bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Characterization of Enterococcus Isolates From Different Sources in Estonia Reveals Potential Transmission of Resistance Genes Among Different Reservoirs
Authors: Aun Erki , Kisand Veljo , Laht Mailis , Telling Kaidi , Kalmus Piret , Väli Ülo , Brauer Age , Remm Maido , Tenson Tanel
Published: March 2021

In this study, we aimed to characterize the population structure, drug resistance mechanisms, and virulence genes of Enterococcus isolates in Estonia. Sixty-one Enterococcus faecalis and 34 Enterococcus faecium isolates were collected between 2012 and 2014 across the country from various sites and sources, including farm animals and poultry (n = 53), humans (n = 12), environment (n = 24), and wild birds (n = 44). Clonal relationships of the strains were determined by whole-genome sequencing and analyzed by multi-locus sequence typing. We determined the presence of acquired antimicrobial resistance genes and 23S rRNA mutations, virulence genes, and also the plasmid or chromosomal origin of the genes using dedicated DNA sequence analysis tools available and/or homology search against an ad hoc compiled database of relevant sequences. Two E. faecalis isolates from human with vanB genes were highly resistant to vancomycin. Closely related E. faecalis strains were isolated from different host species. This indicates interspecies spread of strains and potential transfer of antibiotic resistance. Genomic context analysis of the resistance genes indicated frequent association with plasmids and mobile genetic elements. Resistance genes are often present in the identical genetic context in strains with diverse origins, suggesting the occurrence of transfer events.
Techniques Used for Analyzing Microplastics, Antimicrobial Resistance and Microbial Community Composition: A Mini-Review
Authors: Bartkova Simona , Kahru Anne , Heinlaan Margit , Scheler Ott
Published: March 2021

Antimicrobial resistance (AMR) is a global health threat. Antibiotics, heavy metals, and microplastics are environmental pollutants that together potentially have a positive synergetic effect on the development, persistence, transport, and ecology of antibiotic resistant bacteria in the environment. To evaluate this, a wide array of experimental methods would be needed to quantify the occurrence of antibiotics, heavy metals, and microplastics as well as associated microbial communities in the natural environment. In this mini-review, we outline the current technologies used to characterize microplastics based ecosystems termed “plastisphere” and their AMR promoting elements (antibiotics, heavy metals, and microbial inhabitants) and highlight emerging technologies that could be useful for systems-level investigations of AMR in the plastisphere.
Activation of the Two-Component System LisRK Promotes Cell Adhesion and High Ampicillin Tolerance in Listeria monocytogenes
Authors: Aslan Hüsnü , Petersen Maiken Engelbrecht , De Berardinis Alberto , Zacho Brunhede Maja , Khan Nasar , Vergara Alberto , Kallipolitis Birgitte , Meyer Rikke Louise
Published: March 2021

Graphical Abstract

Listeria monocytogenes activates the two-component system LisRK under stress, and becomes more adhesive and highly tolerant to ampicillin.
Polymyxin Resistance Among XDR ST1 Carbapenem-Resistant Acinetobacter baumannii Clone Expanding in a Teaching Hospital
Authors: Carrasco Letícia Dias de Melo , Dabul Andrei Nicoli Gebieluca , Boralli Camila Maria dos Santos , Righetto Gabriela Marinho , Carvalho Iago Silva e , Dornelas Janaína Valerini , Martins da Mata Camila Pacheco Silveira , Araújo César Augusto de , Leite Edna Mariléa Meireles , Lincopan Nilton , Camargo Ilana Lopes Baratella da Cunha
Published: March 2021

Acinetobacter baumanniiis an opportunistic pathogen primarily associated with multidrug-resistant nosocomial infections, for which polymyxins are the last-resort antibiotics. This study investigated carbapenem-resistantA. baumanniistrains exhibiting an extensively drug-resistant (XDR) phenotype, including four isolates considered locally pan drug-resistant (LPDR), isolated from inpatients during an outbreak at a teaching hospital in Brazil. ApaI DNA macrorestriction followed by PFGE clustered the strains in three pulsotypes, named A to C, among carbapenem-resistantA. baumanniistrains. Pulsotypes A and B clustered six polymyxin-resistantA. baumanniistrains. MLST analysis of representative strains of pulsotypes A, B, and C showed that they belong, respectively, to sequence types ST1 (clonal complex, CC1), ST79 (CC79), and ST903. Genomic analysis of international clones ST1 and ST79 representative strains predicted a wide resistome for β-lactams, aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole, withblaOXA–23andblaOXA–72genes encoding carbapenem resistance. Amino acid substitutions in PmrB (Thr232Ile or Pro170Leu) and PmrC (Arg125His) were responsible for polymyxin resistance. Although colistin MICs were all high (MIC ≥ 128 mg/L), polymyxin B MICs varied; strains with Pro170Leu substitution in PmrB had MICs > 128 mg/L, while those with Thr232Ile had lower MICs (16–64 mg/L), irrespective of the clone. Although the first identified polymyxin-resistantA. baumanniistrain belonged to ST79, the ST1 strains were endemic and caused the outbreak most likely due to polymyxin B use. The genome comparison of two ST1 strains from the same patient, but one susceptible and the other resistant to polymyxin, revealed mutations in 28 ORFs in addition topmrBC. The ORF codifying an acyl-CoA dehydrogenase has gained attention due to its fatty acid breakdown and membrane fluidity involvement. However, the role of these mutations in the polymyxin resistance mechanism remains unknown. To prevent the dissemination of XDR bacteria, the hospital infection control committee implemented the patient bathing practice with a 2% chlorhexidine solution, a higher concentration than allA. baumanniichlorhexidine MICs. In conclusion, we showed the emergence of polymyxin resistance due to mutations in the chromosome of the carbapenem-resistantA. baumanniiST1, a high-risk global clone spreading in this hospital.
How Carbon Source and Degree of Oligosaccharide Polymerization Affect Production of Cellulase-Degrading Enzymes by Fusarium oxysporum f. sp. lycopersici
Authors: Najjarzadeh Nasim , Matsakas Leonidas , Rova Ulrika , Christakopoulos Paul
Published: March 2021

Cellulases are a group of enzymes responsible for the degradation of cellulose, which is one of the most abundant polymers on Earth. The three main groups of cellulases are endoglucosidases, exoglucosidases, and β-glucosidases; however, the mechanism of induction of these enzymes remains poorly characterized. Cellooligosaccharides are among the main inducers of these enzymes in filamentous fungi, yet it is not clear how their degree of polymerization may affect the strength of induction. In the present study, we investigated the effect of different carbohydrate-based inducers, such as lactose, sophorose, cellooligosaccharides, and xylooligosacharides, characterized by different concentrations and degree of polymerization, on cellulases production by the fungus Fusarium oxysporum f. sp. lycopersici, which is one of the most studied lignocellulose degrading fungi with the ability to consume both cellulose and hemicellulose. Moreover, the effect of carbon source on cellulase induction was assessed by growing the biomass on sucrose or glycerol. Results showed a correlation between induction efficiency and the cellooligosaccharides’ concentration and size, as well as the carbon source available. Specifically, cellotetraose was a better inducer when sucrose was the carbon source, while cellobiose yielded a better result on glycerol. These findings can help optimize industrial cellulase production.
Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype
Authors: Theunissen Frances , Anderton Ryan S. , Mastaglia Frank L. , Flynn Loren L. , Winter Samantha J. , James Ian , Bedlack Richard , Hodgetts Stuart , Fletcher Sue , Wilton Steve D. , Laing Nigel G. , MacShane Mandi , Needham Merrilee , Saunders Ann , Mackay-Sim Alan , Melamed Ze’ev , Ravits John , Cleveland Don W. , Akkari P. Anthony
Published: March 2021

Objective

There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.

Methods

The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.

Results

In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.

Conclusions

We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.
Head-Down Tilt Bed Rest Studies as a Terrestrial Analog for Spaceflight Associated Neuro-Ocular Syndrome
Authors: Ong Joshua , Lee Andrew G. , Moss Heather E.
Published: March 2021

Astronauts who undergo prolonged periods of spaceflight may develop a unique constellation of neuro-ocular findings termed Spaceflight Associated Neuro-Ocular Syndrome (SANS). SANS is a disorder that is unique to spaceflight and has no terrestrial equivalent. The prevalence of SANS increases with increasing spaceflight duration and although there have been residual, structural, ocular changes noted, no irreversible or permanent visual loss has occurred after SANS, with the longest spaceflight to date being 14 months. These microgravity-induced findings are being actively investigated by the United States' National Aeronautics Space Administration (NASA) and SANS is a potential obstacle to future longer duration, manned, deep space flight missions. The pathophysiology of SANS remains incompletely understood but continues to be a subject of intense study by NASA and others. The study of SANS is of course partially limited by the small sample size of humans undergoing spaceflight. Therefore, identifying a terrestrial experimental model of SANS is imperative to facilitate its study and for testing of preventative measures and treatments. Head-down tilt bed rest (HDTBR) on Earth has emerged as one promising possibility. In this paper, we review the HDTBR as an analog for SANS pathogenesis; the clinical and imaging overlap between SANS and HDTBR studies; and potential SANS countermeasures that have been or could be tested with HDTBR.
The Effects of Transcranial Direct Current Stimulation on Dual-Task Interference Depend on the Dual-Task Content
Authors: Kimura Takehide , Kaneko Fuminari , Nagamine Takashi
Published: March 2021

Recently, some studies revealed that transcranial direct current stimulation (tDCS) reduces dual-task interference. Since there are countless combinations of dual-tasks, it remains unclear whether stable effects by tDCS can be observed on dual-task interference. An aim of the present study was to investigate whether the effects of tDCS on dual-task interference change depend on the dual-task content. We adopted two combinations of dual-tasks, i.e., a word task while performing a tandem task (word-tandem dual-task) and a classic Stroop task while performing a tandem task (Stroop-tandem dual-task). We expected that the Stroop task would recruit the dorsolateral prefrontal cortex (DLPFC) and require involvement of executive function to greater extent than the word task. Subsequently, we hypothesized that anodal tDCS over the DLPFC would improve executive function and result in more effective reduction of dual-task interference in the Stroop-tandem dual-task than in the word-tandem dual-task. Anodal or cathodal tDCS was applied over the DLPFC or the supplementary motor area using a constant current of 2.0 mA for 20 min. According to our results, dual-task interference and the task performances of each task under the single-task condition were not changed after applying any settings of tDCS. However, anodal tDCS over the left DLPFC significantly improved the word task performance immediately after tDCS under the dual-task condition. Our findings suggested that the effect of anodal tDCS over the left DLPFC varies on the task performance under the dual-task condition was changed depending on the dual-task content.
Memristor Based Binary Convolutional Neural Network Architecture With Configurable Neurons
Authors: Huang Lixing , Diao Jietao , Nie Hongshan , Wang Wei , Li Zhiwei , Li Qingjiang , Liu Haijun
Published: March 2021

The memristor-based convolutional neural network (CNN) gives full play to the advantages of memristive devices, such as low power consumption, high integration density, and strong network recognition capability. Consequently, it is very suitable for building a wearable embedded application system and has broad application prospects in image classification, speech recognition, and other fields. However, limited by the manufacturing process of memristive devices, high-precision weight devices are currently difficult to be applied in large-scale. In the same time, high-precision neuron activation function also further increases the complexity of network hardware implementation. In response to this, this paper proposes a configurable full-binary convolutional neural network (CFB-CNN) architecture, whose inputs, weights, and neurons are all binary values. The neurons are proportionally configured to two modes for different non-ideal situations. The architecture performance is verified based on the MNIST data set, and the influence of device yield and resistance fluctuations under different neuron configurations on network performance is also analyzed. The results show that the recognition accuracy of the 2-layer network is about 98.2%. When the yield rate is about 64% and the hidden neuron mode is configured as −1 and +1, namely ±1 MD, the CFB-CNN architecture achieves about 91.28% recognition accuracy. Whereas the resistance variation is about 26% and the hidden neuron mode configuration is 0 and 1, namely 01 MD, the CFB-CNN architecture gains about 93.43% recognition accuracy. Furthermore, memristors have been demonstrated as one of the most promising devices in neuromorphic computing for its synaptic plasticity. Therefore, the CFB-CNN architecture based on memristor is SNN-compatible, which is verified using the number of pulses to encode pixel values in this paper.
Effects of Apple Form on Energy Intake During a Mid-Afternoon Snack: A Preload Paradigm Study in School-Aged Children
Authors: Schwartz Camille , Person Ophélie , Szleper Emilie , Nicklaus Sophie , Tournier Carole
Published: March 2021

Consuming foods with a form or a texture that requires longer oral processing is a way to decrease food intake. Although this approach is promising for leveraging healthier eating patterns in adults, it has never been explored in children. This study evaluated whether starting a mid-afternoon snack by eating either apple segments or applesauce would modify hunger and subsequent food intake during this meal. Forty-four children (8–10 years old) participated in two videotaped mid-afternoon snacks, during which they received one of the two forms of apple as a food preload followed 10 min later by ad libitum consumption of sweetened cottage cheese. They self-reported their level of hunger throughout consumption, and the weight of cottage cheese consumed was determined at the end of the snack. Children's chewing capabilities and eating traits were parent-reported. Eating a raw apple increased oral exposure time and decreased bite size compared to eating applesauce. However, neither the reported hunger nor consecutive food intake were modified. Regardless of the meal, children eating fast had a higher ad libitum energy intake. The individual eating rate for the cottage cheese was correlated with the eating rate observed for applesauce but not for apple segments, the latter being associated with children's chewing difficulties. This study suggests that the form of a fruit offered at the start of a mid-afternoon snack does not impact food intake; the findings clearly call for more exploration of satiation mechanisms related to food texture properties among children and indicate the need to consider children's oral processing skills.
Advances in Rodent Models for Breast Cancer Formation, Progression, and Therapeutic Testing
Authors: Liu Chong , Wu Pei , Zhang Ailin , Mao Xiaoyun
Published: March 2021

Breast cancer is a highly complicated disease. Advancement in the treatment and prevention of breast cancer lies in elucidation of the mechanism of carcinogenesis and progression. Rodent models of breast cancer have developed into premier tools for investigating the mechanisms and genetic pathways in breast cancer progression and metastasis and for developing and evaluating clinical therapeutics. Every rodent model has advantages and disadvantages, and the selection of appropriate rodent models with which to investigate breast cancer is a key decision in research. Design of a suitable rodent model for a specific research purpose is based on the integration of the advantages and disadvantages of different models. Our purpose in writing this review is to elaborate on various rodent models for breast cancer formation, progression, and therapeutic testing.
Machine Learning-Based Radiomics Nomogram for Detecting Extramural Venous Invasion in Rectal Cancer
Authors: Liu Siye , Yu Xiaoping , Yang Songhua , Hu Pingsheng , Hu Yingbin , Chen Xiaoyan , Li Yilin , Zhang Zhe , Li Cheng , Lu Qiang
Published: March 2021

Objective

To establish and validate a radiomics nomogram based on the features of the primary tumor for predicting preoperative pathological extramural venous invasion (EMVI) in rectal cancer using machine learning.

Methods

The clinical and imaging data of 281 patients with primary rectal cancer from April 2012 to May 2018 were retrospectively analyzed. All the patients were divided into a training set (n = 198) and a test set (n = 83) respectively. The radiomics features of the primary tumor were extracted from the enhanced computed tomography (CT), the T2-weighted imaging (T2WI) and the gadolinium contrast-enhanced T1-weighted imaging (CE-TIWI) of each patient. One optimal radiomics signature extracted from each modal image was generated by receiver operating characteristic (ROC) curve analysis after dimensionality reduction. Three kinds of models were constructed based on training set, including the clinical model (the optimal radiomics signature combining with the clinical features), the magnetic resonance imaging model (the optimal radiomics signature combining with the mrEMVI status) and the integrated model (the optimal radiomics signature combining with both the clinical features and the mrEMVI status). Finally, the optimal model was selected to create a radiomics nomogram. The performance of the nomogram to evaluate clinical efficacy was verified by ROC curves and decision curve analysis curves.

Results

The radiomics signature constructed based on T2WI showed the best performance, with an AUC value of 0.717, a sensitivity of 0.742 and a specificity of 0.621. The radiomics nomogram had the highest prediction efficiency, of which the AUC was 0.863, the sensitivity was 0.774 and the specificity was 0.801.

Conclusion

The radiomics nomogram had the highest efficiency in predicting EMVI. This may help patients choose the best treatment strategy and may strengthen personalized treatment methods to further optimize the treatment effect.
Correlation Between APOBEC3B Expression and Clinical Characterization in Lower-Grade Gliomas
Authors: Zhang Hao , Chen Zhiyang , Wang Zeyu , Dai Ziyu , Hu Zhengang , Zhang Xun , Hu Min , Liu Zhixiong , Cheng Quan
Published: March 2021

Background

As the most aggressive tumors in the central nervous system, gliomas have poor prognosis and limited therapy methods. Immunotherapy has become promising in the treatment of gliomas. Here, we explored the expression pattern of APOBEC3B, a genomic mutation inducer, in gliomas to assess its value as an immune biomarker and immunotherapeutic target.

Methods

We mined transcriptional data from two publicly available genomic datasets, TCGA and CGGA, to investigate the relevance between APOBEC3B and clinical characterizations including tumor classifications, patient prognosis, and immune infiltrating features in gliomas. We especially explored the correlation between APOBEC3B and tumor mutations. Samples from Xiangya cohort were used for immunohistochemistry staining.

Results

Our findings demonstrated that APOBEC3B expression level was relatively high in advanced gliomas and other cancer types, which indicated poorer prognosis. APOBEC3B also stratified patients’ survival in Xiangya cohort. APOBEC3B was significantly associated with infiltrating immune and stromal cell types in the tumor microenvironment. Notably, APOBEC3B was involved in tumor mutation and strongly correlated with the regulation of oncogenic genes.

Conclusion

Our findings identified that APOBEC3B could be a latent molecular target in gliomas.
The Lipoprotein Transport System in the Pathogenesis of Multiple Myeloma: Advances and Challenges
Authors: Lazaris Vasileios , Hatziri Aikaterini , Symeonidis Argiris , Kypreos Kyriakos E.
Published: March 2021

Multiple myeloma (MM) is an incurable neoplastic hematologic disorder characterized by malignant plasma cells, mainly in the bone marrow. MM is associated with multiple factors, such as lipid metabolism, obesity, and age-associated disease development. Although, the precise pathogenetic mechanisms remain unknown, abnormal lipid and lipoprotein levels have been reported in patients with MM. Interestingly, patients with higher APOA1 levels, the major apolipoprotein of high density lipoprotein (HDL), have better overall survival. The limited existing studies regarding serum lipoproteins in MM are inconclusive, and often contradictory. Nevertheless, it appears that deregulation of the lipoprotein transport system may facilitate the development of the disease. Here, we provide a critical review of the literature on the role of lipids and lipoproteins in MM pathophysiology. We also propose novel mechanisms, linking the development and progression of MM to the metabolism of blood lipoproteins. We anticipate that proteomic and lipidomic analyses of serum lipoproteins along with analyses of their functionality may improve our understanding and shed light on novel mechanistic aspects of MM pathophysiology.
Novel Patient Metastatic Pleural Effusion-Derived Xenograft Model of Renal Medullary Carcinoma Demonstrates Therapeutic Efficacy of Sunitinib
Authors: Lee Alex Q. , Ijiri Masami , Rodriguez Ryan , Gandour-Edwards Regina , Lee Joyce , Tepper Clifford G. , Li Yueju , Beckett Laurel , Lam Kit , Goodwin Neal , Satake Noriko
Published: March 2021

Background

Renal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.

Methods

Renal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.

Results

The pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p<0.001) and prolonged survival (p=0.004) compared to the vehicle control.

Conclusions

A metastatic PE-derived RMC PDX model was established and shown to maintain histologic features of the patient cancer. Molecular integrity of the PDX models was well maintained between renal tumor and PE PDX as well as between two successive renal tumor PDX generations. Using the PE PDX model, sunitinib demonstrated therapeutic efficacy for RMC. This model can serve as a foundation for future mechanistic and therapeutic studies for primary and metastatic RMC.
Exosomal Non-Coding RNAs: Regulatory and Therapeutic Target of Hepatocellular Carcinoma
Authors: Xia Haoming , Huang Ziyue , Liu Shuqiang , Zhao Xudong , He Risheng , Wang Zhongrui , Shi Wenguang , Chen Wangming , Li Zhizhou , Yu Liang , Huang Peng , Kang Pengcheng , Su Zhilei , Xu Yi , Yam Judy Wai Ping , Cui Yunfu
Published: March 2021

Exosomes are small extracellular vesicles secreted by most somatic cells, which can carry a variety of biologically active substances to participate in intercellular communication and regulate the pathophysiological process of recipient cells. Recent studies have confirmed that non-coding RNAs (ncRNAs) carried by tumor cell/non-tumor cell-derived exosomes have the function of regulating the cancerous derivation of target cells and remodeling the tumor microenvironment (TME). In addition, due to the unique low immunogenicity and high stability, exosomes can be used as natural vehicles for the delivery of therapeutic ncRNAs in vivo. This article aims to review the potential regulatory mechanism and the therapeutic value of exosomal ncRNAs in hepatocellular carcinoma (HCC), in order to provide promising targets for early diagnosis and precise therapy of HCC.
Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways
Authors: Qu Mei , Duan Yu , Zhao Min , Wang Zhanju , Zhao Mengjie , Zhao Yao , Wang Haihua , Ke Yu , Liu Ying , Liu Hong-Min , Wei Liuya , Hu Zhenbo
Published: March 2021

Differentiation therapy with all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), has been extremely successful in inducing clinical remission in APL patients. However, the differentiation therapy of ATRA-based treatment has not been effective in other subtypes of AML. In this study, we evaluated a small molecule of ent-kaurene diterpenoid, Jiyuan oridonin A (JOA), on the differentiation blockade in AML cells with the mixed lineage leukemia (MLL) gene rearrangements (MLLr) in MV4-11, MOLM-13 and THP-1 cells. We found that JOA could significantly inhibit the proliferation of MOLM-13, MV4-11 and THP-1 cells. Moreover, JOA promoted cell differentiation coupled with cell-cycle exit at G0/G1 and inhibited the colony- forming capacity of these cells. We showed that the anti-proliferative effect of JOA attributed to cell differentiation is most likely through the martens tretinoin response up pathway in the MOLM-13 cell line, and the hematopoietic cell lineage pathway by the inhibition of c-KIT expression and cell adhesion pathway in the THP-1 cell line. Our findings suggest that JOA could be a novel therapeutic agent against human MLLr acute myeloid leukemia.
GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries
Authors: Abramavicius Silvijus , Petersen Asbjørn G. , Renaltan Nirthika S. , Prat-Duran Judit , Torregrossa Roberta , Stankevicius Edgaras , Whiteman Matthew , Simonsen Ulf
Published: March 2021

Donors of H2S may be beneficial in treating cardiovascular diseases where the plasma levels of H2S are decreased. Therefore, we investigated the mechanisms involved in relaxation of small arteries induced by GYY4137 [(4-methoxyphenyl)-morpholin-4-yl-sulfanylidene-sulfido-λ5-phosphane;morpholin-4-ium], which is considered a slow-releasing H2S donor. Sulfides were measured by use of 5,5′-dithiobis-(2-nitro benzoic acid), and small rat mesenteric arteries with internal diameters of 200–250 µm were mounted in microvascular myographs for isometric tension recordings. GYY4137 produced similar low levels of sulfides in the absence and the presence of arteries. In U46619-contracted small mesenteric arteries, GYY4137 (10−6–10–3 M) induced concentration-dependent relaxations, while a synthetic, sulfur-free, GYY4137 did not change the vascular tone. L-cysteine (10−6–10–3 M) induced only small relaxations reaching 24 ± 6% at 10–3 M. Premixing L-cysteine (10–3 M) with Na2S and GYY4137 decreased Na2S relaxation and abolished GYY4137 relaxation, an effect prevented by an nitric oxide (NO) synthase inhibitor, L-NAME (Nω-nitro-L-arginine methyl ester). In arteries without endothelium or in the presence of L-NAME, relaxation curves for GYY4137 were rightward shifted. High extracellular K+ concentrations decreased Na2S and abolished GYY4137 relaxation suggesting potassium channel-independent mechanisms are also involved Na2S relaxation while potassium channel activation is pivotal for GYY4137 relaxation in small arteries. Blockers of large-conductance calcium-activated (BKCa) and voltage-gated type 7 (KV7) potassium channels also inhibited GYY4137 relaxations. The present findings suggest that L-cysteine by reaction with Na2S and GYY4137 and formation of sulfides, inhibits relaxations by these compounds. The low rate of release of H2S species from GYY4137 is reflected by the different sensitivity of these relaxations towards high K+ concentration and potassium channel blockers compared with Na2S. The perspective is that the rate of release of sulfides plays an important for the effects of H2S salt vs. donors in small arteries, and hence for a beneficial effect of GYY4137 for treatment of cardiovascular disease.
Excessive Intake of Longan Arillus Alters gut Homeostasis and Aggravates Colitis in Mice
Authors: Huang Huimin , Li Mingxing , Wang Yi , Wu Xiaoxiao , Shen Jing , Xiao Zhangang , Zhao Yueshui , Du Fukuan , Chen Yu , Wu Zhigui , Ji Huijiao , Zhang Chunyuan , Li Jing , Wen Qinglian , Kaboli Parham Jabbarzadeh , Cho Chi Hin , Wang Shengpeng , Wang Yitao , He Yisheng , Wu Xu
Published: March 2021

Background: Longan is the fruit of Dimocarpus longan Lour. and the longan arillus has long been used in traditional Chinese medicine possessing various health benefits. However, the excessive intake of longan is found in daily life to cause “shanghuo” syndrome. “Shanghuo” has been linked to increased disease susceptibility. The present study thus aimed to investigate the toxicological outcomes after excessive longan treatment.

Methods: Longan extract at a normal dosage of 4 g/kg and two excess dosages of 8 and 16 g/kg was orally administered to normal C57BL/6J mice for two weeks or to C57BL/6J mice with DSS-induced colitis. Mouse gut microbiome were analyzed by 16S rRNA sequencing. Short chain fatty acid (SCFA) contents in colonic contents were measured by GC-MS. Colon tissue was used for histopathological observation after H and E staining, detection of protein expression by western blot, analysis of gene expression by qPCR, and detection of apoptotic cells by TUNEL assay. ELISA was used for biochemical analysis in serum.

Results: In normal mice, repeated longan intake at excess doses, but not the normal dose, increased infiltration of inflammatory cells, elevated serum levels of TNF-α and IL-6 and reduced production of SCFAs. In DSS-induced colitic mice, longan intake at 4 g/kg did not promote colitis in mice, while excessive longan (8 or 16 g/kg) aggravated colitis in mice, showing increased inflammation, more serious histological abnormalities, increased gut permeability, and increased epithelia injury when compared to DSS alone. Excessive longan induced a significant reduction of microbial diversity in colitic mice, accompanied with aggravated alterations of DSS-associated bacteria including the increase of Proteobacteria phylum and genera of Bacteroides, Akkermansia, Turicibacter and Escherchia-Shigella, and the decrease of norank_f__Muribaculaceae. The changed microbial compositions were accompanied with decreased SCFAs when longan was supplemented with DSS. The aggravated colon injury by excessive intake of longan in colitic mice was tightly correlated with the altered microbial communities and decreased SCFAs production.

Conclusion: Excessive longan intake disturbs gut homeostasis and aggravates colitis via promoting inflammation and altering gut microbe compositions and associated metabolism in mice. Our findings warrant rational longan arillus consumption as a dietary supplement or herbal medicine.
Hypericum triquetrifolium and H. neurocalycinum as Sources of Antioxidants and Multi-Target Bioactive Compounds: A Comprehensive Characterization Combining In Vitro Bioassays and Integrated NMR and LC-MS Characterization by Using a Multivariate Approach
Authors: Dall’Acqua Stefano , Ak Gunes , Sinan Kouadio Ibrahime , Elbasan Fevzi , Ferrarese Irene , Sut Stefania , Yıldıztugay Evren , Peron Gregorio , Schievano Elisabetta , Nancy Picot-Allain Marie Carene , Mahomoodally Mohamad Fawzi , Zengin Gokhan
Published: March 2021

Hypericum triquetrifoliumandH. neurocalycinumwere evaluated for their phytochemical content andin vitrobioactivity. NMR analyses were performed on the methanol extract of the aerial parts ofH. triquetrifoliumto establish the main classes of phytoconstituents. Then, LC-DAD-MSnanalyses were performed in order to compare the composition of aerial parts and roots extracts of bothHypericumspecies, obtained using either methanol or water as solvents. Results, processed using multivariate data analysis, showed a significantly higher phenolic content of methanol extracts compared to water extracts, while minor qualitative differences were observed between the two. Distinctive flavonoid and PAC patterns were observed forH. triquetrifoliumandH. neurocalycinum, and specific compounds were exclusively detected in one or the other species. Specifically, the phloroglucinols 7-epiclusianone, hyperfirin and hyperforin were present only inH. neurocalycinum,while hyperforin was detected only inH. triquetrifolium.Extracts were assayed using differentin vitrotests to evaluate their antioxidant properties and their inhibitory activity against several enzymes, showing significant antioxidant and metal chelating activities. Furthermore, inhibitory properties against acetylcholinesterase, butyrylcholinesterase and tyrosinase were observed. Multivariate approaches were used to correlate biological data with the phytochemical composition of the different extracts. The results, showing positive correlations between specific chemical constituents and the measured bioactivities, represent preliminary data that could guide future studies aimed at isolating bioactive constituents fromH. neurocalycinumandH. triquetrifoliumfor further pharmacological evaluations.
Up-Regulation of Glycogen Synthesis and Degradation Enzyme Level Maintained Myocardial Glycogen in Huddling Brandt’s Voles Under Cool Environments
Authors: Xu Jin-Hui , Wang Zhe , Mou Jun-Jie , Wang Chuan-Li , Huang Wei-Mei , Xue Hui-Liang , Wu Ming , Chen Lei , Xu Lai-Xiang
Published: March 2021

Small mammals exhibit limited glucose use and glycogen accumulation during hypothermia. Huddling is a highly evolved cooperative behavioral strategy in social mammals, allowing adaptation to environmental cooling. However, it is not clear whether this behavior affects the utilization of glycogen in cold environments. Here, we studied the effects of huddling on myocardial glycogen content in Brandt’s voles (Lasiopodomys brandtii) under a mild cold environment (15°C). Results showed that (1) Compared to the control (22°C) group (CON), the number of glycogenosomes more than tripled in the cool separated group (CS) in both males and females; whereas the number of glycogenosomes increased in females but was maintained in males in the cool huddling group (CH). (2) Glycogen synthase (GS) activity in the CS group remained unchanged, whereas glycogen phosphorylase (GYPL) activity decreased, which mediated the accumulation of glycogen content of the CS group. (3) Both GS and GYPL activity increased which may contribute to the stability of glycogen content in CH group. (4) The expression levels of glucose transporters GLUT1 and GLUT4 increased in the CS group, accompanied by an increase in glucose metabolism. These results indicate that the reduced glycogen degradation enzyme level and enhanced glucose transport may lead to an increase in myocardial glycogen content of the separated voles under cool environment; while the up-regulation of glycogen synthesis and degradation enzyme level maintained myocardial glycogen content in the huddling vole.
Physiological and Gene Expression Changes of Clematis crassifolia and Clematis cadmia in Response to Heat Stress
Authors: Hu Qingdi , Qian Renjuan , Zhang Yanjun , Zhang Xule , Ma Xiaohua , Zheng Jian
Published: March 2021

Clematis is a superior perennial ornamental vine known for varied colors and shapes of its flowers. Clematis crassifolia is sensitive to high temperature, whereas Clematis cadmia has a certain temperature adaptability. Here we analyzed the potential regulatory mechanisms of C. crassifolia and C. cadmia in response to heat stress by studying the photosynthesis, antioxidant parameters, amino acids, and gene expression patterns under three temperature treatments. Heat stress caused the fading of leaves; decreased net photosynthetic rate, stomatal conductance, superoxide dismutase, and catalase activity; increased 13 kinds of amino acids content; and up-regulated the expression of seven genes, including C194329_G3, C194434_G1, and C188817_g1, etc., in C. crassifolia plants. Under the treatments of heat stress, the leaf tips of C. cadmia were wilted, and the net photosynthetic rate and soluble protein content decreased, with the increase of 12 amino acids content and the expression of c194329_g3, c194434_g1, and c195983_g1. Our results showed that C. crassifolia and C. cadmia had different physiological and molecular response mechanisms to heat stress during the ecological adaptation.
Insights Into the Evolutionary History of the Subfamily Orthotrichoideae (Orthotrichaceae, Bryophyta): New and Former Supra-Specific Taxa So Far Obscured by Prevailing Homoplasy
Authors: Draper Isabel , Garilleti Ricardo , Calleja Juan Antonio , Flagmeier Maren , Mazimpaka Vicente , Vigalondo Beatriz , Lara Francisco
Published: March 2021

Mosses of the subfamily Orthotrichoideae represent one of the main components of the cryptogam epiphytic communities in temperate areas. During the last two decades, this taxonomical group has undergone an extensive revision that has led to its rearrangement at the generic level. However, their phylogenetic relationships and inferences on the evolutionary patterns that have driven the present diversity have little advanced. In this study, we present a dated molecular phylogenetic reconstruction at the subfamily level, including 130 samples that represent the 12 genera currently recognized within the subfamily, and the analysis of four molecular markers: ITS2, rps4, trnG, and trnL-F. We also analyze 13 morphological characters of systematic value to infer their origin and diagnostic utility within the subfamily. The phylogenetic reconstruction yields three main clades within the subfamily, two of which correspond to the tribe Zygodonteae, and one to Orthotricheae. Within Zygodonteae, the genus Zygodon results to be a polyphyletic artificial assembly, and we propose to separate a new genus named Australoria. Conversely, our results do not support the separation of Pentastichella and Pleurorthotrichum at the genus level and we therefore propose to include Pleurorthotrichum in Pentastichella. Regarding Orthotricheae, our analyses clearly allow the distinction of two subtribes: Orthotrichinae and Lewinskyinae. Within the latter, Ulota results a polyphyletic entity, and therefore we propose the segregation of a separate new genus named Atlantichella. Dating analyses allow us to conclude that the split of the tribes within Orthotrichoideae dates from the Middle Jurassic, while the diversification of Orthotrichum and Zygodon probably started during the Late Cretaceous. However, most of the extant genera of this subfamily seem to be younger, and apparently its highest diversification burst took place during the Oligocene. Finally, the analysis of the morphological traits reveals that most of the characters previously used to separate genera and here tested are homoplastic, which has hindered the taxonomical and systematic proposals for decades. However, even if there are no exclusive characters, all of the genera can be defined by the combination of a few characters.
The Candidate Photoperiod Gene MtFE Promotes Growth and Flowering in Medicago truncatula
Authors: Thomson Geoffrey , Zhang Lulu , Wen Jiangqi , Mysore Kirankumar S. , Putterill Joanna
Published: March 2021

Flowering time influences the yield and productivity of legume crops. Medicago truncatula is a reference temperate legume that, like the winter annual Arabidopsis thaliana, shows accelerated flowering in response to vernalization (extended cold) and long-day (LD) photoperiods (VLD). However, unlike A. thaliana, M. truncatula appears to lack functional homologs of core flowering time regulators CONSTANS (CO) and FLOWERING LOCUS C (FLC) which act upstream of the mobile florigen FLOWERING LOCUS T (FT). Medicago truncatula has three LD-induced FT-like genes (MtFTa1, MtFTb1, and MtFTb2) with MtFTa1 promoting M. truncatula flowering in response to VLD. Another photoperiodic regulator in A. thaliana, FE, acts to induce FT expression. It also regulates the FT transport pathway and is required for phloem development. Our study identifies a M. truncatula FE homolog Medtr6g444980 (MtFE) which complements the late flowering fe-1 mutant when expressed from the phloem-specific SUCROSE-PROTON SYMPORTER 2 (SUC2) promoter. Analysis of two M. truncatula Tnt1 insertional mutants indicate that MtFE promotes flowering in LD and VLD and growth in all conditions tested. Expression of MtFTa1, MtFTb1, and MtFTb2 are reduced in Mtfe mutant (NF5076), correlating with its delayed flowering. The NF5076 mutant plants are much smaller than wild type indicating that MtFE is important for normal plant growth. The second mutant (NF18291) displays seedling lethality, like strong fe mutants. We searched for mutants in MtFTb1 and MtFTb2 identifying a Mtftb2 knock out Tnt1 mutant (NF20803). However, it did not flower significantly later than wild type. Previously, yeast-two-hybrid assays (Y2H) suggested that Arabidopsis FE interacted with CO and NUCLEAR FACTOR-Y (NF-Y)-like proteins to regulate FT. We found that MtFE interacts with CO and also M. truncatula NF-Y-like proteins in Y2H experiments. Our study indicates that despite the apparent absence of a functional MtCO-like gene, M. truncatula FE likely influences photoperiodic FT expression and flowering time in M. truncatula via a partially conserved mechanism with A. thaliana.
Direct and Indirect Somatic Embryogenesis Induction in Camellia oleifera Abel
Authors: Zhang Ming , Wang Aibin , Qin Mou , Qin Xuejing , Yang Shiwen , Su Shuchai , Sun Yongjiang , Zhang Lingyun
Published: March 2021

Camellia oleifera Abel. is an important woody oil species; however, the shortage of rapid and industrialized seedling culture is a large constraint on the development of the tea oil industry. Somatic embryogenesis (SE) is one of the main powerful biotechnological tools for plant mass regeneration, but the largely unknown SE in C. oleifera limits the scale production of clonal plants. In this study, we described a high-efficiency SE system via direct and indirect pathways in C. oleifera and investigated the effect of genotype, explant age and phytohormones on SE. In the direct pathway, somatic embryos were highly induced from immature seeds 220 days after full blossom, and the development of embryoids was achieved with a combination of 0.19 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) and 0.05 mg/L thidiazuron (TDZ). In the indirect pathway, embryogenic calli were induced from the same explants in medium containing 1.5 mg/L 2,4-D, while 0.75 mg/L 2,4-D treatment led to high proliferation rates for embryogenic calli. The addition of 0.19 mg/L 2,4-D alone stimulated the production of globular embryos while causing a 75% loss of the induction rate in the heart embryo stage. Upon transfer of the globular embryos to phytohormone-free medium, an optimal induction rate of 62.37% from globular embryos to cotyledonary embryos was obtained. These data suggest that the subsequent differentiation process after the globular embryo stage in ISE is more similar to an endogenous phytohormones-driven process. Mature embryos germinated to produce intact plantlets on half-strength MS basal medium with a regeneration rate of 63.67%. Histological analysis confirmed the vascular bundle isolation of embryoids from the mother tissue. We further studied the different varieties and found that there were no significant genotype differences for SE induction efficiency in C. oleifera. Thus, we established a high-efficiency induction system for direct and indirect somatic embryogenesis (ISE) in C. oleifera and regenerated intact plantlets via SE, not organogenesis. ISE has a more complicated induction and regulatory mechanism than direct somatic embryogenesis. The improved protocol of SE would benefit mass propagation and genetic manipulation in C. oleifera.