Cereal bar enriched with ora-pro-nóbis (Pereskia aculeata Miller): physicochemical and sensory characterization.

Ora-pro-nobis (OPN) is an unconventional food plant with high nutritional value, and its nutritional composition can be altered according to cultivation. Cereal bars are a popular nutrient-poor foods, and OPN could be incorporated to improve the nutritional quality. This study aimed to evaluate the physicochemical characteristics and sensory acceptability of cereal bars enriched with OPN flour (OpnF) from different forms of cultivation. OpnF was obtained by dehydrating and grinding OPN leaves collected in rural (ROpnF) and urban (UOpnF) municipalities. Two formulations of cereal bars, peanut flavor (Bpn) and mango flavor (Bmg), each with 10% OpnF, were prepared. The macronutrients and mineral composition, oxalate content, water activity, texture, color profile, and acceptability were evaluated. ROpnF had the highest protein, iron, and manganese content, whereas UOpnF had the highest ash and magnesium content. The oxalic acid/calcium ratio was 1.43 and did not imply calcium bioavailability. In addition to nutritional and protein values, Bpn and Bmg presented a good sensory acceptability index of > 77.5% with market potential. Bmg has the highest mineral content and is a source of iron, manganese, and magnesium. OpnF can be used in cereal bars and potentially improve nutritional attributes and used in other foods in a similar way.

Effect of street trees shade on perceived thermal comfort in a south temperate climate: The sidewalks of Montevideo (Uruguay).

The use of vegetation in cities is one of the most promising strategies for urban climate change adaptation and mitigation. Tree shade influences heat storage from surfaces reducing long wave radiation emission which directly affects people. People 's heat perception depends more on insolation and the temperature of surrounding objects than on air temperature itself. There is a need for analyzes that include the combined effects of physical and human variables on thermal comfort, as well as location-based studies to address its climatic and social conditions. In order to compare the effect of the trees on microenvironmental temperature and perceived thermal comfort, we measured physical parameters and performed structured interviews on three downtown streets of Montevideo, Uruguay, which had sections with and without trees on four dates during the summer. Generally, people surveyed under both treatments stated they did not feel fully comfortable due to summer heat, but the proportion of people who stated feeling in thermal comfort under tree shade was more than double than the unshaded sections. The seasonal ARIMA analysis supported that the tree shade reduced the microenvironmental temperature by its effect on radiant temperature. By using a statistical decision tree methodology that combines all the variables in the same analysis, we found a greater impact of physical variables than personal variables on people's thermal comfort and thermal preferences. We also identified gender as a significant variable that affects people's thermal preferences, where 46.4 % of females preferred a slightly colder environment.

Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.

Mapping of susceptibility loci for Ebola virus pathogenesis in mice.

Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies.

Use of platelet-rich plasma on in vitro maturation during bovine embryo production.

One of the crucial aspects to be considered for successful in vitro production (IVP) of embryos is the composition of the various media used throughout the stages of this reproductive biotechnology. The cell culture media employed should fulfill the metabolic requirements of both gametes during oocyte maturation and sperm development, as well as the embryo during its initial cell divisions. Most IVP protocols incorporate blood serum into the media composition as a source of hormones, proteins, growth factors, and nutrients. Numerous studies have suggested Platelet-Rich Plasma (PRP) as a substitute for fetal sera in cell culture, particularly for stem cells. Therefore, the objective of this study is to assess the potential use of PRP as a replacement for fetal bovine serum (FBS) during oocyte maturation for in vitro production of bovine embryos. During in vitro maturation (IVM), cumulus-oocyte complexes (COCs) were allocated into the following experimental groups: Group G1 (IVM medium with 5% PRP); Group G2 (MIV medium with 5% PRP and 5% SFB); Group G3 (MIV medium with 5% SFB); and Group G4 (MIV medium without either PRP or SFB). Subsequently, the cumulus-oocyte complexes were fertilized with semen from a single bull, and the resulting zygotes were cultured for seven days. Cleavage and blastocyst formation rates were assessed on days 2 and 7 of embryonic development, respectively. The quality of matured COCs was also evaluated by analyzing the gene expression of HSP70, an important protein associated with cellular stress. The results demonstrated that there were no significant differences among the experimental groups in terms of embryo production rates, both in the initial cleavage stages and blastocyst formation (except for the G4 group, which exhibited a lower blastocyst formation rate on D7, as expected). This indicates that PRP could be a cost-effective alternative to SFB in the IVP of embryos.

Antifungal Susceptibility and Candida sp. Biofilm Production in Clinical Isolates of HIV-Positive Brazilian Patients under HAART Therapy.

The aim of the present study was to characterize biofilms formed by Candida spp. clinical isolates (n = 19), isolated from the oral mucosa of HIV-positive patients. For characterizing the biofilms formed by several Candida sp. strains, isolated from HIV-positive patients, in terms of formed biomass, matrix composition and antifungal susceptibility profile, clinical isolates (n = 19) were collected from oral mucosa and identified. The biofilm of the samples was cultured with fluconazole (1250 mg/L), voriconazole (800 mg/L), anidulafungin (2 mg/L) or amphotericin B (2 mg/L). Afterwards, the quantification of the total biomass was performed using crystal violet assay, while the proteins and carbohydrates levels were quantified in the matrix. The results showed a predominance of C. albicans, followed by C. krusei. Around 58% of the Candida spp. biofilm had susceptibility to fluconazole and voriconazole (800 mg/L), 53% to anidulafungin and 74% to amphotericin B. C. krusei presented both the lowest and the highest biofilm matrix contents in polysaccharides and proteins. The low resistance to antifungal agents reported here was probably due to the fact that none of the participants had a prolonged exposure to these antifungals. A predominance of less virulent Candida spp. strains with low or no resistance to antifungals was observed. This can be attributed to a low fungal selective pressure. This most probably happened due to a low fungal selective pressure but also due to a good adherence to HAART therapy, which guarantees a stable and stronger immune patient response.

The environmental impact of beef and ultra-processed food consumption in Brazil.

OBJECTIVE: This study evaluated the independent and combined environmental impacts of the consumption of beef and ultra-processed foods in Brazil. DESIGN: Cross-sectional study. SETTING: Brazil. PARTICIPANTS: We used food purchases data from a national household budget survey conducted between July 2017 and July 2018, representing all Brazilian households. Food purchases were converted into energy, carbon footprints and water footprints. Multiple linear regression models were used to assess the association between quintiles of beef and ultra-processed foods in total energy purchases and the environmental footprints, controlling for sociodemographic variables. RESULTS: Both beef and ultra-processed foods had a significant linear association with carbon and water footprints (P < 0·01) in crude and adjusted models. In the crude upper quintile of beef purchases, carbon and water footprints were 47·7 % and 30·8 % higher, respectively, compared to the lower quintile. The upper quintile of ultra-processed food purchases showed carbon and water footprints 14·4 % and 22·8 % higher, respectively, than the lower quintile. The greatest reduction in environmental footprints would occur when both beef and ultra-processed food purchases are decreased, resulting in a 21·1 % reduction in carbon footprint and a 20·0 % reduction in water footprint. CONCLUSIONS: Although the environmental footprints associated with beef consumption are higher, dietary patterns with lower consumption of beef and ultra-processed foods combined showed the greatest reduction in carbon and water footprints in Brazil. The high consumption of beef and ultra-processed foods is harmful to human health, as well as to the environment; thus, their reduction is beneficial to both.

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice.

BACKGROUND AIMS: Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. APPROACH RESULTS: We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains. CONCLUSIONS: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

Spatial Relationships in the Tumor Microenvironment Demonstrate Association with Pathologic Response to Neoadjuvant Chemoimmunotherapy in Muscle-invasive Bladder Cancer.

BACKGROUND: Platinum-based neoadjuvant chemotherapy (NAC) is standard for patients with muscle-invasive bladder cancer (MIBC). Pathologic response (complete: ypT0N0 and partial:

Proximal and Distal Bronchioles Contribute to the Pathogenesis of Non-Cystic Fibrosis Bronchiectasis.

Rationale: Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Objectives: Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Methods: Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA in situ hybridization and immunohistochemistry, identified proximal and distal bronchioles in excised NCFB lungs. RNA in situ hybridization and immunohistochemistry assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial cultures tested IL-1α and IL-1ß contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas per section area were increased in proximal, but not distal, bronchioles in NCFB versus control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated nonectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1ß-expressing macrophages. NCFB sterile sputum supernatants induced human bronchial epithelial MUC5B and MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, and IL-1ß-producing macrophages in mucus plugs and downregulation of epithelial ciliogenesis genes. Conclusions: NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia.

Determinantes sociais de saúde de crianças em consulta de puericultura: das condições socioeconômicas aos aspectos relacionados à saúde bucal / Social determinants of health of children in child care consultation: from socioeconomic conditions to aspects related to oral health / Determinantes sociales de la salud de los niños en la consulta infantil: de las condiciones socioeconómicas a los aspectos relacionados con la salud bucal

A imaturidade do sistema imunológico, associado a Determinantes Sociais de Saúde (DSS), promove doenças na infância. Especificamente, na cavidade oral, os DSS, representados pelo consumo elevado de açúcar, limitado acesso aos serviços de saúde e deficiência na higiene bucal, favorecem transtornos locais e sistêmicos. Assim, o estudo objetivou associar os DSS, no contexto das condições socioeconômicas, do acompanhamento pelo serviço de saúde e dos aspectos relacionados à saúde bucal de crianças atendidas em Unidades Básicas de Saúde (UBS) de um município cearense. Trata-se de estudo observacional, analítico, transversal e de abordagem quantitativa, conduzido com crianças e suas mães em Acarape - CE. Após consentimento, essas preencheram um questionário. Os dados foram analisados. Das 70 mães, 87,14% e 90,00% tinham idade inferior ou igual a 30 anos e renda de até um salário mínimo, respectivamente. Das 70 crianças, 87,14% tinham seus dentes/gengiva higienizados por seus pais ou responsável. Do total, 94,29% nunca se submeteram a atendimento odontológico. Observou-se associação significativa entre a mãe ter escolaridade superior ao ensino fundamental incompleto e higienizar os dentes/gengiva do filho com escova dental e dentifrício. Constatou-se associação significativa entre a criança ingerir bolacha doce/recheada, não consumir refrigerante e usar escova dental e dentifrício na higienização oral. Conclui-se que as crianças eram acompanhadas nas UBS regularmente; no entanto, esse serviço não esteve relacionado ao atendimento odontológico. Apesar da ausência desse tipo de acompanhamento e do consumo de alimentos cariogênicos, as mães se preocupavam com a saúde bucal das crianças, higienizando a cavidade oral diariamente, com meios adequados.

The immaturity of the immune system, associated with Social Determi- nants of Health (SDH), promotes diseases in childhood. Specifically, in the oral cavity, SDH, represented by high sugar consumption, limited access to health services, and poor oral hygiene, favors local and systemic disorders. Thus, the study aimed to associate the SDH, in the context of socioeconomic conditions, monitoring by the health service and aspects related to children's oral health assisted in Basic Health Units (BHU) of a muni- cipality in Ceará. This is an observational, analytical, cross-sectional study with a quan- titative approach conducted with children and their mothers in Acarape - CE. After con- sent, they filled out a questionnaire. Data were analyzed. Of the 70 mothers, 87.14% and 90.00% were aged less than or equal to 30 years and had income up to one minimum wage, respectively. Of the 70 children, 87.14% had their teeth/gums cleaned by their pa- rents or guardian. Of the total, 94.29% never underwent dental care. There was a signifi- cant association between the mother having higher education than incomplete elementary school and cleaning the child's teeth/gums with a toothbrush and toothpaste. A significant association was found between the child eating sweet/stuffed biscuits, not consuming soft drink, and using a toothbrush and dentifrice for oral hygiene. It is concluded that the chil- dren were regularly monitored at the BHU; however, this service was not related to dental care. Despite the absence of this type of follow-up and the consumption of cariogenic foods, the mothers were concerned about their children's oral health, cleaning the oral cavity daily with adequate means.

La inmadurez del sistema inmunológico, asociada a los Determinantes So- ciales de la Salud (DSS), promueve enfermedades en la infancia. Específicamente, en la cavidad bucal, los DSS, representados por el alto consumo de azúcar, el acceso limitado a los servicios de salud y la mala higiene bucal, favorecen los trastornos locales y sisté- micos. Así, el estudio tuvo como objetivo asociar el DSS, en el contexto de las condicio- nes socioeconómicas, el seguimiento por el servicio de salud y los aspectos relacionados con la salud bucal de los niños atendidos en las Unidades Básicas de Salud (UBS) de un municipio de Ceará. Se trata de un estudio observacional, analítico, transversal con enfo- que cuantitativo, realizado con niños y sus madres en Acarape ­ CE. Después del consen- timiento, completaron un cuestionario. Los datos fueron analizados. De las 70 madres, 87,14% y 90,00% tenían edad menor o igual a 30 años e ingresos hasta un salario mínimo, respectivamente. De los 70 niños, al 87,14% se les limpió los dientes/encías por sus pa- dres o tutores. Del total, el 94,29% nunca realizó atención odontológica. Hubo una aso- ciación significativa entre la madre con educación superior a la primaria incompleta y la limpieza de los dientes/encías del niño con cepillo y pasta dental. Se encontró una asoci- ación significativa entre el niño que come galletas dulces/rellenas, no consume gaseosas y usa cepillo de dientes y dentífrico para la higiene bucal. Se concluyó que los niños eran monitoreados periódicamente en la UBS; sin embargo, este servicio no estaba relacionado con el cuidado dental. A pesar de la ausencia de este tipo de seguimiento y del consumo de alimentos cariogénicos, las madres se preocupan por la salud bucal de sus hijos, reali- zando la limpieza de la cavidad bucal diariamente, con medios adecuados.

Adjuvant-dependent effects on the safety and efficacy of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Inactivated whole virus SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide (Alum) are among the most widely used COVID-19 vaccines globally and have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous virus infection in healthy recipients, the emergence of novel SARS-CoV-2 variants and the presence of large zoonotic reservoirs provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes including vaccine-associated enhanced respiratory disease (VAERD). To evaluate this possibility, we tested the performance of an inactivated SARS-CoV-2 vaccine (iCoV2) in combination with Alum against either homologous or heterologous coronavirus challenge in a mouse model of coronavirus-induced pulmonary disease. Consistent with human results, iCoV2 + Alum protected against homologous challenge. However, challenge with a heterologous SARS-related coronavirus, Rs-SHC014-CoV (SHC014), up to at least 10 months post-vaccination, resulted in VAERD in iCoV2 + Alum-vaccinated animals, characterized by pulmonary eosinophilic infiltrates, enhanced pulmonary pathology, delayed viral clearance, and decreased pulmonary function. In contrast, vaccination with iCoV2 in combination with an alternative adjuvant (RIBI) did not induce VAERD and promoted enhanced SHC014 clearance. Further characterization of iCoV2 + Alum-induced immunity suggested that CD4+ T cells were a major driver of VAERD, and these responses were partially reversed by re-boosting with recombinant Spike protein + RIBI adjuvant. These results highlight potential risks associated with vaccine breakthrough in recipients of Alum-adjuvanted inactivated vaccines and provide important insights into factors affecting both the safety and efficacy of coronavirus vaccines in the face of heterologous virus infections.

Barriers and facilitators to anal cancer screening among people living with HIV in Puerto Rico.

BACKGROUND: Anal cancer (AC) disproportionally affects people living with HIV (PLWH). Although there are no consensus-based AC screening guidelines, experts recommend anal pap as a primary screening tool in settings where high-resolution anoscopy (HRA) is available. We aimed to assess barriers and facilitators to anal cancer screening in a sample of Hispanic PLWH in Puerto Rico. METHODS: To assess their knowledge and attitudes, we conducted a cross-sectional survey from 2020-2021 among PLWH in Puerto Rico (n = 212). Data was collected through a telephone interview that assessed information on sociodemographics, knowledge, and attitudes about AC, and the history of AC screening. The chi-square test, Fisher exact test, and logistic regression models were used to assess factors associated with screening uptake. RESULTS: Anal Pap and HRA awareness were 60.4% and 30.7%, respectively. Anal Pap and HRA uptake was 51.5% and 19.3%, respectively. The most common barriers for anal Pap and HRA were lack of knowledge about the test and lack of physician recommendation. MSM were more likely to have heard of anal Pap (OR: 2.15, 95% CI:1.30-3.54) than MSW. MSM (OR: 3.04, 95% CI: 1.79-5.19) and women (OR: 3.00, 95% CI: 1.72-5.20) were also more likely to have undergone anal Pap. Similarly, individuals with a history of genital warts were more likely to have heard of anal Pap and HRA and have undergone anal Pap and HRA. Awareness of where to go for concerns about anal health was positively associated with having received anal Pap and HRA. CONCLUSIONS: With emerging evidence on the effectiveness of screening and treatment for anal cancer, several organizations are steering toward generating consensus-based anal cancer screening recommendations. Our study provides foundational data on barriers and facilitators to anal cancer screening in Puerto Rico that will be critical to informing screening implementation in this US territory.

Long-acting injectable multipurpose prevention technology for prevention of HIV and unplanned pregnancy.

Only condoms are proven to protect against both HIV and unplanned pregnancy, however, poor user acceptability and lack of partner cooperation impede effectiveness. We developed an injectable ultra-long-acting, biodegradable, and removable in-situ forming implant (ISFI) as multipurpose prevention technology (MPT). MPT ISFIs co-formulated an antiretroviral (dolutegravir (DTG)) or cabotegravir (CAB)), and a hormonal contraceptive (etonogestrel (ENG) or medroxyprogesterone acetate (MPA)). All formulations were well-tolerated in mice with no signs of chronic local or systemic inflammation. Plasma CAB and DTG concentrations were above 4× PA-IC90 for 90 days with zero-order and diffusion-controlled absorption, respectively, and no differences when co-formulated with either hormone. Plasma ENG and MPA concentrations were quantifiable for 90 days. Complete removal of CAB/MPA ISFIs resulted in MPA concentrations falling below the limit of quantification after 24 h post-removal, but incomplete CAB elimination from plasma. Collectively, we demonstrated the ability to co-formulate antiretrovirals with contraceptives in an ISFI that is well-tolerated with sustained plasma concentrations up to 90 days.

The anti-infective crotalicidin peptide analog RhoB-Ctn[1-9] is harmless to bovine oocytes and able to induce parthenogenesis in vitro.

Crotalicidin is a cathelicidin-related anti-infective (antimicrobial) peptide expressed in the venom glands of the South American rattlesnake Crotalus durissus terrificus. Congener peptides of crotalicidin, named vipericidins, are found in other pit vipers inhabiting South America. Crotalicidin is active against bacteria and pathogenic yeasts and has anti-proliferative activity for some cancer cells. The structural dissection of crotalicidin produced fragments (e.g., Ctn [15-34]) with multiple biological functionalities that mimic the native peptide. Another structural characteristic of crotalidicin and congeners is a unique repetitive stretch of amino acid sequences in tandem embedded in their primary structures. One of the encrypted vipericidn peptides (Ctn [1-9]) was synthesized, and the analog covalently conjugated with rhodamine B (RhoB-Ctn [1-9]) displayed considerable antimicrobial activity and selective cytotoxicity. Methods to evaluate antimicrobial peptides' toxicity include lysis of red blood cells (hemolysis) in vitro and cytotoxicity of healthy cultured cells (e.g., fibroblasts). Here, as a non-conventional model of toxicity, the bovine oocytes were exposed to two standardized concentrations of RhoB-Ctn [1-9], and embryo viability and development at its first stage of cleavage (division of cells) and blastocyst formation were evaluated. Oocytes treated with peptide at 10 and 40 µM induced cleavage rates of 44.94% and 51.53%, resulting in the formation of blastocysts of 7.07% and 11.73%, respectively. Light sheet microscopy and in silico prediction analysis indicated that RhoB-Ctn [1-9] peptide interacts with zona pellucida and internalizes into bovine oocytes and developing embryos. The ADMET prediction estimated good bioavailability of RhoB-Ctn [1-9]. In conclusion, the peptide appeared harmless to bovine oocytes and, remarkably, activated the parthenogenesis in vitro.

Developmental changes in individual alpha frequency: Recording EEG data during public engagement events.

Statistical power in cognitive neuroimaging experiments is often very low. Low sample size can reduce the likelihood of detecting real effects (false negatives) and increase the risk of detecting non-existing effects by chance (false positives). Here, we document our experience of leveraging a relatively unexplored method of collecting a large sample size for simple electroencephalography (EEG) studies: by recording EEG in the community during public engagement and outreach events. We collected data from 346 participants (189 females, age range 6-76 years) over 6 days, totalling 29 hours, at local science festivals. Alpha activity (6-15 Hz) was filtered from 30 seconds of signal, recorded from a single electrode placed between the occipital midline (Oz) and inion (Iz) while the participants rested with their eyes closed. A total of 289 good-quality datasets were obtained. Using this community-based approach, we were able to replicate controlled, lab-based findings: individual alpha frequency (IAF) increased during childhood, reaching a peak frequency of 10.28 Hz at 28.1 years old, and slowed again in middle and older age. Total alpha power decreased linearly, but the aperiodic-adjusted alpha power did not change over the lifespan. Aperiodic slopes and intercepts were highest in the youngest participants. There were no associations between these EEG indexes and self-reported fatigue, measured by the Multidimensional Fatigue Inventory. Finally, we present a set of important considerations for researchers who wish to collect EEG data within public engagement and outreach environments.

The Impact of Routine Vaccinations on Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching.

BACKGROUND: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias. OBJECTIVE: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus. METHODS: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD. RESULTS: For the Tdap/Td vaccine, 7.2% (n = 8,370) of vaccinated patients and 10.2% (n = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68-0.72) and ARR was 0.03 (95% CI, 0.02-0.03). For the HZ vaccine, 8.1% (n = 16,106) of vaccinated patients and 10.7% (n = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73-0.76) and ARR was 0.02 (95% CI, 0.02-0.02). For the pneumococcal vaccine, 7.92% (n = 20,583) of vaccinated patients and 10.9% (n = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71-0.74) and ARR was 0.02 (95% CI, 0.02-0.03). CONCLUSION: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential.

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.