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Efficient management of low energy states is vital for cells to maintain basic functions and metabolism and avoid cell death. While autophagy has long been considered a critical mechanism for ensuring survival during energy depletion, recent research has presented conflicting evidence, challenging the long-standing concept. This recent development suggests that cells prioritize preserving essential cellular components while restraining autophagy induction when cellular energy is limited. This essay explores the conceptual discourse on autophagy regulation during energy stress, navigating through the studies that established the current paradigm and the recent research that has challenged its validity while proposing an alternative model. This exploration highlights the far-reaching implications of the alternative model, which represents a conceptual departure from the established paradigm, offering new perspectives on how cells respond to energy stress.
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Proteínas Quinases Ativadas por AMP , Autofagia , Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologiaRESUMO
Reservoir computing (RC) system is based upon the reservoir layer, which non-linearly transforms input signals into high-dimensional states, facilitating simple training in the readout layer-a linear neural network. These layers require different types of devices-the former demonstrated as diffusive memristors and the latter prepared as drift memristors. The integration of these components can increase the structural complexity of RC system. Here, a reconfigurable resistive switching memory (RSM) capable of implementing both diffusive and drift dynamics is demonstrated. This reconfigurability is achieved by preparing a medium with a 3D ion transport channel (ITC), enabling precise control of the metal filament that determines memristor operation. The 3D ITC-RSM operates in a volatile threshold switching (TS) mode under a weak electric field and exhibits short-term dynamics that are confirmed to be applicable as reservoir elements in RC systems. Meanwhile, the 3D ITC-RSM operates in a non-volatile bipolar switching (BS) mode under a strong electric field, and the conductance modulation metrics forming the basis of synaptic weight update are validated, which can be utilized as readout elements in the readout layer. Finally, an RC system is designed for the application of reconfigurable 3D ITC-RSM, and performs real-time recognition on Morse code datasets.
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INTRODUCTION: Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. METHODS: This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. RESULTS: The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. CONCLUSION: This study enhances the understanding of the clinical and genetic characteristics of KS.
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This study proposes a solid-state two-dimensional beam-steering device based on an electro-optical phased array (EOPA) in thin-film lithium niobate (TFLN) and silicon nitride (SiN) hybrid platforms, thereby eliminating the requirement for the direct etching of TFLN. Electro-optic (EO) phase modulator array comprises cascaded multimode interference couplers with an SiN strip-loaded TFLN configuration, which is designed and fabricated via i-line photolithography. Each EO modulator element with an interaction region length of 1.56â cm consumed a minimum power of 3.2 pJ/π under a half-wave voltage of 3.64â V and had an estimated modulation speed of 1.2â GHz. Subsequently, an SiN dispersive antenna with a waveguide grating was tethered to the modulator array to form an EOPA, facilitating the out-of-plane radiation of highly defined near-infrared beams. A prepared EOPA utilized EO phase control and wavelength tuning near 1550â nm to achieve a field-of-view of 22° × 5° in the horizontal and vertical directions. The proposed hybrid integrated platform can potentially facilitate low-power and high-speed beam steering.
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High-dose ambroxol therapy combined with ERT in patients with neuropathic Gaucher disease.
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Ambroxol , Terapia de Reposição de Enzimas , Doença de Gaucher , Glucosilceramidase , Doença de Gaucher/tratamento farmacológico , Humanos , Ambroxol/administração & dosagem , Ambroxol/uso terapêutico , Glucosilceramidase/uso terapêutico , Glucosilceramidase/administração & dosagem , Masculino , Seguimentos , Feminino , Adulto , Pessoa de Meia-Idade , Quimioterapia CombinadaRESUMO
The emergence of antibiotic-resistant bacteria (ARBs) and genes (ARGs) in aquaculture underscores the urgent need for alternative veterinary strategies to combat antimicrobial resistance (AMR). These measures are vital to reduce the likelihood of entering a post-antibiotic era. Identifying environmentally friendly biotechnological solutions to prevent and treat bacterial diseases is crucial for the sustainability of aquaculture and for minimizing the use of antimicrobials, especially antibiotics. The development of probiotics with quorum-quenching (QQ) capabilities presents a promising non-antibiotic strategy for sustainable aquaculture. Recent research has demonstrated the effectiveness of QQ probiotics (QQPs) against a range of significant fish pathogens in aquaculture. QQ disrupts microbial communication (quorum sensing, QS) by inhibiting the production, replication, and detection of signalling molecules, thereby reducing bacterial virulence factors. With their targeted anti-virulence approach, QQPs have substantial promise as a potential alternative to antibiotics. The application of QQPs in aquaculture, however, is still in its early stages and requires additional research. Key challenges include determining the optimal dosage and treatment regimens, understanding the long-term effects, and integrating QQPs with other disease control methods in diverse aquaculture systems. This review scrutinizes the current literature on antibiotic usage, AMR prevalence in aquaculture, QQ mechanisms and the application of QQPs as a sustainable alternative to antibiotics.
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Aquicultura , Doenças dos Peixes , Probióticos , Percepção de Quorum , Percepção de Quorum/efeitos dos fármacos , Aquicultura/métodos , Probióticos/farmacologia , Animais , Doenças dos Peixes/prevenção & controle , Doenças dos Peixes/microbiologia , Peixes , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Farmacorresistência BacterianaRESUMO
The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.
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Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Animais , Camundongos , Papillomavirus Humano , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/prevenção & controle , RNA Mensageiro/genética , Proteínas E7 de Papillomavirus/genética , Camundongos Endogâmicos C57BL , Vacinação/métodos , Imunização , Neoplasias do Colo do Útero/prevenção & controleRESUMO
The interfacial liquid, situated in proximity to an electrode or catalyst, plays a vital role in determining the activity and selectivity of crucial electrochemical reactions, including hydrogen evolution, oxygen evolution/reduction, and carbon dioxide reduction. Thus, there has been a growing interest in better understanding the behavior and the catalytic effect of its constituents. This minireview examines the impact of interfacial liquids on electrocatalysis, specifically the effects of water molecules and ionic species present at the interface. How the structure of interfacial water, distinct from the bulk, can affect charge transfer kinetics and transport of species is presented. Furthermore, how cations and anions (de)stabilize intermediates and transition states, compete for adsorption with reaction species, and act as local environment modifiers including pH and the surrounding solvent structure are described in detail. These effects can promote or inhibit reactions in various ways. This comprehensive exploration provides valuable insights for tailoring interfacial liquids to optimize electrochemical reactions.
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BACKGROUND: Necrotic enteritis (NE) is a major enteric disease in poultry, yet effective mitigation strategies remain elusive. Deoxycholic acid (DCA) and butyrate, two major metabolites derived from the intestinal microbiota, have independently been shown to induce host defense peptide (HDP) synthesis. However, the potential synergy between these two compounds remains unexplored. METHODS: To investigate the possible synergistic effect between DCA and butyrate in regulating HDP synthesis and barrier function, we treated chicken HD11 macrophage cells and jejunal explants with DCA and sodium butyrate (NaB), either individually or in combination, for 24 h. Subsequently, we performed RNA isolation and reverse transcription-quantitative PCR to analyze HDP genes as well as the major genes associated with barrier function. To further determine the synergy between DCA and NaB in enhancing NE resistance, we conducted two independent trials with Cobb broiler chicks. In each trial, the diet was supplemented with DCA or NaB on the day-of-hatch, followed by NE induction through sequential challenges with Eimeria maxima and Clostridium perfringens on d 10 and 14, respectively. We recorded animal mortality after infection and assessed intestinal lesions on d 17. The impact of DCA and NaB on the microbiota in the ileum and cecum was evaluated through bacterial 16S rRNA gene sequencing. RESULTS: We found that the combination of DCA and NaB synergistically induced multiple HDP genes in both chicken HD11 cells and jejunal explants. Additionally, the gene for claudin-1, a major tight junction protein, also exhibited synergistic induction in response to DCA and NaB. Furthermore, dietary supplementation with a combination of 0.75 g/kg DCA and 1 g/kg NaB led to a significant improvement in animal survival and a reduction in intestinal lesions compared to either compound alone in a chicken model of NE. Notably, the cecal microbiota of NE-infected chickens showed a marked decrease in SCFA-producing bacteria such as Bacteroides, Faecalibacterium, and Cuneatibacter, with lactobacilli becoming the most dominant species. However, supplementation with DCA and NaB largely restored the intestinal microbiota to healthy levels. CONCLUSIONS: DCA synergizes with NaB to induce HDP and claudin-1 expression and enhance NE resistance, with potential for further development as cost-effective antibiotic alternatives.
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Super duplex stainless steel (SDSS) is a suitable structural material for various engineering applications due to its outstanding strength and corrosion resistance. In particular, its high-temperature strength can enhance the safety of electronic products and cars. SDSS AISI2507, known for its excellent strength and high corrosion resistance, was analyzed for its microstructure and electrochemical behavior at the ignition temperature of Li-ion batteries, 700 °C. At 700 °C, AISI2507 exhibited secondary phase precipitation values of 1% and 8% after 5 and 10 h, respectively. Secondary phase precipitation was initiated by the expansion of austenite, forming sigma, chi, and CrN phases. The electrochemical behavior varied with the fraction of secondary phases. Secondary phase precipitation reduced the potential (From -0.25 V to -0.31 V) and increased the current density (From 8 × 10-6 A/cm2 to 3 × 10-6 A/cm2) owing to galvanic corrosion by sigma and chi. As the fraction of secondary phases increased (From 0.0% to 8.1%), the open circuit potential decreased (From -0.25 V to -0.32 V). Secondary phase precipitation is a crucial factor in reducing the corrosion resistance of SDSS AISI2507 and occurs after 1 h of exposure at 700 °C.
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Aluminum, traditionally the primary material for battery casings, is increasingly being replaced by UNS S 30400 for enhanced safety. UNS S 30400 offers superior strength and corrosion resistance compared to aluminum; however, it undergoes a phase transformation owing to stress during processing and a lower high-temperature strength. Duplex stainless steel UNS S 32750, consisting of both austenite and ferrite phases, exhibits excellent strength and corrosion resistance. However, it also precipitates secondary phases at high temperatures, which are known to form through the segregation of Cr and Mo. Various studies have investigated the corrosion resistance of UNS S 32750; however, discrepancies exist regarding the formation and thickness of the passivation layer. This study analyzed the oxygen layer on the surface of UNS S 32750 after secondary-phase precipitation. The microstructure, volume fraction, chemical composition, and depth of O after the precipitation of the secondary phases in UNS S 32750 was examined using FE-SEM, EDS, EPMA and XRD, and the surface chemical composition and passivation layer thickness were analyzed using electron probe microanalysis and glow-discharge spectroscopy. This study demonstrated the segregation of alloy elements and a reduction in the passivation-layer thickness after precipitation from 25 µm to 20 µm. The findings of the analysis aid in elucidating the impact of secondary-phase precipitation on the passivation layer.
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The development of Li-ion battery cases requires superior electrical conductivity, strength, and corrosion resistance for both cathode and anode to enhance safety and performance. Among the various battery case materials, super duplex stainless steel (SDSS), which is composed of austenite and ferrite as two-phase stainless steel, exhibits outstanding strength and corrosion resistance. However, stainless steel, which is an iron-based material, tends to have lower electrical conductivity. Nevertheless, nickel-plating SDSS can achieve excellent electrical conductivity, making it suitable for Li-ion battery cases. Therefore, this study analysed the plating behaviour of SDSS plates after nickel plating to leverage their exceptional strength and corrosion resistance. Electroless Ni plating was performed to analyse the plating behaviour, and the plating behaviour was studied with reference to different plating durations. Heat treatment was conducted at 1000 °C for one hour, followed by cooling at 50 °C/s. Post-heat treatment, the analysis of phases was executed using FE-SEM, EDS, and EPMA. Electroless Ni plating was performed at 60-300 s. The plating duration after the heat treatment was up to 300 s, and the behaviour of the materials was observed using FE-SEM. The phase analysis concerning different plating durations was conducted using XRD. Post-heat treatment, the precipitated secondary phases in SAF2507 were identified as Sigma, Chi, and CrN, approximating a 13% distribution. During the electroless Ni plating, the secondary phase exhibited a plating rate equivalent to that of ferrite, entirely plating at around 180 s. Further increments in plating time displayed growth of the plating layer from the austenite direction towards the ferrite, accompanied by a reduced influence from the substrate. Despite the differences in composition, both the secondary phase and austenite demonstrated comparable plating rates, showing that electroless Ni plating on SDSS was primarily influenced by the substrate, a finding which was primarily confirmed through phase analysis.
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The importance of lung microbiome changes in developing chronic lung allograft dysfunction (CLAD) after lung transplantation is poorly understood. The lung microbiome-immune interaction may be critical in developing CLAD. In this context, examining alterations in the microbiome and immune cells of the lungs following CLAD, in comparison to the lung condition immediately after transplantation, can offer valuable insights. Four adult patients who underwent lung retransplantation between January 2019 and June 2020 were included in this study. Lung tissues were collected from the same four individuals at two different time points: at the time of the first transplant and at the time of the explantation of CLAD lungs at retransplantation due to CLAD. We analyzed whole-genome sequencing using the Kraken2 algorithm and quantified the cell fractionation from the bulk tissue gene expression profile for each lung tissue. Finally, we compared the differences in lung microbiome and immune cells between the lung tissues of these two time points. The median age of the recipients was 57 years, and most (75%) had undergone lung transplants for idiopathic pulmonary fibrosis. All patients were administered basiliximab for induction therapy and were maintained on three immunosuppressants. The median CLAD-free survival term was 693.5 days, and the median time to redo the lung transplant was 843.5 days. Bacterial diversity was significantly lower in the CLAD lungs than at transplantation. Bacterial diversity tended to decrease according to the severity of the CLAD. Aerococcus, Caldiericum, Croceibacter, Leptolyngbya, and Pulveribacter genera were uniquely identified in CLAD, whereas no taxa were identified in lungs at transplantation. In particular, six taxa, including Croceibacter atlanticus, Caldiserium exile, Dolichospermum compactum, Stappia sp. ES.058, Kinetoplastibacterium sorsogonicusi, and Pulveribacter suum were uniquely detected in CLAD. Among immune cells, CD8+ T cells were significantly increased, while neutrophils were decreased in the CLAD lung. In conclusion, unique changes in lung microbiome and immune cell composition were confirmed in lung tissue after CLAD compared to at transplantation.
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Epizootics of Koi herpesvirus (KHV) cause mass mortality in koi carp (Cyprinus rubrofuscus) and common carp (Cyprinus carpio) worldwide. Rapid and accurate virus detection technology is crucial for preventing pathogen spread and minimizing damage. Although several diagnostic assays have been developed for KHV, the analytical and diagnostic performance of the detection methods has not been evaluated. In this study, we developed and validated the diagnostic performance of two molecular diagnostic assays, cross-priming amplification-based lateral flow assay (CPA-LFA) and TaqMan probe-based real-time polymerase chain reaction (PCR). To detect KHV, primers and probe were designed based on the thymidine kinase (TK) genes. The detection limits of developed CPA-LFA and real-time PCR assays were determined to be 675.69 copies/µL and 8.384 copies/µL, respectively. The diagnostic sensitivity and specificity of the developed assay were determined using fish samples (n = 179). CPA-LFA was found to be 93.67% and 100%, respectively, and real-time PCR was found to be 100% and 100%, respectively. Therefore, the newly developed CPA-LFA and real-time PCR assays accurately and rapidly detect KHV. CPA-LFA is particularly suitable for point-of-care diagnosis because of its simple diagnostic process, and real-time PCR analysis is most suitable for precise diagnosis because it can detect low viral loads.
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Carpas , Doenças dos Peixes , Infecções por Herpesviridae , Herpesviridae , Animais , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/veterinária , Reação em Cadeia da Polimerase em Tempo Real , Apresentação Cruzada , Doenças dos Peixes/diagnóstico , Herpesviridae/genéticaRESUMO
Vibrio harveyi strain 22FBVib0145 was isolated from a diseased olive flounder farmed in Jeju, Korea. Here, we report the draft genome sequence of this strain. It is 6,238,277 bp in length with a G + C content of 44.8%.
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Dengue fever, a prevalent and rapidly spreading arboviral disease, poses substantial public health and economic challenges in tropical and sub-tropical regions worldwide. Predicting infectious disease outbreaks on a countrywide scale is complex due to spatiotemporal variations in dengue incidence across administrative areas. To address this, we propose a machine learning ensemble model for forecasting the dengue incidence rate (DIR) in Brazil, with a focus on the population under 19 years old. The model integrates spatial and temporal information, providing one-month-ahead DIR estimates at the state level. Comparative analyses with a dummy model and ablation studies demonstrate the ensemble model's qualitative and quantitative efficacy across the 27 Brazilian Federal Units. Furthermore, we showcase the transferability of this approach to Peru, another Latin American country with differing epidemiological characteristics. This timely forecast system can aid local governments in implementing targeted control measures. The study advances climate services for health by identifying factors triggering dengue outbreaks in Brazil and Peru, emphasizing collaborative efforts with intergovernmental organizations and public health institutions. The innovation lies not only in the algorithms themselves but in their application to a domain marked by data scarcity and operational scalability challenges. We bridge the gap by integrating well-curated ground data with advanced analytical methods, addressing a significant deficiency in current practices. The successful transfer of the model to Peru and its consistent performance during the 2019 outbreak in Brazil showcase its scalability and practical application. While acknowledging limitations in handling extreme values, especially in regions with low DIR, our approach excels where accurate predictions are critical. The study not only contributes to advancing DIR forecasting but also represents a paradigm shift in integrating advanced analytics into public health operational frameworks. This work, driven by a collaborative spirit involving intergovernmental organizations and public health institutions, sets a precedent for interdisciplinary collaboration in addressing global health challenges. It not only enhances our understanding of factors triggering dengue outbreaks but also serves as a template for the effective implementation of advanced analytical methods in public health.
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Dengue , Humanos , Adulto Jovem , Adulto , Dengue/epidemiologia , Surtos de Doenças/prevenção & controle , Saúde Pública/métodos , Clima , Aprendizado de MáquinaRESUMO
BACKGROUND: Mediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks. METHODS: We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors. RESULTS: The logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R2 = 0.033, p < 0.01) and PRU (r = 0.503, R2 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks. CONCLUSIONS: This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03823274.
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Aspirina , Clopidogrel , Resistência a Medicamentos , Humanos , Clopidogrel/uso terapêutico , Clopidogrel/farmacologia , Masculino , Feminino , Aspirina/uso terapêutico , Aspirina/farmacologia , Resistência a Medicamentos/genética , Pessoa de Meia-Idade , Idoso , Epigenômica , Genômica , Estudos Prospectivos , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/farmacologia , Metilação de DNA/efeitos dos fármacosRESUMO
Reducing non-radiative recombination and addressing band alignment mismatches at interfaces remain major challenges in achieving high-performance wide-bandgap perovskite solar cells. This study proposes the self-organization of a thin two-dimensional (2D) perovskite BA2PbBr4 layer beneath a wide-bandgap three-dimensional (3D) perovskite Cs0.17FA0.83Pb(I0.6Br0.4)3, forming a 2D/3D bilayer structure on a tin oxide (SnO2) layer. This process is driven by interactions between the oxygen vacancies on the SnO2 surface and hydrogen atoms of the n-butylammonium cation, aiding the self-assembly of the BA2PbBr4 2D layer. The 2D perovskite acts as a tunneling layer between SnO2 and the 3D perovskite, neutralizing the energy level mismatch and reducing non-radiative recombination. This results in high power conversion efficiencies of 21.54% and 19.16% for wide-bandgap perovskite solar cells with bandgaps of 1.7 and 1.8 eV, with open-circuit voltages over 1.3 V under 1-Sun illumination. Furthermore, an impressive efficiency of over 43% is achieved under indoor conditions, specifically under 200 lux white light-emitting diode light, yielding an output voltage exceeding 1 V. The device also demonstrates enhanced stability, lasting up to 1,200 hours.
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BACKGROUND: As the nasal mucosa is the initial site of infection for COVID-19, intranasal vaccines are more favorable than conventional vaccines. In recent clinical studies, intranasal immunization has been shown to generate higher neutralizing antibodies; however, there is a lack of evidence on sterilizing immunity in the upper airway. Previously, we developed a recombinant measles virus encoding the spike protein of SARS-CoV-2 (rMeV-S), eliciting humoral and cellular immune responses against SARS-CoV-2. OBJECTIVES: In this study, we aim to provide an experiment on nasal vaccines focusing on a measles virus platform as well as injection routes. STUDY DESIGN: Recombinant measles viruses expressing rMeV-S were prepared, and 5 × 105 PFUs of rMeV-S were administered to Syrian golden hamsters via intramuscular or intranasal injection. Subsequently, the hamsters were challenged with inoculations of 1 × 105 PFUs of SARS-CoV-2 and euthanized 4 days post-infection. Neutralizing antibodies and RBD-specific IgG in the serum and RBD-specific IgA in the bronchoalveolar lavage fluid (BALF) were measured, and SARS-CoV-2 clearance capacity was determined via quantitative reverse-transcription PCR (qRT-PCR) analysis and viral titer measurement in the upper respiratory tract and lungs. Immunohistochemistry and histopathological examinations of lung samples from experimental hamsters were conducted. RESULTS: The intranasal immunization of rMeV-S elicits protective immune responses and alleviates virus-induced pathophysiology, such as body weight reduction and lung weight increase in hamsters. Furthermore, lung immunohistochemistry demonstrated that intranasal rMeV-S immunization induces effective SARS-CoV-2 clearance that correlates with viral RNA content, as determined by qRT-PCR, in the lung and nasal wash samples, SARS-CoV-2 viral titers in lung, nasal wash, BALF samples, serum RBD-specific IgG concentration, and RBD-specific IgA concentration in the BALF. CONCLUSION: An intranasal vaccine based on the measles virus platform is a promising strategy owing to the typical route of infection of the virus, the ease of administration of the vaccine, and the strong immune response it elicits.
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COVID-19 , Sarampo , Orthopoxvirus , Vacinas , Animais , Cricetinae , SARS-CoV-2 , Vírus do Sarampo/genética , COVID-19/prevenção & controle , Glicoproteína da Espícula de Coronavírus , Imunização , Mucosa Nasal , Anticorpos Neutralizantes , Imunoglobulina A , Imunoglobulina G , Anticorpos Antivirais , Administração IntranasalRESUMO
BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.