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The COVID-19 pandemic continues to affect several countries. One of the best ways to control its spread is the timely identification of infected patients for isolation and quarantine. While an episode of infection lasts an average of 8–10 days from the onset of symptoms, there is literature describing long-lasting viral persistence events. Here, we report a case of persistence of SARS-CoV-2 for 386 days in a health worker from Santiago de Chile. Our study could be one of the longest reported viral persistence events. RNA sequencing analyses indicated that the first positive diagnosis (8 June 2020) corresponded to a SARS-CoV-2 variant belonging to Clade Nextstrain 20A. Three hundred eighty-six days later (23 September 2021), the second positive result reached the same viral variant (Clade 20A) but without presence or circulation in Chile since May 2021. Both sequencing coverages showed an identity of 99.21%, with some mutations related to the severity of the disease (ORF1b:P314L) and more infectivity (S:D614G). This work reinforces the idea of implementing an RT-qPCR or rapid antigen test once the quarantine is fulfilled to ensure viral absence, identify potential persistence, and, consequently, minimize the risk of local outbreaks of SARS-CoV-2 infection.

Paralichthys adspersus is a native species from the Pacific coast of South America that is of great economic importance for Peruvian aquaculture. Even though establishing sustainable farming depends on avoiding irreversible damage to the population gene pool due to processes such as inbreeding, studies focusing on genetically characterizing farmed stocks are yet to be documented. By using ten microsatellite loci on captive and wild individuals of P. adspersus, we successfully characterized the only commercial broodstock of this species in Peru by means of determining the genetic diversity and inferring relatedness. Although most microsatellite loci showed deviations from Hardy-Weinberg equilibrium, the genetic diversity levels in the commercial broodstock were considered healthy compared to those obtained for a wild population, with an average number of alleles of 17.40, an effective number of alleles of 9.14, and an observed and expected heterozygosity of 0.49 and 0.87. No significant differences between the broodstock and the wild population in terms of genetic diversity were observed. The fixation index and analysis of molecular variance also indicated a low rate of differentiation between both populations. In relatedness estimation, the analysis based on five method-of-moment estimators and a maximum-likelihood estimator showed the category “unrelated” as being the most probable relationship among the individuals within the commercial broodstock. Our findings reveal the conservation of genetic diversity in this population and outline potential breeding strategies that hatchery managers could use to minimize the loss of genetic diversity and long-term inbreeding. This could help establish proper genetic management in captive populations of P. adspersus and should apply to other captive stocks where pedigree information is lacking.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Universidad Nacional Autonoma de Honduras. Introduction Cardiovascular diseases constitute the majority of Noncommunicable Diseases deaths worldwide. In Honduras, cardiovascular diseases represent the fifth cause of death between 45 to 49 years old; 20% of emergency room visits are due to cerebrovascular events, heart failure and acute myocardial infarction. Purpose Create a low-cost ECG and digital platform that provides portability and connectivity with mobile devices and automated diagnosis to support clinicians in primary care. Methods A low-cost 3-lead ECG (Handy EKG) was developed under the technological project approach, which has two general stages: (i) platform design and (ii) field validation. The hardware design was carried out by comparing microcontrollers, 3D printing the cases and beta testing with volunteers to accomplish prototype stability. Second, the mobile application and web platform were designed to host the reference database and establish live communication between the mobile phone and the machine learning process. During the validation stage, an automatic learning model was designed to allow the device to learn from each reading and provide a possible automatic diagnosis to the user. Fifty-one device readings were performed on volunteers and compared with those obtained with a conventional 12-lead ECG and interpreted by clinicians. The results were analysed by calculating central tendency and standard deviation measures, comparing the duration, amplitude and morphology of the different ECG waves, complexes and relevant segments both on the conventional and those made with the prototype. Results The device provided readings of lead 1 of a standard 12-lead ECG to monitor and diagnose bradyarrhythmia and tachyarrhythmias. In addition, it was found that it is possible to obtain leads II and III by alternating the positioning of the electrodes. 96% (49) of the readings showed a similarity in morphology, amplitude and duration of waves, segments and complexes that allowed an interpretation of the trace. In the two cases (4%) where there was a difference, the diagnosis with the conventional ECG was pathological (abnormal). However, the diagnosis with the prototype was non-pathological (normal). Conclusion The clinical study results indicated that the designed platform was safe, had good quality in its operation at all levels and provided results that allow diagnoses equivalent to those of a conventional ECG in most cases. However, the 3-lead capacity shows a lower capacity to detect other pathologies that require a 12-lead or 15-lead ECG. The tests also showed that the prototype is more sensitive to noise (interference) than the conventional device, which made some readings difficult, which is considered one of the immediate steps to improve. The current results open the way to developing more prototypes and conducting larger-scale studies where cardiologists and a more significant number of patients with diagnosed cardiac pathologies.

Mice body weights follow-up during KW-2450 treatment.

Cell cycle profile in p53-wild breast cancer cells treated with KW-2450.

Inhibitory activity of KW-2450 against p-IGF-IR in TNBC cells.

SA-beta-gal assay with KW-2450 in TNBC cells.

Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and, because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell-cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed, this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition. Mol Cancer Ther; 14(12); 2687–99. ©2015 AACR.

Knockout of p53 in HCT116 colon cancer cells treated with KW-2450.

Knockdown of Mad2 or BubR1 in TNBC cells treated with KW-2450.

Inhibitory activity of KW-2450 against CD44+CD24- cancer stem cells in TNBC.

Mitotic accumulation induced by KW-2450 in TNBC cells.

Knockdown of IGF-IR or InsR in TNBC cells.

PDF file, 54K, Estimation of percentage of patients to achieve TSC (15 ug/mL) at Ctrough ss with Q3W dose regimen.

PDF file, 3179K, Representative for visual predictive check.

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PDF file, 1199K, Tumor growth inhibition.

PDF file, 2424K, Observed individual concentration-time profile of onartuzumab in human in comparison with cyno-based prediction.

PDF file, 1651K, Representative individual fits.

PDF file, 2444K, Basic goodness-of-fit plots for PK-PD modeling in KP4 tumor-bearing mice.

Purpose: We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration–effect relationship in tumor-bearing mice to enable estimation of clinical pharmacokinetics and target doses.Experimental Design: A tumor growth inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 3-week (Q3W) dosing.Results: Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 μg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve Ctrough ss of 15 μg/mL in 95% or more of patients.Conclusions: Onartuzumab pharmacokinetics differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 μg/mL as the Ctrough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 μg/mL. These data show effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested in the clinic. Clin Cancer Res; 19(18); 5068–78. ©2013 AACR.

PDF file, 967K, Onartuzumab tumoristatic concentration range.

Supplementary Figure 6 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 2 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 1 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 4 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure Legends 1-6 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 3 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Tables 1 - 4 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

Supplementary Figure 5 from A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life

The productivity of mangrove ecosystems is associated with litterfall production, which continuously contributes large quantities of organic matter, in the form of detritus, to the food web via adjacent ecosystems. However, the degree of deterioration of mangrove ecosystems worldwide has been increasing due to anthropogenic activities, leading to the loss of vegetation cover and changes in hydrological patterns, the chemical conditions of interstitial water and soil, and the litterfall degradation rate and, thus, the integration of organic matter into the ecosystem. In this study, we investigate the relationship between leaf degradation and interstitial water chemistry in two mangrove forests located in Oaxaca, Mexico, that are characterized by differences in environmental conditions, species, and anthropogenic activity. Forty-two 10 cm × 20 cm nylon mesh bags were installed in the Rhizophora mangle forest along two flood-associated lines (21 per line), and twenty-one bags were installed centrally in the Avicennia germinans forest because of the flood conditions in this area. Three bags per line were collected each month. This material was then dried and calcined for determination of the decomposition rate (k). The in situ redox potential and interstitial water salinity of mangrove forests were measured using a HACH HQ40d multiparametric probe and A&O refractometer, and the sulfate concentration was determined by ion chromatography. The results show that daily average decomposition rates were higher in the Salina lagoon (k = 0.01 g·day−1) than in the Chacahua lagoon (k = 0.004 g·day−1). The degradation model was Y = 66.054e−0.010t, R2 = 0.89, p ≤ 0.05, for the Salina lagoon and Y = 67.75e−0.004t, R2 = 0.76, p ≤ 0.05, for the Chacahua lagoon. Leaf decomposition rates differed between the Salina and Chacahua lagoons (F1,206 = 4.8, p < 0.03). In the Salina lagoon, dominated by A. germinans, an inverse relationship was established between the percentage of degraded biomass with respect to salinity concentration (R2 = 0.82, p < 0.013) and redox potential (R2 = 0.89, p < 0. 015), and for the Chacahua lagoon, dominated by R. mangle, the percentage of degraded litter biomass was found to be inversely correlated with redox potential (R2 = 0.94, p < 0.005) and sulfate concentration (R2 = 0.88, p < 0.017). Based on the results obtained in this study, we conclude that variations in the chemical conditions of interstitial water and hydrological patterns can affect the process of mangrove leaf degradation based on species and the integration of organic matter in the soil and in adjacent ecosystems. These findings are potentially useful for mangrove management because they advance understanding of the dynamics of organic matter in mangroves and the importance of maintaining the health of these ecosystems, which is necessary for the maintenance of coastal fishing production.

El presente estudio muestra la caracterización mineralógica de un concentrado de Pb proveniente del distrito minero de Zimapán, Hidalgo, México; así como el análisis preliminar de lixiviación de este concentrado, utilizando iones de zinc y la inyección de oxígeno para favorecer la reacción de disolución de plata en el sistema propuesto. La técnica de difracción de rayos X (DRX) confirmó la matriz de la muestra mineral correspondiente a un sulfuro de plomo (PbS [COD 96-901-3404]) y la presencia de otras especies minerales como esfalerita (ZnS [COD 96-110-1051]), calcopirita (CuFeS2 [COD 96-901-5235]) y Lenaita (AgFeS2 [COD 96-900-4980]) donde se identificó el contenido de plata. Por otro lado, la técnica de microscopia óptica de polarización (MOP) permitió corroborar la matriz del concentrado, además de la presencia de especies minoritarias como pirita (FeS2), calcopirita (CuFeS2), arsenopirita (FeAsS) y esfalerita (ZnS). Mediante microscopia electrónica de barrido-análisis de energía dispersivas (MEB-EDS) se obtuvo el análisis semicuantitativo de los elementos Pb, Al, As, Cu, Fe, S y Si, así como la relación elemental de los contenidos metálicos mediante el mapeo realizado a la muestra mineral. La morfología irregular de las partículas del concentrado fue confirmada por micrografías obtenidas mediante electrones secundarios y retrodispersados. Finalmente, se muestran los resultados obtenidos de la propuesta de lixiviación, en donde la mayor recuperación de plata se obtiene en el sistema S2O3-2-O2-Zn2+.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies decay but persist 6 months postvaccination; lower levels of neutralizing titers persist against Delta than wild-type virus. Of 227 vaccinated healthcare workers tested, only 2 experienced outpatient symptomatic breakthrough infections, despite 59/227 exhibiting serologic evidence of SARS-CoV-2 infection, defined as presence of nucleocapsid protein antibodies.

The main aim of this study is to offer an easy and practical research model to guide the research activity of students and thereby reduce the syndrome of ABD (All but Dissertation) and, at the same time, make it easier for evaluators to visualize the development of research projects to guide students more efficiently. The Canvas model proposed by Osterwalder and Pigneur in 2011—for the formulation of business plans—has been the source of inspiration for the instrument proposed by the authors of this study. That model has been adjusted and reformulated by the researchers for the development, synthesis, and presentation of the research projects in the academic field, resulting in the proposal of the Canvas Model for Research Projects (CMRP). For developing this instrument, the researchers have mainly used a qualitative methodology, although part of the analysis and proposals reflected in this study come from a brief empirical trial carried out with a small group of students to validate the configuration and utility of the ten elements that make up the proposed model. The result—both the documentary review, which served as the basis for the combination and distribution of the components of the proposed model, and the brief trial carried out by the researchers—allowed us to observe, in a first approach, the usefulness of the instrument in the preparation of research projects and its utility as an evaluation tool of academic research projects.

Ca2+is a fundamental determinant of survival in living cells. Excessive intracellular Ca2+causes cellular toxicity and death but the genetic pathways contributing to Ca2+induced cell death are incompletely understood. Here, we performed genome-wide CRISPR knock-out screening in human cells challenged with the Ca2+ionophore ionomycin and identified genes and pathways essential for cell death after Ca2+overload. We discovered 115 protective gene knockouts, 82 of which are non-essential genes and 21 of which belong to the druggable genome. Notably, members of store operated Ca2+entry (SOCE), very long-chain fatty acid synthesis, and SWItch/Sucrose Non-Fermentable (SWI/SNF) pathways provided marked protection against Ca2+toxicity. These results reveal pathways previously unknown to mediate Ca2+-induced cell death and provide a resource for the development of pharmacotherapies against the sequelae of Ca2+overload in disease.

Il n'existe à ce jour aucune méthode permettant de calculer des efficacités de collecte pour des gouttes présentant des oscillations. Pour surmonter cette limitation, une approche eulérienne pour simuler les écoulement internes et externes à la goutte est couplée à une approche lagrangienne pour simuler le transport des aérosols Les écoulements sont simulés par Simulation numérique directe (DNS), en résolvant numériquement les équations incompressibles de Navier-Stokes. La dynamique de l'interface liquide/gaz est modélisée à l'aide des méthodes Volume of Fluid (VOF) et Level Set (Vaudor et al. 2017). Le transport des aérosols est simulé en appliquant itérativement la deuxième loi de Newton, en prenant en compte la force de traînée et le mouvement brownien. Nous montrons que cette approche, appliquée à des gouttes ne présentant aucune oscillation permet de calculer des efficacités de collecte très proches des résultats de la littérature. Cette première étape nous a permis de valider une méthodologie qui permet dans un second temps d'évaluer les efficacités de collecte pour de gouttes présentant des oscillations., At this time, there is no existing method for calculating collection efficiencies for drops exhibiting oscillations. To overcome this limitation, an Eulerian approach to simulate the internal and external flows to the drop is coupled with a Lagrangian approach to simulate the transport of aerosols. The flows are simulated by Direct Numerical Simulation (DNS), by numerically solving the incompressible Navier-Stokes equations. The dynamics of the liquid/gas interface is modeled using the Volume of Fluid (VOF) and Level Set methods (Vaudor et al. 2017). Aerosol transport is simulated by iteratively applying Newton's second law, considering drag force and Brownian motion. We show that this approach, applied to drops presenting no oscillation, allows to calculate collection efficiencies very close to the results of the literature. This first step allowed us to validate a methodology which allows in a second time to evaluate the collection efficiencies for drops presenting oscillations.