bluuebunny/crossref_metadata_2025 huggingface dataset:
C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera
Authors: Silva de França Felipe , Villas-Boas Isadora Maria , Cogliati Bruno , Woodruff Trent M. , Reis Edimara da Silva , Lambris John D. , Tambourgi Denise V.
Published: April 2021

Systemic complement activation drives a plethora of pathological conditions, but its role in snake envenoming remains obscure. Here, we explored complement’s contribution to the physiopathogenesis ofNaja annuliferaenvenomation. We found thatN. annuliferavenom promoted the generation of C3a, C4a, C5a, and the soluble Terminal Complement Complex (sTCC) mediated by the action of snake venom metalloproteinases.N. annuliferavenom also induced the release of lipid mediators and chemokines in a human whole-blood model. This release was complement-mediated, since C3/C3b and C5a Receptor 1 (C5aR1) inhibition mitigated the effects. In an experimental BALB/c mouse model of envenomation,N. annuliferavenom promoted lipid mediator and chemokine production, neutrophil influx, and swelling at the injection site in a C5a-C5aR1 axis-dependent manner.N. annuliferavenom induced systemic complementopathy and increased interleukin and chemokine production, leukocytosis, and acute lung injury (ALI). Inhibition of C5aR1 with the cyclic peptide antagonist PMX205 rescued mice from these systemic reactions and abrogated ALI development. These data reveal hitherto unrecognized roles for complement in envenomation physiopathogenesis, making complement an interesting therapeutic target in envenomation byN. annuliferaand possibly by other snake venoms.
Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes
Authors: Mishto Michele , Mansurkhodzhaev Artem , Rodriguez-Calvo Teresa , Liepe Juliane
Published: April 2021

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.
The Predictive Value of Monocytes in Immune Microenvironment and Prognosis of Glioma Patients Based on Machine Learning
Authors: Zhang Nan , Dai Ziyu , Wu Wantao , Wang Zeyu , Cao Hui , Zhang Yakun , Wang Zhanchao , Zhang Hao , Cheng Quan
Published: April 2021

Gliomas are primary malignant brain tumors. Monocytes have been proved to actively participate in tumor growth. Weighted gene co-expression network analysis was used to identify meaningful monocyte-related genes for clustering. Neural network and SVM were applied for validating clustering results. Somatic mutation and copy number variation were used for defining the features of identified clusters. Differentially expressed genes (DEGs) between the stratified groups after performing elastic regression and principal component analyses were used for the construction of risk scores. Monocytes were associated with glioma patients’ survival and exhibited high predictive value. The prognostic value of risk score in glioma was validated by the abundant expression of immune checkpoint and metabolic profile. Additionally, high risk score was positively associated with the expression of immunogenic and antigen presenting factors, which indicated high immune infiltration. A prognostic model based on risk score demonstrated high accuracy rate of receiver operating characteristic curves. Compared with previous studies, our research dissected functional roles of monocytes from large-scale analysis. Findings of our analyses strongly support an immune modulatory and prognostic role of monocytes in glioma progression. Notably, monocyte could be an effective predictor for therapy responses of glioma patients.
Hematopoietic Multipotent Progenitors and Plasma Cells: Neighbors or Roommates in the Mouse Bone Marrow Ecosystem?
Authors: Bonaud Amélie , Lemos Julia P. , Espéli Marion , Balabanian Karl
Published: April 2021

The bone marrow is a complex ecosystem in which hematopoietic and non-hematopoietic cells reside. In this review, we discuss the bone marrow niches in mice that facilitate the survival, maintenance, and differentiation of cells of hematopoietic origin based on the recent literature. Our review places a special focus on the hematopoietic multipotent progenitors and on plasma cells, corresponding to the last stage of the B-cell lineage, that play a key role in the humoral memory response. We highlight the similarities between the microenvironments necessary for the establishment and the maintenance of these two immune cell subsets, and how the chemokine CXCL12/CXCR4 signaling axis contributes to these processes. Finally, we bring elements to address the following question: are multipotent progenitors and plasma cells neighbors or roommates within the bone marrow?
SAMD9 Is Relating With M2 Macrophage and Remarkable Malignancy Characters in Low-Grade Glioma
Authors: Ma Wenping , Zhang Kenan , Bao Zhaoshi , Jiang Tao , Zhang Ying
Published: April 2021

Immunoreactions regulated by TAMs (Tumor-associated macrophages) play a pivotal role in tumorigenesis and metastasis. In recent decades, treatments based on immune regulation have achieved revolutionary breakthroughs in cancer targeted therapies. The phenotypes of TAMs in gliomas are more heterogeneous and inherently complex than can be simply defined by classification into the M1 and M2 polarized states. The detailed mechanisms surrounding infiltrating macrophage phenotype and glioma characteristics remain undefined. SAMD9 (Sterile Alpha Motif Domain-Containing Protein 9) was found to be highly expressed in glioma and closely related to histological and genetic features in CGGA and TCGA databases. Simultaneously, we present evidence to show that there was a positive association between SAMD9 and malignancy characters in LGG. Univariable and Multivariate proportional hazard Cox analysis showed that SAMD9 was an independent prognostic factor for LGG. Surprisingly, Gene Ontology (GO) analysis showed SAMD9 expression level was remarkably well correlated with immunological responses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis supported the connection with immune responses and tumorigenesis. Immune infiltration analysis demonstrated that high SAMD9 expression resulted in an accumulation of macrophages by CIBERSORT and TIMER databases, especially positively related to macrophage total marker gene AIF1 and Macrophage M2 marker gene CD163. IHC staining further indicated a high correlation of SAMD9 with those specific macrophage markers in the immune response. Human THP-1 cells were induced into M2 macrophages, which were then co-cultured with LN229 cells. Silencing of SAMD9 by shRNA in LN229 cells attenuated the infiltration abilities of M2 macrophage. SAMD9 explored immune response via relating of M2 macrophage in vitro. Our results revealed SAMD9 acted as the malignancy characters in LGG, enrichment with M2 macrophage.
An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens
Authors: Olsson Niclas , Heberling Marlene L. , Zhang Lichao , Jhunjhunwala Suchit , Phung Qui T. , Lin Sarah , Anania Veronica G. , Lill Jennie R. , Elias Joshua E.
Published: April 2021

All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) are necessary for directing T-cell responses against cells harboring non-self antigens derived from pathogens or from somatic mutations. Alterations in tumor-specific antigen repertoires — particularly novel MHC presentation of mutation-bearing peptides (neoantigens) — can be potent targets of anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring how interferon gamma (IFN-γ) alters antigen presentation, using a human lymphoma cell line, GRANTA-519. IFN-γ treatment resulted in 126 differentially expressed proteins (2% of all quantified proteins), which included components of antigen presentation machinery and interferon signaling pathways, and MHC molecules themselves. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells’ antigen/epitope repertoires. Accordingly, MHC immunoprecipitation followed by mass spectrometric analysis of eluted peptide repertoires revealed exclusive signatures of IFN-γ induction, with 951 unique peptides reproducibly presented by MHC-I and 582 presented by MHC-II. Furthermore, an additional set of pMHCs including several candidate neoantigens, distinguished control and the IFN-γ samples by their altered relative abundances. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance could help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.
Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients
Authors: Yang Qiao , Chen Mingjing , Gu Jiaoyang , Niu Kai , Zhao Xianlan , Zheng Linpeng , Xu Zihan , Yu Yongxin , Li Feng , Meng Lingxin , Chen Zhengtang , Zhuo Wenlei , Zhang Luping , Sun Jianguo
Published: April 2021

Background

Immune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic.

Methods

Paired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software.

Results

In 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment.

Conclusion

There was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients.
Gingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review
Authors: Kim Dane , Lee Alisa E. , Xu Qilin , Zhang Qunzhou , Le Anh D.
Published: April 2021

A unique subpopulation of mesenchymal stem cells (MSCs) has been isolated and characterized from human gingival tissues (GMSCs). Similar to MSCs derived from other sources of tissues, e.g. bone marrow, adipose or umbilical cord, GMSCs also possess multipotent differentiation capacities and potent immunomodulatory effects on both innate and adaptive immune cells through the secretion of various types of bioactive factors with immunosuppressive and anti-inflammatory functions. Uniquely, GMSCs are highly proliferative and have the propensity to differentiate into neural cell lineages due to the neural crest-origin. These properties have endowed GMSCs with potent regenerative and therapeutic potentials in various preclinical models of human disorders, particularly, some inflammatory and autoimmune diseases, skin diseases, oral and maxillofacial disorders, and peripheral nerve injuries. All types of cells release extracellular vesicles (EVs), including exosomes, that play critical roles in cell-cell communication through their cargos containing a variety of bioactive molecules, such as proteins, nucleic acids, and lipids. Like EVs released by other sources of MSCs, GMSC-derived EVs have been shown to possess similar biological functions and therapeutic effects on several preclinical diseases models as GMSCs, thus representing a promising cell-free platform for regenerative therapy. Taken together, due to the easily accessibility and less morbidity of harvesting gingival tissues as well as the potent immunomodulatory and anti-inflammatory functions, GMSCs represent a unique source of MSCs of a neural crest-origin for potential application in tissue engineering and regenerative therapy.
Draft Genome of the Sea Cucumber Holothuria glaberrima, a Model for the Study of Regeneration
Authors: Medina-Feliciano Joshua G. , Pirro Stacy , García-Arrarás Jose E. , Mashanov Vladimir , Ryan Joseph F.
Published: April 2021

Regeneration is one of the most fascinating and yet least understood biological processes. Echinoderms, one of the closest related invertebrate groups to humans, can contribute to our understanding of the genetic basis of regenerative processes. Among echinoderms, sea cucumbers have the ability to grow back most of their body parts following injury, including the intestine and nervous tissue. The cellular and molecular events underlying these abilities in sea cucumbers have been most extensively studied in the species Holothuria glaberrima. However, research into the regenerative abilities of this species has been impeded due to the lack of adequate genomic resources. Here, we report the first draft genome assembly of H. glaberrima and demonstrate its value for future genetic studies. Using only short sequencing reads, we assembled the genome into 89,105 scaffolds totaling 1.1 gigabases with an N50 of 25 kilobases. Our BUSCO assessment of the genome resulted in 894 (91.4%) complete and partial genes from 978 genes queried. We incorporated transcriptomic data from several different life history stages to annotate 51,415 genes in our final assembly. To demonstrate the usefulness of the genome, we fully annotated the melanotransferrin (Mtf) gene family, which have a potential role in the regeneration of the sea cucumber intestine. Using these same data, we extracted the mitochondrial genome, which showed high conservation to that of other holothuroids. Thus, these data will be a critical resource for ongoing studies of regeneration and other studies in sea cucumbers.
The Charming World of the Extracellular Matrix: A Dynamic and Protective Network of the Intestinal Wall
Authors: Pompili Simona , Latella Giovanni , Gaudio Eugenio , Sferra Roberta , Vetuschi Antonella
Published: April 2021

The intestinal extracellular matrix (ECM) represents a complex network of proteins that not only forms a support structure for resident cells but also interacts closely with them by modulating their phenotypes and functions. More than 300 molecules have been identified, each of them with unique biochemical properties and exclusive biological functions. ECM components not only provide a scaffold for the tissue but also afford tensile strength and limit overstretch of the organ. The ECM holds water, ensures suitable hydration of the tissue, and participates in a selective barrier to the external environment. ECM-to-cells interaction is crucial for morphogenesis and cell differentiation, proliferation, and apoptosis. The ECM is a dynamic and multifunctional structure. The ECM is constantly renewed and remodeled by coordinated action among ECM-producing cells, degrading enzymes, and their specific inhibitors. During this process, several growth factors are released in the ECM, and they, in turn, modulate the deposition of new ECM. In this review, we describe the main components and functions of intestinal ECM and we discuss their role in maintaining the structure and function of the intestinal barrier. Achieving complete knowledge of the ECM world is an important goal to understand the mechanisms leading to the onset and the progression of several intestinal diseases related to alterations in ECM remodeling.
Molecular Biomarkers for Melanoma Screening, Diagnosis and Prognosis: Current State and Future Prospects
Authors: Deacon Dekker C. , Smith Eric A. , Judson-Torres Robert L.
Published: April 2021

Despite significant progress in the development of treatment options, melanoma remains a leading cause of death due to skin cancer. Advances in our understanding of the genetic, transcriptomic, and morphologic spectrum of benign and malignant melanocytic neoplasia have enabled the field to propose biomarkers with potential diagnostic, prognostic, and predictive value. While these proposed biomarkers have the potential to improve clinical decision making at multiple critical intervention points, most remain unvalidated. Clinical validation of even the most commonly assessed biomarkers will require substantial resources, including limited clinical specimens. It is therefore important to consider the properties that constitute a relevant and clinically-useful biomarker-based test prior to engaging in large validation studies. In this review article we adapt an established framework for determining minimally-useful biomarker test characteristics, and apply this framework to a discussion of currently used and proposed biomarkers designed to aid melanoma detection, staging, prognosis, and choice of treatment.
Stereoselective Bacterial Metabolism of Antibiotics in Environmental Bacteria – A Novel Biochemical Workflow
Authors: Elder Felicity C. T. , Feil Edward J. , Pascoe Ben , Sheppard Samuel K. , Snape Jason , Gaze William H. , Kasprzyk-Hordern Barbara
Published: April 2021

Although molecular genetic approaches have greatly increased our understanding of the evolution and spread of antibiotic resistance genes, there are fewer studies on the dynamics of antibiotic – bacterial (A-B) interactions, especially with respect to stereochemistry. Addressing this knowledge gap requires an interdisciplinary synthesis, and the development of sensitive and selective analytical tools. Here we describe SAM (stereoselective antimicrobial metabolism) workflow, a novel interdisciplinary approach for assessing bacterial resistance mechanisms in the context of A-B interactions that utilise a combination of whole genome sequencing and mass spectrometry. Chloramphenicol was used to provide proof-of-concept to demonstrate the importance of stereoselective metabolism by resistant environmental bacteria. Our data shows that chloramphenicol can be stereoselectively transformed via microbial metabolism with R,R-(-)-CAP being subject to extensive metabolic transformation by an environmental bacterial strain. In contrast S,S-(+)-CAP is not metabolised by this bacterial strain, possibly due to the lack of previous exposure to this isomer in the absence of historical selective pressure to evolve metabolic capacity.
Mycobiomes of Young Beech Trees Are Distinguished by Organ Rather Than by Habitat, and Community Analyses Suggest Competitive Interactions Among Twig Fungi
Authors: Siddique Abu Bakar , Biella Paolo , Unterseher Martin , Albrectsen Benedicte Riber
Published: April 2021

Beech trees (Fagus sylvatica) are prominent keystone species of great economic and environmental value for central Europe, hosting a diverse mycobiome. The composition of endophyte communities may depend on tree health, plant organ or tissue, and growth habitat. To evaluate mycobiome communalities at local scales, buds, and twigs were sampled from two young healthy mountain beech stands in Bavaria, Germany, four kilometers apart. With Illumina high-throughput sequencing, we found 113 fungal taxa from 0.7 million high-quality reads that mainly consisted of Ascomycota (52%) and Basidiomycota (26%) taxa. Significant correlations between richness and diversity indices were observed (p< 0.05), and mycobiomes did not differ between habitats in the current study. Species richness and diversity were higher in twigs compared to spring buds, and the assemblages in twigs shared most similarities. Interaction network analyses revealed that twig-bound fungi shared similar numbers of (interaction) links with others, dominated by negative co-occurrences, suggesting that competitive exclusion may be the predominant ecological interaction in the highly connected twig mycobiome. Combining community and network analyses strengthened the evidence that plant organs may filter endophytic communities directly through colonization access and indirectly by facilitating competitive interactions between the fungi.
De-novo Assembly of Limnospira fusiformis Using Ultra-Long Reads
Authors: Hicks McKenna , Tran-Dao Thuy-Khanh , Mulroney Logan , Bernick David L.
Published: April 2021

The Limnospira genus is a recently established clade that is economically important due to its worldwide use in biotechnology and agriculture. This genus includes organisms that were reclassified from Arthrospira, which are commercially marketed as “Spirulina.” Limnospira are photoautotrophic organisms that are widely used for research in nutrition, medicine, bioremediation, and biomanufacturing. Despite its widespread use, there is no closed genome for the Limnospira genus, and no reference genome for the type strain, Limnospira fusiformis. In this work, the L. fusiformis genome was sequenced using Oxford Nanopore Technologies MinION and assembled using only ultra-long reads (>35 kb). This assembly was polished with Illumina MiSeq reads sourced from an axenic L. fusiformis culture; axenicity was verified via microscopy and rDNA analysis. Ultra-long read sequencing resulted in a 6.42 Mb closed genome assembled as a single contig with no plasmid. Phylogenetic analysis placed L. fusiformis in the Limnospira clade; some Arthrospira were also placed in this clade, suggesting a misclassification of these strains. This work provides a fully closed and accurate reference genome for the economically important type strain, L. fusiformis. We also present a rapid axenicity method to isolate L. fusiformis. These contributions enable future biotechnological development of L. fusiformis by way of genetic engineering.
Thioredoxin Reductase Is a Valid Target for Antimicrobial Therapeutic Development Against Gram-Positive Bacteria
Authors: Felix LewisOscar , Mylonakis Eleftherios , Fuchs Beth Burgwyn
Published: April 2021

There is a drought of new antibacterial compounds that exploit novel targets. Thioredoxin reductase (TrxR) from the Gram-positive bacterial antioxidant thioredoxin system has emerged from multiple screening efforts as a potential target for auranofin, ebselen, shikonin, and allicin. Auranofin serves as the most encouraging proof of concept drug, demonstrating TrxR inhibition can result in bactericidal effects and inhibit Gram-positive bacteria in both planktonic and biofilm states. Minimal inhibitory concentrations are on par or lower than gold standard medications, even among drug resistant isolates. Importantly, existing drug resistance mechanisms that challenge treatment of infections like Staphylococcus aureus do not confer resistance to TrxR targeting compounds. The observed inhibition by multiple compounds and inability to generate a bacterial genetic mutant demonstrate TrxR appears to play an essential role in Gram-positive bacteria. These findings suggest TrxR can be exploited further for drug development. Examining the interaction between TrxR and these proof of concept compounds illustrates that compounds representing a new antimicrobial class can be developed to directly interact and inhibit the validated target.
Frequency, Local Dynamics, and Genomic Characteristics of ESBL-Producing Escherichia coli Isolated From Specimens of Hospitalized Horses
Authors: Kauter Anne , Epping Lennard , Ghazisaeedi Fereshteh , Lübke-Becker Antina , Wolf Silver A. , Kannapin Dania , Stoeckle Sabita D. , Semmler Torsten , Günther Sebastian , Gehlen Heidrun , Walther Birgit
Published: April 2021

Previous research identified veterinary clinics as hotspots with respect to accumulation and spread of multidrug resistant extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (EC). Therefore, promoting the prudent use of antibiotics to decrease selective pressure in that particular clinical environment is preferable to enhance biosecurity for animal patients and hospital staff. Accordingly, this study comparatively investigated the impact of two distinct perioperative antibiotic prophylaxis (PAP) regimens (short-term versus prolonged) on ESBL-EC carriage of horses subjected to colic surgery. While all horses received a combination of penicillin/gentamicin (P/G) as PAP, they were assigned to either the “single-shot group” (SSG) or the conventional “5-day group” (5DG). Fecal samples collected on arrival (t0), on the 3rd (t1) and on the 10th day after surgery (t2) were screened for ESBL-EC. All isolates were further investigated using whole genome sequences. In total, 81 of 98 horses met the inclusion criteria for this study. ESBL-EC identified in samples available at t0, t1 and t2 were 4.8% (SSG) and 9.7% (5DG), 37% (SSG) and 47.2% (5DG) as well as 55.6% (SSG) and 56.8% (5DG), respectively. Regardless of the P/G PAP regimen, horses were 9.12 times (95% CI 2.79–29.7) more likely to carry ESBL-EC at t1 compared to t0 (p < 0.001) and 15.64 times (95% CI 4.57–53.55) more likely to carry ESBL-EC at t2 compared to t0 (p < 0.001). ESBL-EC belonging to sequence type (ST) 10, ST86, ST641, and ST410 were the most prevalent lineages, with blaCTX–M–1 (60%) being the dominant ESBL gene. A close spatio-temporal relationship between isolates sharing a particular ST was revealed by genome analysis, strongly indicating local spread. Consequently, hospitalization itself has a strong impact on ESBL-EC isolation rates in horses, possibly masking differences between distinct PAP regimens. The results of this study reveal accumulation and spread of multi-drug resistant ESBL-EC among horses subjected to colic surgery with different P/G PAP regimens, challenging the local hygiene management system and work-place safety of veterinary staff. Moreover, the predominance of particular ESBL-EC lineages in clinics providing health care for horses needs further investigation.
Protein Aggregation as a Bacterial Strategy to Survive Antibiotic Treatment
Authors: Bollen Celien , Dewachter Liselot , Michiels Jan
Published: April 2021

While protein aggregation is predominantly associated with loss of function and toxicity, it is also known to increase survival of bacteria under stressful conditions. Indeed, protein aggregation not only helps bacteria to cope with proteotoxic stresses like heat shocks or oxidative stress, but a growing number of studies suggest that it also improves survival during antibiotic treatment by inducing dormancy. A well-known example of dormant cells are persisters, which are transiently refractory to the action of antibiotics. These persister cells can switch back to the susceptible state and resume growth in the absence of antibiotics, and are therefore considered an important cause of recurrence of infections. Mounting evidence now suggests that this antibiotic-tolerant persister state is tightly linked to—or perhaps even driven by—protein aggregation. Moreover, another dormant bacterial phenotype, the viable but non-culturable (VBNC) state, was also shown to be associated with aggregation. These results indicate that persisters and VBNC cells may constitute different stages of the same dormancy program induced by progressive protein aggregation. In this mini review, we discuss the relation between aggregation and bacterial dormancy, focusing on both persisters and VBNC cells. Understanding the link between protein aggregation and dormancy will not only provide insight into the fundamentals of bacterial survival, but could prove highly valuable in our future battle to fight them.
Nanostructured β‐tricalcium Phosphate (Ca3(PO4)2 Based Electrochemical Sensor for Detection of Methyl Parathion and Mercury (II) Ions
Authors: Sudhan Narayanan , Sekar Chinnathambi
Published: April 2021

In this work, we have fabricated a new electrochemical sensor based on β‐tricalcium phosphate (Ca3(PO4)2) nanoparticles (NPs) modified glassy carbon electrode (GCE) for the selective nonenzymatic determination of methyl parathion and mercury (II) ions independently. β‐tricalcium phosphate (β‐TCP) NPs were prepared by chemical precipitation method and structural and morphological properties were investigated by XRD, FTIR, and SEM. The electrochemical behavior of MP and mercury (Hg2+) ions were investigated by cyclic voltammetry (CV) and square wave voltammetry (SWV) techniques using β‐TCP/GCE. The modified electrode exhibited excellent electrocatalytic activity towards both the MP and Hg over a wide linear range from 0.15 to 141 μM and 1–381 µM with the lowest detection limits of 88 and 136.4 nM respectively. The sensor has high selectivity towards MP and Hg in the presence of major interfering compounds such as 3-nitrophenol, 4-nitrophenol, 4-aminophenol, catechol, hydroquinone and heavy metals such as lead, cadmium and arsenic. Applicability of the fabricated sensor for detection of MP and Hg (II) ions has been tested in tap water by standard addition method.
Engineering Tunneling Selector to Achieve High Non-linearity for 1S1R Integration
Authors: Upadhyay Navnidhi K. , Blum Thomas , Maksymovych Petro , Lavrik Nickolay V. , Davila Noraica , Katine Jordan A. , Ievlev A. V. , Chi Miaofang , Xia Qiangfei , Yang J. Joshua
Published: April 2021

Memristor devices have been extensively studied as one of the most promising technologies for next-generation non-volatile memory. However, for the memristor devices to have a real technological impact, they must be densely packed in a large crossbar array (CBA) exceeding Gigabytes in size. Devising a selector device that is CMOS compatible, 3D stackable, and has a high non-linearity (NL) and great endurance is a crucial enabling ingredient to reach this goal. Tunneling based selectors are very promising in these aspects, but the mediocre NL value limits their applications in large passive crossbar arrays. In this work, we demonstrated a trilayer tunneling selector based on the Ge/Pt/TaN1+x/Ta2O5/TaN1+x/Pd layers that could achieve a NL of 3 × 105, which is the highest NL achieved using a tunnel selector so far. The record-high tunneling NL is partially attributed to the bottom electrode's ultra-smoothness (BE) induced by a Ge/Pt layer. We further demonstrated the feasibility of 1S1R (1-selector 1-resistor) integration by vertically integrating a Pd/Ta2O5/Ru based memristor on top of the proposed selector.
NF-κB-Induced Upregulation of miR-146a-5p Promoted Hippocampal Neuronal Oxidative Stress and Pyroptosis via TIGAR in a Model of Alzheimer’s Disease
Authors: Lei Bo , Liu Jiaxin , Yao Zhihui , Xiao Yan , Zhang Xiaoling , Zhang Yueting , Xu Jianguo
Published: April 2021

Alzheimer’s disease (AD) is a common neurodegenerative disorder that places a heavy burden on patients and society. Hippocampal neuronal loss is a hallmark of AD progression. Therefore, understanding the mechanism underlying hippocampal neuronal death would be of great importance for the diagnosis and treatment of AD. This study aimed to explore the molecular mechanism via which nuclear factor kappa β (NF-κB) promotes hippocampal neuronal oxidative stress and pyroptosis in AD. We collected serum samples from 101 healthy elderly people and 112 patients with AD at the Affiliated Hospital of Kunming University of Science and Technology between January 2017 and January 2020. Commercially available human hippocampal neurons (HHNs) were used to establish an AD model (AD-HHN) following Aβ25–35 treatment. The mRNA expression levels of NF-κB and pyroptosis markers [NLR family pyrin domain-containing 3, caspase-1, interleukin (IL)-1β, and interleukin-18] mRNA and the expression level of miR-146a-5p in the serum samples of patients with AD and AD-HHNs were determined by quantitative reverse transcription polymerase chain reaction. Oxidative stress indices (reactive oxygen species, malondialdehyde, nicotinamide adenine dinucleotide phosphate, superoxide dismutase, glutathione, and catalase) were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The expression of proteins [NF-κB, TP53-induced glycolysis and apoptosis regulator (TIGAR), and pyroptosis markers] was tested by western blotting. The relationship between miR-146a-5p and TIGAR was investigated using a dual luciferase reporter gene assay. We found that NF-κB and miR-146a-5p were highly expressed, while TIGAR was low expressed in patients with AD and AD-HHNs. In addition, there was a significant positive correlation between the expression levels of NF-κB and miR-146a-5p, but a negative correlation between NF-κB mRNA and TIGAR mRNA in patients with AD, as well as miR-146a-5p and TIGAR mRNA in patients with AD. In AD-HNNs, miR-146a-5p targeted and downregulated the expression of TIGAR. Knockdown of NF-κB or overexpression of TIGAR markedly attenuated oxidative stress and pyroptosis in AD-HHNs, while concurrent overexpression of miR-146a-5p inhibited these effects. In conclusion, NF-κB-induced upregulation of miR-146a-5p promoted oxidative stress and pyroptosis in AD-HNNs by targeting TIGAR.
Dark Rearing Promotes the Recovery of Visual Cortical Responses but Not the Morphology of Geniculocortical Axons in Amblyopic Cat
Authors: Gotou Takahiro , Kameyama Katsuro , Kobayashi Ayane , Okamura Kayoko , Ando Takahiko , Terata Keiko , Yamada Chihiro , Ohta Hiroyuki , Morizane Ayaka , Hata Yoshio
Published: April 2021

Monocular deprivation (MD) of vision during early postnatal life induces amblyopia, and most neurons in the primary visual cortex lose their responses to the closed eye. Anatomically, the somata of neurons in the closed-eye recipient layer of the lateral geniculate nucleus (LGN) shrink and their axons projecting to the visual cortex retract. Although it has been difficult to restore visual acuity after maturation, recent studies in rodents and cats showed that a period of exposure to complete darkness could promote recovery from amblyopia induced by prior MD. However, in cats, which have an organization of central visual pathways similar to humans, the effect of dark rearing only improves monocular vision and does not restore binocular depth perception. To determine whether dark rearing can completely restore the visual pathway, we examined its effect on the three major concomitants of MD in individual visual neurons, eye preference of visual cortical neurons and soma size and axon morphology of LGN neurons. Dark rearing improved the recovery of visual cortical responses to the closed eye compared with the recovery under binocular conditions. However, geniculocortical axons serving the closed eye remained retracted after dark rearing, whereas reopening the closed eye restored the soma size of LGN neurons. These results indicate that dark rearing incompletely restores the visual pathway, and thus exerts a limited restorative effect on visual function.
An Epigenetically Distinct Subset of Children With Autism Spectrum Disorder Resulting From Differences in Blood Cell Composition
Authors: Jangjoo Maryam , Goodman Sarah J. , Choufani Sanaa , Trost Brett , Scherer Stephen W. , Kelley Elizabeth , Ayub Muhammad , Nicolson Rob , Georgiades Stelios , Crosbie Jennifer , Schachar Russell , Anagnostou Evdokia , Grunebaum Eyal , Weksberg Rosanna
Published: April 2021

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that often involves impaired cognition, communication difficulties and restrictive, repetitive behaviors. ASD is extremely heterogeneous both clinically and etiologically, which represents one of the greatest challenges in studying the molecular underpinnings of ASD. While hundreds of ASD-associated genes have been identified that confer varying degrees of risk, no single gene variant accounts for >1% of ASD cases. Notably, a large number of ASD-risk genes function as epigenetic regulators, indicating potential epigenetic dysregulation in ASD. As such, we compared genome-wide DNA methylation (DNAm) in the blood of children with ASD (n = 265) to samples from age- and sex-matched, neurotypical controls (n = 122) using the Illumina Infinium HumanMethylation450 arrays.

Results: While DNAm patterns did not distinctly separate ASD cases from controls, our analysis identified an epigenetically unique subset of ASD cases (n = 32); these individuals exhibited significant differential methylation from both controls than the remaining ASD cases. The CpG sites at which this subset was differentially methylated mapped to known ASD risk genes that encode proteins of the nervous and immune systems. Moreover, the observed DNAm differences were attributable to altered blood cell composition, i.e., lower granulocyte proportion and granulocyte-to-lymphocyte ratio in the ASD subset, as compared to the remaining ASD cases and controls. This ASD subset did not differ from the rest of the ASD cases in the frequency or type of high-risk genomic variants.

Conclusion: Within our ASD cohort, we identified a subset of individuals that exhibit differential methylation from both controls and the remaining ASD group tightly associated with shifts in immune cell type proportions. This is an important feature that should be assessed in all epigenetic studies of blood cells in ASD. This finding also builds on past reports of changes in the immune systems of children with ASD, supporting the potential role of altered immunological mechanisms in the complex pathophysiology of ASD. The discovery of significant molecular and immunological features in subgroups of individuals with ASD may allow clinicians to better stratify patients, facilitating personalized interventions and improved outcomes.
Does Cathodal vs. Sham Transcranial Direct Current Stimulation Over Contralesional Motor Cortex Enhance Upper Limb Motor Recovery Post-stroke? A Systematic Review and Meta-analysis
Authors: Chen Joyce L. , Schipani Ashley , Schuch Clarissa Pedrini , Lam Henry , Swardfager Walter , Thiel Alexander , Edwards Jodi D.
Published: April 2021

Background: During recovery from stroke, the contralesional motor cortex (M1) may undergo maladaptive changes that contribute to impaired interhemispheric inhibition (IHI). Transcranial direct current stimulation (tDCS) with the cathode over contralesional M1 may inhibit this maladaptive plasticity, normalize IHI, and enhance motor recovery.

Objective: The objective of this systematic review and meta-analysis was to evaluate available evidence to determine whether cathodal tDCS on contralesional M1 enhances motor re-learning or recovery post-stroke more than sham tDCS.

Methods: We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials for participants with stroke (>1 week post-onset) with motor impairment and who received cathodal or sham tDCS to contralesional M1 for one or more sessions. The outcomes included a change in any clinically validated assessment of physical function, activity, or participation, or a change in a movement performance variable (e.g., time, accuracy). A meta-analysis was performed by pooling five randomized controlled trials (RCTs) and comparing the change in Fugl–Meyer upper extremity scores between cathodal and sham tDCS groups.

Results: Eleven studies met the inclusion criteria. Qualitatively, four out of five cross-over design studies and three out of six RCTs reported a significant effect of cathodal vs. sham tDCS. In the quantitative synthesis, cathodal tDCS (n = 65) did not significantly reduce motor impairment compared to sham tDCS (n = 67; standardized mean difference = 0.33, z = 1.79, p = 0.07) with a little observed heterogeneity (I2 = 5%).

Conclusions: The effects of cathodal tDCS to contralesional M1 on motor recovery are small and consistent. There may be sub-populations that may respond to this approach; however, further research with larger cohorts is required.
Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions
Authors: Carrarini Claudia , Russo Mirella , Dono Fedele , Barbone Filomena , Rispoli Marianna G. , Ferri Laura , Di Pietro Martina , Digiovanni Anna , Ajdinaj Paola , Speranza Rino , Granzotto Alberto , Frazzini Valerio , Thomas Astrid , Pilotto Andrea , Padovani Alessandro , Onofrj Marco , Sensi Stefano L. , Bonanni Laura
Published: April 2021

Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.
Relationship Between Glycosylated Hemoglobin and Short-Term Mortality of Spontaneous Intracerebral Hemorrhage
Authors: Lu Ping , Cui Lingyun , Wang Yu , Kang Kaijiang , Gu Hongqiu , Li Zixiao , Liu Liping , Wang Yilong , Zhao Xingquan
Published: April 2021

Background: The relationship between glycosylated hemoglobin (HbA1c) and prognosis of spontaneous intracerebral hemorrhage (SICH) patients has not been fully elucidated. This study aimed to reveal the relationship between HbA1c levels and short-term mortality after patient admission with SICH.

Methods: It was a large-scale, multicenter, cross-sectional study. From August 1, 2015, to July 31, 2019, a total of 41910 SICH patients were included in the study from the Chinese Stroke Center Alliance (CSCA) program. Finally, we comprehensively analyzed the data from 21,116 patients with SICH. HbA1c was categorized into four groups by quartile. Univariate and multivariate logistic regression analyses were used to assess the association between HbA1c levels and short-term mortality in SICH patients.

Results: The average age of the 21,116 patients was 62.8 ± 13.2 years; 13,052 (61.8%) of them were male, and 507 (2.4%) of them died. Compared to the higher three quartiles of HbA1c, the lowest quartile (≤5.10%) had higher short-term mortality. In subgroup analysis with or without diabetes mellitus (DM) patients, the mortality of the Q3 group at 5.60–6.10% was significantly lower than that of the Q1 group at ≤5.10%. After adjustment for potential influencing factors, the ROC curve of HbA1c can better predict the short-term mortality of patients with SICH (AUC = 0.6286 P < 0.001).

Conclusions: Therefore, we concluded that low or extremely low HbA1c levels (≤5.10%) after stroke were associated with higher short-term mortality in SICH patients, with or without DM.
Distributed Functional Connectome of White Matter in Patients With Functional Dyspepsia
Authors: Xu Qiang , Weng Yifei , Liu Chang , Qiu Lianli , Yang Yulin , Zhou Yifei , Wang Fangyu , Lu Guangming , Zhang Long Jiang , Qi Rongfeng
Published: April 2021

Purpose: We aimed to find out the distributed functional connectome of white matter in patients with functional dyspepsia (FD).

Methods: 20 patients with FD and 24 age- and gender-matched healthy controls were included into the study. The functional connectome of white matter and graph theory were used to these participants. Two-sample t-test was used for the detection the abnormal graph properties in FD. Pearson correlation was used for the relationship between properties and the clinical and neuropshychological information.

Results: Patients with FD and healthy controls showed small-world properties in functional connectome of white matter. Compared with healthy controls, the FD group showed decreased global properties (Cp, S, Eglobal, and Elocal). Four pairs of fiber bundles that are connected to the frontal lobe, insula, and thalamus were affected in the FD group. Duration and Pittsburgh Sleep Quality Index positively correlated with the betweenness centrality of white matter regions of interest.

Conclusion: FD patients turned to a non-optimized functional organization of WM brain network. Frontal lobe, insula, and thalamus were key regions in brain information exchange of FD. It provided some novel imaging evidences for the mechanism of FD.