bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization and H∞ Performance Analysis for Load Frequency Control of Power Systems With Time-Varying Delays
Authors: Su Kangyou , Li Yan , Chen Jian , Duan Wenyong
Published: October 2021

With the development and expansion of the power grid, the load frequency control (LFC) scheme receives sensor signals and outputs control signals through an open communication network with a mass of data and extensive information exchange, which may introduce constant, and time-varying delays. This paper considers the optimization andH∞performance problem for LFC of power systems with time-varying delays. Some improved criteria for guaranteeing the stability andH∞performance of the closed-loop system with unknown external load disturbances via the Lyapunov stability theory application. An unique delay-dependent proportional-integral (PI) controller and an optimized PI controller are designed for a specifiedH∞performance index and set, respectively. The criteria proposed in this paper are based on linear matrix inequalities (LMIs), which can be easily solved by the MATLAB LMI-Toolbox. Finally, in case studies, the effectiveness of our method is demonstrated.
Risk-Induced Foraging Behavior in a Free-Living Small Mammal Depends on the Interactive Effects of Habitat, Refuge Availability, and Predator Type
Authors: Kelleher Victoria , Hunnick Louis , Sheriff Michael J.
Published: October 2021

Predators have a major influence on prey populations and broader ecosystem dynamics through both their consumptive and non-consumptive effects. Prey employ risk-induced trait responses such as shifts in habitat use or changes in foraging behavior in response to the presence of predators. Risk-induced changes in foraging depend upon both the predator community and the environmental context; however, the influence of these factors have rarely been concurrently examined in free-living animals. We investigated the interactive effects of habitat, refuge availability, and predator type on the foraging behavior of free-living white-footed mice, accounting for the abiotic factor moonlight. We used auditory calls of a local terrestrial cursorial predator and a local avian ambush predator to simulate predation risk in both a forest edge and a forest interior habitat, and measured the foraging of mice under different experimental refuge types. We found that, while mice had reduced foraging when exposed to predation risk, the degree of this response depended on an interaction among habitat, refuge use, and type of predator. Prey had the greatest reduction in foraging and used refuges the most when exposed to cursorial-hunting foxes at the open forest edge. The risk-induced reduction in foraging and the use of refuges was much weaker in the forest interior, but even here foxes elicited a greater response as compared to owls. Generally, foraging tended to decrease with increasing moonlight, but this was not significant. We suggest that it is the temporal nature of cursorial vs. ambush predators in our system that drives such effects as opposed to their hunting mode, and that prey responses to temporal hotspots of risk need further examination. Generally, our results show that wild small-mammal prey species have variable responses to predation risk depending on the environmental context in which risk occurs.
Development and Implementation of In-House Pharmacogenomic Testing Program at a Major Academic Health System
Authors: Mroz Pawel , Michel Stephen , Allen Josiah D. , Meyer Tim , McGonagle Erin J. , Carpentier Rachel , Vecchia Alexandra , Schlichte Allyson , Bishop Jeffrey R. , Dunnenberger Henry M. , Yohe Sophia , Thyagarajan Bharat , Jacobson Pamala A. , Johnson Steven G.
Published: October 2021

Pharmacogenomics (PGx) studies how a person’s genes affect the response to medications and is quickly becoming a significant part of precision medicine. The clinical application of PGx principles has consistently been cited as a major opportunity for improving therapeutic outcomes. Several recent studies have demonstrated that most individuals (> 90%) harbor PGx variants that would be clinically actionable if prescribed a medication relevant to that gene. In multiple well-conducted studies, the results of PGx testing have been shown to guide therapy choice and dosing modifications which improve treatment efficacy and reduce the incidence of adverse drug reactions (ADRs). Although the value of PGx testing is evident, its successful implementation in a clinical setting presents a number of challenges to molecular diagnostic laboratories, healthcare systems, providers and patients. Different molecular methods can be applied to identify PGx variants and the design of the assay is therefore extremely important. Once the genotyping results are available the biggest technical challenge lies in turning this complex genetic information into phenotypes and actionable recommendations that a busy clinician can effectively utilize to provide better medical care, in a cost-effective, efficient and reliable manner. In this paper we describe a successful and highly collaborative implementation of the PGx testing program at the University of Minnesota and MHealth Fairview Molecular Diagnostic Laboratory and selected Pharmacies and Clinics. We offer detailed descriptions of the necessary components of the pharmacogenomic testing implementation, the development and technical validation of the in-house SNP based multiplex PCR based assay targeting 20 genes and 48 SNPs as well as a separate CYP2D6 copy number assay along with the process of PGx report design, results of the provider and pharmacists usability studies, and the development of the software tool for genotype-phenotype translation and gene-phenotype-drug CPIC-based recommendations. Finally, we outline the process of developing the clinical workflow that connects the providers with the PGx experts within the Molecular Diagnostic Laboratory and the Pharmacy.
Screening and Prognostic Analysis of Immune-Related Genes in Pancreatic Cancer
Authors: Wu Xin , Liang Yichao
Published: October 2021

Pancreatic cancer remains to have a high mortality, which is partly due to the lack of effective treatment strategies. In this study, genes with potential associations with immunophenotyping of pancreatic cancer were screened through bioinformatics analysis and the correlation between immune-related genes and the prognosis of pancreatic cancer patients was assessed. Firstly, differentially expressed immune genes were extracted from the pancreatic cancer-related datasets obtained for purposes of this study. The samples were processed by the “Consensus Cluster Plus” R package to determine the number of immune subtypes. Then, the pancreatic cancer immunophenotyping-related gene modules were determined. Differential analysis of immune gene modules was performed, and the function of genes related to pancreatic cancer immune subtypes was identified. The number of immune cells in the samples was calculated, followed by the differential expression analysis of immune cell numbers in each immune subtype of pancreatic cancer. The immune infiltration score was also estimated, and the correlation between the immune infiltration score and the patient prognosis with different immune subtypes was determined. Gene differences between each immune subtype were identified by differential expression analysis, and key immune genes affecting immunophenotyping were obtained. Following the analysis, 426 immune-related genes were identified to have potential involvement in the occurrence and development of pancreatic cancer, of which CD19 may be the most critical gene affecting the immunophenotyping of pancreatic cancer. CD19 played a significant role in the occurrence and development of IS2 and IS3 immune subtypes of pancreatic cancer through its action on B cells and T cells. Moreover, the expression of CD19 was increased in the collected pancreatic cancer tissues. Overall, our findings uncovered the critical role of CD19 in the prognosis of pancreatic cancer patients.
Heterogeneity of Axenfeld–Rieger Syndrome: Molecular and Clinical Findings in Chinese Patients
Authors: Zhang Youjia , Chen Xueli , Wang Li , Sun Xinghuai , Chen Yuhong
Published: October 2021

Axenfeld–Rieger Syndrome (ARS) is a rare disease with a wide spectrum of ocular and systemic manifestations. The genetic spectrum of Chinese patients with ARS and genotype-phenotype correlations have yet to be described. To explore the molecular and clinical features in Chinese patients, fifty-five patients clinically diagnosed with ARS from independent families were recruited. Complete ophthalmic examinations and next generation sequencing of anterior segment dysgenesis associated genes were performed in all patients, and segregation in available relatives was verified using Sanger sequencing. 18 FOXC1 variants, 13 PITX2 variants, and two gross deletions spanning FOXC1 were detected in 35 out of 55 (63.6%) patients. 12 FOXC1 variants, 9 PITX2 variants, and two gross deletions were novel. There was a wide range of variability and severity in ocular and systemic manifestations displayed in our patients. Patients with FOXC1 variants were diagnosed at a younger age and had a lower prevalence of systemic manifestations than patients harboring PITX2 variants and those without variants. To our best knowledge, this is the largest study of Chinese patients with ARS to date. Our findings expand the genetic spectrum of ARS and reveal genotype-phenotype correlations in Chinese patients with ARS. Genetic and clinical heterogeneity were present in our patients. Awareness of the extensive characterization may aid in the clinical management and genetic counseling of patients with this rare disease.
The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time
Authors: Rosendahl Huber Axel , Van Hoeck Arne , Van Boxtel Ruben
Published: October 2021

During life, the DNA of our cells is continuously exposed to external damaging processes. Despite the activity of various repair mechanisms, DNA damage eventually results in the accumulation of mutations in the genomes of our cells. Oncogenic mutations are at the root of carcinogenesis, and carcinogenic agents are often highly mutagenic. Over the past decade, whole genome sequencing data of healthy and tumor tissues have revealed how cells in our body gradually accumulate mutations because of exposure to various mutagenic processes. Dissection of mutation profiles based on the type and context specificities of the altered bases has revealed a variety of signatures that reflect past exposure to environmental mutagens, ranging from chemotherapeutic drugs to genotoxic gut bacteria. In this review, we discuss the latest knowledge on somatic mutation accumulation in human cells, and how environmental mutagenic factors further shape the mutation landscapes of tissues. In addition, not all carcinogenic agents induce mutations, which may point to alternative tumor-promoting mechanisms, such as altered clonal selection dynamics. In short, we provide an overview of how environmental factors induce mutations in the DNA of our healthy cells and how this contributes to carcinogenesis. A better understanding of how environmental mutagens shape the genomes of our cells can help to identify potential preventable causes of cancer.
Construction of an Immune Cell Infiltration Score to Evaluate the Prognosis and Therapeutic Efficacy of Ovarian Cancer Patients
Authors: Liu Jinhui , Wang Yichun , Yuan Shuning , Wei Junting , Bai Jianling
Published: October 2021

Background

Ovarian cancer (OC) is an immunogenetic disease that contains tumor-infiltrating lymphocytes (TILs), and immunotherapy has become a novel treatment for OC. With the development of next-generation sequencing (NGS), profiles of gene expression and comprehensive landscape of immune cells can be applied to predict clinical outcome and response to immunotherapy.

Methods

We obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and applied two computational algorithms (CIBERSORT and ESTIMATE) for consensus clustering of immune cells. Patients were divided into two subtypes using immune cell infiltration (ICI) levels. Then, differentially expressed genes (DEGs) associated with immune cell infiltration (ICI) level were identified. We also constructed ICI score after principle-component analysis (PCA) for dimension reduction.

Results

Patients in ICI cluster B had better survival than those in ICI cluster A. After construction of ICI score, we found that high ICI score had better clinical OS and significantly higher tumor mutation burden (TMB). According to the expression of immune checkpoints, the results showed that patients in high ICI group showed high expression of CTLA4, PD1, PD-L1, and PD-L2, which implies that they might benefit from immunotherapy. Besides, patients in high ICI group showed higher sensitivity to two first-line chemotherapy drugs (Paclitaxel and Cisplatin).

Conclusion

ICI score is an effective prognosis-related biomarker for OC and can provide valuable information on the potential response to immunotherapy.
CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques
Authors: Sarkar Sanghita , Spencer David A. , Barnette Philip , Pandey Shilpi , Sutton William F. , Basu Madhubanti , Burch Reuben E. , Cleveland John D. , Rosenberg Alexander F. , Rangel-Moreno Javier , Keefer Michael C. , Hessell Ann J. , Haigwood Nancy L. , Kobie James J.
Published: October 2021

Induction of broadly neutralizing antibodies (bNAbs) is a major goal for HIV vaccine development. HIV envelope glycoprotein (Env)-specific bNAbs isolated from HIV-infected individuals exhibit substantial somatic hypermutation and correlate with T follicular helper (Tfh) responses. Using the VC10014 DNA-protein co-immunization vaccine platform consisting of gp160 plasmids and gp140 trimeric proteins derived from an HIV-1 infected subject that developed bNAbs, we determined the characteristics of the Env-specific humoral response in vaccinated rhesus macaques in the context of CD4+ T cell depletion. Unexpectedly, both CD4+ depleted and non-depleted animals developed comparable Tier 1 and 2 heterologous HIV-1 neutralizing plasma antibody titers. There was no deficit in protection from SHIV challenge, no diminution of titers of HIV Env-specific cross-clade binding antibodies, antibody dependent cellular phagocytosis, or antibody-dependent complement deposition in the CD4+ depleted animals. These collective results suggest that in the presence of diminished CD4+ T cell help, HIV neutralizing antibodies were still generated, which may have implications for developing effective HIV vaccine strategies.
Stable Isotope Tracer Addition Reveals the Trophic Status of Benthic Infauna at an Intertidal Area Adjacent to a Seagrass Bed
Authors: Xu Wenzhe , Dang Yongxin , Cheung Siu Gin , Zhang Zhinan , Sun Jun , Teng Ankang , Shin Paul K. S.
Published: October 2021

Stable isotope tracer addition can enhance the isotopic differences of primary producers for a wider food-web resolution than the use of natural abundance stable isotopes (NASIs) alone, particularly in ecosystems where primary producers have similar NASI values. To investigate the food sources and the trophic status of benthic infauna in an intertidal area near a Halophila minor seagrass bed within inner Tai Tam Bay, Hong Kong, China, a 15N addition experiment was conducted, and the results were compared with those from NASI data. Only benthic microalgae (BMA) were labeled by applying 15N-enriched NH4Cl to the sediment daily for the first 7 days during a 21-day study. In contrast to the NASI results, Bayesian mixing models based on the isotope tracer experiment suggested a larger dietary contribution of BMA for nematode Daptonema sp. and copepods, whereas a higher reliance on phytoplankton and seagrass detritus was noted for polychaete Neanthes sp. However, both NASI and isotope tracer addition demonstrated that seagrass detritus was a major food source for nematode Spilophorella sp. The present isotope tracer experiment also revealed a contrasting result of the relatively lower contribution of meiofauna in the diets of carnivores/omnivores as compared to the results of NASIs. This finding suggested that the isotope values in these consumers may have not reached an equilibrium with the added isotope in the study period. Thus, there is a need for applying NASI coupled with isotope tracer addition in the investigation of ecosystems in which primary producers have similar isotope values, especially in ecosystems with lower tissue turnover rates, in order for a more accurate determination of dietary contribution and trophic status of consumers in the food-web study.
Phylogeography and Taxonomic Revision of the Pen Shell Atrina pectinata Species Complex in the South China Sea
Authors: Xue Dong-Xiu , Wang Hai-Yan , Zhang Tao
Published: October 2021

Phylogeographic studies contribute to addressing questions regarding the geographic patterns and evolutionary scenarios within and among species and also shed light on the taxonomic status of widely distributed species complexes. The pen shell Atrina pectinata species complex is a widely distributed and economically important bivalve in the northwestern Pacific. Previous phylogeographic studies have identified four genetically distinct cryptic species within the A. pectinata species complex along the coast of China, of which three cryptic species were distributed in the South China Sea. However, less attention has been given to their identification and delimitation. Herein, we report the phylogeography and taxonomic revision of the A. pectinata species complex in the South China Sea using DNA sequence data from mitochondrial cytochrome oxidase I (COI) and 16S ribosomal RNA (16S rRNA), and nuclear 28S ribosomal RNA (28S rRNA) gene markers. Using a combination of phylogenetic and DNA-based species delimitation analysis methods, we found strong support for four genetically valid species in the A. pectinata species complex and defined them as A. japonica, A. lischkeana, Atrina sp., and A. pectinata based on our results as well as on previous morphological and genetic studies. A demographic historical analysis showed that all three species in the South China Sea had populations that were relatively stable over time and then subjected to sudden expansion during the late Pleistocene (60,000–90,000 years ago). These results provide new insights into the systematics and evolution of the A. pectinata species complex and have important conservation and management implications.
Impact of the COVID-19 Pandemic on Survival in the Patients With the Intra-Abdominal Infections
Authors: Gálvez-Benítez Lydia , Rodríguez-Villodres Ángel , Álvarez-Marín Rocío , Jiménez-Rodríguez Rosa , Lepe-Jiménez José Antonio , Pachón Jerónimo , Smani Younes
Published: October 2021

Objective: To analyze the availability and access to the hospital for the patients with intra-abdominal infections (IAIs) by Escherichia coli (E. coli) as a result of the coronavirus disease 2019 (COVID-19) pandemic and the impact of these changes in the diagnosis and their effects on the death of these patients.

Methods: Two prospective observational cohorts of the patients with IAI by E. coli were conducted in 2016 (the pre-COVID-19, n = 108) and in 2020 (during the COVID-19, n = 96) at the University Hospital of Seville, Spain. The demographic and clinical variables of the patients were collected and analyzed. The patients were followed-up for 120 days, until the hospital discharge or death. The bivariate and multivariate analyses were performed.

Results: Both the cohorts were homogeneous according to age, sex, emergency surgery cause, immunosuppression, neutropenia, acquisition type, and previous intervention. The patients attended during the COVID-19 had significantly higher Charlson comorbidity index and the more McCabe score, required more emergency surgery, had more severe infections with the higher rates of septic shock and sepsis, and the presence of additional care support such as a nasogastric tube. They were diagnosed later; the time intervals between the symptoms onset (SO) to the first medical contact or surgical intervention (SI) and between the first medical contact to the admission or SI were significantly higher. The death rates during the COVID-19 and the pre-COVID-19 were 16.7 and 6.5%, respectively (p = 0.02). Finally, the multivariate analysis in both the cohorts together identified the patients diagnosed during the COVID-19, the longer period from SO to SI, septic shock, and the Charlson comorbidity index as the independent factors associated with death.

Conclusion: This study showed the impact of the COVID-19 pandemic on the clinical outcome and death due to IAI with an extension of the time between SO and SI.
Voxel-Based Analysis of [18F]-FDG Brain PET in Rats Using Data-Driven Normalization
Authors: Proesmans Silke , Raedt Robrecht , Germonpré Charlotte , Christiaen Emma , Descamps Benedicte , Boon Paul , De Herdt Veerle , Vanhove Christian
Published: October 2021

Introduction: [18F]-FDG PET is a widely used imaging modality that visualizes cellular glucose uptake and provides functional information on the metabolic state of different tissues in vivo. Various quantification methods can be used to evaluate glucose metabolism in the brain, including the cerebral metabolic rate of glucose (CMRglc) and standard uptake values (SUVs). Especially in the brain, these (semi-)quantitative measures can be affected by several physiological factors, such as blood glucose level, age, gender, and stress. Next to this inter- and intra-subject variability, the use of different PET acquisition protocols across studies has created a need for the standardization and harmonization of brain PET evaluation. In this study we present a framework for statistical voxel-based analysis of glucose uptake in the rat brain using histogram-based intensity normalization.

Methods: [18F]-FDG PET images of 28 normal rat brains were coregistered and voxel-wisely averaged. Ratio images were generated by voxel-wisely dividing each of these images with the group average. The most prevalent value in the ratio image was used as normalization factor. The normalized PET images were voxel-wisely averaged to generate a normal rat brain atlas. The variability of voxel intensities across the normalized PET images was compared to images that were either normalized by whole brain normalization, or not normalized.

To illustrate the added value of this normal rat brain atlas, 9 animals with a striatal hemorrhagic lesion and 9 control animals were intravenously injected with [18F]-FDG and the PET images of these animals were voxel-wisely compared to the normal atlas by group- and individual analyses.

Results: The average coefficient of variation of the voxel intensities in the brain across normal [18F]-FDG PET images was 6.7% for the histogram-based normalized images, 11.6% for whole brain normalized images, and 31.2% when no normalization was applied. Statistical voxel-based analysis, using the normal template, indicated regions of significantly decreased glucose uptake at the site of the ICH lesion in the ICH animals, but not in control animals.

Conclusion: In summary, histogram-based intensity normalization of [18F]-FDG uptake in the brain is a suitable data-driven approach for standardized voxel-based comparison of brain PET images.
Diagnostic Efficacy and Decision-Making Role of Preoperative Endoscopic Ultrasonography in Early Gastric Cancer
Authors: Li Xiao , Zhu Min , Wang Yongjun , Niu Yinglin , Ji Ming , Li Peng , Zhang Shutian
Published: October 2021

Objectives: Endoscopic ultrasonography (EUS) is the most commonly used method for T staging of early gastric cancer (EGC). However, the studies pertaining to EUS for staging EGC reported widely varied sensitivities and specificities. This study aimed to estimate the overall diagnostic accuracy of EUS for staging the depth of EGCs and to explore the influential factors.

Methods: We retrospectively reviewed data from 208 consecutive patients with EGC, and all patients underwent EUS for estimating tumor invasion depth, followed by either curative surgery or endoscopic submucosal dissection (ESD). The diagnostic accuracy of EUS was evaluated by comparing the final histologic results of resected specimens. The correlation between accuracy of EUS and characteristics of EGC lesion was analyzed.

Results: A total of 211 EGC lesions in 208 patients were included. The overall diagnostic accuracy of EUS in assessing the tumor invasion depth of EGC was 55.9%. Multivariate analysis showed that submucosal invasion (OR 2.615; 95% CI 1.203–5.684, P = 0.015) was independently associated with misdiagnosis of the depth of EGC and 0-III type lesions (OR 31.495; 95% CI 2.083–476.256, P = 0.013) were an independent risk factor for over-diagnosis of invasion depth by EUS. However, EUS was only suitable for lesions within absolute indications for endoscopic resection.

Conclusions: The overall accuracy of EUS in diagnosing invasion depth of EGC was relatively low. Thus, EUS is not necessary routinely for determining the therapeutic strategy for EGC.
Effect of Divergent Feeding Regimes During Early Life on the Rumen Microbiota in Calves
Authors: Cristobal-Carballo Omar , McCoard Sue A. , Cookson Adrian L. , Laven Richard A. , Ganesh Siva , Lewis Sarah J. , Muetzel Stefan
Published: October 2021

The objective of this study was to determine whether divergent feeding regimes during the first 41 weeks of the life of a calf are associated with long-term changes in the rumen microbiota and the associated fermentation end-products. Twenty-four calves (9 ± 5 days of age) were arranged in a 2 × 2 factorial design with two divergent treatments across three dietary phases. In phase 1 (P01), calves were offered a low-milk volume/concentrate starter diet with early weaning (CO) or high-milk volume/pasture diet and late weaning (FO). In phase 2 (P02), calves from both groups were randomly allocated to either high-quality (HQ) or low-quality (LQ) pasture grazing groups. In phase 3 (P03), calves were randomly allocated to one of two grazing groups and offered the same pasture-only diet. During each dietary phase, methane (CH4) and hydrogen (H2) emissions and dry matter intake (DMI) were measured in respiration chambers, and rumen samples for the evaluation of microbiota and short-chain fatty acid (SCFA) characterizations were collected. In P01, CO calves had a higher solid feed intake but a lower CH4yield (yCH4) and acetate:propionate ratio (A:P) compared with FO calves. The ruminal bacterial community had lower proportions of cellulolytic bacteria in CO than FO calves. The archaeal community was dominated byMethanobrevibacter boviskoreaniin CO calves and byMbb. gottschalkiiin FO calves. These differences, however, did not persist into P02. Calves offered HQ pastures had greater DMI and lower A:P ratio than calves offered LQ pastures, but yCH4was similar between groups. The cellulolytic bacteria had lower proportions in HQ than LQ calves. In all groups, the archaeal community was dominated byMbb. gottschalkii. No treatment interactions were observed in P02. In P03, all calves had similar DMI, CH4and H2emissions, SCFA proportions, and microbial compositions, and no interactions with previous treatments were observed. These results indicate that the rumen microbiota and associated fermentation end-products are driven by the diet consumed at the time of sampling and that previous dietary interventions do not lead to a detectable long-term microbial imprint or changes in rumen function.
Putative MicroRNA-mRNA Networks Upon Mdfi Overexpression in C2C12 Cell Differentiation and Muscle Fiber Type Transformation
Authors: Huang Bo , Jiao Yiren , Zhu Yifan , Ning Zuocheng , Ye Zijian , Li Qing X. , Hu Chingyuan , Wang Chong
Published: October 2021

Mdfi, an inhibitor of myogenic regulatory factors, is involved in myoblast myogenic development and muscle fiber type transformation. However, the regulatory network of Mdfi regulating myoblasts has not been revealed. In this study, we performed microRNAs (miRNAs)-seq on Mdfi overexpression (Mdfi-OE) and wild-type (WT) C2C12 cells to establish the regulatory networks. Comparative analyses of Mdfi-OE vs. WT identified 66 differentially expressed miRNAs (DEMs). Enrichment analysis of the target genes suggested that DEMs may be involved in myoblast differentiation and muscle fiber type transformation through MAPK, Wnt, PI3K-Akt, mTOR, and calcium signaling pathways. miRNA-mRNA interaction networks were suggested along with ten hub miRNAs and five hub genes. We also identified eight hub miRNAs and eleven hub genes in the networks of muscle fiber type transformation. Hub miRNAs mainly play key regulatory roles in muscle fiber type transformation through the PI3K-Akt, MAPK, cAMP, and calcium signaling pathways. Particularly, the three hub miRNAs (miR-335-3p, miR-494-3p, and miR-709) may be involved in both myogenic differentiation and muscle fiber type transformation. These hub miRNAs and genes might serve as candidate biomarkers for the treatment of muscle- and metabolic-related diseases.
Strategies for RNA Resonance Assignment by 13C/15N- and 1H-Detected Solid-State NMR Spectroscopy
Authors: Aguion Philipp Innig , Marchanka Alexander
Published: October 2021

Magic angle spinning (MAS) solid-state NMR (ssNMR) is an established tool that can be applied to non-soluble or non-crystalline biomolecules of any size or complexity. The ssNMR method advances rapidly due to technical improvements and the development of advanced isotope labeling schemes. While ssNMR has shown significant progress in structural studies of proteins, the number of RNA studies remains limited due to ssNMR methodology that is still underdeveloped. Resonance assignment is the most critical and limiting step in the structure determination protocol that defines the feasibility of NMR studies. In this review, we summarize the recent progress in RNA resonance assignment methods and approaches for secondary structure determination by ssNMR. We critically discuss advantages and limitations of conventional 13C- and 15N-detected experiments and novel 1H-detected methods, identify optimal regimes for RNA studies by ssNMR, and provide our view on future ssNMR studies of RNA in large RNP complexes.
Aberrant Methylation and Immune Microenvironment Are Associated With Overexpressed Fibronectin 1: A Diagnostic and Prognostic Target in Head and Neck Squamous Cell Carcinoma
Authors: Sheng Surui , Guo Bing , Wang Zhentao , Zhang Zhihua , Zhou Jieyu , Huo Zirong
Published: October 2021

Background: Fibronectin 1 (FN1) is involved in cell adhesion and migration processes such as metastasis, wound healing, embryogenesis, blood coagulation, and host defense. However, the role of FN1 in the diagnosis and prognosis of head and neck squamous cell carcinoma (HNSCC) is far from understood.

Methods: FN1 expression profiles and clinical parameters from multiple HNSCC datasets were applied to evaluate the association between FN1 expression and HNSCC survival. We also identified FN1 expression in the mRNA and protein levels in 20 pairs of clinical samples by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Receiver operator characteristic (ROC) analysis was used to demonstrate the potential diagnostic value of FN1 in HNSCC. Aberrant methylation PPI networks were established using multiple bioinformatic tools based on TCGA database. The immune microenvironment and levels of immune checkpoints were investigated between groups with high and low FN1 expression.

Results: FN1 was significantly upregulated in HNSCC compared with para-carcinoma tissues on the basis of TCGA database and our clinical samples. Univariate and multivariate Cox regression analysis revealed that FN1 could be an independent indicator for prognosis of HNSCC. GO enrichment and KEGG pathway analysis demonstrated that cell adhesion, focal adhesion, and the PI3K-Akt signaling pathway might be involved in the potential mechanisms of FN1’s prognostic performance in HNSCC. Methylation of FN1 was also higher and closely associated with poorer survival in HNSCC. In addition, FN1 expression was positively correlated with three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B). Furthermore, FN1 was positively associated with CD4+ T cells, endothelial cells, macrophages, and NK cells and negatively correlated with CD8+ T cells

Conclusion: FN1 might be an independent prognostic biomarker for HNSCC patients. Hypermethylation, the aberrant proportions of immune cells, and the PI3K/Akt signaling pathway might be involved in the mechanism of FN1’s oncogene role in HNSCC.
Aggregation-Prone Structural Ensembles of Transthyretin Collected With Regression Analysis for NMR Chemical Shift
Authors: Yang Wonjin , Kim Beom Soo , Muniyappan Srinivasan , Lee Young-Ho , Kim Jin Hae , Yu Wookyung
Published: October 2021

Monomer dissociation and subsequent misfolding of the transthyretin (TTR) is one of the most critical causative factors of TTR amyloidosis. TTR amyloidosis causes several human diseases, such as senile systemic amyloidosis and familial amyloid cardiomyopathy/polyneuropathy; therefore, it is important to understand the molecular details of the structural deformation and aggregation mechanisms of TTR. However, such molecular characteristics are still elusive because of the complicated structural heterogeneity of TTR and its highly sensitive nature to various environmental factors. Several nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) studies of TTR variants have recently reported evidence of transient aggregation-prone structural states of TTR. According to these studies, the stability of the DAGH β-sheet, one of the two main β-sheets in TTR, is a crucial determinant of the TTR amyloidosis mechanism. In addition, its conformational perturbation and possible involvement of nearby structural motifs facilitates TTR aggregation. This study proposes aggregation-prone structural ensembles of TTR obtained by MD simulation with enhanced sampling and a multiple linear regression approach. This method provides plausible structural models that are composed of ensemble structures consistent with NMR chemical shift data. This study validated the ensemble models with experimental data obtained from circular dichroism (CD) spectroscopy and NMR order parameter analysis. In addition, our results suggest that the structural deformation of the DAGH β-sheet and the AB loop regions may correlate with the manifestation of the aggregation-prone conformational states of TTR. In summary, our method employing MD techniques to extend the structural ensembles from NMR experimental data analysis may provide new opportunities to investigate various transient yet important structural states of amyloidogenic proteins.
Personalized Motor-Cognitive Exergame Training in Chronic Stroke Patients—A Feasibility Study
Authors: Huber Simone K. , Held Jeremia P. O. , de Bruin Eling D. , Knols Ruud H.
Published: October 2021

Purpose: Exergame training may be beneficial for improving long-term outcome in stroke patients. Personalized training prescription applying progression rules, is missing. We adapted a theory-based taxonomy for a rehabilitation approach using user-centered exergames. The aims were primarily to investigate the feasibility of this rehabilitation approach, and secondarily to evaluate its performance of personalizing training progression, as well as explore the effects on secondary outcomes.

Methods: Chronic stroke patients (≥ 18 years) were included, who were able to walk 10 meters and stand for 3 min. The rehabilitation approach was administered twice per week for 8 weeks. As primary outcome, feasibility was evaluated by comparing achieved rates of inclusion, adherence, compliance, attrition, motivation, and satisfaction to pre-defined thresholds for acceptance. Secondary outcomes were (1) perceived motor and cognitive task difficulty throughout the intervention; (2) measures collected during baseline and post-measurements—a gait analysis, the Timed-up-and-go test (TUG), several cognitive tests assessing attentional, executive, and visuospatial functions.

Results: Thirteen patients [median: 68.0 (IQR: 49.5–73.5) years, median: 34.5 (IQR: 12.25–90.75) months post-stroke] were included, of whom ten completed the study. Rates for inclusion (57%), adherence (95%), compliance (99%), motivation (77%), and satisfaction (74%) were acceptable, however, the attrition rate was high (23%). The perceived motor and cognitive task difficulty predominantly moved below the targeted range. We found a significant change in the TUG (p = 0.05, r = 0.46) and medium-to-large effect sizes (p > 0.05) for swing time of the affected leg, the asymmetry index, time needed for the Trail-making test (TMT) A and accuracy for the TMT B and the Mental Rotation Test (MRT; 0.26 ≤ r ≤ 0.46).

Discussion: The intervention was feasible with minor modifications necessary, which warrants a larger trial investigating the effects of the rehabilitation approach following the adapted taxonomy on mobility, gait and cognitive functions. Two main limitations of the rehabilitation approach were; (1) the taxonomy decoupled motor and cognitive progression, which may be improper as motor and cognitive learning is coupled; (2) separate subjective ratings were used to guide the progression. Future studies should develop an instrument to objectively assess motor-cognitive task difficulty for monitoring the progression of an exergame-based training.
Interpreting the Entire Connectivity of Individual Neurons in Micropatterned Neural Culture With an Integrated Connectome Analyzer of a Neuronal Network (iCANN)
Authors: Kim June Hoan , Ryu Jae Ryun , Lee Boram , Chae Uikyu , Son Jong Wan , Park Bae Ho , Cho Il-Joo , Sun Woong
Published: October 2021

The function of a neural circuit can be determined by the following: (1) characteristics of individual neurons composing the circuit, (2) their distinct connection structure, and (3) their neural circuit activity. However, prior research on correlations between these three factors revealed many limitations. In particular, profiling and modeling of the connectivity of complex neural circuits at the cellular level are highly challenging. To reduce the burden of the analysis, we suggest a new approach with simplification of the neural connection in an array of honeycomb patterns on 2D, using a microcontact printing technique. Through a series of guided neuronal growths in defined honeycomb patterns, a simplified neuronal circuit was achieved. Our approach allowed us to obtain the whole network connectivity at cellular resolution using a combination of stochastic multicolor labeling via viral transfection. Therefore, we were able to identify several types of hub neurons with distinct connectivity features. We also compared the structural differences between different circuits using three-node motif analysis. This new model system, iCANN, is the first experimental model of neural computation at the cellular level, providing neuronal circuit structures for the study of the relationship between anatomical structure and function of the neuronal network.
The Relationship of APOE ε4, Race, and Sex on the Age of Onset and Risk of Dementia
Authors: Powell Danielle S. , Kuo Pei-Lun , Qureshi Riaz , Coburn Sally B. , Knopman David S. , Palta Priya , Gottesman Rebecca , Griswold Michael , Albert Marilyn , Deal Jennifer A. , Gross Alden L.
Published: October 2021

Objective: To investigate whether APOE ε4 genotype—an established risk factor for dementia—is associated with earlier age at diagnosis in addition to increased risk overall and in secondary analysis by race and sex.

Methods: We followed up 13,782 dementia-free individuals (n = 10,137 White, n = 3,645 Black, baseline age 60–66 years) in the Atherosclerosis Risk in Communities study for up to 30 years. Dementia was operationalized using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. We used a mixture of generalized gamma distributions to simultaneously estimate time to dementia, time to dementia-free death, and the proportion of individuals with dementia, by APOE ε4 status (≥1 vs. no alleles).

Results: Median age of dementia onset among APOE ε4 carriers was 81.7 (Blacks) and 83.3 years (Whites) compared with 82.6 (Blacks) and 85.7 years (Whites) in non-APOE ε4 carriers (p > 0.05 Blacks; p < 0.01 Whites). Age of dementia diagnosis did not differ by sex in ε4 carriers, but among non-carriers, average age was earlier in males than females regardless of race. APOE ε4 carriers had on average a higher proportion of diagnoses; results did not differ by race or sex.

Conclusions:APOE ε4 carrier status is associated with earlier age of dementia diagnosis with differences across race and sex. These findings clarify the causal role of APOE in dementia etiology, which could help better identify at-risk subgroups and may help facilitate better research trial recruitment and design.
The Efficacy and Tolerability of Selective Serotonin Reuptake Inhibitors for Motor Recovery in Non-depressed Patients After Acute Stroke: A Meta-Analysis
Authors: Su Ning , Wen Changming , Guo Shiqian , Yu Yang , Wang Chenglin
Published: October 2021

Objective: To explore the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) for motor recovery in non-depressed patients after acute stroke.

Methods: According to the predefined retrieval strategy, multiple electronic databases were searched for randomized controlled trials (RCTs) that met the inclusion criteria. The primary efficacy outcome was measured by Fugl-Meyer Motor Scale (FMMS) score and the indicators of tolerability included withdrawal rate and the incidence of adverse events (AEs).

Results: 10RCTs were included, the pooled analyses showed patients who received fluoxetine (endpoint: MD = 21.17, 95% CI 14.13–28.21, P < 0.00001; mean change: MD = 16.27, 95% CI 10.05–22.50, P < 0.00001) and citalopram (endpoint: MD = 22.93, 95% CI 11.13–34.73, P = 0.0001; mean change: MD = 24.06, 95% CI 10.47–37.65, P = 0.0005) experienced greater improvement in FMMS score. There was no evident difference in total withdrawal rate (fluoxetine: OR = 1.11, 95% CI 0.90–1.27, P = 1.38; citalopram: OR = 0.94, 95% CI 0.69–1.28, P = 0.71; escitalopram: OR = 0.87, 95% CI 0.58–1.28, P = 0.47) between two groups. Besides, the incidence of hyponatremia (OR = 2.01, 95% CI 1.16–3.50, P = 0.01), seizure (OR = 1.46, 95% CI 1.03–2.08, P = 0.04) and fracture (OR = 2.34, 95% CI 1.61–3.40, P < 0.00001) in the fluoxetine group was higher than in the placebo group.

Conclusions: Fluoxetine and citalopram can promote motor recovery in non-depressed patients with acute stroke, but it is necessary to pay attention to the possible AEs of fluoxetine, such as hyponatremia, seizure and fracture.

Systematic Review Registration: PROSPERO, identifier [CRD42021227452].
Metabolic and Neural Mechanisms Underlying the Associations Between Gut Bacteroides and Cognition: A Large-Scale Functional Network Connectivity Study
Authors: Zhang Shujun , Qian Yinfeng , Li Qian , Xu Xiaotao , Li Xueying , Wang Chunli , Cai Huanhuan , Zhu Jiajia , Yu Yongqiang
Published: October 2021

There is a proof-of-concept that microbial metabolites provide a molecular connection between the gut and the brain. Extensive research has established a link between gut Bacteroides and human cognition, yet the metabolic and neural mechanisms underlying this association remain largely unknown. Here, we collected fecal samples, resting-state functional MRI, and cognitive data from a large and homogeneous sample of 157 healthy young adults. 16S rRNA gene sequencing was conducted with abundances of Bacteroides and metabolic pathways quantified by species annotation and functional prediction analyses, respectively. Large-scale intra- and internetwork functional connectivity was measured using independent component analysis. Results showed that gut Bacteroides were related to multiple metabolic pathways, which in turn were associated with widespread functional network connectivity. Furthermore, functional network connectivity mediated the associations between some Bacteroides-related metabolic pathways and cognition. Remarkably, arginine and proline metabolism, phenylalanine metabolism, and biosynthesis of unsaturated fatty acids act as the key metabolic pathways that are most contributive, and the executive control and sensorimotor systems contribute most strongly at the neural level. Our findings suggest complex poly-pathway and poly-network processes linking Bacteroides to cognition, more generally yielding a novel conceptualization of targeting gut Bacteroides as an intervention strategy for individuals with cognitive impairment.
A Quantitative Data-Driven Analysis Framework for Resting-State Functional Magnetic Resonance Imaging: A Study of the Impact of Adult Age
Authors: Li Xia , Fischer Håkan , Manzouri Amirhossein , Månsson Kristoffer N. T. , Li Tie-Qiang
Published: October 2021

The objective of this study is to introduce a new quantitative data-driven analysis (QDA) framework for the analysis of resting-state fMRI (R-fMRI) and use it to investigate the effect of adult age on resting-state functional connectivity (RFC). Whole-brain R-fMRI measurements were conducted on a 3T clinical MRI scanner in 227 healthy adult volunteers (N = 227, aged 18–76 years old, male/female = 99/128). With the proposed QDA framework we derived two types of voxel-wise RFC metrics: the connectivity strength index and connectivity density index utilizing the convolutions of the cross-correlation histogram with different kernels. Furthermore, we assessed the negative and positive portions of these metrics separately. With the QDA framework we found age-related declines of RFC metrics in the superior and middle frontal gyri, posterior cingulate cortex (PCC), right insula and inferior parietal lobule of the default mode network (DMN), which resembles previously reported results using other types of RFC data processing methods. Importantly, our new findings complement previously undocumented results in the following aspects: (1) the PCC and right insula are anti-correlated and tend to manifest simultaneously declines of both the negative and positive connectivity strength with subjects’ age; (2) separate assessment of the negative and positive RFC metrics provides enhanced sensitivity to the aging effect; and (3) the sensorimotor network depicts enhanced negative connectivity strength with the adult age. The proposed QDA framework can produce threshold-free and voxel-wise RFC metrics from R-fMRI data. The detected adult age effect is largely consistent with previously reported studies using different R-fMRI analysis approaches. Moreover, the separate assessment of the negative and positive contributions to the RFC metrics can enhance the RFC sensitivity and clarify some of the mixed results in the literature regarding to the DMN and sensorimotor network involvement in adult aging.