bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Metabolomics Study of Papillary Thyroid Carcinoma Based on HPLC-Q-TOF-MS/MS
Authors: Du Yang , Fan Peizhi , Zou Lianhong , Jiang Yu , Gu Xiaowen , Yu Jie , Zhang Chaojie
Published: February 2021

This study examined metabolite profile differences between serum samples of thyroid papillary carcinoma (PTC) patients and healthy controls, aiming to identify candidate biomarkers and pathogenesis pathways in this cancer type. Serum samples were collected from PTC patients (n = 80) and healthy controls (n = 80). Using principal component analysis (PCA), partial least squares discrimination analysis(PLS-DA), orthogonal partial least square discriminant analysis (OPLS-DA), t-tests, and the volcano plot, a model of abnormal metabolic pathways in PTC was constructed. PCA, PLS-DA, and OPLS-DA analysis revealed differences in serum metabolic profiles between the PTC and control group. OPLS-Loading plot analysis, combined with Variable importance in the projection (VIP)>1, Fold change (FC) > 1.5, and p < 0.05 were used to screen 64 candidate metabolites. Among them, 22 metabolites, including proline betaine, taurocholic acid, L-phenylalanine, retinyl beta-glucuronide, alpha-tocotrienol, and threonine acid were upregulated in the PTC group; meanwhile, L-tyrosine, L-tryptophan, 2-arachidonylglycerol, citric acid, and other 42 metabolites were downregulated in this group. There were eight abnormal metabolic pathways related to the differential metabolites, which may be involved in the pathophysiology of PTC. Six metabolites yielded an area under the receiver operating curve of >0.75, specifically, 3-hydroxy-cis-5-tetradecenoylcarnitine, aspartylphenylalanine, l-kynurenine, methylmalonic acid, phenylalanylphenylalanine, and l-glutamic acid. The Warburg effect was observed in PTC. The levels of 3-hydroxy-cis-5-tetradecenoylcarnitine, aspartylphenylalanine, l-kynurenine, methylmalonic acid, phenylalanine, and L-glutamic acid may help distinguish PTC patients from healthy controls. Aspartic acid metabolism, glutamic acid metabolism, urea cycle, and tricarboxylic acid cycle are involved in the mechanism of PTC.
Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease
Authors: Schiavon Cara R. , Shadel Gerald S. , Manor Uri
Published: February 2021

Charcot-Marie-Tooth (CMT) disease is a progressive, peripheral neuropathy and the most commonly inherited neurological disorder. Clinical manifestations of CMT mutations are typically limited to peripheral neurons, the longest cells in the body. Currently, mutations in at least 80 different genes are associated with CMT and new mutations are regularly being discovered. A large portion of the proteins mutated in axonal CMT have documented roles in mitochondrial mobility, suggesting that organelle trafficking defects may be a common underlying disease mechanism. This review will focus on the potential role of altered mitochondrial mobility in the pathogenesis of axonal CMT, highlighting the conceptional challenges and potential experimental and therapeutic opportunities presented by this “impaired mobility” model of the disease.
Complex Organic Matter Synthesis on Siloxyl Radicals in the Presence of CO
Authors: Fioroni Marco , DeYonker Nathan J.
Published: February 2021

Heterogeneous phase astrochemistry plays an important role in the synthesis of complex organic matter (COM) as found on comets and rocky body surfaces like asteroids, planetoids, moons and planets. The proposed catalytic model is based on two assumptions: (a) siliceous rocks in both crystalline or amorphous states show surface-exposed defective centers such as siloxyl (Si-O•) radicals; (b) the second phase is represented by gas phase CO molecules, an abundant C1 building block found in space. By means of quantum chemistry; (DFT, PW6B95/def2-TZVPP); the surface of a siliceous rock in presence of CO is modeled by a simple POSS (polyhedral silsesquioxane) where a siloxyl (Si-O•) radical is present. Four CO molecules have been consecutively added to the Si-O• radical and to the nascent polymeric CO (pCO) chain. The first CO insertion shows no activation free energy with ΔG200K = −21.7 kcal/mol forming the SiO-CO• radical. The second and third CO insertions show ΔG200K‡ ≤ 10.5 kcal/mol. Ring closure of the SiO-CO-CO• (oxalic anhydride) moiety as well as of the SiO-CO-CO-CO• system (di-cheto form of oxetane) are thermodynamically disfavored. The last CO insertion shows no free energy of activation resulting in the stable five member pCO ring, precursor to 1,4-epoxy-1,2,3-butanone. Hydrogenation reactions of the pCO have been considered on the SiO oxygen or on the carbons and oxygens of the pCO chains. The formation of the reactive aldehyde SiO-CHO on the siliceous surface is possible. In principle, the complete hydrogenation of the (CO)1−4 series results in the formation of methanol and polyols. Furthermore, all the SiO-pCO intermediates and the lactone 1,4-epoxy-1,2,3-butanone product in its radical form can be important building blocks in further polymerization reactions and/or open ring reactions with H (aldehydes, polyols) or CN (chetonitriles), resulting in highly reactive multi-functional compounds contributing to COM synthesis.
Case Report: Management of an Elderly Patient With Metastatic Radioiodine-Resistant Differentiated Thyroid Cancer in a Rural Community, Remote From Specialist Oncology Services
Authors: Wybrew Rachael , Loynd Michael , Wybrew Maria , Samuel Leslie
Published: February 2021

This case report describes an elderly patient with radioiodine-resistant differentiated thyroid cancer and additional multiple metastases living in a rural setting, remote from the specialist oncology service. This case is of interest because effective systemic therapies for treatment-resistant cancers, such as lenvatinib, are now available but can potentially cause significant toxicities that require extensive medical management. Here, we discuss how patient care was provided collaboratively by the local community teams integrated with remote specialist oncology services. A 77-year-old patient presented with symptoms of cauda equina secondary to a large metastatic sacral deposit. The deposit was biopsied, and histology revealed a diagnosis of differentiated follicular thyroid cancer that was treated with external beam radiotherapy and thyroidectomy, followed by radioiodine. However, the disease was found to be resistant to radioiodine therapy, and the patient subsequently developed back pain due to new bone metastases. After further palliative external beam radiotherapy, the patient was started on systemic treatment with lenvatinib. Treatment has continued for more than 2.5 years with a slow but steady improvement in symptoms and quality of life. Monitoring and assessment of lenvatinib therapy and management of associated toxicities was coordinated remotely from a specialist cancer center over 200 miles away, using the skills of the local medical and nursing teams. This case report demonstrates how a cooperative effort using local teams and video-conferencing links to a specialist cancer center can be applied to safely treat a patient with a medication that may result in significant potential toxicities that require attentive and dynamic management.
The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease
Authors: Grefhorst Aldo , van de Peppel Ivo P. , Larsen Lars E. , Jonker Johan W. , Holleboom Adriaan G.
Published: February 2021

Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.
Simvastatin and ROCK Inhibitor Y-27632 Inhibit Myofibroblast Differentiation of Graves’ Ophthalmopathy-Derived Orbital Fibroblasts via RhoA-Mediated ERK and p38 Signaling Pathways
Authors: Wei Yi-Hsuan , Liao Shu-Lang , Wang Sen-Hsu , Wang Chia-Chun , Yang Chang-Hao
Published: February 2021

Transforming growth factor-β (TGF-β)-induced differentiation of orbital fibroblasts into myofibroblasts is an important pathogenesis of Graves’ ophthalmopathy (GO) and leads to orbital tissue fibrosis. In the present study, we explored the antifibrotic effects of simvastatin and ROCK inhibitor Y-27632 in primary cultured GO orbital fibroblasts and tried to explain the molecular mechanisms behind these effects. Both simvastatin and Y-27632 inhibited TGF-β-induced α-smooth muscle actin (α-SMA) expression, which serves as a marker of fibrosis. The inhibitory effect of simvastatin on TGF-β-induced RhoA, ROCK1, and α-SMA expression could be reversed by geranylgeranyl pyrophosphate, an intermediate in the biosynthesis of cholesterol. This suggested that the mechanism of simvastatin-mediated antifibrotic effects may involve RhoA/ROCK signaling. Furthermore, simvastatin and Y-27632 suppressed TGF-β-induced phosphorylation of ERK and p38. The TGF-β-mediated α-SMA expression was suppressed by pharmacological inhibitors of p38 and ERK. These results suggested that simvastatin inhibits TGF-β-induced myofibroblast differentiation via suppression of the RhoA/ROCK/ERK and p38 MAPK signaling pathways. Thus, our study provides evidence that simvastatin and ROCK inhibitors may be potential therapeutic drugs for the prevention and treatment of orbital fibrosis in GO.
Centrosomes: Til O-GlcNAc Do Us Apart
Authors: Yuan Aiyun , Tang Xiangyan , Li Jing
Published: February 2021

The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be fine-tuned in space and time. A multitude of post-translational modifications (PTMs) have been implicated in centrosome modulation, including phosphorylation, ubiquitination and acetylation. Among them is the emerging O-linked N-acetylglucosamine (O-GlcNAc) modification. This quintessential PTM has a sole writer, O-GlcNAc transferase (OGT), and the only eraser, O-GlcNAcase (OGA). O-GlcNAc couples glucose metabolism with signal transduction and forms a yin-yang relationship with phosphorylation. Evidence from proteomic studies as well as single protein investigations has pinpointed a role of O-GlcNAc in centrosome number and separation, centriole number and distribution, as well as the cilia machinery emanating from the centrosomes. Herein we review our current understanding of the sweet modification embedded in centrosome dynamics and speculate that more molecular details will be unveiled in the future.
Amphibian Hormones, Calcium Physiology, Bone Weight, and Lung Use Call for a More Inclusive Approach to Understanding Ossification Sequence Evolution
Authors: Rose Christopher S.
Published: February 2021

Skeleton plays a huge role in understanding how vertebrate animals have diversified in phylogeny, ecology and behavior. Recent evo-devo research has used ossification sequences to compare skeletal development among major groups, to identify conserved and labile aspects of a sequence within a group, to derive ancestral and modal sequences, and to look for modularity based on embryonic origin and type of bone. However, questions remain about how to detect and order bone appearances, the adaptive significance of ossification sequences and their relationship to adult function, and the utility of categorizing bones by embryonic origin and type. Also, the singular focus on bone appearances and the omission of other tissues and behavioral, ecological and life history events limit the relevance of such analyses. Amphibians accentuate these concerns because of their highly specialized biphasic life histories and the exceptionally late timing, and high variability of their ossification sequences. Amphibians demonstrate a need for a whole-animal, whole-ontogeny approach that integrates the entire ossification process with physiology, behavior and ecology. I discuss evidence and hypotheses for how hormone mediation and calcium physiology might elicit non-adaptive variability in ossification sequence, and for adaptive strategies to partition larval habitats using bone to offset the buoyancy created by lung use. I also argue that understanding plasticity in ossification requires shifting focus away from embryonic development and adult function, and toward postembryonic mechanisms of regulating skeletal growth, especially ones that respond directly to midlife environments and behaviors.
Breaking Boundaries in the Brain—Advances in Editing Tools for Neurogenetic Disorders
Authors: Coorey Bronte A. , Gold Wendy A.
Published: February 2021

Monogenic neurological disorders are devastating, affecting hundreds of millions of people globally and present a substantial burden to individuals, carers, and healthcare systems. These disorders are predominantly caused by inherited or de novo variants that result in impairments to nervous system development, neurodegeneration, or impaired neuronal function. No cure exists for these disorders with many being refractory to medication. However, since monogenic neurological disorders have a single causal factor, they are also excellent targets for innovative, therapies such as gene therapy. Despite this promise, gene transfer therapies are limited in that they are only suitable for neurogenetic disorders that fit within the technological reach of these therapies. The limitations include the size of the coding region of the gene, the regulatory control of expression (dosage sensitivity), the mode of expression (e.g., dominant negative) and access to target cells. Gene editing therapies are an alternative strategy to gene transfer therapy as they have the potential of overcoming some of these hurdles, enabling the retention of physiological expression of the gene and offers precision medicine-based therapies where individual variants can be repaired. This review focusses on the existing gene editing technologies for neurogenetic disorders and how these propose to overcome the challenges common to neurogenetic disorders with gene transfer therapies as well as their own challenges.
Identification of Serum Circulating MicroRNAs as Novel Diagnostic Biomarkers of Gastric Cancer
Authors: Yao Yunjin , Ding Yongfeng , Bai Yuntong , Zhou Quan , Lee Hyun , Li Xiawei , Teng Lisong
Published: February 2021

Gastric cancer (GC) is one of the leading causes of cancer-associated deaths worldwide. Due to the lack of typical symptoms and effective biomarkers for non-invasive screening, most patients develop advanced-stage GC by the time of diagnosis. Circulating microRNA (miRNA)-based panels have been reported as a promising tool for the screening of certain types of cancers. In this study, we performed differential expression analysis of miRNA profiles of plasma samples obtained from gastric cancer and non-cancer patients using two independent Gene Expression Omnibus (GEO) datasets: GSE113486 and GSE124158. We identified three miRNAs, hsa-miR-320a, hsa-miR-1260b, and hsa-miR-6515-5p, to distinguish gastric cancer cases from non-cancer controls. The three miRNAs showed an area under the curve (AUC) over 0.95 with high specificity (>93.0%) and sensitivity (>85.0%) in both the discovery datasets. In addition, we further validated these three miRNAs in two external datasets: GSE106817 [sensitivity: hsa-miR-320a (99.1%), hsa-miR-1260b (97.4%), and hsa-miR-6515-5p (92.2%); specificity: hsa-miR-320a (88.8%), hsa-miR-1260b (89.6%), and hsa-miR-6515-5p (88.7%); and AUC: hsa-miR-320a (96.3%), hsa-miR-1260b (97.4%), and hsa-miR-6515-5p (94.6%)] and GSE112264 [sensitivity: hsa-miR-320a (100.0%), hsa-miR-1260b (98.0%), and hsa-miR-6515.5p (98.0%); specificity: hsa-miR-320a (100.0%), hsa-miR-1260b (100.0%), and hsa-miR-6515.5p (92.7%); and AUC: hsa-miR-320a (1.000), hsa-miR-1260b (1.000), and hsa-miR-6515-5p (0.988)]. On the basis of these findings, the three miRNAs can be used as potential biomarkers for gastric cancer screening, which can provide patients with a higher chance of curative resection and longer survival.
Recombinant Adiponectin Induces the Production of Pro-Inflammatory Chemokines and Cytokines in Circulating Mononuclear Cells and Fibroblast-Like Synoviocytes From Non-Inflamed Subjects
Authors: Zhang Yuan , Aldridge Jonathan , Vasileiadis Georgios K. , Edebo Helena , Ekwall Anna-Karin H. , Lundell Anna-Carin , Rudin Anna , Maglio Cristina
Published: February 2021

Adiponectin is an adipokine with a modulatory role in metabolism and exerting both anti- and pro-inflammatory effects. Levels of adiponectin are increased in serum and synovial fluid from patients with rheumatoid arthritis (RA). Adiponectin is able to stimulate the production of different pro-inflammatory factors from peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) from subjects with established RA. As increased circulating adiponectin levels are a risk factor for future development of RA in subjects with obesity, we hypothesize that adiponectin is implicated in the development of RA at an early stage by initiating the pro-inflammatory processes associated with the disease pathogenesis. Therefore, we aimed to determine if adiponectin is able to induce pro-inflammatory responses in cells involved in the pathogenesis of RA, but collected from subjects without any known inflammatory disease. PBMCs and FLS were obtained from non-inflamed subjects and stimulated with 5 μg/ml human recombinant adiponectin. Supernatants collected after 48 h were analyzed for the production of 13 chemokines and 12 cytokines using multiplex assay and ELISA. Adiponectin significantly stimulated the production of CXCL1, CXCL5, and interleukin (IL)-6 in both PBMCs and FLS, whereas it induced CCL20, CCL4, CCL3, CCL17, tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor and IL-10 only in PBMCs, and CXCL8, CXCL10, CCL5, CCL11, and CCL2 only in FLS. Pre-stimulation with TNF of FLS from non-inflamed subjects did not significantly enhance the release of most pro-inflammatory factors compared to adiponectin alone. Our findings indicate that PBMCs and FLS from non-inflamed subjects react to adiponectin stimulation with the secretion of several pro-inflammatory chemokines and cytokines. These results suggest that adiponectin is able to initiate pro-inflammatory responses in cells from non-inflamed subjects and support the hypothesis that adiponectin is implicated in the early phases of RA pathogenesis.
Cell Surface Expression of Endosomal Toll-Like Receptors—A Necessity or a Superfluous Duplication?
Authors: Mielcarska Matylda Barbara , Bossowska-Nowicka Magdalena , Toka Felix Ngosa
Published: February 2021

Timely and precise delivery of the endosomal Toll-like receptors (TLRs) to the ligand recognition site is a critical event in mounting an effective antimicrobial immune response, however, the same TLRs should maintain the delicate balance of avoiding recognition of self-nucleic acids. Such sensing is widely known to start from endosomal compartments, but recently enough evidence has accumulated supporting the idea that TLR-mediated signaling pathways originating in the cell membrane may be engaged in various cells due to differential expression and distribution of the endosomal TLRs. Therefore, the presence of endosomal TLRs on the cell surface could benefit the host responses in certain cell types and/or organs. Although not fully understood why, TLR3, TLR7, and TLR9 may occur both in the cell membrane and intracellularly, and it seems that activation of the immune response can be initiated concurrently from these two sites in the cell. Furthermore, various forms of endosomal TLRs may be transported to the cell membrane, indicating that this may be a normal process orchestrated by cysteine proteases—cathepsins. Among the endosomal TLRs, TLR3 belongs to the evolutionary distinct group and engages a different protein adapter in the signaling cascade. The differently glycosylated forms of TLR3 are transported by UNC93B1 to the cell membrane, unlike TLR7, TLR8, and TLR9. The aim of this review is to reconcile various views on the cell surface positioning of endosomal TLRs and add perspective to the implication of such receptor localization on their function, with special attention to TLR3. Cell membrane-localized TLR3, TLR7, and TLR9 may contribute to endosomal TLR-mediated inflammatory signaling pathways. Dissecting this signaling axis may serve to better understand mechanisms influencing endosomal TLR-mediated inflammation, thus determine whether it is a necessity for immune response or simply a circumstantial superfluous duplication, with other consequences on immune response.
Cytokine Storm as a Cellular Response to dsDNA Breaks: A New Proposal
Authors: Shabrish Snehal , Mittra Indraneel
Published: February 2021

Pathogenesis of cytokine storm is poorly understood. In this article we propose a new mechanism and suggest innovative therapeutic avenues for its prevention. We have reported that particles of cell-free chromatin (cfCh) that are released from the billions of cells that die in the body everyday can illegitimately integrate into genomes of healthy cells to trigger dsDNA breaks. The latter leads to apoptosis and/or intense activation of inflammatory cytokines in the affected cells. We hypothesise that a similar phenomenon of dsDNA breaks and inflammation is involved in cytokine storm. The abundant cfCh particles that are released from dying host cells following viral/microbial invasion initiate a cascading effect of more cell death resulting in a vicious cycle of further DNA damage, apoptosis and hyper-inflammation which culminate in cytokine storm. We propose that this unrelenting vicious cycle of cellular DNA damage and cytokine storm may be the underlying cause of high mortality from severe COVID-19. We discuss results of our preclinical studies wherein we have shown that endotoxin induced cytokine storm in mice can be reversed by three different agents that have the ability to inactivate cfCh. These agents may be worthy of investigation in clinical trials to reduce mortality from COVID-19.
Mucocutaneous Manifestations of Behçet's Disease
Authors: Nakamura Koichiro , Tsunemi Yuichiro , Kaneko Fumio , Alpsoy Erkan
Published: February 2021

Behçet's disease (BD) is a chronic, relapsing, systemic inflammatory disease with clinical features showing mucocutaneous lesions involving the ocular, articular, and further miscellaneous organs. Mucocutaneous manifestations, one of the most characteristic signs of BD, have been most commonly observed upon onset or at any disease stage and are exceptionally important in its diagnosis. Given the lack of specific diagnostic laboratory tests for BD, diagnosis has been based on clinical findings. All diagnostic criteria published have thus far relied heavily on mucocutaneous manifestations, particularly oral ulcers (OU), genital ulcers (GU), cutaneous lesions, and pathergy test positivity. Worldwide, OU, GU, cutaneous lesions, and ocular and articular manifestations have been the most common symptoms, with erythema nodosum (EN)-like lesions and papulopustular lesions being the most prevalent cutaneous manifestations. While majority of the patients worldwide have reported OU as the most frequent symptom upon disease onset, GU, and EN-like lesions have also been identified upon onset. Considering that mucocutaneous symptoms precede severe organ involvement in most patients, familiarity with such symptoms is imperative for early diagnosis and prevention of potentially serious organ involvement through appropriate management.
Anticoagulant Related Nephropathy Only Partially Develops in C57BL/6 Mice: Hematuria Is Not Accompanied by Red Blood Cell Casts in the Kidney
Authors: Medipally Ajay K. , Xiao Min , Qaisar Shahzeb , Satoskar Anjali A. , Ivanov Iouri , Rovin Brad , Brodsky Sergey V.
Published: February 2021

Anticoagulant-related nephropathy (ARN) may develop in patients that are on anticoagulation therapy. Rats with 5/6 nephrectomy treated with different anticoagulants showed acute kidney injury (AKI) and red blood cell (RBC) casts in the tubules similar to ARN in humans. The aim of the current study was to investigate the feasibility of inducing ARN in mice. C57BL/6 5/6 nephrectomy mice were treated with warfarin and dabigatran 3 weeks after ablative surgery for 7 days. Two doses of each anticoagulant were used. All anticoagulants resulted in serum creatinine and hematuria increase. Mortality was 63% in 5.0 mg/kg/day of warfarin but only 13% in 2.5 mg/kg/day of warfarin or in 400 mg/kg/day of dabigatran and 0% in 200 mg/kg/day of dabigatran. In spite of increasing hematuria, RBC tubular casts were not seen in mice treated with any anticoagulant. The 5/6 nephrectomy murine model in C57BL/6 mice only partially reproduced ARN in terms of increasing serum creatinine and hematuria, but there were no RBC tubular casts in the remnant kidney.
Genomic Investigation of Virulence Potential in Shiga Toxin Escherichia coli (STEC) Strains From a Semi-Hard Raw Milk Cheese
Authors: Cortimiglia Claudia , Borney Maria Francesca , Bassi Daniela , Cocconcelli Pier Sandro
Published: February 2021

Shiga-toxin-producing Escherichia coli (STEC) represents a significant cause of foodborne disease. In the last years, an increasing number of STEC infections associated with the consumption of raw and pasteurized milk cheese have been reported, contributing to raise the public awareness. The aim of this study is to evaluate the main genomic features of STEC strains isolated from a semi-hard raw milk cheese, focusing on their pathogenic potential. The analysis of 75 cheese samples collected during the period between April 2019 and January 2020 led to the isolation of seven strains from four stx-positive enrichment. The genome investigation evidenced the persistence of two serotypes, O174:H2 and O116:H48. All strains carried at least one stx gene and were negative for eae gene. The virulence gene pattern was homogeneous among the serogroup/ST and included adherence factors (lpfA, iha, ompT, papC, saa, sab, hra, and hes), enterohemolysin (ehxA), serum resistance (iss, tra), cytotoxin-encoding genes like epeA and espP, and the Locus of Adhesion and Autoaggregation Pathogenicity Islands (LAA PAIs) typically found in Locus of Enterocyte Effacement (LEE)-negative STEC. Genome plasticity indicators, namely, prophagic sequences carrying stx genes and plasmid replicons, were detected, leading to the possibility to share virulence determinants with other strains. Overall, our work adds new knowledge on STEC monitoring in raw milk dairy products, underlining the fundamental role of whole genome sequencing (WGS) for typing these unknown isolates. Since, up to now, some details about STEC pathogenesis mechanism is lacking, the continuous monitoring in order to protect human health and increase knowledge about STEC genetic features becomes essential.
Quorum Sensing Inhibition or Quenching in Acinetobacter baumannii: The Novel Therapeutic Strategies for New Drug Development
Authors: Zhong Shan , He Songzhe
Published: February 2021

Acinetobacter baumannii is a Gram-negative opportunistic nosocomial pathogen, which can cause ventilator-related and blood infection in critically ill patients. The resistance of A. baumannii clinical isolates to common antimicrobials and their tolerance to desiccation have emerged as a serious problem to public health. In the process of pathogenesis, bacteria release signals, which regulate virulence and pathogenicity-related genes. Such bacteria coordinate their virulent behavior in a cell density-dependent phenomenon called quorum sensing (QS). In contrast, the two main approaches of QS interference, quorum sensing inhibitors (QSIs) and quorum quenching (QQ) enzymes, have been developed to reduce the virulence of bacteria, thus reducing the pressure to produce bacterial drug resistance. Therefore, QSIs or QQ enzymes, which interfere with these processes, might potentially inhibit bacterial QS and ultimately biofilm formation. In this review, we aim to describe the state-of-art in the QS process in A. baumannii and elaborate on the use of QSIs or QQ enzymes as antimicrobial drugs in various potential sites of the QS pathway.
Targeting the Active Rhizosphere Microbiome of Trifolium pratense in Grassland Evidences a Stronger-Than-Expected Belowground Biodiversity-Ecosystem Functioning Link
Authors: Wahdan Sara Fareed Mohamed , Heintz-Buschart Anna , Sansupa Chakriya , Tanunchai Benjawan , Wu Yu-Ting , Schädler Martin , Noll Matthias , Purahong Witoon , Buscot François
Published: February 2021

The relationship between biodiversity and ecosystem functioning (BEF) is a central issue in soil and microbial ecology. To date, most belowground BEF studies focus on the diversity of microbes analyzed by barcoding on total DNA, which targets both active and inactive microbes. This approach creates a bias as it mixes the part of the microbiome currently steering processes that provide actual ecosystem functions with the part not directly involved. Using experimental extensive grasslands under current and future climate, we used the bromodeoxyuridine (BrdU) immunocapture technique combined with pair-end Illumina sequencing to characterize both total and active microbiomes (including both bacteria and fungi) in the rhizosphere ofTrifolium pratense. Rhizosphere function was assessed by measuring the activity of three microbial extracellular enzymes (β-glucosidase, N-acetyl-glucosaminidase, and acid phosphatase), which play central roles in the C, N, and P acquisition. We showed that the richness of overall and specific functional groups of active microbes in rhizosphere soil significantly correlated with the measured enzyme activities, while total microbial richness did not. Active microbes of the rhizosphere represented 42.8 and 32.1% of the total bacterial and fungal taxa, respectively, and were taxonomically and functionally diverse. Nitrogen fixing bacteria were highly active in this system with 71% of the total operational taxonomic units (OTUs) assigned to this group detected as active. We found the total and active microbiomes to display different responses to variations in soil physicochemical factors in the grassland, but with some degree of resistance to a manipulation mimicking future climate. Our findings provide critical insights into the role of active microbes in defining soil ecosystem functions in a grassland ecosystem. We demonstrate that the relationship between biodiversity-ecosystem functioning in soil may be stronger than previously thought.
Discovery, Bioactivity Evaluation, Biosynthetic Gene Cluster Identification, and Heterologous Expression of Novel Albofungin Derivatives
Authors: She Weiyi , Ye Wenkang , Cheng Aifang , Liu Xin , Tang Jianwei , Lan Yi , Chen Feng , Qian Pei-Yuan
Published: February 2021

The crude extract of Streptomyces chrestomyceticus exhibited strong and broad activities against most “ESKAPE pathogens.” We conducted a comprehensive chemical investigation for secondary metabolites from the S. chrestomyceticus strain and identified two novel albofungin (alb) derivatives, i.e., albofungins A (1) and B (2), along with two known compounds, i.e., albofungin (3) and chloroalbofungin (4). The chemical structures of the novel compounds were elucidated using HRMS, 1D and 2D NMR, and electronic circular dichroism spectroscopy. The draft genome of S. chrestomyceticus was sequenced, and a 72 kb albofungin (alb) gene cluster with 72 open reading frames encoding type II polyketide synthases (PKSs), regulators, and transporters, and tailoring enzymes were identified using bioinformatics analysis. The alb gene cluster was confirmed using the heterologous expression in Streptomyces coelicolor, which successfully produced the compounds 3 and 4. Furthermore, compounds 1–4 displayed remarkable activities against Gram-positive bacteria and antitumor activities toward various cancer cells. Notably, compounds 1 and 3 showed potent activities against Gram-negative pathogenic bacteria. The terminal deoxynucleotidyl transferase (dUTP) nick-end labeling and flow cytometry analysis verified that compound 1 inhibited cancer cell proliferation by inducing cellular apoptosis. These results indicated that albofungins might be potential candidates for the development of antibiotics and antitumor drugs.
Identification of Exploration and Exploitation Balance in the Silkmoth Olfactory Search Behavior by Information-Theoretic Modeling
Authors: Hernandez-Reyes Cesar A. , Fukushima Shumpei , Shigaki Shunsuke , Kurabayashi Daisuke , Sakurai Takeshi , Kanzaki Ryohei , Sezutsu Hideki
Published: February 2021

Insects search for and find odor sources as their basic behaviors, such as when looking for food or a mate. This has motivated research to describe how they achieve such behavior under turbulent odor plumes with a small number of neurons. Among different insects, the silk moth has been studied owing to its clear motor response to olfactory input. In past studies, the “programmed behavior” of the silk moth has been modeled as the average duration of a sequence of maneuvers based on the duration of periods without odor hits. However, this model does not fully represent the fine variations in their behavior. In this study, we used silk moth olfactory search trajectories from an experimental virtual reality device. We achieved an accurate input by using optogenetic silk moths that react to blue light. We then modeled such trajectories as a probabilistic learning agent with a belief of possible source locations. We found that maneuvers mismatching the programmed behavior are related to larger entropy decrease, that is, they are more likely to increase the certainty of the belief. This implies that silkmoths include some stochasticity in their search policy to balance the exploration and exploitation of olfactory information by matching or mismatching the programmed behavior model. We believe that this information-theoretic representation of insect behavior is important for the future implementation of olfactory searches in artificial agents such as robots.
A Critical Review of Cranial Electrotherapy Stimulation for Neuromodulation in Clinical and Non-clinical Samples
Authors: Brunyé Tad T. , Patterson Joseph E. , Wooten Thomas , Hussey Erika K.
Published: February 2021

Cranial electrotherapy stimulation (CES) is a neuromodulation tool used for treating several clinical disorders, including insomnia, anxiety, and depression. More recently, a limited number of studies have examined CES for altering affect, physiology, and behavior in healthy, non-clinical samples. The physiological, neurochemical, and metabolic mechanisms underlying CES effects are currently unknown. Computational modeling suggests that electrical current administered with CES at the earlobes can reach cortical and subcortical regions at very low intensities associated with subthreshold neuromodulatory effects, and studies using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) show some effects on alpha band EEG activity, and modulation of the default mode network during CES administration. One theory suggests that CES modulates brain stem (e.g., medulla), limbic (e.g., thalamus, amygdala), and cortical (e.g., prefrontal cortex) regions and increases relative parasympathetic to sympathetic drive in the autonomic nervous system. There is no direct evidence supporting this theory, but one of its assumptions is that CES may induce its effects by stimulating afferent projections of the vagus nerve, which provides parasympathetic signals to the cardiorespiratory and digestive systems. In our critical review of studies using CES in clinical and non-clinical populations, we found severe methodological concerns, including potential conflicts of interest, risk of methodological and analytic biases, issues with sham credibility, lack of blinding, and a severe heterogeneity of CES parameters selected and employed across scientists, laboratories, institutions, and studies. These limitations make it difficult to derive consistent or compelling insights from the extant literature, tempering enthusiasm for CES and its potential to alter nervous system activity or behavior in meaningful or reliable ways. The lack of compelling evidence also motivates well-designed and relatively high-powered experiments to assess how CES might modulate the physiological, affective, and cognitive responses to stress. Establishing reliable empirical links between CES administration and human performance is critical for supporting its prospective use during occupational training, operations, or recovery, ensuring reliability and robustness of effects, characterizing if, when, and in whom such effects might arise, and ensuring that any benefits of CES outweigh the risks of adverse events.
Non-linear Memristive Synaptic Dynamics for Efficient Unsupervised Learning in Spiking Neural Networks
Authors: Brivio Stefano , Ly Denys R. B. , Vianello Elisa , Spiga Sabina
Published: February 2021

Spiking neural networks (SNNs) are a computational tool in which the information is coded into spikes, as in some parts of the brain, differently from conventional neural networks (NNs) that compute over real-numbers. Therefore, SNNs can implement intelligent information extraction in real-time at the edge of data acquisition and correspond to a complementary solution to conventional NNs working for cloud-computing. Both NN classes face hardware constraints due to limited computing parallelism and separation of logic and memory. Emerging memory devices, like resistive switching memories, phase change memories, or memristive devices in general are strong candidates to remove these hurdles for NN applications. The well-established training procedures of conventional NNs helped in defining the desiderata for memristive device dynamics implementing synaptic units. The generally agreed requirements are a linear evolution of memristive conductance upon stimulation with train of identical pulses and a symmetric conductance change for conductance increase and decrease. Conversely, little work has been done to understand the main properties of memristive devices supporting efficient SNN operation. The reason lies in the lack of a background theory for their training. As a consequence, requirements for NNs have been taken as a reference to develop memristive devices for SNNs. In the present work, we show that, for efficient CMOS/memristive SNNs, the requirements for synaptic memristive dynamics are very different from the needs of a conventional NN. System-level simulations of a SNN trained to classify hand-written digit images through a spike timing dependent plasticity protocol are performed considering various linear and non-linear plausible synaptic memristive dynamics. We consider memristive dynamics bounded by artificial hard conductance values and limited by the natural dynamics evolution toward asymptotic values (soft-boundaries). We quantitatively analyze the impact of resolution and non-linearity properties of the synapses on the network training and classification performance. Finally, we demonstrate that the non-linear synapses with hard boundary values enable higher classification performance and realize the best trade-off between classification accuracy and required training time. With reference to the obtained results, we discuss how memristive devices with non-linear dynamics constitute a technologically convenient solution for the development of on-line SNN training.
The Phantom Satiation Hypothesis of Bariatric Surgery
Authors: Gautron Laurent
Published: February 2021

The excitation of vagal mechanoreceptors located in the stomach wall directly contributes to satiation. Thus, a loss of gastric innervation would normally be expected to result in abrogated satiation, hyperphagia, and unwanted weight gain. While Roux-en-Y-gastric bypass (RYGB) inevitably results in gastric denervation, paradoxically, bypassed subjects continue to experience satiation. Inspired by the literature in neurology on phantom limbs, I propose a new hypothesis in which damage to the stomach innervation during RYGB, including its vagal supply, leads to large-scale maladaptive changes in viscerosensory nerves and connected brain circuits. As a result, satiation may continue to arise, sometimes at exaggerated levels, even in subjects with a denervated or truncated stomach. The same maladaptive changes may also contribute to dysautonomia, unexplained pain, and new emotional responses to eating. I further revisit the metabolic benefits of bariatric surgery, with an emphasis on RYGB, in the light of thisphantom satiation hypothesis.
Roles of Non-coding RNAs in Central Nervous System Axon Regeneration
Authors: Li Pei , Jia Yuanyuan , Tang Wenbo , Cui Qingjun , Liu Ming , Jiang Jingjing
Published: February 2021

Axons in the central nervous system often fail to regenerate after injury due to the limited intrinsic regeneration ability of the central nervous system (CNS) and complex extracellular inhibitory factors. Therefore, it is of vital importance to have a better understanding of potential methods to promote the regeneration capability of injured nerves. Evidence has shown that non-coding RNAs play an essential role in nerve regeneration, especially long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA). In this review, we profile their separate roles in axon regeneration after CNS injuries, such as spinal cord injury (SCI) and optic nerve injury. In addition, we also reveal the interactive networks among non-coding RNAs.
Impact of Intermittent Fasting on Lipid Profile–A Quasi-Randomized Clinical Trial
Authors: Ahmed Naseer , Farooq Javeria , Siddiqi Hasan Salman , Meo Sultan Ayoub , Kulsoom Bibi , Laghari Abid H. , Jamshed Humaira , Pasha Farooq
Published: February 2021

Background: Sub-optimal HDL is a prognostic marker of cardiovascular disease. South Asia has a high prevalence of sub-optimal HDL compared to other parts of the world. Intermittent fasting (IF) is a type of energy restriction which may improve serum HDL and other lipids thereby reducing the risk of cardiovascular diseases.

Objective: The aim of the study was to evaluate the effect of IF on lipid profile and HDL-cholesterol in a sample of South Asian adults.

Methods: A 6-week quasi-experimental (non-randomized) clinical trial was conducted on participants with low HDL (< 40 mg/dl for men and < 50 mg/dl for women). Participants of the control group were recommended not to change their diet. The intervention group was recommended to fast for ~12 h during day time, three times per week for 6 weeks. Pulse rate, blood pressure, body weight, waist circumference, serum lipid profile, and blood glucose levels were measured at baseline and after 6 weeks.

Result: A total of 40 participants were enrolled in the study (N = 20 in each group), while 35 (20 control and 15 intervention) completed the trial and were included in data analysis of the study. Body measurements, including body weight, BMI and waist circumference, showed significant interaction effects (p's < 0.001), indicating that there were larger reductions in the IF group than in the control group. Significant interaction effects were also observed for total (p = 0.033), HDL (p = 0.0001), and LDL cholesterol (p = 0.010) with larger improvements in the IF group.

Conclusion: This study suggests that intermittent fasting may protect cardiovascular health by improving the lipid profile and raising the sub-optimal HDL. Intermittent fasting may be adopted as a lifestyle intervention for the prevention, management and treatment of cardiovascular disorders.

Clinical Trial Registration: NCT03805776, registered on January 16, 2019, https://clinicaltrials.gov/ct2/show/NCT03805776
Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer
Authors: Lv Huifang , Zhang Junling , Sun Keran , Nie Caiyun , Chen Beibei , Wang Jianzheng , Xu Weifeng , Wang Saiqi , Liu Yingjun , Chen Xiaobing
Published: February 2021

Background

PD-L1 and HER-2 are routine biomarkers for gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, immune microenvironment, and clinical features in GC.

Methods

Between January 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). The mRNA and tumor microenvironment of 343 patients with GC from The Cancer Genome Atlas (TCGA) were used to explore the underlying mechanism.

Results

We retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 (P = 0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P = 0.014, mPFS: 5.3 vs. 11.1 months, P = 0.002, respectively), and the PD-L1 negative and HER-2 negative had the best PFS than other groups (P = 0.0008). In a multivariate model, PD-L1 status, HER-2 status, tumor location, and tumor differentiation remained independent prognostic indicators for PFS (P < 0.05). The results of database further analysis showed that the proportion of PD-L1+/CD8A+ in HER-2 negative patients was higher than that in HER-2 positive patients (37.6 vs 20.3%), while PD-L1−/CD8A− was significantly higher in HER-2 positive patients than HER-2 negative patients (57.8 vs. 28.8%). In addition, it showed that not only CD4+T cells, macrophages, and CD8+T cells, but also the associated inflammatory pathways such as IFN-γ/STAT1 were associated with HER-2.

Conclusion

HER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.
The Edge of Perinatal Viability: Understanding the Dutch Position
Authors: De Proost L. , Verweij E. J. T. , Ismaili M'hamdi H. , Reiss I. K. M. , Steegers E. A. P. , Geurtzen R. , Verhagen A. A. E.
Published: February 2021

The current Dutch guideline on care at the edge of perinatal viability advises to consider initiation of active care to infants born from 24 weeks of gestational age on. This, only after extensive counseling of and shared decision-making with the parents of the yet unborn infant. Compared to most other European guidelines on this matter, the Dutch guideline may be thought to stand out for its relatively high age threshold of initiating active care, its gray zone spanning weeks 24 and 25 in which active management is determined by parental discretion, and a slight reluctance to provide active care in case of extreme prematurity. In this article, we explore the Dutch position more thoroughly. First, we briefly look at the previous and current Dutch guidelines. Second, we position them within the Dutch socio-cultural context. We focus on the Dutch prioritization of individual freedom, the abortion law and the perinatal threshold of viability, and a culturally embedded aversion of suffering. Lastly, we explore two possible adaptations of the Dutch guideline; i.e., to only lower the age threshold to consider the initiation of active care, or to change the type of guideline.