bluuebunny/crossref_metadata_2025 huggingface dataset:
A first case report of primary epithelial myoepithelial carcinoma-like renal tumor showing a perivascular pseudorosette-like pattern
Authors: Li Qiuyao , Mou Zheng , Yang Kun , Jiang Huifeng
Published: September 2019

Rationale:

Over the past decade, although several new entities of renal tumors have emerged, a form of renal cell carcinoma (RCC) that morphologically resembles epithelial-myoepithelial carcinoma has not been reported thus far. Herein, we describe a case of an unusual renal tumor that remained unclassified under a current RCC subtype, and briefly present its morphologic, immunophenotypic, and genetic features.

Patient concerns:

The patient was an 85-year-old man who presented with hematuria and flank pain. Imaging studies revealed a left renal mass without enlarged lymph nodes. There were no abnormal masses or nodules in other organs.

Diagnoses:

The patient underwent no other treatment except the left radical nephrectomy under a clinical diagnosis of invasive urothelial carcinoma and was discharged on the thirteenth day. Histologically, the renal tumor showed biphasic proliferation of epithelial (strongly cytokeratin-positive; P63, P40, and vimentin-negative) and myoepithelial (strongly vimentin-positive; focal P63 and P40-positive; and weakly cytokeratin-positive) cells arranged in a perivascular pseudorosette-like pattern. No mutations were detected in multiple gene tests. According to the pathological structure, the patient was diagnosed as primary epithelial myoepithelial carcinoma-like renal tumor.

Interventions:

To the best of our knowledge, the present tumor has not been previously described, and thus, this variant has not been integrated into a known form of PCC. Therefore, we cannot diagnose this type of tumor with other types of kidney tumors.

Outcomes:

Three years after primary diagnosis, the patient died of multiple organ failure result from multiple distant metastases.

Lessons:

We present the first case of carcinoma of the kidney with EMC-like features and a perivascular pseudorosette-like growth pattern. Clinicians should be aware of the features of this uncommon variant of RCC to avoid diagnostic delays or misdiagnosis and prevent unnecessary or inappropriate treatment.
Underlying nonalcoholic fatty liver disease is a significant factor for breast cancer recurrence after curative surgery
Authors: Lee Young-Sun , Lee Ha Seok , Chang Sung Won , Lee Chan Uk , Kim Jung Sun , Jung Young Kul , Kim Ji Hoon , Seo Yeon Seok , Yim Hyung Joon , Lee Chang Hee , Woo Sang Uk , Seo Jae Hong , Yeon Jong Eun , Um Soon Ho , Byun Kwan Soo
Published: September 2019

Breast cancer is the most common cancer among women worldwide, and it is a main cause of death in women. As with breast cancer, metabolic components are important risk factors for the development of nonalcoholic fatty liver disease (NAFLD). In this retrospective cohort study, we aimed to determine the prevalence of NAFLD in patients with breast cancer and the impact of NAFLD on the prognosis of breast cancer.

Patients with breast cancer were enrolled in the study from January 2007 to June 2017. Hepatic steatosis was evaluated through non-enhanced computed tomography scan by measuring Hounsfield Units in the liver and spleen, respectively; 123 healthy controls who underwent non-enhanced computed tomography scan were also analyzed.

The prevalence of NAFLD in patients with breast cancer was 15.8% (251/1587), which was significantly higher than in healthy controls (8.9%, 11/123) (P = .036). Overall survival did not significantly differ between the groups with and without NAFLD (P = .304). However, recurrence-free survival was significantly higher in patients without NAFLD than in those with NAFLD (P = .009). Among breast cancer patients receiving endocrine treatment, the NAFLD group showed a higher cumulative incidence of significant liver injury than the group without NAFLD (P < .001).

The prevalence of NAFLD in patients with breast cancer is significantly higher than in healthy controls. Moreover, breast cancer patients with NAFLD showed poorer prognosis in terms of recurrence. Therefore, diagnostic evaluation for NALFD is important in managing patients with breast cancer.
Effect of the angiotensin-receptor-neprilysin inhibitor in heart failure patients with left ventricular ejection fraction higher than 40%: Retracted
Authors: Zhao Mingyue , Xin Yanguo , Li Junli , Cao Xiaofan , Liu Xiaojing
Published: September 2019

The angiotensin-receptor-neprilysin inhibitor (ARNI) reduced cardiovascular deaths and heart failure hospitalization in patients with heart failure of reduced ejection fraction (HFrEF). Its role in non-HFrEF patients was not clear. This study aims to answer this question.

In this retrospective study, we enrolled 928 patients diagnosed with non-HFrEF, 492 of them received angiotensin converting enzyme inhibitor (ACEI) and the rest 436 received angiotensin-receptor-neprilysin inhibitor. Outcomes were compared by Kaplan-Meier survival analysis and various clinical parameters were investigated using Cox multivariable analysis, followed by interaction analysis. Minnesota living with heart failure Questionnaire (MLHFQ) was employed as one of the criteria to assess heart failure outcome.

The cardiovascular (CV) death or HF hospitalization at 24 months occurred in 49 patients in ACEI group compared with 31 in ARNI group (Hazard Ratio (HR): 1.231, 95% confidence Interval (CI): 1.080–2.460, P = .031). And ARNI showed better prognosis of HF hospitalization (HR: 1.283, 95%CI: 1.065–1.360, P = .038). Cumulative Kaplan-Meier estimates of endpoints, ARNI could reduce the incidence of CV death or HF hospitalization (P = .042) and HF hospitalization (P = .035). The stratified analysis revealed that participants with age less than 70 years old had a lower incidence of CV death or HF hospitalization (HR: 1.194, 95%CI: 1.011–1992, P = .031) after treated with ARNI. Patients received diuretics could benefit from ARNI (HR: 1.383, 95%CI: 1.082–1.471, P = .019). Similar results were also observed in patients with heart rate lower than 90 bpm (HR: 1.556, 95%CI: 1.045–2.386, P = .003) and patients with atrial fibrillation history (HR: 1.873, 95%CI: 1.420–2.809, P = .011). ARNI could improve the quality of life both from the total, emotional and physical aspects.

ARNI is an efficacy treatment strategy to improve the outcome and quality of life in patients with non-HFrEF.
Effect of intraoperative position in single-level transforaminal lumbar interbody fusion at the L4/5 level on segmental and overall lumbar lordosis in patients with lumbar degenerative disease
Authors: Miyazaki Masashi , Ishihara Toshinobu , Abe Tetsutaro , Kanezaki Shozo , Notani Naoki , Kataoka Masashi , Tsumura Hiroshi
Published: September 2019

The purpose of this study was to investigate the effect of intraoperative positions in single-level (L4–5) transforaminal lumbar interbody fusion (TLIF) on segmental and overall lumbar lordosis (LL) in patients with lumbar degenerative disease. Thirty-eight consecutive patients who had undergone single-segment (L4–5) TLIF with 0° polyetheretherketone (PEEK) cage and pedicle screw fixation were evaluated. Twenty patients underwent surgery on the four-poster type frame with hip flexion at 30° (Group I) and 18 patients were operated on a Jackson spinal table to adjust their hip flexion to 0° (Group II). Preoperative standing, intraoperative prone, and postoperative standing lateral radiographs were obtained in each patient. The overall and segmental LL were analyzed according to the position in which the patients were placed for their operation and results compared between Groups I and II. Intraoperative intervertebral segmental LL at L4–5 and L5–S1 was increased in Group II than in Group I, whereas postoperative intervertebral segmental LL at L4–5 (fused level) was increased LL. In Group I intraoperative intervertebral segmental LL at L4–5 did not achieve sufficient lordosis, whereas postoperative intervertebral segmental LL at L3–4 was increased. The overall spinal alignment was unaffected by the decreased segmental LL in the fused level owing to the compensation of the upper adjacent segments. The more the hip was extended intraoperatively, the more the segmental lordosis increased in the lower lumbar spine. Thus, selecting the appropriate surgical table and hip position are very important. Underachievement of segmental lordosis leads to the acceleration of upper adjacent segment load.
A case report of glecaprevir/pibrentasvir-induced severe hyperbilirubinemia in a patient with compensated liver cirrhosis
Authors: Yoon Jae Hyun , Kim Sun Min , Kang Gaeun , Kim Hee Joon , Jun Chung Hwan , Choi Sung Kyu
Published: September 2019

Rationale:

Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication.

Patient concerns:

A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication.

Diagnoses:

On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults.

Interventions:

Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL.

Outcomes:

Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected.

Lessons:

We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.
Long-term aspirin use for cancer primary prevention
Authors: Wu Qibiao , Chen Hongwei , Yao Xiaojun , Li Ting , Xu Cong , Wang Jue , Sui Xinbing , Leung Elaine Lai-Han
Published: September 2019

Background:

Long-term use of aspirin for primary prevention of cancer remains inconclusive, and variation in the effects of aspirin use on cancer outcomes by cancer site, aspirin dose, follow-up duration, or different populations has never been systematically evaluated.

Methods:

Seven electronic databases (PubMed, EMBASE, ClinicalTrials.gov, etc) will be searched from inception to September 30, 2019. Randomized clinical trials (RCTs) comparing aspirin versus no aspirin in participants without pre-existing cancer and reporting cancer incidence, and/or cancer mortality outcomes will be selected and assessed for inclusion. The Cochrane's Risk of Bias Tool and the Jadad scale will be used to evaluate the risk of bias and the methodologic quality of the RCTs. Data will be screened and extracted by independent investigators. Total cancer incidence will be defined as the primary clinical endpoint, and total cancer mortality, all-cause mortality, and the risk of major bleeding will be the secondary outcomes. Subgroup analyses based on cancer site, aspirin dose, follow-up duration, or different populations will be conducted. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 2.0, and Trial Sequential Analysis (TSA) software.

Results:

This study will systematically evaluate the effects of long-term aspirin use on total cancer incidence, cancer mortality, all-cause mortality, and the risk of major bleeding. Subgroup analyses will indicate whether the effects of aspirin on cancer outcomes are associated with cancer site, daily dose of aspirin, follow-up duration, or different subgroup of participants. The results will be submitted and published in a peer-reviewed scientific journal.

Conclusions:

This systematic review will systematically evaluate the efficacy and safety of long-term use of aspirin for primary prevention of cancer and determine whether there are some potential influencing factors affecting the effects of aspirin on cancer outcomes, thus strengthening the evidence base for the clinical practice and future research of this intervention.
An investigation of asymmetric reduction in dopamine transporter density in patients with Parkinson’s disease
Authors: Okizaki Atsutaka , Yamamoto Wakako , Saito Wakako , Miyano Takashi , Kimura Takashi , Suzuki Yasuhiro , Nakayama Michihiro
Published: September 2019

Asymmetric motor symptoms and the contralateral side of dopaminergic deficits are commonly observed in patients with Parkinson’s disease. The laterality of the specific binding ratio (SBR) for dopamine transporter single-photon emission computed tomography may be useful for estimation of reduced dopamine transporter density in striatum of patients with Parkinson’s disease. SBR with Southampton method (S-SBR) is widely used to evaluate in our country, but the results occasionally contradict with that of motor symptoms or visual evaluation in clinical practice, thus preventing a confident diagnosis. We reported dopamine transporter evaluation with distance-weighted histogram (DWH). We hypothesized that the SBR calculated using DWH (DWH-SBR) may also be useful to evaluate the laterality. The purpose of this study was to investigate the laterality of the SBR versus the asymmetry of motor symptoms, and versus visual evaluation. In total, 100 adult patients with Parkinson’s disease were enrolled in our study. The symptom-affected side, the visual-affected side, and the lower SBR side were evaluated. The evaluation was performed in a blinded manner. Correlations between the Hoehn and Yahr scale (HY scale) and both the SBRs were also investigated. Concordance of lower DWH-SBR side for visual-affected side was significantly higher (99.0%) than it of lower S-SBR side (86.0%, P < 0.01). The HY scale was significantly related to both lower S-SBR and DWH-SBR (P < 0.01). The DWH method might minimize the disagreement of laterality between the SBR and visual evaluation, and be useful for making a confident diagnosis in patients with Parkinson’s disease.
A simple prediction model using fluorodeoxyglucose-PET and high-resolution computed tomography for discrimination of invasive adenocarcinomas among solitary pulmonary ground-glass opacity nodules
Authors: Shao Xiaonan , Shao Xiaoliang , Niu Rong , Xing Wei , Wang Yuetao
Published: September 2019

Objective

To analyze the FDG-PET and high-resolution computed tomography (HRCT) features of early lung adenocarcinoma manifesting as solitary ground-glass opacity nodules (GGNs), and to establish a new risk model for predicting the invasiveness of early lung adenocarcinoma.

Methods

We retrospectively analyzed the data of clinical stage IA lung adenocarcinoma patients who received preoperative PET/CT and HRCT examination. Patients were divided into invasive adenocarcinoma (IVA) group and preinvasive minimally invasive adenocarcinoma (MIA) group. The correlations between FDG-PET parameters, HRCT parameters and histopathological invasiveness, and their predictive efficacy were analyzed. A mathematical model for predicting histopathological invasiveness of early lung adenocarcinoma was established and assessed.

Results

This study enrolled 56 patients, 48 were in IVA group and 8 were in preinvasive MIA group. Compared with those in preinvasive MIA group, GGNs in IVA group showed larger diameter, higher ground-glass opacity (GGO) density and more pleural indentation signs (70.8%) on HRCT; they also showed higher maximum standardized uptake value (SUV) and SUV index on FDG-PET (P = 0.001–0.037). Logistic regression analysis found a risk model for predicting IVA of solitary GGNs that were established by CTGGO and SUV index. Receiver operating characteristic curves showed that this model had the highest area under the curve (AUC), sensitivity, specificity and accuracy (AUC, 0.948; sensitivity, 95.8%; specificity, 87.5%; accuracy, 94.6%).

Conclusion

Using HRCT combined with FDG-PET to establish the corresponding mathematical prediction model has the potential to identify IVA in early lung adenocarcinoma preoperatively.
Periosteal Reaction Possibly Induced by Pazopanib: A Case Report and Literature Review
Authors: Hosokawa Takahiro , Hara Tomoko , Arakawa Yuki , Oguma Eiji , Yamada Yoshitake
Published: September 2019

Background:

Although complications associated with pazopanib, a multitarget tyrosine kinase inhibitor, are known, periosteal reaction as a side effect has never been reported.

Observation:

We present a case involving a male pediatric patient with desmoid tumors treated for 6 months with pazopanib who presented with pain and periosteal reaction in the ilium and scapula. Three months after termination of pazopanib therapy, the periosteal reaction in the scapula resolved and that in the ilium improved.

Conclusion:

Children receiving pazopanib presenting with focal pain should be examined for the periosteal reaction; this knowledge may facilitate correct diagnosis of symptoms as a drug-associated finding.
Near Miss in Intraoperative Magnetic Resonance Imaging: A Case for In Situ Simulation
Authors: Rama Asheen , Knight Lynda J. , Berg Marc , Chen Michael , Gonzales Ralph , Delhagen Timothy , Copperman Lucas , Caruso Thomas J.
Published: September 2019

Introduction:

Pediatric patients in intraoperative magnetic resonance imaging (iMRI) settings are at high risk for morbidity should an adverse event occur. We describe an experience in the iMRI scanner where no harm occurred, yet revealed an opportunity to improve the safety of patients utilizing the iMRI. The perioperative quality improvement team, resuscitation team, and radiology nurse leadership collaborated to understand the process better through in situ simulation.

Methods:

After a problem analysis, the team planned an in situ, high-fidelity simulation with predefined learning objectives to identify previously overlooked opportunities for improvement. The iMRI simulation had unique considerations, including the use of a magnetic resonance imaging (MRI)-compatible mannequin and ensuring participants' safety. Audiovisual equipment was placed in strategic locations to record the MRI and operating room (OR) segments of the simulation, and trained health-care simulation experts provided debriefing.

Results:

After completion of the iMRI simulation, the quality improvement team solicited feedback from participants and reviewed the video-recorded simulation. Several opportunities for improvement surrounding staff responsibilities and unique aspects of the iMRI environment were identified.

Conclusions:

iMRI in situ simulation has not been previously described. It presents unique challenges given the integration of personnel from OR and radiology environments, anesthetized patients, and risks from the high-powered MRI magnet. Other institutions utilizing hybrid ORs with iMRI may consider conducting in situ simulations using the described methods.
Management of Pediatric Mandibular Fractures Using Resorbable Plates
Authors: Chocron Yehuda , Azzi Alain J. , Davison Peter
Published: September 2019

Introduction:

Despite there being several clinical studies reporting promising outcomes of resorbable plates for fixation of pediatric mandible fractures, the literature is devoid of large studies or comprehensive reviews assessing safety rates, complications and long-term outcomes. The purpose of the current review is to obtain a global consensus, shed light on efficacy and complications, and provide the reader with evidence-based data to help guide clinical management.

Methods:

A systematic review of clinical studies assessing outcomes for resorbable plates in pediatric mandibular fractures was carried out. The main outcomes included infection, hardware failure, hardware exposure, malocclusion, reoperation and nonunion. Overall rates were pooled and stratified by fracture and implant type.

Results:

Ten studies were included yielding 232 patients with 269 fractures. The mean age at surgery was 8.24 years with a mean follow up of 1.03 years. The overall complication rate was 5.2% (n = 12). Complications included infection (n = 4, 1.7%), hardware exposure (n = 3, 1.29%), wound dehiscence (n = 2, .86%) and intra-oral fistula formation (n = 2, .86%). One patient (0.43%) had malocclusion and none (0%) had hardware failure, nonunion or revision surgery. Patients with multiple fractures (≥ 2) had higher complication rates compared to isolated fractures (12.5% versus 1.7%).

Conclusion:

The use of resorbable plates for pediatric mandibular fractures is a viable option with similar rates of post-operative complications and outcomes compared to standard metallic counterparts. In the absence of large studies or systematic reviews, this study provides craniofacial surgeons with an evidence-based reference to guide decision making and improve informed consent.
Exploring Integrative Analysis using the BioMedical Evidence Graph
Authors: Struck Adam , Walsh Brian , Buchanan Alexander , Lee Jordan A. , Spangler Ryan , Stuart Josh , Ellrott Kyle
Published: September 2019

The analysis of cancer biology data involves extremely heterogeneous datasets including information from RNA sequencing, genome-wide copy number, DNA methylation data reporting on epigenomic regulation, somatic mutations from whole-exome or whole-genome analyses, pathology estimates from imaging sections or subtyping, drug response or other treatment outcomes, and various other clinical and phenotypic measurements. Bringing these different resources into a common framework, with a data model that allows for complex relationships as well as dense vectors of features, will unlock integrative analysis. We introduce a graph database and query engine for discovery and analysis of cancer biology, called the BioMedical Evidence Graph (BMEG). The BMEG is unique from other biological data graphs in that sample level molecular information is connected to reference knowledge bases. It combines gene expression and mutation data, with drug response experiments, pathway information databases and literature derived associations. The construction of the BMEG has resulted in a graph containing over 36M vertices and 29M edges. The BMEG system provides a graph query based API to enable analysis, with client code available for Python, Javascript and R, and a server online at bmeg.io. Using this system we have developed several forms of integrated analysis to demonstrate the utility of the system. The BMEG is an evolving resource dedicated to enabling integrative analysis. We have demonstrated queries on the system that illustrate mutation significance analysis, drug response machine learning, patient level knowledge base queries and pathway level analysis. We have compared the resulting graph to other available integrated graph systems, and demonstrated that it is unique in the scale of the graph and the type of data it makes available.

Highlights

Data resource connected extremely diverse set of cancer data sets

Graph query engine that can be easily deployed and used on new datasets

Easily installed python client

Server online at bmeg.io

The analysis of cancer biology data involves extremely heterogeneous datasets including information. Bringing these different resources into a common framework, with a data model that allows for complex relationships as well as dense vectors of features, will unlock integrative analysis. We introduce a graph database and query engine for discovery and analysis of cancer biology, called the BioMedical Evidence Graph (BMEG). The construction of the BMEG has resulted in a graph containing over 36M vertices and 29M edges. The BMEG system provides a graph query based API to enable analysis, with client code available for Python, Javascript and R, and a server online at bmeg.io. Using this system we have developed several forms of integrated analysis to demonstrate the utility of the system.
Applications of the Microphysiology Systems Database for Experimental ADME-Tox and Disease Models
Authors: Schurdak Mark , Vernetti Lawrence , Bergenthal Luke , Wolter Quinn K. , Shun Tong Ying , Karcher Sandra , Taylor D. Lansing , Gough Albert
Published: September 2019

To accelerate the development and application of Microphysiological Systems (MPS) in biomedical research and drug discovery/development, a centralized resource is required to provide the detailed design, application, and performance data that enables industry and research scientists to select, optimize, and/or develop new MPS solutions, as well as to harness data from MPS models. We have previously implemented an open source Microphysiology Systems Database (MPS-Db), with a simple icon driven interface, as a resource for MPS researchers and drug discovery/development scientists (https://mps.csb.pitt.edu). The MPS-Db captures and aggregates data from MPS, ranging from static microplate models to integrated, multi-organ microfluidic models, and associates those data with reference data from chemical, biochemical, pre-clinical, clinical and post-marketing sources to support the design, development, validation, application and interpretation of the models. The MPS-Db enables users to manage their multifactor, multichip studies, then upload, analyze, review, computationally model and share data. Here we discuss how the sharing of MPS study data in the MS-Db is under user control and can be kept private to the individual user, shared with a select group of collaborators, or be made accessible to the general scientific community. We also present a test case using our liver acinus MPS model (LAMPS) as an example and discuss the use of the MPS-Db in managing, designing, and analyzing MPS study data, assessing the reproducibility of MPS models, and evaluating the concordance of MPS model results with clinical findings. We introduce the Disease Portal module with links to resources for the design of MPS disease models and studies and discuss the integration of computational models for the prediction of PK/PD and disease pathways using data generated from MPS models.
LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages
Authors: Lee Heyne , Flynn Rowan , Sharma Ishta , Carling Phillippa J. , Nicholls Francesca J. , Stegmann Monika , Vowles Jane , Wade-Martins Richard , James William S. , Cowley Sally A.
Published: September 2019

The Parkinson’s disease-associated gene, LRRK2, is also associated with immune disorders and infectious disease, and is expressed in immune subsets. Here, we characterise a platform for interrogating the expression and function of endogenous LRRK2 in authentic human phagocytes, using human induced Pluripotent Stem Cell-derived macrophages and microglia. Endogenous LRRK2 is expressed and upregulated by interferon-γ in these cells, including a 187kD cleavage product. Using LRRK2 knockout and G2019S isogenic repair lines, we find that LRRK2 is not involved in initial phagocytic uptake of bioparticles, but is recruited to LAMP1(+)/Rab9(+) ‘maturing’ phagosomes, and LRRK2 kinase inhibition enhances its residency at the phagosome. Importantly, LRRK2 is required for Rab8a and Rab10 recruitment to phagosomes, implying that LRRK2 operates at the intersection between phagosome maturation and recycling pathways in these professional phagocytes.
GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number
Authors: Cameron Daniel L. , Baber Jonathan , Shale Charles , Papenfuss Anthony T. , Valle-Inclan Jose Espejo , Besselink Nicolle , Cuppen Edwin , Priestley Peter
Published: September 2019

We have developed a novel, integrated and comprehensive purity, ploidy, structural variant and copy number somatic analysis toolkit for whole genome sequencing data of paired tumor/normal samples. We show that the combination of using GRIDSS for somatic structural variant calling and PURPLE for somatic copy number alteration calling allows highly sensitive, precise and consistent copy number and structural variant determination, as well as providing novel insights for short structural variants and regions of complex local topology. LINX, an interpretation tool, leverages the integrated structural variant and copy number calling to cluster individual structural variants into higher order events and chains them together to predict local derivative chromosome structure. LINX classifies and extensively annotates genomic rearrangements including simple and reciprocal breaks, LINE, viral and pseudogene insertions, and complex events such as chromothripsis. LINX also comprehensively calls genic fusions including chained fusions. Finally, our toolkit provides novel visualisation methods providing insight into complex genomic rearrangements.
Transposable elements in individual genotypes ofDrosophila simulans
Authors: Signor Sarah
Published: September 2019

Transposable elements are mobile DNA sequences that are able to copy themselves within a host’s genome. Within insects they often make up a substantial proportion of the genome. While they are the subject of intense research, often times when copy number is estimated it is estimated only at the population level, or in a limited number of individuals within a population. However, an important aspect of transposable element spread is the variance between individuals in activity. Do transposable elements accumulate at different rates in different genetic backgrounds? Using two populations ofDrosophila simulansfrom California and Africa I estimated transposable element copy number in individual genotypes. Some active transposable elements seem to be a property of the species, while others of the populations. I find that in addition to population level differences in transposable element load certain genotypes accumulate transposable elements at a much higher rate than others. Most likely active transposable elements are fairly rare, and were inherited only by specific genotypes that were used to create the inbred lines. Whether or not this reflects dynamics in natural populations, where transposable elements may accumulate in specific genotypes and maintain themselves in the population rather than being active at low levels population wide, is an open question.
Coordination amongst quadriceps muscles suggests neural regulation of internal joint stresses, not simplification of task performance
Authors: Alessandro Cristiano , Prashara Adarsh , Tentler David P. , Yeh Hsin-Yun , Barroso Filipe O. , Tresch Matthew C.
Published: September 2019

Many studies have demonstrated co-variation between muscle activations during behavior, suggesting that muscles are not controlled independently. According to one common proposal, this co-variation reflects simplification of task performance by the nervous system, so that muscles with similar contributions to task variables are controlled together. Alternatively, this co-variation might reflect regulation of low-level aspects of movements that are common across tasks, such as stresses within joints. We examined these issues by analyzing co-variation patterns in quadriceps muscle activity during locomotion in rats. The three mono-articular quadriceps muscles (vastus medialis, VM; vastus lateralis, VL; vastus intermedius, VI) produce knee extension and so have identical contributions to task performance; the bi-articular rectus femoris (RF) produces an additional hip flexion. Consistent with the proposal that muscle co-variation is related to similarity of muscle actions on task variables, we found that the co-variation between VM and VL was stronger than their co-variations with RF. However, co-variation between VM and VL was also stronger than their co-variations with VI. Since all vastii have identical actions on task variables, this finding suggests that co-variation between muscle activity is not solely driven by simplification of task performance. Instead, the preferentially strong co-variation between VM and VL is consistent with the control of internal joint stresses: since VM and VL produce opposing mediolateral forces on the patella, the high positive correlation between their activation minimizes the net mediolateral patellar force. These results provide important insights into the interpretation of muscle co-variations and their role in movement control.
It’s about time: Analysing an alternative approach for reductionist modelling of linear pathways in systems biology
Authors: Korsbo Niklas , Jönsson Henrik
Published: September 2019

Thoughtful use of simplifying assumptions is crucial to make systems biology models tractable while still representative of the underlying biology. A useful simplification can elucidate the core dynamics of a system. A poorly chosen assumption can, however, either render a model too complicated for making conclusions or it can prevent an otherwise accurate model from describing experimentally observed dynamics.

Here, we perform a computational investigation of linear pathway models that contain fewer pathway steps than the system they are designed to emulate. We demonstrate when such models will fail to reproduce data and how detrimental truncation of a linear pathway leads to detectable signatures in model dynamics and its optimised parameters.

An alternative assumption is suggested for simplifying linear pathways. Rather than assuming a truncated number of pathway steps, we propose to use the assumption that the rates of information propagation along the pathway is homogeneous and instead letting the length of the pathway be a free parameter. This results in a three-parameter representation of arbitrary linear pathways which consistently outperforms its truncated rival and a delay differential equation alternative in recapitulating observed dynamics.

Our results provide a foundation for well-informed decision making during model simplifications.

1

Author summary

Mathematical modelling can be a highly effective way of condensing our understanding of biological processes and highlight the most important aspects of them. Effective models are based on simplifying assumptions that reduce complexity while still retaining the core dynamics of the original problem. Finding such assumptions is, however, not trivial.

In this paper, we explore ways in which one can simplify long chains of simple reactions wherein each step is linearly dependent on its predecessor. After generating synthetic data from models that describe such chains in explicit detail, we compare how well different simplifications retain the original dynamics. We show that the most common such simplification, which is to ignore parts of the chain, often renders models unable to account for time delays. However, we also show that when such a simplification has had a detrimental effect, it leaves a detectable signature in its optimal parameter values. We also propose an alternative assumption which leads to a highly effective model with only three parameters. By comparing the effects of these simplifying assumptions in thousands of different cases and for different conditions we are able to clearly show when and why one is preferred over the other.
A qPCR assay for Bordetella pertussis cells that enumerates both live and dead bacteria
Authors: Ramkissoon Stacy , MacArthur Iain , Ibrahim Muktar , de Graaf Hans , Read Robert C. , Preston Andrew
Published: September 2019

Bordetella pertussis is the causative agent of whooping cough, commonly referred to as pertussis. Although the incidence of pertussis was reduced through vaccination, during the last thirty years it has returned to high levels in a number of countries. This resurgence has been linked to the switch from the use of whole-cell to acellular vaccines. Protection afforded by acellular vaccines appears to be short-lived compared to that afforded by whole cell vaccines. In order to inform future vaccine improvement by identifying immune correlates of protection, a human challenge model of B. pertussis colonisation has been developed. Accurate measurement of colonisation status in this model has required development of a qPCR-based assay to enumerate B. pertussis in samples that distinguishes between viable and dead bacteria. Here we report the development of this assay and its performance in the quantification of B. pertussis from human challenge model samples. This assay has future utility in diagnostic labs and in research where a quantitative measure of both B. pertussis number and viability is required.
Structure-Guided Mutagenesis Alters Deubiquitinating Activity and Attenuates Pathogenesis of a Murine Coronavirus
Authors: Deng Xufang , Chen Yafang , Mielech Anna M. , Hackbart Matthew , Kesely Kristina R. , Mettelman Robert C. , O’Brien Amornrat , Chapman Mackenzie E. , Mesecar Andrew D. , Baker Susan C.
Published: September 2019

Coronaviruses express a multifunctional papain-like protease, termed PLP2. PLP2 acts as a protease that cleaves the viral replicase polyprotein, and a deubiquitinating (DUB) enzyme which removes ubiquitin moieties from ubiquitin-conjugated proteins. Previous in vitro studies implicated PLP2 DUB activity as a negative regulator of the host interferon (IFN) response, but the role of DUB activity during virus infection was unknown. Here, we used X-ray structure-guided mutagenesis and functional studies to identify amino acid substitutions within the ubiquitin-binding surface of PLP2 that reduced DUB activity without affecting polyprotein processing activity. We engineered a DUB mutation (Asp1772 to Ala) into a murine coronavirus and evaluated the replication and pathogenesis of the DUB mutant virus (DUBmut) in cultured macrophages and in mice. We found that the DUBmut virus replicates similarly as the wild-type virus in cultured cells, but the DUBmut virus activates an IFN response at earlier times compared to the wild-type virus infection in macrophages, consistent with DUB activity negatively regulating the IFN response. We compared the pathogenesis of the DUBmut virus to the wild-type virus and found that the DUBmut-infected mice had a statistically significant reduction (p<0.05) in viral titer in livers and spleens at day 5 post-infection, albeit both wild-type and DUBmut virus infections resulted in similar liver pathology. Overall, this study demonstrates that structure-guided mutagenesis aids the identification of critical determinants of PLP2-ubiquitin complex, and that PLP2 DUB activity plays a role as an interferon antagonist in coronavirus pathogenesis.

Importance

Coronaviruses employ a genetic economy by encoding multifunctional proteins that function in viral replication and also modify the host environment to disarm the innate immune response. The coronavirus papain-like protease 2 (PLP2) domain possesses protease activity, which cleaves the viral replicase polyprotein, and also DUB activity (de-conjugating ubiquitin/ubiquitin-like molecules from modified substrates) using identical catalytic residues. To separate the DUB activity from the protease activity, we employed a structure-guided mutagenesis approach and identified residues that are important for ubiquitin-binding. We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity. We engineered a recombinant murine coronavirus to express the DUB mutant and showed that the DUB mutant virus activated an earlier type I interferon response in macrophages and exhibited reduced pathogenesis in mice. The results of this study demonstrate that PLP2/DUB is an interferon antagonist and a virulence trait of coronaviruses.
Principles of 3D Nucleus Organization and Epigenetic Regulation in Diploid Genome Revealed by Multi-omic Data from Hybrid Mouse
Authors: Han Zhijun , Kairong Cui , Placek Katarzyna , Hong Ni , Lin Chengqi , Chen Wei , Zhao Keji , Jin Wenfei
Published: September 2019

Most mammalian genomes are diploid and previous studies have extensively investigated the average epigenetic profiles of homologous chromosomes. Here we use hybrid mice to distinguish the epigenetic status and three-dimensional organization of homologous chromosomes. We generated Hi-C, ChIP-seq and RNA-seq datasets from CD4 T cells of B6, Cast and hybrid mice, respectively, and systematically analyzed the 3D nucleus organization and epigenetic regulation. Our data indicate that the inter-chromosomal interaction patterns between homologous chromosomes are similar and the similarity is highly correlated with their allelic co-expression levels. Construction of 3D nucleus based on allele-specific interaction frequency revealed symmetric positioning of homologous chromosomes in the 3D nuclear space. The inter-chromosomal interactions at centromeres are significantly weaker than those at telomeres, indicating positioning of centromeres toward the inside of chromosome territories and telomeres toward the surface of chromosome territories. The majority A|B compartments or topologically associated domains (TADs) are consistent between B6 and Cast. We found 58% of the haploids in hybrids maintain their parental compartment status at B6/Cast divergent compartments due to cis-effect. About 95% of the trans-effected B6/Cast divergent compartments converge to same compartment status potentially due to a shared cellular environment. We found the differentially expressed genes between the two haploids in hybrid were associated with either genetic associated cis-effects or epigenetic associated trans-effects. The widespread epigenetic differences between B6 and Cast suggest that epigenetic changes may be major contributors to differences between B6 and Cast. Our data revealed symmetrical positioning of homologous chromosomes in 3D nucleus and enhanced our understanding of allele-specific epigenetic regulation.
Clickable methionine as a universal probe for labelling intracellular bacteria
Authors: Atwal Sharanjeet , Giengkam Suparat , Jaiyen Yanin , Feaga Heather , Dworkin Jonathan , Salje Jeanne
Published: September 2019

Despite their clinical and biological importance, the cell biology of obligate intracellular bacteria is less well understood than that of many free-living model organisms. One reason for this is that they are mostly genetically intractable. As a consequence, it is not possible to engineer strains expressing fluorescent proteins and therefore fluorescence light microscopy – a key tool in host-pathogen cell biology studies – is difficult. Strain diversity limits the universality of antibody-based immunofluorescence approaches. Here, we have developed a universal labelling protocol for intracellular bacteria based on a clickable methionine analog. Whilst we have applied this to obligate intracellular bacteria, we expect it to be useful for labelling free living bacteria as well as other intracellular pathogens.
Double asymmetric percolation drives a quadruple transition in sexual contact networks
Authors: Zheng Hongyu , Zeng Xiangrui
Published: September 2019

Since 2007, ZIKV outbreaks have been occurring around the world. While ZIKV is mainly spread by mosquito vectors, transmission via sex activities enables the virus to spread in regions without mosquito vectors. Modeling the patterns of ZIKV outbreak in these regions remain challenging. We consider age as an asymmetric factor in transmitting ZIKV, in addition to gender as seen in previous literature, and modify the graph structure for better modeling of such patterns. We derived our results by both solving the underlying differential equations and simulation on population graph. Based on a double asymmetric percolation process on sexual contact networks. we discovered a quadruple ZIKV epidemic transition. Moreover, we explored the double asymmetric percolation on scale-free networks. Our work provides more insight into the ZIKV transmission dynamics through sexual contact networks, which may potentially provide better public health control and prevention means in a ZIKV outbreak.
Cytoskeletal organization in isolated plant cells under geometry control
Authors: Durand-Smet P. , Spelman Tamsin A. , Meyerowitz E. M. , Jönsson H.
Published: September 2019

Specific cell and tissue form is essential to support many biological functions of living organisms. During development, the creation of different shapes at the cellular and tissue level fundamentally requires the integration of genetic, biochemical and physical inputs.

It is well established that the cortical microtubule network plays a key role in the morphogenesis of the plant cell wall by guiding the organisation of new cell wall material. Moreover, it has been suggested that light or mechanical stresses can orient the microtubules thereby controlling wall architecture and plant cell shape. The cytoskeleton is thus a major determinant of plant cell shape. What is less clear is how cell shape in turn influences cytoskeletal organization.

Recent in vitro experiments and numerical simulations predicted that a geometry-based rule is sufficient to explain some of the microtubule organization observed in cells. Due to their high flexural rigidity and persistence length of the order of a few millimeters, MTs are rigid over cellular dimensions and are thus expected to align along their long axis if constrained in specific geometries. This hypothesis remains to be tested in cellulo.

Here we present an experimental approach to explore the relative contribution of geometry to the final organization of actin and microtubule cytoskeletons in single plant cells. We show that, in cells constrained in rectangular shapes, the cytoskeleton align along the long axis of the cells. By studying actin and microtubules in cells with the same system we show that while actin organisation requires microtubules to be present to align the converse is not the case. A model of self organizing microtubules in 3D predicts that severing of microtubules is an important parameter controlling the anisotropy of the microtubule network. We experimentally confirmed the model predictions by analysing the response to shape change in plant cells with altered microtubule severing dynamics. This work is a first step towards assessing quantitatively how cell geometry contributes to the control of cytoskeletal organization in living plant cells.
Impact of female directors on the board and foreign institutional investors on earning manipulation of Chinese listed companies
Authors: Sial Muhammad Safdar , Vo Xuan Vinh , Al-Haddad Lara , Trang Thao Nguyen
Published: September 2019

Purpose

The purpose of this paper is to check the impact of female directors on the board and foreign institutional investors on earnings manipulation.

Design/methodology/approach

The data sample includes Chinese listed companies on the Shenzhen and Shanghai stock exchanges. The data are collected from China Stock Market and Accounting Research database covering the period from 2010 to 2017. The authors use a dynamic generalized method of moments in the study.

Findings

The findings show that the presence of female director on the board has a significant negative impact on both discretionary accruals and real earning management. However, the authors obtain different results for foreign institutional investor investors. This may be the result of myopia as the foreign institutional stockholders in Chinese companies are looking for quick profit encouraging management to manipulate earnings. the findings survive several robustness tests.

Originality/value

The authors expect the research results provide ample evidence about how female directors affects earnings manipulation, and also hope the research helps to understand how, in China, institutional ownership affects earnings manipulation.