bluuebunny/crossref_metadata_2025 huggingface dataset:
CircHIPK3 Plays Vital Roles in Cardiovascular Disease
Authors: Zhang Lei , Wang Yin , Yu Fei , Li Xin , Gao Huijuan , Li Peifeng
Published: September 2021

Circular RNAs (circRNAs) are covalently closed RNAs that function in various physiological and pathological processes. CircRNAs are widely involved in the development of cardiovascular disease (CVD), one of the leading causes of morbidity and mortality worldwide. CircHIPK3 is generated from the second exon of the HIPK3 gene, a corepressor of homeodomain transcription factors. As an exonic circRNA (ecRNA), circHIPK3 is produced through intron-pairing driven circularization facilitated by Alu elements. In the past 5 years, a growing number of studies have revealed the multifunctional roles of circHIPK3 in different diseases, such as cancer and CVD. CircHIPK3 mainly participates in CVD pathogenesis through interacting with miRNAs. This paper summarizes the current literature on the biogenesis and functions of circHIPK3, elucidates the role of circHIPK3 in different CVD patterns, and explores future perspectives.
Risk Factors for Anthracycline-Induced Cardiotoxicity
Authors: Qiu Shuo , Zhou Tian , Qiu Bo , Zhang Yuxin , Zhou Yonggang , Yu Huihui , Zhang Jingyi , Liu Li , Yuan Lijun , Yang Guodong , Duan Yunyou , Xing Changyang
Published: September 2021

Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus.

Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis.

Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43–2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11–2.74), and obesity (OR: 1.72; 95% CI: 1.13–2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1–35.8% vs. 16.4%, 95% CI: 13.4–19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9–36.1%), which is similar with the overall result of GLS.

Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.
Accessibility and Digital Mental Health: Considerations for More Accessible and Equitable Mental Health Apps
Authors: Bunyi John , Ringland Kathryn E. , Schueller Stephen M.
Published: September 2021

Digital mental health is often touted as a solution to issues of access to mental health care. However, there has been little research done to understand the accessibility of digital mental health, especially for those with disabilities. In this piece, we define accessibility as it relates to mental health apps, describe the current state of accessibility in the digital world broadly and in mental health apps more specifically, outline why accessibility matters in mental health apps, and identify future steps to better incorporate accessibility into research and development of mental health apps.
Design, Implementation and Testing of a Network-Based Earthquake Early Warning System in Greece
Authors: Bracale M. , Colombelli S. , Elia L. , Karakostas V. , Zollo A.
Published: September 2021

In this study we implemented and tested the Earthquake Early Warning system PRESTo (PRobabilistic and Evolutionary early warning System, Satriano et al., 2011) on the Greek Ionian islands of Lefkada, Zakynthos and Kefalonia. PRESTo is a free and open source platform for regional Earthquake Early Warning developed at the University of Naples Federico II, which is currently under experimentation in Southern Italy, in the area covered by the Irpinia Seismic Network. The three Ionian islands selected for this study are located on the North-Western part of the Hellenic trench. Here the seismicity rate and the seismic hazard, coupled with the vulnerability of existing critical infrastructures, make this region among the highest seismic risk areas in Europe, where the application of Earthquake Early Warning systems may become a useful strategy to mitigate the potential damage caused by earthquakes. Here we studied the feasibility of implementing an Earthquake Early Warning system on an existing seismic network, which was not specifically made for earthquake early warning purposes, and evaluated the performance of the system, using a data set of real-earthquake recordings. We first describe the technical details of the implementation of PRESTo in the area of interest, including the preliminary parameter configuration and the empirical scaling relationship calibration. Then we evaluated the performance of the system through the off-line analysis of a database of real earthquake records belonging to the most recent M > 4.0 earthquakes occurred in the area. We evaluated the performance in terms of source parameter estimation (location, magnitude), accuracy of ground shaking prediction and lead-time analysis. Finally, we show the preliminary results of the real-time application of PRESTo, performed during the period 01–31 July 2019.
A Comparative Study on Microscopic Characteristics of Volcanic Reservoirs in the Carboniferous Kalagang and Haerjiawu Formations in the Santanghu Basin, China
Authors: Wang Weiming , La Weihao , Fan Tanguang , Xu Xiongfei , Liu Yingnan , Lv Qixia
Published: September 2021

Self-jetting high-yield oil flow was obtained from Ma 67 and Ma 36 wells drilled in the volcanic reservoirs of the Haerjiawu Formation in the Santanghu Basin, China. This has shifted the prospectors’ attention to the Haerjiawu Formation from the Kalagang Formation, which is generally considered to have favorable physical properties. To further explain the geological reasons why oil flow can jet itself from the volcanic rocks in the Haerjiawu Formation with poor physical properties, this study carries out a systematic comparison on the microscopic pore structures of volcanic rocks through unconventional tests such as low-temperature nitrogen adsorption, high-pressure mercury injection, and constant-rate mercury injection based on the analyses of physical properties and minerals. The results obtained are as follows. The volcanic rocks of the Kalagang Formation have relatively high pore permeability. However, their micropores have a wide distribution range of pore size and feature highly meandering structures and strong heterogeneity. Meanwhile, small pore throats connect large pores in the volcanic rocks, resulting in a relatively high pore/throat ratio. All these are conducive to the occurrence of tight oil and gas but unfavorable for the flow of oil and gas. The volcanic rocks in the Haerjiawu Formation have relatively low volcanic permeability. However, small pores connect large pore throats in the volcanic rocks; thus, leading to a relatively low pore/throat ratio. Meanwhile, the volcanic rocks feature low meandering structures, strong homogeneity, and high connectivity. All these are favorable for the formation of tight oil and gas reservoirs. These assessment results also indicate that the assessment indices of tight volcanic reservoirs should not only include porosity and permeability. Instead, more attention should be paid to the microscopic pore structures, and it is necessary to analyze the charging and flow of tight oil from the configuration of pores and pore throats. This study not only explains the geological factors of the wells with self-jetting high-yield oil flow in the Haerjiawu Formation from the perspective of microscopic pore structures but also provides a new idea and comparison method for the assessment of tight reservoirs in other areas.
Strengthened Impacts of November Snow Cover Over Siberia on the Out-of-phase Change in the Siberian High Between December and January Since 2000 and Implication for Intraseasonal Climate Prediction
Authors: Yang Hongqing , Fan Ke
Published: September 2021

This study investigates the out-of-phase change in the Siberian High (SH) between December and January (stronger than normal in December and weaker than normal in January, and vice versa). The results show that the monthly reversal frequency of the SH between December and January increases significantly after 2000 from 30% (1981–2000) to 63% (2001-2019). Correspondingly, the influence of November snow cover over Siberia on the phase reversal of the SH has intensified after 2000. The reasons may be as follows. Higher snow depth over Siberia (SSD) in November corresponds to stronger diabatic cooling and increased snow accumulation over Siberia in November and December, which may strengthen the SH in December via the positive feedback of snow albedo. The dynamic mechanisms between the higher SSD in November and weaker SH in January are further investigated from the perspective of troposphere–stratosphere interaction. Such anomalously higher SSD with strong upward heat flux induces the upward-propagating wave activity flux in November and December over the Urals and Siberia, leading to a weaker and warmer stratospheric polar vortex in January. Subsequently, the anomalies of the stratospheric polar vortex signal propagate downwards, giving rise to a negative Arctic Oscillation–like structure in the troposphere and a weakening of the SH in January. This mechanism can be partly reproduced in CMIP6. Additionally, the variability of the September–October Arctic sea ice mainly leads to coherent variations of the SH in December and January via the eddy–mean flow interaction before 2000. Furthermore, the preceding November snow cover over Siberia enhances the intraseasonal prediction skill for the winter SH after 2000. Meanwhile, considering the previous November SSD, the prediction accuracy for the out-of-phase change in the SH between December and January increases from 16% (outputs of the NCEP’s Climate Forecast System, version 2) to 75%.
COVID-19-Associated Subacute Thyroiditis: Evidence-Based Data From a Systematic Review
Authors: Trimboli Pierpaolo , Cappelli Carlo , Croce Laura , Scappaticcio Lorenzo , Chiovato Luca , Rotondi Mario
Published: September 2021

Subacute thyroiditis (SAT) is a thyroid disease of viral or post-viral origin. Whether SAT represents a complication of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still unclear. Our aim was to systematically review the literature to 1) explore the size of the literature about SAT in COVID-19 and 2) evaluate the clinical characteristics of SAT. PubMed/MEDLINE, Embase, and Scopus were searched until April 20, 2021. Original papers, case reports, and case series reporting SAT in COVID-19 patients were included. Authors and their country, journal, year of publication, COVID-19 and SAT clinical presentation, thyroid function, therapy, and follow-up data were extracted. Nineteen papers (17 case reports and 2 case series) were included, describing 27 patients, 74.1% females, aged 18 to 69 years. COVID-19 was diagnosed by nasopharyngeal swab in 66.7% cases and required hospitalization in 11.1%. In 83.3% cases, SAT occurred after COVID-19. Neck pain was present in 92.6% cases and fever in 74.1%. Median TSH, fT3, and fT4 were 0.01 mU/l, 10.79 pmol/l, and 27.2 pmol/l, respectively. C-reactive-protein and erythrocyte sedimentation rate were elevated in 96% of cases. Typical ultrasonographic characteristics of SAT were observed in 83.3% of cases. Steroids were the most frequent SAT therapy. Complete remission of SAT was recorded in most cases. In conclusion, the size and quality of published data of SAT in COVID-19 patients are poor, with only case reports and case series being available. SAT clinical presentation in COVID-19 patients seems to be similar to what is generally expected.
MIRAGE Syndrome Caused by a De Novo c.3406G>C (p. Glu1136Gln) Mutation in the SAMD9 Gene Presenting With Neonatal Adrenal Insufficiency and Recurrent Intussusception: A Case Report
Authors: Chin Xinyi , Sreedharan Aravind Venkatesh , Tan Ene Choo , Wei Heming , Kuan Jyn Ling , Ho Christopher Wen Wei , Lam Joyce Ching Mei , Ting Teck Wah , Vasanwala Rashida Farhad
Published: September 2021

Introduction

Primary adrenal insufficiency (PAI) presenting in the neonatal period can be life threatening and requires early recognition, diagnosis, and management. PAI due to adrenal hypoplasia (syndromic/non-syndromic) is a rare disorder. MIRAGE is a recently described syndrome with PAI and multisystem involvement.

Case Presentation

A preterm female neonate presenting with PAI and persistent severe thrombocytopenia was diagnosed to have MIRAGE syndrome due to a de novo pathogenic variant c.3406G>C (p. Glu1136Gln) in the SAMD9 gene. In the first year of life, she had recurrent respiratory and gastrointestinal infection causing failure to thrive. At 17 months, she suffered recurrent intussusception requiring treatment with parenteral nutrition and high-dose steroids. Subsequently, she established oral feeds with hydrolysed formula and demonstrated good weight gain.

Conclusion

In neonates presenting with PAI and associated multisystem involvement, a thoughtful approach and genetic testing is valuable in discerning an etiological diagnosis. This case of MIRAGE adds to the spectrum of reported cases and is the first to report on recurrent intussusception and its management with high-dose steroids.
Vulnerability of Street Trees in Upper Midwest Cities to Climate Change
Authors: Brandt Leslie A. , Johnson Gary R. , North Eric A. , Faje Jack , Rutledge Annamarie
Published: September 2021

Urban trees play an important role in helping cities adapt to climate change, but also are vulnerable to changes in climate themselves. We developed an approach for assessing vulnerability of urban tree species and cultivars commonly planted in cities in the United States Upper Midwest to current and projected climate change through the end of the 21st century. One hundred seventy-eight tree species were evaluated for their adaptive capacity to a suite of current and future-projected climate and urban stressors using a weighted scoring system based on an extensive literature review. These scores were then evaluated and adjusted by leading experts in arboriculture in the region. Each species or cultivar’s USDA Hardiness Zone and American Horticultural Society Heat Zone tolerance was compared to current and future heat and hardiness zones for 14 municipalities across Michigan, Wisconsin, and Minnesota using statistically downscaled climate data. Species adaptive capacity and zone tolerance was combined to assign each species one of five vulnerability categories for each location. We determined the number of species and trees in each category based on the most recent municipal street tree data for each location. Under a scenario of less climate change (RCP 4.5), fewer than 2% of trees in each municipality were considered highly vulnerable across all 14 municipalities. Under a scenario of greater change (RCP 8.5), upward of 25% of trees were considered highly vulnerable in some locations. However, the number of vulnerable trees varied greatly by location, primarily because of differences in projected summer high temperatures rather than differences in species composition. Urban foresters can use this information as a complement to other more traditional considerations used when selecting trees for planting.
In-depth Phylogenomic Analysis of Arbuscular Mycorrhizal Fungi Based on a Comprehensive Set of de novo Genome Assemblies
Authors: Montoliu-Nerin Merce , Sánchez-García Marisol , Bergin Claudia , Kutschera Verena Esther , Johannesson Hanna , Bever James D. , Rosling Anna
Published: September 2021

Morphological characters and nuclear ribosomal DNA (rDNA) phylogenies have so far been the basis of the current classifications of arbuscular mycorrhizal (AM) fungi. Improved understanding of the evolutionary history of AM fungi requires extensive ortholog sampling and analyses of genome and transcriptome data from a wide range of taxa. To circumvent the need for axenic culturing of AM fungi we gathered and combined genomic data from single nuclei to generate de novo genome assemblies covering seven families of AM fungi. We successfully sequenced the genomes of 15 AM fungal species for which genome data was not previously available. Comparative analysis of the previously published Rhizophagus irregularis DAOM197198 assembly confirm that our novel workflow generates genome assemblies suitable for phylogenomic analysis. Predicted genes of our assemblies, together with published protein sequences of AM fungi and their sister clades, were used for phylogenomic analyses. We evaluated the phylogenetic placement of Glomeromycota in relation to its sister phyla (Mucoromycota and Mortierellomycota), and found no support to reject a polytomy. Finally, we explored the phylogenetic relationships within Glomeromycota. Our results support family level classification from previous phylogenetic studies, and the polyphyly of the order Glomerales with Claroideoglomeraceae as the sister group to Glomeraceae and Diversisporales.
Location and Species Matters: Variable Influence of the Environment on the Gene Flow of Imperiled, Native and Invasive Cottontails
Authors: McGreevy Thomas J. , Michaelides Sozos , Djan Mihajla , Sullivan Mary , Beltrán Diana M. , Buffum Bill , Husband Thomas
Published: September 2021

The environment plays an important role in the movement of individuals and their associated genes among populations, which facilitates gene flow. Gene flow can help maintain the genetic diversity both within and between populations and counter the negative impact of genetic drift, which can decrease the fitness of individuals. Sympatric species can have different habitat preferences, and thus can exhibit different patterns of genetic variability and population structure. The specialist-generalist variation hypothesis (SGVH) predicts that specialists will have lower genetic diversity, lower effective population sizes (Ne), and less gene flow among populations. In this study, we used spatially explicit, individual-based comparative approaches to test SGVH predictions in two sympatric cottontail species and identify environmental variables that influence their gene flow. New England cottontail (Sylvilagus transitionalis) is the only native cottontail in the Northeast US, an early successional habitat specialist, and a species of conservation concern. Eastern cottontail (S. floridanus) is an invasive species in the Northeast US and a habitat generalist. We characterized each species’ genomic variation by developing double-digest Restriction-site Associated DNA sequence single nucleotide polymorphism markers, quantified their habitat with Geographic Information System environmental variables, and conducted our analyses at multiple scales. Surprisingly, both species had similar levels of genetic diversity and eastern cottontail’s Ne was only higher than New England cottontail in one of three subregions. At a regional level, the population clusters of New England cottontail were more distinct than eastern cottontail, but the subregional levels showed more geographic areas of restricted gene flow for eastern cottontail than New England cottontail. In general, the environmental variables had the predicted effect on each species’ gene flow. However, the most important environmental variable varied by subregion and species, which shows that location and species matter. Our results provide partial support for the SGVH and the identification of environmental variables that facilitate or impede gene flow can be used to help inform management decisions to conserve New England cottontail.
Identification of Gene Signature as Diagnostic and Prognostic Blood Biomarker for Early Hepatocellular Carcinoma Using Integrated Cross-Species Transcriptomic and Network Analyses
Authors: Al-Harazi Olfat , Kaya Ibrahim H. , Al-Eid Maha , Alfantoukh Lina , Al Zahrani Ali Saeed , Al Sebayel Mohammed , Kaya Namik , Colak Dilek
Published: September 2021

Background: Hepatocellular carcinoma (HCC) is considered the most common type of liver cancer and the fourth leading cause of cancer-related deaths in the world. Since the disease is usually diagnosed at advanced stages, it has poor prognosis. Therefore, reliable biomarkers are urgently needed for early diagnosis and prognostic assessment.

Methods: We used genome-wide gene expression profiling datasets from human and rat early HCC (eHCC) samples to perform integrated genomic and network-based analyses, and discovered gene markers that are expressed in blood and conserved in both species. We then used independent gene expression profiling datasets for peripheral blood mononuclear cells (PBMCs) for eHCC patients and from The Cancer Genome Atlas (TCGA) database to estimate the diagnostic and prognostic performance of the identified gene signature. Furthermore, we performed functional enrichment, interaction networks and pathway analyses.

Results: We identified 41 significant genes that are expressed in blood and conserved across species in eHCC. We used comprehensive clinical data from over 600 patients with HCC to verify the diagnostic and prognostic value of 41-gene-signature. We developed a prognostic model and a risk score using the 41-geneset that showed that a high prognostic index is linked to a worse disease outcome. Furthermore, our 41-gene signature predicted disease outcome independently of other clinical factors in multivariate regression analysis. Our data reveals a number of cancer-related pathways and hub genes, including EIF4E, H2AFX, CREB1, GSK3B, TGFBR1, and CCNA2, that may be essential for eHCC progression and confirm our gene signature’s ability to detect the disease in its early stages in patients’ biological fluids instead of invasive procedures and its prognostic potential.

Conclusion: Our findings indicate that integrated cross-species genomic and network analysis may provide reliable markers that are associated with eHCC that may lead to better diagnosis, prognosis, and treatment options.
Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study
Authors: Bensenor Isabela , Padilha Kallyandra , Lima Isabella Ramos , Santos Raul Dias , Lambert Gilles , Ramin-Mangata Stéphane , Bittencourt Marcio S , Goulart Alessandra C , Santos Itamar S. , Mill Jose G , Krieger Jose E , Lotufo Paulo A. , Pereira Alexandre C.
Published: September 2021

Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10−6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.
Transcriptomic Time-Series Analyses of Gene Expression Profile During Zygotic Embryo Development in Picea mongolica
Authors: Yan Jia , buer Ha , Wang Ya ping , zhula Gegen , Bai Yu´e
Published: September 2021

Zygotic embryogenesis is a critical process during seed development in gymnosperms. However, knowledge on the genome-wide transcriptional activation that guides this process in conifers is limited, especially in Picea mongolica. This tree species is endemic to semiarid habitats of Inner Mongolia in China. To extend what is known about the molecular events underpinning its zygotic embryogenesis, comparative transcriptomic analyses of gene expression in zygotic embryos were performed by RNA sequencing in P. mongolica. Our results showed that most changes in transcript levels occurred in the early embryonic pattering determination and formation of mature embryos. Transcripts related to embryogenic competence, cell division pattern, hormones, and stress response genes were identified during embryogenesis. Auxin is essential for early embryo patterning and pre-cotyledon embryonic formation. However, ABA is a major regulator of embryo maturation. Moreover, we found that methylation-related gene expression is associated with activation of early-stage embryos, late embryogenesis abundant proteins, and storage/energy-related genes with late and mature embryos. Furthermore, network analysis revealed stage-specific and multistage gene expression clusters during embryogenesis. WOX, MYB, AP2, and HLH transcription factors seem more relevant to embryogenesis in different stages. Our results provide large-scale and comprehensive transcriptome data for embryo development in P. mongolica. These data will lay a foundation for the protection and utilization of P. mongolica resources.
Making Connections: Integrative Signaling Mechanisms Coordinate DNA Break Repair in Chromatin
Authors: Sanchez Anthony , Lee Doohyung , Kim Dae In , Miller Kyle M.
Published: September 2021

DNA double-strand breaks (DSBs) are hazardous to genome integrity and can promote mutations and disease if not handled correctly. Cells respond to these dangers by engaging DNA damage response (DDR) pathways that are able to identify DNA breaks within chromatin leading ultimately to their repair. The recognition and repair of DSBs by the DDR is largely dependent on the ability of DNA damage sensing factors to bind to and interact with nucleic acids, nucleosomes and their modified forms to target these activities to the break site. These contacts orientate and localize factors to lesions within chromatin, allowing signaling and faithful repair of the break to occur. Coordinating these events requires the integration of several signaling and binding events. Studies are revealing an enormously complex array of interactions that contribute to DNA lesion recognition and repair including binding events on DNA, as well as RNA, RNA:DNA hybrids, nucleosomes, histone and non-histone protein post-translational modifications and protein-protein interactions. Here we examine several DDR pathways that highlight and provide prime examples of these emerging concepts. A combination of approaches including genetic, cellular, and structural biology have begun to reveal new insights into the molecular interactions that govern the DDR within chromatin. While many questions remain, a clearer picture has started to emerge for how DNA-templated processes including transcription, replication and DSB repair are coordinated. Multivalent interactions with several biomolecules serve as key signals to recruit and orientate proteins at DNA lesions, which is essential to integrate signaling events and coordinate the DDR within the milieu of the nucleus where competing genome functions take place. Genome architecture, chromatin structure and phase separation have emerged as additional vital regulatory mechanisms that also influence genome integrity pathways including DSB repair. Collectively, recent advancements in the field have not only provided a deeper understanding of these fundamental processes that maintain genome integrity and cellular homeostasis but have also started to identify new strategies to target deficiencies in these pathways that are prevalent in human diseases including cancer.
Transcriptome Profiling Reveals Important Transcription Factors and Biological Processes in Skin Regeneration Mediated by Mechanical Stretch
Authors: Liu Wei , Xiong Shaoheng , Zhang Yu , Du Jing , Dong Chen , Yu Zhou , Ma Xianjie
Published: September 2021

Background: Mechanical stretch is utilized to promote skin regeneration during tissue expansion for reconstructive surgery. Although mechanical stretch induces characteristic morphological changes in the skin, the biological processes and molecular mechanisms involved in mechanically induced skin regeneration are not well elucidated.

Methods: A male rat scalp expansion model was established and the important biological processes related to mechanical stretch-induced skin regeneration were identified using Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA). Analysis was also conducted by constructing a protein–protein interaction (PPI) network, identifying key modules and hub genes, determining transcription factor (TF)-mRNA regulatory relationships, and confirming the expression pattern of the TFs and hub genes.

Results: We identified nine robust hub genes (CXCL1, NEB, ACTN3, MYOZ1, ACTA1, TNNT3, PYGM, AMPD1, and CKM) that may serve as key molecules in skin growth. These genes were determined to be involved in several important biological processes, including keratinocyte differentiation, cytoskeleton reorganization, chemokine signaling pathway, glycogen metabolism, and voltage-gated ion channel activity. The potentially significant pathways, including the glucagon signaling pathway, the Wnt signaling pathway, and cytokine–cytokine receptor interaction, were distinguished. In addition, we identified six TFs (LEF1, TCF7, HMGA1, TFAP2C, FOSL1, and ELF5) and constructed regulatory TF–mRNA interaction networks.

Conclusion: This study generated a comprehensive overview of the gene networks underlying mechanically induced skin regeneration. The functions of these key genes and the pathways in which they participate may reveal new aspects of skin regeneration under mechanical strain. Furthermore, the identified TF regulators can be used as potential candidates for clinical therapeutics for skin pretreatment before reconstructive surgery.
Why Are Newcomers so Happy? Subjective Well-Being of First-Generation Immigrants in Germany
Authors: Brockmann Hilke
Published: September 2021

First-generation immigrants are surprisingly satisfied with their life compared to the local population in Germany. Is this because newcomers are particularly resourceful? We test if personality selectivity, purposive adaptation, and social resilience separately or in tandem explain why subjective well-being remains high even in times of objective disadvantage. Using German panel data (GSOEP) from 5,008 first-generation immigrants for the years 1984–2014 and official data, growth curve models show that newcomers are a selected group with respect to their open and less neurotic personalities and that these personal characteristics are distinctly associated with happiness. Also, newcomers immediately compare their income to the standards in the host society but not their family life. This contributes to boosting their subjective well-being as well. For more than 30 years, first-generation immigrants use their country of origin as a reference point thus protecting the positive association of intimate relationships and happiness. Finally, newcomers are highly capable of recovering from social loss. Since the resources used by first-generation migrants to preserve their subjective well-being are unlikely to be confined to Germany, our findings can inform policy-making. Most importantly, they suggest that the economic integration of newcomers should be fast and easy while family reunification and integration should follow only with a time lag.
CGAT: Cell Graph ATtention Network for Grading of Pancreatic Disease Histology Images
Authors: Baranwal Mayank , Krishnan Santhoshi , Oneka Morgan , Frankel Timothy , Rao Arvind
Published: September 2021

Early detection of Pancreatic Ductal Adenocarcinoma (PDAC), one of the most aggressive malignancies of the pancreas, is crucial to avoid metastatic spread to other body regions. Detection of pancreatic cancer is typically carried out by assessing the distribution and arrangement of tumor and immune cells in histology images. This is further complicated due to morphological similarities with chronic pancreatitis (CP), and the co-occurrence of precursor lesions in the same tissue. Most of the current automated methods for grading pancreatic cancers rely on extensive feature engineering involving accurate identification of cell features or utilising single number spatially informed indices for grading purposes. Moreover, sophisticated methods involving black-box approaches, such as neural networks, do not offer insights into the model’s ability to accurately identify the correct disease grade. In this paper, we develop a novel cell-graph based Cell-Graph Attention (CGAT) network for the precise classification of pancreatic cancer and its precursors from multiplexed immunofluorescence histology images into the six different types of pancreatic diseases. The issue of class imbalance is addressed through bootstrapping multiple CGAT-nets, while the self-attention mechanism facilitates visualization of cell-cell features that are likely responsible for the predictive capabilities of the model. It is also shown that the model significantly outperforms the decision tree classifiers built using spatially informed metric, such as the Morisita-Horn (MH) indices.
BNT162b2 Vaccination Elicits Strong Serological Immune Responses Against SARS-CoV-2 Including Variants of Concern in Elderly Convalescents
Authors: Jahrsdörfer Bernd , Fabricius Dorit , Scholz Judith , Ludwig Carolin , Grempels Aline , Lotfi Ramin , Körper Sixten , Adler Guido , Schrezenmeier Hubert
Published: September 2021

Elderly residents of long-term care facilities (LTCFs) have long been underrepresented in studies on vaccine efficacy, particularly in light of currently emerging variants of concern (VOCs). In this prospective observational cohort study, we analyzed serological immune responses in 190 individuals before, 3 weeks after 1st and 3 weeks after 2nd vaccination with BNT162b2. Unvaccinated COVID-19-convalescent subjects served as reference. End points comprised serum anti-spike IgG and IgA titers as well as neutralization capacities against unmutated and mutated SARS-CoV-2 receptor binding domains including B.1.1.7, B.1.351 and P.1. We found that antibody titers and neutralization capacities up to 3 weeks after 2nd vaccination with BNT162b2 were significantly higher in COVID-19-convalescent as compared to COVID-19-naive vaccinees. Moreover, pre-vaccination anti-NCP IgG titers, but not age or gender, had a high impact on the strength and kinetics of post-vaccination neutralization capacity development. Most importantly, BNT162b2-induced neutralization capacity was cross-reactive with VOCs. In contrast to unvaccinated convalescents, vaccinated convalescent individuals of all ages acquired strong neutralizing capacities against current VOCs. The present study suggests that COVID-19-convalescent individuals with a broad age range between 18 and 98 years benefit from BNT162b2 vaccination by developing strong and broad neutralizing immune responses against SARS-CoV-2 including current VOCs.
Unpaid Work in Marine Science: A Snapshot of the Early-Career Job Market
Authors: Osiecka Anna N. , Quer Susanna , Wróbel Aleksandra , Osiecka-Brzeska Katarzyna
Published: September 2021

Graphical Abstract

Brief summary of the early-career job market in marine biology and conservation.
Comparison of the Efficacy of Melasma Treatments: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Liu Yi , Wu Shanshan , Wu Haixuan , Liang Xuelei , Guo Dechao , Zhuo Fenglin
Published: September 2021

Background: Melasma is an acquired pigmentation disorder with challenges in treatment because of its refractory nature and high risk of recurrence.

Objectives: This study aimed to compare the efficacy and side effects of 14 common therapies for melasma using a systematic review and network meta-analysis (NMA).

Methods: The PubMed, Embase, and Cochrane Library databases were searched till December 2020 using the melasma area and severity index as a therapeutic index. A total of 59 randomized controlled trials (RCTs) met the inclusion criteria and were selected.

Results: The ranking of relative efficacy compared with placebo in descending order was Q-switched Nd:Yag 1,064-nm laser (QSND), intense pulsed light, ablative fractional laser (AFL), triple combined cream (TCC), topical vitamin C, oral tranexamic acid (oTA), peeling, azelaic acid, microneedles (MNs), topical tranexamic acid (tTA), tretinoin, picosecond laser, hydroquinone (HQ), and non-AFL. Moreover, QSND was more effective than HQ and tTA against melasma. The ranking of percentage (%) of side effects in ascending order for each of 14 therapies with more than 80 participants was tretinoin (10.1%), oTA (17.6%), HQ (18.2%), AFL (20.0%), QSND (21.5%), TCC (25.7%), tTA (36.75%), peeling (38.0%), and MN (52.3%). Taking both efficacy and safety into consideration, TCC was found to be the most favorable selection among the topical drugs for melasma. QSND and AFL were still the best ways to treat melasma among photoelectric devices. oTA as system administration was a promising way recommended for melasma. Among 31 studies, 87% (27/31) studies showed that the efficacy of combination therapies is superior to that of single therapy. The quality of evidence in this study was generally high because of nearly 50% of split-face RCTs.

Conclusions: Based on the published studies, this NMA indicated that QSND, AFL, TCC, and oTA would be the preferred ways to treat melasma for dermatologists. However, more attention should be paid to the efficacy and safety simultaneously during the clinical application. Most of the results were in line with those of the previous studies, but a large number of RCTs should be included for validation or update.

Systematic Review Registration: identifier: CRD42021239203.
Time-Varying Effects of Meteorological Variables on Malaria Epidemiology in the Context of Interrupted Control Efforts in the Amazon Rainforest, 2000–2017
Authors: Carrasco-Escobar Gabriel , Qquellon Jazmin , Villa Diego , Cava Renato , Llanos-Cuentas Alejandro , Benmarhnia Tarik
Published: September 2021

Successful malaria control interventions, mostly based on the training of health workers, distribution of insecticide-treated nets, and spraying, decrease malaria incidence; however, when these interventions are interrupted, a resurgence may occur. In the Peruvian Amazon, after discontinuing the control activities implemented by the PAMAFRO project (2006–2010)-a Global Fund-sponsored project for the strengthening of malaria control and surveillance in multiple countries in Latin America– malaria cases re-emerged dramatically. In parallel, meteorological factors determine the conditions suitable for the development, reproduction, and survival of mosquito vectors and parasites. This study hypothesized that interruption of malaria interventions may have modified the meteorological-malaria relationships over time (i.e., temporal changes in the dose-response between meteorological variables and malaria incidence). In this panel data analysis, we assessed the extent that relationships between meteorological variables and malaria changed temporally using data of monthly malaria incidence due to Plasmodium vivax or P. falciparum in Loreto, Peru (2000–2017). Generalized additive models were used to explore how the effects of meteorological variables changed in magnitude before, during, and after the PAMAFRO intervention. We found that once the PAMAFRO intervention had been interrupted, the estimated effects (dose-response) of meteorological variables on incidence rates decreased for both malaria parasite species. However, these fitted effect estimates did not reach their baseline levels (before the PAMAFRO period); variations of time-varying slopes between 0.45 and 2.07 times were observed after the PAMAFRO intervention. We also reported significant heterogeneity in the geographical distributions of malaria, parasite species, and meteorological variables. High malaria transmission occurred consistently in the northwestern provinces of Loreto Department. Since the end of the PAMAFRO period, a higher effect of precipitation and actual evapotranspiration was described on P. falciparum compared to P. vivax. The effect of temperature on malaria was greater over a shorter time (1-month lag or less), compared with precipitation and actual evapotranspiration (12-month lag). These findings demonstrate the importance of sustained malaria control efforts since interruption may enhance the links between meteorological factors and malaria. Our results also emphasize the importance of considering the time-varying effect of meteorological factors on malaria incidence to tailor control interventions, especially to better manage the current and future climate change crisis.
Crosstalk Between SMPDL3b and NADPH Oxidases Mediates Radiation-Induced Damage of Renal Podocytes
Authors: Azzam Patrick , Francis Marina , Youssef Tarek , Mroueh Manal , Daher Alaa Abou , Eid Assaad A. , Fornoni Alessia , Marples Brian , Zeidan Youssef H.
Published: September 2021

Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo, the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.
Extracorporeal Membrane Oxygenation for Acute Toxic Inhalations: Case Reports and Literature Review
Authors: Yu Dun , Xiaolin Zhang , Lei Pan , Feng Li , Lin Zhang , Jie Shen
Published: September 2021

Previous studies have shown that poisoning is a major threat to human health. Inhalation of acute toxic gas has been linked to serious health consequences. Among the antidotes for poisoning currently used, supportive care is the most common intervention in clinical practice. Severe acute respiratory distress syndrome (ARDS) and/or refractory cardiogenic shock or cardiac arrest caused by toxins are associated with high mortality and are difficult to treat. Extracorporeal membrane oxygenation (ECMO) is an aggressive supportive measure used to manage severely poisoned patients. This study presents two cases of acute toxic gases inhalation, severe ARDS and circulatory instability induced by bromine inhalation, and ARDS induced by nitric acid inhalation which were successfully treated with ECMO. The ECMO techniques used in the animal models and in human cases to treat severe poisoning are described as well as the indications, contraindications, complications, and weaning of ECMO.
Genome Sequence Analysis of Clostridium chauvoei Strains of European Origin and Evaluation of Typing Options for Outbreak Investigations
Authors: Thomas Prasad , Abdel-Glil Mostafa Y. , Eichhorn Inga , Semmler Torsten , Werckenthin Christiane , Baumbach Christina , Murmann Wybke , Bodenthin-Drauschke Anne , Zimmermann Pia , Schotte Ulrich , Galante Domenico , Slavic Durda , Wagner Martin , Wieler Lothar H. , Neubauer Heinrich , Seyboldt Christian
Published: September 2021

Black quarter caused by Clostridium (C.) chauvoei is an important bacterial disease that affects cattle and sheep with high mortality. A comparative genomics analysis of 64 C. chauvoei strains, most of European origin and a few of non-European and unknown origin, was performed. The pangenome analysis showed limited new gene acquisition for the species. The accessory genome involved prophages and genomic islands, with variations in gene composition observed in a few strains. This limited accessory genome may indicate that the species replicates only in the host or that an active CRISPR/Cas system provides immunity to foreign genetic elements. All strains contained a CRISPR type I-B system and it was confirmed that the unique spacer sequences therein can be used to differentiate strains. Homologous recombination events, which may have contributed to the evolution of this pathogen, were less frequent compared to other related species from the genus. Pangenome single nucleotide polymorphism (SNP) based phylogeny and clustering indicate diverse clusters related to geographical origin. Interestingly the identified SNPs were mostly non-synonymous. The study demonstrates the possibility of the existence of polymorphic populations in one host, based on strain variability observed for strains from the same animal and strains from different animals of one outbreak. The study also demonstrates that new outbreak strains are mostly related to earlier outbreak strains from the same farm/region. This indicates the last common ancestor strain from one farm can be crucial to understand the genetic changes and epidemiology occurring at farm level. Known virulence factors for the species were highly conserved among the strains. Genetic elements involved in Nicotinamide adenine dinucleotide (NAD) precursor synthesis (via nadA, nadB, and nadC metabolic pathway) which are known as potential anti-virulence loci are completely absent in C. chauvoei compared to the partial inactivation in C. septicum. A novel core-genome MLST based typing method was compared to sequence typing based on CRISPR spacers to evaluate the usefulness of the methods for outbreak investigations.