bluuebunny/crossref_metadata_2025 huggingface dataset:
Viral Sequences Recovered From Puma Tooth DNA Reconstruct Statewide Viral Phylogenies
Authors: Gagne Roderick B. , Kraberger Simona , McMinn Rebekah , Trumbo Daryl R. , Anderson Charles R. , Logan Ken A. , Alldredge Mathew W. , Griffin Karen , Vandewoude Sue
Published: September 2021

Monitoring pathogens in wildlife populations is imperative for effective management, and for identifying locations for pathogen spillover among wildlife, domestic species and humans. Wildlife pathogen surveillance is challenging, however, as sampling often requires the capture of a significant proportion of the population to understand host pathogen dynamics. To address this challenge, we assessed the ability to use hunter-collected teeth from puma across Colorado to recover genetic data of two feline retroviruses, feline foamy virus (FFV) and feline immunodeficiency virus (FIVpco) and show they can be utilized for this purpose. Comparative phylogenetic analyses of FIVpco and FFV from tooth and blood samples to previous analyses conducted with blood samples collected over a nine-year period from two distinct areas was undertaken highlighting the value of tooth derived samples. We found less FIVpco phylogeographic structuring than observed from sampling only two regions and that FFV data confirmed previous findings of endemic infection, minimal geographic structuring, and supported frequent cross-species transmission from domestic cats to pumas. Viral analysis conducted using intentionally collected blood samples required extensive financial, capture and sampling efforts. This analysis illustrates that viral genomic data can be cost effectively obtained using tooth samples incidentally-collected from hunter harvested pumas, taking advantage of samples collected for morphological age identification. This technique should be considered as an opportunistic method to provide broad geographic sampling to define viral dynamics more accurately in wildlife.
Use of Fatty Acids From Aquatic Prey Varies With Foraging Strategy
Authors: Twining Cornelia W. , Parmar Tarn Preet , Mathieu-Resuge Margaux , Kainz Martin J. , Shipley Jeremy Ryan , Martin-Creuzburg Dominik
Published: September 2021

Across ecosystems, resources vary in their nutritional composition and thus their dietary value to consumers. Animals can either access organic compounds, such as fatty acids, directly from diet or through internal biosynthesis, and the extent to which they use these two alternatives likely varies based on the availability of such compounds across the nutritional landscape. Cross-ecosystem subsidies of important dietary nutrients, like omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA), may provide consumers with the opportunity to relax the demands of synthesis and rely upon dietary flexibility rather than internal metabolic processes. Here, we examined how dietary flexibility and distance from a lake influenced the degree to which generalist insectivores relied upon dietary n-3 LC-PUFA from emergent aquatic insects versus n-3 LC-PUFA synthesized from precursor compounds found in terrestrial insects. We used bulk and compound-specific stable isotope analyses to understand spider and insectivorous bird (Blue Tit;Cyanistes caeruleus) reliance on aquatic and terrestrial resources, including dietary PUFA sources, along a riparian to upland gradient from a lake. We simultaneously investigated n-3 LC-PUFA synthesis ability in nestlings using13C fatty acid labeling. We found that riparian spiders took advantage of emergent aquatic insect subsidies, deriving their overall diet and their n-3 PUFA from aquatic resources whereas nestling birds at all distances and upland spiders relied upon terrestrial resources, including PUFA. Our13C labeling experiment demonstrated that nestling tits were able to synthesize the n-3 LC-PUFA docosahexaenoic acid from the dietary precursor α-linolenic acid, suggesting that they are not limited by aquatic resources to satisfy their LC-PUFA requirements. Overall, this study suggests that habitat generalist insectivores vary in the degree to which they can shift diet to take advantage of high-quality aquatic resources depending upon both their foraging flexibility and internal synthesis capacity.
Multi-View Spectral Clustering Based on Multi-Smooth Representation Fusion for Cancer Subtype Prediction
Authors: Liu Jian , Ge Shuguang , Cheng Yuhu , Wang Xuesong
Published: September 2021

It is a vital task to design an integrated machine learning model to discover cancer subtypes and understand the heterogeneity of cancer based on multiple omics data. In recent years, some multi-view clustering algorithms have been proposed and applied to the prediction of cancer subtypes. Among them, the multi-view clustering methods based on graph learning are widely concerned. These multi-view approaches usually have one or more of the following problems. Many multi-view algorithms use the original omics data matrix to construct the similarity matrix and ignore the learning of the similarity matrix. They separate the data clustering process from the graph learning process, resulting in a highly dependent clustering performance on the predefined graph. In the process of graph fusion, these methods simply take the average value of the affinity graph of multiple views to represent the result of the fusion graph, and the rich heterogeneous information is not fully utilized. To solve the above problems, in this paper, a Multi-view Spectral Clustering Based on Multi-smooth Representation Fusion (MRF-MSC) method was proposed. Firstly, MRF-MSC constructs a smooth representation for each data type, which can be viewed as a sample (patient) similarity matrix. The smooth representation can explicitly enhance the grouping effect. Secondly, MRF-MSC integrates the smooth representation of multiple omics data to form a similarity matrix containing all biological data information through graph fusion. In addition, MRF-MSC adaptively gives weight factors to the smooth regularization representation of each omics data by using the self-weighting method. Finally, MRF-MSC imposes constrained Laplacian rank on the fusion similarity matrix to get a better cluster structure. The above problems can be transformed into spectral clustering for solving, and the clustering results can be obtained. MRF-MSC unifies the above process of graph construction, graph fusion and spectral clustering under one framework, which can learn better data representation and high-quality graphs, so as to achieve better clustering effect. In the experiment, MRF-MSC obtained good experimental results on the TCGA cancer data sets.
PD-L1-Mediated Immunosuppression in Oral Squamous Cell Carcinoma: Relationship With Macrophage Infiltration and Epithelial to Mesenchymal Transition Markers
Authors: Wu Tiantian , Tang Caijin , Tao Renchuan , Yong Xiangzhi , Jiang Qiaozhi , Feng Cong
Published: September 2021

To date, immune check-point inhibitors (ICIs), particularly inhibitors of programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) have become prominent in cancer treatment and also improved life expectancy of cancer patients. As key regulators of PD-1/PD-L1 axis, the recruitment of tumor-associated macrophages (TAMs) enhances aggressive and invasive properties of tumors in immunosuppressive tumor microenvironment (TME) and promotes epithelial-mesenchymal transition (EMT). The aims of the study were first to characterize the critical links among PD-L1, TME and EMT process and, further, to explore the sensitivity of different chemical agents to different PD-L1 expression groups. Bioinformatical analysis revealed that PD-L1 was highly expressed in OSCC and higher PD-L1 expression correlated with worse survival in patients. Notably, PD-L1 was positively correlated with macrophages infiltration and EMT markers gene expression. Moreover, patients in the PD-L1high group were at a significant chance of benefiting from ICI treatment and they also showed higher sensitivity to the chemical drugs (olaparib, paclitaxel, docetaxel, and pazopanib). These findings implicate PD-L1 could serve as a novel target for prognostic and therapeutic approaches in OSCC patients; PD-L1-mediated immune evasion might be attributable to the infiltration of macrophages, resulting EMT progress; Chemical agents in combination with PD-L1 inhibitor could be served as personalized treatment plan for OSCC patients so as to maximize patient benefit.
The Associations of Lymphocyte Ratio and Neutrophil Ratio on Liver Dysfunction in COVID-19 Patients
Authors: Liu Fang , Liu Hong , Yu Wen-Yan , Liu Zhan , Zhang Xia , Wang Yi , Miao Liang-Bin , Li Zhao-Yi , Huang Jin-Song , Bao Jian-Feng
Published: September 2021

Data on the impact of lymphocytes and neutrophils on the incidence of liver dysfunction in COVID-19 patients are limited. This study aimed to investigate the lateral and longitudinal associations of lymphocyte ratio (LR) and neutrophil ratio (NR) on liver dysfunction in COVID-19 patients. We tested 1,409 blood samples from 245 COVID-19 patients in China between January 2020 and June 2021. The lateral U-shaped relationships, determined by smooth curve fitting and the piecewise-linear mixed-effect model, were observed between LR, NR, and AST and the incidence of AST-linked liver dysfunction, with the threshold cutoffs of 26.1 and 62.0, respectively. Over the 1,409 tests, the LR ≤ 26.1 and NR ≥ 62.0 related to the occurrence of mild liver dysfunction (HR: 1.36; 95% CI: 1.01, 1.82), moderate liver dysfunction (HR: 1.37; 95% CI: 1.01, 1.85), and severe liver dysfunction (HR: 1.72; 95% CI: 1.02, 2.90). For the patients with preexisting AST ≥ 35 U/L, the baseline LR ≤ 26.1 and NR ≥ 62.0 (b.LLCHN) groups had a fully adjusted 8.85-, 7.88-, and 5.97-fold increased risk of mild and moderate liver dysfunction after being hospitalized of 3, 6, and 9 days compared to the baseline LR > 26.1 and NR < 62.0 (b.normal) groups. Severe liver dysfunction only presents significant differences after being adjusted for age, sex, and BMI. Consistently, Kaplan–Meier analyses showed that b.LLCHN reflects a better predictive value for different subsequent magnitude liver dysfunctions after admission of 3 and 6 days. To improve liver function in patients with preexisting AST ≥35 U/L, future management strategies should pay more attention to baseline LR ≤ 26.1 and NR ≥ 62.0 patients.
Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia
Authors: de Porto Alexander P. , Liu Zhe , de Beer Regina , Florquin Sandrine , Roelofs Joris J. T. H. , de Boer Onno J. , den Haan Joke M. M. , Hendriks Rudi W. , van ‘t Veer Cornelis , van der Poll Tom , de Vos Alex F.
Published: September 2021

Bruton’s tyrosine kinase (Btk) is a cytoplasmic kinase expressed in B cells and myeloid cells. It is essential for B cell development and natural antibody-mediated host defense against bacteria in humans and mice, but little is known about the role of Btk in innate host defensein vivo. Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense againstStreptococcus (S.) pneumoniaein patients and mice with a deficiency in functional Btk. In the present study, we re-examined the role of Btk in B cells and myeloid cells during pneumococcal pneumonia and sepsis in mice. The antibacterial defense of Btk-/-mice was severely impaired during pneumococcal pneumosepsis and restoration of natural antibody production in Btk-/-mice by transgenic expression of Btk specifically in B cells did not suffice to protect against infection. Btk-/-mice with reinforced Btk expression in MhcII+cells, including B cells, dendritic cells and macrophages, showed improved antibacterial defense as compared to Btk-/-mice. Bacterial outgrowth in Lysmcre-Btkfl/Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btkfl/Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btkfl/Y mice displayed reduced release of granule content after pulmonary installation of lipoteichoic acid, a gram-positive bacterial cell wall component relevant for pneumococci. Moreover, Btk deficient neutrophils showed impaired degranulation and phagocytosis upon incubation with pneumococciex vivo. Taken together, the results of our study indicate that besides regulating B cell-mediated immunity, Btk is critical for regulation of myeloid cell-mediated, and particularly neutrophil-mediated, innate host defense againstS. pneumoniae in vivo.
C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms
Authors: Potempa Lawrence A. , Rajab Ibraheem M. , Olson Margaret E. , Hart Peter C.
Published: September 2021

C-reactive protein (CRP) was first recognized in the 1940s as a protein that appeared in blood during acute episodes of infectious disease. Its presence and pharmacodynamics were found in essentially all diseases that involved tissue damage and inflammation. Identified as a major component of the innate, unlearned immunity, it became a useful diagnostic marker for the extent of inflammation during disease exacerbation or remission. Efforts to define its true biological role has eluded clear definition for over a half-century. Herein, a unifying concept is presented that explains both pro-inflammatory and anti-inflammatory activities of CRP. This concept involves the recognition and understanding that CRP can be induced to undergo a pronounced, non-proteolytic reorganization of its higher-level protein structures into conformationally distinct isomers with distinctive functional activities. This process occurs when the non-covalently associated globular subunits of the pentameric isoform (“pCRP”) are induced to dissociate into a monomeric isoform (“mCRP”). mCRP consistently and potently provides pro-inflammatory activation and amplification activities. pCRP provides weak anti-inflammatory activities consistent with low-level chronic inflammation. mCRP can spontaneously form in purified pCRP reagents in ways that are not immediately recognized during purification and certification analyses. By now understanding the factors that influence pCRP dissociate into mCRP, many published reports investigating CRP as a biological response modifier of host defense can be reevaluated to include a discussion of how each CRP isoform may have affected the generated results. Specific attention is given toin vitroandin vivostudies of CRP as an anti-cancer agent.
Periostin: An Emerging Molecule With a Potential Role in Spinal Degenerative Diseases
Authors: Zhu Daxue , Zhou Wupin , Wang Zhen , Wang Yidian , Liu Mingqiang , Zhang Guangzhi , Guo Xudong , Kang Xuewen
Published: September 2021

Periostin, an extracellular matrix protein, is widely expressed in a variety of tissues and cells. It has many biological functions and is related to many diseases: for example, it promotes cell proliferation and differentiation in osteoblasts, which are closely related to osteoporosis, and mediates cell senescence and apoptosis in chondrocytes, which are involved in osteoarthritis. Furthermore, it also plays an important role in mediating inflammation and reconstruction during bronchial asthma, as well as in promoting bone development, reconstruction, repair, and strength. Therefore, periostin has been explored as a potential biomarker for various diseases. Recently, periostin has also been found to be expressed in intervertebral disc cells as a component of the intervertebral extracellular matrix, and to play a crucial role in the maintenance and degeneration of intervertebral discs. This article reviews the biological role of periostin in bone marrow-derived mesenchymal stem cells, osteoblasts, osteoclasts, chondrocytes, and annulus fibrosus and nucleus pulposus cells, which are closely related to spinal degenerative diseases. The study of its pathophysiological effects is of great significance for the diagnosis and treatment of spinal degeneration, although additional studies are needed.
Pyomelanin Synthesis in Alternaria alternata Inhibits DHN-Melanin Synthesis and Decreases Cell Wall Chitin Content and Thickness
Authors: Fernandes Chantal , Mota Marta , Barros Lillian , Dias Maria Inês , Ferreira Isabel C. F. R. , Piedade Ana P. , Casadevall Arturo , Gonçalves Teresa
Published: September 2021

The genus Alternaria includes several of fungi that are darkly pigmented by DHN-melanin. These are pathogenic to plants but are also associated with human respiratory allergic diseases and with serious infections in immunocompromised individuals. The present work focuses on the alterations of the composition and structure of the hyphal cell wall of Alternaria alternata occuring under the catabolism of L-tyrosine and L-phenylalanine when cultured in minimal salt medium (MM). Under these growing conditions, we observed the released of a brown pigment into the culture medium. FTIR analysis demonstrates that the produced pigment is chemically identical to the pigment released when the fungus is grown in MM with homogentisate acid (HGA), the intermediate of pyomelanin, confirming that this pigment is pyomelanin. In contrast to other fungi that also synthesize pyomelanin under tyrosine metabolism, A. alternata inhibits DHN-melanin cell wall accumulation when pyomelanin is produced, and this is associated with reduced chitin cell wall content. When A. alternata is grown in MM containing L-phenylalanine, a L-tyrosine percursor, pyomelanin is synthesized but only at trace concentrations and A. alternata mycelia display an albino-like phenotype since DHN-melanin accumulation is inhibited. CmrA, the transcription regulator for the genes coding for the DHN-melanin pathway, is involved in the down-regulation of DHN-melanin synthesis when pyomelanin is being synthetized, since the CMRA gene and genes of the enzymes involved in DHN-melanin synthesis pathway showed a decreased expression. Other amino acids do not trigger pyomelanin synthesis and DHN-melanin accumulation in the cell wall is not affected. Transmission and scanning electron microscopy show that the cell wall structure and surface decorations are altered in L-tyrosine- and L-phenylalanine-grown fungi, depending on the pigment produced. In summary, growth in presence of L-tyrosine and L-phenylalanine leads to pigmentation and cell wall changes, which could be relevant to infection conditions where these amino acids are expected to be available.
KPC-2-Producing Carbapenem-Resistant Klebsiella pneumoniae of the Uncommon ST29 Type Carrying OXA-926, a Novel Narrow-Spectrum OXA β-Lactamase
Authors: Liu Lina , Feng Yu , Wei Li , Xiao Yuling , Zong Zhiyong
Published: September 2021

We isolated and characterized a carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical strain from blood carrying a novel blaOXA gene, blaOXA–926, and belonging to ST29, an uncommon CRKP type. The strain, 130002, was genome sequenced using both short- and long-read sequencing and has a 94.9-kb self-transmissible IncFII plasmid carrying blaKPC–2. K. pneumoniae genomes of the ST29 complex (ST29 and its single-allele variants) were retrieved and were subjected to single nucleotide polymorphism-based phylogenomic analysis. A total of 157 genomes of the ST29 complex were identified. This complex is commonly associated with extended-spectrum β-lactamase-encoding genes, in particular, blaCTX–M–15 but rarely has carbapenemase genes. The novel plasmid-encoded β-lactamase-encoding gene blaOXA–926 was identified on a 117.8-kb IncFIA-IncFII plasmid, which was transferrable in the presence of the blaKPC–2-carrying plasmid. blaOXA–926 was cloned and MICs of β-lactams in the transformants were determined using microdilution. OXA-926 has a narrow spectrum conferring reduced susceptibility only to piperacillin, piperacillin-tazobactam, and cephalothin. Avibactam cannot fully inhibit OXA-926. blaOXA–926 and its variants have been seen in Klebsiella strains in Asia and Brazil. OXA-926 is the closest in sequence identity (89.9%) to a chromosome-encoding OXA-type enzyme of Variovorax guangxiensis. In conclusion, OXA-926 is novel plasmid-borne narrow-spectrum β-lactamase that cannot be fully inhibited by avibactam. It is likely that blaOXA–926 originates from a species closely related to V. guangxiensis and was introduced into Klebsiella > 10 years ago.
Microbial Diversity and Non-volatile Metabolites Profile of Low-Temperature Sausage Stored at Room Temperature
Authors: Han Hongjiao , Li Mohan , Peng Yanqi , Zhang Zhenghan , Yue Xiqing , Zheng Yan
Published: September 2021

Sausage is a highly perishable food with unique spoilage characteristics primarily because of its specific means of production. The quality of sausage during storage is determined by its microbial and metabolite changes. This study developed a preservative-free low-temperature sausage model and coated it with natural casing. We characterized the microbiota and non-volatile metabolites in the sausage after storage at 20°C for up to 12 days. Bacillus velezensis was the most prevalent species observed after 4 days. Lipids and lipid-like molecules, organoheterocyclic compounds, and organic acids and their derivatives were the primary non-volatile metabolites. The key non-volatile compounds were mainly involved in protein catabolism and β-lipid oxidation. These findings provide useful information for the optimization of sausage storage conditions.
Manipulation of the Upper Respiratory Microbiota to Reduce Incidence and Severity of Upper Respiratory Viral Infections: A Literature Review
Authors: Nesbitt Henry , Burke Catherine , Haghi Mehra
Published: September 2021

There is a high incidence of upper respiratory viral infections in the human population, with infection severity being unique to each individual. Upper respiratory viruses have been associated previously with secondary bacterial infection, however, several cross-sectional studies analyzed in the literature indicate that an inverse relationship can also occur. Pathobiont abundance and/or bacterial dysbiosis can impair epithelial integrity and predispose an individual to viral infection. In this review we describe common commensal microorganisms that have the capacity to reduce the abundance of pathobionts and maintain bacterial symbiosis in the upper respiratory tract and discuss the potential and limitations of localized probiotic formulations of commensal bacteria to reduce the incidence and severity of viral infections.
Dynamic Microbiome Changes Reveal the Effect of 1-Methylcyclopropene Treatment on Reducing Post-harvest Fruit Decay in “Doyenne du Comice” Pear
Authors: Zhang Yang , Gao Congcong , Masum Md. Mahidul Islam , Cheng Yudou , Wei Chuangqi , Guan Yeqing , Guan Junfeng
Published: September 2021

Pathogen-induced decay is one of the most common causes of fruit loss, resulting in substantial economic loss and posing a health risk to humans. As an ethylene action inhibitor, 1-methylcyclopropene (1-MCP) can significantly reduce fruit decay, but its effect on fruit pathogens remains unclear. Herein, the change in microbial community structure was analyzed using the high-throughput sequencing technology, and characteristics related to fruit quality were determined after 1-MCP (1.0 M l L–1) treatment in “Doyenne du Comiceis” pear fruit during storage at ambient temperature. Overall, 1-MCP was highly effective in reducing disease incidence and induced multiple changes of the fungal and bacterial microbiota. At day 15, the microbial diversity of fungi or bacteria was reduced significantly in the control fruit (non-treated with 1-MCP), which had the most severe decay incidence. For fungi, in addition to Alternaria being the most abundant in both 1-MCP treatment (59.89%) and control (40.18%), the abundances of Botryosphaeria (16.75%), Penicillium (8.81%), and Fusarium (6.47%) increased significantly with the extension of storage time. They became the primary pathogens to cause fruit decay in control, but they were markedly decreased in 1-MCP treatment, resulting in reduced disease incidence. For bacteria, the abundance of Gluconobacter (50.89%) increased dramatically at day 15 in the control fruit, showing that it also played a crucial role in fruit decay. In addition, Botryosphaeria, Fusarium fungi, and Massilia, Kineococcus bacteria were identified as biomarkers to distinguish 1-MCP treatment and control using Random Forest analysis. The redundancy analysis (RDA) result showed that the amount of Botryosphaeria, Penicillium, and Fusarium were positively correlated with disease incidence and respiration rate of pear fruits while negatively correlated with fruit firmness. This investigation is the first comprehensive analysis of the microbiome response to 1-MCP treatment in post-harvest pear fruit, and reveals the relationship between fruit decay and microbial composition in pear fruit.
Long-Term Intrahost Evolution of Staphylococcus aureus Among Diabetic Patients With Foot Infections
Authors: Lavigne Jean-Philippe , Hosny Michel , Dunyach-Remy Catherine , Boutet-Dubois Adeline , Schuldiner Sophie , Cellier Nicolas , Yahiaoui-Martinez Alex , Molle Virginie , La Scola Bernard , Marchandin Hélène , Sotto Albert
Published: September 2021

Staphylococcus aureus is one of the main pathogens isolated from diabetic foot infections (DFI). The purpose of this study was to evaluate the importance of the persistence of S. aureus in this environment and the possible modifications of the bacterial genome content over time. Molecular typing of S. aureus isolates cultured from patients with the same DFI over a 7-year study revealed a 25% rate of persistence of this species in 48 patients, with a short median persistence time of 12weeks (range: 4–52weeks). Non-specific clonal complexes were linked to this persistence. During the follow-up, bla genes were acquired in three cases, whereas some virulence markers were lost in all cases after a long period of colonization (21.5weeks). Only one patient (2%) had a long-term persistence of 48weeks. The genome sequencing of a clonal pair of early/late strains isolated in this patient showed mutations in genes encoding bacterial defence and two-component signal transduction systems. Although, this study suggests that the long-term persistence of S. aureus in DFI is a rare event, genomic evolution is observed, highlighting the low adaptive ability of S. aureus to the specific environment and stressful conditions of diabetic foot ulcers. These results provide the basis for better understanding of S. aureus dynamics during persistent colonization in chronic wounds.
Morchella importuna Flavones Improve Intestinal Integrity in Dextran Sulfate Sodium-Challenged Mice
Authors: Xu Yingyin , Xie Liyuan , Tang Jie , He Xiaolan , Zhang Zhiyuan , Chen Ying , Zhou Jie , Gan Bingcheng , Peng Weihong
Published: September 2021

Morchella importuna, as an edible fungus, has various health benefits. However, the effects of M. importuna on intestinal health are rarely investigated. Hence, this study aims to ascertain the influences of flavones from the fruiting bodies of M. importuna (hereinafter abbreviated as MIF) on dextran sulfate sodium (DSS)-induced damage to intestinal epithelial barrier in C57BL/6J mice. In this (14-day) study, 144 C57BL/6J mice were divided into four groups: (1) Control; (2) DSS treatment; (3) DSS treatment + 100 mg/kg MIF (LMIF); (4) DSS treatment + 200 mg/kg MIF (HMIF). On days 8-14, mice in the challenged groups were challenged with 3.5% DSS, while the control group received an equal volume of normal saline. Then, serum and intestinal samples were obtained from all mice. The results showed that MIF ingestion enhanced intestinal integrity in DSS-challenged mice, as evinced by the elevated (p < 0.05) abundances of occludin, claudin-1, and zonula occludens-1 proteins. Meanwhile, MIF ingestion reduced (p < 0.05) the colonic interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) concentrations and increased the superoxide dismutase and catalase activities and Shannon and Simpson indices in DSS-challenged mice. Moreover, MIF ingestion reduced (p < 0.05) the abundance of phospho-nuclear factor (NF)-κB and increased the abundance of phospho-Nrf2 in DSS-challenged mice. Taken together, MIF protects against intestinal barrier injury in C57BL/6J mice via a mechanism that involves inhibiting NF-κB activation and promoting Nrf2 activation, as well as regulating intestinal microbiota.
Tetris in the Nervous System: What Principles of Neuronal Tiling Can Tell Us About How Glia Play the Game
Authors: DeSantis Dana F. , Smith Cody J.
Published: September 2021

The precise organization and arrangement of neural cells is essential for nervous system functionality. Cellular tiling is an evolutionarily conserved phenomenon that organizes neural cells, ensuring non-redundant coverage of receptive fields in the nervous system. First recorded in the drawings of Ramon y Cajal more than a century ago, we now have extensive knowledge of the biochemical and molecular mechanisms that mediate tiling of neurons. The advent of live imaging techniques in both invertebrate and vertebrate model organisms has enhanced our understanding of these processes. Despite advancements in our understanding of neuronal tiling, we know relatively little about how glia, an essential non-neuronal component of the nervous system, tile and contribute to the overall spatial arrangement of the nervous system. Here, we discuss lessons learned from neurons and apply them to potential mechanisms that glial cells may use to tile, including cell diversity, contact-dependent repulsion, and chemical signaling. We also discuss open questions in the field of tiling and what new technologies need to be developed in order to better understand glial tiling.
Cortical Venous Changes on Susceptibility-Weighted Imaging Predict the Cerebral Collateral Circulation as Confirmed by Digital Subtraction Angiography
Authors: Zhan Yun-Hao , Chen Yang-Kun , Li Run-Xiong , Luo Gen-Pei , Wu Zhi-Qiang , Liu Yong-Lin , Xiao Wei-Min , Hu Wei-Dong , Xie Cai-Qin
Published: September 2021

Objective: Asymmetrical cortical vein sign (ACVS) shown on susceptibility-weighted imaging (SWI) can reflect regional hypoperfusion. We investigated if ACVS could predict the cerebral collateral circulation (CC) as assessed by digital subtraction angiography (DSA) in acute ischemic stroke patients with ipsilateral severe stenosis/occlusion of the anterior circulation.

Methods: Clinical data and imaging data of 62 acute ischemic stroke patients with ipsilateral severe stenosis or occlusion of the anterior circulation confirmed by DSA were collected retrospectively. Participants underwent magnetic resonance imaging, including an SWI sequence. ACVS was defined as more and/or larger venous signals in the cerebral cortex of one side of SWI than that in the contralateral side. ACVS was measured using the Alberta Stroke Program Early Computed Tomography score based on SWI. The grading of the cerebral CC was judged using DSA.

Results: Of the 62 patients, 30 patients (48.4%) had moderate-to-severe ACVS. According to DSA assessment, 19 patients (30.6%) had a good CC (grade 3–4), and 43 (69.4%) patients had a poor-to-moderate CC (grade 0–2). Among the 30 patients with moderate-to-severe ACVS, only three (10%) patients had a good CC, and 27 (90%) patients had a poor-to-moderate CC; among the 32 patients with none or mild ACVS, 16 (50%) of them had a good CC, and the other 50% had a moderate-to-severe CC. We constructed two logistic regression models with ACVS grading and none or mild ACVS entered into the models, respectively, together with age and large-artery occlusion. In model 1, no ACVS (compared with severe ACVS; OR = 40.329, 95%CI = 2.817–577.422, P = 0.006), mild ACVS (compared with severe ACVS; OR = 17.186, 1.735–170.224, 0.015) and large-artery occlusion (OR = 45.645, 4.603–452.592, 0.001) correlated with a good CC. In model 2, none or mild ACVS (OR = 36.848, 95%CI = 5.516–246.171, P < 0.001) was significantly associated with a good CC as judged by DSA, adjusted by age and large-artery occlusion.

Conclusions: Cortical venous changes in SWI may be a useful indicator for the cerebral CC as confirmed by DSA.
Frontotemporal Dementias in Latin America: History, Epidemiology, Genetics, and Clinical Research
Authors: Llibre-Guerra Jorge J. , Behrens Maria Isabel , Hosogi Mirna Lie , Montero Lucia , Torralva Teresa , Custodio Nilton , Longoria-Ibarrola Erika Mariana , Giraldo-Chica Margarita , Aguillón David , Hardi Angela , Maestre Gladys E. , Contreras Valeria , Doldan Celeste , Duque-Peñailillo Lissette , Hesse Heike , Roman Norbel , Santana-Trinidad Dhara Angelina , Schenk Christian , Ocampo-Barba Ninoska , López-Contreras Ricardo , Nitrini Ricardo
Published: September 2021

Introduction:The historical development, frequency, and impact of frontotemporal dementia (FTD) are less clear in Latin America than in high-income countries. Although there is a growing number of dementia studies in Latin America, little is known collectively about FTD prevalence studies by country, clinical heterogeneity, risk factors, and genetics in Latin American countries.

Methods:A systematic review was completed, aimed at identifying the frequency, clinical heterogeneity, and genetics studies of FTD in Latin American populations. The search strategies used a combination of standardized terms for FTD and related disorders. In addition, at least one author per Latin American country summarized the available literature. Collaborative or regional studies were reviewed during consensus meetings.

Results:The first FTD reports published in Latin America were mostly case reports. The last two decades marked a substantial increase in the number of FTD research in Latin American countries. Brazil (165), Argentina (84), Colombia (26), and Chile (23) are the countries with the larger numbers of FTD published studies. Most of the research has focused on clinical and neuropsychological features (n= 247), including the local adaptation of neuropsychological and behavioral assessment batteries. However, there are little to no large studies on prevalence (n= 4), biomarkers (n= 9), or neuropathology (n= 3) of FTD.

Conclusions:Future FTD studies will be required in Latin America, albeit with a greater emphasis on clinical diagnosis, genetics, biomarkers, and neuropathological studies. Regional and country-level efforts should seek better estimations of the prevalence, incidence, and economic impact of FTD syndromes.
Efficacy and Tolerability of Perampanel as Adjunctive Therapy in Chinese Patients With Focal-Onset Seizures: An Observational, Prospective Study
Authors: Zhang Ranran , Qiao Shan , Fang Xiqin , Wang Kemo , Shi Yanting , Du Qianwen , Yang Tingting , Liu Xuewu
Published: September 2021

Purpose: To evaluate the efficacy and tolerability of adjunctive perampanel (PER) in Chinese patients with focal-onset seizures, with or without secondarily generalized tonic-clonic seizures.

Methods: Fifty-six patients aged 14–72 years were recruited consecutively in this single-center prospective observational study. All patients received PER as add-on treatment on the basis of clinical judgment. Seizure frequency, adverse events (AEs), and retention rates were obtained at 3 and 6 months after PER introduction.

Results: The overall response rates were 60 and 71.1% after 3 and 6 months, respectively, and the freedom of seizures at the same points were reached in 8 and 15.8%. The retention rates were 89.3% at the 3-month follow-up and 67.9% at the 6-month follow-up. The overall incidence of adverse events was 55.4%. The leading reported AEs were dizziness (39.3%) and somnolence (25%).

Conclusions: Our study confirmed the efficacy and tolerability of adjunctive PER in Chinese patients in real-life conditions. Based on our treatment experience, a lower maintenance dose of PER would be needed in Chinese patients.
Effect of Electro-Acupuncture at ST36 and SP6 on the cAMP -CREB Pathway and mRNA Expression Profile in the Brainstem of Morphine Tolerant Mice
Authors: Wang Qisheng , Qin Fenfen , Wang Hui , Yang Huanya , Liu Qingyang , Li Zhonghao , Jiang Yongwei , Lu Shengfeng , Wang Qian , Lu Zhigang
Published: September 2021

Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.
Fluorescence Imaging Using Enzyme-Activatable Probes for Real-Time Identification of Pancreatic Cancer
Authors: Takahashi Ryugen , Ishizawa Takeaki , Sato Masumitsu , Inagaki Yoshinori , Takanka Mariko , Kuriki Yugo , Kamiya Mako , Ushiku Tetsuo , Urano Yasuteru , Hasegawa Kiyoshi
Published: September 2021

Introduction

Radical resection is the only curative treatment for pancreatic cancer, which is a life-threatening disease. However, it is often not easy to accurately identify the extent of the tumor before and during surgery. Here we describe the development of a novel method to detect pancreatic tumors using a tumor-specific enzyme-activatable fluorescence probe.

Methods

Tumor and non-tumor lysate or small specimen collected from the resected specimen were selected to serve as the most appropriate fluorescence probe to distinguish cancer tissues from noncancerous tissues. The selected probe was sprayed onto the cut surface of the resected specimen of cancer tissue to acquire a fluorescence image. Next, we evaluated the ability of the probe to detect the tumor and calculated the tumor-to-background ratio (TBR) by comparing the fluorescence image with the pathological extent of the tumor. Finally, we searched for a tumor-specific enzyme that optimally activates the selected probe.

Results

Using a library comprising 309 unique fluorescence probes, we selected GP-HMRG as the most appropriate activatable fluorescence probe. We obtained eight fluorescence images of resected specimens, among which four approximated the pathological findings of the tumor, which achieved the highest TBR. Finally, dipeptidyl-peptidase IV (DPP-IV) or a DPP-IV-like enzyme was identified as the target enzyme.

Conclusion

This novel method may enable rapid and real-time visualization of pancreatic cancer through the enzymatic activities of cancer tissues.
Gamma Knife Radiosurgery-Based Combination Treatment Strategies Improve Survival in Patients With Central Nervous System Metastases From Epithelial Ovarian Cancer: A Retrospective Analysis of Two Academic Institutions in Korea and Taiwan
Authors: Lai Yen-Ling , Kang Jun-Hyeok , Hsu Che-Yu , Lee Jung-Il , Cheng Wen-Fang , Chen Yu-Li , Lee Yoo-Young
Published: September 2021

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p=0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p=0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p=0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p<0.001] significantly impacted survival after diagnosis of CNS metastases. In a subgroup analysis, superior survival was observed in patients with CNS involvement not in first tumor recurrence who underwent GKS-based combination therapeutic regimens. The survival benefit of GKS-based treatment was not significant in patients with CNS involvement in first disease relapse, but a trend for longer survival was still observed. In conclusion, GKS-based combination treatment can be considered for the treatment of EOC patients with CNS metastases. The patients with CNS involvement not in first disease relapse could significantly benefit from GKS-based combination strategies.
ALK Rearrangement–Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report
Authors: Ou Kai , Liu Xiu , Li Weihua , Yang Yi , Ying Jianming , Yang Lin
Published: September 2021

Patients with metastatic pancreatic cancer typically have poor prognosis due to the limited effectiveness of existing treatment options. ALK rearrangement–positive is rare in pancreatic cancer, but may occur in those with KRAS-wild type. We present a 34-year-old young man with ALK rearrangement–positive and KRAS-wild pancreatic cancer who had a remarkable response to crizotinib after resistance to prior chemotherapy and re-response to alectinib after brain metastases developed. This clinical observation suggests that comprehensive molecular profiling to guide targeted therapies is not only feasible, but also significantly improves survival outcomes for a subgroup of patients with pancreatic cancer.
The Clinical Relevance and Tumor Promoting Function of C19orf10 in Kidney Renal Clear Cell Carcinoma
Authors: Lu Yanxin , Liao Ximian , Wang Tongyu , Hong Xiaowei , Li Zesong
Published: September 2021

Kidney renal clear cell carcinoma (KIRC) is the most common primary renal neoplasms. Currently, there are few molecular indicators and therapeutic targets that can be used in diagnostic and prognostic assessment. In this study, we identified the C19orf10 expression in KIRC specimens and explored the diagnostic and prognostic value of C19orf10 in KIRC using TCGA and CPTAC database. Loss-of- and gain-of- function of C19orf10 was performed to investigate the roles of C19orf10 on KIRC cell viability, proliferation, migration and invasion via CCK-8, Edu incorporation and Transwell assays respectively. C19orf10 was overexpressed in KIRC tissues and the elevated C19orf10 expression was closely associated with clinicopathological characteristics of KIRC including histological grade, TNM stage, metastatic status. Silencing C19orf10 significantly suppressed the viability, proliferation, migration and invasion ability, while overexpression of C19orf10 promoted the progression and malignant phenotype in KIRC cells. Furthermore, C19orf10 exerted its carcinogenic function by regulating ZO-1 and PTEN/Akt signaling pathway. Moreover, the Kaplan–Meier survival analysis, Cox regression analysis and receiver operating curve analysis showed that patients with C19orf10 overexpression have poor survival time. C19orf10 could discriminate KIRC patients with high-risk from low-risk. Taken together, C19orf10 contributes to KIRC development via ZO-1 and PTEN/Akt signaling pathway and C19orf10 could serve as a potential diagnostic and prognostic candidate and therapeutic target of KIRC.
Efficacy and Safety of Abiraterone Acetate and Enzalutamide for the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Wei ZhenHeng , Chen ChuXin , Li BoWen , Li YongYue , Gu Hong
Published: September 2021

Objective

The androgen receptor-targeting drugs abiraterone acetate and enzalutamide have shown positive results as treatments for metastatic castration-resistant prostate cancer (mCRPC). Therefore, a meta-analysis was conducted to compare the efficacy and safety of abiraterone acetate and enzalutamide in patients with mCRPC.

Methods

We retrieved relevant articles from PubMed, Cochrane, and EMBASE published before December 31, 2020. Eleven articles were initially selected, and four phase III, double-blind, randomized controlled trials of abiraterone acetate and enzalutamide that involved 5199 patients with mCRPC were included. The end points were time to prostate-specific antigen progression (TTPP), according to the prostate-specific antigen working group criteria; overall survival (OS); and radiographic progression-free survival (rPFS).

Results

Four randomized, controlled clinical trials involving 5199 patients were included in this study. The results of the meta-analysis showed that compared with placebo alone, abiraterone significantly improved OS (HR=0.69, 95% CI: 0.60-0.8, P<0.00001), rPFS (HR=0.64, 95% CI: 0.57-0.71, P < 0.00001), and TTPP (HR=0.52, 95% CI: 0.45-0.59, P < 0.00001) in patients with mCRPC. Compared with placebo, enzalutamide significantly improved OS (HR=0.67, 95% CI: 0.59-0.75, P<0.00001), rPFS (HR=0.33, 95% CI: 0.29-0.37, P< 0.00001), and TTPP (HR=0.19, 95% CI: 0.17-0.22, P < 0.00001). An indirect comparison was performed to compare the efficacy of abiraterone and enzalutamide. The results showed that there was no significant difference between abiraterone and enzalutamide with regard to improving the OS of patients with mCRPC (HR=1.03, 95% CI: 0.854-1.242). Enzalutamide was superior to abiraterone with regard to improving rPFS in patients with mCRPC (HR=0.516, 95% CI: 0.438-0.608). With regard to improving TTPP, the efficacy of enzalutamide was better than that of abiraterone (HR=0.365, 95% CI: 0.303-0.441). In sAE, there was no difference between abiraterone and enzalutamide (P=0.21, I2 = 38%).

Conclusions

Compared with placebo, both abiraterone and enzalutamide significantly prolonged OS, rPFS, and TTPP in patients with mCRPC. There was no difference in safety between abiraterone and enzalutamide. In addition, enzalutamide had better efficacy than abiraterone with regard to improving rPFS and TTPP but not OS, but the level of evidence was low. Therefore, a large direct comparison trial is needed to compare the efficacy of the two drugs.

Systematic Review Registration

PROSPERO, identifier (CRD42021226808)