bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of circRNAs encoded by MERS-CoV, SARS-CoV-1 and SARS-CoV-2
Authors: Cai Zena , Lu Congyu , He Jun , Liu Li , Zou Yuanqiang , Zhang Zheng , Zhu Zhaozhong , Ge Xingyi , Wu Aiping , Jiang Taijiao , Zheng Heping , Peng Yousong
Published: October 2020

The life-threatening coronaviruses MERS-CoV, SARS-CoV-1 and SARS-CoV-2 (SARS-CoV-1/2) have caused and will continue to cause enormous morbidity and mortality to humans. Virus-encoded noncoding RNAs are poorly understood in coronaviruses. Data mining of viral-infection-related RNA-sequencing data has resulted in the identification of 28 754, 720 and 3437 circRNAs encoded by MERS-CoV, SARS-CoV-1 and SARS-CoV-2, respectively. MERS-CoV exhibits much more prominent ability to encode circRNAs in all genomic regions than those of SARS-CoV-1/2. Viral circRNAs typically exhibit low expression levels. Moreover, majority of the viral circRNAs exhibit expressions only in the late stage of viral infection. Analysis of the competitive interactions of viral circRNAs, human miRNAs and mRNAs in MERS-CoV infections reveals that viral circRNAs up-regulated genes related to mRNA splicing and processing in the early stage of viral infection, and regulated genes involved in diverse functions including cancer, metabolism, autophagy, viral infection in the late stage of viral infection. Similar analysis in SARS-CoV-2 infections reveals that its viral circRNAs down-regulated genes associated with metabolic processes of cholesterol, alcohol, fatty acid and up-regulated genes associated with cellular responses to oxidative stress in the late stage of viral infection. A few genes regulated by viral circRNAs from both MERS-CoV and SARS-CoV-2 were enriched in several biological processes such as response to reactive oxygen and centrosome localization. This study provides the first glimpse into viral circRNAs in three deadly coronaviruses and would serve as a valuable resource for further studies of circRNAs in coronaviruses.
Dorsal Hippocampus to Infralimbic Cortex Circuit is Essential for the Recall of Extinction Memory
Authors: Qin Cheng , Bian Xin-Lan , Wu Hai-Yin , Xian Jia-Yun , Cai Cheng-Yun , Lin Yu-Hui , Zhou Ying , Kou Xiao-Lin , Chang Lei , Luo Chun-Xia , Zhu Dong-Ya
Published: October 2020

Posttraumatic stress disorder subjects usually show impaired recall of extinction memory, leading to extinguished fear relapses. However, little is known about the neural mechanisms underlying the impaired recall of extinction memory. We show here that the activity of dorsal hippocampus (dHPC) to infralimbic (IL) cortex circuit is essential for the recall of fear extinction memory in male mice. There were functional neural projections from the dHPC to IL. Using optogenetic manipulations, we observed that silencing the activity of dHPC-IL circuit inhibited recall of extinction memory while stimulating the activity of dHPC-IL circuit facilitated recall of extinction memory. “Impairment of extinction consolidation caused by” conditional deletion of extracellular signal-regulated kinase 2 (ERK2) in the IL prevented the dHPC-IL circuit-mediated recall of extinction memory. Moreover, silencing the dHPC-IL circuit abolished the effect of intra-IL microinjection of ERK enhancer on the recall of extinction memory. Together, we identify a dHPC to IL circuit that mediates the recall of extinction memory, and our data suggest that the dysfunction of dHPC-IL circuit and/or impaired extinction consolidation may contribute to extinguished fear relapses.
Orientation Tuning and End-stopping in Macaque V1 Studied with Two-photon Calcium Imaging
Authors: Ju Nian-Sheng , Guan Shu-Chen , Tao Louis , Tang Shi-Ming , Yu Cong
Published: October 2020

Orientation tuning is a fundamental response property of V1 neurons and has been extensively studied with single-/multiunit recording and intrinsic signal optical imaging. Long-term 2-photon calcium imaging allows simultaneous recording of hundreds of neurons at single neuron resolution over an extended time in awake macaques, which may help elucidate V1 orientation tuning properties in greater detail. We used this new technology to study the microstructures of orientation functional maps, as well as population tuning properties, in V1 superficial layers of 5 awake macaques. Cellular orientation maps displayed horizontal and vertical clustering of neurons according to orientation preferences, but not tuning bandwidths, as well as less frequent pinwheels than previous estimates. The orientation tuning bandwidths were narrower than previous layer-specific single-unit estimates, suggesting more precise orientation selectivity. Moreover, neurons tuned to cardinal and oblique orientations did not differ in quantities and bandwidths, likely indicating minimal V1 representation of the oblique effect. Our experimental design also permitted rough estimates of length tuning. The results revealed significantly more end-stopped cells at a more superficial 150 μm depth (vs. 300 μm), but unchanged orientation tuning bandwidth with different length tuning. These results will help construct more precise models of V1 orientation processing.
Evergreening in the Euro Area: Evidence from Survey Data and a Conceptual Framework
Authors: Steinkamp Sven , Tornell Aaron , Westermann Frank
Published: October 2020

Since the beginning of the financial crisis in 2007/2008, new lending in the euro area has slowed sharply and the old loans experienced ‘evergreening’, that is, bad loans have been rolled over rather than being liquidated. Even though ameliorating evergreening is key to promote lending for new investment projects and growth, no systematic evergreening measures exist. In this paper, we propose a new cross-country evergreening index and develop a public-choice model to explain why evergreening may reflect the incentives of regulators to forebear. Our evergreening index is based on a survey we designed and was administered by the ifo Institute to about 1000 experts in over 80 countries. We bring the model to the data using a heteroscedastic probit model and find that evergreening is higher in: (i) euro-area countries than in the rest of the world; (ii) in countries facing bank distress; and (iii) is highest in countries which experience banking distress and are members of the euro area. These results are consistent with our theoretical model. (JEL codes: F33, F55 and E58)
The Influence of Cognitive Parameters on Olfactory Assessment in Healthy Children and Adolescents
Authors: Gellrich Janine , Sparing-Paschke Lisa-Marie , Hummel Thomas , Schriever Valentin A
Published: October 2020

Olfactory threshold and odor identification tests are frequently used for assessment of olfactory function in children and adolescents. Whether olfactory test results are influenced by cognitive parameters or sex in children and adolescents is largely unknown. The aim of this study was to investigate the influence of cognition, age and sex on “Sniffin’ Sticks” olfactory threshold and “U-Sniff” odor identification performance in a pediatric population. A total of 200 participants between age 6 and 17 years were included. Olfactory function (olfactory threshold and odor identification) was assessed using the “Sniffin’ Sticks.” In addition, age appropriate cognitive testing was applied. The results of this study indicate that odor identification test performance is positively correlated with age (r = 0.31) and verbal abilities of children (r = 0.24). Olfactory threshold results are only marginally influenced by age (r = 0.18) and are not associated with cognitive test performance. Olfactory assessment using olfactory threshold and “U-Sniff” odor identification testing is suitable for children and adolescents when considering age in the interpretation of test results.
Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria
Authors: Sahu Praveen K , Hoffmann Angelika , Majhi Megharay , Pattnaik Rajyabardhan , Patterson Catriona , Mahanta Kishore C , Mohanty Akshaya K , Mohanty Rashmi R , Joshi Sonia , Mohanty Anita , Bage Jabamani , Maharana Sameer , Seitz Angelika , Bendszus Martin , Sullivan Steven A , Turnbull Ian W , Dondorp Arjen M , Gupta Himanshu , Pirpamer Lukas , Mohanty Sanjib , Wassmer Samuel C
Published: October 2020

Background

Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults.

Methods

Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases.

Results

We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death.

Conclusions

Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.
A Cluster of Nontuberculous Mycobacterial Tenosynovitis Following Hurricane Relief Efforts
Authors: Turner Nicholas A , Sweeney Mollie I , Xet-Mull Ana M , Storm Jeremy , Mithani Suhail K , Jones David B , Miles Jeremy J , Tobin David M , Stout Jason E
Published: October 2020

Background

Nontuberculous mycobacteria (NTM) are a rare cause of infectious tenosynovitis of the upper extremity. Using molecular methods, clinical microbiology laboratories are increasingly reporting identification down to the species level. Improved methods for speciation are revealing new insights into the clinical and epidemiologic features of rare NTM infections.

Methods

We encountered 3 cases of epidemiologically linked upper extremity NTM tenosynovitis associated with exposure to hurricane-damaged wood. We conducted whole-genome sequencing to assess isolate relatedness followed by a literature review of NTM infections that involved the upper extremity.

Results

Despite shared epidemiologic risk, the cases were caused by 3 distinct organisms. Two cases were rare infections caused by closely related but distinct species within the Mycobacterium terrae complex that could not be differentiated by traditional methods. The third case was caused by Mycobacterium intracellulare. An updated literature review that focused on research that used modern molecular speciation methods found that several species within the M. terrae complex are increasingly reported as a cause of upper extremity tenosynovitis, often in association with environmental exposures.

Conclusions

These cases illustrate the importance of molecular methods for speciating phenotypically similar NTM, as well as the limitations of laboratory-based surveillance in detecting point-source outbreaks when the source is environmental and may involve multiple organisms.
Blood analytes of immature Kemp’s ridley sea turtles (Lepidochelys kempii) from Georgia, USA: reference intervals and body size correlations
Authors: Perrault Justin R , Arendt Michael D , Schwenter Jeffrey A , Byrd Julia L , Harms Craig A , Cray Carolyn , Tuxbury Kathryn A , Wood Lawrence D , Stacy Nicole I
Published: October 2020

Health assessments of wildlife species are becoming increasingly important in an ever-changing environment. Kemp’s ridley sea turtles (Lepidochelys kempii; hereafter, Kemp’s ridleys) are critically endangered and incur several on-going threats to their population recovery; therefore, it is imperative to advance the understanding of baseline blood analyte data as a diagnostic and monitoring tool. For in-water, trawl-captured, immature Kemp’s ridleys (minimum N = 31) from Georgia, USA, the objectives of this study were to (1) establish reference intervals (RIs) for packed cell volume (PCV) and 27 plasma biochemistry analytes and (2) determine length-specific relationships in blood analytes. We observed significant positive correlations between minimum straight carapace length and PCV, amylase, calcium:phosphorus ratio, cholesterol, magnesium, triglycerides, total solids, total protein and all protein fractions (e.g. alpha-, beta- and gamma-globulins); aspartate aminotransferase and chloride showed significant negative relationships. These results suggest that certain blood analytes in Kemp’s ridleys change as these animals grow, presumptively due to somatic growth and dietary shifts. The information presented herein, in due consideration of capture technique that may have impacted glucose and potassium concentrations, represents the first report of blood analyte RIs for Kemp’s ridley sea turtles established by guidelines of the American Society for Veterinary Clinical Pathology and will have direct applications for stranded individuals in rehabilitative care and for future investigations into the health status of wild individuals from this population.
Applying a gene-suite approach to examine the physiological status of wild-caught walleye (Sander vitreus)
Authors: Jeffrey Jennifer D , Carlson Hunter , Wrubleski Dale , Enders Eva C , Treberg Jason R , Jeffries Ken M
Published: October 2020

Molecular techniques have been increasingly used in a conservation physiology framework to provide valuable information regarding the mechanisms underlying responses of wild organisms to environmental and anthropogenic stressors. In the present study, we developed a reference gill transcriptome for walleye (Sander vitreus), allowing us to pair a gene-suite approach (i.e. multiple genes across multiple cellular processes) with multivariate statistics to examine the physiological status of wild-caught walleye. For molecular analyses of wild fish, the gill is a useful target for conservation studies, not only because of its importance as an indicator of the physiological status of fish but also because it can be biopsied non-lethally. Walleye were non-lethally sampled following short- (~1.5 months) and long-term (~3.5 months) confinement in the Delta Marsh, which is located south of Lake Manitoba in Manitoba, Canada. Large-bodied walleye are confined in the Delta Marsh from late April to early August by exclusion screens used to protect the marsh from invasive common carp (Cyprinus carpio), exposing fish to potentially stressful water quality conditions. Principal components analysis revealed patterns of transcript abundance consistent with exposure of fish to increasingly high temperature and low oxygen conditions with longer holding in the marsh. For example, longer-term confinement in the marsh was associated with increases in the mRNA levels of heat shock proteins and a shift in the mRNA abundance of aerobic to anaerobic metabolic genes. Overall, the results of the present study suggest that walleye confined in the Delta Marsh may be exhibiting sub-lethal responses to high temperature and low oxygen conditions. These results provide valuable information for managers invested in mediating impacts to a local species of conservation concern. More broadly, we highlight the usefulness of pairing transcriptomic techniques with multivariate statistics to address potential confounding factors that can affect measured physiological responses of wild-caught fish.
Cardiac fibrosis
Authors: Frangogiannis Nikolaos G
Published: October 2020

Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4], and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.
‘The Birds Were in the Net’: Reactions in the Netherlands to News of the St Bartholomew’s Day Massacre, 1572
Authors: Baars Rosanne M
Published: October 2020

This article analyses reactions in the Netherlands to news of the St Bartholomew’s Day massacre in 1572. Although historians have previously studied international reactions to the massacre, they have largely neglected the Netherlands due to the paucity of printed responses to the event in the Low Countries. Through the study of a great number of diaries and chronicles, this article demonstrates how news about the massacre spread rapidly throughout the Netherlands. Chroniclers in the Low Countries reflected on the content and credibility of the horrible news reports from France while writing them down. The ongoing religious wars had made them aware of manipulative strategies that influenced news and its media, including false reports that were spread deliberately by the enemy. This article argues that the study of transnational news reports illuminates contemporary questions on authority and trustworthiness in a rapidly polarizing religious climate.
Clinical Characteristics and Risk Factors for Mortality in Very Old Patients Hospitalized With COVID-19 in Spain
Authors: Ramos-Rincon Jose-Manuel , Buonaiuto Verónica , Ricci Michele , Martín-Carmona Jesica , Paredes-Ruíz Diana , Calderón-Moreno María , Rubio-Rivas Manel , Beato-Pérez José-Luis , Arnalich-Fernández Francisco , Monge-Monge Daniel , Vargas-Núñez Juan-Antonio , Acebes-Repiso Gonzalo , Mendez-Bailon Manuel , Perales-Fraile Isabel , García-García Gema-María , Guisado-Vasco Pablo , Abdelhady-Kishta Alaaeldeen , Pascual-Pérez Maria-de-los-Reyes , Rodríguez-Fernández-Viagas Cristina , Montaño-Martínez Adrián , López-Ruiz Antonio , Gonzalez-Juarez Maria-Jesus , Pérez-García Cristina , Casas-Rojo José-Manuel , Gómez-Huelgas Ricardo ,   SEMI-COVID-19 Network
Published: October 2020

Background

Advanced age is a well-known risk factor for poor prognosis in COVID-19. However, few studies have specifically focused on very old inpatients with COVID-19. This study aims to describe the clinical characteristics of very old inpatients with COVID-19 and identify risk factors for in-hospital mortality at admission.

Methods

We conducted a nationwide, multicenter, retrospective, observational study in patients ≥ 80 years hospitalized with COVID-19 in 150 Spanish hospitals (SEMI-COVID-19) Registry (March 1–May 29, 2020). The primary outcome was in-hospital mortality. A uni- and multivariate logistic regression was performed to assess predictors of mortality at admission.

Results

A total of 2772 consecutive patients (49.4% men, median age 86.3 years) were analyzed. Rates of atherosclerotic cardiovascular disease, diabetes mellitus, dementia, and Barthel Index < 60 were 30.8%, 25.6%, 30.5%, and 21.0%, respectively. The overall case-fatality rate was 46.9% (n: 1301) and increased with age (80–84 years: 41.6%; 85–90 years: 47.3%; 90–94 years: 52.7%; ≥95 years: 54.2%). After analysis, male sex and moderate-to-severe dependence were independently associated with in-hospital mortality; comorbidities were not predictive. At admission, independent risk factors for death were: oxygen saturation < 90%; temperature ≥ 37.8°C; quick sequential organ failure assessment (qSOFA) score ≥ 2; and unilateral–bilateral infiltrates on chest x-rays. Some analytical findings were independent risk factors for death, including estimated glomerular filtration rate < 45 mL/min/1.73 m2; lactate dehydrogenase ≥ 500 U/L; C-reactive protein ≥ 80 mg/L; neutrophils ≥ 7.5 × 103/μL; lymphocytes < 0.8 × 103/μL; and monocytes < 0.5 × 103/μL.

Conclusions

This first large, multicenter cohort of very old inpatients with COVID-19 shows that age, male sex, and poor preadmission functional status—not comorbidities—are independently associated with in-hospital mortality. Severe COVID-19 at admission is related to poor prognosis.
In It Together: A Qualitative Meta-Synthesis of Common and Unique Psychosocial Stressors and Adaptive Coping Strategies of Persons With Young-Onset Dementia and Their Caregivers
Authors: Bannon Sarah , Reichman Mira , Popok Paula , Wagner Juliana , Gates Melissa , Uppal Simrit , LeFeber Lisa , Wong Bonnie , Dickerson Bradford C , Vranceanu Ana-Maria
Published: October 2020

Background and Objectives

The common and unique psychosocial stressors and adaptive coping strategies of people with young-onset dementia (PWDs) and their caregivers (CGs) are poorly understood. This meta-synthesis used the stress and coping framework to integrate and organize qualitative data on the common and unique psychosocial stressors and adaptive coping strategies employed by PWDs and CGs after a diagnosis of young-onset dementia (YOD).

Research Design and Methods

Five electronic databases were searched for qualitative articles from inception to January 2020. Qualitative data were extracted from included articles and synthesized across articles using taxonomic analysis.

Results

A total of 486 articles were obtained through the database and hand searches, and 322 articles were screened after the removal of duplicates. Sixty studies met eligibility criteria and are included in this meta-synthesis. Four themes emerged through meta-synthesis: (a) common psychosocial stressors experienced by both PWDs and CGs, (b) unique psychosocial stressors experienced by either PWDs or CGs, (c) common adaptive coping strategies employed by both PWDs and CGs, and (d) unique adaptive coping strategies employed by either PWDs or CGs. Within each meta-synthesis theme, subthemes pertaining to PWDs, CGs, and dyads (i.e., PWD and CG as a unit) emerged.

Discussion and Implications

The majority of stressors and adaptive coping strategies of PWDs and CGs were common, supporting the use of dyadic frameworks to understand the YOD experience. Findings directly inform the development of resiliency skills interventions to promote adaptive coping in the face of a YOD diagnosis for both PWDs and CGs.
Renewable hybrid energy systems using geothermal energy: hybrid solar thermal–geothermal power plant
Authors: El Haj Assad Mamdouh , Ahmadi Mohammad Hossein , Sadeghzadeh Milad , Yassin Ameera , Issakhov Alibek
Published: October 2020

New and innovative solutions are being developed to overcome the challenges of detrimental effects that the traditional energy systems cause. This means that sustainable methods are implemented to do so, noting that when such developments are taken into consideration and are studied, this leads to a significant drop in the cost of renewable energy systems. In this work, a hybrid system consisting of a single flash steam geothermal power plant and a solar thermal system using a parabolic trough collector (PTC) is studied. Based on the available works in literature, the required design materials and modeling equations are chosen and discussed. The heat transfer fluid (HTF) as water is chosen as the working fluid for the PTC due to its low cost and high specific heat capacity. The calculations are carried out for the PTC on a specific day, time and location, and the simulations for the geothermal power plant (GPP) are carried out using System Advisor Model (SAM) software, assuming a specific increase in the temperature of the geofluid due to the additional heat transfer from the HTF of the PTC. The power plant output is 20 MW powered by four production wells. The results show that the energy production is ~15 GWh in January, which is the highest during the year due to the required energy demand for electricity consumption and district heating. Moreover, a mini review of the mathematical modeling of PTC and single flash geothermal power plant is presented.
A Horse of a Different Color?: Tensile Strength and Elasticity of Sloth Flexor Tendons
Authors: Mossor A M , Austin B L , Avey-Arroyo J A , Butcher M T
Published: October 2020

Tendons must be able to withstand the tensile forces generated by muscles to provide support while avoiding failure. The properties of tendons in mammal limbs must therefore be appropriate to accommodate a range of locomotor habits and posture. Tendon collagen composition provides resistance to loading that contributes to tissue strength which could, however, be modified to not exclusively confer large strength and stiffness for elastic energy storage/recovery. For example, sloths are nearly obligate suspenders and cannot run, and due to their combined low metabolic rate, body temperature, and rate of digestion, they have an extreme need to conserve energy. It is possible that sloths have a tendon “suspensory apparatus” functionally analogous to that in upright ungulates, thus allowing for largely passive support of their body weight below-branch, while concurrently minimizing muscle contractile energy expenditure. The digital flexor tendons from the fore- and hindlimbs of two-toed (Choloepus hoffmanni) and three-toed (Bradypus variegatus) sloths were loaded in tension until failure to test this hypothesis. Overall, tensile strength and elastic (Young’s) modulus of sloth tendons were low, and these material properties were remarkably similar to those of equine suspensory “ligaments.” The results also help explain previous findings in sloths showing relatively low levels of muscle activation in the digital flexors during postural suspension and suspensory walking.
Group II Introns Generate Functional Chimeric Relaxase Enzymes with Modified Specificities through Exon Shuffling at Both the RNA and DNA Level
Authors: LaRoche-Johnston Félix , Bosan Rafia , Cousineau Benoit
Published: October 2020

Group II introns are large self-splicing RNA enzymes with a broad but somewhat irregular phylogenetic distribution. These ancient retromobile elements are the proposed ancestors of approximately half the human genome, including the abundant spliceosomal introns and non-long terminal repeat retrotransposons. In contrast to their eukaryotic derivatives, bacterial group II introns have largely been considered as harmful selfish mobile retroelements that parasitize the genome of their host. As a challenge to this view, we recently uncovered a new intergenic trans-splicing pathway that generates an assortment of mRNA chimeras. The ability of group II introns to combine disparate mRNA fragments was proposed to increase the genetic diversity of the bacterial host by shuffling coding sequences. Here, we show that the Ll.LtrB and Ef.PcfG group II introns from Lactococcus lactis and Enterococcus faecalis respectively can both use the intergenic trans-splicing pathway to catalyze the formation of chimeric relaxase mRNAs and functional proteins. We demonstrated that some of these compound relaxase enzymes yield gain-of-function phenotypes, being significantly more efficient than their precursor wild-type enzymes at supporting bacterial conjugation. We also found that relaxase enzymes with shuffled functional domains are produced in biologically relevant settings under natural expression levels. Finally, we uncovered examples of lactococcal chimeric relaxase genes with junctions exactly at the intron insertion site. Overall, our work demonstrates that the genetic diversity generated by group II introns, at the RNA level by intergenic trans-splicing and at the DNA level by recombination, can yield new functional enzymes with shuffled exons, which can lead to gain-of-function phenotypes.
ProThermDB: thermodynamic database for proteins and mutants revisited after 15 years
Authors: Nikam Rahul , Kulandaisamy A , Harini K , Sharma Divya , Gromiha M Michael
Published: October 2020

ProThermDB is an updated version of the thermodynamic database for proteins and mutants (ProTherm), which has ∼31 500 data on protein stability, an increase of 84% from the previous version. It contains several thermodynamic parameters such as melting temperature, free energy obtained with thermal and denaturant denaturation, enthalpy change and heat capacity change along with experimental methods and conditions, sequence, structure and literature information. Besides, the current version of the database includes about 120 000 thermodynamic data obtained for different organisms and cell lines, which are determined by recent high throughput proteomics techniques using whole-cell approaches. In addition, we provided a graphical interface for visualization of mutations at sequence and structure levels. ProThermDB is cross-linked with other relevant databases, PDB, UniProt, PubMed etc. It is freely available at https://web.iitm.ac.in/bioinfo2/prothermdb/index.html without any login requirements. It is implemented in Python, HTML and JavaScript, and supports the latest versions of major browsers, such as Firefox, Chrome and Safari.
3DIV update for 2021: a comprehensive resource of 3D genome and 3D cancer genome
Authors: Kim Kyukwang , Jang Insu , Kim Mooyoung , Choi Jinhyuk , Kim Min-Seo , Lee Byungwook , Jung Inkyung
Published: October 2020

Three-dimensional (3D) genome organization is tightly coupled with gene regulation in various biological processes and diseases. In cancer, various types of large-scale genomic rearrangements can disrupt the 3D genome, leading to oncogenic gene expression. However, unraveling the pathogenicity of the 3D cancer genome remains a challenge since closer examinations have been greatly limited due to the lack of appropriate tools specialized for disorganized higher-order chromatin structure. Here, we updated a 3D-genome Interaction Viewer and database named 3DIV by uniformly processing ∼230 billion raw Hi-C reads to expand our contents to the 3D cancer genome. The updates of 3DIV are listed as follows: (i) the collection of 401 samples including 220 cancer cell line/tumor Hi-C data, 153 normal cell line/tissue Hi-C data, and 28 promoter capture Hi-C data, (ii) the live interactive manipulation of the 3D cancer genome to simulate the impact of structural variations and (iii) the reconstruction of Hi-C contact maps by user-defined chromosome order to investigate the 3D genome of the complex genomic rearrangement. In summary, the updated 3DIV will be the most comprehensive resource to explore the gene regulatory effects of both the normal and cancer 3D genome. ‘3DIV’ is freely available at http://3div.kr.
Functional analysis of low-grade glioma genetic variants predicts key target genes and transcription factors
Authors: Manjunath Mohith , Yan Jialu , Youn Yeoan , Drucker Kristen L , Kollmeyer Thomas M , McKinney Andrew M , Zazubovich Valter , Zhang Yi , Costello Joseph F , Eckel-Passow Jeanette , Selvin Paul R , Jenkins Robert B , Song Jun S
Published: October 2020

Background

Large-scale genome-wide association studies (GWAS) have implicated thousands of germline genetic variants in modulating individuals’ risk to various diseases, including cancer. At least 25 risk loci have been identified for low-grade gliomas (LGGs), but their molecular functions remain largely unknown.

Methods

We hypothesized that GWAS loci contain causal single nucleotide polymorphisms (SNPs) that reside in accessible open chromatin regions and modulate the expression of target genes by perturbing the binding affinity of transcription factors (TFs). We performed an integrative analysis of genomic and epigenomic data from The Cancer Genome Atlas and other public repositories to identify candidate causal SNPs within linkage disequilibrium blocks of LGG GWAS loci. We assessed their potential regulatory role via in silico TF binding sequence perturbations, convolutional neural network trained on TF binding data, and simulated annealing–based interpretation methods.

Results

We built an interactive website (http://education.knoweng.org/alg3/) summarizing the functional footprinting of 280 variants in 25 LGG GWAS regions, providing rich information for further computational and experimental scrutiny. We identified as case studies PHLDB1 and SLC25A26 as candidate target genes of rs12803321 and rs11706832, respectively, and predicted the GWAS variant rs648044 to be the causal SNP modulating ZBTB16, a known tumor suppressor in multiple cancers. We showed that rs648044 likely perturbed the binding affinity of the TF MAFF, as supported by RNA interference and in vitro MAFF binding experiments.

Conclusions

The identified candidate (causal SNP, target gene, TF) triplets and the accompanying resource will help accelerate our understanding of the molecular mechanisms underlying genetic risk factors for gliomas.
A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR
Authors: Sievers Philipp , Sill Martin , Schrimpf Daniel , Stichel Damian , Reuss David E , Sturm Dominik , Hench Jürgen , Frank Stephan , Krskova Lenka , Vicha Ales , Zapotocky Michal , Bison Brigitte , Castel David , Grill Jacques , Debily Marie-Anne , Harter Patrick N , Snuderl Matija , Kramm Christof M , Reifenberger Guido , Korshunov Andrey , Jabado Nada , Wesseling Pieter , Wick Wolfgang , Solomon David A , Perry Arie , Jacques Thomas S , Jones Chris , Witt Olaf , Pfister Stefan M , von Deimling Andreas , Jones David T W , Sahm Felix
Published: October 2020

Background

Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern.

Methods

Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas.

Results

EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.

Conclusions

Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials
Authors: Ellingson Benjamin M , Brown Matthew S , Boxerman Jerrold L , Gerstner Elizabeth R , Kaufmann Timothy J , Cole Patricia E , Bacha Jeffrey A , Leung David , Barone Amy , Colman Howard , van den Bent Martin J , Wen Patrick Y , Alfred Yung W K , Cloughesy Timothy F , Goldin Jonathan G
Published: October 2020

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.
Antimicrobial Management of Respiratory Infections in Severe Acute Respiratory Syndrome Coronavirus 2 Patients: Clinical and Antimicrobial Stewardship Programs Conundrums
Authors: Goldstein Ellie J C , Tillotson Glenn , Redell Mark
Published: October 2020

The role of empirical and even directed antimicrobial management of patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is problematic; antibiotics are used frequently among these patients to treat confirmed or suspected coinfection or just the symptoms. In the rapidly changing clinical landscape of SARS-CoV-2, there is minimal guidance for selecting appropriate treatment versus non-antimicrobial treatment, and clinicians are pressed to make daily decisions under the stress of absence of data while watching patients deteriorate. We review current data and patterns of antimicrobial use and the potential approach for antimicrobial stewardship in the context of SARS-CoV-2.
Radial-velocity search and statistical studies for short-period planets in the Pleiades open cluster
Authors: Takarada Takuya , Sato Bun’ei , Omiya Masashi , Hori Yasunori , Fujii Michiko S
Published: October 2020

We report on a radial-velocity search for short-period planets in the Pleiades open cluster. We observed 30 Pleiades member stars at the Okayama Astrophysical Observatory with the High Dispersion Echelle Spectrograph. To evaluate and mitigate the effects of stellar activity on radial-velocity (RV) measurements, we computed four activity indicators (full width at half maximum, Vspan, Wspan, and SHα). Among our sample, no short-period planet candidates were detected. Stellar intrinsic RV jitter was estimated to be 52 m s−1, 128 m s−1, and 173 m s−1 for stars with $v$ sin i of 10 km s−1, 15 km s−1, and 20 km s−1, respectively. We determined the planet occurrence rate from our survey and set the upper limit to 11.4% for planets with masses 1–13 MJUP and period 1–10 d. To set a more stringent constraint on the planet occurrence rate, we combined the result of our survey with those of other surveys targeting open clusters with ages in the range 30–300 Myr. As a result, the planet occurrence rate in young open clusters was found to be less than 7.4%, 2.9%, and 1.9% for planets with an orbital period of 3 d and masses of 1–5, 5–13, and 13–80 MJUP, respectively.
How is Liquidity Priced in Global Markets?
Authors: Chaieb Ines , Errunza Vihang , Langlois Hugues
Published: October 2020

We develop a new global asset pricing model to study how illiquidity interacts with market segmentation and investability constraints in 42 markets. Noninvestable stocks that can only be held by foreign investors earn higher expected returns compared to freely investable stocks due to limited risk sharing and higher illiquidity. In addition to the world market premium, on average, developed and emerging market noninvestables earn an annual unspanned local market risk premium of $1.17\%$ and $9.04\%$, and a liquidity level premium of $1.06\%$ and $2.39\%$, respectively. These results obtained in a conditional setup are robust to the choice of liquidity measure.
Safety and efficacy of fostamatinib in rheumatoid arthritis patients with an inadequate response to methotrexate in phase II OSKIRA-ASIA-1 and OSKIRA-ASIA-1X study
Authors: Tanaka Yoshiya , Millson David , Iwata Shigeru , Nakayamada Shingo
Published: October 2020

Objective

The primary objectives of two phase II studies of fostamatinib were to evaluate efficacy (OSKIRA-Asia-1: NCT01569074) and long-term safety/tolerability (OSKIRA-Asia-1X: NCT01640054) in patients from Asia with active RA despite MTX treatment.

Methods

OSKIRA-Asia-1 was a 12-week, multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive one of four fostamatinib doses (groups A–D; n = 31, 33, 33, 33) or placebo (group E; n = 33). OSKIRA-Asia-1X was a long-term extension study (100 mg fostamatinib qd) of patients who completed OSKIRA-Asia-1. RA signs and symptoms were measured by ACR response criteria and DAS based on a 28-joint count. Physical function status was assessed with the HAQ–Disability Index. Safety findings were monitored.

Results

In OSKIRA-Asia-1, fostamatinib revealed numerical improvements in ACR 20% response (ACR20) at week 12 in group A (100 mg bid) and group B (100 mg bid, then 150 mg qd) vs placebo. Statistically significant improvements in ACR20 and ACR50 at week 8 and in ACR70 at week 12, and statistically significant achievement in low disease activity (defined as DAS based on a 28-joint count ≤3.2 based on C-reactive protein) occurred in groups A and B. Improvement in physical function was numerically higher in group A. The most common adverse events were hypertension, diarrhoea and neutropenia. In OSKIRA-Asia-1X, the most common adverse events were nasopharyngitis, hypertension, RA and neutropenia.

Conclusion

Fostamatinib achieved both statistically and clinically significant improvements in RA signs and symptoms. The safety and tolerability of fostamatinib (plus MTX) were consistent with previous studies.

Trial registration

OSKIRA-Asia-1 trial registration: https://clinicaltrials.gov, NCT01569074; OSKIRA-Asia-1X trial registration: https://clinicaltrials.gov, NCT01640054.
Remote Ecological Momentary Testing of Learning and Memory in Adults With Serious Mental Illness
Authors: Parrish Emma M , Kamarsu Snigdha , Harvey Philip D , Pinkham Amy , Depp Colin A , Moore Raeanne C
Published: October 2020

Smartphone-based ecological mobile cognitive tests (EMCTs) can measure cognitive abilities in the real world, complementing traditional neuropsychological assessments. We evaluated the validity of an EMCT of recognition memory designed for use with people with serious mental illness, as well as relevant contextual influences on performance. Participants with schizophrenia (SZ), schizoaffective disorder, and bipolar disorder (BD) completed in-lab assessments of memory (Hopkins Verbal Learning Test, HVLT), other cognitive abilities, functional capacity, and symptoms, followed by 30 days of EMCTs during which they completed our Mobile Variable Difficulty List Memory Test (VLMT) once every other day (3 trials per session). List length on the VLMT altered between 6, 12, and 18 items. On average, participants completed 75.3% of EMCTs. Overall performance on VLMT 12 and 18 items was positively correlated with HVLT (ρ = 0.52, P < .001). People with BD performed better on the VLMT than people with SZ. Intraindividual variability on the VLMT was more specifically associated with HVLT than nonmemory tests and not associated with symptoms. Performance during experienced distraction, low effort, and out of the home location was reduced yet still correlated with the in-lab HVLT. The VLMT converged with in-lab memory assessment, demonstrating variability within person and by different contexts. Ambulatory cognitive testing on participants’ personal mobile devices offers more a cost-effective and “ecologically valid” measurement of real-world cognitive performance.
Mycetoma – a history of the first contributions to the description of the disease and its pathogenesis
Authors: Hay R J
Published: October 2020

Tracking the history of the discovery of mycetoma is not simple because identifying the roots of medical knowledge depends on utilising sources that employ imprecise and sometimes confusing descriptions when compared with those based on modern medical terminology. Ancient sources of information include writings, such as poetry, archaeology and paleopathology, as well as legend and folklore. The earliest precise descriptions of mycetoma were recorded in the mid-19th century by medical officers working in southern India. But interest in the disease spread rapidly both among doctors in India and elsewhere, from Algeria to Mexico to Sudan. Although over time the names of organisms have changed, the clinical and pathological descriptions still stand as testament to those early detailed studies. Some of the conclusions of the early investigators, particularly the general lack of effective treatment and the difficulty in diagnosis, remain true today.