bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of immunoglobulin loci in the gigantic genome of Ambystoma mexicanum
Authors: Martinez-Barnetche Jesús , Godoy-Lozano Elizabeth Ernestina , Saint Remy-Hernández Stephanie , Pacheco-Olvera Diana Laura , Téllez-Sosa Juan , Valdovinos-Torres Humberto , Pastelin-Palacios Rodolfo , Mena Horacio , Zambrano Luis , López-Macías Constantino
Published: January 2023

Background

The axolotl, Ambystoma mexicanum is a unique biological model for complete tissue regeneration. Is a neotenic endangered species and is highly susceptible to environmental stress, including infectious disease. In contrast to other amphibians, the axolotl is particularly vulnerable to certain viral infections. Like other salamanders, the axolotl genome is one of the largest (32 Gb) and the impact of genome size on Ig loci architecture is unknown. To better understand the immune response in axolotl, we aimed to characterize the immunoglobulin loci of A. mexicanum and compare it with other model vertebrates.

Methods

The most recently published genome sequence of A. mexicanum (V6) was used for alignment-based annotation and manual curation using previously described axolotl Ig sequences or reference sequences from other vertebrates. Gene models were further curated using A. mexicanum spleen RNA-seq data. Human, Xenopus tropicalis, Danio rerio (zebrafish), and eight tetrapod reference genomes were used for comparison.

Results

Canonical A. mexicanum heavy chain (IGH), lambda (IGL), sigma (IGS), and the putative surrogate light chain (SLC) loci were identified. No kappa locus was found. More than half of the IGHV genes and the IGHF gene are pseudogenes and there is no clan I IGHV genes. Although the IGH locus size is proportional to genome size, we found local size restriction in the IGHM gene and the V gene intergenic distances. In addition, there were V genes with abnormally large V-intron sizes, which correlated with loss of gene functionality.

Conclusion

The A. mexicanum immunoglobulin loci share the same general genome architecture as most studied tetrapods. Consistent with its large genome, Ig loci are larger; however, local size restrictions indicate evolutionary constraints likely to be imposed by high transcriptional demand of certain Ig genes, as well as the V(D)J recombination over very long genomic distance ranges. The A. mexicanum has undergone an extensive process of Ig gene loss which partially explains a reduced potential repertoire diversity that may contribute to its impaired antibody response.
Single-cell sequencing combined with machine learning reveals the mechanism of interaction between epilepsy and stress cardiomyopathy
Authors: Ji Xuanrui , Pei Quanwei , Zhang Junpei , Lin Pengqi , Li Bin , Yin Hongpeng , Sun Jingmei , Su Dezhan , Qu Xiufen , Yin Dechun
Published: January 2023

Background

Epilepsy is a disorder that can manifest as abnormalities in neurological or physical function. Stress cardiomyopathy is closely associated with neurological stimulation. However, the mechanisms underlying the interrelationship between epilepsy and stress cardiomyopathy are unclear. This paper aims to explore the genetic features and potential molecular mechanisms shared in epilepsy and stress cardiomyopathy.

Methods

By analyzing the epilepsy dataset and stress cardiomyopathy dataset separately, the intersection of the two disease co-expressed differential genes is obtained, the co-expressed differential genes reveal the biological functions, the network is constructed, and the core modules are identified to reveal the interaction mechanism, the co-expressed genes with diagnostic validity are screened by machine learning algorithms, and the co-expressed genes are validated in parallel on the epilepsy single-cell data and the stress cardiomyopathy rat model.

Results

Epilepsy causes stress cardiomyopathy, and its key pathways are Complement and coagulation cascades, HIF-1 signaling pathway, its key co-expressed genes include SPOCK2, CTSZ, HLA-DMB, ALDOA, SFRP1, ERBB3. The key immune cell subpopulations localized by single-cell data are the T_cells subgroup, Microglia subgroup, Macrophage subgroup, Astrocyte subgroup, and Oligodendrocytes subgroup.

Conclusion

We believe epilepsy causing stress cardiomyopathy results from a multi-gene, multi-pathway combination. We identified the core co-expressed genes (SPOCK2, CTSZ, HLA-DMB, ALDOA, SFRP1, ERBB3) and the pathways that function in them (Complement and coagulation cascades, HIF-1 signaling pathway, JAK-STAT signaling pathway), and finally localized their key cellular subgroups (T_cells subgroup, Microglia subgroup, Macrophage subgroup, Astrocyte subgroup, and Oligodendrocytes subgroup). Also, combining cell subpopulations with hypercoagulability as well as sympathetic excitation further narrowed the cell subpopulations of related functions.
Network analyses of upper and lower airway transcriptomes identify shared mechanisms among children with recurrent wheezing and school-age asthma
Authors: Wang Zhili , He Yu , Li Qinyuan , Zhao Yan , Zhang Guangli , Luo Zhengxiu
Published: January 2023

Background

Predicting which preschool children with recurrent wheezing (RW) will develop school-age asthma (SA) is difficult, highlighting the critical need to clarify the pathogenesis of RW and the mechanistic relationship between RW and SA. Despite shared environmental exposures and genetic determinants, RW and SA are usually studied in isolation. Based on network analysis of nasal and tracheal transcriptomes, we aimed to identify convergent transcriptomic mechanisms in RW and SA.

Methods

RNA-sequencing data from nasal and tracheal brushing samples were acquired from the Gene Expression Omnibus. Combined with single-cell transcriptome data, cell deconvolution was used to infer the composition of 18 cellular components within the airway. Consensus weighted gene co-expression network analysis was performed to identify consensus modules closely related to both RW and SA. Shared pathways underlying consensus modules between RW and SA were explored by enrichment analysis. Hub genes between RW and SA were identified using machine learning strategies and validated using external datasets and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the potential value of hub genes in defining RW subsets was determined using nasal and tracheal transcriptome data.

Results

Co-expression network analysis revealed similarities in the transcriptional networks of RW and SA in the upper and lower airways. Cell deconvolution analysis revealed an increase in mast cell fraction but decrease in club cell fraction in both RW and SA airways compared to controls. Consensus network analysis identified two consensus modules highly associated with both RW and SA. Enrichment analysis of the two consensus modules indicated that fatty acid metabolism-related pathways were shared key signals between RW and SA. Furthermore, machine learning strategies identified five hub genes, i.e., CST1, CST2, CST4, POSTN, and NRTK2, with the up-regulated hub genes in RW and SA validated using three independent external datasets and qRT-PCR. The gene signatures of the five hub genes could potentially be used to determine type 2 (T2)-high and T2-low subsets in preschoolers with RW.

Conclusions

These findings improve our understanding of the molecular pathogenesis of RW and provide a rationale for future exploration of the mechanistic relationship between RW and SA.
Neutrophil extracellular traps in autoimmune diseases: Analysis of the knowledge map
Authors: Wang Wei , Su Jing , Kang Wenjuan , Yan Meiqin , Pan Jie , Zhang Xianhui
Published: January 2023

Introduction

Recent studies have shown much progress in the research of neutrophil extracellular traps (NETs) in autoimmune diseases (AIDs). However, there is no bibliometric analysis in this research field. This study aimed to provide a bibliometrics review of the knowledge structure and research hotspots of NETs in AIDs.

Methods

Articles relevant to NETs in AIDs from 2010 to 2022 were retrieved through the Web of Science Core Collection (WoSCC) database. This bibliometric analysis was performed by VOSview, CiteSpace, and Scimago Graphica.

Results

A total of 289 papers analyzed in this research were from 493 organizations in 47 countries by 1537 authors. They were published in 133 journals and cited 20,180 citations from 2,465 journals. The number of annual publications in this field is growing steadily and rapidly, with the United States, China and Germany leading the research effort. Frontiers in Immunology and Journal of Immunology have significantly impacted research in this field. Kaplan, Mariana J, from the National Institutes of Health (The United States), has the most published articles, and Brinkmann, v, from Max Planck Institute for Infection Biology (Germany), is the most co-cited author. Systemic lupus erythematosus and rheumatoid arthritis are the leading topics in this field. The trend of clinical application in the future is the development of new therapies by controlling NETs in the progression of AIDs.

Conclusions

Our study summarized the research trends and developments of NETs in AIDs in recent years and would provide a reference for scholars in this field.
Dual roles of anesthetics in postoperative cognitive dysfunction: Regulation of microglial activation through inflammatory signaling pathways
Authors: Zhang Mengxue , Yin Yiqing
Published: January 2023

Postoperative cognitive dysfunction (POCD) is a prevalent clinical entity following surgery and is characterized by declined neurocognitive function. Neuroinflammation mediated by microglia is the essential mechanism of POCD. Anesthetics are thought to be a major contributor to the development of POCD, as they promote microglial activation and induce neuroinflammation. However, this claim remains controversial. Anesthetics can exert both anti- and pro-inflammatory effects by modulating microglial activation, suggesting that anesthetics may play dual roles in the pathogenesis of POCD. Here, we review the mechanisms by which the commonly used anesthetics regulate microglial activation via inflammatory signaling pathways, showing both anti- and pro-inflammatory properties of anesthetics, and indicating how perioperative administration of anesthetics might either relieve or worsen POCD development. The potential for anesthetics to enhance cognitive performance based on their anti-inflammatory properties is further discussed, emphasizing that the beneficial effects of anesthetics vary depending on dose, exposure time, and patients’ characteristics. To minimize the incidence of POCD, we recommend considering these factors to select appropriate anesthetics.
T lymphocyte cell: A pivotal player in lung cancer
Authors: Wu Yanan , Yuan Meng , Wang Chenlin , Chen Yanfei , Zhang Yan , Zhang Jiandong
Published: January 2023

Lung cancer is responsible for the leading cause of cancer-related death worldwide, which lacks effective therapies. In recent years, accumulating evidence on the understanding of the antitumor activity of the immune system has demonstrated that immunotherapy is one of the powerful alternatives in lung cancer therapy. T cells are the core of cellular immunotherapy, which are critical for tumorigenesis and the treatment of lung cancer. Based on the different expressions of surface molecules and functional points, T cells can be subdivided into regulatory T cells, T helper cells, cytotoxic T lymphocytes, and other unconventional T cells, including γδ T cells, nature killer T cells and mucosal-associated invariant T cells. Advances in our understanding of T cells’ functional mechanism will lead to a number of clinical trials on the discovery and development of new treatment strategies. Thus, we summarize the biological functions and regulations of T cells on tumorigenesis, progression, metastasis, and prognosis in lung cancer. Furthermore, we discuss the current advancements of technologies and potentials of T-cell-oriented therapeutic targets for lung cancer.
Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress
Authors: Perrino Matteo , De Vincenzo Fabio , Cordua Nadia , Borea Federica , Aliprandi Marta , Santoro Armando , Zucali Paolo Andrea
Published: January 2023

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient’s selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated.

In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed.
Modelling distribution and fate of coralligenous habitat in the Northern Adriatic Sea under a severe climate change scenario
Authors: Vitelletti Maria Letizia , Manea Elisabetta , Bongiorni Lucia , Ricchi Antonio , Sangelantoni Lorenzo , Bonaldo Davide
Published: January 2023

Due to their well-acknowledged capability in predicting habitat distributions, Habitat Suitability Models (HSMs) are particularly useful for investigating ecological patterns variations under climate change scenarios. The shallow coastal regions of the Northern Adriatic Sea, a sub-basin of the Mediterranean Sea, are studded with coralligenous outcrops recognized as important biodiversity hotspots exposed to the effects of climate change. In this research, we investigate the distributions of the Northern Adriatic Sea coralligenous habitats characterized by diverse species assemblages differently influenced by environmental factors, and provide a projection of how these might be impacted by climate change. Two models (Random Forest and MaxEnt), populated with occurrence data gathered from previous publications, environmental parameters’ from online databases (CMEMS, Bio-Oracle), and a set of dedicated ocean model simulations, are applied in recent past conditions and under a future severe climate change scenario (RCP 8.5). The model performance metrics confirm the ability of both approaches for predicting habitat distribution and their relationship with environmental conditions. The results show that salinity, temperature, and nitrate concentration are generally the most relevant variables in affecting the coralligenous outcrops distribution. The environmental variations projected under climate change conditions are expected to favour the spreading of opportunistic organisms, more tolerant to stressful conditions, at the expense of more vulnerable species. This will result in a shift in the distribution of these habitats, with a consequent potential loss of biodiversity in the Northern Adriatic Sea.
Flow current field observation with underwater moving acoustic tomography
Authors: Xu Shijie , Feng Rendong , Xu Pan , Hu Zhengliang , Huang Haocai , Li Guangming
Published: January 2023

Underwater environment observation with underwater acoustic tomography has been considerably developed in recent years. Moving sound transmission can obtain the observation of entire spatial area with sound station moving. Various internal structures, unique surface and submarine boundaries and changing environment constitutes a complex acoustic propagation channel. This paper focus on the inversion method and signal resampling for sound moving transmission. Also, the current field in three-dimensional (3D) scale is also studied. A five-station sound transmission experiment with four moored station and one moving station that conducted in range of 500m×500m at Huangcai reservoir, Changsha, China is presented. Signal resampling is performed to get correlation of received acoustic data. The vertical layer-averaged flow current results between moving station and moored station are inversed with 2D grid method. 3D flow current field result is composed by grid-averaged inversion current of vertical profile via moving station at different moment. The received results of reciprocal signal transmission between two moored stations and one moving station were used for layer-averaged current variations at vertical scale and grid-averaged current. The feasibility of the method in underwater moving acoustic tomography research is proved and its applicability is discussed. The proposed underwater acoustic tomography technology develops an innovative idea for the further development of temporal- spatial grided tomography observation.
Assessment of the physiological vulnerability of the endemic and critically endangered Daggernose Shark: A comparative approach to other Carcharhiniformes
Authors: Wosnick Natascha , Chaves Ana Paula , Dias Héllida Negrão , Onodera Palmeira Nunes Ana Rita , Nunes Jorge Luiz Silva , Hauser-Davis Rachel Ann
Published: January 2023

Introduction

The current Isogomphodon oxyrhynchus (Daggernose Shark) population status Q7points to 99% losses in the last decade due to certain biological traits, site fidelity, and historical high representativeness as bycatch in artisanal fisheries. This species is listed as Critically Endangered (CR), both in the IUCN and the Brazilian Red Lists. Its vulnerability is so high that its recovery potential requires protection from ongoing fishing pressure.

Objective

In this context, this study aimed to evaluate the health status of Daggernose sharks and their ability to cope with allostatic overload in a comparative analysis with other Carcharhinid and Sphyrnid sharks.

Methods

Sharks incidentally caught by the artisanal fleet in the state of Maranhão, on the Brazilian Amazon Coast, were sampled for blood, and serum was used to assess biochemical markers.

Results

The findings indicate significant differences in Daggernose Shark homeostatic capacity for ALP, ALT/GTP, creatinine, lactate, urea, total cholesterol, and triglycerides, pointing to lower health scores and recovery capacity when compared to other Carcharhiniformes inhabiting the same region.

Discussion and conclusions

It is possible that such vulnerability is a result of fisheries-induced evolution, leading to remaining populations with very low chances of fully recovering. Conservation planning is thus urgent, as current legislation based on fishing bans does very little for the species. International collaboration and longterm recovery measures are necessary, including the creation of MPAs specially designed for the species and captive maintenance aiming to monitor health status and carry out breeding attempts.
Influence of Caribbean eddies on the Loop current system evolution
Authors: Ntaganou Nektaria , Kourafalou Vassiliki , Beron-Vera Francisco Javier , Olascoaga Maria Josefina , Le Hénaff Matthieu , Androulidakis Yannis
Published: January 2023

The Loop Current (LC) system dynamics are an essential component of the processes influencing circulation and transport in the Gulf of Mexico (GoM). The LC evolution is influenced by various factors, including the rich eddy field of the region and the flow exchange through the Yucatan Strait with the neighboring Caribbean Sea. These factors contribute to the complexity of the LC and, as a result, to the limitations in the predictability of the system. The focus of this study is to further elucidate the evolution of the LC, by quantifying the influence of coherent eddy fluxes originating in the Caribbean Sea. This is achieved by employing the Lagrangian-Averaged Vorticity Deviation (LAVD) method, an objective metric to evaluate eddy coherence in the Caribbean Sea that allows, for the first time, to quantify at different depths the evolution of coherent Caribbean eddies through the Yucatan Channel towards the GoM. The physical connectivity between the Caribbean Sea and the GoM is addressed using Lagrangian techniques to analyze processes that take place south of the Yucatan Channel and help quantify their strong relationship with the GoM eddy field. Coherent anticyclonic vorticity fluxes, as well as the net coherent anticyclonic volume transport between the Caribbean Sea and the GoM are associated with Loop Current Eddy (LCE) detachments through direct connectivity between the coherent Caribbean anticyclones and the forming LCE. The findings have important implications for understanding and predicting the LC system and the physical connectivity processes between the GoM and the Caribbean Sea.
Gene differential co-expression analysis of male infertility patients based on statistical and machine learning methods
Authors: Jia Xuan , Yin ZhiXiang , Peng Yu
Published: January 2023

Male infertility has always been one of the important factors affecting the infertility of couples of gestational age. The reasons that affect male infertility includes living habits, hereditary factors, etc. Identifying the genetic causes of male infertility can help us understand the biology of male infertility, as well as the diagnosis of genetic testing and the determination of clinical treatment options. While current research has made significant progress in the genes that cause sperm defects in men, genetic studies of sperm content defects are still lacking. This article is based on a dataset of gene expression data on the X chromosome in patients with azoospermia, mild and severe oligospermia. Due to the difference in the degree of disease between patients and the possible difference in genetic causes, common classical clustering methods such as k-means, hierarchical clustering, etc. cannot effectively identify samples (realize simultaneous clustering of samples and features). In this paper, we use machine learning and various statistical methods such as hypergeometric distribution, Gibbs sampling, Fisher test, etc. and genes the interaction network for cluster analysis of gene expression data of male infertility patients has certain advantages compared with existing methods. The cluster results were identified by differential co-expression analysis of gene expression data in male infertility patients, and the model recognition clusters were analyzed by multiple gene enrichment methods, showing different degrees of enrichment in various enzyme activities, cancer, virus-related, ATP and ADP production, and other pathways. At the same time, as this paper is an unsupervised analysis of genetic factors of male infertility patients, we constructed a simulated data set, in which the clustering results have been determined, which can be used to measure the effect of discriminant model recognition. Through comparison, it finds that the proposed model has a better identification effect.
Functional microorganisms in Baijiu Daqu: Research progress and fortification strategy for application
Authors: Li Haideng , Liu Shengyuan , Liu Yanbo , Hui Ming , Pan Chunmei
Published: January 2023

Daqu is a saccharifying and fermenting starter in the production of Chinese Baijiu; its quality directly affects the quality of Baijiu. The production of Daqu is highly environment-dependent, and after long-term natural domestication, it is rich in a wide variety of microorganisms with a stable composition, which provide complex and diverse enzymes and flavor (precursor) substances and microbiota for Jiupei (Fermented grains) fermentation. However, inoculation with a relatively stable microbial community can lead to a certain upper limit or deficiencies of the physicochemical properties (e.g., saccharification capacity, esterification capacity) of the Daqu and affect the functional expression and aroma formation of the Daqu. Targeted improvement of this problem can be proposed by selecting functional microorganisms to fortify the production of Daqu. This review introduced the isolation, screening, identification and functional characteristics of culture-dependent functional microorganisms in Baijiu-brewing, the core functional microbiota community of Daqu, and the related research progress of functional microorganisms fortified Daqu, and summarized the fortifying strategies of functional microorganisms, aiming to further deepen the application of functional microorganisms fortification in Daqu fermentation and provide ideas for the flavor regulation and quality control of Baijiu.
Physicochemical property, volatile flavor quality, and microbial community composition of Jinhua fatty ham and lean ham: A comparative study
Authors: Zhang Jin , Zhao Ke , Li Huanhuan , Li Shuangxi , Xu Weimin , Chen Lihong , Xie Jing , Tang Honggang
Published: January 2023

The physicochemical property, volatile flavor compounds, and microbial community structure of Jinhua fatty ham (FH) and lean ham (LH) were investigated and compared by high-throughput sequencing and HS-GC-IMS. Results showed that FH had higher pH and slightly lighter and yellower color than LH. Meanwhile, 33 volatile flavor compounds were identified from FH and LH, among which LH showed higher abundance of total alcohols and acids, but FH had generally richer aldehydes, ketones, esters, heterocyclic, and sulfur-containing compounds. Moreover, FH and LH did not have significant difference in α-diversity of bacterial community, but LH presented a much lower α-diversity of fungal community than FH. Besides, the dominant microorganisms (relative abundance >2%) in FH were Ruminococcaceae UCG-005, Staphylococcus, Ruminococcaceae UCG-014, Meyerozyma, and Aspergillus at the genus level, while in LH were Staphylococcus, Psychrobacter, Halomonas, Propionicicella, Ruminococcaceae UCG-005, Meyerozyma, Yamadazyma, and Aspergillus. Furthermore, the analysis of Pearson’s correlation and metabolic network confirmed that the discriminative flavor compounds of FH were mainly β-oxidation and degradation products of fatty acids, while those of LH were mostly derived from the Strecker reaction or microbial metabolism of amino acids. The present study could help understand the potential pathway of characteristic microorganisms affecting flavor formation of fat-deficient dry-cured hams and provide theoretical supports for developing healthier fermented meat products.
Effects of sequential inhibitory and facilitatory repetitive transcranial magnetic stimulation on neurological and functional recovery of a patient with chronic stroke: A case report and literature review
Authors: Chen Nan , Qiu Xiao , Hua Yan , Hu Jian , Bai Yulong
Published: January 2023

Background and purpose

The effects of conventional protocols of repetitive transcranial magnetic stimulation (rTMS) in the chronic phase of stroke are limited. This study aimed to apply the sequential inhibitory and facilitatory rTMS for upper limb motor dysfunction post-stroke to observe the efficacy and explore the possible neurophysiological mechanism. We hypothesize that this protocol would both enhance the excitability of affected M1 and promote connections among motor areas.

Case description

We reported a 55-year-old female patient with a 1-year chronic stroke and right-sided hemiplegia, who underwent the 14-session rTMS with seven sessions of low frequency (LF) and with seven sessions of high frequency (HF). Clinical scales mainly including Fugl-Meyer Assessment of Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), neurophysiological measures, and functional near-infrared spectroscopy (fNIRS) were assessed before (T0), at the midpoint (T1), and after the intervention (T2).

Outcomes

The patient exhibited post-intervention improvement in upper extremity function. There was increased excitability in the ipsilesional hemisphere and the opposite in the contralesional hemisphere. The interhemispheric inhibition (IHI) ratio increased from 2.70 to 10.81 and finally decreased to 1.34. Oxy-Hb signal was significantly decreased in affected M1 and mildly decreased in unaffected M1, while that of PMC and SMA on the affected side increased significantly.

Conclusion

The sequential inhibitory and facilitatory rTMS significantly promoted motor recovery in the patient. Related mechanisms include upregulation of excitability in the ipsilesional hemisphere, return of interhemispheric balance, and neuroplasticity-induced cortical reorganization.
Case report: Novel ETFDH compound heterozygous mutations identified in a patient with late-onset glutaric aciduria type II
Authors: Zhu Sijia , Ding Dongxue , Jiang Jianhua , Liu Meirong , Yu Liqiang , Fang Qi
Published: January 2023

Glutaric aciduria type II (GA II) is an autosomal recessive metabolic disorder of fatty acid, amino acid, and choline metabolism. The late-onset form of this disorder is caused by a defect in the mitochondrial electron transfer flavoprotein dehydrogenase or the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Thus far, the high clinical heterogeneity of late-onset GA II has brought a great challenge for its diagnosis. In this study, we reported a 21-year-old Chinese man with muscle weakness, vomiting, and severe pain. Muscle biopsy revealed myopathological patterns of lipid storage myopathy, and urine organic acid analyses showed a slight increase in glycolic acid. All the aforementioned results were consistent with GA II. Whole-exome sequencing (WES), followed by bioinformatics and structural analyses, revealed two compound heterozygous missense mutations: c.1034A > G (p.H345R) on exon 9 and c.1448C>A (p.P483Q) on exon 11, which were classified as “likely pathogenic” according to American College of Medical Genetics and Genomics (ACMG). In conclusion, this study described the phenotype and genotype of a patient with late-onset GA II. The two novel mutations in ETFDH were found in this case, which further expands the list of mutations found in patients with GA II. Because of the treatability of this disease, GA II should be considered in all patients with muscular symptoms and acute metabolism decompensation such as hypoglycemia and acidosis.
Serum metabolomic analysis reveals key metabolites in drug treatment of central precocious puberty in female children
Authors: Chen Guo-you , Wang Li-zhe , Cui Yue , Liu Jin-cheng , Wang Li-qiu , Wang Long-long , Sun Jing-yue , Liu Chang , Tan Hai-ling , Li Qi , Jin Yi-si , Xu Zhi-chun , Yu De-jun
Published: January 2023

Precocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl–tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid–biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice.
Adaptive hypofractionted and stereotactic body radiotherapy for lung tumors with real-time MRI guidance
Authors: Bryant John M. , Sim Austin J. , Feygelman Vladimir , Latifi Kujtim , Rosenberg Stephen A.
Published: January 2023

The treatment of central and ultracentral lung tumors with radiotherapy remains an ongoing clinical challenge. The risk of Grade 5 toxicity with ablative radiotherapy doses to these high-risk regions is significant as shown in recent prospective studies. Magnetic resonance (MR) image-guided adaptive radiotherapy (MRgART) is a new technology and may allow the delivery of ablative radiotherapy to these high-risk regions safely. MRgART is able to achieve this by utilizing small treatment margins, real-time gating/tracking and on-table plan adaptation to maintain dose to the tumor but limit dose to critical structures. The process of MRgART is complex and has nuances and challenges for the treatment of lung tumors. We outline the critical steps needed for appropriate delivery of MRgART for lung tumors safely and effectively.
STK11 loss and SMARCB1 deficiency mutation in a dedifferentiated lung cancer patient present response to neo-adjuvant treatment with pembrolizumab and platinum doublet: A case report
Authors: Chen Jianxin , Wang Junhui
Published: January 2023

Cancers harboring serine threonine kinase (STK11) alteration or SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) mutation are conventionally considered as treatment-refractory to immune checkpoint inhibitors or chemotherapy, respectively. However in the present report, we demonstrated a case of dedifferentiated non-small cell lung cancer, characterized by STK11 loss (due to promoter loss) mutation co-mutated with SMARCB1 deficiency mutation, has achieved significantly partial response to neo-adjuvant treatment with pembrolizumab and platinum doublet regimen. Our case highlighted that either STK11 loss, or SMARCB1 deficiency mutation, might not be used to select patients for PD-(L)1 blockade therapy or chemotherapy, respectively. SKT11 loss accompanied with SMARCB1 deficiency mutation may benefit from immunotherapy combined with chemotherapy.
Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model
Authors: Babl Nathalie , Hofbauer Joshua , Matos Carina , Voll Florian , Menevse Ayse Nur , Rechenmacher Michael , Mair Ruth , Beckhove Philipp , Herr Wolfgang , Siska Peter J. , Renner Kathrin , Kreutz Marina , Schnell Annette
Published: January 2023

Introduction

The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro.

Methods

Experiments were performed with different LDL dosages (LDLlow = 50 μg/ml and LDLhigh = 200 μg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade.

Results

The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh.

Discussion

Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.
Network pharmacology and experimental study of phenolic acids in salvia miltiorrhiza bung in preventing ischemic stroke
Authors: Liu Chengdi , Du Lida , Zhang Sen , Wang Haigang , Kong Linglei , Du Guanhua
Published: January 2023

At present, the preventive effect of ischemic stroke is not ideal, and the preventive drugs are limited. Danshen, the dried root of Salvia miltiorrhiza Bge, is a common medicinal herb in Traditional Chinese Medicine, which has been used for the treatment of cardiovascular diseases for many years. Phenolic Acids extracted from danshen, which showed multiple biological activities, have been developed as an injection for the treatment of ischemic stroke. However, its preventive effect on ischemic stroke has not been fully reported. The current study aimed to identify the potential active phenolic acids for the prevention of ischemic stroke and explore its mechanism using network pharmacology and experimental analyses. The targets of phenolic acids and ischemic stroke were obtained from public databases. Network pharmacology predicted that 35 kinds of phenolic acids had 201 core targets with ischemic stroke. The core prevention targets of ischemic stroke include IL-6, AKT1, VEGFA, etc. The signaling pathways involved in core targets include AGE-RAGE signaling pathway, HIF-1 signaling pathway, and cAMP signaling pathways, etc. Then, the antiplatelet effect of phenolic acids was screened by in vitro antiplatelet experiment. Our results showed that phenolic acids have a good inhibitory effect on ADP-induced platelet aggregation and salvianolic acid A had a good antiplatelet effect. We further demonstrated that SAA preventive administration reduced neurobehavioral scores, decreased infarct size, and protected tight junction proteins in autologous thrombus stroke model. These studies not only shed light on the potential mechanisms of phenolic acids active components on ischemic stroke, but also provided theoretical and experimental information for the development of new medicines from Danshen for the prevention of ischemic stroke. In addition, our results suggest that SAA has the potential to be a candidate for ischemic stroke prevention drug.
Changes in cystic fibrosis transmembrane conductance regulator protein expression prior to and during elexacaftor-tezacaftor-ivacaftor therapy
Authors: Stanke Frauke , Pallenberg Sophia T. , Tamm Stephanie , Hedtfeld Silke , Eichhorn Ella M. , Minso Rebecca , Hansen Gesine , Welte Tobias , Sauer-Heilborn Annette , Ringshausen Felix C. , Junge Sibylle , Tümmler Burkhard , Dittrich Anna-Maria
Published: January 2023

Background: Defects in expression, maturation or function of the epithelial membrane glycoprotein CFTR are causative for the progressive disease cystic fibrosis. Recently, molecular therapeutics that improve CFTR maturation and functional defects have been approved. We aimed to verify whether we could detect an improvement of CFTR protein expression and maturation by triple therapy with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA).

Methods: Rectal suction biopsies of 21 p.Phe508del homozygous or compound heterozygous CF patients obtained pre- and during treatment with ELX/TEZ/IVA were analyzed by CFTR Western blot that was optimized to distinguish CFTR glycoisoforms.

Findings: CFTR western immunoblot analysis revealed that—compared to baseline—the levels of CFTR protein increased by at least twofold in eight out of 12 patients upon treatment with ELX/TEZ/IVA compared to baseline (p < 0.02). However, polydispersity of the mutant CFTR protein was lower than that of the fully glycosylated wild type CFTR Golgi isoform, indicating an incompletely glycosylated p.Phe508el CFTR protein isoform C* in patients with CF which persists after ELX/TEZ/IVA treatment.

Interpretation: Treatment with ELX/TEZ/IVA increased protein expression by facilitating the posttranslational processing of mutant CFTR but apparently did not succeed in generating the polydisperse spectrum of N-linked oligosaccharides that is characteristic for the wild type CFTR band C glycoisoform. Our results caution that the lower amounts or immature glycosylation of the C* glycoisoform observed in patients’ biomaterial might not translate to fully restored function of mutant CFTR necessary for long-term provision of clinical benefit.
Phytoremediation technologies and their mechanism for removal of heavy metal from contaminated soil: An approach for a sustainable environment
Authors: Sharma Jitendra Kumar , Kumar Nitish , Singh N. P. , Santal Anita Rani
Published: January 2023

The contamination of soils with heavy metals and its associated hazardous effects are a thrust area of today’s research. Rapid industrialization, emissions from automobiles, agricultural inputs, improper disposal of waste, etc., are the major causes of soil contamination with heavy metals. These contaminants not only contaminate soil but also groundwater, reducing agricultural land and hence food quality. These contaminants enter the food chain and have a severe effect on human health. It is important to remove these contaminants from the soil. Various economic and ecological strategies are required to restore the soils contaminated with heavy metals. Phytoremediation is an emerging technology that is non-invasive, cost-effective, and aesthetically pleasing. Many metal-binding proteins (MBPs) of the plants are significantly involved in the phytoremediation of heavy metals; the MBPs include metallothioneins; phytochelatins; metalloenzymes; metal-activated enzymes; and many metal storage proteins, carrier proteins, and channel proteins. Plants are genetically modified to enhance their phytoremediation capacity. In Arabidopsis, the expression of the mercuric ion-binding protein in Bacillus megaterium improves the metal accumulation capacity. The phytoremediation efficiency of plants is also enhanced when assisted with microorganisms, biochar, and/or chemicals. Removing heavy metals from agricultural land without challenging food security is almost impossible. As a result, crop selections with the ability to sequester heavy metals and provide food security are in high demand. This paper summarizes the role of plant proteins and plant–microbe interaction in remediating soils contaminated with heavy metals. Biotechnological approaches or genetic engineering can also be used to tackle the problem of heavy metal contamination.
H+-pyrophosphatases enhance low nitrogen stress tolerance in transgenic Arabidopsis and wheat by interacting with a receptor-like protein kinase
Authors: Zhang Huijuan , Chen Ming , Xu Chengjie , Liu Rongbang , Tang Wensi , Chen Kai , Zhou Yongbin , Xu Zhaoshi , Chen Jun , Ma Youzhi , Chen Weiguo , Sun Daizhen , Fan Hua
Published: January 2023

Introduction

Nitrogen is a major abiotic stress that affects plant productivity. Previous studies have shown that plant H+-pyrophosphatases (H+-PPases) enhance plant resistance to low nitrogen stress. However, the molecular mechanism underlying H+-PPase-mediated regulation of plant responses to low nitrogen stress is still unknown. In this study, we aimed to investigate the regulatory mechanism of AtAVP1 in response to low nitrogen stress.

Methods and Results

AtAVP1 in Arabidopsis thaliana and EdVP1 in Elymus dahuricus belong to the H+-PPase gene family. In this study, we found that AtAVP1 overexpression was more tolerant to low nitrogen stress than was wild type (WT), whereas the avp1-1 mutant was less tolerant to low nitrogen stress than WT. Plant height, root length, aboveground fresh and dry weights, and underground fresh and dry weights of EdVP1 overexpression wheat were considerably higher than those of SHI366 under low nitrogen treatment during the seedling stage. Two consecutive years of low nitrogen tolerance experiments in the field showed that grain yield and number of grains per spike of EdVP1 overexpression wheat were increased compared to those in SHI366, which indicated that EdVP1 conferred low nitrogen stress tolerance in the field. Furthermore, we screened interaction proteins in Arabidopsis; subcellular localization analysis demonstrated that AtAVP1 and Arabidopsis thaliana receptor-like protein kinase (AtRLK) were located on the plasma membrane. Yeast two-hybrid and luciferase complementary imaging assays showed that the AtRLK interacted with AtAVP1. Under low nitrogen stress, the Arabidopsis mutants rlk and avp1-1 had the same phenotypes.

Discussion

These results indicate that AtAVP1 regulates low nitrogen stress responses by interacting with AtRLK, which provides a novel insight into the regulatory pathway related to H+-pyrophosphatase function in plants.
Genome-wide analysis of transcriptome and histone modifications in Brassica napus hybrid
Authors: Ma Meng , Zhong Wenying , Zhang Qing , Deng Li , Wen Jing , Yi Bin , Tu Jinxing , Fu Tingdong , Zhao Lun , Shen Jinxiong
Published: January 2023

Although utilization of heterosis has largely improved the yield of many crops worldwide, the underlying molecular mechanism of heterosis, particularly for allopolyploids, remains unclear. Here, we compared epigenome and transcriptome data of an elite hybrid and its parental lines in three assessed tissues (seedling, flower bud, and silique) to explore their contribution to heterosis in allopolyploid B. napus. Transcriptome analysis illustrated that a small proportion of non-additive genes in the hybrid compared with its parents, as well as parental expression level dominance, might have a significant effect on heterosis. We identified histone modification (H3K4me3 and H3K27me3) variation between the parents and hybrid, most of which resulted from the differences between parents. H3K4me3 variations were positively correlated with gene expression differences among the hybrid and its parents. Furthermore, H3K4me3 and H3K27me3 were rather stable in hybridization and were mainly inherited additively in the B. napus hybrid. Together, our data revealed that transcriptome reprogramming and histone modification remodeling in the hybrid could serve as valuable resources for better understanding heterosis in allopolyploid crops.