bluuebunny/crossref_metadata_2025 huggingface dataset:
Accounting for Uncertainties in Biodiversity Estimations: A New Methodology and Its Application to the Mesopelagic Sound Scattering Layer of the High Arctic
Authors: Herrmann Bent , Cerbule Kristine , Brčić Jure , Grimaldo Eduardo , Geoffroy Maxime , Daase Malin , Berge Jørgen
Published: April 2022

Measures of biological diversity (biodiversity) are important for monitoring the state of ecosystems. Several indices and methods are used to describe biodiversity from field observations. Marine faunal biodiversity is often quantified based on analysis of samples collected using a trawl during research surveys. To monitor spatial and temporal changes in biodiversity between surveys, samples are generally collected from a series of stations. Inference regarding changes in biodiversity must account for uncertainties in the estimation of the values for the different biodiversity indices used. Estimation for a single station is affected by spatial-temporal variation in the species composition in the area and by uncertainty due to the finite sample size taken by the trawl. Therefore, variation between stations needs to be accounted for when estimating uncertainty for values of different indices during a survey as total or as mean for the survey. Herein, we present a method based on nested bootstrapping that accounts for uncertainties in the estimation of various indices and which can be used to infer changes in biodiversity. Application of this methodology is demonstrated using data collected in the mesopelagic sound scattering layer in the high Arctic.
Incising and Double Impregnation of Beech Sleepers—Investigation of an Alternative Preservation System for Wooden Railway Sleepers
Authors: Starck Michael , Heidel Andreas , Brischke Christian , Militz Holger
Published: April 2022

For nearly 200 years wooden railway sleepers are impregnated with creosote. After initially using vacuum pressure processes for impregnation, empty-cell processes have been developed quickly and are used until today. Because of political developments and its alarming properties against human health and environment the use of creosote is already restricted to certain industrial and commercially used products and will probably be banned on the European market and elsewhere in the near future. Today, most of the sleepers in track are concrete sleepers, but wooden sleepers are still essential for particular applications such as tracks with narrow curve radii, mountain tracks with uneven underground conditions and low ballast bed thicknesses, for switches, for railway bridges and for shunting stations. Without a successor product, wooden sleepers have to be installed either again without adequate protection against wood destroying organisms or will possibly be replaced by sleepers made from alternative materials like concrete, steel or polymers. The Fürstenberg-System-Sleeper, which combines a mechanical pre-treatment (incising), a double impregnation of sleepers including an alternative oily wood preservative and a water-borne copper salt as well as a modernized quality control shall on the one hand serve as an alternative to creosoted sleepers and on the other hand ensure future use of wooden sleepers in track superstructure. Incising reduced the formation of checks regarding their length, width, and depth in sleepers made from European beech (Fagus sylvatica L.) until they are sufficiently seasoned for impregnation. A decrease of the seasoning speed was not observed. During seasoning, the average global moisture content (MC) as well as the local MC showed hardly any differences between incised and not incised sleepers. Additionally, incising showed no influence on the dimensional stability, which would have reduced the number of sleepers being culled based on excessive deformation. Furthermore, positive effects on preservative retention and penetration were observed, where incising doubled the penetration depth up to over 30 mm and increased the mean retention from 46.5 to 72.0 kg/m3. During double impregnation with the water-borne preservative first and the oily preservative afterward, it became evident, that a gross weight of at least 950 kg/m3 was needed for penetrating the peripheral area of the sleepers to achieve an additional homogenous envelope treatment during the second impregnation with an average retention of approximately 30 kg/m3.
Prognostic Value and Therapeutic Perspectives of CXCR Members in the Glioma Microenvironment
Authors: He Jiarong , Jiang Zhongzhong , Lei Jiawei , Zhou Wen , Cui Yan , Luo Biao , Zhang Mingming
Published: April 2022

Background: CXCR (CXC Chemokine Receptor) is a complex of the immune-associated protein involved in tumor activation, invasion, migration, and angiogenesis through various chemical signals in the tumor microenvironment (TME). However, significant prognostic characteristics of CXCR members and their impact on the occurrence and progression of glioma have not yet been fully elucidated.

Methods: In this research, we used Oncomine, TCGA, GTEx, and CGGA databases to analyze the transcription and survival data of glioma patients. Afterward, the influence of CXCR members on the TME was explored using comprehensive bioinformatics analysis.

Results: The mRNA expression levels of CXCR1/2/3/4/7 were significantly up-regulated in glioma than in normal samples, whereas the mRNA expression level of CXCR5 was decreased. We then summarized the genetic alteration landscape of CXCR and identified two molecular subtypes based on CXCR expression patterns in glioma. The characteristics of CXCRs were also investigated, including the clinicopathological parameters, TME cell infiltration, and prognosis of patients with glioma. After Lasso and multivariable Cox regression, a CR-Score for predicting overall survival (OS) was constructed and the predictive performance of the signature was validated. The high-risk group was a significantly poorer prognostic group than the low-risk group as judged by the CR-Score (TCGA cohort, p < 0.001, CGGA cohort, p < 0.001). Moreover, the CR-Score was significantly correlated to the tumor-immune infiltration and cancer stem cell (CSC) index. A risk scale-based nomogram incorporating clinical factors for individual risk estimation was established thereby.

Conclusion: These findings may pave the way for enhancing our understanding of CXCR modification patterns and developing better immune therapeutic approaches for glioma.
Apoptosis-Related Signature Predicts Prognosis and Immune Microenvironment Infiltration in Lung Adenocarcinoma
Authors: Zou Xiaoli , He Rong , Zhang Zhenzhen , Yan Yulan
Published: April 2022

Lung adenocarcinoma (LUAD), a malignancy with high incidence and mortality rates worldwide, contains multiple genomic and epigenomic abnormalities. And the useful tumor markers associated with these abnormalities need further investigation. Whereas apoptosis is a form of programmed cell death, the expression of apoptosis-related genes in LUAD and its relationship with prognosis is unclear. In the present study, we identified 64 differentially expressed apoptosis-related genes (DEARGs) that were differentially expressed between LUAD tissue and normal lung tissue. Based on these DEARGs, all LUAD cases were classified into two subtypes using The Cancer Genome Atlas (TCGA) cohort to assess the prognostic value of apoptosis-related genes for survival. An 11-gene signature was established by applying the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression method to construct a multigene prediction model and classify all LUAD patients in the TCGA cohort into high or low AS-score groups. Patients in the low AS-score group had significantly higher survival and prognosis than those in the high AS-score group. Taking the median risk score of the AS-score, LUAD patients in the GSE68465 cohort were divided into two risk groups, low and high. The overall survival (OS) time was longer in the low AS-score group. Combined with clinical characteristics, the AS-score was an independent predictor of LUAD patients. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses showed that the differential genes between the two groups were mainly enriched in cellular immunity. Further analysis revealed higher immune checkpoint protein expression and higher tumor mutational burden (TMB) in the high AS-score group, suggesting better efficacy of immunotherapy in the high AS-score group than the low AS-score group. And the high AS-score group was better in chemotherapy and targeted therapy efficiency. In conclusion, the AS-score constructed based on apoptosis-related genes can predict the prognosis of LUAD patients and provide some guidance for the antitumor treatment of LUAD patients.
Molecular Epidemiology of Na+-Taurocholate Cotransporting Polypeptide Deficiency in Guangdong Province, China: A Pilot Study by Screening for Four Prevalent Variants of the Causative Gene SLC10A1
Authors: Li Hua , Chen Rong , Lin Gui-Zhi , Lin Wei-Xia , Yaqub Muhammad-Rauf , Song Yuan-Zong
Published: April 2022

Na+-taurocholate cotransporting polypeptide deficiency (NTCPD) is an autosomal recessive disorder arising from biallelic SLC10A1 mutations. As a newly-described inborn error of bile acid metabolism, the epidemiology of this condition remains largely unclear in Chinese population so far. In this study, a total of 2,828 peripheral blood samples were collected from 12 cities in Guangdong, a province with the largest population in China, and the four prevalent SLC10A1 variants c.800C > T (p.Ser267Phe), c.263T > C (p.Ile88Thr), c.595A > C (p.Ser199Arg) and c.665T > C (p.Leu222Ser) were screened for by using polymerase chain reaction (PCR)- restriction fragment length polymorphism (RFLP). As a result, 663 mutated SLC10A1 alleles were detected, and the mutated allele frequency was calculated to be 11.72% (663/5,656), with a carrier frequency 20.69% (1/5) and a theoretical morbidity rate 1.37% (1/73) of NTCPD in Guangdong province. The variant c.800C > T (p.Ser267Phe) exhibited highest allele frequency among the four prevalent variants (χ2 = 1501.27, p < 0.0001) as well as higher allele frequency in the peripheral region than that within the Pearl River Delta (χ2 = 4.834, p < 0.05). The results suggested that NTCPD might be a disorder rather common in Guangdong province. The findings depicted the molecular epidemiologic features of NTCPD, providing preliminary but significant laboratory evidences for the subsequent NTCPD diagnosis and management in Guangdong population.
Interaction Between Non-Coding RNAs and Interferons: With an Especial Focus on Type I Interferons
Authors: Ghafouri-Fard Soudeh , Poornajaf Yadollah , Dashti Farzaneh , Hussen Bashdar Mahmud , Taheri Mohammad , Jamali Elena
Published: April 2022

Interferons (IFNs) are a group of cellular proteins with critical roles in the regulation of immune responses in the course of microbial infections. Moreover, expressions of IFNs are dysregulated in autoimmune disorders. IFNs are also a part of immune responses in malignant conditions. The expression of these proteins and activities of related signaling can be influenced by a number of non-coding RNAs. IFN regulatory factors (IRFs) are the most investigated molecules in the field of effects of non-coding RNAs on IFN signaling. These interactions have been best assessed in the context of cancer, revealing the importance of immune function in the pathoetiology of cancer. In addition, IFN-related non-coding RNAs may contribute to the pathogenesis of neuropsychiatric conditions, systemic sclerosis, Newcastle disease, Sjögren’s syndrome, traumatic brain injury, lupus nephritis, systemic lupus erythematosus, diabetes mellitus, and myocardial ischemia/reperfusion injury. In the current review, we describe the role of microRNAs and long non-coding RNAs in the regulation of IFN signaling.
In Silico Analysis Predicts a Limited Impact of SARS-CoV-2 Variants on CD8 T Cell Recognition
Authors: Isaeva Olga I. , Ketelaars Steven L. C. , Kvistborg Pia
Published: April 2022

Since the start of the COVID-19 pandemic, mutations have led to the emergence of new SARS-CoV-2 variants, and some of these have become prominent or dominant variants of concern. This natural course of development can have an impact on how protective the previously naturally or vaccine induced immunity is. Therefore, it is crucial to understand whether and how variant specific mutations influence host immunity. To address this, we have investigated how mutations in the recent SARS-CoV-2 variants of interest and concern influence epitope sequence similarity, predicted binding affinity to HLA, and immunogenicity of previously reported SARS-CoV-2 CD8 T cell epitopes. Our data suggests that the vast majority of SARS-CoV-2 CD8 T cell recognized epitopes are not altered by variant specific mutations. Interestingly, for the CD8 T cell epitopes that are altered due to variant specific mutations, our analyses show there is a high degree of sequence similarity between mutated and reference SARS-CoV-2 CD8 T cell epitopes. However, mutated epitopes, primarily derived from the spike protein, in SARS-CoV-2 variants Delta, AY.4.2 and Mu display reduced predicted binding affinity to their restriction element. These findings indicate that the recent SARS-CoV-2 variants of interest and concern have limited ability to escape memory CD8 T cell responses raised by vaccination or prior infection with SARS-CoV-2 early in the pandemic. The overall low impact of the mutations on CD8 T cell cross-recognition is in accordance with the notion that mutations in SARS-CoV-2 are primarily the result of receptor binding affinity and antibody selection pressures exerted on the spike protein, unrelated to T cell immunity.
Deep Brain Stimulation of the Nucleus Accumbens in Severe Enduring Anorexia Nervosa: A Pilot Study
Authors: Scaife Jessica C. , Eraifej John , Green Alexander L. , Petric Beth , Aziz Tipu Z. , Park Rebecca J.
Published: April 2022

Introduction

Anorexia nervosa (AN) is one of the most debilitating psychiatric disorders, becoming severe and enduring in a third of cases; with few effective treatments. Deep brain stimulation is a reversible, adjustable neurosurgical procedure that has been gaining ground in psychiatry as a treatment for depression and obsessive–compulsive disorder, yet few studies have investigated AN. Abnormal eating behavior and the compulsive pursuit of thinness in AN is, in part, a consequence of dysfunction in reward circuitry and the nucleus accumbens (NAcc) is central to reward processing.

Methods

Phase 1 prospective open-label pilot study of seven individuals with severe enduring AN. Electrodes were implanted bilaterally into the NAcc with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. The protocol of 15 months included 12 months of deep brain stimulation incorporating two consecutive, randomized blind on-off fortnights 9 months after stimulation onset. The primary objectives were to investigate safety and feasibility, together with changes in eating disorder psychopathology.

Results

Feasibility and safety was demonstrated with no serious adverse events due to deep brain stimulation. Three patients responded to treatment [defined as > 35% reduction in Eating Disorders Examination (EDE) score at 12 months] and four patients were non-responders. Responders had a statistically significant mean reduction in EDE scores (50.3% reduction; 95% CI 2.6–98.2%), Clinical Impairment Assessment (45.6% reduction; 95% CI 7.4–83.7%). Responders also had a statistically significant mean reduction in Hamilton Depression Scale, Hamilton Anxiety Scale and Snaith-Hamilton pleasure scale. There were no statistically significant changes in Body Mass Index, Yale-Brown-Cornell Eating Disorder Scale, Yale-Brown Obsessive–Compulsive Scale and World Health Organization Quality of Life Psychological subscale.

Conclusion

This study provides some preliminary indication that deep brain stimulation to the NAcc. Might potentially improve some key features of enduring AN. In this small study, the three responders had comorbid obsessive-compulsive disorder which predated AN diagnosis. Future studies should aim to further elucidate predictors of outcome.

Clinical Trial Registration

[www.ClinicalTrials.gov], identifier [Project ID 128658].
Designing AAV Vectors for Monitoring the Subtle Calcium Fluctuations of Inferior Olive Network in vivo
Authors: Dorgans Kevin , Guo Da , Kurima Kiyoto , Wickens Jeff , Uusisaari Marylka Yoe
Published: April 2022

Adeno-associated viral (AAV) vectors, used as vehicles for gene transfer into the brain, are a versatile and powerful tool of modern neuroscience that allow identifying specific neuronal populations, monitoring and modulating their activity. For consistent and reproducible results, the AAV vectors must be engineered so that they reliably and accurately target cell populations. Furthermore, transgene expression must be adjusted to sufficient and safe levels compatible with the physiology of studied cells. We undertook the effort to identify and validate an AAV vector that could be utilized for researching the inferior olivary (IO) nucleus, a structure gating critical timing-related signals to the cerebellum. By means of systematic construct generation and quantitative expression profiling, we succeeded in creating a viral tool for specific and strong transfection of the IO neurons without adverse effects on their physiology. The potential of these tools is demonstrated by expressing the calcium sensor GCaMP6s in adult mouse IO neurons. We could monitor subtle calcium fluctuations underlying two signatures of intrinsic IO activity: the subthreshold oscillations (STOs) and the variable-duration action potential waveforms both in-vitro and in-vivo. Further, we show that the expression levels of GCaMP6s allowing such recordings are compatible with the delicate calcium-based dynamics of IO neurons, inviting future work into the network dynamics of the olivo-cerebellar system in behaving animals.
Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory
Authors: Gustavsson Jonatan , Papenberg Goran , Falahati Farshad , Laukka Erika J. , Kalpouzos Grégoria
Published: April 2022

Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of COMT Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample (n = 208, age 20–79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50–79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20–49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan.
Enhanced Nerve Regeneration by Bionic Conductive Nerve Scaffold Under Electrical Stimulation
Authors: Liu Zhenhui , Liu Yanshi , Yushan Maimaiaili , Yusufu Aihemaitijiang
Published: April 2022

Repair of peripheral nerve defect (PND) with a poor prognosis is hard to deal with. Neural conduit applied to nerve defect at present could not achieve the effect of autologous nerve transplantation. We prepared bionic conductive neural scaffolds to provide a new strategy for the treatment of PNDs. The highly aligned poly (L-lactic acid) (PLLA) fiber mats and the multi-microchannel conductive scaffolds were combined into bionic conductive nerve scaffolds, which were implanted into rats with sciatic nerve defects. The experimental animals were divided into the scaffold group (S), scaffold with electrical stimulation (ES) group (S&E), and autologous nerve transplantation group (AT). The regenerative effect of bionic conductive nerve scaffolds was analyzed. Compared with aligned PLLA fiber mats (APFMs), highly aligned fiber mats had a higher fiber orientation and did not change the tensile strength, Young’s modulus, degradation rate, elongation at break of the fiber membrane, and biocompatibility. The bionic conductive nerve scaffolds were well matched with the rat sciatic nerve. The evaluations of the sciatic nerve in Group S&E were close to those in Group AT and better than those in Group S. Immunohistochemical results showed that the expression levels of neurofilament heavy polypeptide (NF-H) and protein S100-B (S100-β) in Group S&E were higher than those in Group S, and the expression levels of low-density lipoprotein receptor-related protein 4 (LRP4), mitogen-activated protein kinase (MAPK) p38, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase kinase (MEK) in Group AT were higher than those in Group S. Bionic conductive nerve scaffolds combined with ES could enhance peripheral nerve regeneration and achieve satisfactory nerve regeneration close to autologous nerve grafts. ERK, p38 MAPK, MEK, and LRP4 may be involved in peripheral nerve regeneration under ES.
Alzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint
Authors: Alawode Deborah O. T. , Fox Nick C. , Zetterberg Henrik , Heslegrave Amanda J.
Published: April 2022

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid beta (Aβ) is one of the proteins which aggregate in AD, and its key role in the disease pathogenesis is highlighted in the amyloid cascade hypothesis, which states that the deposition of Aβ in the brain parenchyma is a crucial initiating step in the future development of AD. The sensitivity of instruments used to measure proteins in blood and cerebrospinal fluid has significantly improved, such that Aβ can now successfully be measured in plasma. However, due to the peripheral production of Aβ, there is significant overlap between diagnostic groups. The presence of pathological Aβ within the AD brain has several effects on the cells and surrounding tissue. Therefore, there is a possibility that using markers of tissue responses to Aβ may reveal more information about Aβ pathology and pathogenesis than looking at plasma Aβ alone. In this manuscript, using the amyloid cascade hypothesis as a starting point, we will delve into how the effect of Aβ on the surrounding tissue can be monitored using biomarkers. In particular, we will consider whether glial fibrillary acidic protein, triggering receptor expressed on myeloid cells 2, phosphorylated tau, and neurofilament light chain could be used to phenotype and quantify the tissue response against Aβ pathology in AD.
Altered Mitochondrial Protein Homeostasis and Proteinopathies
Authors: Jishi Aya , Qi Xin
Published: April 2022

Increasing evidence implicates mitochondrial dysfunction as key in the development and progression of various forms of neurodegeneration. The multitude of functions carried out by mitochondria necessitates a tight regulation of protein import, dynamics, and turnover; this regulation is achieved via several, often overlapping pathways that function at different levels. The development of several major neurodegenerative diseases is associated with dysregulation of these pathways, and growing evidence suggests direct interactions between some pathogenic proteins and mitochondria. When these pathways are compromised, so is mitochondrial function, and the resulting deficits in bioenergetics, trafficking, and mitophagy can exacerbate pathogenic processes. In this review, we provide an overview of the regulatory mechanisms employed by mitochondria to maintain protein homeostasis and discuss the failure of these mechanisms in the context of several major proteinopathies.
Fiscal Reform in Costa Rica: Price Elasticities of Major Food Categories to Inform Decision-Making
Authors: Dal Eléonore , Rivera Rodrigo , Morales Opazo Cristian , Madrigal Mariela
Published: April 2022

In the context of fiscal reform in Costa Rica (value added tax revision), the definition of a new basic tax basket, “canasta básica tributaria” (CBT) in Spanish, incorporating nutritional criteria is underway in the country. In this study, price elasticities of major food categories were analyzed using a Quadratic Almost Ideal Demand System (QUAIDS) model. Data from the 2018 National Survey of Household Income and Expenditures was used. Measuring price elasticities is essential because it allows: knowing the extent to which food demand reacts to price changes, anticipating changes in the quantities demanded as a result of fiscal policy changes, measuring potential substitution and complementary effects between food groups, and potential nutritional effects of fiscal policies. As a result, it helps providing recommendations on the content of a CBT with nutritional criteria. Results show that the food categories with the most elastic demand are “Bread and cereals,” soft drinks and “Milk, cheese and eggs.” Substitution effects exist between the following groups: “Fruits” and “Oils and fats,” “Fruits” and “Bread and cereals,” and between “Milk, cheese and eggs” and “Oils and fats.” For this last food category and for the one which includes sweets and chocolates, the consumption decreases when the price of “Bread and cereals” increases. They are complementary goods. These relations between food groups need to be taken into account when defining a national CBT with nutritional criteria and with the objective of promoting the consumption of healthier food groups while disincentivizing the consumption of the unhealthy ones. Lastly, it is important that the consumption of the healthiest foods within each food group be fiscally promoted.

Clinical Trial Registration

JEL codes: D12, H3, I18.
Preventive Effect of Limosilactobacillus fermentum SCHY34 on Lead Acetate-Induced Neurological Damage in SD Rats
Authors: Long Xingyao , Wu Haibo , Zhou Yujing , Wan Yunxiao , Kan Xuemei , Gong Jianjun , Zhao Xin
Published: April 2022

Lead poisoning caused by lead pollution seriously affects people's health. Lactic acid bacteria has been shown to be useful for biological scavenging of lead. In this experiment, Sprague-Dawley (SD) rats were treated with 200 mg/L of lead acetate solution daily to induce chronic lead poisoning, and oral Limosilactobacillus fermentum (L. fermentum) SCHY34 to study its mitigation effects and mechanisms on rat neurotoxicity. The L. fermentum SCHY34 showed competent results on in vitro survival rate and the lead ion adsorption rate. Animal experiments showed that L. fermentum SCHY34 maintained the morphology of rat liver, kidney, and hippocampi, reduced the accumulation of lead in the blood, liver, kidney, and brain tissue. Further, L. fermentum SCHY34 alleviated the lead-induced decline in spatial memory and response capacity of SD rats, and also regulated the secretion of neurotransmitters and related enzyme activities in the brain tissue of rats, such as glutamate (Glu), monoamine oxidase (MAO), acetylcholinesterase (AchE), cyclic adenosine monophosphate (cAMP), and adenylate cyclase (AC). In addition, the expression of genes related to cognitive capacity, antioxidation, and anti-apoptotic in rat brain tissues were increased L. fermentum SCHY34 treatment, such as brain-derived neurotrophic factor (BDNF), c-fos, c-jun, superoxide dismutase (SOD)1/2, Nuclear factor erythroid 2-related factor 2 (Nrf2), and B-cell lymphoma 2 (Bcl-2), and so on. L. fermentum SCHY34 showed a great biological scavenging and potential effect on alleviating the toxicity of lead ions.
Integrated Whole-Transcriptome Profiling and Bioinformatics Analysis of the Polypharmacological Effects of Ganoderic Acid Me in Colorectal Cancer Treatment
Authors: Chen Nianhong , Wan Guoqing , Zeng Xiaobin
Published: April 2022

Ganoderic acid Me (GA-Me) is a natural bioactive compound derived from Ganoderma lucidum. Our present results suggested that GA-Me inhibited proliferation, induced DNA fragmentation and significantly activated caspase-9 and caspase-3 in HCT116 cells. As shown in our previous studies, GA-Me targets several genes to prevent cancer, including colorectal cancer (CRC). Thus, we hypothesized that GA-Me might be a multitarget ligand against cancer. However, its exact mechanism in CRC remains unclear. Here, whole-transcriptome sequencing was employed to assess the long noncoding RNA (lncRNA), circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) profiles of GA-Me-treated HCT116 cells. In total, 1572 differentially expressed (DE) lncRNAs, 123 DEcircRNAs, 87 DEmiRNAs, and 1508 DEmRNAs were identified. DCBLD2 and RAPGEF5 were validated as two core mRNAs in the DElncRNA, DEcircRNA, and DEmiRNA networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed the biological functions and potential mechanisms of TCONS-00008997, XR-925056.2, circRNA-07908, hsa-miR-100-3p, hsa-miR-1257, hsa-miR-3182, NAV3, ADAM20, and STARD4, which were altered after GA-Me treatment. The regulatory relationships of the XR-925056.2-hsa-miR-3182-NAV3/ADAM20/STARD4, circRNA-07908|Chr22:38986298-39025349-hsa-miR-3182-NAV3/ADAM20, ENST00000414039/ENST00000419190-novel874_mature-MMP9 and circRNA-00314|Chr1:35470863-35479212/circRNA-05460|Chr17:72592203-72649268-novel874_mature-MMP9 immune-regulatory networks involved both noncoding RNAs (ncRNAs) and mRNAs. Molecular docking studies showed that Zn2+ and the His201, His205, His211, Glu202, and Ala165 residues of MMP2 contributed to its high affinity for GA-Me. Zn2+ and the Glu402 and Gly186 residues of MMP9 are important for its interaction with GA-Me. Our results suggested and confirmed that GA-Me is a potential multitarget lead compound for CRC treatment with unique polypharmacological advantages.
MET Inhibition Sensitizes Rhabdomyosarcoma Cells to NOTCH Signaling Suppression
Authors: Perrone Clara , Pomella Silvia , Cassandri Matteo , Pezzella Michele , Milano Giuseppe Maria , Colletti Marta , Cossetti Cristina , Pericoli Giulia , Di Giannatale Angela , de Billy Emmanuel , Vinci Maria , Petrini Stefania , Marampon Francesco , Quintarelli Concetta , Taulli Riccardo , Roma Josep , Gallego Soledad , Camero Simona , Mariottini Paolo , Cervelli Manuela , Maestro Roberta , Miele Lucio , De Angelis Biagio , Locatelli Franco , Rota Rossella
Published: April 2022

Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through γ-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition.
Hypofractionated Radiotherapy for Palliation of Main Portal Vein Tumor Thrombosis
Authors: Fang Fang , Qiu Bin , Zhen Peng , Wang Junjie
Published: April 2022

Background

Hypofractionated radiotherapy delivered for portal vein tumor thrombosis (PVTT) located in the main portal vein is rarely exploited. The study aimed to evaluate the efficacy and safety of hypofractionated radiotherapy as palliative treatment for PVTT in cirrhotic patients with hepatocellular carcinoma.

Methods

From March 2016 to July 2020, 16 patients (mean age, 59.1 ± 6.3 years; 15 men) with hepatocellular carcinoma and hepatitis virus-related cirrhosis who underwent hypofractionated radiotherapy for PVTT (located in the main portal vein) in our institute were retrospectively reviewed.

Results

Complete response of the PVTT was observed in 4 cases (25%) with partial response in 7 cases (43.75%) and stable disease in 5 cases (31.25%). Symptom relief was observed in all 7 patients suffering from ventosity. The median time to progression was 6 months (interquartile range, IQR: 6–12 months). Eight patients (50%) failed due to primary cancer progression, 7 patients failed due to extrahepatic metastasis, and only 1 patient failed due to PVTT progression. The median overall survival was 17.4 months (IQR: 8–25 months). Grade I/II anorexia/nausea was observed in 14 patients (87.5%) and Grade I/II leukopenia was observed in 14 patients (87.5%). No complications ≥ Grade III were observed.

Conclusions

Hypofractionated radiotherapy as palliative treatment appears effective and safe for PVTT located in the main portal vein in cirrhotic patients with advanced hepatocellular carcinoma, yielding a high rate of tumor response. Further study is warranted.
Prognostic Nomogram Based on the Metastatic Lymph Node Ratio for T1-4N0-1M0 Pancreatic Neuroendocrine Tumors After Surgery
Authors: Shi Jingxiang , Liu Sifan , Cao Jisen , Shan Shigang , Ren Chaoyi , Zhang Jinjuan , Wang Yijun
Published: April 2022

Purpose

This study aimed to investigate the prognostic significance of the metastatic lymph node ratio (LNR) in patients with pancreatic neuroendocrine tumors (pNETs) and to develop and validate nomograms to predict 5-, 7-, and 10-year overall survival (OS) and cancer-specific survival (CSS) rates for pNETs after surgical resection.

Methods

The demographics and clinicopathological information of T1-4N0-1M0 pNET patients between 2004 and 2018 were extracted from the Surveillance, Epidemiology and End Results database. X-tile software was used to determine the best cutoff value for the LNR. Patients were randomly divided into the training and the validation groups. A Cox regression model was used in the training group to obtain independent prognostic factors to develop nomograms for predicting OS and CSS. The concordance index (C-index), calibration curves, area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to assess the nomograms. Patients were divided into four groups according to the model scores, and their survival curves were generated by the Kaplan–Meier method.

Results

A total of 806 patients were included in this study. The best cutoff value for the LNR was 0.16. The LNR was negatively correlated with both OS and CSS. Age, sex, marital status, primary site, grade, the LNR and radiotherapy were used to construct OS and CSS nomograms. In the training group, the C-index was 0.771 for OS and 0.778 for CSS. In the validation group, the C-index was 0.737 for OS and 0.727 for CSS. The calibration curves and AUC also indicated their good predictability. DCA demonstrated that the nomograms displayed better performance than the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition). Risk stratification indicated that patients with higher risk had a worse prognosis.

Conclusions

The LNR is an independent negative prognostic factor for pNETs. The nomograms we built can accurately predict long-term survival for pNETs after surgery.
Emergence and Persistence of Resistance-Associated Substitutions in HCV GT3 Patients Failing Direct-Acting Antivirals
Authors: Mushtaq Saima , Hashmi Asraf Hussain , Khan Amjad , Asad Raza Kazmi Syed Muhammad , Manzoor Sobia
Published: April 2022

Background: The hepatitis C virus has a high mutation rate, which results in the emergence of resistance-associated substitutions (RASs). Despite direct-acting antivirals (DAAs) efforts to treat chronically infected HCV genotype 3 (GT3) patients, there are concerns about the emergence and persistence of RASs in DAA failures. The objective of this study was to determine the prevalence of clinically relevant RASs in HCV NS5A and NS5B regions before and after treatment to better understand the role of RASs in treatment failures.

Methods: Viral RNA was extracted before and after treatment from serum samples. NS5A and NS5B regions of HCV were amplified by nested PCR, followed by Sanger sequencing. The nucleotide sequences were aligned against HCV GT3 reference sequences, and amino acid substitutions were analyzed using the geno2pheno [hcv] webserver.

Results: A total of 76 patients failing DAA therapy were stratified from the cohort of 1388. RASs were detected at the baseline in 15/76 patients and at relapse in 20/76 patients with cirrhosis and previously treated with interferons. The most prevalent NS5A RAS was Y93H found in all treatment-failing patients (14/54 in DCV vs. 6/22 in VEL), followed by A62S/T and A30K. No RASs were identified in NS5B. RASs that were present at the baseline persisted through the 24-week follow-up period and were enriched with emerging RASs during the treatment. The presence of RASs may be one of the causes of treatment failures in 26.3% of patients. Amino acid substitutions were present at the baseline in most of the patients with RASs against NS5A inhibitors. Patients with the baseline Y93H and/or A30K relapse more frequently than patients harboring A62S/T.

Conclusion: Treatment-failing patients harbored NS5A RASs, and the most frequent were A30K (5/20), A62S/T (20/20), and Y93H (20/20). Direct resistance testing is recommended for optimizing re-treatment strategies in treatment-failing patients.
Observer-Based Adaptive Fuzzy Output Feedback Control of Fractional-Order Chaotic Systems With Input Quantization
Authors: Qiu Hongling , Huang Chengdai , Tian Huanhuan , Liu Heng
Published: April 2022

This study investigates the adaptive fuzzy output feedback control of strict-feedback fractional-order chaotic systems with unmeasurable states and quantized input. First, the functional uncertainties are approximated by fuzzy logic systems (FLSs). Second, combining the FLS and the system output signal, an observer is constructed to estimate the unmeasurable states. A command filter is defined to cope with the “explosion of complexity” problem resulting from the repeated derivatives of virtual control inputs in each backstepping step. To compensate for quantization errors, a hyperbolic tangent function is introduced to transform the control signal, which can not only guarantee that the tracking error converges to an arbitrarily small region near the origin but also reduce the chattering phenomenon of the control input. In addition, the stability analysis is carried out relying on the fractional Lyapunov stability criterion such that all the signals keep bounded. Finally, a numerical simulation example is put forward to verify the effectiveness of our method.
A New Four-Dimensional Chaotic System and its Circuit Implementation
Authors: Wang Xuan , Feng Yiran , Chen Yixin
Published: April 2022

A new four-dimensional chaotic system is designed in the paper. The equilibrium point and stability of the chaotic system are analyzed, and the dynamical behaviors of the system under different parameters are analyzed by using Lyapunov exponents, Bfurcation diagram, SE and C0 complexity algorithms. The special phenomenon of the coexistence of attractors is also found. Finally, the implementation of circuit of the new system is carried out using digital signal processing (DSP) technology, and the results are consistent with the numerical simulation results, which prove the validity of the theoretical analysis. Through analysis and simulation of the system, it can be found that it has relatively rich dynamic characteristics and can be applied in areas such as confidential communication and image encryption.
CmWRKY15-1 Promotes Resistance to Chrysanthemum White Rust by Regulating CmNPR1 Expression
Authors: Gao Ge , Jin Ruibing , Liu Di , Zhang Xin , Sun Xiaomei , Zhu Pengfang , Mao Hongyu
Published: April 2022

Chrysanthemum white rust (CWR), a disease caused by the fungus Puccinia horiana Henn., seriously impairs the production and ornamental value of chrysanthemums. We previously isolated the disease-resistance gene CmWRKY15-1 from the chrysanthemum and generated CmWRKY15-1 transgenic plants. Here, we determined that CmWRKY15-1-overexpressing lines of the susceptible cultivar ‘Jinba’ show higher defensive enzyme activity and lower H2O2 levels than a wild type after inoculation with P. horiana, indicating that CmWRKY15-1 positively regulates plant responses to P. horiana. To further explore the mechanism underlying this effect, we performed RNA sequencing using the leaves of wild-type and CmWRKY15-1-RNA interference lines of the resistant cultivar ‘C029’ after treatment with P. horiana. We identified seven differentially expressed genes in the salicylic acid (SA) pathway, including CmNPR1 (Non-expressor of pathogenesis-related genes 1), encoding an important regulator of this pathway. We isolated the CmNPR1 promoter by hiTAIL-PCR and predicted that it contains pathogen-induced W-box elements. The promoter region of CmNPR1 was activated by P. horiana in a β-glucuronidase activity assay. Yeast one-hybrid assays showed that CmWRKY15-1 binds to the CmNPR1 promoter region to regulate its expression. Finally, we confirmed the interaction between CmWRKY15-1 and CmNPR1 in a bimolecular fluorescence complementation assay. We propose that CmWRKY15-1 interacts with CmNPR1 to activate the expression of downstream pathogenesis-related genes that enhance resistance to P. horiana through the SA pathway. These findings shed light on the mechanism underlying resistance to CWR.
Lockdown Social Isolation and Lockdown Stress During the COVID-19 Pandemic in China: The Impact of Mindfulness
Authors: Li Jianfeng , Zhou Luyang , Van der Heijden Beatrice , Li Shengxiao , Tao Hong , Guo Zhiwen
Published: April 2022

This study is aimed to examine the impact of mindfulness in the relationship between social isolation, job and financial insecurity, and stress during the lockdown period of the COVID-19 pandemic. Drawing on Conservation of Resources theory, Psychological Contract theory, Mindfulness theory, and Awareness notion, we propose that lockdown job insecurity partially mediates the link from lockdown social isolation to lockdown financial insecurity, and that the relationship between lockdown social isolation and lockdown stress is mediated as follows: first, simple partial mediation through both lockdown job and financial insecurity and second, sequential mediation through lockdown job and financial insecurity, respectively. Moreover, we assume that mindfulness moderates the relationship between lockdown financial insecurity and lockdown stress. The results from our SEM analyses, using a sample of 1,356 respondents in China, support all the research hypotheses. Based on this empirical work, this study concludes that mindfulness, which is considered by many people to play a role in reducing stress during the COVID-19 lockdown period, is de facto endangering their mental health (that is, they experience more stress) instead. Theoretical and practical implications, as well as limitations and proposals for future research are discussed.
Morphosyntactic Skills Influence the Written Decoding Accuracy of Italian Children With and Without Developmental Dyslexia
Authors: Casani Emanuele , Vulchanova Mila , Cardinaletti Anna
Published: April 2022

Some types of developmental dyslexia (DD) are associated with morphology. Deep DD leads to morphological and semantic errors, and possible comorbidity with syntactic deficits; phonological-output-buffer DD causes problems in decoding longer morphologically complex words. In addition, cross-linguistic studies highlight the effects of morphological awareness on reading accuracy and fluency. The role of morphosyntactic abilities on reading is, however, not clear. This study explores the influence of morphosyntactic competence on reading in Italian children with and without DD. A total of 14 children with DD and 28 with Typical Development (TD) attending the Italian primary school were tested on written decoding, syntactic comprehension of different grammatical structures, and syntactic production of direct object clitic pronouns. DD children were significantly less accurate and slower in reading than TD children. Syntactic skills of the two groups did not differ significantly, but some differences in their acquisitional pace emerged. Syntactic comprehension and production of direct-object-clitic pronouns predicted reading accuracy standard scores, thus suggesting that morphosyntactic abilities, beyond clitics’ weak phonological status, affect decoding accuracy. Decoding accuracy was influenced by reading errors related to morphology (morphological, semantic, and phonological-output-buffer errors). Decoding speed was a specific weakness of DD children and was rather affected by multi-letter combinations. Consistent with a dual-route approach to orthographic processing, we argue that accuracy depends on fine-grained decoding strategies maximizing the precise ordering of letters, thus it is more sensitive to morphosyntactic skills. Morphological reading errors were associated with phonologically weak (determiners, clitic pronouns, and prepositions) and salient words (verbs). This suggests that the decoding of function words and morphologically complex words is particularly demanding and related to both phonological and morphosyntactic skills. Age had a negative predictive effect on semantic errors, compatible with the gradual acquisition of lexical decoding strategies, which seemed to be slowed down by DD. We conclude that oral morphosyntactic skills play a role in reading accuracy in the Italian shallow orthography for both DD and TD children. It is then advisable to assess children’s linguistic profile during DD diagnoses to establish whether some reading errors are related to morphosyntactic weakness. In this case, ad hoc morphosyntactic training might support reading accuracy.
English Teachers’ Conceptualizations of Key Competencies in English Language Teaching and Challenges to Their Implementation
Authors: Lu Huashan , Jiang Changgang , Guo Fei
Published: April 2022

Limited empirical research on the key competencies of front-line English teachers, particularly primary and middle school English teachers in rural regions, exists in the current literature. This research focuses on front-line instructors and examines their mastery of the key competencies in English language teaching. Through in-depth interviews, this paper examined eight rural junior middle school English teachers on their understanding of developing students’ key competencies in English language teaching, as well as the obstacles and challenges they experienced in curriculum implementation. The study found that although front-line teachers have a positive attitude toward the key competencies, there is still a certain gap between their comprehension of key competencies and policy requirements and practical demands. In order to implement core qualities and effectively promote curriculum reform, we need to strengthen teacher development training for front-line English teachers, especially for primary and secondary school English teachers in rural areas, to improve their understanding and professionalization of the new round of curriculum reform.