bluuebunny/crossref_metadata_2025 huggingface dataset:
Depletion of T cells via Inducible Caspase 9 Increases Safety of Adoptive T-Cell Therapy Against Chronic Hepatitis B
Authors: Klopp Alexandre , Schreiber Sophia , Kosinska Anna D. , Pulé Martin , Protzer Ulrike , Wisskirchen Karin
Published: October 2021

T-cell therapy with T cells that are re-directed to hepatitis B virus (HBV)-infected cells by virus-specific receptors is a promising therapeutic approach for treatment of chronic hepatitis B and HBV-associated cancer. Due to the high number of target cells, however, side effects such as cytokine release syndrome or hepatotoxicity may limit safety. A safeguard mechanism, which allows depletion of transferred T cells on demand, would thus be an interesting means to increase confidence in this approach. In this study, T cells were generated by retroviral transduction to express either an HBV-specific chimeric antigen receptor (S-CAR) or T-cell receptor (TCR), and in addition either inducible caspase 9 (iC9) or herpes simplex virus thymidine kinase (HSV-TK) as a safety switch. Real-time cytotoxicity assays using HBV-replicating hepatoma cells as targets revealed that activation of both safety switches stopped cytotoxicity of S-CAR- or TCR-transduced T cells within less than one hour. In vivo, induction of iC9 led to a strong and rapid reduction of transferred S-CAR T cells adoptively transferred into AAV-HBV-infected immune incompetent mice. One to six hours after injection of the iC9 dimerizer, over 90% reduction of S-CAR T cells in the blood and the spleen and of over 99% in the liver was observed, thereby limiting hepatotoxicity and stopping cytokine secretion. Simultaneously, however, the antiviral effect of S-CAR T cells was diminished because remaining S-CAR T cells were mostly non-functional and could not be restimulated with HBsAg. A second induction of iC9 was only able to deplete T cells in the liver. In conclusion, T cells co-expressing iC9 and HBV-specific receptors efficiently recognize and kill HBV-replicating cells. Induction of T-cell death via iC9 proved to be an efficient means to deplete transferred T cells in vitro and in vivo containing unwanted hepatotoxicity.
Low GNG12 Expression Predicts Adverse Outcomes: A Potential Therapeutic Target for Osteosarcoma
Authors: Yuan Jinghong , Yuan Zhao , Ye Aifang , Wu Tianlong , Jia Jingyu , Guo Jia , Zhang Jian , Li Tao , Cheng Xigao
Published: October 2021

Background

G protein subunit gamma 12 (GNG12) is observed in some types of cancer, but its role in osteosarcoma is unknown. This study hypothesized that GNG12 may be a potential biomarker and therapeutic target. We aimed to identify an association between GNG12 and osteosarcoma based on the Gene Expression Omnibus and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases.

Methods

Osteosarcoma samples in GSE42352 and TARGET database were selected as the test cohorts. As the external validation cohort, 78 osteosarcoma specimens from The Second Affiliated Hospital of Nanchang University were collected. Patients with osteosarcoma were divided into high and low GNG12 mRNA-expression groups; differentially expressed genes were identified as GNG12-related genes. The biological function of GNG12 was annotated using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and immune infiltration analysis. Gene expression correlation analysis and competing endogenous RNA regulatory network construction were used to determine potential biological regulatory relationships of GNG12. Overall survival, Kaplan–Meier analysis, and log-rank tests were calculated to determine GNG12 reliability in predicting survival prognosis.

Results

GNG12 expression decreased in osteosarcoma samples. GNG12 was a highly effective biomarker for osteosarcoma [area under the receiver operating characteristic (ROC) curve (AUC) = 0.920], and the results of our Kaplan–Meier analysis indicated that overall survival and progression-free survival differed significantly between low and high GNG-expression group (p < 0.05). Functional analyses indicated that GNG12 may promote osteosarcoma through regulating the endoplasmic reticulum. Expression correlation analysis and competing endogenous RNA network construction showed that HOTTIP/miR-27a-3p may regulate GNG12 expression. Furthermore, the subunit suppresses adaptive immunity via inhibiting M1 and M2 macrophage infiltration. GNG12 was inhibited in metastatic osteosarcoma compared with non-metastatic osteosarcoma, and its expression predicted survival of patients (1, 3, and 5-year AUCs were 0.961, 0.826, and 0.808, respectively).

Conclusion

This study identified GNG12 as a potential biomarker for osteosarcoma prognosis, highlighting its potential as an immunotherapy target.
Modeling Oyster Reef Restoration: Larval Supply and Reef Geometry Jointly Determine Population Resilience and Performance
Authors: Lipcius Romuald N. , Zhang Yi , Zhou Jingyi , Shaw Leah B. , Shi Junping
Published: October 2021

Restoration of native oyster (Crassostrea virginica) populations in Chesapeake Bay shows great promise after three decades of failed attempts. Population models used to inform oyster restoration had integrated reef habitat quality, demonstrating that reef height determines oyster population persistence and resilience. Larval recruitment drives population dynamics of marine species, yet its impact with reef height and sediment deposition upon reef restoration is unknown. To assess the influence of reef height, sediment deposition and larval supply, we adapted a single-stage population model to incorporate stage structure using a system of four differential equations modeling change in juvenile density (J), and changes in volume of adults (A), oyster shell reef (R), and sediment (S) on an oyster reef. The JARS model was parameterized with empirical data from field experiments. Larval supply included larvae from the natal population and from outside populations. The stage-structured model possessed multiple non-negative equilibria (i.e., alternative stable states). Different initial conditions (e.g., oyster shell reef height) resulted in different final states. The main novel findings were that the critical reef height for population persistence and resilience was jointly dependent on sediment input and larval supply. A critical minimum larval supply was necessary for a reef to persist, even when initial sediment deposition was zero. As larval supply increased, the initial reef height needed for reef persistence was lowered, and oyster reef resilience was enhanced. A restoration oyster reef with higher larval influx could recover from more severe disturbances than a reef with lower larval influx. To prevent local extinction and assure a positive population state, higher levels of larval supply were required at greater sediment concentrations to overcome the negative effects of sediment accumulation on the reef. In addition, reef persistence was negatively related to sediment deposited on a reef prior to larval settlement and recruitment, implying that restoration reefs should be constructed immediately before settlement and recruitment to minimize sediment accumulation on a reef before settlement. These findings are valuable in oyster reef restoration because they can guide reef construction relative to larval supply and sediment deposition on a reef to yield effective and cost-efficient restoration strategies.
FiberGrowth Pipeline: A Framework Toward Predicting Fiber-Specific Growth From Human Gut Bacteroidetes Genomes
Authors: Colnet Bénédicte , Sieber Christian M. K. , Perraudeau Fanny , Leclerc Marion
Published: October 2021

Dietary fibers impact gut colonic health, through the production of short-chain fatty acids. A low-fiber diet has been linked to lower bacterial diversity, obesity, type 2 diabetes, and promotion of mucosal pathogens. Glycoside hydrolases (GHs) are important enzymes involved in the bacterial catabolism of fiber into short-chain fatty acids. However, the GH involved in glycan breakdown (adhesion, hydrolysis, and fermentation) are organized in polysaccharide utilization loci (PUL) with complex modularity. Our goal was to explore how the capacity of strains, from the Bacteroidetes phylum, to grow on fiber could be predicted from their genome sequences. We designed an in silico pipeline called FiberGrowth and independently validated it for seven different fibers, on 28 genomes from Bacteroidetes-type strains. To do so, we compared the existing GH annotation tools and built PUL models by using published growth and gene expression data. FiberGrowth’s prediction performance in terms of true positive rate (TPR) and false positive rate (FPR) strongly depended on available data and fiber: arabinoxylan (TPR: 0.89 and FPR: 0), inulin (0.95 and 0.33), heparin (0.8 and 0.22) laminarin (0.38 and 0.17), levan (0.3 and 0.06), mucus (0.13 and 0.38), and starch (0.73 and 0.41). Being able to better predict fiber breakdown by bacterial strains would help to understand their impact on human nutrition and health. Assuming further gene expression experiment along with discoveries on structural analysis, we hope computational tools like FiberGrowth will help researchers prioritize and design in vitro experiments.
Endophytic Microbes Are Tools to Increase Tolerance in Jasione Plants Against Arsenic Stress
Authors: González-Benítez Natalia , Martín-Rodríguez Irene , Cuesta Isabel , Arrayás Manuel , White James Francis , Molina María Carmen
Published: October 2021

Seed microbiota is becoming an emergent area of research. Host plant microbial diversity is increasingly well described, yet relatively little is known about the stressors driving plant endomicrobiota at the metaorganism level. The present work examines the role of horizontal and vertical transmission of bacterial microbiota in response to abiotic stress generated by arsenic. Horizontal transmission is achieved by bioaugmentation with the endophyte Rhodococcus rhodochrous, while vertical transmission comes via maternal inheritance from seeds. To achieve this goal, all experiments were conducted with two Jasione species. J. montana is tolerant to arsenic (As), whereas J. sessiliflora, being phylogenetically close to J. montana, was not previously described as As tolerant. The Jasione core bacterial endophytes are composed of genera Pseudomonas, Ralstonia, Undibacterium, Cutibacterium, and Kocuria and family Comamanadaceae across different environmental conditions. All these operational taxonomic units (OTUs) coexisted from seeds to the development of the seedling, independently of As stress, or bioaugmentation treatment and Jasione species. R. rhodochrous colonized efficiently both species, driving the endomicrobiota structure of Jasione with a stronger effect than As stress. Despite the fact that most of the OTUs identified inside Jasione seeds and seedlings belonged to rare microbiota, they represent a large bacterial reservoir offering important physiological and ecological traits to the host. Jasione traits co-regulated with R. rhodochrous, and the associated microbiota improved the host response to As stress. NGS-Illumina tools provided further knowledge about the ecological and functional roles of plant endophytes.
Bacterial Inhibition on Beauveria bassiana Contributes to Microbiota Stability in Delia antiqua
Authors: Zhou Fangyuan , Gao Yunxiao , Liu Mei , Xu Letian , Wu Xiaoqing , Zhao Xiaoyan , Zhang Xinjian
Published: October 2021

Given the multiple roles of associated microbiota in improving animal host fitness in a microbial environment, increasing numbers of researchers have focused on how the associated microbiota keeps stable under complex environmental factors, especially some biological ones. Recent studies show that associated microbiota interacts with pathogenic microbes. However, whether and how the interaction would influence microbiota stability is limitedly investigated. Based on the interaction among Delia antiqua, its associated microbiota, and one pathogen Beauveria bassiana, the associated microbiota's response to the pathogen was determined in this study. Besides, the underlying mechanism for the response was also preliminarily investigated. Results showed that B. bassiana neither infect D. antiqua larvae nor did it colonize inside the associated microbiota, and both the bacterial and fungal microbiota kept stable during the interaction. Further experiments showed that bacterial microbiota almost completely inhibited conidial germination and mycelial growth of B. bassiana during its invasion, while fungal microbiota did not inhibit conidial germination and mycelial growth of B. bassiana. According to the above results, individual dominant bacterial species were isolated, and their inhibition on conidial germination and mycelial growth of B. bassiana was reconfirmed. Thus, these results indicated that bacterial instead of fungal microbiota blocked B. bassiana conidia and stabilized the associated microbiota of D. antiqua larvae during B. bassiana invasion. The findings deepened the understanding of the role of associated microbiota–pathogen microbe interaction in maintaining microbiota stability. They may also contribute to the development of novel biological control agents and pest management strategies.
The Microbiome–Gut–Brain Axis, a Potential Therapeutic Target for Substance-Related Disorders
Authors: Fu Xuan , Chen Ti , Cai Jingda , Liu Bo , Zeng Yaohui , Zhang Xiaojie
Published: October 2021

Substance addiction is a complex worldwide public health problem. It endangers both personal life and social stability, causing great loss on economy. Substance-related disorder is considered to be a complicated chronic brain disorder. It resulted from interactions among pharmacological properties of addictive substances, individual susceptibility, and social–environmental factors. Unfortunately, there is still no ideal treatment for this disorder. Recent lines of evidence suggest that gut microbiome may play an important role in the pathogenesis of neuropsychiatric disorders, including substance-related disorders. This review summarizes the research on the relationship between gut microbiome and substance-related disorders, including different types of substance, different individual susceptibility, and the occurrence and development of substance-induced mental disorders. We also discuss the potentiation of gut microbiome in the treatment of substance-related disorders, especially in the treatment of substance-induced mental disorders and manipulation on individuals’ responsiveness to addictive substances.
Concurrent Resistance to Carbapenem and Colistin Among Enterobacteriaceae Recovered From Human and Animal Sources in Nigeria Is Associated With Multiple Genetic Mechanisms
Authors: Ngbede Emmanuel O. , Adekanmbi Folasade , Poudel Anil , Kalalah Anwar , Kelly Patrick , Yang Yi , Adamu Andrew M. , Daniel Salem T. , Adikwu Alex A. , Akwuobu Chinedu A. , Abba Paul O. , Mamfe Levi M. , Maurice Nanven A. , Adah Mohammed I. , Lockyear Olivia , Butaye Patrick , Wang Chengming
Published: October 2021

Resistance to last resort drugs such as carbapenem and colistin is a serious global health threat. This study investigated carbapenem and colistin resistance in 583 non-duplicate Enterobacteriaceae isolates utilizing phenotypic methods and whole genome sequencing (WGS). Of the 583 isolates recovered from humans, animals and the environment in Nigeria, 18.9% (110/583) were resistant to at least one carbapenem (meropenem, ertapenem, and imipenem) and 9.1% (53/583) exhibited concurrent carbapenem-colistin resistance. The minimum inhibitory concentrations of carbapenem and colistin were 2–32 μg/mL and 8 to >64 μg/mL, respectively. No carbapenem resistant isolates produced carbapenemase nor harbored any known carbapenemase producing genes. WGS supported that concurrent carbapenem-colistin resistance was mediated by novel and previously described alterations in chromosomal efflux regulatory genes, particularly mgrB (M1V) ompC (M1_V24del) ompK37 (I70M, I128M) ramR (M1V), and marR (M1V). In addition, alterations/mutations were detected in the etpA, arnT, ccrB, pmrB in colistin resistant bacteria and ompK36 in carbapenem resistant bacteria. The bacterial isolates were distributed into 37 sequence types and characterized by the presence of internationally recognized high-risk clones. The results indicate that humans and animals in Nigeria may serve as reservoirs and vehicles for the global spread of the isolates. Further studies on antimicrobial resistance in African countries are warranted.
Multiple Roles of Flagellar Export Chaperones for Efficient and Robust Flagellar Filament Formation in Salmonella
Authors: Minamino Tohru , Morimoto Yusuke V. , Kinoshita Miki , Namba Keiichi
Published: October 2021

FlgN, FliS, and FliT are flagellar export chaperones specific for FlgK/FlgL, FliC, and FliD, respectively, which are essential component proteins for filament formation. These chaperones facilitate the docking of their cognate substrates to a transmembrane export gate protein, FlhA, to facilitate their subsequent unfolding and export by the flagellar type III secretion system (fT3SS). Dynamic interactions of the chaperones with FlhA are thought to determine the substrate export order. To clarify the role of flagellar chaperones in filament assembly, we constructed cells lacking FlgN, FliS, and/or FliT. Removal of either FlgN, FliS, or FliT resulted in leakage of a large amount of unassembled FliC monomers into the culture media, indicating that these chaperones contribute to robust and efficient filament formation. The ∆flgN ∆fliS ∆fliT (∆NST) cells produced short filaments similarly to the ∆fliS mutant. Suppressor mutations of the ∆NST cells, which lengthened the filament, were all found in FliC and destabilized the folded structure of FliC monomer. Deletion of FliS inhibited FliC export and filament elongation only after FliC synthesis was complete. We propose that FliS is not involved in the transport of FliC upon onset of filament formation, but FliS-assisted unfolding of FliC by the fT3SS becomes essential for its rapid and efficient export to form a long filament when FliC becomes fully expressed in the cytoplasm.
Characterization of IncHI1B Plasmids Encoding Efflux Pump TmexCD2-ToprJ2 in Carbapenem-Resistant Klebsiella variicola, Klebsiella quasipneumoniae, and Klebsiella michiganensis Strains
Authors: Wang Yujiao , Zhu Bo , Liu Min , Dong Xiutao , Ma Jianping , Li Xiaofeng , Cheng Fang , Guo Jianzhuang , Lu Sumei , Wan Furong , Hao Yingying , Ma Wanshan , Hao Mingju , Chen Liang
Published: October 2021

Tigecycline serves as one of the last-resort antibiotics to treat severe infections caused by carbapenem-resistant Enterobacterales. Recently, a novel plasmid-mediated resistance-nodulation-division (RND)-type efflux pump gene cluster, TmexCD1-ToprJ1, and its variants, TmexCD2-ToprJ2 and TmexCD3-ToprJ3, encoding tetracyclines and tigecycline resistance, were revealed. In this study, we reported three TmexCD2-ToprJ2-harboring Klebsiella species strains, collected from two teaching tertiary hospitals in China, including one K. quasipneumoniae, one K. variicola, and one K. michiganensis. The three strains were characterized by antimicrobial susceptibility testing (AST), conjugation assay, WGS, and bioinformatics analysis. AST showed that K. variicola and K. quasipneumoniae strains were resistant to tigecycline with MIC values of 4μg/ml, whereas the K. michiganensis was susceptible to tigecycline with an MIC value of 1μg/ml. The TmexCD2-ToprJ2 clusters were located on three similar IncHI1B plasmids, of which two co-harbored the metallo-β-lactamase gene blaNDM-1. Conjugation experiments showed that all three plasmids were capable of self-transfer via conjugation. Our results showed, for the first time, that this novel plasmid-mediated tigecycline resistance mechanism TmexCD2-ToprJ2 has spread into different Klebsiella species, and clinical susceptibility testing may fail to detect. The co-occurrence of blaNDM-1 and TmexCD2-ToprJ2 in the same plasmid is of particular public health concern as the convergence of “mosaic” plasmids can confer both tigecycline and carbapenem resistance. Its further spread into other clinical high-risk Klebsiella clones will likely exacerbate the antimicrobial resistance crisis. A close monitoring of the dissemination of TmexCD-ToprJ encoding resistance should be considered.
Potential Value of TNF-α (–376 G/A) Polymorphism and Cystatin C (CysC) in the Diagnosis of Sepsis Associated Acute Kidney Injury (S-AK I) and Prediction of Mortality in Critically Ill patients
Authors: Al-Amodi Hiba S , Abdelsattar Shimaa , Kasemy Zeinab A. , Bedair Hanan M. , Elbarbary Hany S. , Kamel Hala F. M.
Published: October 2021

Sepsis Associated Kidney Injury represents a major health concern as it is frequently associated with increased risk of mortality and morbidity. We aimed to evaluate the potential value of TNF-α (−376 G/A) and cystatin C in the diagnosis of S-AKI and prediction of mortality in critically ill patients. This study included 200 critically ill patients and 200 healthy controls. Patients were categorized into 116 with acute septic shock and 84 with sepsis, from which 142 (71%) developed S-AKI. Genotyping of TNF-α (−376 G/A) was performed by RT-PCR and serum CysC was assessed by Enzyme Linked Immunosorbent Assay. Our results showed a highly significant difference in the genotype frequencies of TNF-α (−376 G/A) SNP between S-AKI and non-AKI patients (p< 0.001). Additionally, sCysC levels were significantly higher in the S-AKI group (p= 0.011). The combination of both sCysC and TNF-α (−376 G/A) together had a better diagnostic ability for S-AKI than sCysC alone (AUC = 0.610, 0.838, respectively). Both GA and AA genotypes were independent predictors of S-AKI (p= < 0.001,p= 0.002 respectively). Additionally, sCysC was significantly associated with the risk of S-AKI development (Odds Ratio = 1.111). Both genotypes and sCysC were significant predictors of non-survival (p< 0.001), suggesting their potential role in the diagnosis of S-AKI and prediction of mortality.
Altered Volume and Structural Connectivity of the Hippocampus in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment
Authors: Feng Feng , Huang Weijie , Meng Qingqing , Hao Weijun , Yao Hongxiang , Zhou Bo , Guo Yan’e , Zhao Cui , An Ningyu , Wang Luning , Huang Xusheng , Zhang Xi , Shu Ni
Published: October 2021

Background: Hippocampal atrophy is a characteristic of Alzheimer’s disease (AD). However, alterations in structural connectivity (number of connecting fibers) between the hippocampus and whole brain regions due to hippocampal atrophy remain largely unknown in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI).

Methods: We collected high-resolution structural MRI (sMRI) and diffusion tensor imaging (DTI) data from 36 AD patients, 30 aMCI patients, and 41 normal control (NC) subjects. First, the volume and structural connectivity of the bilateral hippocampi were compared among the three groups. Second, correlations between volume and structural connectivity in the ipsilateral hippocampus were further analyzed. Finally, classification ability by hippocampal volume, its structural connectivity, and their combination were evaluated.

Results: Although the volume and structural connectivity of the bilateral hippocampi were decreased in patients with AD and aMCI, only hippocampal volume correlated with neuropsychological test scores. However, positive correlations between hippocampal volume and ipsilateral structural connectivity were displayed in patients with AD and aMCI. Furthermore, classification accuracy (ACC) was higher in AD vs. aMCI and aMCI vs. NC by the combination of hippocampal volume and structural connectivity than by a single parameter. The highest values of the area under the receiver operating characteristic (ROC) curve (AUC) in every two groups were all obtained by combining hippocampal volume and structural connectivity.

Conclusions: Our results showed that the combination of hippocampal volume and structural connectivity (number of connecting fibers) is a new perspective for the discrimination of AD and aMCI.
Physically Active Lifestyle Is Associated With Attenuation of Hippocampal Dysfunction in Cognitively Intact Older Adults
Authors: Eisenstein Tamir , Giladi Nir , Hendler Talma , Havakuk Ofer , Lerner Yulia
Published: October 2021

Alterations in hippocampal function have been shown in older adults, which are expressed as changes in hippocampal activity and connectivity. While hippocampal activation during memory demands has been demonstrated to decrease with age, some older individuals present increased activity, or hyperactivity, of the hippocampus which is associated with increased neuropathology and poor memory function. In addition, lower functional coherence between the hippocampus and core hubs of the default mode network (DMN), namely, the posteromedial and medial prefrontal cortices, as well as increased local intrahippocampal connectivity, were also demonstrated in cognitively intact older adults. Aerobic exercise has been shown to elicit neuroprotective effects on hippocampal structure and vasculature in aging, and improvements in cardiorespiratory fitness have been suggested to mediate these exercise-related effects. However, how these lifestyle factors relate to hippocampal function is not clear. Fifty-two cognitively intact older adults (aged 65–80 years) have been recruited and divided into physically active (n = 29) or non-active (n = 23) groups based on their aerobic activity lifestyle habits. Participants underwent resting-state and task-based fMRI experiments which included an associative memory encoding paradigm followed by a post-scan memory recognition test. In addition, 44 participants also performed cardiopulmonary exercise tests to evaluate cardiorespiratory fitness by measuring peak oxygen consumption (Vo2peak). While both groups demonstrated increased anterior hippocampal activation during memory encoding, a physically active lifestyle was associated with significantly lower activity level and higher memory performance in the recognition task. In addition, the physically active group also demonstrated higher functional connectivity of the anterior and posterior hippocampi with the core hubs of the DMN and lower local intra-hippocampal connectivity within and between hemispheres. Vo2peak was negatively associated with the hippocampal activation level and demonstrated a positive correlation with hippocampal-DMN connectivity. According to these findings, an aerobically active lifestyle may be associated with attenuation of hippocampal dysfunction in cognitively intact older adults.
Comparison Between the Effects of Continuous and Intermittent Light-Intensity Aerobic Dance Exercise on Mood and Executive Functions in Older Adults
Authors: Hyodo Kazuki , Suwabe Kazuya , Yamaguchi Daisuke , Soya Hideaki , Arao Takashi
Published: October 2021

There is a growing body of evidence suggesting that one bout of moderate-intensity exercise enhances executive functions in older adults. However, in terms of safety, feasibility, and continuity, older individuals prefer light, easy, and fun exercises to moderate and stressful exercises for improving executive functions. Therefore, light-intensity aerobic dance exercise (LADE) could be suitable if it produces potential benefits related to executive functions. As for continuous vs. intermittent exercise, intermittent exercise has received a lot of attention, as it results in greater effects on mood and executive functions than continuous exercise; however, its effects in older adults remain uncertain. Thus, in this study, we aimed to examine the acute effects of intermittent LADE (I-LADE) in comparison with those of continuous LADE (C-LADE) on mood and executive functions. Fifteen healthy older adults participated in 10-min I-LADE and C-LADE conditions on separate days. Perceived enjoyment following exercise was assessed using the Physical Activity Enjoyment Scale (PACES). The pleasantness of the mood during exercise and pleasure and arousal levels after exercise were assessed using the Feeling Scale and Two-Dimensional Mood Scale, respectively. Executive function was assessed using the Stroop task before and after exercise. As a result, pleasantness of the mood during exercise and exercise enjoyment levels were greater in I-LADE than in C-LADE. Arousal and pleasure levels and Stroop task performance increased after both LADEs and did not differ between the two exercise conditions. These findings suggest that although enhancement of mood and executive functions after exercise did not differ between C-LADE and I-LADE, I-LADE could be more enjoyable and fun than C-LADE. This study will help in the development of exercise conditions that can enable the elderly to enhance their executive functions in a fun way.
Role of Blood Neurofilaments in the Prognosis of Amyotrophic Lateral Sclerosis: A Meta-Analysis
Authors: Zhou Yan-ni , Chen You-hong , Dong Si-qi , Yang Wen-bo , Qian Ting , Liu Xiao-ni , Cheng Qi , Wang Jiu-cun , Chen Xiang-jun
Published: October 2021

Background: Neurofilaments in cerebrospinal fluid (CSF) and in blood are considered promising biomarkers of amyotrophic lateral sclerosis (ALS) because their levels can be significantly increased in patients with ALS. However, the roles of neurofilaments, especially blood neurofilaments, in the prognosis of ALS are inconsistent. We performed a meta-analysis to explore the prognostic roles of blood neurofilaments in ALS patients.

Methods: We searched all relevant studies on the relationship between blood neurofilament levels and the prognosis of ALS patients in PubMed, Embase, Scopus, and Web of Science before February 2, 2021. The quality of the included articles was assessed using the Quality in Prognosis Studies (QUIPS) scale, and R (version 4.02) was used for statistical analysis.

Results: Fourteen articles were selected, covering 1,619 ALS patients. The results showed that higher blood neurofilament light chain (NfL) levels in ALS patients were associated with a higher risk of death [medium vs. low NfL level: HR = 2.43, 95% CI (1.34–4.39), p < 0.01; high vs. low NfL level: HR = 4.51, 95% CI (2.45–8.32), p < 0.01]. There was a positive correlation between blood phosphorylated neurofilament heavy chain (pNfH) levels and risk of death in ALS patients [HR = 1.87, 95% CI (1.35–2.59), p < 0.01]. The levels of NfL and pNfH in blood positively correlated with disease progression rate (DPR) of ALS patients [NfL: summary r = 0.53, 95% CI (0.45–0.60), p < 0.01; pNfH: summary r = 0.51, 95% CI (0.24–0.71), p < 0.01].

Conclusion: The blood neurofilament levels can predict the prognosis of ALS patients; specifically, higher levels of blood neurofilaments are associated with a greater risk of death.
Alterations of Regional Homogeneity in Children With Congenital Sensorineural Hearing Loss: A Resting-State fMRI Study
Authors: Guo Pingping , Lang Siyuan , Jiang Muliang , Wang Yifeng , Zeng Zisan , Wen Zuguang , Liu Yikang , Chen Bihong T.
Published: October 2021

Background: Brain functional alterations have been observed in children with congenital sensorineural hearing loss (CSNHL). The purpose of this study was to assess the alterations of regional homogeneity in children with CSNHL.

Methods: Forty-five children with CSNHL and 20 healthy controls were enrolled into this study. Brain resting-state functional MRI (rs-fMRI) for regional homogeneity including the Kendall coefficient consistency (KCC-ReHo) and the coherence-based parameter (Cohe-ReHo) was analyzed and compared between the two groups, i.e., the CSNHL group and the healthy control group.

Results: Compared to the healthy controls, children with CSNHL showed increased Cohe-ReHo values in left calcarine and decreased values in bilateral ventrolateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC). Children with CSNHL also had increased KCC-ReHo values in the left calcarine, cuneus, precentral gyrus, and right superior parietal lobule (SPL) and decreased values in the left VLPFC and right DLPFC. Correlations were detected between the ReHo values and age of the children with CSNHL. There were positive correlations between ReHo values in the pre-cuneus/pre-frontal cortex and age (p < 0.05). There were negative correlations between ReHo values in bilateral temporal lobes, fusiform gyrus, parahippocampal gyrus and precentral gyrus, and age (p < 0.05).

Conclusion: Children with CSNHL had RoHo alterations in the auditory, visual, motor, and other related brain cortices as compared to the healthy controls with normal hearing. There were significant correlations between ReHo values and age in brain regions involved in information integration and processing. Our study showed promising data using rs-fMRI ReHo parameters to assess brain functional alterations in children with CSNHL.
Comparing Object Recognition in Humans and Deep Convolutional Neural Networks—An Eye Tracking Study
Authors: van Dyck Leonard Elia , Kwitt Roland , Denzler Sebastian Jochen , Gruber Walter Roland
Published: October 2021

Deep convolutional neural networks (DCNNs) and the ventral visual pathway share vast architectural and functional similarities in visual challenges such as object recognition. Recent insights have demonstrated that both hierarchical cascades can be compared in terms of both exerted behavior and underlying activation. However, these approaches ignore key differences in spatial priorities of information processing. In this proof-of-concept study, we demonstrate a comparison of human observers (N = 45) and three feedforward DCNNs through eye tracking and saliency maps. The results reveal fundamentally different resolutions in both visualization methods that need to be considered for an insightful comparison. Moreover, we provide evidence that a DCNN with biologically plausible receptive field sizes called vNet reveals higher agreement with human viewing behavior as contrasted with a standard ResNet architecture. We find that image-specific factors such as category, animacy, arousal, and valence have a direct link to the agreement of spatial object recognition priorities in humans and DCNNs, while other measures such as difficulty and general image properties do not. With this approach, we try to open up new perspectives at the intersection of biological and computer vision research.
Effects of Different Methionine Levels in Low Protein Diets on Production Performance, Reproductive System, Metabolism, and Gut Microbiota in Laying Hens
Authors: Ma Miaolin , Geng Shunju , Liu Meiling , Zhao Lihong , Zhang Jianyun , Huang Shimeng , Ma Qiugang
Published: October 2021

This study investigated the effects of different levels of methionine (Met) in a low protein diet on the production performance, reproductive system, metabolism, and gut microbial composition of laying hens to reveal the underlying molecular mechanism of Met in a low protein diet on the host metabolism and gut microbial composition and function of hens. A total of 360 healthy 38-week-old Peking Pink laying hens with similar body conditions and egg production (EP) were randomly divided into four groups with nine replicates per treatment and 10 hens per replicate. The hens in each treatment group were fed low protein diets containing different levels of Met (0.25, 0.31, 0.38, and 0.47%, respectively) for 12 weeks. Feed and water were provided ad libitum throughout the trial period. The results showed that, compared with the 0.25% Met group, the final body weight (FBW), average daily gain (ADG), EP, egg weight (EW), and average daily feed intake (ADFI) in the other groups were significantly increased and feed egg ratio (FER) was decreased. Meanwhile, the EW and yield of abdominal fat (AFY) in the 0.47% Met group were higher than those in other groups. The triglyceride (TG), estradiol (E2), total protein (TP), albumin (ALB), and immunoglobulin A (IgA) in the 0.38 and 0.47% Met groups were higher than those in other groups. In addition, 16S rRNA gene sequencing revealed that there was no difference in the Sobs index, ACE index, and Shannon index among all groups. However, it is worth noting that feeding low protein diets with Met changed the gut microbial composition (e.g., the supplementation of Met increased the level of Lactobacillus and decreased the proportion of Faecalibacterium). Also, our results showed that the changes in gut microbial composition induced by the diets with different levels of Met were closely related to the changes of key parameters: ADFI, EW, FBW, TG, EM, EP, ADG, FER, and uric acid (UA). Our results highlight the role of adding an appropriate amount of Met to the low protein diet in laying hens, which could improve the gut microbial composition, production performance, reproductive system, and nutrient metabolism of laying hens. In conclusion, this study suggested that when the Met level was 0.38%, the production performance of the laying hens was pretty good.
Genetic Variants of CLEC4E and BIRC3 in Damage-Associated Molecular Patterns-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival
Authors: Liu Lihua , Liu Hongliang , Luo Sheng , Patz Edward F. , Glass Carolyn , Su Li , Lin Lijuan , Christiani David C. , Wei Qingyi
Published: October 2021

Accumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P=0.001) and 0.82 (0.73-0.91 and P=0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets (Ptrend=0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes.
Case Report: Pulmonary Metastases From Epithelioid Sarcoma in Extremity Favourably Responding to Immunotherapy With Camrelizumab
Authors: Gong Tao-Jun , Tang Fan , Zheng Chuan-Xi , Wang Jie , Wang Yi-Tian , Zhang Ya-Han , Luo Yi , Zhou Yong , Min Li , Tu Chong-Qi
Published: October 2021

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment.
RETRACTED: Circular RNA Circ-0002570 Accelerates Cancer Progression by Regulating VCAN via MiR-587 in Gastric Cancer
Authors: Yang Lei , Zhou Yong-ning , Zeng Miao-miao , Zhou Nan , Wang Bin-sheng , Li Bo , Zhu Xiao-liang , Guan Quan-lin , Chai Chen
Published: October 2021

Background

Circular RNAs (circRNAs) are closely associated with the occurrences and progress of gastric cancer (GC). We aimed to delve into the function and pathological mechanism of Circular RNA-0002570 (circ-0002570) in GC progression.

Methods

CircRNAs differentially expressed in GC were screened using bioinformatics technology. The expression of circ-0002570 was detected in GC specimens and cells via qRT-PCR, and the prognostic values of circ-0002570 were determined. The functional roles of circ-0002570 on proliferation, migration, and invasion in GC cells were explored in vitro and in vivo. Interaction of circ-0002570, miR-587, and VCAN was confirmed by dual-luciferase reporter assays, Western blotting, and rescue experiments.

Results

Circ-0002570 expression was distinctly increased in GC tissues compared to adjacent normal specimens, and GC patients with higher circ-0002570 expressions displayed a short survival. Functionally, knockdown of circ-0002570 resulted in the inhibition of cell proliferation, migration, and invasion, and suppressed tumor growth in vivo. Mechanistically, miR-587 was sponged by circ-0002570. VCAN expression in NSCLC was directly inhibited by miR-587. Overexpression of circ-0002570 prevented VCAN from miR-587-mediated degradation and thus facilitated GC progression.

Conclusion

The circ-0002570-miR-587-VCAN regulatory pathway promoted the progression of GC. Our findings provided potential new targets for the diagnosis and therapy of GC.
SUZ12 Loss Amplifies the Ras/ERK Pathway by Activating Adenylate Cyclase 1 in NF1-Associated Neurofibromas
Authors: Li Weijie , Hu Chenhao , Zhang Xingnan , Wang Binbin , Li Zhen , Ling Miao , Sun Shengqiao , Guo Chao , Li Dezhi , Liu Song
Published: October 2021

Patients with germline neurofibromatosis type 1 (NF1) microdeletions frequently exhibit hereditary syndromes such as cardiovascular anomalies and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). This study aimed to identify the genes codeleted with SUZ12 that are related to MPNST. We used differential gene expression and enrichment analyses to analyze the SUZ12-mutant and SUZ12-wild-type gene expression profiles in the GSE118186 and GSE66743 datasets in Gene Expression Omnibus (GEO). PPI network analysis combined with MPNST patient survival analysis was used to identify ADCY1, which catalyzes the conversion of ATP to cAMP, as a key gene. Moreover, chromatin immunoprecipitation sequencing (ChIP-Seq) showed that the distribution of H3K27me3 in the ADCY1 promoter region and gene body was significantly reduced in SUZ12-mutant cells. To verify the role of ADCY1 in SUZ12 mutation, we used RNA interference and plasmid transfection to interfere with SUZ12 expression in plexiform neurofibroma (pNF) and MPNST cell lines and then treated the cells with forskolin, IBMX and H89. ERK phosphorylation was accelerated and prolonged after siRNA transfection, especially in ipNF05.5 cells, and the intensity and duration of ERK activation were reduced after SUZ12 overexpression. Importantly, the level of p-ERK was consistent with that of Rap1-GTP. Moreover, H89 completely blocked Rap1 activation and the changes in the p-ERK level after SUZ12 siRNA transfection. In conclusion, our findings suggested that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras signaling through the ADCY1/cAMP/Rap1/ERK pathway and that SUZ12 may serve as a therapeutic and prognostic biomarker in NF1-associated neurofibromas.
Atractylenolide-I Sensitizes Triple-Negative Breast Cancer Cells to Paclitaxel by Blocking CTGF Expression and Fibroblast Activation
Authors: Wang Meng , Li Xue-Zhen , Zhang Ming-Xing , Ye Qian-Yu , Chen Ying-Xia , Chang Xu
Published: October 2021

This investigation was conducted to elucidate whether atractylenolide-I (ATL-1), which is the main component of Atractylodes macrocephala Koidz, can sensitize triple-negative breast cancer (TNBC) cells to paclitaxel and investigate the possible mechanism involved. We discovered that ATL-1 could inhibit tumor cell migration and increase the sensitivity of tumor cells to paclitaxel. ATL-1 downregulated the expression and secretion of CTGF in TNBC cells. Apart from inhibiting TNBC cell migration via CTGF, ATL-1 downregulated the expression of CTGF in fibroblasts and decreased the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblasts (CAFs), which in turn increased the sensitivity of TNBC cells to paclitaxel. In a mouse model, we found that ATL-1 treatments could enhance the chemotherapeutic effect of paclitaxel on tumors and reduce tumor metastasis to the lungs and liver. Primary cultured fibroblasts derived from inoculated tumors in mice treated with ATL-1 combined with paclitaxel expressed relatively low levels of CAF markers. Collectively, our data indicate that ATL-1 can sensitize TNBC cells to paclitaxel by blocking CTGF expression and fibroblast activation and could be helpful in future research to determine the value of ATL-1 in the clinical setting.
Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells
Authors: Soni Vivek Kumar , Mehta Arundhati , Ratre Yashwant Kumar , Chandra Vikas , Shukla Dhananjay , Kumar Ajay , Vishvakarma Naveen Kumar
Published: October 2021

Along with direct anticancer activity, curcumin hinders the onset of chemoresistance. Among many, high glucose condition is a key driving factor for chemoresistance. However, the ability of curcumin remains unexplored against high glucose-induced chemoresistance. Moreover, chemoresistance is major hindrance in effective clinical management of liver cancer. Using hepatic carcinoma HepG2 cells, the present investigation demonstrates that high glucose induces chemoresistance, which is averted by the simultaneous presence of curcumin. Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production. Modulated molecular regulators are suggested to play a crucial role as curcumin pretreatment also prevented the onset of chemoresistance by high glucose. High glucose instigated suppression in the intracellular accumulation of anticancer drug doxorubicin and drug-induced chromatin compactness along with declined expression of drug efflux pump MDR-1 and transcription factors and signal transducers governing the survival, aggressiveness, and apoptotic cell death (p53, HIF-1α, mTOR, MYC, STAT3). Curcumin alleviated the suppression of drug retention and nuclear condensation along with hindering the high glucose-induced alterations in transcription factors and signal transducers. High glucose-driven resistance in cancer cells was associated with elevated expression of metabolic enzymes HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, transporters, and receptors in cancer cells. Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition. Taken together, the findings of the present investigation first time demonstrate the ability of curcumin against high glucose-induced chemoresistance, along with its molecular mechanism. This will have implication in therapeutic management of malignancies in diabetic conditions.