bluuebunny/crossref_metadata_2025 huggingface dataset:
An NIR-II Responsive Nanoplatform for Cancer Photothermal and Oxidative Stress Therapy
Authors: Huang Bin , Huang Yuanpeng , Han Han , Ge Qiuyue , Yang Dongliang , Hu Yanling , Ding Meng , Su Yanqing , He Yanbin , Shao Jinjun , Chu Jianfeng
Published: October 2021

Chemodynamic therapy as an emerging therapeutic strategy has been implemented for oncotherapy. However, the reactive oxygen species can be counteracted by the exorbitant glutathione (GSH) produced by the tumor cells before exerting the antitumor effect. Herein, borneol (NB) serving as a monoterpenoid sensitizer, and copper sulfide (CuS NPs) as an NIR-II photothermal agent were loaded in a thermo-responsive vehicle (NB/CuS@PCM NPs). Under 1,060-nm laser irradiation, the hyperthermia produced by CuS NPs can be used for photothermal therapy and melt the phase change material for drug delivery. In the acidity microenvironment, the CuS NPs released from NB/CuS@PCM NPs could degrade to Cu2+, then Cu2+ was reduced to Cu+ during the depletion of GSH. As Fenton-like catalyst, the copper ion could convert hydrogen peroxide into hydroxyl radicals for chemodynamic therapy. Moreover, the NB originated from NB/CuS@PCM NPs could increase the intracellular ROS content to improve the treatment outcome of chemodynamic therapy. The animal experimental results indicated that the NB/CuS@PCM NPs could accumulate at the tumor site and exhibit an excellent antitumor effect. This work confirmed that the combination of oxidative stress–induced damage and photothermal therapy is a potential therapeutic strategy for cancer treatment.
Vitamin D Analogs Can Retard the Onset or Progression of Diabetic Kidney Disease: A Systematic Review
Authors: Uwaezuoke Samuel N.
Published: October 2021

Introduction

Previous studies have shown that vitamin D analogs (such as paricalcitol) can reduce albuminuria in patients with diabetes mellitus and retard the progression of diabetic kidney disease (DKD). A recent systematic review reported significant improvement of renal function in patients with DKD who received vitamin D or its analogs. Study-driven data about their use in improving DKD outcomes have continued to accumulate over the years.

Aim

This paper aims to systematically review the contemporary evidence about the effectiveness of vitamin D analogs in retarding the onset or progression of DKD.

Methods

With appropriate descriptors, two electronic databases (PubMed and Google Scholar) were searched for articles published between 2015 and 2021 in the English language. Primary studies that fulfilled the inclusion criteria were selected; their titles and abstracts were screened, and duplicates were removed. Relevant data were retrieved from the final selected studies using a preconceived data-extraction form.

Results

A total of eight studies (three randomized-controlled trials, one prospective study, and four cross-sectional studies) were reviewed. A total of 6,243 participants were investigated in the eight studies and comprised young adults, middle-aged adults, and the elderly with a male-gender predominance. One randomized controlled trial reported that paricalcitol significantly improved renal function in type 1 diabetes patients with renal impairment when combined with renin-angiotensin-aldosterone system (RAAS) blockers. A strong correlation between vitamin D deficiency and DKD risk was noted in the majority of the cross-sectional studies. High doses of cholecalciferol (4,000 or 10,000 IU/day), given early in DKD, significantly reduced disease prevalence.

Conclusion

Paricalcitol may retard the onset or progression of DKD, especially if administered in combination with RAAS blockers. The association of vitamin D deficiency with DKD risk also supports this therapeutic effect. Future systematic reviews are still needed to strengthen the current evidence on therapeutic benefit of vitamin D or its analogs in DKD.
Emerging Role of Dermal White Adipose Tissue in Modulating Hair Follicle Development During Aging
Authors: Chen Jian , Fan Zhe-Xiang , Zhu De-Cong , Guo Yi-Long , Ye Ke , Dai Damao , Guo Zhi , Hu Zhi-Qi , Miao Yong , Qu Qian
Published: October 2021

Hair follicle stem cells are extensively reprogrammed by the aging process, manifesting as diminished self-renewal and delayed responsiveness to activating cues, orchestrated by both intrinsic microenvironmental and extrinsic macroenvironmental regulators. Dermal white adipose tissue (dWAT) is one of the peripheral tissues directly adjacent to hair follicles (HFs) and acts as a critical macroenvironmental niche of HF. dWAT directly contributes to HF aging by paracrine signal secretion. However, the altered interrelationship between dWAT and HF with aging has not been thoroughly understood. Here, through microdissection, we separated dWAT from the skin of aged mice (18 months) and young mice (2 months) in telogen and depilation-induced anagen for transcriptome comparing. Notably, compared with young dWAT, aberrant inflammatory regulators were recapitulated in aging dWAT in telogen, including substantial overexpressed inflammatory cytokines, matrix metalloproteinases, and prostaglandin members. Nonetheless, with anagen initiation, inflammation programs were mostly abolished in aging dWAT, and instead of which, impaired collagen biosynthesis, angiogenesis, and melanin synthesis were identified. Furthermore, we confirmed the inhibitory effect on hair growth of CXCL1, one of the most significantly upregulated inflammation cytokines in aging dWAT. Besides this, we also identified the under-expressed genes related to Wnt signaling fibroblast growth factor family members and increased BMP signaling in aging dWAT, further unraveling the emerging role of dWAT in aging HFs malfunction. Finally, we proved that relieving inflammation of aging dWAT by injecting high-level veratric acid stimulated HF regenerative behavior in aged mice. Concomitantly, significantly decreased TNF-a, CCL2, IL-5, CSF2, and increased IL10 in dWAT was identified. Overall, the results elaborated on the complex physiological cycling changes of dWAT during aging, providing a basis for the potential regulatory effect of dWAT on aging HFs.
Molecular and Clinical Significance of Stanniocalcin-1 Expression in Breast Cancer Through Promotion of Homologous Recombination-Mediated DNA Damage Repair
Authors: Hou Jing , Cheng Jigan , Dai ZeHua , Wei Na , Chen Huan , Wang Shu , Dai Min , Li Leilei , Wang Hua , Ni Qing
Published: October 2021

Stanniocalcin-1 (STC1) is a glycoprotein hormone whose abnormal expression has been reported to be associated with a variety of tumors, but its function in breast cancer is not well understood. Through modulation of STC1 expression in different breast cancer cell lines, our study found that STC1 could promote the proliferation and growth of breast cancer cells and promote metastasis. Furthermore, STC1 reduced apoptosis induction by irradiation. We also found that STC1 could promote a homologous recombination-mediated DNA damage repair by recruiting BRCA1 to sites of damage. Moreover, STC1 silencing sensitized breast cancer cells to treatment with irradiation (IR), olaparib, or cisplatin in vitro. In clinical settings, the serum concentration of STC1 was higher in breast cancer patients than in healthy women, as detected by enzyme-linked immunosorbent assay (ELISA). In addition, immunohistochemical staining of breast cancer specimens showed that a high expression of STC1 was negatively correlated with recurrence-free survival in breast cancer, indicating that STC1 expression could be used as a predictive marker for a poor prognosis in breast cancer. All these findings indicate that STC1 promotes breast cancer tumorigenesis and that breast cancers with a high level of STC1 are more resistant to treatment, probably through homologous recombination (HR) promotion. Furthermore, combining STC1 inhibition and DNA damage-inducing drugs may be a novel approach to improve the survival of patients with STC1-expressing breast cancer.
Gut Microbiota Composition and Fecal Metabolic Profiling in Patients With Diabetic Retinopathy
Authors: Zhou Zixi , Zheng Zheng , Xiong Xiaojing , Chen Xu , Peng Jingying , Yao Hao , Pu Jiaxin , Chen Qingwei , Zheng Minming
Published: October 2021

Recent evidence suggests there is a link between metabolic diseases and gut microbiota. To investigate the gut microbiota composition and fecal metabolic phenotype in diabetic retinopathy (DR) patients. DNA was extracted from 50 fecal samples (21 individuals with type 2 diabetes mellitus-associated retinopathy (DR), 14 with type 2 diabetes mellitus but without retinopathy (DM) and 15 sex- and age-matched healthy controls) and then sequenced by high-throughput 16S rDNA analysis. Liquid chromatography mass spectrometry (LC-MS)-based metabolomics was simultaneously performed on the samples. A significant difference in the gut microbiota composition was observed between the DR and healthy groups and between the DR and DM groups. At the genus level, Faecalibacterium, Roseburia, Lachnospira and Romboutsia were enriched in DR patients compared to healthy individuals, while Akkermansia was depleted. Compared to those in the DM patient group, five genera, including Prevotella, were enriched, and Bacillus, Veillonella, and Pantoea were depleted in DR patients. Fecal metabolites in DR patients significantly differed from those in the healthy population and DM patients. The levels of carnosine, succinate, nicotinic acid and niacinamide were significantly lower in DR patients than in healthy controls. Compared to those in DM patients, nine metabolites were enriched, and six were depleted in DR patients. KEGG annotation revealed 17 pathways with differentially abundant metabolites between DR patients and healthy controls, and only two pathways with differentially abundant metabolites were identified between DR and DM patients, namely, the arginine-proline and α-linolenic acid metabolic pathways. In a correlation analysis, armillaramide was found to be negatively associated with Prevotella and Subdoligranulum and positively associated with Bacillus. Traumatic acid was negatively correlated with Bacillus. Our study identified differential gut microbiota compositions and characteristic fecal metabolic phenotypes in DR patients compared with those in the healthy population and DM patients. Additionally, the gut microbiota composition and fecal metabolic phenotype were relevant. We speculated that the gut microbiota in DR patients may cause alterations in fecal metabolites, which may contribute to disease progression, providing a new direction for understanding DR.
Regulation of Nuclear Factor-kappaB Function by O-GlcNAcylation in Inflammation and Cancer
Authors: Liu Angela Rose , Ramakrishnan Parameswaran
Published: October 2021

Nuclear factor-kappaB (NF-κB) is a pleiotropic, evolutionarily conserved transcription factor family that plays a central role in regulating immune responses, inflammation, cell survival, and apoptosis. Great strides have been made in the past three decades to understand the role of NF-κB in physiological and pathological conditions. Carcinogenesis is associated with constitutive activation of NF-κB that promotes tumor cell proliferation, angiogenesis, and apoptosis evasion. NF-κB is ubiquitously expressed, however, its activity is under tight regulation by inhibitors of the pathway and through multiple posttranslational modifications. O-GlcNAcylation is a dynamic posttranslational modification that controls NF-κB-dependent transactivation. O-GlcNAcylation acts as a nutrient-dependent rheostat of cellular signaling. Increased uptake of glucose and glutamine by cancer cells enhances NF-κB O-GlcNAcylation. Growing evidence indicates that O-GlcNAcylation of NF-κB is a key molecular mechanism that regulates cancer cell proliferation, survival and metastasis and acts as link between inflammation and cancer. In this review, we are attempting to summarize the current understanding of the cohesive role of NF-κB O-GlcNAcylation in inflammation and cancer.
SENP3 Promotes an Mff-Primed Bcl-xL-Drp1 Interaction Involved in Cell Death Following Ischemia
Authors: Guo Chun , Hildick Keri L. , Jiang Juwei , Zhao Alice , Guo Wenbin , Henley Jeremy M. , Wilkinson Kevin A.
Published: October 2021

Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-xL, an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-xL interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-xL interaction. Our data suggest that Mff primes Drp1 binding to Bcl-xL at the mitochondria and that Mff and Bcl-xL can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-xL interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-xL interaction. Expressing a Bcl-xL mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-xL interaction that contributes to cell death following ischemia.
Long Non-coding RNA DANCR in Cancer: Roles, Mechanisms, and Implications
Authors: Wang Maoye , Gu Jianmei , Zhang Xu , Yang Jianping , Zhang Xiaoxin , Fang Xinjian
Published: October 2021

Long non-coding RNA (lncRNA) DANCR (also known as ANCR)—differentiation antagonizing non-protein coding RNA, was first reported in 2012 to suppress differentiation of epithelial cells. Emerging evidence demonstrates that DANCR is a cancer-associated lncRNA abnormally expressed in many cancers (e.g., lung cancer, gastric cancer, breast cancer, hepatocellular carcinoma). Increasing studies suggest that the dysregulation of DANCR plays critical roles in cancer cell proliferation, apoptosis, migration, invasion, and chemoresistance in vitro and tumor growth and metastasis in vivo. Mechanistic analyses show that DANCR can serve as miRNA sponges, stabilize mRNAs, and interact with proteins. Recent research reveals that DANCR can be detected in many body fluids such as serum, plasma, and exosomes, providing a quick and convenient method for cancer monitor. Thus DANCR can be used as a promising diagnostic and prognostic biomarker and therapeutic target for various types of cancer. This review focuses on the role and mechanism of DANCR in cancer progression with an emphasis on the clinical significance of DANCR in human cancers.
Effects of Tumor-Derived Exosome Programmed Death Ligand 1 on Tumor Immunity and Clinical Applications
Authors: Shao Bo , Dang Qin , Chen Zhuang , Chen Chen , Zhou Quanbo , Qiao Bingbing , Liu Jinbo , Hu Shengyun , Wang Guixian , Yuan Weitang , Sun Zhenqiang
Published: October 2021

Programmed death ligand 1 (PD-L1) is a typical immune surface protein that binds to programmed cell death 1 (PD-1) on T cells through its extracellular domain. Subsequently, T cell activity is inhibited, and tumor immune tolerance is enhanced. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the combination of PD-1/PD-L1 and rejuvenates depleted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid bilayer nanovesicles secreted by various cell types, which mediate signal communication between cells. Studies have shown that PD-L1 can not only be expressed on the surface of tumor cells, immune cells, and other cells in the tumor microenvironment, but also be released from tumor cells and exist in an extracellular form. In particular, exosome PD-L1 plays an unfavorable role in tumor immunosuppression. The immunomodulatory effect of exosome PD-L1 and its potential in fluid diagnosis have attracted our attention. This review aims to summarize the available evidence regarding the biological characteristics of exosome PD-L1 in tumor immunity, with a particular focus on the mechanisms in different cancers and clinical prospects. In addition, we also summarized the current possible and effective detection methods for exosome PD-L1 and proposed that exosome PD-L1 has the potential to become a target for overcoming anti-PD-1/PD-L1 antibody treatment resistance.
RETRACTED: PBTNet: A New Computer-Aided Diagnosis System for Detecting Primary Brain Tumors
Authors: Lu Si-Yuan , Satapathy Suresh Chandra , Wang Shui-Hua , Zhang Yu-Dong
Published: October 2021

Brain tumors are among the leading human killers. There are over 120 different types of brain tumors, but they mainly fall into two groups: primary brain tumors and metastatic brain tumors. Primary brain tumors develop from normal brain cells. Early and accurate detection of primary brain tumors is vital for the treatment of this disease. Magnetic resonance imaging is the most common method to diagnose brain diseases, but the manual interpretation of the images suffers from high inter-observer variance. In this paper, we presented a new computer-aided diagnosis system named PBTNet for detecting primary brain tumors in magnetic resonance images. A pre-trained ResNet-18 was selected as the backbone model in our PBTNet, but it was fine-tuned only for feature extraction. Then, three randomized neural networks, Schmidt neural network, random vector functional-link, and extreme learning machine served as the classifiers in the PBTNet, which were trained with the features and their labels. The final predictions of the PBTNet were generated by the ensemble of the outputs from the three classifiers. 5-fold cross-validation was employed to evaluate the classification performance of the PBTNet, and experimental results demonstrated that the proposed PBTNet was an effective tool for the diagnosis of primary brain tumors.
Autophagy in Viral Infection and Pathogenesis
Authors: Liang Shan , Wu Yun-Shan , Li Dong-Yi , Tang Ji-Xin , Liu Hua-Feng
Published: October 2021

As an evolutionarily conserved cellular process, autophagy plays an essential role in the cellular metabolism of eukaryotes as well as in viral infection and pathogenesis. Under physiological conditions, autophagy is able to meet cellular energy needs and maintain cellular homeostasis through degrading long-lived cellular proteins and recycling damaged organelles. Upon viral infection, host autophagy could degrade invading viruses and initial innate immune response and facilitate viral antigen presentation, all of which contribute to preventing viral infection and pathogenesis. However, viruses have evolved a variety of strategies during a long evolutionary process, by which they can hijack and subvert host autophagy for their own benefits. In this review, we highlight the function of host autophagy in the key regulatory steps during viral infections and pathogenesis and discuss how the viruses hijack the host autophagy for their life cycle and pathogenesis. Further understanding the function of host autophagy in viral infection and pathogenesis contributes to the development of more specific therapeutic strategies to fight various infectious diseases, such as the coronavirus disease 2019 epidemic.
Epigenetic Signaling of Cancer Stem Cells During Inflammation
Authors: Liu Zaoqu , Ren Yuqing , Meng Lingfang , Li Lifeng , Beatson Richard , Deng Jinhai , Zhang Tengfei , Liu Junqi , Han Xinwei
Published: October 2021

Malignant tumors pose a great challenge to human health, which has led to many studies increasingly elucidating the tumorigenic process. Cancer Stem Cells (CSCs) have profound impacts on tumorigenesis and development of drug resistance. Recently, there has been increased interest in the relationship between inflammation and CSCs but the mechanism underlying this relationship has not been fully elucidated. Inflammatory cytokines produced during chronic inflammation activate signaling pathways that regulate the generation of CSCs through epigenetic mechanisms. In this review, we focus on the effects of inflammation on cancer stem cells, particularly the role of signaling pathways such as NF-κB pathway, STAT3 pathway and Smad pathway involved in regulating epigenetic changes. We hope to provide a novel perspective for improving strategies for tumor treatment.
Metal-Free Heptazine-Based Porous Polymeric Network as Highly Efficient Catalyst for CO2 Capture and Conversion
Authors: Sharma Neha , Ugale Bharat , Kumar Sunil , Kailasam Kamalakannan
Published: October 2021

The capture and catalytic conversion of CO2 into value-added chemicals is a promising and sustainable approach to tackle the global warming and energy crisis. The nitrogen-rich porous organic polymers are excellent materials for CO2 capture and separation. Herein, we present a nitrogen-rich heptazine-based microporous polymer for the cycloaddition reaction of CO2 with epoxides in the absence of metals and solvents. HMP-TAPA, being rich in the nitrogen site, showed a high CO2 uptake of 106.7 mg/g with an IAST selectivity of 30.79 toward CO2 over N2. Furthermore, HMP-TAPA showed high chemical and water stability without loss of any structural integrity. Besides CO2 sorption, the catalytic activity of HMP-TAPA was checked for the cycloaddition of CO2 and terminal epoxides, resulting in cyclic carbonate with high conversion (98%). They showed remarkable recyclability up to 5 cycles without loss of activity. Overall, this study represents a rare demonstration of the rational design of POPs (HMP-TAPA) for multiple applications.
Caenorhabditis elegans as an Infection Model for Pathogenic Mold and Dimorphic Fungi: Applications and Challenges
Authors: Ahamefule Chukwuemeka Samson , Ezeuduji Blessing C. , Ogbonna James C. , Moneke Anene N. , Ike Anthony C. , Jin Cheng , Wang Bin , Fang Wenxia
Published: October 2021

The threat burden from pathogenic fungi is universal and increasing with alarming high mortality and morbidity rates from invasive fungal infections. Understanding the virulence factors of these fungi, screening effective antifungal agents and exploring appropriate treatment approaches in in vivo modeling organisms are vital research projects for controlling mycoses. Caenorhabditis elegans has been proven to be a valuable tool in studies of most clinically relevant dimorphic fungi, helping to identify a number of virulence factors and immune-regulators and screen effective antifungal agents without cytotoxic effects. However, little has been achieved and reported with regard to pathogenic filamentous fungi (molds) in the nematode model. In this review, we have summarized the enormous breakthrough of applying a C. elegans infection model for dimorphic fungi studies and the very few reports for filamentous fungi. We have also identified and discussed the challenges in C. elegans-mold modeling applications as well as the possible approaches to conquer these challenges from our practical knowledge in C. elegans-Aspergillus fumigatus model.
Interleukin-9 in Immunopathology of Trypanosoma cruzi Experimental Infection
Authors: Silva Nadjania Saraiva de Lira , Orikaza Cristina Mary , Santana Fabiana Rodrigues de , dos Santos Luana Aguiar , Salu Bruno Ramos , Oliva Maria Luiza Vilela , Sinigaglia Rita de Cássia , Mortara Renato Arruda
Published: October 2021

Chagas’ disease is a parasitosis caused by Trypanosoma cruzi, which affects approximately 8 million people worldwide. The balance between pro- and anti-inflammatory cytokines produced during immunological responses contributes to disease prognosis and progression. Parasite tissue persistence can induce chronic inflammatory stimuli, which can cause long-term tissue injury and fibrosis. Chronic Chagas’ patients exhibit increased levels of interleukin (IL)-9, an important cytokine in the regulation of inflammatory and fibrogenic processes. Data on the role of IL-9 in other pathologies are sometimes contradictory, and few studies have explored this cytokine’s influence in Chagas’ disease pathology. Hence, the aim of this study was to evaluate the role of IL-9 in the progression of T. cruzi infection in vivo and in vitro. In vitro infection demonstrated that IL-9 reduced the number of infected cells and decreased the multiplication of intracellular amastigotes in both C2C12 myoblasts and bone marrow-derived macrophages. In myoblasts, the increased production of nitric oxide (NO) was essential for reduced parasite multiplication, whereas macrophage responses resulted in increased IL-6 and reduced TGF-β levels, indicating that parasite growth restriction mechanisms induced by IL-9 were cell-type specific. Experimental infection of BALB/c mice with T. cruzi trypomastigotes of the Y strain implicated a major role of IL-9 during the chronic phase, as increased Th9 and Tc9 cells were detected among splenocytes; higher levels of IL-9 in these cell populations and increased cardiac IL-9 levels were detected compared to those of uninfected mice. Moreover, rIL9 treatment decreased serum IL-12, IL-6, and IL-10 levels and cardiac TNF-α levels, possibly attempting to control the inflammatory response. IL-9 neutralization increased cardiac fibrosis, synthesis of collagens I and III, and mastocyte recruitment in BALB/c heart tissue during the chronic phase. In conclusion, our data showed that IL-9 reduced the invasion and multiplication of T. cruzi in vitro, in both myoblasts and macrophages, favoring disease control through cell-specific mechanisms. In vivo, IL-9 was elevated during experimental chronic infection in BALB/c mice, and this cytokine played a protective role in the immunopathological response during this phase by controlling cardiac fibrosis and proinflammatory cytokine production.
Stage-Specific Class I Nucleases of Leishmania Play Important Roles in Parasite Infection and Survival
Authors: Freitas-Mesquita Anita Leocadio , Meyer-Fernandes José Roberto
Published: October 2021

Protozoans of the genusLeishmaniaare the causative agents of an important neglected tropical disease referred to as leishmaniasis. During their lifecycle, the parasites can colonize the alimentary tract of the sand fly vector and the parasitophorous vacuole of the mammalian host, differentiating into distinct stages. Motile promastigotes are found in the sand fly vector and are transmitted to the mammalian host during the insect blood meal. Once in the vertebrate host, the parasites differentiate into amastigotes and multiply inside macrophages. To successfully establish infection in mammalian hosts,Leishmaniaparasites exhibit various strategies to impair the microbicidal power of the host immune system. In this context, stage-specific class I nucleases play different and important roles related to parasite growth, survival and development. Promastigotes express 3’-nucleotidase/nuclease (3’-NT/NU), an ectoenzyme that can promote parasite escape from neutrophil extracellular traps (NET)-mediated death through extracellular DNA hydrolysis and increaseLeishmania-macrophage interactions due to extracellular adenosine generation. Amastigotes express secreted nuclease activity during the course of human infection that may be involved in the purine salvage pathway and can mobilize extracellular nucleic acids available far from the parasite. Another nuclease expressed in amastigotes (P4/LmC1N) is located in the endoplasmic reticulum of the parasite and may be involved in mRNA stability and DNA repair. Homologs of this class I nuclease can induce protection against infection by eliciting a T helper 1-like immune response. These immunogenic properties render these nucleases good targets for the development of vaccines against leishmaniasis, mainly because amastigotes are the form responsible for the development and progression of the disease. The present review aims to present and discuss the roles played by different class I nucleases during theLeishmanialifecycle, especially regarding the establishment of mammalian host infection.
Pronominalization and Expectations for Re-Mention: Modeling Coreference in Contexts With Three Referents
Authors: Hoek Jet , Kehler Andrew , Rohde Hannah
Published: October 2021

The relationship between pronoun production and pronoun interpretation has been proposed to follow Bayesian principles, combining a comprehender’s expectation about which referent will be mentioned next and their estimate of how likely it is that a potential referent will be re-mentioned using a pronoun. The Bayesian Model has received support from studies in several languages (English, Mandarin Chinese, Catalan, German), but tested contexts have been limited to two event participants, whereas natural language discourse often involves contexts with more than two event participants. In this study, we conducted three story continuation experiments to assess how the Bayesian Model performs in more complex contexts. Our results show that even in contexts with three event participants, comprehenders can behave rationally when interpreting pronouns, but that they appear to require sufficient context to build up a coherent representation of the situation to do so. In addition to testing the basic claim of the Bayesian Model (Weak Bayes), we test the central prediction of the Strong form of the hypothesis: that the two components of the model (next-mention expectations and choice of referring expression) are influenced by dissociated sets of factors. In a model comparison, Experiments 2 and 3 confirm the closest fit from the Bayesian Model, which supports Weak Bayes, and none of our experiments find evidence that the predictability of a referent affects pronominalization rates, which corroborates Strong Bayes. Finally, we test whether the rate of pronominalization is sensitive to factors related to ambiguity and argument/adjunct status of referents; we find that participants vary their production of pronouns most strongly based on the grammatical role of the antecedent (subject or not), with a smaller effect from the presence/absence of a gender-matched competitor and no effect from the syntactic position of this competing referent.
Severe Cardiac Toxicity Induced by Cancer Therapies Requiring Intensive Care Unit Admission
Authors: Montisci Andrea , Palmieri Vittorio , Liu Jennifer E. , Vietri Maria T. , Cirri Silvia , Donatelli Francesco , Napoli Claudio
Published: October 2021

Graphical Abstract
Incremental Value of Left Ventricular Mechanical Dyssynchrony Assessment by Nitrogen-13 Ammonia ECG-Gated PET in Patients With Coronary Artery Disease
Authors: Zheng Danzha , Liu Yanyun , Zhang Lei , Hu Fan , Tan Xubo , Jiang Dawei , Zhou Weihua , Lan Xiaoli , Qin Chunxia
Published: October 2021

Background: Phase analysis is a technique used to assess left ventricular mechanical dyssynchrony (LVMD) in nuclear myocardial imaging. Previous studies have found an association between LVMD and myocardial ischemia. We aim to assess the potential diagnostic value of LVMD in terms of myocardial viability, and ability to predict major adverse cardiac events (MACE), using Nitrogen-13 ammonia ECG-gated positron emission tomography (gPET).

Methods: Patients with coronary artery disease (CAD) who underwent Nitrogen-13 ammonia and Fluorine-18 FDG myocardial gPET were enrolled, and their gPET imaging data were retrospectively analyzed. Patients were followed up and major adverse cardiac events (MACE) were recorded. The Kruskal-Wallis test and Mann-Whitney U test were performed to compare LVMD parameters among the groups. Binary logistic regression analysis, receiver operating characteristic (ROC) curve analysis, and multiple stepwise analysis curves were applied to identify the relationship between LVMD parameters and myocardial viability. Kaplan–Meier survival curves and the log-rank test were used to look for differences in the incidence of MACE.

Results: In total, 79 patients were enrolled and divided into three groups: Group 1 (patients with only viable myocardium, n = 7), Group 2 (patients with more viable myocardium than scar, n = 33), and Group 3 (patients with less viable myocardium than scar, n = 39). All LVMD parameters were significantly different among groups. The median values of systolic phase standard deviation (PSD), systolic phase histogram bandwidth (PHB), diastolic PSD, and diastolic PHB between Group 1 and Group 3, and Group 2 and Group 3 were significantly different. A diastolic PHB of 204.5° was the best cut-off value to predict the presence of myocardial scar. In multiple stepwise analysis models, diastolic PSD, ischemic extent, and New York Heart Association (NYHA) classification were independent predictive factors of viable myocardium and myocardial scar. The incidence of MACE in patients with diastolic PHB > 204.5° was 25.0%, higher than patients with diastolic PHB <204.5° (11.8%), but the difference was not significant.

Conclusions: LVMD generated from Nitrogen-13 ammonia ECG-gated myocardial perfusion imaging had added diagnostic value for myocardial viability assessment in CAD patients. LVMD did not show a definite prognostic value.
Molecular Interactions Between Vascular Smooth Muscle Cells and Macrophages in Atherosclerosis
Authors: Beck-Joseph Jahnic , Tabrizian Maryam , Lehoux Stephanie
Published: October 2021

Atherosclerosis is the largest contributor toward life-threatening cardiovascular events. Cellular activity and cholesterol accumulation lead to vascular remodeling and the formation of fatty plaques. Complications arise from blood clots, forming at sites of plaque development, which may detach and result in thrombotic occlusions. Vascular smooth muscle cells and macrophages play dominant roles in atherosclerosis. A firm understanding of how these cells influence and modulate each other is pivotal for a better understanding of the disease and the development of novel therapeutics. Recent studies have investigated molecular interactions between both cell types and their impact on disease progression. Here we aim to review the current knowledge. Intercellular communications through soluble factors, physical contact, and extracellular vesicles are discussed. We also present relevant background on scientific methods used to study the disease, the general pathophysiology and intracellular factors involved in phenotypic modulation of vascular smooth muscle cells. We conclude this review with a discussion of the current state, shortcomings and potential future directions of the field.
Common Polymorphisms in the RGMa Promoter Are Associated With Cerebrovascular Atherosclerosis Burden in Chinese Han Patients With Acute Ischemic Cerebrovascular Accident
Authors: Hu Qingzhe , Chen Zhenlei , Yuan Xiaofan , Li Shucheng , Zhang Rongrong , Qin Xinyue
Published: October 2021

Repulsive guidance molecule a (RGMa) plays a vital role in the progression of numerous inflammatory diseases. However, whether it participates in atherosclerosis development is not known. Here, we explored the influence of RGMa in atherogenesis by investigating whether an association exists between functional polymorphisms in the RGMa promoter and cerebrovascular atherosclerosis burden (CAB) in Chinese Han patients diagnosed with acute ischemic cerebrovascular accident. To this end, we conducted a genetic association study on 201 patients with prior diagnoses of acute ischemic stroke or transient ischemic attack recruited from our hospital. After admission, we conducted three targeted single-nucleotide polymorphisms (SNPs) genotyping and evaluated CAB by computed tomography angiography. We used logistic regression modeling to analyze genetic associations. Functional polymorphism analysis indicated an independent association between the rs725458 T allele and increased CAB in patients with acute ischemic cerebrovascular accident [adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.01–2.74, P = 0.046]. In contrast, an association between the rs4778099 AA genotype and decreased CAB (adjusted OR = 0.10, 95% CI = 0.01–0.77, P = 0.027) was found. Our Gene Expression Omnibus analysis revealed lower RGMa levels in the atherosclerotic aortas and in the macrophages isolated from plaques than that in the normal aortas and macrophages from normal tissue, respectively. In conclusion, the relationship between RGMa and cerebrovascular atherosclerosis suggests that RGMa has a potential vasoprotective effect. The two identified functional SNPs (rs725458 and rs4778099) we identified in the RGMa promoter are associated with CAB in patients diagnosed with acute ischemic cerebrovascular accident. These findings offer a promising research direction for RGMa-related translational studies on atherosclerosis.
Late Cardiac Pathology in Severe Covid-19. A Postmortem Series of 30 Patients
Authors: Ferrer-Gómez Ana , Pian-Arias Héctor , Carretero-Barrio Irene , Navarro-Cantero Antonia , Pestaña David , de Pablo Raúl , Zamorano José Luis , Galán Juan Carlos , Pérez-Mies Belén , Ruz-Caracuel Ignacio , Palacios José
Published: October 2021

The role of SARS-CoV-2 as a direct cause in the cardiac lesions in patients with severe COVID-19 remains to be established. Our objective is to report the pathological findings in cardiac samples of 30 patients who died after a prolonged hospital stay due to Sars-Cov-2 infection. We performed macroscopic, histological and immunohistochemical analysis of the hearts of 30 patients; and detected Sars-Cov-2 RNA by RT-PCR in the cardiac tissue samples. The median age of our cohort was 69.5 years and 76.6% were male. The median time between symptoms onset and death was 36.5 days. The main comorbidities were arterial hypertension (13 patients, 43.3%), dyslipidemia (11 patients, 36.7%), cardiovascular conditions (8 patients, 26.7%), and obesity (8 patients, 26.7%). Cardiovascular conditions included ischemic cardiopathy in 4 patients (13.3%), hypertrophic cardiomyopathy in 2 patients (6.7%) and valve replacement and chronic heart failure in one patient each (3.3%). At autopsy, the most frequent histopathological findings were coronary artery atherosclerosis (8 patients, 26.7%), left ventricular hypertrophy (4 patients, 13.3%), chronic epicardial inflammation (3 patients, 10%) and adipose metaplasia (2 patients, 6.7%). Two patients showed focal myocarditis, one due to invasive aspergillosis. One additional patient showed senile amyloidosis. Sars-Cov-2 RNA was detected in the heart of only one out of 30 patients, who had the shortest disease evolution of the series (9 days). However, no relevant cardiac histological alterations were identified. In present series, cardiac pathology was only modest in most patients with severe COVID-19. At present, the contribution of a direct effect of SARS-CoV-2 on cardiac lesions remains to be established.
Reappraisal of Non-vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients: A Systematic Review and Meta-Analysis
Authors: Liu Fuwei , Yang Yunyao , Cheng Winglam , Ma Jianyong , Zhu Wengen
Published: October 2021

Background: Recent observational studies have compared effectiveness and safety profiles between non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in patients with atrial fibrillation (AF). Nevertheless, the confounders may exist due to the nature of clinical practice-based data, thus potentially influencing the reliability of results. This systematic review and meta-analysis were conducted to compare the effect of NOACs with warfarin based on the propensity score-based observational studies vs. randomized clinical trials (RCTs).

Methods: Articles included were systematically searched from the PubMed and EMBASE databases until March 2021 to obtain relevant studies. The primary outcomes were stroke or systemic embolism (SSE) and major bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the outcomes were extracted and then pooled by the random-effects model.

Results: A total of 20 propensity score-based observational studies and 4 RCTs were included. Compared with warfarin, dabigatran (HR, 0.82 [95% CI, 0.71–0.96]), rivaroxaban (HR, 0.80 [95% CI, 0.75–0.85]), apixaban (HR, 0.75 [95% CI, 0.65–0.86]), and edoxaban (HR, 0.71 [95% CI, 0.60–0.83]) were associated with a reduced risk of stroke or systemic embolism, whereas dabigatran (HR, 0.76 [95% CI, 0.65–0.87]), apixaban (HR, 0.61 [95% CI, 0.56–0.67]), and edoxaban (HR, 0.58 [95% CI, 0.45–0.74]) but not rivaroxaban (HR, 0.92 [95% CI, 0.84–1.00]) were significantly associated with a decreased risk of major bleeding based on the observational studies. Furthermore, the risk of major bleeding with dabigatran 150 mg was significantly lower in observational studies than that in the RE-LY trial, whereas the pooled results of observational studies were similar to the data from the corresponding RCTs in other comparisons.

Conclusion: Data from propensity score-based observational studies and NOAC trials consistently suggest that the use of four individual NOACs is non-inferior to warfarin for stroke prevention in AF patients.
Bulk Crustal Properties and Layered Velocity Structure in Fujian, SE China: Constraints From P and S Receiver Functions
Authors: Goyal Ayush , Hung Shu-Huei
Published: October 2021

Multiple tectonic events since the Neoproterozoic era have framed the present-day lithosphere in the Fujian province affiliated with the eastern part of the South China Block. Comprehensive information of the crustal structure and bulk properties can aid to understand the geological features and tectonic processes of still much debate in this region. An attempt is made in this study to explore crustal thickness and internal velocities across Fujian using the teleseismic receiver functions (RFs). The H-V stacking of joint P and S RFs improves to simultaneously estimate crustal thickness, average Vp and Vs, and derived Vp/Vs ratio and bulk sound speed in three backazimuth sectors for each of 17 stations. Furthermore, a Neighborhood Algorithm nonlinear inversion of P RFs is employed to determine the layered structures of Vs and Vp/Vs beneath all the stations. Results indicate the crustal thickness varies from at most ∼35 km in northwest Fujian to 30–35 km in the inland mountains and 27–30 km in the southeastern coasts. The inferred Moho geometry is nonplanar or inclined across the Zhenghe-Dapu (ZD) and Changle-Zhaoan (CZ) fault zones, especially in the southern ZD fault area. The average Vp/Vs suggests that the crust is predominantly felsic in the Wuyi-Yunkai orogen and intermediate-to-mafic in the Cretaceous magmatic and metamorphic zones. A high-velocity upper crust along the coastline is revealed, which attributes to the Pingtan-Dongshan metamorphic belt. At the sites near the ZD fault zone, the intracrustal negative discontinuity occurs at a shallower depth of ∼15 km marking an abrupt Vs decrease into the low-velocity mid-to-lower crustal layer, probably linked to the closed paleo-rift basin remnants. The lower crust across the Fujian is generally characterized by relatively lower Vs and higher Vp/Vs (1.80–1.84) consistent with those of the mafic-ultramafic rocks, which do not support the proposed extensive magmatic underplating in the Late Mesozoic.
Risk Factors and a Prediction Model of Lateral Lymph Node Metastasis in CN0 Papillary Thyroid Carcinoma Patients With 1–2 Central Lymph Node Metastases
Authors: Wang Yuanyuan , Deng Chang , Shu Xiujie , Yu Ping , Wang Huaqiang , Su Xinliang , Tan Jinxiang
Published: October 2021

Background

Papillary thyroid cancer (PTC) in clinically lymph node-negative (cN0) patients is prone toward lymph node metastasis. As a risk factor for tumor persistence and local recurrence, lateral lymph node metastasis (LLNM) is related to the number of central lymph node metastases (CLNMs).

Methods

We performed LLNM risk stratification based on the number of CLNMs for cN0 PTC patients who underwent thyroidectomy and lymph node dissection between January 2013 and December 2018. A retrospective analysis was applied to the 274 collected patients with 1-2 CLNMs. We examined the clinicopathological characteristics of the patients and constructed a LASSO model.

Results

In the 1–2 CLNM group, tumors >10 mm located in the upper region and nodular goiters were independent risk factors for LLNM. Specifically, tumors >20 mm and located in the upper region contributed to metastasis risk at level II. Hashimoto’s thyroiditis reduced this risk (p = 0.045, OR = 0.280). Age ≤ 30 years and calcification (microcalcification within thyroid nodules) correlated with LLNM. The LASSO model divided the population into low- (25.74%) and high-risk (57.25%) groups for LLNM, with an AUC of 0.715.

Conclusions

For patients with 1–2 CLNMs, young age, calcification, nodular goiter, tumor >10 mm, and tumor in the upper region should alert clinicians to considering a higher occult LLNM burden. Close follow-up and therapy adjustment may be warranted for high-risk patients.
Energetics of Li+ Coordination with Asymmetric Anions in Ionic Liquids by Density Functional Theory
Authors: Penley Drace , Vicchio Stephen P. , Getman Rachel B. , Gurkan Burcu
Published: October 2021

The energetics, coordination, and Raman vibrations of Li solvates in ionic liquid (IL) electrolytes are studied with density functional theory (DFT). Li+ coordination with asymmetric anions of cyano(trifluoromethanesulfonyl)imide ([CTFSI]) and (fluorosulfonyl)(trifluoro-methanesulfonyl)imide ([FTFSI]) is examined in contrast to their symmetric analogs of bis(trifluoromethanesulfonyl)imide ([TFSI]), bis(fluorosulfonyl)imide ([FSI]), and dicyanamide ([DCA]). The dissociation energies that can be used to describe the solvation strength of Li+ are calculated on the basis of the energetics of the individual components and the Li solvate. The calculated dissociation energies are found to be similar for Li+-[FTFSI], Li+-[TFSI], and Li+-[FSI] where only Li+-O coordination exists. Increase in asymmetry and anion size by fluorination on one side of the [TFSI] anion does not result in significant differences in the dissociation energies. On the other hand, with [CTFSI], both Li+-O and Li+-N coordination are present, and the Li solvate has smaller dissociation energy than the solvation by [DCA] alone, [TFSI] alone, or a 1:1 mixture of [DCA]/[TFSI] anions. This finding suggests that the Li+ solvation can be weakened by asymmetric anions that promote competing coordination environments through enthalpic effects. Among the possible Li solvates of (Li[CTFSI]n)−(n−1), where n = 1, 2, 3, or 4, (Li[CTFSI]2)−1 is found to be the most stable with both monodentate and bidentate bonding possibilities. Based on this study, we hypothesize that the partial solvation and weakened solvation energetics by asymmetric anions may increase structural heterogeneity and fluctuations in Li solvates in IL electrolytes. These effects may further promote the Li+ hopping transport mechanism in concentrated and multicomponent IL electrolytes that is relevant to Li-ion batteries.