bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenovirus infection and disease in recipients of hematopoietic cell transplantation
Authors: Dailey Garnes Natalie J.M. , Ragoonanan Dristhi , Aboulhosn Aya
Published: September 2019

Purpose of review

To provide an update on risk factors associated with adenovirus (ADV) infection in patients after hematopoietic cell transplant (HCT) and on options for ADV monitoring and treatment in the setting of HCT.

Recent findings

Among patients undergoing HCT, ADV infection continues to be more common amongst those receiving a T-cell-depleted or graft other than from a matched-related donor. Among children undergoing HCT, reactivation in the gastrointestinal tract appears to be the most common source, and the virus is detectable by quantitative PCR in the stool before it is detectable in the blood. Thus, screening for the virus in the stool of these children may allow for preemptive therapy to reduce mortality. Brincidofovir, although still not approved by any regulatory agency, remains a potential agent for preemptive therapy and for salvage in cases not responding to cidofovir. Rapidly generated off-the-shelf virus-specific T cells may facilitate adoptive cell therapy in populations with a special need and previously not eligible for adoptive cell therapy, such as cord blood recipients.

ADV infection continues to adversely affect survival in HCT recipients. Screening stool in children and preemptive therapy may reduce mortality. Brincidofovir and adoptive T-cell therapy remain potential options for treatment.
Resistant or refractory cytomegalovirus infections after hematopoietic cell transplantation: diagnosis and management
Authors: Khawaja Fareed , Batista Marjorie V. , El Haddad Lynn , Chemaly Roy F.
Published: September 2019

Purpose of review

Refractory or resistant cytomegalovirus (CMV) infections are challenging complications after hematopoietic cell transplantation (HCT). Most refractory or resistant CMV infections are associated with poor outcomes and increased mortality. Prompt recognition of resistant or refractory CMV infections, understanding the resistance pathways, and the treatment options in HCT recipients are imperative.

Recent findings

New definitions for refractory and resistant CMV infections in HCT recipients have been introduced for future clinical trials. Interestingly, refractory CMV infections are more commonly encountered in HCT recipients when compared with resistant CMV infections. CMV terminase complex mutations in UL56, UL89, and UL51 could be associated with letermovir resistance; specific mutations in UL56 are the most commonly encountered in clinical practice. Finally, brincidofovir, maribavir, letermovir, and CMV-specific cytotoxic T-cell therapy expanded our treatment options for refractory or resistant CMV infections.

Many advances have been made to optimize future clinical trials for management of refractory or resistant CMV infections, and to better understand new resistance mechanisms to novel drugs. New drugs or strategies with limited toxicities are needed to improve outcomes of difficult to treat CMV infections in HCT recipients.
Forecasting Patient Discharge Before Noon: A Comparison Between Holt's and Box-Jenkins' Models
Authors: Berríos Rolando A.
Published: September 2019

Background:

The uncertainty and ambiguity of not knowing how many patients will be discharged impact patient throughput in hospitals, causing concerns for responding to demand for admissions. Understanding the potential number of patients to be discharged can support caregivers, ability to concentrate on the range of interactions that patients require to ensure early discharge. Accurate forecasting of patients expected to be discharged by noon is beneficial in accommodating patients who need services and in achieving sustainable patient satisfaction.

Method:

Models to predict patient discharge before noon (DBN) were formulated using Holt's double exponential smoothing and Box-Jenkins' methods with the aim of achieving minimal errors in each model. The models are applied to 24 months of weekly patient discharge historic data in a medical observation unit and a short-stay clinical unit of a health care hospital system located on the East Coast of United States.

Results:

DBN prediction outcomes were more accurate when applying Box-Jenkins' method than Holt's method. Analysis revealed that the model of ARIMA(3,1,2) is most suitable for forecasting. Upon the outcomes of forecast error metrics, the study identifies the mean absolute percent error for the ARIMA model is 14%.

Conclusion:

Box-Jenkins forecasting performance is superior in predicting DBN with the least forecast error. Predicted values are significant to decision-making interventions aimed at taking new patients, improving quality patient care, and meeting patient throughput performance goals.
A National Cohort Study Evaluating the Association Between Short-term Outcomes and Long-term Survival After Esophageal and Gastric Cancer Surgery
Authors: van der Werf Leonie R. , Wijnhoven Bas P. L. , Fransen Laura F. C. , van Sandick Johanna W. , Nieuwenhuijzen Grard A. P. , Busweiler Linde A. D. , van Hillegersberg Richard , Wouters Michel W. J. M. , Luyer Misha D. P. , van Berge Henegouwen Mark I.
Published: September 2019

Objective:

The aim of this study was to investigate the association between short-term outcome indicators and long-term survival after esophagogastric resections.

Summary Background Data:

Short-term outcome indicators are often used to compare performance between care providers. Some short-term outcome indicators concern the direct quality of care, that is, complications, others are used because they are expected to be associated with long-term outcomes.

Method:

For this national cohort study, all patients who underwent esophagectomy or gastrectomy for cancer with curative intent between 2011 and 2016 and were registered in the Dutch Upper gastrointestinal Cancer Audit were included. Primary outcome was conditional survival (under the condition of surviving the first postoperative 30 days and hospital admission). Cox regression modeling was used to study the independent association between “textbook outcome” with survival. “Textbook outcome,” a composite quality indicator, was defined as a pathological complete resection with at least 15 retrieved lymph nodes, an uneventful postoperative course, and no hospital readmission.

Results:

In total, 4414 and 2943 patients with esophageal or gastric cancer, respectively, were included. The 1-, 2-, and 3-year overall survival rates were 76%, 62%, and 54%, and 71%, 56%, and 49% for esophageal and gastric cancer, respectively. Textbook outcome was achieved in 33% and 35% of patients respectively. “Textbook outcome” was independently associated with longer conditional survival [hazard ratio: 0.75 (95% confidence interval, 0.68–0.84) and 0.69 (0.60–0.79), respectively].

Conclusion:

This study showed that the short-term outcome indicator textbook outcome is associated with long-term overall survival and therefore may accentuate the importance of using these indicators in clinical audits.
The path forward for anti-programmed cell death-1 therapy in gliomas
Authors: Majd Nazanin , Kamiya-Matsuoka Carlos , de Groot John
Published: September 2019

Purpose of review

Checkpoint inhibitors (CPIs) represent the forefront of novel immunotherapeutic approaches for the treatment of solid cancers. However, the clinical development of CPIs in glioblastoma (GBM) has been challenging owing to an immunosuppressive tumor microenvironment and, possibly, low tumor mutation burden. Here, we review possible mechanisms responsible for the success of programmed cell death-1 (PD-1) blockade in patients with hypermutated GBM, recent clinical trials of anti-PD-1 monotherapy, trials incorporating neoadjuvant strategies, and trials of immunotherapy combination approaches in GBM. Mechanisms of resistance to immunotherapy and methods to overcome these challenges are also discussed.

Recent findings

Although two large phase III trials failed to demonstrate the superior efficacy of CPI in comparison with the standard of care in newly diagnosed and recurrent GBM, recent studies suggest that opportunities exist in some patients with GBM. A phase II study showed longer survival in patients with recurrent GBM who received neoadjuvant anti-PD-1 therapy than in those who received it as adjuvant therapy. In addition, cases of response to anti-PD-1 therapy in GBM patients with clonal hypermutator tumors have been reported.

Even though anti-PD-1 therapy does not seem to provide a benefit for molecularly unselected GBM patients, the success of PD-1 blockade in certain subsets of patients is encouraging.
Connecting the molecular function of microRNAs to cell differentiation dynamics
Authors: Posner Russell , Laubenbacher Reinhard
Published: September 2019

MicroRNAs form a class of short, non-coding RNA molecules which are essential for proper development in tissue-based plants and animals. To help explain their role in gene regulation, a number of mathematical and computational studies have demonstrated the potential canalizing effects of microRNAs. However, such studies have typically focused on the effects of microRNAs on only one or a few target genes. Consequently, it remains unclear how these small-scale effects add up to the experimentally observed developmental outcomes resulting from microRNA perturbation at the whole-genome level. To answer this question, we built a general computational model of cell differentiation to study the effect of microRNAs in genome-scale gene regulatory networks. Our experiments show that in large gene regulatory networks, microRNAs can control differentiation time without significantly changing steady-state gene expression profiles. This temporal regulatory role cannot be naturally replicated using protein-based transcription factors alone. While several microRNAs have been shown to regulate differentiation time
in vivo
, our findings provide a new explanation of how the cumulative molecular actions of individual microRNAs influence genome-scale cellular dynamics. Taken together, these results may help explain why tissue-based organisms exclusively depend on miRNA-mediated regulation, while their more primitive counterparts do not.
Anteroposterior balance reactions of children with and without cerebral palsy: a cross-sectional, observational study of children age 5-12 years
Authors: Crenshaw Jeremy R. , Petersen Drew A. , Conner Benjamin C. , Tracy James B. , Pigman Jamie , Wright Henry G. , Miller Freeman , Johnson Curtis L. , Modlesky Christopher M.
Published: September 2019

Aim

To compare anterior and posterior standing balance reactions, as measured by single-stepping thresholds, of children with and without cerebral palsy (CP).

Method

Seventeen ambulatory children with CP and 28 typically developing children, all 5-12 years of age, were recruited for this cross-sectional, observational study. Balance reaction skill was quantified as anterior and posterior single-stepping thresholds, or the treadmill-induced perturbations that consistently elicited a step in that direction. In order to understand underlying mechanisms of between-group differences in stepping thresholds, dynamic stability was quantified using the minimum margin of stability. Ankle muscle activation latency, magnitude, and co-contraction were assessed with surface electromyography.

Results

We observed large between-group differences in anterior, but not posterior, thresholds. Between-group differences were most evident in older children, with typically developing children having larger anterior thresholds than those with CP. In response to near-threshold anterior perturbations, older typically developing children recovered from more instability than their CP peers. Older children had no between-group differences in ankle muscle activity.

Interpretation

The effects of CP on balance reactions are age- and direction-specific. In response to an anterior perturbation, older typically developing children recovered from more instability than their peers with CP.

What this paper adds

Children with CP have age- and direction-specific balance-reaction impairments.

Impairment was most evident in the anterior reactions of older children (≈11 years).

Typically developing children recovered from more anterior instability than those with CP.

Graphical Abstract
Predicting Under-five mortality across 21 Low and Middle-Income Countries using Deep Learning Methods
Authors: Adegbosin Adeyinka E , Stantic Bela , Sun Jing
Published: September 2019

Objectives

To explore the efficacy of Machine Learning (ML) techniques in predicting under-five mortality in LMICs and to identify significant predictors of under-five mortality (U5M).

Design

This is a cross-sectional, proof-of-concept study.

Settings and participants

We analysed data from the Demographic and Health Survey (DHS). The data was drawn from 21 Low-and-Middle Income Countries (LMICs) countries (N = 1,048,575). Eligible mothers in each household were asked information about their children and the reproductive care they received during the pregnancy.

Primary and secondary outcome measures

The primary outcome measure was under-five mortality; secondary outcome was comparing the efficacy of deep learning algorithms: Deep Neural Network (DNN); Convolution Neural Network (CNN); Hybrid CNN-DNN with Logistic Regression (LR) for the prediction of child survival.

Results

We found that duration of breast feeding, household wealth index and the level of maternal education are the most important predictors of under-five mortality. We found that deep learning techniques are superior to LR for the classification of child survival: LR sensitivity = 0.47, specificity = 0.53; DNN sensitivity = 0.69, specificity = 0.83; CNN sensitivity = 0.68, specificity = 0.83; CNN-DNN sensitivity = 0.71, specificity = 0.83.

Conclusion

Our findings provide an understanding of interventions that needs to be prioritized, in order to reduce levels of U5M in LMICs. It also demonstrates that deep learning models are more efficacious than a traditional analytical approach.

Strengths and limitations of this study

The models were tested using a very large data sample, drawn from over 1 million households.

The survey utilised a cluster sampling approach and are representative of each country included.

Socio-economic, political and cultural differences between the included countries may limit generalisability of the results.

The cross-sectional design of the study means we can only infer association and not causality.
Evaluation of Reproducibility in Urology Publications
Authors: Rauh Shelby Lynn , Johnson Bradley S. , Bowers Aaron , Tritz Daniel , Vassar Benjamin Matthew
Published: September 2019

Take Home Message

Many components of transparency and reproducibility are lacking in urology publications, making study replication, at best, difficult.

Introduction

Reproducibility is essential for the integrity of scientific research. Reproducibility is measured by the ability of investigators to replicate the outcomes of an original publication by using the same materials and procedures.

Methods

We sampled 300 publications in the field of urology for assessment of multiple indicators of reproducibility, including material availability, raw data availability, analysis script availability, pre-registration information, links to protocols, and whether the publication was freely available to the public. Publications were also assessed for statements about conflicts of interest and funding sources.

Results

Of the 300 sample publications, 171 contained empirical data and could be analyzed for reproducibility. Of the analyzed articles, 0.58% (1/171) provided links to protocols, and none of the studies provided analysis scripts. Additionally, 95.91% (164/171) did not provide accessible raw data, 97.53% (158/162) did not provide accessible materials, and 95.32% (163/171) did not state they were pre-registered.

Conclusion

Current urology research does not consistently provide the components needed to reproduce original studies. Collaborative efforts from investigators and journal editors are needed to improve research quality, while minimizing waste and patient risk.
Cannabis, Connectivity, and Coming of Age: Associations between Cannabis Use and Anterior Cingulate Cortex Connectivity during the Transition to Adulthood
Authors: Lichenstein Sarah D. , Shaw Daniel S. , Forbes Erika E.
Published: September 2019

Background

Cannabis use is common among adolescents and emerging adults and is associated with significant adverse consequences for a subset of users. Rates of use peak between the ages of 18-25, yet the neurobiological consequences for neural systems that are actively developing during this time remain poorly understood. In particular, cannabis exposure may interfere with adaptive development of white matter pathways underlying connectivity of the anterior cingulate cortex, including the cingulum and anterior thalamic radiations (ATR).

Methods

The current study examined the association between cannabis use during adolescence and emerging adulthood and white matter microstructure of the cingulum and ATR among 158 male subjects enrolled in the Pitt Mother & Child Project, a prospective, longitudinal study of risk and resilience among men of low socioeconomic status. Participants were recruited in infancy, completed follow-up assessments throughout childhood and adolescence, and underwent diffusion imaging at age 20 and 22.

Results

At age 20, moderate cannabis use across adolescence (age 12-19) was associated with higher fractional anisotropy of the cingulum and ATR, relative to both minimal and heavy adolescent use. Longitudinally, moderate and heavy extended cannabis use (age 12-21) was associated with reduced positive change in FA in both pathways from age 20 to 22, relative to minimal use.

Conclusions

These results suggest that precocious white matter development may be linked to increased risk for use, whereas cannabis exposure may delay white matter maturation during the transition to adulthood and potentially impact individuals’ functioning later in development.
Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition
Authors: Nido Gonzalo S. , Dick Fiona , Toker Lilah , Petersen Kjell , Alves Guido , Tysnes Ole-Bjørn , Jonassen Inge , Haugarvoll Kristoffer , Tzoulis Charalampos
Published: September 2019

Background

The etiology of Parkinson’s disease (PD) is largely unknown. Genome-wide transcriptomic studies in bulk brain tissue have identified several molecular signatures associated with the disease. While these studies have the potential to shed light into the pathogenesis of PD, they are also limited by two major confounders: RNA post mortem degradation and heterogeneous cell type composition of bulk tissue samples. We performed RNA sequencing following ribosomal RNA depletion in the prefrontal cortex of 49 individuals from two independent case-control cohorts. Using cell-type specific markers, we estimated the cell-type composition for each sample and included this in our analysis models to compensate for the variation in cell-type proportions.

Results

Ribosomal RNA depletion results in substantially more even transcript coverage, compared to poly(A) capture, in post mortem tissue. Moreover, we show that cell-type composition is a major confounder of differential gene expression analysis in the PD brain. Correcting for cell-type proportions attenuates numerous transcriptomic signatures that have been previously associated with PD, including vesicle trafficking, synaptic transmission, immune and mitochondrial function. Conversely, pathways related to endoplasmic reticulum, lipid oxidation and unfolded protein response are strengthened and surface as the top differential gene expression signatures in the PD prefrontal cortex.

Conclusions

Differential gene expression signatures in PD bulk brain tissue are significantly confounded by underlying differences in cell-type composition. Modeling cell-type heterogeneity is crucial in order to unveil transcriptomic signatures that represent regulatory changes in the PD brain and are, therefore, more likely to be associated with underlying disease mechanisms.
Closed mitosis requires local disassembly of the nuclear envelope
Authors: Dey Gautam , Culley Siân , Curran Scott , Henriques Ricardo , Kukulski Wanda , Baum Buzz
Published: September 2019

At the end of mitosis, eukaryotic cells must segregate both copies of their replicated genome into two new nuclear compartments (1). They do this either by first dismantling and later reassembling the nuclear envelope in a so called “open mitosis”, or by reshaping an intact nucleus and then dividing into two in a “closed mitosis” (2, 3). However, while mitosis has been studied in a wide variety of eukaryotes for over a century (4), it is not known how the double membrane of the nuclear envelope is split into two at the end of a closed mitosis without compromising the impermeability of the nuclear compartment (5). In studying this problem in the fission yeastSchizosaccharomyces pombe, a classical model for closed mitosis (5), we use genetics, live cell imaging and electron tomography to show that nuclear fission is achieved via local disassembly of the nuclear envelope (NE) within the narrow bridge that links segregating daughter nuclei. In doing so, we identify a novel inner NE-localised protein Les1 that restricts the process of local NE breakdown (local NEB) to the bridge midzone and prevents the leakage of material from daughter nuclei. The mechanics of local NEB in a closed mitosis closely mirror those of NEB in open mitosis (3), revealing an unexpectedly deep conservation of nuclear remodelling mechanisms across diverse eukaryotes.
Tissue ingrowth markedly reduces mechanical anisotropy and stiffness in fibre direction of highly aligned electrospun polyurethane scaffolds
Authors: Krynauw Hugo , Buescher Jannik , Koehne Josepha , Verrijt Loes , Limbert Georges , Davies Neil H , Bezuidenhout Deon , Franz Thomas
Published: September 2019

Purpose

The lack of long-term patency of synthetic vascular grafts currently available on the market has directed research towards improving the performance of small diameter grafts. Improved radial compliance matching and tissue ingrowth into the graft scaffold are amongst the main goals for an ideal vascular graft.

Methods

Biostable polyurethane scaffolds were manufactured by electrospinning and implanted in subcutaneous and circulatory positions in the rat for 7, 14 and 28 days. Scaffold morphology, tissue ingrowth, and mechanical properties of the scaffolds were assessed before implantation and after retrieval.

Results

Tissue ingrowth after 24 days was 96.5 ± 2.3% in the subcutaneous implants and 77.8 ± 5.4% in the circulatory implants. Over the 24 days implantation, the elastic modulus at 12% strain decreased by 59% in direction of the fibre alignment whereas it increased by 1379% transverse to the fibre alignment of the highly aligned scaffold of the subcutaneous implants. The lesser aligned scaffold of the circulatory graft implants exhibited an increase of the elastic modulus at 12% strain by 77% in circumferential direction.

Conclusion

Based on the observations, it is proposed that the mechanism underlying the softening of the highly aligned scaffold in the predominant fibre direction is associated with scaffold compaction and local displacement of fibres by the newly formed tissue. The stiffening of the scaffold, observed transverse to highly aligned fibres and for more a random fibre distribution, represents the actual mechanical contribution of the tissue that developed in the scaffold.
Illuminating the dark side of the human transcriptome with TAMA Iso-Seq analysis
Authors: Kuo Richard I. , Cheng Yuanyuan , Smith Jacqueline , Archibald Alan L. , Burt David W.
Published: September 2019

The human transcriptome is one of the most well-annotated of the eukaryotic species. However, limitations in technology biased discovery toward protein coding spliced genes. Accurate high throughput long read RNA sequencing now has the potential to investigate genes that were previously undetectable. Using our Transcriptome Annotation by Modular Algorithms (TAMA) tool kit to analyze the Pacific Bioscience Universal Human Reference RNA Sequel II Iso-Seq dataset, we discovered thousands of potential novel genes and identified challenges in both RNA preparation and long read data processing that have major implications for transcriptome annotation.
Disease swamps molecular signatures of genetic-environmental associations to abiotic factors in Tasmanian devil (Sarcophilus harrisii) populations
Authors: Fraik Alexandra K. , Margres Mark J. , Epstein Brendan , Barbosa Soraia , Jones Menna , Hendricks Sarah , Schönfeld Barbara , Stahlke Amanda R. , Veillet Anne , Hamede Rodrigo , McCallum Hamish , Lopez-Contreras Elisa , Kallinen Samantha J. , Hohenlohe Paul A. , Kelley Joanna L. , Storfer Andrew
Published: September 2019

Landscape genomics studies focus on identifying candidate genes under selection via spatial variation in abiotic environmental variables, but rarely by biotic factors such as disease. The Tasmanian devil (Sarcophilus harrisii) is found only on the environmentally heterogeneous island of Tasmania and is threatened with extinction by a nearly 100% fatal, transmissible cancer, devil facial tumor disease (DFTD). Devils persist in regions of long-term infection despite epidemiological model predictions of species’ extinction, suggesting possible adaptation to DFTD. Here, we test the extent to which spatial variation and genetic diversity are associated with the abiotic environment and/or by DFTD. We employ genetic-environment association (GEAs) analyses using a RAD-capture panel consisting of 6,886 SNPs from 3,286 individuals sampled pre- and post-disease arrival. Pre-disease, we find significant correlations of allele frequencies with environmental variables, including 349 unique loci linked to 64 genes, suggesting local adaptation to abiotic environment. Following DFTD arrival, however, we detected few of the pre-disease candidate loci, but instead frequencies of candidate loci linked to 14 genes correlated with disease prevalence. Loss of apparent signal of abiotic local adaptation following disease arrival suggests swamping by the strong selection imposed by DFTD. Further support for this result comes from the fact that post-disease candidate loci are in linkage disequilibrium with genes putatively involved in immune response, tumor suppression and apoptosis. This suggests the strength GEA associations of loci with the abiotic environment are swamped resulting from the rapid onset of a biotic selective pressure.
Processive activity of the replicative DNA polymerases in the replisome of live eukaryotic cells
Authors: Kapadia Nitin , El-Hajj Ziad W. , Zheng Huan , Beattie Thomas R. , Yu Angela , Reyes-Lamothe Rodrigo
Published: September 2019

DNA replication is carried out by a multi-protein machine called the replisome. InSaccharomyces cerevisiae, the replisome is composed of over 30 different proteins arranged into multiple subassemblies, each performing distinct activities. Synchrony of these activities is required for efficient replication and preservation of genomic integrity. How this is achieved is particularly puzzling at the lagging strand, where current models of the replisome architecture propose turnover of the canonical lagging strand polymerase, Pol δ, at every cycle of Okazaki fragment synthesis. Here we established single-molecule fluorescence microscopy protocols to study the binding kinetics of individual replisome subunits in liveS. cerevisiae. Our results show long residence times for most subunits at the active replisome, supporting a model where all subassemblies bind tightly and work in a coordinated manner for extended periods, including Pol δ, hence redefining the architecture of the active eukaryotic replisome.
Single cell transcriptome profiling of the human alcohol-dependent brain
Authors: Brenner Eric , Tiwari Gayatri R. , Liu Yunlong , Brock Amy , Mayfield R. Dayne
Published: September 2019

Background

Alcoholism remains a prevalent health concern throughout the world. Previous studies have identified transcriptomic patterns in the brain associated with alcohol dependence in both humans and animal models. But none of these studies have systematically investigated expression within the unique cell types present in the brain.

Results

We utilized single nucleus RNA sequencing (snRNA-seq) to examine the transcriptomes of over 16,000 nuclei isolated from prefrontal cortex of alcoholic and control individuals. Each nucleus was assigned to one of seven major cell types by unsupervised clustering. Cell type enrichment patterns varied greatly among neuroinflammatory-related genes, which are known to play roles in alcohol dependence and neurodegeneration. Differential expression analysis identified cell type-specific genes with altered expression in alcoholics. The largest number of differentially expressed genes (DEGs), including both protein-coding and non-coding, were detected in astrocytes, oligodendrocytes, and microglia.

Conclusions

To our knowledge, this is the first single cell transcriptome analysis of alcohol-associated gene expression in any species, and the first such analysis in humans for any addictive substance. These findings greatly advance understanding of transcriptomic changes in the brain of alcohol-dependent individuals.
HYPK scaffolds the Nedd8 and LC3 proteins to initiate formation of autophagosome around polyneddylated huntingtin exon1 aggregates
Authors: Ghosh Debasish Kumar , Ranjan Akash
Published: September 2019

Selective degradation of protein aggregates by autophagy is an essential homeostatic process of safeguarding cells from the effects of proteotoxicity. Among the ubiquitin-like modifier proteins, Nedd8 conjugation to misfolded proteins is prominent in stress-induced protein aggregates, albeit the function of neddylation in autophagy is unclear. Here, we report that polyneddylation functions as a post-translational modification for autophagic degradation of proteotoxic-stress induced protein aggregates. We also show that HYPK functions as an autophagy receptor in the polyneddylation-dependent aggrephagy. The scaffolding function of HYPK is facilitated by its C-terminal ubiquitin-associated domain and N-terminal tyrosine-type LC3 interacting region which bind to Nedd8 and LC3 respectively. Both Nedd8 and HYPK are positive modulators of basal and induced-autophagy, leading to desensitizing cells from protein aggregates, such as aggregates of mutant huntingtin-exon1. Thus, we propose an additive role of neddylation and HYPK in clearance of protein aggregates by autophagy, resulting in cytoprotective effect during proteotoxic stress.
Hue tuning curves in V4 change with visual context
Authors: Benjamin Ari S. , Ramkumar Pavan , Fernandes Hugo , Smith Matthew , Kording Konrad P.
Published: September 2019

Neurons are often probed by presenting a set of stimuli that vary along one dimension (e.g. color) and quantifying how this stimulus property affect neural activity. An open question, in particular where higher-level areas are involved, is how much tuning measured with one stimulus set reveals about tuning to a new set. Here we ask this question by estimating tuning to hue in macaque V4 from a set of natural scenes and a set of simple color stimuli. We found that hue tuning was strong in each dataset but was not correlated across the datasets, a finding expected if neurons have strong mixed selectivity. We also show how such mixed selectivity may be useful for transmitting information about multiple dimensions of the world. Our finding suggest that tuning in higher visual areas measured with simple stimuli may thus not generalize to naturalistic stimuli.

New & Noteworthy

Visual cortex is often investigated by mapping neural tuning to variables selected by the researcher such as color. How much does this approach tell us a neuron’s general ‘role’ in vision? Here we show that for strongly hue-tuned neurons in V4, estimating hue tuning from artificial stimuli does not reveal the hue tuning in the context of natural scenes. We show how models of optimal information processing suggest that such mixed selectivity maximizes information transmission.
Long-read-based Human Genomic Structural Variation Detection with cuteSV
Authors: Jiang Tao , Liu Bo , Jiang Yue , Li Junyi , Gao Yan , Cui Zhe , Liu Yadong , Wang Yadong
Published: September 2019

Long-read sequencing enables the comprehensive discovery of structural variations (SVs). However, it is still non-trivial to achieve high sensitivity and performance simultaneously due to the complex SV characteristics implied by noisy long reads. Therefore, we propose cuteSV, a sensitive, fast and scalable long-read-based SV detection approach. cuteSV uses tailored methods to collect the signatures of various types of SVs and employs a clustering-and-refinement method to analyze the signatures to implement sensitive SV detection. Benchmarks on real PacBio and ONT datasets demonstrate that cuteSV has better yields and scalability than state-of-the-art tools. cuteSV is available at https://github.com/tjiangHIT/cuteSV.
Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers
Authors: Markunas Christina A. , Semick Stephen A. , Quach Bryan C. , Tao Ran , Deep-Soboslay Amy , Bierut Laura J. , Hyde Thomas M. , Kleinman Joel E. , Johnson Eric O. , Jaffe Andrew E. , Hancock Dana B.
Published: September 2019

Numerous DNA methylation (DNAm) biomarkers of cigarette smoking have been identified in peripheral blood studies, but their relevance as neurobiological indicators is unknown due to DNAm tissue-specificity. In contrast, blood-based studies may not detect brain-specific smoking-related DNAm differences that may provide greater insight into the neurobiology of smoking behaviors. We report the first epigenome-wide association study (EWAS) of smoking in human postmortem brain, focusing on nucleus accumbens (NAc) as a key brain region in developing addiction. Following Illumina HumanMethylation EPIC array data generation and quality control, 221 decedents (120 European American [23% current smokers], 101 African American [26% current smokers]) were analyzed. DNAm by smoking (current vs. nonsmoking) was tested using robust linear regression models adjusted for age, sex, cell-type proportion, DNAm-derived negative control principal components (PCs), and genotype-derived PCs. Separate ancestry-specific results were combined via meta-analysis, resulting in 7 CpGs that exceeded false discovery rate (FDR)<0.05. Using published smoking EWAS results in blood, we extended our NAc findings to identify DNAm smoking effects that are unique (tissue-specific) versus shared between tissues (tissue-shared). Of the 7 CpGs identified in NAc, 3 CpGs were located near genes previously indicated with blood-based smoking DNAm biomarkers: ZIC1, ZCCHC24, and PRKDC. The other 4 CpGs are novel for smoking-related DNAm changes: ABLIM3, APCDD1L, MTMR6, and CTCF. Our results provide the first evidence for smoking-related DNAm changes in human NAc, highlighting CpGs that were previously undetected as peripheral biomarkers and may reflect brain-specific processes.
PHF2 regulates homology-directed DNA repair by controlling the resection of DNA double strand breaks
Authors: Alonso-de Vega Ignacio , Paz-Cabrera M. Cristina , Wiegant Wouter W. , Checa-Rodríguez Cintia , Huertas Pablo , Freire Raimundo , van Attikum Haico , Smits Veronique A.J.
Published: September 2019

Post-translational histone modifications and chromatin remodelling play a critical role in the mechanisms controlling the integrity of the genome. Here we identify histone lysine demethylase PHF2 as a novel regulator of the DNA damage response by regulating the balance between DNA damage-induced focus formation by 53BP1 and BRCA1, critical factors in the pathway choice for DNA double strand break repair. PHF2 knock down leads to impaired BRCA1 focus formation and delays the resolution of 53BP1 foci. Moreover, irradiation-induced RPA phosphorylation and focus formation, as well as localization of CtIP, required for DNA end resection, to sites of DNA lesions are affected by depletion of PHF2. These results are indicative of a defective resection of double strand breaks and thereby an impaired homologous recombination upon PHF2 depletion. In accordance with these data, Rad51 focus formation and homology-directed double strand break repair is inhibited in cells depleted for PHF2. Importantly, we demonstrate that PHF2 knock down decreases CtIP and BRCA1 protein and mRNA levels and cells depleted of PHF2 display genome instability and are sensitive to the inhibition of PARP. Together these results demonstrate that PHF2 promotes DNA repair by homologous recombination by controlling CtIP-dependent resection of double strand breaks.
Corporate tax disclosure on a CSR basis: a new reporting framework in the post-BEPS era
Authors: De la Cuesta-González Marta , Pardo Eva
Published: September 2019

Purpose

The purpose of this paper is to explore the emerging discourse on corporate taxation from a corporate social responsibility perspective to develop a consensual definition of corporate tax responsibility (CTR) and to identify a set of indicators that firms should publicly communicate to their stakeholders as an accountability mechanism.

Design/methodology/approach

Data were obtained from semi-structured interviews with representatives of stakeholders closely related to taxation: tax authorities, companies, NGOs, tax advisors and academics. Based on a discourse analysis approach, data were coded and analyzed using computer-assisted qualitative data analysis software.

Findings

CTR is defined as the set of tax-related practices and policies that allow companies to pay a fair share of taxes as a function of the generated value in each jurisdiction in which they operate and to then publicly disclose them. Disclosure should cover disaggregated quantitative data and information on practices and policies.

Originality/value

Despite the wealth of research on sustainability reporting and increasing public awareness of tax aggressiveness and disclosure, academic research has not explored tax-responsible reporting. Moreover, no consensual definition of CTR has been formulated, and no indicators to properly account for responsible taxation have been identified. This paper contributes to filling these gaps by providing rich interview evidence regarding the nature of the emerging discourse on CTR reporting and a set of material indicators for CTR disclosure. This paper encourages researchers to foster the development of social accountability by engaging in future empirical studies of CTR.
A scheme for the sticky policy representation supporting secure cyber-threat intelligence analysis and sharing
Authors: Osliak Oleksii , Saracino Andrea , Martinelli Fabio
Published: September 2019

Purpose

This paper aims to propose a structured threat information expression (STIX)-based data representation for privacy-preserving data analysis to report format and semantics of specific data types and to represent sticky policies in the format of embedded human-readable data sharing agreements (DSAs). More specifically, the authors exploit and extend the STIX standard to represent in a structured way analysis-ready pieces of data and the attached privacy policies.

Design/methodology/approach

The whole scheme is designed to be completely compatible with the STIX 2.0 standard for cyber-threat intelligence (CTI) representation. The proposed scheme will be implemented in this work by defining the complete scheme for representing an email, which is more expressive than the standard one defined for STIX, designed specifically for spam email analysis.

Findings

Moreover, the paper provides a new scheme for general DSA representation that has been practically applied for the process of encoding specific attributes in different CTI reports.

Research limitations/implications

Because of the chosen approach, the research results may have limitations. Specifically, current practice for entity recognition has the limitation that was discovered during the research. However, its effect on process time was minimized and the way for improvement was proposed.

Originality/value

This paper has covered the existing gap including the lack of generality in DSA representation for privacy-preserving analysis of structured CTI. Therefore, the new model for DSA representation was introduced, as well as its practical implementation.
Leveraging open-standard interorganizational information systems for process adaptability and alignment
Authors: Pu Xiaodie , Chong Alain Yee Loong , Cai Zhao , Lim Ming K. , Tan Kim Hua
Published: September 2019

Purpose

The purpose of this paper is to understand the value creation mechanisms of open-standard inter-organizational information system (OSIOS), which is a key technology to achieve Industry 4.0. Specifically, this study investigates how the internal assimilation and external diffusion of OSIOS help manufactures facilitate process adaptability and alignment in supply chain network.

Design/methodology/approach

A survey instrument was designed and administrated to collect data for this research. Using three-stage least squares estimation, the authors empirically tested a number of hypothesized relationships based on a sample of 308 manufacturing firms in China.

Findings

The results of the study show that OSIOS can perform as value creation mechanisms to enable process adaptability and alignment. In addition, the impact of OSIOS internal assimilation is inversely U-shaped where the positive effect on process adaptability will become negative after an extremum point is reached.

Originality/value

This study contributes to the existing literature by providing insights on how OSIOS can improve supply chain integration and thus promote the achievement of industry 4.0. By revealing a U-shaped relationship between OSIOS assimilation and process adaptability, this study fills previous research gap by advancing the understanding on the value creation mechanisms of information systems deployment.
Unemployment and self-rated health in Ghana: are there gender differences?
Authors: Sulemana Iddisah , Anarfo Ebenezer Bugri , Doabil Louis
Published: September 2019

Purpose

A large extant literature examines the association between unemployment and self-rated health. Most of these studies reveal that unemployment diminishes self-rated health. Another strand of this literature, albeit sparse, suggests that the relationship between unemployment and self-rated health is gendered. The purpose of this paper is twofold: first, to examine whether unemployment is correlated with self-rated health in Ghana; and second, to explore whether and to what extent men differ from women on the basis of this relationship.

Design/methodology/approach

The authors used data from the Wave 6 of World Values Survey in Ghana (n=1552) and probit and instrumental variable probit regressions to empirically examine the association between unemployment and self-rated health in Ghana.

Findings

The results confirm that unemployment is negatively correlated with self-rated health among Ghanaians. Specifically, the unemployed are about 6.84–7.20 percent less likely to report good health status in a pooled sample. Further, after correcting for endogeneity, unemployed men are about 26.68 percent less likely to report good health. However, the association is not statistically significant for unemployed women.

Originality/value

The study contributes to the literature by providing empirical evidence from Ghana.
Power-based behaviors between supply chain partners of diverse national and organizational cultures: the crucial role of boundary spanners’ cultural intelligence
Authors: Murphy Wiliam H. , Gölgeci Ismail , Johnston David A.
Published: September 2019

Purpose

This paper aims to explain the effects of national and organizational cultures of boundary spanners on their choices of using three archetype power-based behaviors – dominance, egalitarian and submissive – with supply chain partners. Improved outcomes for global supply chain (GSC) partners are anticipated due to the ways that cultural intelligence affects these culturally guided decisions.

Design/methodology/approach

Drawing on multiple streams of literature and focusing on boundary spanners in GSCs, the authors build a conceptual framework that highlights cultural antecedents of predispositions toward power-based behaviors and explains the moderating role of cultural intelligence of boundary spanners on behaviors performed.

Findings

The authors propose that boundary spanners’ national and organizational cultural values influence predispositions toward applying and accepting power-based behaviors. They also discuss how cultural intelligence moderates the relationship between culturally determined predispositions and power-based behaviors applied by partners. The cultural intelligence of boundary spanners is argued to have a pivotal role in making power-based decisions, resulting in healthier cross-cultural buyer–supplier relationships.

Originality/value

This paper is the first paper to advance an understanding of the cultural antecedents of boundary spanners’ power-based behaviors that are exercised and interpreted by partners in GSCs. Furthermore, the potential role of cultural intelligence in inter-organizational power dynamics and power-based partner behaviors in supply chains has not previously been discussed.
Reputational risk management in conditions of credibility gap in the banking system
Authors: Trostianska Karyna , Semencha Ilona
Published: September 2019

Purpose

This paper aims to provide appropriate and effective methods for diagnosing and managing the reputational risk of a bank.

Design/methodology/approach

Using the data-mining system CONFOR, the authors have defined and arranged in the objective way the factors influencing the reputational risk level of a bank, with specific factor groups assigned. The mathematical tools of the theory of graphs and cognitive mapping are used for building the cognitive map of reputational risk assessment of a bank. To enable choosing which risk management strategies to use, the methods of impulse modeling and scenario analysis are applied for the purpose of prognostication.

Findings

The authors proposed an integrated approach to the objective determination of the reputational risk level and an easy-to-use choice of risk management scenarios considering all components of management decision making and the main managerial functions.

Practical implications

The range of tools proposed can be used as a simple measure of the bank's reputational risk level, as a component of risk management model, and as a strategic risk management tool. Implementing this approach at the level of the central bank will facilitate realization of its strategic program for restoring confidence in the banking system as a whole.

Originality/value

A relatively greater objectivity in the reputational risk assessment of the bank was achieved, with each stage formalized and confirmed by an economic and mathematical basis, risk parameters quantified. The authors have developed a comprehensive approach to the reputational risk level assessment (the integral assessment included) as well as the management algorithm.