scholarly journals Influenza A Hemagglutinin Passage Bias Sites and Host Specificity Mutations

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 958
Author(s):  
Lee ◽  
Chang ◽  
Russell ◽  
Lipsitch ◽  
Maurer-Stroh
Keyword(s):  
Host Specificity ◽  
Influenza A ◽  
Animal Studies ◽  
Large Scale ◽  
Structural Changes ◽  
Cell Types ◽  
Receptor Binding Site ◽  
Genetic Changes ◽  
Safety Requirements ◽  
Influenza Hemagglutinin

Animal studies aimed at understanding influenza virus mutations that change host specificity to adapt to replication in mammalian hosts are necessarily limited in sample numbers due to high cost and safety requirements. As a safe, higher-throughput alternative, we explore the possibility of using readily available passage bias data obtained mostly from seasonal H1 and H3 influenza strains that were differentially grown in mammalian (MDCK) and avian cells (eggs). Using a statistical approach over 80,000 influenza hemagglutinin sequences with passage information, we found that passage bias sites are most commonly found in three regions: (i) the globular head domain around the receptor binding site, (ii) the region that undergoes pH-dependent structural changes and (iii) the unstructured N-terminal region harbouring the signal peptide. Passage bias sites were consistent among different passage cell types as well as between influenza A subtypes. We also find epistatic interactions of site pairs supporting the notion of host-specific dependency of mutations on virus genomic background. The sites identified from our large-scale sequence analysis substantially overlap with known host adaptation sites in the WHO H5N1 genetic changes inventory suggesting information from passage bias can provide candidate sites for host specificity changes to aid in risk assessment for emerging strains.

scholarly journals Type 1 Diabetic Neuropathy and C-peptide

2004 ◽  
Vol 5 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Anders A. F. Sima ◽  
Weixian Zhang ◽  
George Grunberger
Keyword(s):  
Clinical Trials ◽  
Animal Studies ◽  
Large Scale ◽  
Structural Changes ◽  
Diabetic Complication ◽  
Diabetic Patients ◽  
C Peptide ◽  
Beneficial Effects ◽  
Regulatory Effects

The most common microvascular diabetic complication, diabetic peripheral polyneuropathy (DPN), affects type 1 diabetic patients more often and more severely. In recent decades, it has become increasingly clear that perpetuating pathogenetic mechanisms, molecular, functional, and structural changes and ultimately the clinical expression of DPN differ between the two major types of diabetes. Impaired insulin/C-peptide action has emerged as a crucial factor to account for the disproportionate burden affecting type 1 patients. C-peptide was long believed to be biologically inactive. However, it has now been shown to have a number of insulin-like glucoseindependent effects. Preclinical studies have demonstrated dose-dependent effects onNa+,K+-ATPase activity, endothelial nitric oxide synthase (eNOS), and endoneurial blood flow. Furthermore, it has regulatory effects on neurotrophic factors and molecules pivotal to the integrity of the nodal and paranodal apparatus and modulatory effects on apoptotic phenomena affecting the diabetic nervous system. In animal studies, C-peptide improves nerve conduction abnormalities, prevents nodal degenerative changes, characteristic of type 1 DPN, promotes nerve fiber regeneration, and prevents apoptosis of central and peripheral nerve cell constituents. Limited clinical trials have confirmed the beneficial effects of C-peptide on autonomic and somatic nerve function in patients with type 1 DPN. Therefore, evidence accumulates that replacement of C-peptide in type 1 diabetes prevents and even improves DPN. Large-scale food and drug administration (FDA)-approved clinical trials are necessary to make this natural substance available to the globally increasing type 1 diabetic population.

scholarly journals Influenza Hemagglutinin Nanoparticle Vaccine Elicits Broadly Neutralizing Antibodies against Structurally Distinct Domains of H3N2 HA

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 99 ◽  
Author(s):  
Alyse D. Portnoff ◽  
Nita Patel ◽  
Michael J. Massare ◽  
Haixia Zhou ◽  
Jing-Hui Tian ◽  
...  
Keyword(s):  
Older Adults ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Phase 1 ◽  
Protein Docking ◽  
Receptor Binding Site ◽  
Influenza Hemagglutinin ◽  
Transmission Electron ◽  
Antibody Competition

Influenza vaccine effectiveness varies annually due to the fast evolving seasonal influenza A(H3N2) strain and egg-derived mutations—both of which can cause a mismatch between the vaccine and circulating strains. To address these limitations, we have developed a hemagglutinin (HA)-based protein-detergent nanoparticle influenza vaccine (NIV) with a saponin-based Matrix-M™ adjuvant. In a phase 1 clinical trial of older adults, the vaccine demonstrated broadly cross-reactive A(H3N2) HA antibody responses. Two broadly neutralizing monoclonal antibodies derived from NIV-immunized mice were characterized by transmission electron microscopy (TEM), antibody competition assays, fluorescence-activated cell sorting (FACS) analysis, and protein–protein docking. These antibodies recognize two conserved regions of the head domain, namely the receptor binding site and the vestigial esterase subdomain, thus demonstrating the potential for an HA subunit vaccine to elicit antibodies targeting structurally and antigenically distinct but conserved sites. Antibody competition studies with sera from the phase 1 trial in older adults confirmed that humans also make antibodies to these two head domains and against the highly conserved stem domain. This data supports the potential of an adjuvanted recombinant HA nanoparticle vaccine to induce broadly protective immunity and improved vaccine efficacy.

scholarly journals A cross-neutralizing antibody between HIV-1 and influenza virus

2021 ◽  
Vol 17 (3) ◽  
pp. e1009407
Author(s):  
Chang-Chun D. Lee ◽  
Yasunori Watanabe ◽  
Nicholas C. Wu ◽  
Julianna Han ◽  
Sonu Kumar ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Neutralizing Antibody ◽  
Influenza Viruses ◽  
Receptor Binding Site ◽  
Influenza Hemagglutinin ◽  
Glycosylation Sites ◽  
Antigenic Evolution ◽  
Hiv 1 ◽  
Shed Light

Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.

Neuronal mRNA Translation in Addiction

2018 ◽  
Author(s):  
Emma Puighermanal ◽  
Emmanuel Valjent
Keyword(s):  
Structural Changes ◽  
Drugs Of Abuse ◽  
Mrna Translation ◽  
Cell Types ◽  
Behavioral Changes ◽  
Translational Machinery ◽  
Addictive Drugs ◽  
Specific Mrnas ◽  
Cell Type Specific ◽  
Future Work

Addictive drugs trigger persistent synaptic and structural changes in the neuronal reward circuits that are thought to underlie the development of drug-adaptive behavior. While transcriptional and epigenetic modifications are known to contribute to these circuit changes, accumulating evidence indicates that altered mRNA translation is also a key molecular mechanism. This chapter reviews recent studies demonstrating how addictive drugs alter protein synthesis and/or the translational machinery and how this leads to neuronal circuit remodeling and behavioral changes. Future work will determine precisely which neuronal circuits and cell types participate in these changes. The chapter summarizes current methodologies for identifying cell type-specific mRNAs whose translation is affected by drugs of abuse and gives recent examples of the mechanistic insights into addiction they provide.

scholarly journals Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field

2021 ◽  
Author(s):  
Miguel Dasilva ◽  
Christian Brandt ◽  
Marc Alwin Gieselmann ◽  
Claudia Distler ◽  
Alexander Thiele
Keyword(s):  
Attentional Control ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Cell Types ◽  
Receptor Activation ◽  
Frontal Eye Field ◽  
Control Signals ◽  
Cognitive Operations ◽  
Eye Field ◽  
Large Scale Networks

Abstract Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

scholarly journals Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Que ◽  
David Lukacsovich ◽  
Wenshu Luo ◽  
Csaba Földy
Keyword(s):  
Large Scale ◽  
Cell Types ◽  
Rna Seq ◽  
Neuronal Identity ◽  
Parvalbumin Interneurons ◽  
Different Types ◽  
Parvalbumin Interneuron ◽  
Cam Profile ◽  
Developmental Domains

AbstractThe diversity reflected by >100 different neural cell types fundamentally contributes to brain function and a central idea is that neuronal identity can be inferred from genetic information. Recent large-scale transcriptomic assays seem to confirm this hypothesis, but a lack of morphological information has limited the identification of several known cell types. In this study, we used single-cell RNA-seq in morphologically identified parvalbumin interneurons (PV-INs), and studied their transcriptomic states in the morphological, physiological, and developmental domains. Overall, we find high transcriptomic similarity among PV-INs, with few genes showing divergent expression between morphologically different types. Furthermore, PV-INs show a uniform synaptic cell adhesion molecule (CAM) profile, suggesting that CAM expression in mature PV cells does not reflect wiring specificity after development. Together, our results suggest that while PV-INs differ in anatomy and in vivo activity, their continuous transcriptomic and homogenous biophysical landscapes are not predictive of these distinct identities.

scholarly journals Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 149
Author(s):  
Sreekumar Othumpangat ◽  
William G. Lindsley ◽  
Donald H. Beezhold ◽  
Michael L. Kashon ◽  
Carmen N. Burrell ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Influenza A ◽  
Influenza Infection ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Differentially Expressed ◽  
Influenza B ◽  
Airway Epithelial ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Approach

MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression.

scholarly journals Efficacy and Underlying Mechanism of Acupuncture in the Treatment of Posttraumatic Stress Disorder: A Systematic Review of Animal Studies

2021 ◽  
Vol 10 (8) ◽  
pp. 1575
Author(s):  
Chan-Young Kwon ◽  
Boram Lee ◽  
Sang-Ho Kim
Keyword(s):  
Posttraumatic Stress Disorder ◽  
Posttraumatic Stress ◽  
Stress Responses ◽  
Methodological Quality ◽  
Animal Studies ◽  
Large Scale ◽  
Stress Disorder ◽  
Spatial Learning And Memory ◽  
Expectancy Effects ◽  
Therapeutic Mechanisms

Acupuncture is a nonpharmacological intervention that can be useful in the clinical management of posttraumatic stress disorder (PTSD), especially in situations with a lack of medical resources, including large-scale PTSD events such as disasters. Some clinical studies have reported the clinical effect of acupuncture in improving PTSD symptoms, but the underlying therapeutic mechanism has yet to be explored. Therefore, this review summarized the underlying therapeutic mechanisms of acupuncture in animal PTSD models. A comprehensive search was conducted in 14 electronic databases, and two independent researchers performed study selection, data extraction, and the methodological quality assessment. Twenty-four relevant studies were included in this review and summarized according to the proposed main mechanisms. In behavioral evaluation, acupuncture, including manual acupuncture and electro-acupuncture, reduced anxiety and fear responses and weakened fear conditioning, improved sleep architecture, reduced depressive symptoms, and alleviated disturbance of spatial learning and memory of PTSD animal models. The therapeutic mechanisms of acupuncture proposed in the included studies could be classified into two categories: (1) regulation of stress responses in the neuroendocrine system and (2) promotion of neuroprotection, neurogenesis, and synaptic plasticity in several brain areas. However, the methodological quality of the included animal studies was not high enough to produce robust evidence. In addition, mechanistic studies on specific aspects of acupuncture that may affect PTSD, including expectancy effects, in human PTSD subjects are also needed.

scholarly journals Infection, dissemination, and transmission efficiencies of Zika virus in Aedes aegypti after serial passage in mosquito or mammalian cell lines or alternating passage in both cell types

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lourdes G. Talavera-Aguilar ◽  
Reyes A. Murrieta ◽  
Sungmin Kiem ◽  
Rosa C. Cetina-Trejo ◽  
Carlos M. Baak-Baak ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Cell Lines ◽  
Zika Virus ◽  
Cell Types ◽  
Mosquito Cell ◽  
Cell Passage ◽  
Genetic Changes ◽  
Synonymous Substitutions ◽  
Vertebrate Cell

Abstract Background Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) with an urban transmission cycle that primarily involves humans and Aedes aegypti. Evidence suggests that the evolution of some arboviruses is constrained by their dependency on alternating between disparate (vertebrate and invertebrate) hosts. The goals of this study are to compare the genetic changes that occur in ZIKV after serial passaging in mosquito or vertebrate cell lines or alternate passaging in both cell types and to compare the replication, dissemination, and transmission efficiencies of the cell culture-derived viruses in Ae. aegypti. Methods An isolate of ZIKV originally acquired from a febrile patient in Yucatan, Mexico, was serially passaged six times in African green monkey kidney (Vero) cells or Aedes albopictus (C6/36) cells or both cell types by alternating passage. A colony of Ae. aegypti from Yucatan was established, and mosquitoes were challenged with the cell-adapted viruses. Midguts, Malpighian tubules, ovaries, salivary glands, wings/legs and saliva were collected at various times after challenge and tested for evidence of virus infection. Results Genome sequencing revealed the presence of two non-synonymous substitutions in the premembrane and NS1 regions of the mosquito cell-adapted virus and two non-synonymous substitutions in the capsid and NS2A regions of both the vertebrate cell-adapted and alternate-passaged viruses. Additional genetic changes were identified by intrahost variant frequency analysis. Virus maintained by continuous C6/36 cell passage was significantly more infectious in Ae. aegypti than viruses maintained by alternating passage and consecutive Vero cell passage. Conclusions Mosquito cell-adapted ZIKV displayed greater in vivo fitness in Ae. aegypti compared to the other viruses, indicating that obligate cycling between disparate hosts carries a fitness cost. These data increase our understanding of the factors that drive ZIKV adaptation and evolution and underscore the important need to consider the in vivo passage histories of flaviviruses to be evaluated in vector competence studies. Graphic abstract "Image missing"

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