bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular Vesicles Derived From Regeneration Associated Cells Preserve Heart Function After Ischemia-Induced Injury
Authors: Salybekov Amankeldi A. , Salybekova Ainur , Sheng Yin , Shinozaki Yoshiko , Yokoyama Keiko , Kobayashi Shuzo , Asahara Takayuki
Published: October 2021

Under vasculogenic conditioning, pro-inflammatory cell subsets of peripheral blood mononuclear cells (PBMCs) shift their phenotype to pro-regenerative cells such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells, collectively designated as regeneration-associated cells (RACs). In this study, we evaluated the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared to mesenchymal stem cell-derived EVs (MSCev) in the context of myocardial ischemia reperfusion injury (M-IRI). Human PBMCs were cultured with defined growth factors for seven days to harvest RACs. RACev and MSCev were isolated via serial centrifugation and ultracentrifugation. EV quantity and size were characterized by nanoparticle tracking analysis. In vitro, RACev markedly enhanced the viability, and proliferation of human umbilical vein endothelial cells in a dose-dependent manner compared to MSCev. Notably, systemic injection of RACev improved cardiac functions at 4 weeks, such as fractional shortening, and protection from mitral regurgitation than the MSCev-treated group. Histologically, the RACev-transplanted group showed less interstitial fibrosis and enhanced capillary densities compared to the MSCev group. These beneficial effects were coupled with significant expression of angiogenesis, anti-fibrosis, anti-inflammatory, and cardiomyogenesis-related miRs in RACev, while modestly in MSCev. In vivo bioluminescence analysis showed preferential accumulation of RACev in the IR-injured myocardium, while MSCev accumulation was limited. Immune phenotyping analysis confirmed the immunomodulatory effect of MSCev and RACev. Overall, repetitive systemic transplantation of RACev is superior to MSCev in terms of cardiac function enhancements via crucial angiogenesis, anti-fibrosis, anti-inflammation miR delivery to the ischemic tissue.
On-Site Measurement on Compaction Characteristics of Coal Gangue and Surface Subsidence Disaster in Deep Backfilling Mining
Authors: Wang Jiaqi , Zhang Qiang , Yin Wei , Qi Shengming , Gao Difa , Ma Dan
Published: October 2021

Gangue is the main backfilling material in solid backfilling mining, and its compaction characteristics determine the overburden control effect and surface subsidence. Under the action of compaction force and overburden pressure, the gangue will be broken, rotated and occluded, resulting in different compaction characteristics of gangue in the field and laboratory. To this end, a laboratory gangue compaction test system was established to test the compaction characteristics of gangue in the laboratory, such as stress-strain, stress bulk density and stress deformation modulus. Based on actual geological conditions of backfilling mining in the Tangshan coal mine, the characteristics of stress deformation modulus of gangue under different inclination angles and mining heights were tested on-site. Through the Beidou satellite CORS system, the surface subsidence of working face F5001was monitored. The research results show that the stress deformation modulus of gangue measured in the field is slightly less than that measured in the laboratory, and it is maintained at about 27 MPa under the overburden pressure in the on-site measurement. Backfilling technology with an initial compaction force of 2.5MPa can be used to effectively control the surface subsidence, and the maximum subsidence value is only 61 mm.
Detection, Attribution, and Future Response of Global Soil Moisture in Summer
Authors: Qiao Liang , Zuo Zhiyan , Xiao Dong , Bu Lulei
Published: October 2021

Soil moisture variations and its relevant feedbacks (e.g., soil moisture–temperature and soil moisture–precipitation) have a crucial impact on the climate system. This study uses reanalysis and Coupled Model Intercomparison Project phase 6 simulations datasets to detect, attribute, and project soil moisture variations. The effect of anthropogenic forcings [greenhouse gases (GHG), anthropogenic aerosols (AA), and land use (LU) change] on soil moisture is much larger than that of the natural forcing. Soil moisture shows a drying trend at a global scale, which is mainly attributed to GHG forcing. The effects of external forcings vary with the regions significantly. Over eastern South America, GHG, AA, and natural forcings make soil dry, while LU forcing makes the soil wet. Over severely drying Europe, all the external forcings including GHG, AA, LU, and natural forcing exhibit drying effect. The optimal fingerprint method detection results show that some of GHG, AA, LU, and natural signals can be detected in soil moisture variations in some regions such as Europe. The soil will keep drying in all scenarios over most parts of the globe except Sahel and parts of mid-latitudes of Asia. With the increase of anthropogenic emissions, the variation of global soil moisture will be more extreme, especially in hotspots where the land–atmosphere coupling is intensive. The drying trend of soil moisture will be much larger on the surface than in middle and deep layers in the future, and this phenomenon will be more severe under the high-emission scenario. It may be affected by increased evaporation and the effect of carbon dioxide fertilization caused by global warming.
Easy Abacus Calculation in Early Childhood to Support Executive Function: An Educational Pilot Case Study of Comparing Brain Activity in the Prefrontal Cortex
Authors: Watanabe Nobuki
Published: October 2021

The development of executive functions is remarkable in early childhood. Therefore, research on how to support the development of executive functions is actively being conducted. It has already been indicated that executive functions are related to the prefrontal cortex. Recent evidence suggests that the prefrontal cortex is involved in mental abacus (MA). Further, the study of the abacus—the base of MA—is good for not only mathematics but also nurturing the brain. However, although the abacus is easy to learn, learning opportunities have shrunk because of the widespread use of calculators. Through this educational pilot case study, I examined whether it is possible that even easy calculations during the introduction of abacus calculation in early childhood may have an effect on executive function support. I measured the activation of cerebral blood flow in the prefrontal cortex of a young child while he worked on the Wechsler Intelligence Scale for Children-IV; Working Memory Index tasks (forward digit-span task, backward digit-span task, and letter–number sequencing task); and the abacus calculation task using HOT-2000 (NeU, Japan), a two-channel wearable functional near-infrared spectroscopy device. The results revealed a significant difference between the abacus calculation task and the forward digit-span task; however, there was no significant difference between the abacus calculation task and other tasks. In other words, the brain in the prefrontal cortex was more activated in the abacus task than in the forward digit-span task. Difficulty levels were found to be in the order of the forward digit-span task, backward digit-span task, and letter–number sequencing task. Thus, there is a possibility that even simple abacus calculation has a positive effect on executive functions, especially working memory support, in early childhood. This study’s results provide a breakthrough in cognitive psychology, educational psychology, neuropsychology, and other fields related to child support, which are struggling to find valuable, practical practices for children in the field (i.e., schools and homes) beyond the laboratory.
Quasi-Zero Dimensional Halide Perovskite Derivates: Synthesis, Status, and Opportunity
Authors: Trifiletti Vanira , Asker Ceyla , Tseberlidis Giorgio , Riva Stefania , Zhao Keran , Tang Weidong , Binetti Simona , Fenwick Oliver
Published: October 2021

In recent decades, many technological advances have been enabled by nanoscale phenomena, giving rise to the field of nanotechnology. In particular, unique optical and electronic phenomena occur on length scales less than 10 nanometres, which enable novel applications. Halide perovskites have been the focus of intense research on their optoelectronic properties and have demonstrated impressive performance in photovoltaic devices and later in other optoelectronic technologies, such as lasers and light-emitting diodes. The most studied crystalline form is the three-dimensional one, but, recently, the exploration of the low-dimensional derivatives has enabled new sub-classes of halide perovskite materials to emerge with distinct properties. In these materials, low-dimensional metal halide structures responsible for the electronic properties are separated and partially insulated from one another by the (typically organic) cations. Confinement occurs on a crystal lattice level, enabling bulk or thin-film materials that retain a degree of low-dimensional character. In particular, quasi-zero dimensional perovskite derivatives are proving to have distinct electronic, absorption, and photoluminescence properties. They are being explored for various technologies beyond photovoltaics (e.g. thermoelectrics, lasing, photodetectors, memristors, capacitors, LEDs). This review brings together the recent literature on these zero-dimensional materials in an interdisciplinary way that can spur applications for these compounds. The synthesis methods, the electrical, optical, and chemical properties, the advances in applications, and the challenges that need to be overcome as candidates for future electronic devices have been covered.
Sex-Specific Limitations in Physical Health in Primary Adrenal Insufficiency
Authors: Didriksen Nora Møller , Sævik Åse Bjorvatn , Sortland Linn Solveig , Øksnes Marianne , Husebye Eystein Sverre
Published: October 2021

Background

Patients with primary adrenal insufficiency (PAI) suffer reduced quality of life (QoL), but comparisons with large-scale normative data are scarce. The clinical characteristics associated with reduced QoL are largely unknown.

Methods

Cross-sectional data on clinical characteristics and QoL scores from 494 patients were included. QoL was measured using RAND-36 (generic) and AddiQoL (-30 and -8, disease-specific). RAND-36 is reported as subdomain scores as well as physical (PCS) and metal (MCS) summary scores and compared with normative data.

Results

Perception of physical role was consistently decreased across age groups in patients with PAI compared with normative data [75 (0-100) vs. 100 (50-100), p<0.001]. Men with PAI reported significantly lower scores for social functioning [88 (75-100) vs. 100 (75-100), p<0.001], as well as for vitality and physical role. In women, the greatest impairment was seen in physical role [50 (0-100) vs. 100 (50-100), p<0.001], followed by social functioning, vitality, physical function, general health, mental health, and emotional role. Overall, better QoL was associated with male sex (AddiQoL-30: 89 ± 13 vs. 82 ± 13, p<0.002), younger age (e.g. 20-29 vs. 80-89 years: PCS 59 [50-62] vs. 46 [37-53], p<0.001), autoimmune etiology [PCS: 53 (45-59) vs.. 45 (38-54), p<0.001], and absence of autoimmune comorbidity [PCS: 54 (45-59) vs. 50 (43-58), p<0.001]. There were no significant differences in QoL scores between different doses or dosing regimens of glucocorticoid or mineralocorticoid replacement.

Conclusion

QoL is reduced in patients with PAI, especially perception of physical role in women and social functioning in men. Among patients with PAI, female sex, higher age, non-autoimmune etiology, and autoimmune comorbidity was associated with lower QoL-scores.
Characterisation of Growth Plate Dynamics in Murine Models of Osteoarthritis
Authors: Samvelyan Hasmik J. , Madi Kamel , Törnqvist Anna E. , Javaheri Behzad , Staines Katherine A.
Published: October 2021

The purpose of this study was to investigate growth plate dynamics in surgical and loading murine models of osteoarthritis, to understand whether abnormalities in these dynamics are associated with osteoarthritis development. 8-week-old C57BL/6 male mice underwent destabilisation of medial meniscus (DMM) (n = 8) surgery in right knee joints. Contralateral left knee joints had no intervention (controls). In 16-week-old C57BL/6 male mice (n = 6), osteoarthritis was induced using non-invasive mechanical loading of right knee joints with peak force of 11N. Non-loaded left knee joints were internal controls. Chondrocyte transiency in tibial articular cartilage and growth plate was confirmed by histology and immunohistochemistry. Tibial subchondral bone parameters were measured using microCT and correlated to 3-dimensional (3D) growth plate bridging analysis. Higher expression of chondrocyte hypertrophy markers; Col10a1 and MMP13 were observed in tibial articular cartilage chondrocytes of DMM and loaded mice. In tibial growth plate, Col10a1 and MMP13 expressions were widely expressed in a significantly enlarged zone of proliferative and hypertrophic chondrocytes in DMM (p=0.002 and p<0.0001, respectively) and loaded (both p<0.0001) tibiae of mice compared to their controls. 3D quantification revealed enriched growth plate bridging and higher bridge densities in medial compared to lateral tibiae of DMM and loaded knee joints of the mice. Growth plate dynamics were associated with increased subchondral bone volume fraction (BV/TV; %) in medial tibiae of DMM and loaded knee joints and epiphyseal trabecular bone volume fraction in medial tibiae of loaded knee joints. The results confirm articular cartilage chondrocyte transiency in a surgical and loaded murine models of osteoarthritis. Herein, we reveal spatial variation of growth plate bridging in surgical and loaded osteoarthritis models and how these may contribute to anatomical variation in vulnerability of osteoarthritis development.
Oestradiol Contributes to Differential Antitumour Effects of Adjuvant Zoledronic Acid Observed Between Pre- and Post-Menopausal Women
Authors: Canuas-Landero Victor G. , George Christopher N. , Lefley Diane V. , Corness Hannah , Muthana Munitta , Wilson Caroline , Ottewell Penelope D.
Published: October 2021

Clinical trials have demonstrated that adding zoledronic acid (Zol) to (neo)adjuvant standard of care has differential antitumour effects in pre- and post-menopausal women: Both benefit from reduced recurrence in bone; however, while postmenopausal women also incur survival benefit, none is seen in premenopausal women treated with adjuvant bisphosphonates. In the current study, we have used mouse models to investigate the role of oestradiol in modulating potential antitumour effects of Zol. Pre-, peri-, and post-menopausal concentrations of oestradiol were modelled in BALB/c wild-type, BALB/c nude, and C57BL/6 mice by ovariectomy followed by supplementation with oestradiol. Mice also received 40 mg/kg/day goserelin to prevent ovariectomy-induced increases in follicle-stimulating hormone (FSH). Metastasis was modelled following injection of MDA-MB-231, 4T1, or E0771 cells after ovariectomy and saline or 100 μg/kg Zol administered weekly. Supplementing ovariectomised mice with 12.5 mg/ml, 1.38 mg/ml, and 0 ng/ml oestradiol, in the presence of goserelin, resulted in serum concentrations of 153.16 ± 18.10 pg/ml, 48.64 ± 18.44 pg/ml, and 1.00 ± 0.27 pg/ml oestradiol, which are equivalent to concentrations found in pre-, peri-, and post-menopausal humans. Osteoclast activity was increased 1.5–1.8-fold with peri- and post-menopausal compared with premenopausal oestradiol, resulting in a 1.34–1.69-fold reduction in trabecular bone. Zol increased trabecular bone in all groups but did not restore bone to volumes observed under premenopausal conditions. In tumour-bearing mice, Zol reduced bone metastases in BALB/c (wild-type and nude), with greatest effects seen under pre- and post-menopausal concentrations of oestradiol. Zol did not affect soft tissue metastases in immunocompetent BALB/c mice but increased metastases 3.95-fold in C57BL/6 mice under premenopausal concentrations of oestradiol. In contrast, Zol significantly reduced soft tissue metastases 2.07 and 4.69-fold in immunocompetent BALB/c and C57BL/6 mice under postmenopausal oestradiol, mirroring the results of the clinical trials of (neo)adjuvant bisphosphonates. No effects on soft tissue metastases were observed in immunocompromised mice, and differences in antitumour response did not correlate with musculoaponeurotic fibrosarcoma (MAF), macrophage capping protein (CAPG), or PDZ domain containing protein GIPC1 (GIPC1) expression. In conclusion, oestradiol contributes to altered antitumour effects of Zol observed between pre- and post-menopausal women. However, other immunological/microenvironmental factors are also likely to contribute to this phenomenon.
New Regions With Molecular Alterations in a Rare Case of Insulinomatosis: Case Report With Literature Review
Authors: Anoshkin Kirill , Vasilyev Ivan , Karandasheva Kristina , Shugay Mikhail , Kudryavtseva Valeriya , Egorov Alexey , Gurevich Larisa , Mironova Anna , Serikov Alexey , Kutsev Sergei , Strelnikov Vladimir
Published: October 2021

Insulinomatosis is characterized by monohormonality of multiple macro-tumors and micro-tumors that arise synchronously and metachronously in all regions of the pancreas, and often recurring hypoglycemia. One of the main characteristics of insulinomatosis is the presence of insulin-expressing monohormonal endocrine cell clusters that are exclusively composed of proliferating insulin-positive cells, are less than 1 mm in size, and show solid islet-like structure. It is presumed that insulinomatosis affects the entire population of β-cells. With regards to molecular genetics, this phenomenon is not related to mutation in MEN1 gene and is more similar to sporadic benign insulinomas, however, at the moment molecular genetics of this disease remains poorly investigated. NGS sequencing was performed with a panel of 409 cancer-related genes. Results of sequencing were analyzed by bioinformatic algorithms for detecting point mutations and copy number variations. DNA copy number variations were detected that harbor a large number of genes in insulinoma and fewer genes in micro-tumors. qPCR was used to confirm copy number variations at ATRX, FOXL2, IRS2 and CEBPA genes. Copy number alterations involving FOXL2, IRS2, CEBPA and ATRX genes were observed in insulinoma as well as in micro-tumors samples, suggesting that alterations of these genes may promote malignization in the β-cells population.
Surface Properties of LaNi5 and TiFe—Future Opportunities of Theoretical Research in Hydrides
Authors: Łodziana Zbigniew
Published: October 2021

Hydrogen in the solid state compounds is still considered as a safe method of energy storage. The ultimate metal hydrides or other materials that can be used for this purpose remain unknown. Such metal hydrides shall have favorable thermodynamics and kinetics of hydrogen ad/desorption, and it shall be resistant to contamination of H2 and should not constitute any environmental hazards. Theoretical investigations, based on quantum mechanics approach, have a well-established position in modern materials research; however, their application for design of new alloys with tailored properties for reversible hydrogen storage is rarely present in the literature. The mainstream research deals with accurate prediction of thermodynamic and structural properties of hydrides as a function of composition or external parameters. On the other hand, the kinetic effects related to hydrogen transport or interaction between solid and pure or contaminated H2 are more demanding. They cannot be easily automated. We present calculations of the equilibrium crystal shapes for LaNi5 and TiFe—two important materials that show reversible hydrogen cycling near ambient conditions. Understanding of the surface properties is crucial for development of materials with better cyclability or resistance to hydrogen impurities. Indeed, the calculated adsorption energy of carbon oxides or water is stronger than hydrogen. These molecules block the active sites for H2 dissociation, leading to formation of surface oxides. Particularly strong adsorption of CO/CO2 on TiFe explains large degradation of hydrogen storage capacity of this compound by carbon oxides. Over-representation of La on exposed facets of LaNi5 is related to formation of La2O3 and La(OH)3. Such examples show that the present development of computational methods allows reliable studies of intermetallic properties related to their surface or novel catalytic applications.
Lifetime Study of Organic Solar Cells with O-IDTBR as Non-Fullerene Acceptor
Authors: López-Vicente R. , Fernández-Castro M. , Abad J. , Mazzolini E. , Andreasen J. W. , Espindola-Rodriguez M. , Urbina A.
Published: October 2021

Organic solar cells (OSCs) have increased their power conversion efficiency above 18% thanks to the use of non-fullerene acceptors in binary or ternary blends or in tandem configurations. In this article, a study on the lifetime of P3HT:O-IDTBR bulk heterojunction OSCs on ITO-free flexible substrates is presented. A direct comparison of glass–glass and plastic–plastic encapsulation performance, with a special focus on its effect on the lifetime of the devices after degradation procedures, has been carried out complying with the ISOS protocols for organic photovoltaic devices. The manufactured OSCs with 1 cm2 active layer have power conversion efficiencies ranging from 1.9 to 3.4% depending on the encapsulant material, encapsulation process, and substrate. An exponential degradation rate has been found, with a similar functional behavior for glass and plastic differing in the degradation constants, which ranges from k = 0.01 to 0.002 h−1. Only in one case, the ISOS-T3 essay for plastic encapsulation, a double exponential process, was observed with degradation rates of k1 = 0.03 h−1 and a second slower process with k2 = 0.001 h−1. The longest achieved T80 lifetime is 86 h for glass-encapsulated devices under an accelerated ISOS-T3 protocol.
Selective Logging Shows No Impact on the Dietary Breadth of a Generalist Bat Species: The Fawn Leaf-Nosed Bat (Hipposideros cervinus)
Authors: Hemprich-Bennett David R. , Kemp Victoria A. , Blackman Joshua , Lewis Owen T. , Struebig Matthew J. , Bernard Henry , Kratina Pavel , Rossiter Stephen J. , Clare Elizabeth L.
Published: October 2021

Logging activities degrade forest habitats across large areas of the tropics, but the impacts on trophic interactions that underpin forest ecosystems are poorly understood. DNA metabarcoding provides an invaluable tool to investigate such interactions, allowing analysis at a far greater scale and resolution than has previously been possible. We analysed the diet of the insectivorous fawn leaf-nosed bat Hipposideros cervinus across a forest disturbance gradient in Borneo, using a dataset of ecological interactions from an unprecedented number of bat-derived faecal samples. Bats predominantly consumed insects from the orders Lepidoptera, Diptera, Blattodea, and Coleoptera, and the taxonomic composition of their diet remained relatively consistent across sites regardless of logging disturbance. There was little difference in the richness of prey consumed per-bat in each logging treatment, indicating potential resilience of this species to habitat degradation. In fact, bats consumed a high richness of prey items, and intensive sampling is needed to reliably compare feeding ecology over multiple sites. Multiple bioinformatic parameters were used, to assess how they altered our perception of sampling completeness. While parameter choice altered estimates of completeness, a very high sampling effort was always required to detect the entire prey community.
Ypd1 Is an Essential Protein of the Major Fungal Pathogen Aspergillus fumigatus and a Key Element in the Phosphorelay That Is Targeted by the Antifungal Drug Fludioxonil
Authors: Schruefer Sebastian , Spadinger Anja , Kleinemeier Christoph , Schmid Laura , Ebel Frank
Published: October 2021

Aspergillus fumigatus is a major fungal pathogen causing life threatening infections in immunocompromised humans and certain animals. The HOG pathway is for two reasons interesting in this context: firstly, it is a stress signaling pathway that contributes to the ability of this pathogen to adapt to various stress conditions and secondly, it is the target of antifungal agents, such as fludioxonil or pyrrolnitrin. In this study, we demonstrate that Ypd1 is an essential protein in A. fumigatus. As the central component of the multistep phosphorelay it represents the functional link between the sensor histidine kinases and the downstream response regulators SskA and Skn7. A GFP-Ypd1 fusion was found to reside in both, the cytoplasm and the nucleus and this pattern was only slightly affected by fludioxonil. A strain in which the ypd1 gene is expressed from a tet-on promoter construct is unable to grow under non-inducing conditions and shows the characteristic features of A. fumigatus wild type hyphae treated with fludioxonil. Expression of wild type Ypd1 prevents this lethal phenotype, but expression of an Ypd1 mutant protein lacking the conserved histidine at position 89 was unable to do so, which confirms that A. fumigatus Ypd1 is a phosphotransfer protein. Generation of ypd1tet−on variants of several mutant strains revealed that the lethal phenotype associated with low amounts of Ypd1 depends on SskA, but not on TcsC or Skn7. The ΔsskA ypd1tet−on, but not the ΔsskAΔskn7 ypd1tet−on mutant, was sensitive to fludioxonil, which underlines the importance of Skn7 in this context. We finally succeeded to delete ypd1, but only if sskA and skn7 were both inactivated, not in a ΔsskA single mutant. Hence, a deletion of ypd1 and an inactivation of Ypd1 by fludioxonil result in similar phenotypes and the two response regulators SskA and Skn7 are involved in both processes albeit with a different relative importance.
Development and Validation of a Five-RNA–Based Signature and Identification of Candidate Drugs for Neuroblastoma
Authors: Zhang PeiPei , Ma KeXin , Ke XiaoFei , Liu Liu , Li Ying , Liu YaJuan , Wang YouJun
Published: October 2021

Neuroblastoma (NBL) originating from the sympathetic nervous system is the most prevalent solid tumor in infancy. Although there is sufficient variability in prognosis among different age pyramids, age-related gene expression profiles and biomarkers remain poorly explored. The present study aimed to construct a signature based on differentially expressed genes (DEGs) between two age groups in NBL. Univariate Cox regression, multivariate Cox regression, and LASSO analyses were used to identify the optimal prognostic factors. The prediction ability of the model was assessed using the receiver operating characteristic (ROC) curve and C-index. Functional enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes and gene ontology databases. A total of 1,160 DEGs were identified between the two groups, and 204 DEGs impacted the survival of NBL. Functional enrichment analysis revealed that the DEGs were involved in retinol metabolism, cholesterol metabolism, and glycolysis/gluconeogenesis pathways. Five RNAs, namely F8A3, PDF, ANKRD24, FAXDC2, and TMEM160 were recruited into the signature. They were correlated with COG risk classification, INSS stage, and histology. MYCN amplification was linked to FAXDC2, TMEM160, PDF, and F8A3. The expression levels of ANKRD24, PDF, and TMEM160 were lower in the hyperdiploid groups. Only FAXDC2 levels were different in the different MKI grades. The ROC curve showed that the five-RNA–based signatures effectively predicted the OS of NBL (3-years AUC = 0.791, 5-years AUC = 0.816) in the TARGET cohort. The predictive capability was also validated by the GSE49711 cohort (3-years AUC = 0.851, 5-years AUC = 0.848). The C-index in the TARGET and GSE49711 cohorts was 0.749 and 0.809, respectively. The potential mechanisms of the five RNAs were also explored via gene set enrichment analysis, and candidate drugs targeting the five genes, including dabrafenib, vemurafenib, and bafetinib, were screened. In conclusion, we constructed a five-RNA–based signature to predict the survival of NBL and screened candidate agents against NBL.
Investigating Causal Relationships Between Psychiatric Traits and Intracranial Aneurysms: A Bi-directional Two-Sample Mendelian Randomization Study
Authors: Peng Peng , Chen Zirong , Zhang Xiaolin , Guo Zhongyin , Dong Fangyong , Xu Yu , He Yue , Guo Dongsheng , Wan Feng
Published: October 2021

Background Despite psychiatric traits were associated with intracranial aneurysms (IAs) in observational studies, their causal relationships remain largely undefined. We aimed to assess the causality between psychiatric traits and IAs.

Methods We firstly collected the genome-wide association statistics of IAs (sample size, n = 79,429) and ten psychiatric traits from Europeans, including insomnia (n = 1,331,010), mood instability (n = 363,705), anxiety disorder (n = 83,566), major depressive disorder (MDD) (n = 480,359), subjective wellbeing (n = 388,538), attention deficit/hyperactivity disorder (ADHD) (n = 53,293), autism spectrum disorder (ASD) (n = 46,350), bipolar disorder (BIP) (n = 51,710), schizophrenia (SCZ) (n = 105,318), and neuroticism (n = 168,105). We then conducted a series of bi-directional two-sample Mendelian randomization (MR) analyses, of which the Robust Adjusted Profile Score (RAPS) was the primary method to estimate the causal effects between these psychiatric traits and IAs.

Results We found that insomnia exhibited a significant risk effect on IAs with the odds ratio (OR) being 1.22 (95% CI: 1.11–1.34, p = 4.61 × 10–5) from the RAPS method. There was suggestive evidence for risk effect of mood instability on IAs (RAPS, OR = 4.16, 95% CI: 1.02–17.00, p = 0.047). However, no clear evidence of causal effects on IAs for the rest eight psychiatric traits (anxiety disorder, MDD, subjective wellbeing, ADHD, ASD, BIP, SCZ, and neuroticism) was identified. In the reverse MR analyses, no causal effects of IAs on psychiatric traits were found.

Conclusions Our findings provide strong evidence for a causal risk effect of insomnia on IAs and suggestive evidence for mood instability as a causal risk effect on IAs. These results could inform the prevention and clinical intervention of IAs.
An Exploration of Mutagenesis in a Family with Cleidocranial Dysplasia without RUNX2 Mutation
Authors: Liu Dandan , Liu Yang , Zhang XianLi , Wang Yixiang , Zhang Chenying , Zheng Shuguo
Published: October 2021

Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia, and dental abnormalities. Mutations involving Runt-related transcription factor 2 (RUNX2) are currently the only known molecular etiology for CCD but are not identified in all CCD patients. NoRUNX2abnormality can be detected in about 20–30% of patients, and the molecular cause remains unknown. The present study includes a family case with typical features of CCD.RUNX2mutation was first screened by sequencing analysis, and no mutation was detected. Copy number alterations of theRUNX2gene were then measured by quantitative PCR and multiplex ligation-dependent probe amplification (MLPA). No copy number variation inRUNX2could be detected. We performed whole-exome sequencing (WES) to identify the underlying genetic mutations. Unexpectedly, no abnormalities could be detected in genes related to the RUNX2 signaling pathway. Therefore, it was supposed that other new unknown gene variations might contribute to the CCD phenotype. We focused on Immunoglobulin superfamily member 10 (IGSF10), a gene related to bone development. AnIGSF10frameshift mutation (c.6001_6002delCT, p.Leu2001Valfs*24) was detected by WES. Sanger sequencing verified that this mutation was only detected in the patient and her affected mother but not in her unaffected father. Bioinformatics studies demonstrated that this mutation could change the 3D structure of the IGSF10 protein and severely damage its function. In addition, alkaline phosphatase (ALP) activity and the ability to form mineralized nodules were inhibited by IGSF10 knockdown compared with normal controls. The expression of bone sialoprotein (BSP) was significantly reduced by IGSF10 knockdown, but not that of other osteogenic markers. Our results provide new genetic evidence thatIGSF10mutation might contribute to CCD.
Taurine and Indicine Haplotype Representation in Advanced Generation Individuals From Three American Breeds
Authors: Crum Tamar E. , Schnabel Robert D. , Decker Jared E. , Taylor Jeremy F.
Published: October 2021

Development of the American Breeds of beef cattle began in the 1920s as breeders and U. S. Experiment Station researchers began to create Bos taurus taurus × Bos taurus indicus hybrids using Brahman as the B. t. indicus source. By 1954, U.S. Breed Associations had been formed for Brangus (5/8 Angus × 3/8 Brahman), Beefmaster (½ Brahman × ¼ Shorthorn × ¼ Hereford), and Santa Gertrudis (5/8 Shorthorn × 3/8 Brahman). While these breeds were developed using mating designs expected to create base generation animals with the required genome contributions from progenitor breeds, each association has now registered advanced generation animals in which selection or drift may have caused the realized genome compositions to differ from initial expected proportions. The availability of high-density SNP genotypes for 9,161 Brangus, 3,762 Beefmaster, and 1,942 Santa Gertrudis animals allowed us to compare the realized genomic architectures of breed members to the base generation expectations. We used RFMix to estimate local ancestry and identify genomic regions in which the proportion of Brahman ancestry differed significantly from a priori expectations. For all three breeds, lower than expected levels of Brahman composition were found genome-wide, particularly in early-generation animals where we demonstrate that selection on beef production traits was likely responsible for the taurine enrichment. Using a proxy for generation number, we also contrasted the genomes of early- and advanced-generation animals and found that the indicine composition of the genome has increased with generation number likely due to selection on adaptive traits. Many of the most-highly differentiated genomic regions were breed specific, suggesting that differences in breeding objectives and selection intensities exist between the breeds. Global ancestry estimation is commonly performed in admixed animals to control for stratification in association studies. However, local ancestry estimation provides the opportunity to investigate the evolution of specific chromosomal segments and estimate haplotype effects on trait variation in admixed individuals. Investigating the genomic architecture of the American Breeds not only allows the estimation of indicine and taurine genome proportions genome-wide, but also the locations within the genome where either taurine or indicine alleles confer a selective advantage.
To bnAb or Not to bnAb: Defining Broadly Neutralising Antibodies Against HIV-1
Authors: Griffith Sarah A. , McCoy Laura E.
Published: October 2021

Since their discovery, antibodies capable of broad neutralisation have been at the forefront of HIV-1 research and are of particular interest due to in vivo passive transfer studies demonstrating their potential to provide protection. Currently an exact definition of what is required for a monoclonal antibody to be classed as a broadly neutralising antibody (bnAb) has not yet been established. This has led to hundreds of antibodies with varying neutralisation breadth being studied and has given insight into antibody maturation pathways and epitopes targeted. However, even with this knowledge, immunisation studies and vaccination trials to date have had limited success in eliciting antibodies with neutralisation breadth. For this reason there is a growing need to identify factors specifically associated with bnAb development, yet to do this a set of criteria is necessary to distinguish bnAbs from non-bnAbs. This review aims to define what it means to be a HIV-1 bnAb by comparing neutralisation breadth, genetic features and epitopes of bnAbs, and in the process highlights the challenges of comparing the array of antibodies that have been isolated over the years.
T-Cell Receptor Profiling and Prognosis After Stereotactic Body Radiation Therapy For Stage I Non-Small-Cell Lung Cancer
Authors: Wu Lirong , Zhu Jun , Rudqvist Nils-Petter , Welsh James , Lee Percy , Liao Zhongxing , Xu Ting , Jiang Ming , Zhu Xiangzhi , Pan Xuan , Li Pansong , Zhou Zhipeng , He Xia , Yin Rong , Feng Jifeng
Published: October 2021

Radiotherapy is known to influence immune function, including T cell receptor (TCR) repertoire. We evaluated the TCR repertoire before and after stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) and explored correlations between TCR indexes and distant failure after SBRT. TCR repertoires were analyzed in peripheral blood mononuclear cells (PBMCs) collected before and after SBRT from 19 patients. TCR combinational diversity in V and J genes was assessed with multiplex PCR of genomic DNA from PBMCs and tested for associations with clinical response. All patients received definitive SBRT to a biologically effective dose of >=100 Gy. The number of unique TCR clones was decreased after SBRT versus before, but clonality and the Shannon Entropy did not change. Four patients (21%) developed distant metastases after SBRT (median 7 months); those patients had lower Shannon Entropy in post-SBRT samples than patients without metastasis. Patients with a low change in Shannon Entropy from before to after SBRT [(post-SBRT Shannon Entropy minus baseline Shannon)/(baseline Shannon) * 100] had poorer metastasis-free survival than those with high change in Shannon Entropy (P<0.001). Frequencies in V/J gene fragment expression in the TCR β chain were also different for patients with or without metastases (two V fragments in baseline samples and 2 J and 9 V fragments in post-treatment samples). This comprehensive analysis of immune status before and after SBRT showed that quantitative assessments of TCRs can help evaluate prognosis in early-stage NSCLC.
Decreased IgG Antibody Response to Viral Protein Mimotopes of Oncogenic Merkel Cell Polyomavirus in Sera From Healthy Elderly Subjects
Authors: Mazziotta Chiara , Lanzillotti Carmen , Govoni Marcello , Pellielo Giulia , Mazzoni Elisa , Tognon Mauro , Martini Fernanda , Rotondo John Charles
Published: October 2021

Merkel cell polyomavirus (MCPyV) is the main causative agent of Merkel cell carcinoma (MCC), a rare but aggressive skin tumor with a typical presentation age >60 years. MCPyV is ubiquitous in humans. After an early-age primary infection, MCPyV establishes a clinically asymptomatic lifelong infection. In immunocompromised patients/individuals, including elders, MCC can arise following an increase in MCPyV replication events. Elders are prone to develop immunesenescence and therefore represent an important group to investigate. In addition, detailed information on MCPyV serology in elders has been debated. These findings cumulatively indicate the need for new research verifying the impact of MCPyV infection in elderly subjects (ES). Herein, sera from 226 ES, aged 66–100 years, were analyzed for anti-MCPyV IgGs with an indirect ELISA using peptides mimicking epitopes from the MCPyV capsid proteins VP1-2. Immunological data from sera belonging to a cohort of healthy subjects (HS) (n = 548) aged 18–65 years, reported in our previous study, were also included for comparisons. Age-/gender-specific seroprevalence and serological profiles were investigated. MCPyV seroprevalence in ES was 63.7% (144/226). Age-specific MCPyV seroprevalence resulted as 62.5% (25/40), 71.7% (33/46), 64.9% (37/57), 63.8% (30/47), and 52.8% (19/36) in ES aged 66–70, 71–75, 76–80, 81–85, and 86–100 years, respectively (p > 0.05). MCPyV seroprevalence was 67% (71/106) and 61% (73/120) in ES males and females, respectively (p > 0.05). Lack of age-/gender-related variations in terms of MCPyV serological profiles was found in ES (p > 0.05). Notably, serological profile analyses indicated lower optical densities (ODs) in ES compared with HS (p < 0.05), while lower ODs were also determined in ES males compared with HS males (p < 0.05). Our data cumulatively suggest that oncogenic MCPyV circulates in elders asymptomatically at a relatively high prevalence, while immunesenescence might be responsible for a decreased IgG antibody response to MCPyV, thereby potentially leading to an increase in MCPyV replication levels. In the worse scenario, alongside other factors, MCPyV might drive MCC carcinogenesis, as described in elders with over 60 years of age.
Profiling the T Cell Receptor Alpha/Delta Locus in Salmonids
Authors: Edholm Eva-Stina , Fenton Christopher Graham , Mondot Stanislas , Paulssen Ruth H. , Lefranc Marie-Paule , Boudinot Pierre , Magadan Susana
Published: October 2021

In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids (familySalmonidae) include two key teleost species for aquaculture, rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar)which constitute important models for fish immunology and important targets for vaccine development. The growing interest to decipher the dynamics of adaptive immune responses against pathogens or vaccines has resulted in recent efforts to sequence the immunoglobulin (IG) or antibodies and T cell receptor (TR) repertoire in these species. In this context, establishing a comprehensive and coherent locus annotation is the fundamental basis for the analysis of high-throughput repertoire sequencing data. We therefore decided to revisit the description and annotation of TRA/TRD locus in Atlantic salmon and two strains of rainbow trout (Swanson and Arlee) using the now available high-quality genome assemblies. Phylogenetic analysis of functional TRA/TRD V genes from these three genomes led to the definition of 25 subgroups shared by both species, some with particular feature. A total of 128 TRAJ genes were identified inSalmo, the majority with a close counterpart inOncorhynchus. Analysis of expressed TRA repertoire indicates that most TRAV gene subgroups are expressed at mucosal and systemic level. The present work on TRA/TRD locus annotation along with the analysis of TRA repertoire sequencing data show the feasibility and advantages of a common salmonid TRA/TRD nomenclature that allows an accurate annotation and analysis of high-throughput sequencing results, across salmonid T cell subsets.
Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease and Varicella Zoster Virus Infection - Frequency of an Association
Authors: Di Pauli Franziska , Morschewsky Paul , Berek Klaus , Auer Michael , Bauer Angelika , Berger Thomas , Bsteh Gabriel , Rhomberg Paul , Schanda Kathrin , Zinganell Anne , Deisenhammer Florian , Reindl Markus , Hegen Harald
Published: October 2021

To determine whether there is a correlation between myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases and varicella zoster virus (VZV) infection. We provide a case report and performed a study to determine the frequency of MOG antibodies (MOG-IgG) in neurological VZV infections. Patients admitted to the Medical University of Innsbruck from 2008–2020 with a diagnosis of a neurological manifestation of VZV infection (n=59) were included in this study; patients with neuroborreliosis (n=34) served as control group. MOG-IgG was detected using live cell-based assays. In addition, we performed a literature review focusing on MOG and aquaporin-4 (AQP4) antibodies and their association with VZV infection. Our case presented with VZV-associated longitudinally extensive transverse myelitis and had MOG-IgG at a titer of 1:1280. In the study, we did not detect MOG-IgG in any other patient neither in the VZV group (including 15 with VZV encephalitis/myelitis) nor in the neuroborreliosis group. In the review of the literature, 3 cases with MOG-IgG and additional 9 cases with AQP4 IgG associated disorders in association with a VZV infection were identified. MOG-IgG are rarely detected in patients with VZV infections associated with neurological diseases.
Zooxanthellae Diversity and Coral-Symbiont Associations in the Philippine Archipelago: Specificity and Adaptability Across Thermal Gradients
Authors: Torres Andrew F. , Valino Darryl Anthony M. , Ravago-Gotanco Rachel
Published: October 2021

Prolonged thermal stress and high levels of solar irradiance can disrupt the coral-algal symbiosis and cause bleaching and lowered overall fitness that lead to the likely death of the cnidarian host. Adaptive bleaching and acclimatization of corals, which posits bleaching as an opportunity for the coral host to switch its currently susceptible endosymbionts to more stress-tolerant taxa, offers hope for survival of reefs amid rapidly warming oceans. In this study, we explored the diversity and distribution of coral-zooxanthellae associations in the context of geospatial patterns of sea surface temperature (SST) and thermal anomalies across the Philippine archipelago. Thermal clusters based on annual sea surface temperature means and each site’s frequency of exposure to heat stress were described using three-decade (1985–2018) remotely sensed data. Haphazard sampling of 628 coral fragments was conducted in 14 reef sites over 3 years (2015–2018). Using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) fingerprinting and sequencing of the zooxanthellae ITS2 region, we characterized endosymbiont diversity within four reef-building coral families across archipelagic thermal regimes. Consistency in dominant Symbiodiniaceae taxon was observed in Acropora spp., Porites spp., and Heliopora coerulea. In contrast, the family Pocilloporidae (Pocillopora spp., Seriatopora spp., and Stylophora pistillata) exhibited biogeographic variability in zooxanthellae composition, concordant with inferred occurrences of sustained thermal stress. Multivariate analyses identify two broad Pocilloporidae clusters that correspond with mean SST ranges and frequency of exposure to bleaching-level thermal stress which are largely supported by ANOSIM. Differences in zooxanthellae assemblages may reflect host-specific responses to ecological or environmental gradients across biogeographic regions. Such patterns of variability provide insight and support for the adaptability and potential resilience of coral communities in geographically and oceanographically complex regions, especially amidst the increasing severity of global and local-scale stressors.