correlated with the number of CD3+, CD4+, and CD8+ tumor-infiltrating T cells and with the number of CD14+ tumor-infiltrating macrophages, but was not significantly related to caspase-3 staining. These results support the concept that high levels of B7-H4 expression are inversely correlated with tumor T-cell infiltration and with CD14-labeled macrophages but not caspase-3 expression in CC carcinomas. We did not, however, find clear evidence of a relationship between the lower levels of B7-H4 seen in EM and SE carcinomas and T cell or macrophage infiltration. Thus, high levels of B7-H4, as seen in CC carcinomas, is associated with decreased tumor infiltration by T cells and macrophages but the lower levels of expression, as observed in EM and SE carcinomas, appear less likely to play an effective role in protection from immune surveillance. Furthermore, we found no evidence of a correlation between B7-H4 expression and apoptosis. These findings highlight the importance of further investigation of B7-H4 as an immunomodulatory protein, to support the development of novel therapeutic interventions for improved efficacy of treatments for CC carcinoma.
Cutaneous Metastases of the Glioma
Authors: Chang Hao , Ding Yasuo , Wang Peng , Wang Qing , Lin Yuchang , Li Bing
Published: November 2017

Low grade glioma (LGG) is a very common primary brain neoplasm with a very good prognosis and the median survival of patients is approximately 8 years. With the development of current treatments such as surgery resection, radiotherapy, and chemotherapy, the recurrence rate and the distant metastasis rate of LGGs are largely decreased. Extracranial metastases are seldom happened. However, the authors present a pathologically proven patient with scalp metastasis, which was metastasized from LGG occurring site to the surgical scar 8 months following initial craniotomy and chemotherapy. The histopathologic examination of the primary site and the recurrent under the scalp are exactly similar. This grade of glioma was increased along with cutaneous metastases. A discussion of a series of the extracranial metastases of the glioma, especially for the surgical considerations, is also provided advice for the cutaneous metastases of the glioma.
Decrease of Sphincter Preserving Length Lowers the Postoperative Genital Function for Patients With Rectal Cancer
Authors: Liu Zhihua , Kang Liang , Huang Meijin , Li Chao , Tong Chao , Zhang Xingwei , Luo Yanxin , Wang Lei , Wu Xiaojian , Lan Ping , Cui Ji , Wang Jianping
Published: November 2017

Background and Objective:

With the increase in sphincter preserving rate of rectal cancer (RC) cancer, postoperative quality-of-life, such as genital dysfunction, has become a major issue in the patient management. In this study, we proposed a measurement, namely, the sphincter preserving length (SPL), and investigated the relationship between SPL and postoperative genital function and survival in RC patients.

Methods:

A total of 536 male patients who had a diagnosis of RC and underwent sphincter preserving rectal resection in the Sixth Affiliated Hospital of Sun Yat-sen University and the First Affiliated Hospital of Sun Yat-sen University between October 1997 and December 2013 were included in our study. SPL was defined as the distance between the lowest edge of the tumor to dentate line. Postoperative genital function was evaluated by erection function and ejaculation function. Five-year survival status was extracted from the hospital database.

Results:

Larger SPL was significantly associated with poorer postoperative erection and ejaculation function. For a SPL of 7.25 cm, the sensitivity and specificity of the diagnosis of erection dysfunction was 68.6% and 68.8%, respectively. The corresponding sensitivity and specificity for the diagnosis of ejaculation dysfunction was 70.9% and 75.7%, respectively. SPL was also negatively associated with survival rate. Compared with lower anterior resection, patients with lower RC who underwent local resection or draw-out colon-anal anastomosis had better postoperative genital function.

Conclusions:

SPL might be a useful measurement to assess the risk of postoperative genital dysfunction and survival status and an indicator for initiation of early preventative treatment in patients with RC.
Royal Society Scientific Meeting: Extracellular vesicles in the tumour microenvironment
Authors: Pink Ryan Charles , Elmusrati Areeg A. , Lambert Daniel , Carter David Raul Francisco
Published: November 2017

Cancer cells do not grow as an isolated homogeneous mass; tumours are, in fact, complex and heterogeneous collections of cancer and surrounding stromal cells, collectively termed the tumour microenvironment. The interaction between cancer cells and stromal cells in the tumour microenvironment has emerged as a key concept in the regulation of cancer progression. Understanding the intercellular dialogue in the tumour microenvironment is therefore an important goal. One aspect of this dialogue that has not been appreciated until recently is the role of extracellular vesicles (EVs). EVs are small vesicles released by cells under both normal and pathological conditions; they can transfer biological molecules between cells leading to changes in phenotype. EVs have emerged as important regulators of biological processes and can be dysregulated in diseases such as cancer; rapidly growing interest in their biology and therapeutic potential led to the Royal Society hosting a Scientific Meeting to explore the roles of EVs in the tumour microenvironment. This cross-disciplinary meeting explored examples of how aberrant crosstalk between tumour and stromal cells can promote cancer progression, and how such signalling can be targeted for diagnostic, prognostic and therapeutic benefit. In this review, and the special edition of
Philosophical Transactions of the Royal Society B
that follows, we will provide an overview of the content and outcomes of this exciting meeting.

This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.
Mapping neurons and brain regions underlying sensorimotor decisions and sequences inDrosophila
Authors: Jovanic Tihana , Masson Jean-Baptiste , Truman James William , Zlatic Marta
Published: November 2017

Nervous systems across the animal kingdom have the ability to select appropriate actions and sequences of actions in response to sensory cues. The circuit mechanisms by which nervous systems achieve choice, stability and transitions between behaviors are still incompletely understood. To identify neurons and brain areas involved in controlling these processes, we developed an approach where we combined a large-scale neuronal inactivation screen with an automated action detection of sensorimotor decisions and sequences in response to a sensory cue inDrosophilalarva. We analyzed behaviors from 2.9×105larvae and identified 51 candidate lines for sensory processing and 24 candidate lines for competitive interactions between actions during sensorimotor decisions. We also detected phenotype categories for sequence transitions consistent with a model of sequence generation where transitions and reversals are independently controlled. These findings provide the basis for understanding how sensorimotor decisions and sequence transition are controlled by the nervous system
Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease
Authors: Khera Amit V. , Chaffin Mark , Aragam Krishna G. , Emdin Connor A. , Klarin Derek , Haas Mary E. , Roselli Carolina , Natarajan Pradeep , Kathiresan Sekar
Published: November 2017

Identification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.

One Sentence Summary

A genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.
Current CRISPR gene drive systems are likely to be highly invasive in wild populations
Authors: Noble Charleston , Adlam Ben , Church George M. , Esvelt Kevin M. , Nowak Martin A.
Published: November 2017

Recent reports have suggested that CRISPR-based gene drives are unlikely to invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption. We show that although resistance prevents drive systems from spreading to fixation in large populations, even the least effective systems reported to date are highly invasive. Releasing a small number of organisms often causes invasion of the local population, followed by invasion of additional populations connected by very low gene flow rates. Examining the effects of mitigating factors including standing variation, inbreeding, and family size revealed that none of these prevent invasion in realistic scenarios. Highly effective drive systems are predicted to be even more invasive. Contrary to the National Academies report on gene drive, our results suggest that standard drive systems should not be developed nor field-tested in regions harboring the host organism.
Quantitative imaging of chromatin decompaction in living cells
Authors: Dultz Elisa , Mancini Roberta , Polles Guido , Vallotton Pascal , Alber Frank , Weis Karsten
Published: November 2017

Chromatin organization is highly dynamic and regulates transcription. Upon transcriptional activation, chromatin is remodeled and referred to as “open”, but quantitative and dynamic data of this decompaction process are lacking. Here, we have developed a quantitative high-resolution microscopy assay in living yeast cells to visualize and quantify chromatin dynamics using the GAL7-10-1 locus as a model system. Upon transcriptional activation of these three clustered genes, we detect an increase of the mean distance across this locus by >100 nm. This decompaction is linked to active transcription but is not sensitive to the histone deacetylase inhibitor trichostatin A or to deletion of the histone acetyl transferase Gcn5. By contrast, the deletion of SNF2 (encoding the ATPase of the SWI/SNF chromatin remodeling complex) or the deactivation of the histone chaperone complex FACT lead to a strongly reduced decompaction without significant effects on transcriptional induction. Our findings are consistent with nucleosome remodeling and eviction activities being major contributors to chromatin reorganization during transcription but also suggest that transcription can occur in the absence of detectable decompaction.
Method to estimate the approximate samples size that yield a certain number of significant GWAS signals in polygenic traits
Authors: Bacanu Silviu-Alin , Kendler Kenneth S.
Published: November 2017

To argue for increased sample collection for disorders without significant findings, researchers retorted to plotting, for multiple traits, the number of significant findings as a function of the sample size. However, for polygenic traits, the prevalence of the disorder confounds the relationship between the number of significant findings and the sample size. To adjust the number of significant findings for prevalence, we develop a method that uses the expected noncentrality of the contrast between liabilities of cases and controls. We empirically find that, when compared to the sample size, this measure is a better predictor of number of significant findings. Even more, we show that the sample size effect on the number of signals is explained by the noncetrality measure. Finally, we provide an R script to estimate the required sample size (non-centrality) needed to yield a pre-specified number of significant findings.
Metaproteomics of colonic microbiota unveils discrete protein functions among colitic mice and control groups
Authors: Moon Clara , Stupp Gregory S. , Su Andrew I. , Wolan Dennis W.
Published: November 2017

Metaproteomics can greatly assist established high-throughput sequencing methodologies to provide systems biological insights into the alterations of microbial protein functionalities correlated with disease-associated dysbiosis of the intestinal microbiota. Here, we utilized the well-characterized murine T cell transfer model of colitis to find specific changes within the intestinal luminal proteome associated with inflammation. MS proteomic analysis of colonic samples permitted the identification of ∽10,000-12,000 unique peptides that corresponded to 5,610 protein clusters identified across three groups, including the coliticRag1-/-T cell recipients, isogenicRag1-/-controls, and wild-type mice. We demonstrate that the colitic mice exhibited a significant increase inProteobacteriaandVerrucomicrobiaand show that such alterations in the microbial communities contributed to the enrichment of specific proteins with transcription and translation gene ontology terms. In combination with 16S sequencing, our metaproteomics-based microbiome studies provide a foundation for assessing alterations in intestinal luminal protein functionalities in a robust and well-characterized mouse model of colitis, and set the stage for future studies to further explore the functional mechanisms of altered protein functionalities associated with dysbiosis and inflammation.

Statement of significance of the study

The commensal gut microbiota is essential to maintaining health and has a primary role in digestion/metabolism, homeostasis, and protection from pathogenic bacteria. High-throughput sequencing has establishedBacteroidetes, Firmicutes, Proteobacteria,andActinobacteriaas the four major bacterial phyla that comprise the ecological makeup of the intestinal microbiota. However, the tremendous inter-/intra-variability in microbial composition across individuals, as well as along the length of the intestinal tract has made it difficult to definitively ascertain specific bacterial species associated with health or as drivers of disease states, including inflammatory bowel disease. In this study, we expanded upon the current metaproteomics techniques and use the robust and highly reproducible murine T cell transfer model of colitis as well as a comprehensive database of mouse, human, plant, and all microbial genomes sequenced to date to elucidate alterations in both host and gut microbial proteins associated with intestinal inflammation. Our results show that host genetics, gut microbiota, and inflammation have tremendous influences on the intestinal luminal proteomic landscape.
Combining optical imaging of cleared tissue with mathematical modelling to predict drug delivery and therapeutic response
Authors: d’Esposito Angela , Sweeney Paul , Ali Morium , Saleh Magdy , Ramasawmy Rajiv , Roberts Thomas A , Desjardins Adrien , Lythgoe Mark F , Pedley R Barbara , Shipley Rebecca , Walker-Samuel Simon
Published: November 2017

Understanding how drugs are delivered to diseased tissue, and their subsequent spatial and temporal distribution, is a key factor in the development of effective, targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary significantly between individuals. In cancer, suboptimal dosing resulting from poor delivery can cause reduced treatment efficacy, upregulation of resistance mechanisms and can even stimulate growth. Preclinical tools to better understand drug delivery are therefore urgently required, which incorporate the inherent variability and heterogeneity of human disease. To meet this need, we have combined multiscale mathematical modelling, high-resolution optical imaging of intact, optically-cleared tumour tissue from animal models, and in vivo magnetic resonance imaging (MRI). Our framework, named REANIMATE (REAlistic Numerical Image-based Modelling of biologicAl Tissue substratEs) allows large tissue samples to be investigated as if it were a living sample, in detailed, highly controlled, computational experiments. Specifically, we show that REANIMATE can be used to predict the heterogeneous delivery of specific therapeutic agents, in disparate two murine xenograft models of human colorectal carcinoma. Given the wide adoption of optical clearing equipment in biomedical research laboratories, REANIMATE enables a new paradigm in cancer drug development, which could also be applied to other disease areas.
Changes in global brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor
Authors: Preller Katrin H. , Burt Joshua B. , Ji Jie Lisa , Schleifer Charles , Adkinson Brendan , Stämpfli Philipp , Repovs Grega , Krystal John H. , Murray John D. , Vollenweider Franz X. , Anticevic Alan
Published: November 2017

Lysergic acid diethylamide (LSD) is a psychedelic drug with predominantly agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, the specific receptor contributions to its neurobiological effects remain largely unknown. To address this knowledge gap, we conducted a double-blind, randomized, counterbalanced, cross-over study during which 24 healthy participants received either i) placebo+placebo, ii) placebo+LSD (100 μg po), or iii) ketanserin – a selective 5-HT2A receptor antagonist. Here we focus on resting-state fMRI, a measure of spontaneous neural fluctuations that can map functional brain connectivity. We collected resting-state data 75 and 300 minutes after LSD/placebo administration. We quantified resting-state functional connectivity via a fully data-driven global brain connectivity (GBC) method to comprehensively map LSD neuropharmacological effects. LSD administration caused widespread GBC alterations that followed a specific topography: LSD reduced connectivity in associative areas, but concurrently increased connectivity across sensory and somatomotor areas. The 5-HT2A receptor antagonist, ketanserin, fully blocked the subjective and neural LSD effects. We show that whole-brain data-driven spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans, which along with ketanserin effects, strongly implicates the 5-HT2A receptor in LSD’s neuropharmacology. Critically, the LSD-induced subjective effects were associated with somatomotor networks GBC changes. These data-driven neuropharmacological results pinpoint the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics
SMN1 and SMN2 Copy Number Determination by droplet digital PCR (ddPCR) based on Extreme Value Theory for Threshold Estimation
Authors: Niknazar Mohammad , Jansen Michael , Puig Oscar
Published: November 2017

Spinal muscular atrophy (SMA) is the most frequent genetic cause of infantile death. Homozygous deletion screening of survival of motor neuron (SMN1) represents the first tier in diagnostic testing. In this work, we adopted and optimized a method to increase the accuracy of SMN1 and SMN2 copy number determination on ddPCR platform. This method, which makes no assumption about the distribution of the fluorescence readouts, was shown to significantly increase accuracy and outperform QuantaSoft software on problematic SMN1 samples.

Method Summary

In order to increase the accuracy of SMN1 and SMN2 copy number determination by ddPCR, we adopted and optimized a method based on extreme value theory for threshold estimation. Our method increases total accuracy and improves resolution of problematic samples.
Latent variable model for aligning barcoded short-reads improves downstream analyses
Authors: Shajii Ariya , Numanagić Ibrahim , Berger Bonnie
Published: November 2017

Recent years have seen the emergence of several “third-generation” sequencing platforms, each of which aims to address shortcomings of standard next-generation short-read sequencing by producing data that capture long-range information, thereby allowing us to access regions of the genome that are inaccessible with short-reads alone. These technologies either produce physically longer reads typically with higher error rates or instead capture long-range information at low error rates by virtue of read “barcodes” as in 10x Genomics’ Chromium platform. As with virtually all sequencing data, sequence alignment for third-generation sequencing data is the foundation on which all downstream analyses are based. Here we introduce a latent variable model for improving barcoded read alignment, thereby enabling improved downstream genotyping and phasing. We demonstrate the feasibility of this approach through developing EMerAld— or EMA for short— and testing it on the barcoded short-reads produced by 10x’s sequencing technologies. EMA not only produces more accurate alignments, but unlike other methods also assigns interpretable probabilities to the alignments it generates. We show that genotypes called from EMA’s alignments contain over 30% fewer false positives than those called from Lariat’s (the current 10x alignment tool), with a fewer number of false negatives, on datasets of NA12878 and NA24385 as compared to NIST GIAB gold standard variant calls. Moreover, we demonstrate that EMA is able to effectively resolve alignments in regions containing nearby homologous elements— a particularly challenging problem in read mapping— through the introduction of a novel statistical binning optimization framework, which allows us to find variants in the pharmacogenomically important CYP2D region that go undetected when using Lariat or BWA. Lastly, we show that EMA’s alignments improve phasing performance compared to Lariat’s in both NA12878 and NA24385, producing fewer switch/mismatch errors and larger phase blocks on average.

EMA software and datasets used are available at http://ema.csail.mit.edu.
Decision by sampling implements efficient coding of psychoeconomic functions
Authors: Bhui Rahul , Gershman Samuel J.
Published: November 2017

The theory of decision by sampling (DbS) proposes that an attribute’s subjective value is its rank within a sample of attribute values retrieved from memory. This can account for instances of context dependence beyond the reach of classic theories which assume stable preferences. In this paper, we provide a normative justification for DbS that is based on the principle of efficient coding. The efficient representation of information in a noiseless communication channel is characterized by a uniform response distribution, which the rank transformation implements. However, cognitive limitations imply that decision samples are finite, introducing noise. Efficient coding in a noisy channel requires smoothing of the signal, a principle that leads to a new generalization of DbS. This generalization is closely connected to range-frequency theory, and helps descriptively account for a wider set of behavioral observations, such as how context sensitivity varies with the number of available response categories.
Temporal neural mechanisms underlying conscious access to different levels of facial stimulus contents
Authors: Hsu Shen-Mou , Yang Yu-Fang
Published: November 2017

An important issue facing the empirical study of consciousness concerns how the contents of incoming stimuli gain access to conscious processing. According to classic theories, facial stimuli are processed in a hierarchical manner. However, it remains unclear how the brain determines which level of stimulus contents is consciously accessible when facing an incoming facial stimulus. Accordingly, with a magnetoencephalography technique, this study aims to investigate the temporal dynamics of the neural mechanism mediating which level of stimulus content is consciously accessible. Participants were instructed to view masked target faces at threshold, so that according to behavioral responses, their perceptual awareness alternated from consciously accessing facial identity in some trials to being able to consciously access facial configuration features but not facial identity in other trials. Conscious access at these two levels of facial contents were associated with a series of differential neural events. Before target presentation, different patterns of phase angle adjustment were observed between the two types of conscious access. This effect was followed by stronger phase clustering for awareness of facial identity immediately during stimulus presentation. After target onset, conscious access to facial identity, as opposed to facial configural features, was able to elicit more robust late positivity. In conclusion, we suggest that the stages of neural events, ranging from prestimulus to stimulus-related activities, may operate in combination to determine which level of stimulus contents is consciously accessed. Conscious access may thus be better construed as comprising various forms that depend on the level of stimulus contents accessed.
Bases of antisense IncRNA-associated regulation of gene expression in fission yeast
Authors: Wery Maxime , Gautier Camille , Descrimes Marc , Yoda Mayuko , Migeot Valérie , Hermand Damien , Morillon Antonin
Published: November 2017

Antisense (as)lncRNAs can regulate gene expression but the underlying mechanisms and the different cofactors involved remain unclear. Using Native Elongating Transcript sequencing, here we show that stabilization of antisense Exo2-sensitivite IncRNAs (XUTs) results in the attenuation, at the nascent transcription level, of a subset of highly expressed genes displaying prominent promoter-proximal nucleosome depletion and histone acetylation. Mechanistic investigations on the catalase genectt1revealed that its induction following oxidative stress is impaired in Exo2-deficient cells, correlating with the accumulation of an asXUT. Interestingly, expression of this asXUT was also activated in wild-type cells upon oxidative stress, concomitant toctt1induction, indicating a potential attenuation feedback. This attenuation correlates with asXUT abundance, it is transcriptional, characterized by low RNAPII-ser5 phosphorylation, and it requires an histone deacetylase activity and the conserved Set2 histone methyltransferase. Finally, we identified Dicer as another RNA processing factor acting onctt1induction, but independently of Exo2. We propose that asXUTs could modulate the expression of their paired-sense genes when it exceeds a critical threshold, using a conserved mechanism independent of RNAi.

AUTHOR SUMMARY

Examples of regulatory antisense (as)lncRNAs acting on gene expression have been reported in multiple model organisms. However, despite their regulatory importance, aslncRNAs have been poorly studied, and the molecular bases for aslncRNAs-mediated regulation remain incomplete. One reason for the lack of global information on aslncRNAs appears to be their low cellular abundance. Indeed, our previous studies in budding and fission yeasts revealed that aslncRNAs are actively degraded by the Xrn1/Exo2-dependent cytoplasmic 5′-3′ RNA decay pathway. Using a combination of single-gene and genome-wide analyses in fission yeast, here we report that the stabilization of a set of Exo2-sensitive aslncRNAs correlates with attenuation of paired-sense genes transcription. Our work provides fundamental insights into the mechanism by which aslncRNAs could regulate gene expression. It also highlights for the first time that the level of sense gene transcription and the presence of specific chromatin features could define the potential of aslncRNA-mediated attenuation, raising the idea that aslncRNAs only attenuate those genes with expression levels above a “regulatory threshold”. This opens novel perspectives regarding what the potential determinants of aslncRNA-dependent regulation, as previous models in budding yeast rather proposed that aslncRNA-mediated repression is restricted to lowly expressed genes.
Allele-specific control of replication timing and genome organization during development
Authors: Rivera-Mulia Juan Carlos , Dimond Andrew , Vera Daniel , Trevilla-Garcia Claudia , Sasaki Takayo , Zimmerman Jared , Dupont Catherine , Gribnau Joost , Fraser Peter , Gilbert David M.
Published: November 2017

DNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus X castaneus mouse crosses and exploited the high single nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (nuclear RNA-seq) and chromatin accessibility (ATAC-seq). We also presentHARP: a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of 6 different hybrid mESC clones with different genomes (C57BL/6, 129/sv and CAST/Ei), parental configurations and gender revealed significant RT asynchrony between alleles across ~12 % of the autosomal genome linked to sub-species genomes but not to parental origin, growth conditions or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not SNP density, gene expression, imprinting or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types including extraembryonic endoderm stem (XEN) cells, 4 male and female primary mouse embryonic fibroblasts (MEFs) and neural precursors (NPCs) differentiatedin vitrofrom mESCs with opposite parental configurations. Surprisingly, we found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs was largely lost in all differentiated cell types, coordinated with a more uniform Hi-C compartment arrangement, suggesting that genome organization of homologues converges to similar folding patterns during cell fate commitment.
Fronto-limbic dysconnectivity leads to impaired brain network controllability in young people with bipolar disorder and those at high genetic risk
Authors: Jeganathan Jayson , Perry Alistair , Bassett Danielle S. , Roberts Gloria , Mitchell Philip B. , Breakspear Michael
Published: November 2017

Recent investigations have used diffusion-weighted imaging to reveal disturbances in the neurocircuitry that underlie cognitive-emotional control in bipolar disorder (BD) and in unaffected siblings or children at high genetic risk (HR). It has been difficult to quantify the mechanism by which structural changes disrupt the superimposed brain dynamics, leading to the emotional lability that is characteristic of BD. Average controllability is a concept from network control theory that extends structural connectivity data to estimate the manner in which local neuronal fluctuations spread from a node or subnetwork to alter the state of the rest of the brain. We used this theory to ask whether structural connectivity deficits previously observed in HR (n=84, mean age 22.4) individuals, patients with BD (n=38, mean age 23.9), and age- and gender-matched controls (n=96, mean age 22.6) translate to differences in the ability of brain systems to be manipulated between states. Localized impairments in network controllability were seen in the left parahippocampal, left middle occipital, left superior frontal, right inferior frontal, and right precentral gyri in BD and HR groups. Subjects with BD had distributed deficits in a subnetwork containing the left superior and inferior frontal gyri, postcentral gyrus, and insula (p=0.004). HR participants had controllability deficits in a right-lateralized subnetwork involving connections between the dorsomedial and ventrolateral prefrontal cortex, the superior temporal pole, putamen, and caudate nucleus (p=0.008). Between-group controllability differences were attenuated after removal of topological factors by network randomization. Some previously reported differences in network connectivity were not associated with controllability-differences, likely reflecting the contribution of more complex brain network properties. These analyses highlight the potential functional consequences of altered brain networks in BD, and may guide future clinical interventions.

Highlights

Control theory estimates how neuronal fluctuations spread from local networks.

We compare brain controllability in bipolar disorder and their high-risk relatives.

These groups have impaired controllability in networks supporting cognitive and emotional control.

Weaker connectivity as well as topological alterations contribute to these changes.
cycleX: multi-dimensional pseudotime reveals cell cycle and differentiation relationship of dendritic cell progenitors
Authors: Tan Yong Kee , Zhang Xiaomeng , Chen Jinmiao
Published: November 2017

Advances in single-cell RNA-sequencing have helped reveal the previously underappreciated level of cellular heterogeneity present during cellular differentiation. A static snapshot of single-cell transcriptomes provides a good representation of the various stages of differentiation as differentiation is rarely synchronized between cells. Data from numerous single-cell analyses has suggested that cellular differentiation and development can be conceptualized as continuous processes. Consequently, computational algorithms have been developed to infer pseudotimes and re-ordered cells along developmental trajectories. However, existing pseudotime inference methods generate one-dimensional pseudotime in an unsupervised manner, which is inadequate to elucidate the effects of individual biological processes such as cell cycle and differentiation and the links between them. Here we present a method called cycleX which infers multi-dimensional pseudotimes to reveal putative relationship between cell cycle and differentiation during dendritic cell development. cycleX can be also applied to generate multi-dimensional pseudotime for the relationship among cell cycle, differentiation, trafficking, activation, metabolism and etc.
Investigating on relationship between effective quantum efficiency and irradiance
Authors: Ye Zi-Piao , Zhou Shuang-Xi , Yang Xiao-Long , Kang Hua-Jing , Robakowski Piotr
Published: November 2017

Models describing the relationship between effective quantum efficiency of PS II (ΦPSII) and irradiance (I) are routinely used to determine how irradiance influences effective quantum efficiency and photosynthetic electron transport rate (ETR). However, with no single model one can accurately describe the relationship betweenΦPSIIand I, and explain the interdependence betweenΦPSIIand biophysical properties of photosynthetic pigments, especially in plants growing under low level irradiances. Basing on the mechanistic model of photosynthetic electron transport rate we have developed the model of the relationship betweenΦPSIIandI. The new model reveals thatΦPSIIincreases with photochemistry (kP) and heat dissipation (kD). Furthermore, the values of key parameters calculated using the new model were compared with the values calculated with two other empirical models. The new model was perfectly fitted to the light-response curves ofΦPSII. The key calculated photosynthetic parameters: maximumΦPSII, maximumETRand their corresponding saturation irradiance were close to the measured values. In addition, our model associatesΦPSIIwith intrinsic features of photosynthetic pigments. We concluded thatΦPSIIdecreased with increasingIdue to the decrease in the effective absorption cross-section of photosynthetic pigments molecules.

Highlight

A model of the relationship between effective quantum efficiency of PS II (ΦPSII) and irradiance (I) has been developed. Using this new model it was found thatΦPSIIdecreased with increasingIdue to the decrease in the effective absorption cross-section of photosynthetic pigments molecules.

Abbreviations

ETR

Electron transport rate

ETRmax

Maximum electron transport rate

F

Steady-state fluorescence

Fm′

Maximum fluorescence in the light

Fv

Variable fluorescence yield of the dark-adapted leaf

gi

Degeneration of energy level of photosynthetic pigment molecules in the ground statei

gk

Degeneration of energy level of photosynthetic pigment molecules in the excited statek

I

Irradiance

NPQ

Non-photochemical quenching

N0

Total light-harvesting pigment molecules

PARsat

Saturation irradiance corresponding toETRmax

kP

Rate of photochemical reaction

kD

Rate of non-radiative heat dissipation

PS II

Photosystem II

ae

Initial slope of light-response curve of electron transport rate

α′

Fraction of light absorbed by PS II

β′

Leaf absorptance

ξ1

Probability of photochemistry

ξ2

Probability of non-radiative heat dissipation

ξ3

Probability of fluorescence

σik

Eigen-absorption cross-section of photosynthetic pigment from ground stateito excited statekdue to light illumination

Effective optical absorption cross-section of photosynthetic pigment molecule from ground stateito excited statekdue to light illumination

φ

Exciton-use efficiency in PS II

τ

Average lifetime of the photosynthetic pigment molecules in the lowest excited state

ΣPSII

Effective quantum efficiency of PS II
Higher eukaryote-specific APC/C composition is a determinant of spindle assembly checkpoint importance
Authors: Wild Thomas , Budzowska Magda , Karemore Gopal , Choudhary Chunaram
Published: November 2017

The multisubunit ubiquitin ligase APC/C (anaphase promoting complex/cyclosome) is essential for mitosis by promoting timely degradation of cyclin B1. Proper timing of APC/C activation is regulated by the spindle assembly checkpoint (SAC), which is initiated by the kinase MPS1 and implemented by MAD2-dependent inhibition of the APC/C. Here we analysed the contribution of the higher eukaryote-specific APC/C subunits APC7 and APC16 to APC/C composition, function and regulation. APC16 is required for APC7 assembly into the APC/C, while APC16 assembles independently of APC7. ΔAPC7 and ΔAPC16 cells display no major defects in mitotic progression, cyclin B1 degradation or SAC response. Strikingly, however, deletion of either APC7 or APC16 is sufficient to provide synthetic viability to MAD2 deletion. ΔAPC7ΔMAD2 cells display an accelerated mitosis and require SAC-independent MPS1 function for maintaining their genome stability. Overall, these results show how human APC/C composition critically influences the cellular fate upon loss of SAC activity.
Patterns of Z chromosome divergence amongHeliconiusspecies highlight the importance of historical demography
Authors: Van Belleghem Steven M. , Baquero Margarita , Papa Riccardo , Salazar Camilo , McMillan W. Owen , Counterman Brian A. , Jiggins Chris D. , Martin Simon H.
Published: November 2017

Sex chromosomes are disproportionately involved in reproductive isolation and adaptation. In support of such a ‘large-X’ effect, genome scans between recently diverged populations or species pairs often identify distinct patterns of divergence on the sex chromosome compared to autosomes. When measures of divergence between populations are higher on the sex chromosome compared to autosomes, such patterns could be interpreted as evidence for faster divergence on the sex chromosome, i.e. ‘faster-X’, or barriers to gene flow on the sex chromosome. However, demographic changes can strongly skew divergence estimates and are not always taken into consideration. We used 224 whole genome sequences representing 36 populations from twoHeliconiusbutterfly clades (H. eratoandH. melpomene) to explore patterns of Z chromosome divergence. We show that increased divergence compared to equilibrium expectations can in many cases be explained by demographic change. AmongHeliconius eratopopulations, for instance, population size increase in the ancestral population can explain increased absolute divergence measures on the Z chromosome compared to the autosomes, as a result of increased ancestral Z chromosome genetic diversity. Nonetheless, we do identify increased divergence on the Z chromosome relative to the autosomes in parapatric or sympatric species comparisons that imply post-zygotic reproductive barriers. Using simulations, we show that this is consistent with reduced gene flow on the Z chromosome, perhaps due to greater accumulation of species incompatibilities. Our work demonstrates the importance of constructing an appropriate demographic null model in order to interpret patterns of divergence on the Z chromosome, but nonetheless provides evidence to support the Z chromosome as a strong barrier to gene flow in incipientHeliconiusbutterfly species.
Peptidomimetic blockade of MYB in acute myeloid leukemia
Authors: Ramaswamy Kavitha , Forbes Lauren , Minuesa Gerard , Gindin Tatyana , Brown Fiona , Kharas Michael , Krivtsov Andrei , Armstrong Scott , Still Eric , de Stanchina Elisa , Knoechel Birgit , Koche Richard , Kentsis Alex
Published: November 2017

Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, largely due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP)/P300 is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex at micromolar concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, led to the displacement of the MYB:CBP/P300 complex in cells, displacement of MYB from oncogenic enhancers and promoters enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. Both human MLL-rearranged and non-rearranged AML cells, underwent mitochondrial apoptosis in response to MYBMIM treatment, which could be partially rescued by ectopic expression of BCL2. We observed that MYBMIM treatment impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings emphasize the exquisite dependence of human AML on MYB:CBP/P300 transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.