bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of FAM20A, Ectopic Gingival Mineralization and Chondro/Osteogenic Modifications in Enamel Renal Syndrome
Authors: Simancas Escorcia Victor , Diarra Abdoulaziz , Naveau Adrien , Dessombz Arnaud , Felizardo Rufino , Cannaya Vidjeacoumary , Chatziantoniou Christos , Quentric Mickaël , Vikkula Miikka , Cases Olivier , Berdal Ariane , De La Dure-Molla Muriel , Kozyraki Renata
Published: December 2020

Enamel renal syndrome (ERS) is a rare recessive disorder caused by loss-of-function mutations in FAM20A (family with sequence similarity 20 member A, OMIM #611062). Enamel renal syndrome is characterized by amelogenesis imperfecta, delayed or failed tooth eruption, intrapulpal calcifications, gingival overgrowth and nephrocalcinosis. Although gingival overgrowth has consistently been associated with heterotopic calcifications the pathogenesis, structure and interactions of the mineral deposits with the surrounding connective tissue are largely unknown. We here report a novel FAM20A mutation in exon 1 (c.358C > T) introducing a premature stop codon (p.Gln120*) and resulting in a complete loss of FAM20A. In addition to the typical oral findings and nephrocalcinosis, ectopic calcified nodules were also seen in the cervical and thoracic vertebrae regions. Histopathologic analysis of the gingiva showed an enlarged papillary layer associated with aberrant angiogenesis and a lamina propria displaying significant changes in its extracellular matrix composition, including disruption of the collagen I fiber network. Ectopic calcifications were found throughout the connective gingival tissue. Immunomorphological and ultrastructural analyses indicated that the calcification process was associated with epithelial degeneration and transformation of the gingival fibroblasts to chondro/osteoblastic-like cells. Mutant gingival fibroblasts cultures were prone to calcify and abnormally expressed osteoblastic markers such as RUNX2 or PERIOSTIN. Our findings expand the previously reported phenotypes and highlight some aspects of ERS pathogenesis.
Discovery of a Potent RIPK3 Inhibitor for the Amelioration of Necroptosis-Associated Inflammatory Injury
Authors: Xia Kaijiang , Zhu Fang , Yang Chengkui , Wu Shuwei , Lin Yu , Ma Haikuo , Yu Xiaoliang , Zhao Cong , Ji Yuting , Ge Wenxiang , Wang Jingrui , Du Yayun , Zhang Wei , Yang Tao , Zhang Xiaohu , He Sudan
Published: December 2020

Necroptosis is a form of regulated necrosis that requires the activation of receptor-interacting kinase 3 (RIPK3 or RIP3) and its phosphorylation of the substrate MLKL (mixed lineage kinase domain-like protein). Necroptosis has emerged as important cell death involved in the pathogenesis of various diseases including inflammatory diseases, degenerative diseases, and cancer. Here, we discovered a small molecule Zharp-99 as a potent inhibitor of necroptosis through blocking the kinase activity of RIPK3. Zharp-99 efficiently blocks necroptosis induced by ligands of the death receptor and Toll-like receptor as well as viral infection in human, rat and mouse cells. Zharp-99 strongly inhibits cellular activation of RIPK3, and MLKL upon necroptosis stimuli. Zharp-99 directly blocks the kinase activity of RIPK3 without affecting RIPK1 kinase activity at the tested concentration. Importantly, Zharp-99 exerts effective protection against TNF-α induced systemic inflammatory response syndrome in the mouse model. Zharp-99 displays favorable in vitro safety profiles and in vivo pharmacokinetic parameters. Thus, our study demonstrates Zharp-99 as a potent inhibitor of RIPK3 kinase and also highlights its potential for further development of new approaches for treating necroptosis-associated inflammatory disorders.
Template-Sacrificing Synthesis of Ni-Co Layered Double Hydroxides Polyhedron as Advanced Anode for Lithium Ions Battery
Authors: Lu Youjun , Du Yingjie , Li Haibo
Published: December 2020

The novel hollowed Ni-Co layered double hydroxide polyhedron (H-(Ni, Co)-LDHP) is synthesized via a template-sacrificing approach using ZIF-67 as template. The morphology, crystallinity, porous texture, and chemical state of H-(Ni, Co)-LDHP are examined. It demonstrates that the H-(Ni, Co)-LDHP not only provides rich redox sites but also promotes the kinetics due to presence of numerous rational channels. As a result, the H-(Ni, Co)-LDHP manifests the desirable lithium ions storage performance when employed as anode. This study paves a new way for preparing hollowed nanostructure toward advanced electrochemical applications.
Metal Ions Doping for Boosting Luminescence of Lanthanide-Doped Nanocrystals
Authors: Pei Shihao , Ge Xiaoqian , Sun Lining
Published: December 2020

With the developing need for luminous materials with better performance, lanthanide-doped nanocrystals have been widely studied for their unique luminescence properties such as their narrow bandwidth emission, excellent chemical stability, and photostability, adjustable emission color, high signal-to-background ratio, deeper tissue penetration with less photo-damage, and low toxicity, etc., which triggered enthusiasm for research on the broad applications of lanthanide-doped nanocrystals in bioimaging, anti-counterfeiting, biosensing, and cancer diagnosis and treatment. Considerable progress has been made in the past few decades, but low upconversion luminescence efficiency has been a hindrance in achieving further progress. It is necessary to summarize the recently relevant literature and find solutions to improve the efficiency. The latest experimental and theoretical studies related to the deliberate design of rare earth luminescent nanocrystals have, however, shown the development of metal ion-doped approaches to enhance the luminescent intensity. Host lattice manipulation can enhance the luminescence through increasing the asymmetry, which improves the probability of electric dipole transition; and the energy transfer modulation offers a reduced cross-relaxation pathway to improve the efficiency of the energy transfer. Based on the mechanisms of host lattice manipulation and energy transfer modulation, a wide range of enhancements at all wavelengths or even within a particular wavelength have been accomplished with an enhancement of up to a hundred times. In this mini review, we present the strategy of metal ion-doped lanthanide nanocrystals to cope with the issue of enhancing luminescence, overview the advantages and tricky challenges in boosting the luminescence, and provide a potential trend of future study in this field.
Morphometric Characterization of Human Coronary Veins and Subvenous Epicardial Adipose Tissue—Implications for Cardiac Resynchronization Therapy Leads
Authors: Keiler Jonas , Meinel Felix G. , Ortak Jasmin , Weber Marc-André , Wree Andreas , Streckenbach Felix
Published: December 2020

Subvenous epicardial fat tissue (SEAT), which acts as an electrical insulation, and the venous diameter (VD) both constitute histomorphological challenges for optimal application and lead design in cardiac synchronization therapy (CRT). In this study, we characterized the morphology of human coronary veins to improve the technical design of future CRT systems and to optimize the application of CRT leads. We retrospectively analyzed data from cardiac computed tomography (CT) of 53 patients and did studies of 14 human hearts using the postmortem freeze section technique and micro CT. Morphometric parameters (tributary distances, offspring angles, luminal VD, and SEAT thickness) were assessed. The left posterior ventricular vein (VVSP) had a mean proximal VD of 4.0 ± 1.4 mm, the left marginal vein (VMS) of 3.2 ± 1.5 mm and the anterior interventricular vein (VIA) of 3.9 ± 1.3 mm. More distally (5 cm), VDs decreased to 2.4 ± 0.6 mm, 2.3 ± 0.7 mm, and 2.4 ± 0.6 mm, respectively. In their proximal portions (15 mm), veins possessed mean SEAT thicknesses of 3.2 ± 2.4 (VVSP), 3.4 ± 2.4 mm (VMS), and 4.2 ± 2.8 mm (VIA), respectively. More distally (20–70 mm), mean SEAT thicknesses decreased to alternating low levels of 1.3 ± 1.1 mm (VVSP), 1.7 ± 1.1 mm (VMS), and 4.3 ± 2.6 mm (VIA), respectively. In contrast to the VD, SEAT thicknesses alternated along the further distal vein course and did not display a continuous decrease. Besides the CRT responsiveness of different areas of the LV myocardium, SEAT is a relevant electrophysiological factor in CRT, potentially interfering with sensing and pacing. A sufficient VD is crucial for successful CRT lead placement. Measurements revealed a trend toward greater SEAT thickness for the VIA compared to VVSP and VMS, suggesting a superior signal-to-noise-ratio in VVSP and VMS.
The Resilience of Inter-basin Transfers to Severe Droughts With Changing Spatial Characteristics
Authors: Murgatroyd Anna , Hall Jim W.
Published: December 2020

Faced with the prospect of climate change and growing demands for water, water resources managers are increasingly examining the potential for inter-basin water transfers to alleviate water shortages. However, water transfers are vulnerable to large-scale spatially coherent droughts which may lead to water shortages in neighboring river basins at the same time. Under climate change, increasingly severe droughts are also expected to have greater spatial extent. We have integrated climate, hydrological and water resource modeling to explore the resilience of new transfer schemes between two neighboring water companies in Southern England. An extended historical record of river flows and large ensemble of future flows derived from climate simulations were used to explore the effects of spatial and temporal drought variability. The analysis examines meteorological, hydrological and water resource drought events and how the spatial characteristics of these droughts may change with different transfer arrangements. Results indicate that all drought types examined are expected to increase in frequency and intensity throughout the twenty-first century, but a new transfer has the capability to increase the resilience of water supplies. The analysis also highlights the importance of testing new water infrastructure against drought events that are more extreme and have different spatial patterns to those in historical records, demonstrating the value of scenario-based approaches to adaptive water resource planning.
Genome-Wide Association Mapping and Genomic Prediction of Anther Extrusion in CIMMYT Hybrid Wheat Breeding Program via Modeling Pedigree, Genomic Relationship, and Interaction With the Environment
Authors: Adhikari Anil , Basnet Bhoja Raj , Crossa Jose , Dreisigacker Susanne , Camarillo Fatima , Bhati Pradeep Kumar , Jarquin Diego , Manes Yann , Ibrahim Amir M. H.
Published: December 2020

Anther extrusion (AE) is the most important male floral trait for hybrid wheat seed production. AE is a complex quantitative trait that is difficult to phenotype reliably in field experiments not only due to high genotype-by-environment effects but also due to the short expression window in the field condition. In this study, we conducted a genome-wide association scan (GWAS) and explored the possibility of applying genomic prediction (GP) for AE in the CIMMYT hybrid wheat breeding program. An elite set of male lines (n= 603) were phenotype for anther count (AC) and anther visual score (VS) across three field experiments in 2017–2019 and genotyped with the 20K Infinitum is elect SNP array. GWAS produced five marker trait associations with small effects. For GP, the main effects of lines (L), environment (E), genomic (G) and pedigree relationships (A), and their interaction effects with environments were used to develop seven statistical models of incremental complexity. The base model used only L and E, whereas the most complex model included L, E, G, A, and G × E and A × E. These models were evaluated in three cross-validation scenarios (CV0, CV1, and CV2). In cross-validation CV0, data from two environments were used to predict an untested environment; in random cross-validation CV1, the test set was never evaluated in any environment; and in CV2, the genotypes in the test set were evaluated in only a subset of environments. The prediction accuracies ranged from −0.03 to 0.74 for AC and −0.01 to 0.54 for VS across different models and CV schemes. For both traits, the highest prediction accuracies with low variance were observed in CV2, and inclusion of the interaction effects increased prediction accuracy for AC only. In CV0, the prediction accuracy was 0.73 and 0.45 for AC and VS, respectively, indicating the high reliability of across environment prediction. Genomic prediction appears to be a very reliable tool for AE in hybrid wheat breeding. Moreover, high prediction accuracy in CV0 demonstrates the possibility of implementing genomic selection across breeding cycles in related germplasm, aiding the rapid breeding cycle.
Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism
Authors: Wang Xiao-Lan , Wolff Samantha E. C. , Korpel Nikita , Milanova Irina , Sandu Cristina , Rensen Patrick C. N. , Kooijman Sander , Cassel Jean-Christophe , Kalsbeek Andries , Boutillier Anne-Laurence , Yi Chun-Xia
Published: December 2020

Microglia are brain immune cells responsible for immune surveillance. Microglial activation is, however, closely associated with neuroinflammation, neurodegeneration, and obesity. Therefore, it is critical that microglial immune response appropriately adapts to different stressors. The circadian clock controls the cellular process that involves the regulation of inflammation and energy hemostasis. Here, we observed a significant circadian variation in the expression of markers related to inflammation, nutrient utilization, and antioxidation in microglial cells isolated from mice. Furthermore, we found that the core clock gene-Brain and Muscle Arnt-like 1 (Bmal1) plays a role in regulating microglial immune function in mice and microglial BV-2 cells by using quantitative RT-PCR. Bmal1 deficiency decreased gene expression of pro-inflammatory cytokines, increased gene expression of antioxidative and anti-inflammatory factors in microglia. These changes were also observed in Bmal1 knock-down microglial BV-2 cells under lipopolysaccharide (LPS) and palmitic acid stimulations. Moreover, Bmal1 deficiency affected the expression of metabolic associated genes and metabolic processes, and increased phagocytic capacity in microglia. These findings suggest that Bmal1 is a key regulator in microglial immune response and cellular metabolism.
Sharing and Distinction in Biodiversity and Ecological Role of Bryozoans in Mediterranean Mesophotic Bioconstructions
Authors: Giampaoletti Jacopo , Cardone Frine , Corriero Giuseppe , Gravina Maria F. , Nicoletti Luisa
Published: December 2020

Bryozoan assemblages of three mesophotic habitats, recently found in the Adriatic and Ionian Seas, were investigated in terms of species composition and diversity, colonial growth forms, and species ecological affinity, with the purposes to analyze variations and similarities between the different bioconstructions and to compare the mesophotic assemblages with those of other benthic habitats. Bryozoans came from three sites off the Apulian coast: Monopoli, 30–55-m depth, where scleractinians are dominant; Otranto, 45–64-m depth; and Santa Maria di Leuca, 45–70-m depth, where the bivalve Neopycnodonte cochlear is the main bioconstructor. A total number of 50 species of bryozoans were recorded, accounting for about 10% of the total number of Mediterranean species. Only few species were shared between the three sites, whereas a considerable pool of species was characteristic of each site. The β-diversity and Sörensen similarity analyses highlighted the highest similarity between the two southern sites, Otranto and Santa Maria di Leuca, with respect to the northern site of Monopoli, in agreement with the hydrological pattern of the area. The encrusting zoarial type was the most abundant in each site, and few species with erect, celleporiform and petraliform colonies were found. The Sörensen similarity, based on data of zoarial forms composition, revealed values considerably higher than those based on species composition, thus highlighting the similar ecological role played by the bryozoans in all the sites. Moreover, significant differences between the mesophotic bryozoan assemblages and those of other benthic Mediterranean habitats were highlighted, showing higher affinity with the coralligenous and detritic sciaphilic habitats. The relevant ecological role of bryozoans as binders in the bioconstructions of the Mediterranean mesophotic zone has been exhibited.
A Study on an Anticyclonic-Cyclonic Eddy Pair Off Fraser Island, Australia
Authors: Li Zhibing , Wang Xiaohua , Hu Jianyu , Andutta Fernando Pinheiro , Liu Zhiqiang
Published: December 2020

This research examines a cyclonic-anticyclonic eddy (AE) pair off Fraser Island next to the eastern Australian coast in 2009 using the Bluelink Reanalysis data, where the local eddies are poorly understood. This eddy pair formed in July and dissipated in November. We detailed the horizontal and vertical structures of the eddy pair in terms of three-dimensional variations in relative vorticity, hydrographic properties, velocity, and dynamic structures, which presented notable scales of the eddy pair. The AE formed beside the meandering of the East Australian Current (EAC) at 24°S and had a tilting structure in the upper 1,000 m toward the EAC. A cyclonic eddy (CE) formed a month later and interacted with the AE, which had a tilting structure toward the AE in the upper 1,000 m. Heterogeneity in the AE and CE composing this eddy pair was observed in the horizontal and vertical planes. The AE had a stronger and more coherent dynamic structure than the CE. The AE and the EAC interacted in the generation stage when the EAC path shifted eastward, away from the coast. As the EAC subsequently swung back to the coastal area, the AE and the EAC separated. The AE then interacted with the surrounding eddy fields, propagated westward, before finally merging again with the EAC. The energy transfer during this process also indicated the interactions among the eddy pair, the surrounding eddy fields and the EAC. Baroclinic instability (BCI) was a main contributor to the AE in the generation stage. Barotropic instability (BTI) also contributed energy to the AE when it interacted with the EAC but accounted for a much smaller proportion. Both BCI and BTI contributed to the CE for most of its life cycle but to a much less extend than to the AE. The zonal heat and salt mass transported by the AE and CE were calculated based on a Lagrangian framework method, and these amounts were considerable compared with global zonal averaged heat and salt mass transported by other mesoscale eddies.
Coral Disease Time Series Highlight Size-Dependent Risk and Other Drivers of White Syndrome in a Multi-Species Model
Authors: Greene Austin , Donahue Megan J. , Caldwell Jamie M. , Heron Scott F. , Geiger Erick , Raymundo Laurie J.
Published: December 2020

Coral diseases contribute to the decline of reef communities, but factors that lead to disease are difficult to detect. In the present study, we develop a multi-species model of colony-scale risk for the class of coral diseases referred to as White Syndromes, investigating the role of current or past conditions, including both environmental stressors and biological drivers at the colony and community scales. Investigating 7 years of coral survey data at five sites in Guam we identify multiple environmental and ecological associations with White Syndrome, including a negative relationship between short-term heat stress and White Syndrome occurrence, and strong evidence of increasing size-dependent White Syndrome risk across coral species. Our findings result in a generalized model used to predict colony-scale White Syndrome risk for multiple species, highlighting the value of long-term monitoring efforts to detect drivers of coral disease.
Sponges in a Changing Climate: Survival of Agelas oroides in a Warming Mediterranean Sea
Authors: Idan Tal , Goren Liron , Shefer Sigal , Ilan Micha
Published: December 2020

Sponges hold a key role in benthic environments, and specifically in the Mediterranean Sea. Past events of mass mortality in sponge communities have been linked to extended periods of high-temperature anomalies, yet it is unknown how a gradual change, such as the constant rise in global seawater temperatures, will affect biodiversity. Here we present a case study of Agelas oroides, a common massive sponge in the Mediterranean Sea, found at a wide depth range of 1–150 m. Last documented in the 1970s, A. oroides was considered lost from the Israeli coastal fauna. However, its recent rediscovery in mesophotic depths, where environmental conditions are stable, provided an opportunity to examine whether it can survive the present conditions in the shallow Israeli coast – where temperatures increased by 3°C during the past 60 years, while the nutrients concentration decreased following the damming of the Nile River. To test this hypothesis, A. oroides individuals were collected during winter from mesophotic sponge grounds (100–120 m) and transplanted to a shallow rocky habitat (10 m). Control individuals were transplanted back to the mesophotic habitat. Sponge survival, temperature, and nutrient concentrations were measured in both habitats. The shallow-transplanted sponges’ survival decreased only when the ambient temperature exceeded 28°C. In contrast, the control group at the mesophotic depth, where the temperature never rose above 20°C, survived the duration of the experiment. Our findings suggest that a prolonged period of high temperatures may constitute a major factor in A. oroides survival and disappearance from the Israeli shallow habitats.
Systematics and Multi-Gene Phylogeny of the Subfamily Nothoholostichinae (Ciliophora, Hypotrichia), With Integrative Description of a New Marine Species Nothoholosticha luporinii n. sp.
Authors: Zhang Tengyue , Wang Yurui , Cheng Ting , Ma Jiyang , Vd’ačný Peter , Song Weibo , Shao Chen
Published: December 2020

Morphogenesis of ciliated protists attracts a lot of attention, because their huge morphological diversity is related to formation of ciliary structures during cell division. In the present work, the morphology and morphogenesis as well as the phylogenetic position of a new, marine hypotrich ciliate, Nothoholosticha luporinii n. sp., were investigated. The new species is characterized by having a combination of the following features: a bicorona whose anterior row contains four frontal cirri and posterior row includes only two cirri, a single buccal cirrus, midventral complex composed of about 30 cirral pairs, one pretransverse cirrus, 3–6 transverse cirri, one left and one right marginal cirral row; three bipolar dorsal kineties; contractile vacuole located in about 2/3 of the body length, two types of cortical granules, and many macronuclear nodules scattered throughout the cytoplasm. The morphogenesis of N. luporinii follows the ontogenetic mode of Pseudokeronopsis, a well-known and closely related genus except that the macronucleus fuses into a single mass in the middle fission stage. Phylogenetic analyses based on the rDNA operon classify Nothoholosticha in the family Pseudokeronopsidae and support the distinctness of the new taxon as well as the monophyletic origin of the subfamily Nothoholostichinae.
Hydrogen Diffusion and Its Effect on Hydrogen Embrittlement in DP Steels With Different Martensite Content
Authors: Wang Zhen , Liu Jing , Huang Feng , Bi Yun-jie , Zhang Shi-qi
Published: December 2020

The hydrogen diffusion behavior and hydrogen embrittlement susceptibility of dual phase (DP) steels with different martensite content were investigated using the slow strain-rate tensile test and hydrogen permeation measurement. Results showed that a logarithmic relationship was established between the hydrogen embrittlement index (IHE) and the effective hydrogen diffusion coefficient (Deff). When the martensite content is low, ferrite/martensite interface behaves as the main trap that captures the hydrogen atoms. Also, when the Deff decreases, IHE increases with increasing martensite content. However, when the martensite content reaches approximately 68.3%, the martensite grains start to form a continuous network, Deff reaches a plateau and IHE continues to increase. This is mainly related to the reduction of carbon content in martensite and the length of ferrite/martensite interface, which promotes the diffusion of hydrogen atoms in martensite and the aggregation of hydrogen atoms at the ferrite/martensite interface. Finally, a model describing the mechanism of microstructure-driven hydrogen diffusion with different martensite distribution was established.
A Novel Risk-Stratification Models of the High-Flow Nasal Cannula Therapy in COVID-19 Patients With Hypoxemic Respiratory Failure
Authors: Xu Jiqian , Yang Xiaobo , Huang Chaolin , Zou Xiaojing , Zhou Ting , Pan Shangwen , Yang Luyu , Wu Yongran , Ouyang Yaqi , Wang Yaxin , Xu Dan , Zhao Xin , Shu Huaqing , Jiang Yongxiang , Xiong Wei , Ren Lehao , Liu Hong , Yuan Yin , Qi Hong , Fu Shouzhi , Chen Dechang , Zhang Dingyu , Yuan Shiying , Shang You
Published: December 2020

Background: High-flow nasal cannula (HFNC) has been recommended as a suitable choice for the management of coronavirus disease 2019 (COVID-19) patients with acute hypoxemic respiratory failure before mechanical ventilation (MV); however, delaying MV with HFNC therapy is still a dilemma between the technique and clinical management during the ongoing pandemic.

Methods: Retrospective analysis of COVID-19 patients treated with HFNC therapy from four hospitals of Wuhan, China. Demographic information and clinical variables before, at, and shortly after HFNC initiation were collected and analyzed. A risk-stratification model of HFNC failure (the need for MV) was developed with the 324 patients of Jin Yin-tan Hospital and validated its accuracy with 69 patients of other hospitals.

Results: Among the training cohort, the median duration of HFNC therapy was 6 (range, 3–11), and 147 experienced HFNC failure within 7 days of HFNC initiation. Early predictors of HFNC failure on the basis of a multivariate regression analysis included age older than 60 years [odds ratio (OR), 1.93; 95% confidence interval (CI), 1.08–3.44; p = 0.027; 2 points], respiratory rate-oxygenation index (ROX) <5.31 (OR, 5.22; 95% CI, 2.96–9.20; p < 0.001; 5 points) within the first 4 h of HFNC initiation, platelets < 125 × 109/L (OR, 3.04; 95% CI, 1.46–6.35; p = 0.003; 3 points), and interleukin 6 (IL-6) >7.0 pg/mL (OR, 3.34; 95% CI, 1.79–6.23; p < 0.001; 3 points) at HFNC initiation. A weighted risk-stratification model of these predictors showed sensitivity of 80.3%, specificity of 71.2% and a better predictive ability than ROX index alone [area under the curve (AUC) = 0.807 vs. 0.779, p < 0.001]. Six points were used as a cutoff value for the risk of HFNC failure stratification. The HFNC success probability of patients in low-risk group (84.2%) was 9.84 times that in the high-risk group (34.8%). In the subsequent validation cohort, the AUC of the model was 0.815 (0.71–0.92).

Conclusions: Aged patients with lower ROX index, thrombocytopenia, and elevated IL-6 values are at increased risk of HFNC failure. The risk-stratification models accurately predicted the HFNC failure and early stratified COVID-19 patients with HFNC therapy into relevant risk categories.
Deleterious Effects of an Air Pollutant (NO2) on a Selection of Commensal Skin Bacterial Strains, Potential Contributor to Dysbiosis?
Authors: Janvier Xavier , Alexandre Stéphane , Boukerb Amine M. , Souak Djouhar , Maillot Olivier , Barreau Magalie , Gouriou Frantz , Grillon Catherine , Feuilloley Marc G. J. , Groboillot Anne
Published: December 2020

The skin constitutes with its microbiota the first line of body defense against exogenous stress including air pollution. Especially in urban or sub-urban areas, it is continuously exposed to many environmental pollutants including gaseous nitrogen dioxide (gNO2). Nowadays, it is well established that air pollution has major effects on the human skin, inducing various diseases often associated with microbial dysbiosis. However, very few is known about the impact of pollutants on skin microbiota. In this study, a new approach was adopted, by considering the alteration of the cutaneous microbiota by air pollutants as an indirect action of the harmful molecules on the skin. The effects of gNO2 on this bacterial skin microbiota was investigated using a device developed to mimic the real-life contact of the gNO2 with bacteria on the surface of the skin. Five strains of human skin commensal bacteria were considered, namely Staphylococcus aureus MFP03, Staphylococcus epidermidis MFP04, Staphylococcus capitis MFP08, Pseudomonas fluorescens MFP05, and Corynebacterium tuberculostearicum CIP102622. Bacteria were exposed to high concentration of gNO2 (10 or 80 ppm) over a short period of 2 h inside the gas exposure device. The physiological, morphological, and molecular responses of the bacteria after the gas exposure were assessed and compared between the different strains and the two gNO2 concentrations. A highly significant deleterious effect of gNO2 was highlighted, particularly for S. capitis MFP08 and C. tuberculostearicum CIP102622, while S. aureus MFP03 seems to be the less sensitive strain. It appeared that the impact of this nitrosative stress differs according to the bacterial species and the gNO2 concentration. Thus the exposition to gNO2 as an air pollutant could contribute to dysbiosis, which would affect skin homeostasis. The response of the microbiota to the nitrosative stress could be involved in some pathologies such as atopic dermatitis.
Targeting the Histone Methyltransferase Disruptor of Telomeric Silencing 1-Like Restricts Avian Leukosis Virus Subgroup J Replication by Restoring the Innate Immune Response in Chicken Macrophages
Authors: Chen Shihao , Wang Dedong , Liu Yinyin , Zhao Ruihan , Wu Ting , Hu Xuming , Pan Zhiming , Cui Hengmi
Published: December 2020

Avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, is known to cause immunosuppression and various types of cancer in chickens. Recent reports have shown that epigenetic changes in DNA and chromatin are widely implicated in the life cycle of diverse viruses, and reversal of these changes in host cells can lead to alterations in the propagation of viruses. In the present study, we found that disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine79 (H3K79) methyltransferase, was upregulated during ALV-J infection in chicken macrophage HD11 cells. Subsequently, we show that targeting DOT1L with a specific inhibitor can significantly decrease the ALV-J replication and viral production. By generating of DOT1L-knockout (KO) HD11 cells using the CRISPR/Cas9 system, we show that deletion of the DOT1L led to an increase in the induction of IFNβ and interferon-stimulated genes (ISGs) in HD11 cells in response to ALV-J infection. Importantly, we confirmed that ALV-J infection impaired the activation of the melanoma differentiation-associated protein 5 (MDA5)-mediated-IFN pathway by suppressing the MDA5 expression, and knockout DOT1L rescued the expression of MDA5 and signal transducer and activator of transcription 1 (STAT1), both of which tightly control the antiviral innate immunity. Collectively, it can be deduced from the current data that blocking DOT1L activity or deletion of DOT1L can lead to ALV-J replication inhibition and restoration of the virally suppressed host innate immunity. Thus, we suggest that DOT1L might be a potential drug target for modulating host innate immune responses to combat ALV-J infection.
Synthetic Sequencing Standards: A Guide to Database Choice for Rumen Microbiota Amplicon Sequencing Analysis
Authors: Smith Paul E. , Waters Sinead M. , Gómez Expósito Ruth , Smidt Hauke , Carberry Ciara A. , McCabe Matthew S.
Published: December 2020

Our understanding of complex microbial communities, such as those residing in the rumen, has drastically advanced through the use of high throughput sequencing (HTS) technologies. Indeed, with the use of barcoded amplicon sequencing, it is now cost effective and computationally feasible to identify individual rumen microbial genera associated with ruminant livestock nutrition, genetics, performance and greenhouse gas production. However, across all disciplines of microbial ecology, there is currently little reporting of the use of internal controls for validating HTS results. Furthermore, there is little consensus of the most appropriate reference database for analyzing rumen microbiota amplicon sequencing data. Therefore, in this study, a synthetic rumen-specific sequencing standard was used to assess the effects of database choice on results obtained from rumen microbial amplicon sequencing. Four DADA2 reference training sets (RDP, SILVA, GTDB, and RefSeq + RDP) were compared to assess their ability to correctly classify sequences included in the rumen-specific sequencing standard. In addition, two thresholds of phylogenetic bootstrapping, 50 and 80, were applied to investigate the effect of increasing stringency. Sequence classification differences were apparent amongst the databases. For example the classification ofClostridiumdiffered between all databases, thus highlighting the need for a consistent approach to nomenclature amongst different reference databases. It is hoped the effect of database on taxonomic classification observed in this study, will encourage research groups across various microbial disciplines to develop and routinely use their own microbiome-specific reference standard to validate analysis pipelines and database choice.
Reduced Impact of Endovascular Thrombectomy on Disability in Real-World Practice, Relative to Randomized Controlled Trial Evidence in Australia
Authors: Gao Lan , Tan Elise , Moodie Marj , Parsons Mark , Spratt Neil J. , Levi Christopher , Butcher Kenneth , Kleinig Timothy , Yan Bernard , Chen Chushuang , Lin Longting , Choi Philip , Bivard Andrew
Published: December 2020

Background and Aims: Disability-adjusted life years (DALYs) are an important measure of the global burden of disease that informs patient outcomes and policy decision-making. Our study aimed to compare the DALYs saved by endovascular thrombectomy (EVT) in the Australasian-based EXTEND-IA trial vs. clinical registry data from EVT in Australian routine clinical practice.

Methods: The 3-month modified Rankin scale (mRS) outcome and treatment status of consecutively enrolled Australian patients with large vessel occlusion (LVO) stroke were taken from the International Stroke Perfusion Imaging Registry (INSPIRE). DALYs were calculated as the summation of years of life lost (YLL) due to premature death and years lived with a disability (YLD). A generalized linear model (GLM) with gamma family and log link was used to compare the difference in DALYs for patients receiving/not receiving EVT while controlling for key covariates. Ordered logit regression model was utilized to compare the difference in functional outcome at 3 months between the treatment groups. Cox regression analysis was undertaken to compare the difference in survival over an 18-year time horizon. Estimated long-term DALYs saved based on the EXTEND-IA randomized controlled trial (RCT) results were used as the comparator.

Results: INSPIRE patients who received EVT treatment only achieved nominally better functional outcomes than the non-EVT group (p = 0.181) at 3 months. There was no significant survival gain from EVT over the first 3 months of stroke in both INSPIRE and EXTEND-IA patients. However, measured against no EVT in the long-term, EVT in INSPIRE was associated with no significant survival gain [hazard ratio (HR): 0.92, 95% confidence interval (CI): 0.78–1.08, p = 0.287] compared with the survival benefit extrapolated from the EXTEND-IA trial (HR: 0.42, 95% CI: 0.22–0.82, p = 0.01]. Offering EVT to patients with LVO stroke was also associated with fewer DALYs lost (11.04, 95% CI: 10.45–11.62) than those not receiving EVT in INSPIRE (12.13, 95% CI: 11.75–12.51), a reduction of −1.09 DALY (95% CI: −1.76 to −0.43, p = 0.002). The absolute magnitude of the treatment effect was lower than that seen in EXTEND-IA (−2.72 DALY reduction in EVT vs non-EVT patients).

Conclusions: EVT for the treatment of LVO in a registry of routine care was associated with significantly lower DALYs lost than medical care alone, but the saved DALYs are less than those reported in clinical trials, as there were major differences in the baseline characteristics of the patients.
Case Report: Candida dubliniensis as a Cause of Chronic Meningitis
Authors: Tahir Madiha , Peseski Andrew M. , Jordan Stephen J.
Published: December 2020

Background:Candida dubliniensis is closely related to Candida albicans and rarely isolated in clinical specimens. C. dubliniensis is increasingly recognized as a pathogen in immunocompromised hosts. We present the third known case of Candida dubliniensis meningitis in a young immunocompetent host.

Case Presentation: A 27-year-old female with a history of intravenous heroin use and chronic hepatitis C presented with a 10-month history of headaches and progressive bilateral vision loss. On physical examination, visual acuity was 20/20 in her right eye and grade II papilledema was noted. Examination of her left eye revealed complete loss of vision and grade IV papilledema. An MRI with and without contrast revealed increased leptomeningeal enhancement involving the posterior fossa and spinal cord. After multiple lumbar punctures, cerebrospinal fluid fungal cultures grew Candida dubliniensis. The patient was successfully treated with a combination of liposomal amphotericin and fluconazole for 6 weeks with complete resolution of her CNS symptoms, with the exception of irreversible vision loss.

Conclusion: We report a case of chronic meningitis due to Candida dubliniensis in an immunocompetent woman with hepatitis C and a history of intravenous heroin use. Additional studies are needed to confirm risk factors for Candida dubliniensis colonization, which likely predisposes individuals to invasive candidiasis.
Transient Global Amnesia: An Electrophysiological Disorder Based on Cortical Spreading Depression—Transient Global Amnesia Model
Authors: Ding Xuejiao , Peng Dantao
Published: December 2020

Transient global amnesia (TGA) is a benign memory disorder with etiologies that have been debated for a long time. The prevalence of stressful events before a TGA attack makes it hard to overlook these precipitating factors, given that stress has the potential to organically effect the brain. Cortical spreading depression (CSD) was proposed as a possible cause decades ago. Being a regional phenomenon, CSD seems to affect every aspect of the micro-mechanism in maintaining the homeostasis of the central nervous system (CNS). Corresponding evidence regarding hemodynamic and morphological changes from TGA and CSD have been accumulated separately, but the resemblance between the two has not been systematically explored so far, which is surprising especially considering that CSD had been confirmed to cause secondary damage in the human brain. Thus, by deeply delving into the anatomic and electrophysiological properties of the CNS, the CSD-TGA model may render insights into the basic pathophysiology behind the façade of the enigmatic clinical presentation.
Development of a Non-invasive Deep Brain Stimulator With Precise Positioning and Real-Time Monitoring of Bioimpedance
Authors: Wang Heng , Shi Zhongyan , Sun Weiqian , Zhang Jianxu , Wang Jing , Shi Yue , Yang Ruoshui , Li Chunlin , Chen Duanduan , Wu Jinglong , Gongyao Guo , Xu Yifei
Published: December 2020

Methods by which to achieve non-invasive deep brain stimulation via temporally interfering with electric fields have been proposed, but the precision of the positioning of the stimulation and the reliability and stability of the outputs require improvement. In this study, a temporally interfering electrical stimulator was developed based on a neuromodulation technique using the interference modulation waveform produced by several high-frequency electrical stimuli to treat neurodegenerative diseases. The device and auxiliary software constitute a non-invasive neuromodulation system. The technical problems related to the multichannel high-precision output of the device were solved by an analog phase accumulator and a special driving circuit to reduce crosstalk. The function of measuring bioimpedance in real time was integrated into the stimulator to improve effectiveness. Finite element simulation and phantom measurements were performed to find the functional relations among the target coordinates, current ratio, and electrode position in the simplified model. Then, an appropriate approach was proposed to find electrode configurations for desired target locations in a detailed and realistic mouse model. A mouse validation experiment was carried out under the guidance of a simulation, and the reliability and positioning accuracy of temporally interfering electric stimulators were verified. Stimulator improvement and precision positioning solutions promise opportunities for further studies of temporally interfering electrical stimulation.
Management of Intractable Pain in Patients With Implanted Spinal Cord Stimulation Devices During the COVID-19 Pandemic Using a Remote and Wireless Programming System
Authors: Lu Yang , Xie Duo , Zhang Xiaolei , Dong Sheng , Zhang Huifang , Yu Beibei , Wang Guihuai , Wang James Jin , Li Luming
Published: December 2020

As COVID-19 rampages throughout the world and has a major impact on the healthcare system, non-emergency medical procedures have nearly come to a halt due to appropriate resource reallocation. However, pain never stops, particularly for patients with chronic intractable pain and implanted spinal cord stimulation (SCS) devices. The isolation required to fight this pandemic makes it impossible for such patients to adjust the parameters or configuration of the device on site. Although telemedicine has shown a great effect in many healthcare scenarios, there have been fewer applications of such technology focusing on the interaction with implanted devices. Here, we introduce the first remote and wireless programming system that enables healthcare providers to perform video-based real-time programming and palliative medicine for pain patients with a SCS implant. During the COVID-19 pandemic from January 23, 2020, the date of lockdown of Wuhan, to April 30, 2020, 34 sessions of remote programming were conducted with 16 patients. Thirteen of the 16 patients required programming for parameter optimization. Improvement was achieved with programming adjustment in 12 of 13 (92.3%) cases. Eleven of the 16 (68.8%) patients reported that the system was user-friendly and met their needs. Five patients complained of an unstable connection resulting from the low network speed initially, and three of these patients solved this problem. In summary, we demonstrated that a remote wireless programming system can deliver safe and effective programming operations of implantable SCS device, thereby providing palliative care of value to the most vulnerable chronic pain patients during a pandemic.

Clinical Trial Registration

www.clinicaltrials.gov, identifier NCT 03858790.
Targeting EGFR in Esophagogastric Cancer
Authors: Maron Steven B. , Xu James , Janjigian Yelena Y.
Published: December 2020

Esophagogastric cancer (EGC) remains a major cause of cancer-related mortality. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to-date: only first line anti-HER2 therapy in ERBB2-expressing tumors, second line anti-VEGFR2 therapy with ramucirumab in unselected patients, and pembrolizumab in PD-L1 expressing or MSI-H patients. EGFR inhibitors were extensively studied in EGC, including phase III trials with cetuximab (EXPAND), panitumumab (REAL3), and gefitinib (COG). All three trials were conducted in unselected populations, and therefore, failed to demonstrate clinical benefit. Here, we review previous attempts at targeting EGFR in EGC and potential future biomarkers for targeting this pathway in patients with EGFR-amplified tumors.
Salvage Radiation Therapy for Patients With Relapsing Glioblastoma Multiforme and the Role of Slow Fractionation
Authors: Ciernik I. Frank , Gager Yann , Renner Christof , Spieker Sybille , Arndt Nicole , Neumann Karsten
Published: December 2020

Background

Salvage radiation therapy (SRT) can be offered to patients with relapsing glioblastoma multiforme (GBM). Here we report our experience with a schedule extending the treatment time of SRT with the aim to prolong the cytotoxic effect of ionizing radiation while minimizing the cytotoxic hazards for the surrounding brain.

Methods and Patients

From 2009 until 2017, 124 of 218 patients received radical resection, adjuvant chemo-radiation with photons and temozolomide (TMZ) followed by adjuvant TMZ. Re-irradiation was performed in 26 patients due to local relapse. Treatment schedules varied. Survival and molecular markers were assessed.

Results

The median survival was respectively 12 months (9–14.5) of the 124 patients treated with tri-modal therapy and 19.2 months (14.9–24.6) for the 26 patients retreated with SRT (p=0.038). Patients who received daily fractions of 1,6 to 1,65 Gy to a total dose of >40 Gy had a median survival time of 24,6 months compared to patients treated with higher daily doses or a total dose of <40 Gy (p= 0.039), consistent with the observation that patients treated with 21–28 fractions had a median survival of 21,9 months compared to 15,8 months of patients who received 5–20 fractions (p=.0.05). Patients with Ki-67 expression of >30% seemed to perform better than patients with expression levels of ≤20% (p=0.03). MGMT methylation status, TERT promoter or ATRX mutations, overexpression of p53, p16, PD-L1, and EGFR were not prognostic.

Conclusions

Re-irradiation of relapsing GBM is a highly valid treatment option. Our observation challenges hypofractionated stereotactic radiotherapy for retreatment and controlled trials on the fractionation dose for SRT are needed. Robust predictive molecular markers could be beneficial in the selection of patients for SRT.
Daphnetin Attenuated Cisplatin-Induced Acute Nephrotoxicity With Enhancing Antitumor Activity of Cisplatin by Upregulating SIRT1/SIRT6-Nrf2 Pathway
Authors: Fan Xiaoye , Wei Wei , Huang Jingbo , Peng Liping , Ci Xinxin
Published: December 2020

Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2−/− mice on CDDP-induced renal dysfunction in vivo. We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2−/− mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.