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In pandemic scenarios involving novel human pathogenic viruses, it is highly desirable that vaccines induce strong neutralizing antibodies as quickly as possible. However, current vaccine strategies require multiple immunization doses to produce high titers of neutralizing antibodies and are poorly protective after a single vaccination. We therefore wished to design a vaccine candidate that would induce increased protective immune responses following the first vaccine dose. We hypothesized that antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein could be increased by drawing upon immunity to a previous infection. We generated a fusion protein containing the influenza H1N1 PR8 virus nucleoprotein (NP) and the SARS-CoV-2 spike RBD. Mice with or without preexisting immunity to PR8 were then vaccinated with NP/RBD. We observed significantly increased SARS-CoV-2 neutralizing antibodies in mice with PR8 immunity compared to mice without preexisting PR8 immunity. Vaccination with NP/RBD protected mice from SARS-CoV-2-induced morbidity and mortality after a single dose. Additionally, we compared SARS-CoV-2 virus titers in the lungs and nasal turbinates 4 days post-challenge of mice vaccinated with NP/RBD. SARS-CoV-2 virus was detectable in the lungs and nasal turbinate of mice without preexisting PR8 immunity, while SARS-CoV-2 virus was completely undetectable in mice with preexisting PR8 immunity. We also found that CD4-positive T cells in mice with preexisting immunity to PR8 play an essential role in producing the increased antibody response against RBD. This vaccine strategy potentially can be modified to target other pathogens of concern and offers extra value in future pandemic scenarios.IMPORTANCEIncreased globalization and changes in human interactions with wild animals has increased the likelihood of the emergence of novel viruses with pandemic potential. Vaccines can be effective in preventing severe disease caused by pandemic viruses. However, it takes time to develop protective immunity via prime-boost vaccination. More effective vaccine designs should quickly induce protective immunity. We propose leveraging preexisting immunity to a different pathogen to boost protection against emerging viruses. We targeted SARS-CoV-2 as a representative pandemic virus and generated a fusion protein vaccine that combines the nucleoprotein from influenza A virus and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Our vaccine design significantly increased the production of RBD-specific antibodies in mice that had previously been exposed to influenza virus, compared to those without previous exposure. This enhanced immunity reduced SARS-CoV-2 replication in mice. Our results offer a vaccine design that could be valuable in a future pandemic setting.

Abstract Rubinstein-Taybi syndrome (RTS) is a rare and severe genetic developmental disorder characterized by multiple congenital anomalies and intellectual disability. CREBBP and EP300, the two genes known to cause RTS encode transcriptional coactivators with a catalytic lysine acetyltransferase (KAT) activity. Loss of CBP or p300 function results in a deficit in protein acetylation, in particular at histones. In RTS, nothing is known on the consequences of the loss of histone acetylation on the transcriptomic profiles during neuronal differentiation. To address this question, we differentiated induced pluripotent stem cells from RTS patients carrying a recurrent CREBBP mutation that inactivates the KAT domain into cortical and pyramidal neurons. By comparing their acetylome and their transcriptome at different neuronal differentiation time points, we identified 25 specific acetylated histone residues altered in RTS. We also identified the transition between neural progenitors and immature neurons as a critical step of the differentiation process, with a delayed neuronal maturation in RTS. Overall, this study opens new perspectives in the definition of epigenetic biomarkers for RTS, whose methodology could be extended to other chromatinopathies.

Abstract The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Tip-enhanced photoluminescence (TRPL) is a powerful technique for spatially and spectrally probing local optical properties of 2-dimensional (2D) materials that are modulated by the local heterogeneities, revealing inaccessible dark states due to bright state overlap in conventional far-field microscopy at room temperature. While scattering-type near-field probes have shown the potential to selectively enhance and reveal dark exciton emission, their technical complexity and sensitivity can pose challenges under certain experimental conditions. Here, we present a highly reproducible and easy-to-fabricate near-field probe based on nanoimprint lithography and fiber-optic excitation and collection. The novel near-field measurement configuration provides an ∼3 orders of magnitude out-of-plane Purcell enhancement, diffraction-limited excitation spot, and subdiffraction hyperspectral imaging resolution (below 50 nm) of dark exciton emission. The effectiveness of this high spatial XD mapping technique was then demonstrated through reproducible hyperspectral mapping of oxidized sites and bubble areas.

IntroductionThis research investigates into the complex dynamics of climate finance in Somalia, a vulnerable region facing the dire consequences of climate change. The study aims to assess how financial inputs for climate-related projects align with the actual needs and identify critical factors that influence funding effectiveness.MethodsA dual-methodological approach was employed, integrating both multiple regression analysis and Support Vector Machine (SVM) techniques. This mixed-method analysis facilitates a robust examination of climate finance data to dissect the relationships and impacts of various determinants on funding effectiveness.ResultsThe results indicate that adaptation finance, robust governance, and the scale of financial interventions significantly enhance the effectiveness of climate finance flows. However, mitigation finance and aspects related to gender equality displayed less significant impacts. Notably, the study identifies a pervasive underfinancing of climate projects in Somalia, illustrating a significant gap between the needed and actual funds disbursed.DiscussionThe findings underscore the need for enhanced governance frameworks and targeted large-scale financial interventions to optimize the allocation and impact of climate finance in vulnerable regions like Somalia. By quantifying the influence of adaptation finance and governance, this study contributes new insights to the literature on climate finance effectiveness and suggests practical strategies for policymakers and practitioners to improve climate resilience initiatives.

Abstract The Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6) is the primary effort of CMIP6 (Coupled Model Intercomparison Project–Phase 6) focusing on ice sheets, designed to provide an ensemble of process‐based projections of the ice‐sheet contribution to sea‐level rise over the twenty‐first century. However, the behavior of the Antarctic Ice Sheet beyond 2100 remains largely unknown: several instability mechanisms can develop on longer time scales, potentially destabilizing large parts of Antarctica. Projections of Antarctic Ice Sheet evolution until 2300 are presented here, using an ensemble of 16 ice‐flow models and forcing from global climate models. Under high‐emission scenarios, the Antarctic sea‐level contribution is limited to less than 30 cm sea‐level equivalent (SLE) by 2100, but increases rapidly thereafter to reach up to 4.4 m SLE by 2300. Simulations including ice‐shelf collapse lead to an additional 1.1 m SLE on average by 2300, and can reach 6.9 m SLE. Widespread retreat is observed on that timescale in most West Antarctic basins, leading to a collapse of large sectors of West Antarctica by 2300 in 30%–40% of the ensemble. While the onset date of retreat varies among ice models, the rate of upstream propagation is highly consistent once retreat begins. Calculations of sea‐level contribution including water density corrections lead to an additional ∼10% sea level and up to 50% for contributions accounting for bedrock uplift in response to ice loading. Overall, these results highlight large sea‐level contributions from Antarctica and suggest that the choice of ice sheet model remains the leading source of uncertainty in multi‐century projections.

The objective of the study was to determine if there would be statistically significant differences or trends among apolipoprotein E genotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4) for each member of the cluster of seven associated with type 2 diabetes (T2D). The cluster of seven includes abdominal obesity, hypertension, platelet hyperaggregability, hyperglycemia, dyslipidemia (decreased plasma levels of high-density lipoprotein cholesterol (HDL-C) and increased plasma levels of triglycerides)), increased low-density lipoprotein (LDL) oxidation, and increased inflammation.

This commentary reflects on the first Global Stocktake (GST) under the Paris Agreement on climate change to offer insights for advancing climate actions and informing future GST cycles. The first GST, which concluded at COP28 in 2023, demonstrates the vital importance of a comprehensive, balanced, and inclusive approach to multilateral climate action. The GST's call to transition away from fossil fuels is an important political achievement. Yet, the GST outcome also reveals gaps, shortcomings, and potential dangers ahead. Future climate negotiations, we argue, would benefit from a more integrated, holistic perspective, and more nuanced balancing of ambition and implementation. More needs to be done to protect human rights, increase loss and damage funding, go beyond technological solutions, and address gender-differentiated consequences of climate change. Moreover, a great deal of work, including by nonstate actors, will be required to ensure the first GST translates into real action on the ground.

La harina obtenida de granos amaranto es considerada una fuente rica en compuestos bioactivos por lo que ha llamado el interés en industrias como la alimentaria. Este trabajo tuvo como objetivo evaluar el efecto de la incorporación de harina de Amaranthu spp y chocolate en las características sensoriales y bromatológicas de galletas. Para lo cual, se empleó un Diseño Completamente al Azar (DCA) con un arreglo factorial A*B, donde el factor A = Porcentaje de sustitución de harina de amaranto y B = Adición de chocolate, se evaluaron los perfiles sensoriales mediante una escala hedónica y características bromatólogicas (humedad, cenizas, fibra, grasas y proteínas). Además, al tratamiento que presentó mejor caracterización bromatológica se analizó la presencia de Aerobeos mesófilos, mohos y levaduras. En cuanto a la caracterización sensorial, se demostró que los tratamientos T1, T3 y T7 presentaron la mayor intensidad en los perfiles evaluados. Sin embargo, en el T7 (20 % de HA +0 % de chocolate) se observó una mayor concentración de proteína (8.37 %); fibra (4.69 %); y ceniza (2.31 %); así como también, un bajo contenido de grasa (17.84 %) y humedad (2.94 %), también se evidenció una presencia de 0,31𝑥103 A. mesófilos y ausencia de mohos y levaduras. Con esto se concluye que la harina de amaranto puede ser utilizadas en la elaboración de galletas en concentraciones del 20 % y permite obtener un producto con buena calidad nutricional. DOI: https://doi.org/10.54167/tch.v18i2.1484

Este ensaio visual foca em um dos cartões postais mais famosos do mundo: o Pão de Açúcar, do Rio de Janeiro. Desde os primeiros trabalhos fotográficos sobre as paisagens naturais do Rio no final do século 19 (seguindo as primeiras representações pintadas nos séculos 17 e 18) até representações contemporâneas envolvendo megaeventos, renovação urbana e o marketing da cidade, o Pão de Açúcar percorreu um longo caminho na encenação de monumentos verticais e panorâmicos ao longo do tempo. O ensaio explora visualmente os diversos contextos – favoráveis ​​ou críticos – em que o monumento nato do Rio (assim apelidado pelo famoso arquiteto e urbanista brasileiro Lúcio Costa) possibilitou a encenação do Rio enquanto Cidade Maravilhosa, desde o advento da fotografia moderna junto com a estátua do Cristo Redentor – seu duplo visual vertical.

Ecuadorian educational policy for English as Foreign Language instruction in Ecuador mandated in 2016 to introduce Content and Language Integrated-Learning (CLIL) methodology to improve the teaching and learning process. This research aims to analyze the implementation of CLIL methodology in zone 4 of Ecuador during 2019-2021. This work subscribed to the transformative paradigm and administrated quantitative and qualitative methods of educational research. The participants were 70 English as a Foreign Language teachers from nine public and private educational institutions located in Manabi Province of Ecuador. The instrument used was the Instructor Perceptions of Differentiated Instruction of Turner, Solis, and Kincade (2017) in an observation format. The information collection techniques used were in-depth interview and focus group discussion. The results allowed the research team to determine the impact of the pandemic on the CLIL implementation in zone 4 of Ecuador. The results show differences in the implementation of the methodology between public and private schools which are linked to internet and technology devices access, teachers' knowledge regarding CLIL methodology, and institutional policies. In regards COVID19 pandemic, it is concluded that it has pacted the implementation of CLIL methodology in both public and private secondary schools that participated in the study.

Abstract Background The continuous evolution of drug-resistant influenza viruses highlights the necessity for repurposing naturally-derived and safe phytochemicals with anti-influenza activity as novel broad-spectrum anti-influenza medications. Methods In this study, nitrogenous alkaloids were tested for their viral inhibitory activity against influenza A/H1N1 and A/H5N1 viruses. The cytotoxicity of tested alkaloids on MDCK showed a high safety range (CC50 > 200 µg/ml), permitting the screening for their anti-influenza potential. Results Herein, atropine sulphate, pilocarpine hydrochloride and colchicine displayed anti-H5N1 activities with IC50 values of 2.300, 0.210 and 0.111 µg/ml, respectively. Validation of the IC50 values was further depicted by testing the three highly effective alkaloids, based on their potent IC50 values against seasonal influenza A/H1N1 virus, showing comparable IC50 values of 0.204, 0.637 and 0.326 µg/ml, respectively. Further investigation suggests that colchicine could suppress viral infection by primarily interfering with IAV replication and inhibiting viral adsorption, while atropine sulphate and pilocarpine hydrochloride could directly affect the virus in a cell-free virucidal effect. Interestingly, the in silico molecular docking studies suggest the abilities of atropine, pilocarpine, and colchicine to bind correctly inside the active sites of the neuraminidases of both influenza A/H1N1 and A/H5N1 viruses. The three alkaloids exhibited good binding energies as well as excellent binding modes that were similar to the co-crystallized ligands. On the other hand, consistent with in vitro results, only colchicine could bind correctly against the M2-proton channel of influenza A viruses (IAVs). This might explicate the in vitro antiviral activity of colchicine at the replication stage of the virus replication cycle. Conclusion This study highlighted the anti-influenza efficacy of biologically active alkaloids including colchicine. Therefore, these alkaloids should be further characterized in vivo (preclinical and clinical studies) to be developed as anti-IAV agents.

Introduction: Gram-negative bacteria have developed a broad spectrum of resistance due to antibiotic degradation enzymes, including Extended-spectrum Beta-lactamases (ESBL), AmpC β-lactamases, and carbapenemases. Carbapenemase-producing organisms, such as Escherichia coli, Klebsiella species, Acinetobacter species, and Pseudomonas species, have become one of the most important causes of nosocomial and community-acquired infections. Aim: To identify carbapenemase-producing organisms among Multidrug-resistant (MDR) clinical isolates and detect Metallo β-Lactam Carbapenemases (MBL). Materials and Methods: The present study is a cross-sectional study that included 1266 clinical samples from patients visiting the Department of Microbiology, Ranagaraya Medical College, Kakinada, Andhra Pradesh, India. from July 2022 to December 2022. The samples were processed using the standard culture and antimicrobial susceptibility test, employing the Kirby-Bauer Disk Diffusion method. The present study included organisms that were resistant to either imipenem or meropenem. Carbapenemases were detected using the Modified Hodge test (MHT), and MBL carbapenemases were detected using the Imipenem Ethylene Diamine Tetraacetic acid (EDTA) Double Disk Test (DDT) following the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Descriptive statistics were performed on the collected data. Results: The study samples comprised 842 (66.5%) Gram-negative isolates and 424 (33.5%) Gram-positive isolates. Among the Gram-negative isolates, 80 (9.5%) were carbapenem-resistant, of which MHT showed 56 (70%) positive isolates (carbapenemase-producing) and 24 (30%) negative isolates. Imipenem-EDTA DDT showed 50 (62.5%) positive isolates (MBL-producing) and 30 (37.5%) negative isolates. Conclusion: Carbapenemase production in Gram-negative organisms has reduced the clinical utility of the carbapenem group of drugs, posing a major challenge in the treatment of severe infections. In summary, the majority of carbapenem-resistant isolates in the present study were from the Enterobacteriaceae family. These isolates were subjected carbapenem-resistant isolates to MHT and DDT tests to identify carbapenemase and metallo-beta-lactamase-producing strains that were resistant to a wide spectrum of antibiotics. The present study enables the early detection of these MDR strains, ensuring appropriate management.