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1.
Front Neurosci ; 18: 1279708, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38660225

RESUMEN

A neuromorphic system is composed of hardware-based artificial neurons and synaptic devices, designed to improve the efficiency of neural computations inspired by energy-efficient and parallel operations of the biological nervous system. A synaptic device-based array can compute vector-matrix multiplication (VMM) with given input voltage signals, as a non-volatile memory device stores the weight information of the neural network in the form of conductance or capacitance. However, unlike software-based neural networks, the neuromorphic system unavoidably exhibits non-ideal characteristics that can have an adverse impact on overall system performance. In this study, the characteristics required for synaptic devices and their importance are discussed, depending on the targeted application. We categorize synaptic devices into two types: conductance-based and capacitance-based, and thoroughly explore the operations and characteristics of each device. The array structure according to the device structure and the VMM operation mechanism of each structure are analyzed, including recent advances in array-level implementation of synaptic devices. Furthermore, we reviewed studies to minimize the effect of hardware non-idealities, which degrades the performance of hardware neural networks. These studies introduce techniques in hardware and signal engineering, as well as software-hardware co-optimization, to address these non-idealities through compensation approaches.

2.
Emerg Microbes Infect ; 13(1): 2339949, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38572657

RESUMEN

Understanding the mammalian pathogenesis and interspecies transmission of HPAI H5N8 virus hinges on mapping its adaptive markers. We used deep sequencing to track these markers over five passages in murine lung tissue. Subsequently, we evaluated the growth, selection, and RNA load of eight recombinant viruses with mammalian adaptive markers. By leveraging an integrated non-linear regression model, we quantitatively determined the influence of these markers on growth, adaptation, and RNA expression in mammalian hosts. Furthermore, our findings revealed that the interplay of these markers can lead to synergistic, additive, or antagonistic effects when combined. The elucidation distance method then transformed these results into distinct values, facilitating the derivation of a risk score for each marker. In vivo tests affirmed the accuracy of scores. As more mutations were incorporated, the overall risk score of virus heightened, and the optimal interplay between markers became essential for risk augmentation. Our study provides a robust model to assess risk from adaptive markers of HPAI H5N8, guiding strategies against future influenza threats.


Asunto(s)
Subtipo H5N8 del Virus de la Influenza A , Gripe Aviar , Gripe Humana , Animales , Humanos , Ratones , Subtipo H5N8 del Virus de la Influenza A/genética , Pulmón , ARN , Mamíferos
3.
Emerg Microbes Infect ; 13(1): 2332652, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38517705

RESUMEN

A diverse population of avian influenza A viruses (AIVs) are maintained in wild birds and ducks yet the zoonotic potential of AIVs in these environmental reservoirs and the host-virus interactions involved in mammalian infection are not well understood. In studies of a group of subtype H1N1 AIVs isolated from migratory wild birds during surveillance in North America, we previously identified eight amino acids in the polymerase genes PB2 and PB1 that were important for the transmissibility of these AIVs in a ferret model of human influenza virus transmission. In this current study we found that PB2 containing amino acids associated with transmissibility at 67, 152, 199, 508, and 649 and PB1 at 298, 642, and 667 were associated with more rapid viral replication kinetics, greater infectivity, more active polymerase complexes and greater kinetics of viral genome replication and transcription. Pathogenicity in the mouse model was also impacted, evident as greater weight loss and lung pathology associated with greater inflammatory lung cytokine expression. Further, these AIVs all contained the avian-type amino acids of PB2-E627, D701, G590, Q591 and T271. Therefore, our study provides novel insights into the role of the AIV polymerase complex in the zoonotic transmission of AIVs in mammals.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Aviar , Ratones , Animales , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Aminoácidos/genética , Interacciones Microbiota-Huesped , Proteínas Virales/genética , Proteínas Virales/metabolismo , Hurones , Virus de la Influenza A/metabolismo , Aves , Nucleotidiltransferasas , Replicación Viral/genética , Filogenia
4.
Adv Healthc Mater ; : e2302803, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38329411

RESUMEN

The decreasing efficacy of antiviral drugs due to viral mutations highlights the challenge of developing a single agent targeting multiple strains. Using host cell viral receptors as competitive inhibitors is promising, but their low potency and membrane-bound nature have limited this strategy. In this study, the authors show that angiotensin-converting enzyme 2 (ACE2) in a planar membrane patch can effectively neutralize all tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that emerged during the COVID-19 pandemic. The ACE2-incorporated membrane patch implemented using nanodiscs replicated the spike-mediated membrane fusion process outside the host cell, resulting in virus lysis, extracellular RNA release, and potent antiviral activity. While neutralizing antibodies became ineffective as the SARS-CoV-2 evolved to better penetrate host cells the ACE2-incorporated nanodiscs became more potent, highlighting the advantages of using receptor-incorporated nanodiscs for antiviral purposes. ACE2-incorporated immunodisc, an Fc fusion nanodisc developed in this study, completely protected humanized mice infected with SARS-CoV-2 after prolonged retention in the airways. This study demonstrates that the incorporation of viral receptors into immunodisc transforms the entry gate into a potent virucide for all current and future variants, a concept that can be extended to different viruses.

5.
ACS Appl Mater Interfaces ; 16(1): 1054-1065, 2024 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-38163259

RESUMEN

We propose a hardware-friendly architecture of a convolutional neural network using a 32 × 32 memristor crossbar array having an overshoot suppression layer. The gradual switching characteristics in both set and reset operations enable the implementation of a 3-bit multilevel operation in a whole array that can be utilized as 16 kernels. Moreover, a binary activation function mapped to the read voltage and ground is introduced to evaluate the result of training with a boundary of 0.5 and its estimated gradient. Additionally, we adopt a fixed kernel method, where inputs are sequentially applied to a crossbar array with a differential memristor pair scheme, reducing unused cell waste. The binary activation has robust characteristics against device state variations, and a neuron circuit is experimentally demonstrated on a customized breadboard. Thanks to the analogue switching characteristics of the memristor device, the accurate vector-matrix multiplication (VMM) operations can be experimentally demonstrated by combining sequential inputs and the weights obtained through tuning operations in the crossbar array. In addition, the feature images extracted by VMM during the hardware inference operations on 100 test samples are classified, and the classification performance by off-chip training is compared with the software results. Finally, inference results depending on the tolerance are statistically verified through several tuning cycles.

6.
Emerg Microbes Infect ; 13(1): 2302854, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38189114

RESUMEN

During the 2021/2022 winter season, we isolated highly pathogenic avian influenza (HPAI) H5N1 viruses harbouring an amino acid substitution from Asparagine(N) to Aspartic acid (D) at residue 193 of the hemagglutinin (HA) receptor binding domain (RBD) from migratory birds in South Korea. Herein, we investigated the characteristics of the N193D HA-RBD substitution in the A/CommonTeal/Korea/W811/2021[CT/W811] virus by using recombinant viruses engineered via reverse genetics (RG). A receptor affinity assay revealed that the N193D HA-RBD substitution in CT/W811 increases α2,6 sialic acid receptor binding affinity. The rCT/W811-HA193N virus caused rapid lethality with high virus titres in chickens compared with the rCT/W811-HA193D virus, while the rCT/W811-HA193D virus exhibited enhanced virulence in mammalian hosts with multiple tissue tropism. Surprisingly, a ferret-to-ferret transmission assay revealed that rCT/W811-HA193D virus replicates well in the respiratory tract, at a rate about 10 times higher than that of rCT/W811-HA193N, and all rCT/W811-HA193D direct contact ferrets were seroconverted at 10 days post-contact. Further, competition transmission assay of the two viruses revealed that rCT/W811-HA193D has enhanced growth kinetics compared with the rCT/W811-HA193N, eventually becoming the dominant strain in nasal turbinates. Further, rCT/W811-HA193D exhibits high infectivity in primary human bronchial epithelial (HBE) cells, suggesting the potential for human infection. Taken together, the HA-193D containing HPAI H5N1 virus from migratory birds showed enhanced virulence in mammalian hosts, but not in avian hosts, with multi-organ replication and ferret-to-ferret transmission. Thus, this suggests that HA-193D change increases the probability of HPAI H5N1 infection and transmission in humans.


Asunto(s)
Subtipo H5N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Aviar , Animales , Humanos , Subtipo H5N1 del Virus de la Influenza A/genética , Hemaglutininas , Virulencia , Hurones , Pollos
7.
Pharmaceutics ; 15(11)2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-38004519

RESUMEN

Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and FABP4, and lipogenic markers such as pACC were significantly reduced in epididymal white adipose tissues (eWATs). Conversely, increased expression of lipolytic markers such as ATGL and pHSL and AMPK phosphorylation were noted. Treating obese mice with selegiline significantly increased expression levels of UCP1 and promoted eWAT browning, indicating increased energy expenditure. These results suggest that selegiline, by inhibiting MAO-B activity, is a potential anti-obesity treatment.

8.
ACS Appl Mater Interfaces ; 15(40): 47229-47237, 2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37782228

RESUMEN

Neuromorphic computing, an innovative technology inspired by the human brain, has attracted increasing attention as a promising technology for the development of artificial intelligence systems. This study proposes synaptic transistors with a Li1-xAlxTi2-x(PO4)3 (LATP) layer to analyze the conductance modulation linearity, which is essential for weight mapping and updating during on-chip learning processes. The high ionic conductivity of the LATP electrolyte provides a large hysteresis window and enables linear weight update in synaptic devices. The results demonstrate that optimizing the LATP layer thickness improves the conductance modulation and linearity of synaptic transistors during potentiation and degradation. A 20 nm-thick LATP layer results in the most nonlinear depression (αd = -6.59), whereas a 100 nm-thick LATP layer results in the smallest nonlinearity (αd = -2.22). Additionally, a device with the optimal 100 nm-thick LATP layer exhibits the highest average recognition accuracy of 94.8% and the smallest fluctuation, indicating that the linearity characteristics of a device play a crucial role in weight update during learning and can significantly affect the recognition accuracy.

9.
Adv Sci (Weinh) ; 10(32): e2303817, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37752771

RESUMEN

The progress of artificial intelligence and the development of large-scale neural networks have significantly increased computational costs and energy consumption. To address these challenges, researchers are exploring low-power neural network implementation approaches and neuromorphic computing systems are being highlighted as potential candidates. Specifically, the development of high-density and reliable synaptic devices, which are the key elements of neuromorphic systems, is of particular interest. In this study, an 8 × 16 memcapacitor crossbar array that combines the technological maturity of flash cells with the advantages of NAND flash array structure is presented. The analog properties of the array with high reliability are experimentally demonstrated, and vector-matrix multiplication with extremely low error is successfully performed. Additionally, with the capability of weight fine-tuning characteristics, a spiking neural network for CIFAR-10 classification via off-chip learning at the wafer level is implemented. These experimental results demonstrate a high level of accuracy of 92.11%, with less than a 1.13% difference compared to software-based neural networks (93.24%).

10.
Cell Rep ; 42(9): 113077, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37676771

RESUMEN

With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmissibility. Specifically, SARS-CoV-2 variants containing the NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C and high transmissibility. Molecular dynamics simulations and microscale thermophoresis demonstrate that the NSP12 P323L and P323L/G671S mutations stabilize the NSP12-NSP7-NSP8 complex through hydrophobic effects, leading to increased viral RdRp activity. Furthermore, competitive transmissibility assay reveals that reverse genetic (RG)-P323L or RG-P323L/G671S NSP12 outcompetes RG-WT (wild-type) NSP12 for replication in the upper respiratory tract, allowing markedly rapid transmissibility. This suggests that NSP12 P323L or P323L/G671S mutation of SARS-CoV-2 is associated with increased RdRp complex stability and enzymatic activity, promoting efficient transmissibility.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Humanos , SARS-CoV-2/genética , Hurones , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/química , Mutación/genética , Replicación Viral/genética
11.
PLoS One ; 18(9): e0291537, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37708114

RESUMEN

In a short time, several types of injectable and oral therapeutics have been developed and used to effectively manage patients with coronavirus disease 2019 (COVID-19). BEN815 is an improved mixture of three extracts (Psidium guajava, Camellia sinensis, and Rosa hybrida) recognized by the Ministry of Food and Drug Safety of Korea as a health food ingredient that alleviates allergic rhinitis. The current animal efficacy study was performed to assess its probability of improving COVID-19 symptoms. BEN815 treatment significantly increased the survival of K18-hACE2 transgenic mice and reduced viral titers in the lungs at 5 days post infection (DPI). Furthermore, the lungs of the treated mice showed mild tissue damage at 5 DPI and nearly complete recovery from COVID-19 at 14 DPI. BEN815 appears to be an effective and minimally toxic anti-SARS-CoV-2 agent in mice and has potential for clinical applications.


Asunto(s)
COVID-19 , Camellia sinensis , Animales , Ratones , Animales de Laboratorio , SARS-CoV-2 , Ratones Transgénicos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico
12.
Antiviral Res ; 216: 105669, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37437781

RESUMEN

Even though the World Health Organization announced the end of the COVID-19 pandemic as a global public health emergency on May 5, 2023, SARS-CoV-2 continues to pose a significant health threat worldwide, resulting in substantial numbers of infections and fatalities. This study investigated the antiviral potential of Z-FA-FMK (FMK), a novel host cathepsin L protease inhibitor, against SARS-CoV-2 infection using both in vitro and in vivo models. In vitro assessments of FMK against a diverse set of SARS-CoV-2 strains, including the Wuhan-like strain and nine variants, demonstrated potent inhibition with EC50 values ranging from 0.55 to 2.41 µM, showcasing similar or superior efficacy compared to FDA-approved antivirals nirmatrelvir (NTV) and molnupiravir (MPV). In vivo experiments using orally administered FMK (25 mg/kg) in SARS-CoV-2-infected K18 hACE2 transgenic mice revealed improved survival rates of 60% and accelerated recovery compared to NTV and MPV treatments. Additionally, FMK displayed a longer half-life (17.26 ± 8.89 h) than NTV and MPV in the mouse model. Due to its host-targeting mechanism, FMK offers potential advantages such as reduced drug resistance and broad-spectrum antiviral activity against multiple coronaviruses. These findings indicate that FMK may serve as a promising candidate for further clinical evaluation in the fight against SARS-CoV-2.


Asunto(s)
Antiinfecciosos , COVID-19 , Animales , Ratones , Humanos , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , SARS-CoV-2 , Catepsina L , Pandemias , Antivirales/farmacología , Antivirales/uso terapéutico , Inhibidores Enzimáticos
13.
Int J Mol Sci ; 24(11)2023 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-37298530

RESUMEN

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.


Asunto(s)
COVID-19 , SARS-CoV-2 , Ratas , Humanos , Animales , Ratones , Antivirales/farmacología , Antivirales/uso terapéutico , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/uso terapéutico , Pandemias , Modelos Animales de Enfermedad , Ratas Sprague-Dawley
14.
Microbiol Spectr ; : e0338522, 2023 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-36877070

RESUMEN

The appearance of SARS-CoV-2 variants in late 2020 raised alarming global public health concerns. Despite continued scientific progress, the genetic profiles of these variants bring changes in viral properties that threaten vaccine efficacy. Thus, it is critically important to investigate the biologic profiles and significance of these evolving variants. In this study, we demonstrate the application of circular polymerase extension cloning (CPEC) to the generation of full-length clones of SARS-CoV-2. We report that, combined with a specific primer design scheme, this yields a simpler, uncomplicated, and versatile approach for engineering SARS-CoV-2 variants with high viral recovery efficiency. This new strategy for genomic engineering of SARS-CoV-2 variants was implemented and evaluated for its efficiency in generating point mutations (K417N, L452R, E484K, N501Y, D614G, P681H, P681R, Δ69-70, Δ157-158, E484K+N501Y, and Ins-38F) and multiple mutations (N501Y/D614G and E484K/N501Y/D614G), as well as a large truncation (ΔORF7A) and insertion (GFP). The application of CPEC to mutagenesis also allows the inclusion of a confirmatory step prior to assembly and transfection. This method could be of value in the molecular characterization of emerging SARS-CoV-2 variants as well as the development and testing of vaccines, therapeutic antibodies, and antivirals. IMPORTANCE Since the first emergence of the SARS-CoV-2 variant in late 2020, novel variants have been continuously introduced to the human population, causing severe public health threats. In general, because these variants acquire new genetic mutation/s, it is critical to analyze the biological function of viruses that such mutations can confer. Therefore, we devised a method that can construct SARS-CoV-2 infectious clones and their variants rapidly and efficiently. The method was developed based on a PCR-based circular polymerase extension cloning (CPEC) combined with a specific primer design scheme. The efficiency of the newly designed method was evaluated by generating SARS-CoV-2 variants with single point mutations, multiple point mutations, and a large truncation and insertion. This method could be of value for the molecular characterization of emerging SARS-CoV-2 variants and the development and testing of vaccines and antiviral agents.

15.
Microbiol Spectr ; 11(1): e0316722, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36651758

RESUMEN

Enteroviruses (EVs) have been associated with several human diseases. Due to their continuous emergence and divergence, EV species have generated more than 100 types and recombinant strains, increasing the public health threat caused by them. Hence, an efficient and universal cloning system for reverse genetics (RG) of highly divergent viruses is needed to understand the molecular mechanisms of viral pathology and evolution. In this study, we generated a versatile human EV whole-genome cDNA template by enhancing the template-switching method and designing universal primers capable of simultaneous cloning and rapid amplification of cDNA ends (RACE)-PCR of EVs. Moreover, by devising strategies to overcome limitations of previous cloning methods, we simplified significant cloning steps to be completed within a day. Of note, we successfully verified our efficient universal cloning system enabling RG of a broad range of human EVs, including EV-A (EV-A71), EV-B (CV-B5, ECHO6, and ECHO30), EV-C (CV-A24), and EV-D (EV-D68), with viral titers and phenotypes comparable to those of their wild types. This rapid and straightforward universal EV cloning strategy will help us elucidate molecular characteristics, pathogenesis, and applications of a broad range of EV serotypes for further development of genetic vaccines and delivery tools using various replication systems. IMPORTANCE Due to the broad spread, incidence, and genetic divergence of enteroviruses (EVs), it has been challenging to deal with this virus that causes severe human diseases, including aseptic meningitis, myocarditis, encephalitis, and poliomyelitis. Therefore, an efficient and universal cloning system for the reverse genetics of highly divergent EVs contributes to an understanding of the viral pathology and molecular mechanisms of evolution. We have simplified the important cloning steps, hereby enhancing the template-switching method and designing universal primers, which enable the important cloning steps to be completed in a day. We have also successfully demonstrated recovery of a broad range of human EVs, including EV-A to -D types, using this advanced universal cloning system. This rapid and robust universal EV cloning strategy will aid in elucidating the molecular characteristics, pathogenesis, and applications of a wide range of EVs for further development of genetic vaccines and antiviral screening using various replication systems.


Asunto(s)
Infecciones por Enterovirus , Enterovirus , Vacunas , Humanos , ADN Complementario/genética , Genética Inversa , Enterovirus/genética , Infecciones por Enterovirus/prevención & control , Infecciones por Enterovirus/epidemiología , Antígenos Virales/genética , Clonación Molecular
16.
Proc Natl Acad Sci U S A ; 120(4): e2208425120, 2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36669119

RESUMEN

Recurrent spillovers of α- and ß-coronaviruses (CoV) such as severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome-CoV, SARS-CoV-2, and possibly human CoV have caused serious morbidity and mortality worldwide. In this study, six receptor-binding domains (RBDs) derived from α- and ß-CoV that are considered to have originated from animals and cross-infected humans were linked to a heterotrimeric scaffold, proliferating cell nuclear antigen (PCNA) subunits, PCNA1, PCNA2, and PCNA3. They assemble to create a stable mosaic multivalent nanoparticle, 6RBD-np, displaying a ring-shaped disk with six protruding antigens, like jewels in a crown. Prime-boost immunizations with 6RBD-np in mice induced significantly high Ab titers against RBD antigens derived from α- and ß-CoV and increased interferon (IFN-γ) production, with full protection against the SARS-CoV-2 wild type and Delta challenges. The mosaic 6RBD-np has the potential to induce intergenus cross-reactivity and to be developed as a pan-CoV vaccine against future CoV spillovers.


Asunto(s)
COVID-19 , Nanopartículas , Humanos , Animales , Ratones , SARS-CoV-2 , Anticuerpos Antivirales , COVID-19/prevención & control , Anticuerpos Neutralizantes , Glicoproteína de la Espiga del Coronavirus/genética
17.
Microorganisms ; 11(1)2023 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-36677475

RESUMEN

Influenza infection is serious and debilitating for humans and animals. The influenza virus undergoes incessant mutation, segment recombination, and genome reassortment. As a result, new epidemics and pandemics are expected to emerge, making the elimination challenging of the disease. Antiviral therapy has been used for the treatment of influenza since the development of amantadine in the 1960s; however, its use is hampered by the emergence of novel strains and the development of drug resistance. Thus, combinational therapy with two or more antivirals or immunomodulators with different modes of action is the optimal strategy for the effective treatment of influenza infection. In this review, we describe current options for combination therapy, their performance, and constraints imposed by resistance, calling attention to the advantages of combination therapy against severe influenza infections. We also discuss the challenges of influenza therapy and the limitations of approved antiviral drugs.

18.
Cell Mol Neurobiol ; 43(5): 1975-1988, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36083390

RESUMEN

The success rate of regenerative medicine largely depends on the type of stem cells applied in such procedures. Consequently, to achieve the needed level for clinical standardization, we need to investigate the viability of accessible sources with sufficient quantity of cells. Since the oral region partly originates from the neural crest, which naturally develops in niche with decreased levels of oxygen, the main goal of this work was to test if human oral mucosa stem cells (hOMSC) might be used to treat neurons damaged by anoxia. Here we show that hOMSC are more resistant to anoxia than human induced pluripotent stem cells and that they secrete BDNF, GDNF, VEGF and NGF. When hOMSC were added to human neurons damaged by anoxia, they significantly improved their survival. This regenerative capability was at least partly achieved through miR-514A-3p and SHP-2 and it decreased in hOMSC exposed to neural cells for 14 or 28 days. In addition, the beneficial effect of hOMSC were also confirmed in mice affected by stroke. Hence, in this work we have confirmed that hOMSC, in a time-limited manner, improve the survival of anoxia-damaged neurons and significantly contribute to the recovery of experimental animals following stroke.


Asunto(s)
Células Madre Pluripotentes Inducidas , MicroARNs , Accidente Cerebrovascular , Humanos , Ratones , Animales , Mucosa Bucal , Neuronas , MicroARNs/genética , Hipoxia
19.
Virulence ; 13(1): 990-1004, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36560870

RESUMEN

Novel highly pathogenic avian influenza (HPAI) H5Nx viruses are predominantly circulating worldwide, with an increasing potential threat of an outbreak in humans. It remains largely unknown how the stably maintained HPAI H5N1 suddenly altered its neuraminidase (NA) to other NA subtypes, which resulted in the emergence and evolution of H5Nx viruses. Here, we found that a combination of four specific amino acid (AA) substitutions (S123P-T156A-D183N- S223 R) in the hemagglutinin (HA) protein consistently observed in the H5Nx markedly altered the NA preference of H5N1 viruses. These molecular changes in H5N1 impaired its fitness, particularly viral growth and the functional activities of the HA and NA proteins. Among the AA substitutions identified, the T156A substitution, which contributed to the NA shift, also dramatically altered the antigenicity of H5N1 viruses, suggesting an occurrence of antigenic drift triggered by selective pressure. Our study shows the importance of how HA and NA complement each other and that antigenic drift in HA can potentially cause a shift in the NA protein in influenza A virus evolution.


Asunto(s)
Subtipo H5N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Aviar , Animales , Humanos , Hemaglutininas , Neuraminidasa/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Virus de la Influenza A/genética , Virus de la Influenza A/metabolismo , Filogenia
20.
Micromachines (Basel) ; 13(11)2022 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-36363890

RESUMEN

In this work, two types of InGaZnO (IGZO) memristors were fabricated to confirm the conduction mechanism and degradation characteristics of memristors with different electrode materials. The IGZO memristor exhibits abrupt switching characteristics with the Pd electrode owing to the formation and destruction of conductive filaments but shows gradual switching characteristics with the p-type Si electrode according to the amount of generated oxygen vacancy. The electrical characteristics and conduction mechanisms of the device are analyzed using an energy band diagram and experimentally verified with random telegraph noise characteristics confirming the trap effects on the device conduction.

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