bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of SGLT2 Inhibitors on Renal Outcomes in Patients With Chronic Kidney Disease: A Meta-Analysis
Authors: Li Ning , Lv Dan , Zhu Xiangjun , Wei Ping , Gui Yuan , Liu Shijia , Zhou Enchao , Zheng Min , Zhou Dong , Zhang Lu
Published: November 2021

Introduction: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on renal outcomes in patients with chronic kidney disease (CKD) were initially demonstrated in recent trials. However, the magnitude of renal benefits for CKD patients with different baseline features and underlying diseases remains unclear.

Method: We systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021 to identify eligible trials. The primary outcome was a composite of worsening kidney function, end-stage kidney disease (ESKD), or renal death. Efficacy and safety outcomes were stratified by baseline features, such as type 2 diabetes, heart failure, atherosclerotic cardiovascular disease, proteinuria, and renal function.

Results: A total of nine studies were included. These studies included 25,749 patients with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and 12,863 patients with urine albumin-to-creatinine ratio (UACR) >300 mg/g. SGLT2 inhibitors reduced the risk of the primary renal outcome by 30% in patients with eGFR<60 mL/min/1.73 m2 (HR 0.70, [95% CI 0.58–0.83], I2 = 0.00%) and by 43% in patients with UACR > 300 mg/g (HR 0.57, [95% CI 0.48–0.67], I2 = 16.59%). A similar benefit was observed in CKD patients with type 2 diabetes. SGLT2 inhibitors had no clear effects on renal outcomes in patients with eGFR<60 mL/min/1.73 m2 combined with atherosclerotic cardiovascular disease (HR 0.74, [95% CI 0.51–1.06], I2 = 0.00%). However, they reduced the risk of major renal outcomes by 46% (HR 0.54, [95% CI 0.38–0.76], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR > 300 mg/g). SGLT2 inhibitors did not significantly reduce the risk of major renal outcomes in CKD patients with heart failure (eGFR<60 mL/min/1.73 m2: HR 0.81, [95% CI 0.47–1.38], I2 = 0.00%; UACR > 300 mg/g: HR 0.66, [95% CI 0.41–1.07], I2 = 0.00%). SGLT2 inhibitors showed consistent renal benefits across different levels of eGFR (P interaction = 0.48).

Conclusion: SGLT2 inhibitors significantly reduced the risk of the primary outcome in CKD patients. However, for patients with different features and underlying diseases, there exists differences in the renal protective effect.
Biomarker and Companion Diagnostics—A Review of Medicinal Products Approved by the European Medicines Agency
Authors: Orellana García Laura Patricia , Ehmann Falk , Hines Philip A. , Ritzhaupt Armin , Brand Angela
Published: November 2021

Background: An increasing number of medicines authorised in Europe recommend or require biomarker-based patient selection. For some of these the use of a companion diagnostic (CDx), a subset of in vitro diagnostics (IVDs), to identify patient populations eligible for a specific medicinal product may be required. The information and recommendations of use of a medicinal product for which a CDx is required is particularly important to healthcare professionals for correct patient identification.

Methods: We reviewed the existing information in SmPCs and European Public Assessment Reports (EPARs) of EU medicinal products approved via the centralised procedure at EMA where reference was made to biomarker testing, including by CDx, for patient selection.

Results: The results show that varying levels of detail are provided for the biomarker and the diagnostic test, including variability in where the information was presented. The overall results demonstrate transparent but sometimes heterogeneous reporting of CDx in the SmPC and EPAR.

Conclusions: With the introduction of the new Regulation (EU) 2017/746 on in vitro diagnostic medical devices, medicines regulatory authorities' will be required to be consulted during the review of CDx conformity assessment and so, there is opportunity for more consistent and transparent information on CDx to be provided in the SmPC and EPAR.
RNA-Seq Reveals that Light and Darkness Are Different Stimuli in Freshwater Heterotrophic Actinobacteria
Authors: Hempel Priscilla P. , Keffer Jessica L. , Maresca Julia A.
Published: November 2021

Light is a ubiquitous source of both energy and information in surface environments, and regulates gene expression not only in photosynthetic microorganisms, but in a broad range of photoheterotrophic and heterotrophic microbes as well. Actinobacteria are keystone species in surface freshwater environments, where the ability to sense light could allow them to coordinate periods of nutrient uptake and metabolic activity with primary production. The model freshwater Actinobacteria Rhodoluna (R.) lacicola strain MWH-Ta8 and Aurantimicrobium (A.) photophilum strain MWH-Mo1 grow faster in the light than in the dark, but do not use light energy to support growth. Here, we characterize transcription throughout a light-dark cycle in R. lacicola and A. photophilum. In both species, some genes encoding carbohydrate metabolism and storage are upregulated in the light. However, expression of genes of the TCA cycle is only coordinated with light availability in R. lacicola. In fact, the majority of genes that respond to light and darkness in these two species are different, even though their light-responsive phenotypes are similar. The ability to respond to light and darkness may be widespread in freshwater Actinobacteria, but the genetic networks controlled by these two stimuli may vary significantly.
Biogenic Synthesis of MnO2 Nanoparticles With Leaf Extract of Viola betonicifolia for Enhanced Antioxidant, Antimicrobial, Cytotoxic, and Biocompatible Applications
Authors: Lu Haibin , Zhang Xueyang , Khan Shakeel Ahmad , Li Wenqiang , Wan Lei
Published: November 2021

In this study, we propose to synthesize NPs using plant extract containing active biomedical components, with the goal of obtaining NPs that inherit the biomedical activities of the plant. Herein, we report the synthesis of manganese dioxide nanoparticles (VBLE-MnO2 NPs) using the leaves extract of Viola betonicifolia, in which the biological active plant’s secondary metabolites function as both reducing and capping agents. The synthesized NPs were successfully characterized with different spectroscopic techniques. The antibacterial, antifungal, and biofilm inhibition properties of the synthesized VBLE-MnO2 NPs were further explored against a variety of bacteria (Gram-positive and Gram-negative) and mycological species. Additionally, their antioxidant ability against linoleic acid peroxidation inhibition, cytobiocompatibility with hMSC cells, and cytotoxicity against MCF-7 cells were investigated compared to leaves extract and chemically synthesized manganese dioxide NPs (CH-MnO2 NPs). The results were demonstrated that the synthesized VBLE-MnO2 NPs presented excellent antibacterial, antifungal, and biofilm inhibition performance against all the tested microbial species compared to plant leaves extract and CH-MnO2 NPs. Moreover, they also exhibited significant antioxidant potential, which was comparable to the external standard (ascorbic acid); however, it was higher than plant leaves extract and CH-MnO2 NPs. Furthermore, the synthesized CH-MnO2 NPs displayed good cytobiocompatibility with hMSC cells compared to CH-MnO2 NPs. The enhanced antioxidant, antibacterial, antifungal, and biofilm inhibition efficacy as compared to CH-MnO2 NPs might be attributed to the synergistic effect of the VBLE-MnO2 NPs’ physical properties and the adsorbed biologically active phytomolecules from the leaves extract of V. betonicifolia on their surface. Thus, our study establishes a novel ecologically acceptable route for nanomaterials’ fabrication with increased and/or extra medicinal functions derived from their herbal origins.
Cell Division Control Protein 42 Interacts With Hepatitis E Virus Capsid Protein and Participates in Hepatitis E Virus Infection
Authors: Fan Mengnan , Luo Yuhang , Zhang Beibei , Wang Jiaxi , Chen Tianxiang , Liu Baoyuan , Sun Yani , Nan Yuchen , Hiscox Julian A. , Zhao Qin , Zhou En-Min
Published: November 2021

Hepatitis E Virus (HEV) causes viral hepatitis in humans worldwide, while a subset of HEV species, avian HEV, causes hepatitis-splenomegaly syndrome in chickens. To date, there are few reports on the host proteins interacting with HEV and being involved in viral infection. Previous pull-down assay combining mass spectrometry indicated that cell division control protein 42 (CDC42), a member belonging to the Rho GTPase family, was pulled down by avian HEV capsid protein. We confirmed the direct interaction between CDC42 and avian and mammalian HEV capsid proteins. The interaction can increase the amount of active guanosine triphosphate binding CDC42 state (GTP-CDC42). Subsequently, we determined that the expression and activity of CDC42 were positively correlated with HEV infection in the host cells. Using the different inhibitors of CDC42 downstream signaling pathways, we found that CDC42-MRCK (a CDC42-binding kinase)-non-myosin IIA (NMIIA) pathway is involved in naked avian and mammalian HEV infection, CDC42-associated p21-activated kinase 1 (PAK1)-NMIIA/Cofilin pathway is involved in quasi-enveloped mammalian HEV infection and CDC42-neural Wiskott-Aldrich syndrome protein-actin-polymerizing protein Arp2/3 pathway (CDC42-(N-)WASP-Arp2/3) pathway participates in naked and quasi-enveloped mammalian HEV infection. Collectively, these results demonstrated for the first time that HEV capsid protein can directly bind to CDC42, and non- and quasi-enveloped HEV use different CDC42 downstream signaling pathways to participate in viral infection. The study provided some new insights to understand the life cycle of HEV in host cells and a new target of drug design for combating HEV infection.
Neurofunctional Segmentation Shifts in the Hippocampus
Authors: Robinson Jennifer L. , Zhou Xinyu , Bird Ryan T. , Leavitt Mackenzie J. , Nichols Steven J. , Blaine Sara K. , Deshpande Gopikrishna
Published: November 2021

The hippocampus is one of the most phylogenetically preserved structures in the mammalian brain. Engaged in a host of diverse cognitive processes, there has been increasing interest in understanding how the hippocampus dynamically supports these functions. One of the lingering questions is how to reconcile the seemingly disparate cytoarchitectonic organization, which favors a dorsal-ventral layering, with the neurofunctional topography, which has strong support for longitudinal axis (anterior-posterior) and medial-lateral orientation. More recently, meta-analytically driven (e.g., big data) approaches have been employed, however, the question remains whether they are sensitive to important task-specific features such as context, cognitive processes recruited, or the type of stimulus being presented. Here, we used hierarchical clustering on functional magnetic resonance imaging (fMRI) data acquired from healthy individuals at 7T using a battery of tasks that engage the hippocampus to determine whether stimulus or task features influence cluster profiles in the left and right hippocampus. Our data suggest that resting state clustering appears to favor the cytoarchitectonic organization, while task-based clustering favors the neurofunctional clustering. Furthermore, encoding tasks were more sensitive to stimulus type than were recognition tasks. Interestingly, a face-name paired associate task had nearly identical clustering profiles for both the encoding and recognition conditions of the task, which were qualitatively morphometrically different than simple encoding of words or faces. Finally, corroborating previous research, the left hippocampus had more stable cluster profiles compared to the right hippocampus. Together, our data suggest that task-based and resting state cluster profiles are different and may account for the disparity or inconsistency in results across studies.
Mismatch of Visual-Vestibular Information in Virtual Reality: Is Motion Sickness Part of the Brains Attempt to Reduce the Prediction Error?
Authors: Nürnberger Matthias , Klingner Carsten , Witte Otto W. , Brodoehl Stefan
Published: October 2021

Visually induced motion sickness (VIMS) is a relevant limiting factor in the use of virtual reality (VR) devices. Understanding the origin of this problem might help to develop strategies to circumvent this limitation. Previous studies have attributed VIMS to a mismatch between visual, and vestibular information, causing ambiguity of the position of the body in relation to its surrounding. Studies using EEG have shown a shift of the power spectrum to lower frequencies while VIMS is experienced. However, little is known about the relationship between the intensity of the VIMS and the changes in these power spectra. Moreover, the effect of different varieties of VIMS on the causal relationship between brain areas is largely unknown. Here, we used EEG to study 14 healthy subjects in a VR environment who were exposed to increasing levels of mismatch between vestibular and visual information. The frequency power and the bivariate transfer entropy as a measure for the information transfer were calculated. We found a direct association between increasing mismatch levels and subjective VIMS. With increasing VIMS, the proportion of slow EEG waves (especially 1–10 Hz) increases, especially in temporo-occipital regions. Furthermore, we found a general decrease in the information flow in most brain areas but especially in brain areas involved in the processing of vestibular signals and the detection of self-motion. We hypothesize that the general shift of frequency power and the decrease in information flow while experiencing high intensity VIMS represent a brain state of a reduced ability to receive, transmit and process information. We further hypothesize that the mechanism of reduced information flow is a general reaction of the brain to an unresolvable mismatch of information. This reaction aims on transforming a currently unstable model with a high prediction error into a stable model in an environment of minimal contradictory information.
Appraisal of Triglyceride-Related Markers as Early Predictors of Metabolic Outcomes in the PREVIEW Lifestyle Intervention: A Controlled Post-hoc Trial
Authors: Navas-Carretero Santiago , San-Cristobal Rodrigo , Siig Vestentoft Pia , Brand-Miller Jennie C. , Jalo Elli , Westerterp-Plantenga Margriet , Simpson Elizabeth J. , Handjieva-Darlenska Teodora , Stratton Gareth , Huttunen-Lenz Maija , Lam Tony , Muirhead Roslyn , Poppitt Sally , Pietiläinen Kirsi H. , Adam Tanja , Taylor Moira A. , Handjiev Svetoslav , McNarry Melitta A. , Hansen Sylvia , Brodie Shannon , Silvestre Marta P. , Macdonald Ian A. , Boyadjieva Nadka , Mackintosh Kelly A. , Schlicht Wolfgang , Liu Amy , Larsen Thomas M. , Fogelholm Mikael , Raben Anne , Martinez J. Alfredo
Published: November 2021

Background: Individuals with pre-diabetes are commonly overweight and benefit from dietary and physical activity strategies aimed at decreasing body weight and hyperglycemia. Early insulin resistance can be estimated via the triglyceride glucose index {TyG = Ln [TG (mg/dl) × fasting plasma glucose (FPG) (mg/dl)/2]} and the hypertriglyceridemic-high waist phenotype (TyG-waist), based on TyG x waist circumference (WC) measurements. Both indices may be useful for implementing personalized metabolic management. In this secondary analysis of a randomized controlled trial (RCT), we aimed to determine whether the differences in baseline TyG values and TyG-waist phenotype predicted individual responses to type-2 diabetes (T2D) prevention programs.

Methods: The present post-hoc analyses were conducted within the Prevention of Diabetes through Lifestyle intervention and population studies in Europe and around the world (PREVIEW) study completers (n = 899), a multi-center RCT conducted in eight countries (NCT01777893). The study aimed to reduce the incidence of T2D in a population with pre-diabetes during a 3-year randomized intervention with two sequential phases. The first phase was a 2-month weight loss intervention to achieve ≥8% weight loss. The second phase was a 34-month weight loss maintenance intervention with two diets providing different amounts of protein and different glycemic indices, and two physical activity programs with different exercise intensities in a 2 x 2 factorial design. On investigation days, we assessed anthropometrics, glucose/lipid metabolism markers, and diet and exercise questionnaires under standardized procedures.

Results: Diabetes-related markers improved during all four lifestyle interventions. Higher baseline TyG index (p < 0.001) was associated with greater reductions in body weight, fasting glucose, and triglyceride (TG), while a high TyG-waist phenotype predicted better TG responses, particularly in those randomized to physical activity (PA) of moderate intensity.

Conclusions: Two novel indices of insulin resistance (TyG and TyG-waist) may allow for a more personalized approach to avoiding progression to T2D.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT01777893 reference, identifier: NCT01777893.
Evaluation Expression of miR-146a and miR-155 in Non-Small-Cell Lung Cancer Patients
Authors: Dezfuli Neda K. , Alipoor Shamila D. , Dalil Roofchayee Neda , Seyfi Sharareh , Salimi Babak , Adcock Ian M. , Mortaz Esmaeil
Published: November 2021

Background

Non−small-cell lung cancer (NSCLC) is the major type of lung cancer. MicroRNAs (miRNAs) are novel markers and targets in cancer therapy and can act as both tumor suppressors and oncogenes and affect immune function. The aim of this study was to investigate the expression of miR146a and miR155 in linked to blood immune cell phenotypes and serum cytokines in NSCLC patients.

Methods

Thirty-three NSCLC patients and 30 healthy subjects were enrolled in this study. The allele frequencies of potential DNA polymorphisms were studied using polymerase chain reaction (PCR)–restriction fragment length polymorphism (PCR-RFLP) analysis in peripheral blood samples. Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of miR-146a and miR-155 in peripheral blood mononuclear cells (PBMCs). Serum cytokine (IL-1β, IL-6, TNF-α, TGF-β, IL-4, IFN-γ) levels were determined by ELISA. The frequency of circulating CD3+CTLA-4+ and CD4+CD25+FOXP3+ (T regulatory cells/Treg) expression was measured by flow cytometry.

Results

miR-146a was significantly downregulated in PBMC of NSCLC patients (P ≤ 0.001). Moreover, IL-6 and TGF-β levels were elevated in NSCLC patients (P ≤ 0.001, P ≤ 0.018, respectively). CD3+ CTLA-4+ and Treg cells frequencies were higher in patients than in control subjects (P ≤ 0.0001, P ≤ 0.0001, respectively). There was a positive correlation between miR-155 and IL-1β levels (r=0.567, p ≤ 0.001) and a negative correlation between miR-146a and TGF-β levels (r=-0.376, P ≤ 0.031) in NSCLC patients. No significant differences were found in the relative expression of miR-146a and miR-155, cytokine levels or immune cell numbers according to miR-146a and miR-155 (GG/GC/CC, TT/AT/AA) genotypes. However, there was a positive correlation between miR-146a and IL-1β levels (r=0.74, P ≤ 0.009) in GG subjects and a positive correlation between miR-146a expression and CD3+CTLA4+ cell frequency (r=0.79, P ≤ 0.01) in CC genotyped subjects. Conversely, a negative correlation between miR-146a expression and Treg cell frequency (r=−0.87, P ≤ 0.05) was observed with the GG genotype. A positive correlation between miR-155 and IL-1β expression (r=0.58, p ≤ 0.009) in the TT genotype and between miR-155 expression and CD3+CTLA-4 cell frequency (r=0.75, P ≤ 0.01) was observed in the AT genotype.

Conclusions

The current data suggest that the miR-146a expression in PBMC and serum TGF-β and IL-1β levels may act as blood markers in NSCLC patients. Further study is needed to elucidate the link between immune cells and serum miR146 at early disease stages.
Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome
Authors: Alhujaily Muhanad , Abbas Hafsa , Xue Mingzhan , de la Fuente Alberto , Rabbani Naila , Thornalley Paul J.
Published: November 2021

Background

Tumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. We investigated the role of MG and Glo1 in cancer chemotherapy related in multidrug resistance (MDR).

Methods

Human Glo1 was overexpressed in HEK293 cells and the effect on anticancer drug potency, drug-induced increase in MG and mechanism of cytotoxicity characterized. Drug-induced increased MG and the mechanisms driving it were investigated and the proteomic response to MG-induced cytotoxicity explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. Glo1 expression data of 1,040 human tumor cell lines and 7,489 tumors were examined for functional correlates and impact of cancer patient survival.

Results

Overexpression of Glo1 decreased cytotoxicity of antitumor drugs, impairing antiproliferative activity of alkylating agents, topoisomerase inhibitors, antitubulins, and antimetabolites. Antitumor drugs increased MG to cytotoxic levels which contributed to the cytotoxic, antiproliferative mechanism of action, consistent with Glo1-mediated MDR. This was linked to off-target effects of drugs on glycolysis and was potentiated in hypoxia. MG activated the intrinsic pathway of apoptosis, with decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. Spliceosomal gene expression correlated positively with Glo1 in human tumor cell lines and tumors. In clinical chemotherapy of breast cancer, increased expression of Glo1 was associated with decreased patient survival, with hazard ratio (HR) = 1.82 (logrank p < 0.001, n = 683) where upper quartile survival of patients was decreased by 64% with high Glo1 expression.

Conclusions

We conclude that MG-mediated cytotoxicity contributes to the cancer chemotherapeutic response and targets the spliceosome. High expression of Glo1 contributes to multidrug resistance by shielding the spliceosome from MG modification and decreasing survival in the chemotherapy of breast cancer. Adjunct chemotherapy with Glo1 inhibitor may improve treatment outcomes.
Identification of miR-499a-5p as a Potential Novel Biomarker for Risk Stratification in Endometrial Cancer
Authors: Ravegnini Gloria , De Leo Antonio , Coada Camelia , Gorini Francesca , de Biase Dario , Ceccarelli Claudio , Dondi Giulia , Tesei Marco , De Crescenzo Eugenia , Santini Donatella , Corradini Angelo Gianluca , Tallini Giovanni , Hrelia Patrizia , De Iaco Pierandrea , Angelini Sabrina , Perrone Anna Myriam
Published: October 2021

Introduction

The Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups in endometrial cancer (EC), among which two are correlated with an intermediate prognosis: the MisMatch Repair-deficient (MMRd) and the No Specific Molecular Profile (NSMP) groups. The two groups represent a heterogeneous subset of patients frequently harboring CTNNB1 alterations with distinctive clinicopathologic features. The study aimed to evaluate the miRNA expression in ECs to identify potential biomarkers of prognosis.

Methods

We analyzed miRNA expression in 72 ECs classified as MMRd or NSMP including 15 ECs with CTNNB1 mutations. In the discovery step, miRNA expression was evaluated in 30 cases through TaqMan miRNA arrays. Subsequently, four miRNAs were validated in the total cohort of ECs. The data were further tested in the TCGA cohort, and correlations with overall survival (OS) and progression-free interval (PFI) were evaluated.

Results

miR-499a-3p and miR-499a-5p resulted to be overexpressed in CTNNB1 mutant EC patients at intermediate risk. Similarly, in the TCGA cohort, miR-499a-3p and miR-499a-5p were differentially expressed between CTNNB1 mutant and wild-type patients (p < 0.0001). NSMP patients with low miR-499a-5p expression showed longer OS (p = 0.03, log-rank test). By combining miR-499a-3p or -5p expression levels with the CTNNB1 status, ECs with CTNNB1 mutation and lower miR-499a-5p expression showed better OS compared with the other subgroups (p = 0.03, log-rank test), among the NSMP patients. Moreover, in a multivariate analysis, combination of wild type CTNNB1 status and high miR-499a-5p expression was indipendently associated with high risk of death [HR (95%CI): 3.53 (1.1-10.5), p = 0.02].

Conclusion

Our results suggest that the combination of CTNNB1 status and miR-499a-5p allows a better stratification of NSMP patients and could promote a personalization of the treatment in intermediate-risk patients.
Reference Interval for Pulse Oxygen Saturation in Neonates at Different Altitudes: A Systematic Review
Authors: Wang Bo , Zhang Jia , Wu Ya-Zhen , Lu Zhi-Hui , Wang Na , Yu Zhang-Bin
Published: November 2021

Introduction: The reference interval for pulse oxygen saturation (SpO2) in neonates born at high altitudes has not been defined to date. The purpose of this study was to systematically review published studies and determine the reference interval of SpO2 in neonates at different altitudes.

Methods: Databases of PubMed, Embase, Cochrane Library, Clinicaltrials.Gov, Chinese National Knowledge Infrastructure Database, Wanfang Database, Chinese Science Technology Journals Database, and Chinese Clinical Trial Registry were searched for studies reporting SpO2 in healthy neonates at different altitudes. Retrieval time was from inception of the database to August 16, 2021. The Agency for Healthcare Research and Quality checklist was used to evaluate the quality of studies. Python v3.8 was used to analyze the data. This systematic review was drafted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Results: Seven cross-sectional studies, published between 1991 and 2020, were identified. They were from US, Mexico, Israel, Ecuador, and China. Three studies were rated as high quality and four as moderate quality. The mean SpO2 (with standard deviation or standard error) of neonates born in 40 different altitudes (ranging from 25 meters to 3,100 meters) were obtained. The prediction equation for calculation of the lower limit of the reference interval was established, and the reference intervals for SpO2 at different altitudes were determined.

Conclusions: In healthy neonates, the lower limit of the reference interval of SpO2 decreases with increase in altitude. High-quality prospective studies are need to confirm our findings.
A Genome-Wide Association Study Pinpoints Quantitative Trait Genes for Plant Height, Heading Date, Grain Quality, and Yield in Rye (Secale cereale L.)
Authors: Siekmann Dörthe , Jansen Gisela , Zaar Anne , Kilian Andrzej , Fromme Franz Joachim , Hackauf Bernd
Published: October 2021

Rye is the only cross-pollinating Triticeae crop species. Knowledge of rye genes controlling complex-inherited traits is scarce, which, currently, largely disables the genomics assisted introgression of untapped genetic variation from self-incompatible germplasm collections in elite inbred lines for hybrid breeding. We report on the first genome-wide association study (GWAS) in rye based on the phenotypic evaluation of 526 experimental hybrids for plant height, heading date, grain quality, and yield in 2 years and up to 19 environments. We established a cross-validated NIRS calibration model as a fast, effective, and robust analytical method to determine grain quality parameters. We observed phenotypic plasticity in plant height and tiller number as a resource use strategy of rye under drought and identified increased grain arabinoxylan content as a striking phenotype in osmotically stressed rye. We used DArTseq™ as a genotyping-by-sequencing technology to reduce the complexity of the rye genome. We established a novel high-density genetic linkage map that describes the position of almost 19k markers and that allowed us to estimate a low genome-wide LD based on the assessed genetic diversity in elite germplasm. We analyzed the relationship between plant height, heading date, agronomic, as well as grain quality traits, and genotype based on 20k novel single-nucleotide polymorphism markers. In addition, we integrated the DArTseq™ markers in the recently established ‘Lo7' reference genome assembly. We identified cross-validated SNPs in ‘Lo7' protein-coding genes associated with all traits studied. These include associations of the WUSCHEL-related homeobox transcription factor DWT1 and grain yield, the DELLA protein gene SLR1 and heading date, the Ethylene overproducer 1-like protein gene ETOL1 and thousand-grain weight, protein and starch content, as well as the Lectin receptor kinase SIT2 and plant height. A Leucine-rich repeat receptor protein kinase and a Xyloglucan alpha-1,6-xylosyltransferase count among the cross-validated genes associated with water-extractable arabinoxylan content. This study demonstrates the power of GWAS, hybrid breeding, and the reference genome sequence in rye genetics research to dissect and identify the function of genes shaping genetic diversity in agronomic and grain quality traits of rye. The described links between genetic causes and phenotypic variation will accelerate genomics-enabled rye improvement.
Evolution Analyses of CAMTA Transcription Factor in Plants and Its Enhancing Effect on Cold-tolerance
Authors: Xiao Peixuan , Feng Jia-Wu , Zhu Xi-Tong , Gao Junxiang
Published: November 2021

The calmodulin binding transcription activator (CAMTA) is a transcription factor that is widely present in eukaryotes with conserved structure. It contributes to the response to biotic and abiotic stresses and promotes the growth and development of plants. Although previous studies have investigated the number and function of CAMTAs in some species, there is still a lack of comprehensive understanding of the evolutionary process, phylogenetic relationship, expression patterns, and functions of CAMTAs in plants. Here we identified 465 CMATA genes from 112 plants and systematically studied the origin of CAMTA family, gene expansion, functional differentiation, gene structure, and conservative motif distribution. Based on these analyses, we presented the evidence that CAMTA family was originated from chlorophyta, and we speculated that CAMTA might experience obvious structure variation during its early evolution, and that the number of CAMTA genes might gradually increase in higher plants. To reveal potential functions of CAMTA genes, we analyzed the expression patterns of 12 representative species and found significant species specificity, tissue specificity, and developmental stage specificity of CAMTAs. The results also indicated that the CAMTA genes might promote the maturation and senescence. The expression levels and regulatory networks of CAMTAs revealed that CAMTAs could enhance cold tolerance of rice by regulating carbohydrate metabolism-related genes to accumulate carbohydrates or by modulating target genes together with other transcription factors. Our study provides an insight into the molecular evolution of CAMTA family and lays a foundation for further study of related biological functions.
Identification and Characterization of NBS Resistance Genes in Akebia trifoliata
Authors: Yu Xiaojiao , Zhong Shengfu , Yang Huai , Chen Chen , Chen Wei , Yang Hao , Guan Ju , Fu Peng , Tan Feiquan , Ren Tianheng , Shen Jinliang , Zhang Min , Luo Peigao
Published: October 2021

Akebia trifoliata is an important multiuse perennial plant that often suffers attacks from various pathogens due to its long growth cycle, seriously affecting its commercial value. The absence of research on the resistance (R) genes of A. trifoliata has greatly limited progress in the breeding of resistant varieties. Genes encoding proteins containing nucleotide binding sites (NBSs) and C-terminal leucine-rich repeats (LRRs), the largest family of plant resistance (R) genes, are vital for plant disease resistance. A comprehensive genome-wide analysis showed that there were only 73 NBS genes in the A. trifoliata genome, including three main subfamilies (50 coiled coil (CC)-NBS-LRR (CNL), 19 Toll/interleukin-1 receptor (TIR)-NBS-LRR (TNL) and four resistance to powdery mildew8 (RPW8)-NBS-LRR (RNL) genes). Additionally, 64 mapped NBS candidates were unevenly distributed on 14 chromosomes, most of which were assigned to the chromosome ends; 41 of these genes were located in clusters, and the remaining 23 genes were singletons. Both the CNLs and TNLs were further divided into four subgroups, and the CNLs had fewer exons than the TNLs. Structurally, all eight previously reported conserved motifs were identified in the NBS domains, and both their order and their amino acid sequences exhibited high conservation. Evolutionarily, tandem and dispersed duplications were shown to be the two main forces responsible for NBS expansion, producing 33 and 29 genes, respectively. A transcriptome analysis of three fruit tissues at four developmental stages showed that NBS genes were generally expressed at low levels, while a few of these genes showed relatively high expression during later development in rind tissues. Overall, this research is the first to identify and characterize A. trifoliata NBS genes and is valuable for both the development of new resistant cultivars and the study of molecular mechanisms of resistance.
P300 Event-Related Potentials Mediate the Relationship Between Child Physical Abuse and Externalizing Behavior
Authors: Cui Naixue , Raine Adrian , Connolly Cynthia A. , Richmond Therese S. , Hanlon Alexandra L. , McDonald Catherine C. , Liu Jianghong
Published: November 2021

The psychophysiological mechanism linking early childhood experiences to behavior problems remains unclear. This study aimed to examine the association of child physical abuse with P300 event-related potentials (ERP), and to test the mediating effect of P300 amplitude and latency in the relationship between child physical abuse and externalizing behaviors. Cross-sectional secondary data were obtained from 155 children (55.5% boys, mean age: 11.28 ± 0.57 years) who participated in the China Jintan Child Cohort Study. Children self-reported maternal and paternal physical abuse and externalizing behaviors, as well as P300 were obtained in 2013. Additionally, parents and teachers reported child externalizing behaviors in preschool in 2007. P300 were recorded during a standard novel auditory oddball task. Path analysis shows that after controlling for child sex, socioeconomic status, area of residence, IQ, and child externalizing behavior in preschool, children exposed to maternal physical abuse exhibited increased novelty P300 amplitude, which links to more externalizing behavior. Novelty P300 amplitude partially mediated the relationship between maternal physical abuse and externalizing behavior. These findings are the first to document the partial mediating effect of P300 amplitude on the abuse-externalizing relationship and are consistent with the view that physical abuse affects the attention bias to novel cues that likely places them at increased risk for the development and maintenance of externalizing behavior.
Self- but Not Other-Dimensions of Mentalizing Moderate the Impairment Associated With Social Anxiety in Adolescents From the General Population
Authors: Ballespí Sergi , Vives Jaume , Nonweiler Jacqueline , Perez-Domingo Ariadna , Barrantes-Vidal Neus
Published: November 2021

Mentalizing, or social cognition, refers to the brain’s higher order capacity that allows humans to be aware of one’s own and others’ mental states (e.g., emotions, feelings, intentions). While cognition in social anxiety has been broadly analyzed, there is a paucity of research regarding the role of social cognition. Moreover, mentalizing or social cognition research is traditionally focused on the understanding of others’ mental states, rather than self-mentalizing. Finally, most studies analyze the role of social cognition in the development or maintenance of social anxiety, yet no study to date has analyzed whether social cognition moderates functional impairment associated with it. This study analyzes whether self- and other-mentalizing moderate the relationship between social anxiety and impairment in social and self-functioning. A sample of 262 adolescents from the non-clinical population was assessed on measures of social anxiety, self- and other- mentalization, indicators of social functioning (social competence and sociometric status), and indicators of self-functioning (depression and self-esteem). Multiple linear regressions were conducted to test possible moderation effects of self-mentalizing and other-mentalizing on the relationships between social anxiety and social and self-functioning. Results revealed that other-mentalizing does not moderate social- nor self-functioning, while self-mentalizing moderates the impairment of all of them. While impairment in social functioning is buffered by one dimension of self-mentalizing (emotional clarity; b = 0.003, p = 0.043 and b = 0.016, p = 0.008 for social competence and sociometric status, respectively), impairment in self-functioning is strengthened by the other dimension (attention to emotions; b = −0.007, p = 0.008 and b = 0.009, p = 0.047 for self-esteem and depression, respectively). Probing the moderation at the 16th, 50th, and 84th percentiles revealed that the negative imbalance between dimensions (i.e., high attention and low clarity) tended to exacerbate impairment most on all indicators, while the positive imbalance (i.e., low attention and high clarity) was usually the most buffering condition. This supports that “low-flying” or implicit mentalizing provides more resilience than explicit mentalizing (i.e., high attention and high clarity). Findings suggest that the work on emotional self-awareness should be stressed in the intervention of the social anxiety spectrum conditions in order to improve prevention, functioning, and ultimately, treatments, of people impaired by symptoms of social anxiety.
Fostering EFL/ESL Students’ Language Achievement: The Role of Teachers’ Enthusiasm and Classroom Enjoyment
Authors: Liu Yang , Zhang Mingjie , Zhao Xuetao , Jia Fang
Published: November 2021

Thanks to the inflow of positive psychology (PP) in language education in general and language learning in particular, extensive consideration has been drawn to the role of emotion in second language acquisition (SLA). Enjoyment as a mutual constructive sensation experienced by students has engrossed academic attention. Likewise, teachers are redirected as the most remarkable figure of any educational association, and their enthusiasm is substantial for students in the classroom. In line with the inquiries of teacher enthusiasm, principles of PP, and classroom enjoyment, the current review strives for this form of connection and its impacts on learners’ achievement. Subsequently, the suggestions of this review for teachers, learners, and educator trainers are deliberated.
Temporal Stability of Phytoplankton Functional Groups Within Two Agricultural Irrigation Ponds in Maryland, USA
Authors: Smith Jaclyn E. , Wolny Jennifer L. , Stocker Matthew D. , Hill Robert L. , Pachepsky Yakov A.
Published: November 2021

Phytoplankton functional groups and their influence on water quality have been studied in various types of water bodies but have yet to be studied in agricultural irrigation ponds. Freshwater sources (e.g., lakes, rivers, and reservoirs) have been previously shown to exhibit high spatial and temporal variability in phytoplankton populations. Improvements in the monitoring of phytoplankton populations may be achieved if patterns of stable spatial variability can be found in the phytoplankton populations through time. The objective of this work was to determine if temporally stable spatial patterns in phytoplankton communities could be detected in agricultural irrigation ponds using a functional group approach. The study was performed at two working agricultural irrigation ponds located in Maryland, USA over two summer sampling campaigns in 2017 and 2018. Concentrations of four phytoplankton groups, along with sensor-based and fluorometer based water quality parameters were measured. Temporal stability was assessed using mean relative differences between measurements in each location and averaged measurements across ponds on each sampling date. Temporally stable spatial patterns of three phytoplankton functional groups were found for both ponds over the two sampling seasons. Both ponds had locations where specific phytoplankton functional group concentrations were consistently higher or lower than the pond's average concentration for each sampling date. Zones of consistently higher or lower than average concentrations were associated with flow conditions, pond morphology, and human activities. The existence of temporally stable patterns of phytoplankton functional group concentrations can affect the outcome of a water quality assessment and should be considered in water quality monitoring designs.
Quantification of Cold-Ion Beams in a Magnetic Reconnection Jet
Authors: Li Yu-Xuan , Li Wen-Ya , Tang Bin-Bin , Norgren C. , He Jian-Sen , Wang Chi , Zong Qiu-Gang , Toledo-Redondo S. , André M. , Chappell C. , Dargent J. , Fuselier S. A. , Glocer A. , Graham D. B. , Haaland S. , Kistler L. , Lavraud B. , Moore T. E. , Tenfjord P. , Vines S. K. , Burch J.
Published: October 2021

Cold (few eV) ions of ionospheric origin are widely observed in the lobe region of Earth’s magnetotail and can enter the ion jet region after magnetic reconnection is triggered in the magnetotail. Here, we investigate a magnetotail crossing with cold ions in one tailward and two earthward ion jets observed by the Magnetospheric Multiscale (MMS) constellation of spacecraft. Cold ions co-existing with hot plasma-sheet ions form types of ion velocity distribution functions (VDFs) in the three jets. In one earthward jet, MMS observe cold-ion beams with large velocities parallel to the magnetic fields, and we perform quantitative analysis on the ion VDFs in this jet. The cold ions, together with the hot ions, are reconnection outflow ions and are a minor population in terms of number density inside this jet. The average bulk speed of the cold-ion beams is approximately 38% larger than that of the hot plasma-sheet ions. The cold-ion beams inside the explored jet are about one order of magnitude colder than the hot plasma-sheet ions. These cold-ion beams could be accelerated by the Hall electric field in the cold ion diffusion region and the shrinking magnetic field lines through the Fermi effect.
Hypothalamic Transcriptome Analysis Reveals the Crucial MicroRNAs and mRNAs Affecting Litter Size in Goats
Authors: Liang Chen , Han Miaoceng , Zhou Zuyang , Liu Yufang , He Xiaoyun , Jiang Yanting , Ouyang Yina , Hong Qionghua , Chu Mingxing
Published: November 2021

The hypothalamus was the coordination center of the endocrine system, which played an important role in goat reproduction. However, the molecular mechanism of hypothalamus regulating litter size in goats was still poorly understood. This study aims to investigate the key functional genes associated with prolificacy by hypothalamus transcriptome analysis of goats. In this research, an integrated analysis of microRNAs (miRNAs)-mRNA was conducted using the hypothalamic tissue of Yunshang black goats in the follicular stage. A total of 72,220 transcripts were detected in RNA-seq. Besides, 1,836 differentially expressed genes (DEGs) were identified between high fecundity goats at the follicular phase (FP-HY) and low fecundity goats at the follicular phase (FP-LY). DEGs were significantly enriched in 71 Gene Ontology (GO) terms and 8 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The transcriptome data suggested that DEGs such as BMPR1B, FGFR1, IGF1 and CREB1 are directly or indirectly involved in many processes like hypothalamic gonadal hormone secretion. The miRNA-seq identified 1,837 miRNAs, of which 28 differentially expressed miRNAs (DEMs). These DEMs may affect the nerve cells survival of goat hypothalamic regulating the function of target genes and further affect the hormone secretion activities related to reproduction. They were enriched in prolactin signaling pathway, Jak-STAT signaling pathway and GnRH signaling pathway, as well as various metabolic pathways. Integrated analysis of DEMs and DEGs showed that 87 DEGs were potential target genes of 28 DEMs. After constructing a miRNA-mRNA pathway network, we identified several mRNA-miRNAs pairs by functional enrichment analysis, which was involved in hypothalamic nerve apoptosis. For example, NTRK3 was co-regulated by Novel-1187 and Novel-566, as well as another target PPP1R13L regulated by Novel-566. These results indicated that these key genes and miRNAs may play an important role in the development of goat hypothalamus and represent candidate targets for further research. This study provides a basis for further explanation of the basic molecular mechanism of hypothalamus, but also provides a new idea for a comprehensive understanding of prolificacy characteristics in Yunshang black goats.
Multimodal Estimation of Sine Dwell Vibrational Responses from Aeroelastic Flutter Flight Tests
Authors: Abou-Kebeh Sami , Gil-Pita Roberto , Rosa-Zurera Manuel
Published: November 2021

Aircraft envelope expansion during new underwing stores installation is a challenging problem, mainly related to the aeroelastic flutter phenomenon. Aeroelastic models are usually very hard to model, and therefore flight tests are usually required to validate the aeroelastic model predictions, which given the catastrophic consequences of reaching the flutter point pose an important problem. This constraint favors using short time excitations like Sine Dwell to perform the flight tests, so that the aircraft stays close to the flutter point as little time as possible, but short time data implies a poor spectrum resolution and therefore leads to inaccurate and non repetitive results. The present paper will address the problem related to processing Sine Dwell signals from aeroelastic Flutter Flight Tests, characterized by very short data length (less than 5 s) and low frequency (less than 10 Hz) and used to identify the natural modes associated with the structure. In particular, a new robust technique, the PRESTO algorithm, will be presented and compared to a Matching Pursuit estimation based on Laplace Wavelet. Both techniques have demonstrated to be very accurate and robust procedures on very short time (Sine Dwell) signals, with the particularity that the Laplace Wavelet estimation has already been validated over F-18 real Flutter Flight Test data as described in different papers. However, the PRESTO algorithm improves the performance and accuracy of the Laplace Wavelet processing while keeping its robustness, both on real and simulated data.
Redistribution of Energy during Interaction of a Shock Wave with a Temperature Layered Plasma Region at Hypersonic Speeds
Authors: Azarova O. A. , Lapushkina T. A. , Krasnobaev K. V. , Kravchenko O. V.
Published: November 2021

The paper is devoted to the problem of the interaction between a shock wave and a thermally stratified energy source for the purpose of supersonic/hypersonic flow control realization. The effect of the thermally stratified energy source on a shock wave with the Mach number in the range of 6–12 is researched numerically based on the Navier-Stokes system of equations. Redistribution of specific internal energy and volume density of kinetic energy behind the wave front is investigated. Multiple manifestations of the Richtmyer-Meshkov instability has been obtained which has caused the blurring and disappearance of shock wave and contact discontinuity fronts in density fields. A study of the efficiency of using a stratified energy source instead of a homogeneous one with the same value of the full energy is carried out. The agreement with the available experimental data for the shock wave Mach number 6 has been obtained.