The effect of natural toxicants and other chemicals on the kidney.

Repeated administration of ochratoxin A (OTA) caused renal morphological dose-related changes, that were associated with proximal tubular and glomerular damage the latter showing oedema and prominent PAS staining suggestive of glomerular basement membrane thickening. On the other hand, the combined administration of repeated doses of OTA and aflatoxin B[1] (2. 5 mg and 100 ug per kg, respectively), appeared to have a synergistic effect, characterized by severe disruption of proximal tubules and general morphological derrangement of the glomerulus, involving intense and faint staining nuclei (suggestive of cell necrosis) and cytoplasmic vacuolation, which was not seen with either toxin alone. When clinical biochemical parameters were measured after repeated administration of a low dose of OTA, enzymuria, glucosuria, polyuria and proteinuria were observed, with glucose and alkaline phosphatase as the most sensitive parameters. Metabolic studies performed in vitro showed that isolated pig and rat glomeruli incorporate different amino acids linearly for several hours at different rates and perform oxidative metabolism of glucose and fatty acids to CO[2] also linearly. For pig glomeruli the order of amino acid incorporation was LEU >> PRO = HIS > LYS > GLY and for rat glomeruli it was TRP >> PHE > TYR = LEU > PRO > HIS. The same amino acids were incorporated in a similar way in rat tubules, but the incorporation rate is 10-fold lower. When de novo synthesis of protein by pig glomeruli exposed to different chemicals was assessed, using proline (PRO) as the precursor, adriamycin (ADR) and ethacrynic acid (ETA) inhibited protein synthesis more than 2-bromoethanamine (BEA) and streptomycin (STR), and much more than puromycin aminonucleoside (PAN). When isolated rat glomeruli were exposed to low concentrations of OTA, there was a generalized inhibition on de novo synthesis of protein from the six amino acids tested and the aromatic amino acids (TRP, TYR and PHE) were more sensitive to OTA effect than PRO. Low concentrations of OTA (10 - 100 uM) enhanced glomerular and tubular glucose metabolism to CO[2] and only high concentrations of the mycotoxin (1000 uM) caused significant inhibition of glomerular and proximal tubular linolenic acid metabolism

The Impact of Incentivizing the Use of Feedback on Learning and Performance in Educational Videogames

Educational videogames can be designed to provide instructional feedback responsive to specific actions. However, existing research indicates that students tend to ignore the feedback provided. That is, students often use ineffective help-seeking strategies. Research on the topic of help-seeking in learning environments have primarily focused on the role of cognitive factors, the nature of the help, or issues of timing and frequency. There is a noticeable gap in understanding how to motivate the use provided feedback. This study examined the relation between incentivizing the use of feedback and providing an explanation of the game's scoring rules on math learning in a pre-algebra videogame. A randomized-control design was used, comparing learning outcomes of students who received the incentive with those who did not. Results indicated that students given the incentive to use feedback had significantly higher normalized change scores on math items (d = .53), with stronger effects for students with low academic intrinsic motivation (d = .88 - 1.17)

Plastic adjustments in xylem vessel traits to drought events in three Cedrela species from Peruvian Tropical Andean forests

Cedrela species occur within the Tropical montane cloud forest (TMCF) and rainforest in North America (Mexico), Central and South America. We assessed the hypothesis that functional xylem hydraulic architecture might be influenced by specific climatic variations. We investigated the effect of climate on tree-ring width and vessel traits (diameter, vessel density, vulnerability index and hydraulic diameter) of three relict-endemic and threatened Cedrela species (Cedrela fissilis, C. nebulosa and C. angustifolia) inhabiting Peruvian Tropical Andean cloud forests. All Cedrela species showed a significant reduction in radial growth and adjusted vessel trait linked with temperature, precipitation, and evapotranspiration. Ring-width and vessel traits showed adaptation within Cedrela species, crucial to understanding a rough indication of the plant’s ability to withstand drought-induced embolism or cavitation. Our results provide evidence for hydraulic mechanisms that determine specific wood anatomical functionality to climatic variation and drought responses. Therefore, changing the frequency or intensity of future drought events might exceed the adaptive limits of TMCF tree species, resulting in a substantial reduction of hydraulic functionality in Peruvian Cedrela species.Fil: Rodríguez Ramírez, Ernesto C.. Universidad Continental; PerúFil: Ferrero, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Acevedo-Vega, Ingrith. Universidad Continental; PerúFil: Crispin DelaCruz, Doris B.. Universidad Continental; Perú. Universidade Federal de Pernambuco; BrasilFil: Ticse Otarola, Ginette Vilma Alicia. Universidad Continental; Perú. Asociación ANDINUS; PerúFil: Requena Rojas, Edilson Jimmy. Universidad Continental; Per

Juxtaposition of Chemical and Mutation-Induced Developmental Defects in Zebrafish Reveal a Copper-Chelating Activity for Kalihinol F

SummaryA major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis, and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a copper-chelating activity. Our data support this mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying therapeutic and target pathways

A phase II trial of ixabepilone in Asian patients with advanced gastric cancer previously treated with fluoropyrimidine-based chemotherapy

PURPOSE: The highest rates of gastric cancer occur in Eastern Asia. Fluoropyrimidine-based therapy is used initially in unresectable and metastatic disease, but no single standard of care exists following disease progression. Ixabepilone, an epothilone B analog, is a non-taxane microtubule-stabilizing agent with clinical activity across multiple tumor types approved by the United States Food and Drug Administration for treatment of metastatic breast cancer. METHODS: Asian patients with unresectable or metastatic gastric adenocarcinoma who had failed fluoropyrimidine-based chemotherapy received ixabepilone 40 mg/m(2) by 3-h intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR). RESULTS: Fifty-two patients were treated (65.4 % men; median age: 56.5 years). The ORR was 15.4 % (95 % confidence interval [CI] 6.9-28.1); 8 patients achieved partial responses for a median duration of 3.1 months (95 % CI 2.6-4.1 months) and 26 patients (50.0 %) had stable disease. Median progression-free survival was 2.8 months (95 % CI 2.1-3.5 months). The most common grade 3 non-hematological toxicities were fatigue (9.6 %), decreased appetite (7.7 %), sensory neuropathy (5.8 %), and diarrhea (5.8 %). Grade 3/4 neutropenia occurred in 46.2 % of patients. CONCLUSIONS: Ixabepilone is active in Asian patients with advanced gastric cancer and shows a toxicity profile similar to those previously reported in other tumor types.published_or_final_versio

Revealing Polylepis microphylla as a suitable tree species for dendrochronology and quantitative wood anatomy in the Andean montane forests

In the tropical Andes climate change is expected to increase temperatures and change precipitation patterns. To overcome the lack of systematic weather records that limits the performance of climate models in this region, the use of the environmental information contained in tree rings from tropical Andean species have been found useful to reconstruct spatio-temporal climate variability. Because classical dendrochronology based on ring-width patterns is often challenging in the tropics, alternative approaches such as Quantitative Wood Anatomy (QWA) based on the measurement and quantification of anatomical traits within tree rings can be a significant advance in the field. Here we assess the dendrochronological potential of Polylepis microphylla and its climate sensitivity by using i) classic dendrochronological methods to generate the first Tree-ring Width (TRW) chronology for this tree species spanning from 1965 to 2018; ii) radiocarbon (¹⁴C) analyses as an independent validation method to assess the annual periodicity of the tree growth layers; and iii) QWA to generate tree-ring annual records of the number (VN) and size (VS) of vessels to investigate the climate sensitivity of these anatomical traits. The annual periodicity in P. microphylla radial growth was confirmed by both dendrochronological and ¹⁴C analyses. We found that VN and VS are promising new proxies to reconstruct climate variability in this region and that they provide different information than TRW. While TRW provides information at inter-annual resolution (i.e., year-to-year variability), VN and VS generated with sectorial QWA provide intra-annual resolution for each stage of the growing process. The TRW and the anatomical traits (i.e., VN and VS) showed strong positive correlation with maximum temperature for different periods of the growing season: while VS is higher with warmer conditions prior to the growing season onset, tree-rings are wider and present higher number of vessels when warmer conditions occur during the current growing season. Our findings pointed out the suitability of P. microphylla for dendrochronological studies and may suggest a good performance of this species under the significant warming expected according to future projections for the tropical Andes.Fil: Rodríguez Morata, C.. Columbia University; Estados UnidosFil: Pacheco Solana, A.. Columbia University; Estados UnidosFil: Ticse Otarola, Ginette Vilma Alicia. Universidad Continental; Perú. Asociación ANDINUS; PerúFil: Boza Espinoza, T. E.. Pontificia Universidad Católica de Perú; PerúFil: Crispín-DelaCruz, D.B.. Universidad Federal Rural Pernambuco; Brasil. Universidad Continental; PerúFil: Santos, G. M.. University of California; Estados UnidosFil: Morales, Mariano Santos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina. Universidad Continental; PerúFil: Requena Rojas, Edilson Jimmy. Universidad Continental; PerúFil: Andreu Hayles, Laia. Institució Catalana de Recerca I Estudis Avançats; España. Consejo Superior de Investigaciones Científicas. Centre de Recerca Ecológica I Aplicacions Forestals; España. Columbia University; Estados Unido

Adaptive genetic potential and plasticity of trait variation in the foundation prairie grass Andropogon gerardii across the US Great Plains’ climate gradient: Implications for climate change and restoration

Plant response to climate depends on a species’ adaptive potential. To address this, we used reciprocal gardens to detect genetic and environmental plasticity effects on phenotypic variation and combined with genetic analyses. Four reciprocal garden sites were planted with three regional ecotypes of Andropogon gerardii, a dominant Great Plains prairie grass, using dry, mesic, and wet ecotypes originating from western KS to Illinois that span 500–1,200 mm rainfall/year. We aimed to answer: (a) What is the relative role of genetic constraints and phenotypic plasticity in controlling phenotypes? (b) When planted in the homesite, is there a trait syndrome for each ecotype? (c) How are genotypes and phenotypes structured by climate? and (d) What are implications of these results for response to climate change and use of ecotypes for restoration? Surprisingly, we did not detect consistent local adaptation. Rather, we detected co-gradient variation primarily for most vegetative responses. All ecotypes were stunted in western KS. Eastward, the wet ecotype was increasingly robust relative to other ecotypes. In contrast, fitness showed evidence for local adaptation in wet and dry ecotypes with wet and mesic ecotypes producing little seed in western KS. Earlier flowering time in the dry ecotype suggests adaptation to end of season drought. Considering ecotype traits in homesite, the dry ecotype was characterized by reduced canopy area and diameter, short plants, and low vegetative biomass and putatively adapted to water limitation. The wet ecotype was robust, tall with high biomass, and wide leaves putatively adapted for the highly competitive, light-limited Eastern Great Plains. Ecotype differentiation was supported by random forest classification and PCA. We detected genetic differentiation and outlier genes associated with primarily precipitation. We identified candidate gene GA1 for which allele frequency associated with plant height. Sourcing of climate adapted ecotypes should be considered for restoration

Ethnoracial Disparities in SARS-CoV-2 Seroprevalence in a Large Cohort of Individuals in Central North Carolina from April to December 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths around the world within the past 2 years. Transmission within the United States has been heterogeneously distributed by geography and social factors with little data from North Carolina. Here, we describe results from a weekly cross-sectional study of 12,471 unique hospital remnant samples from 19 April to 26 December 2020 collected by four clinical sites within the University of North Carolina Health system, with a majority of samples from urban, outpatient populations in central North Carolina. We employed a Bayesian inference model to calculate SARS-CoV-2 spike protein immunoglobulin prevalence estimates and conditional odds ratios for seropositivity. Furthermore, we analyzed a subset of these seropositive samples for neutralizing antibodies. We observed an increase in seroprevalence from 2.9 (95% confidence interval [CI], 1.8 to 4.5) to 12.8 (95% CI, 10.6 to 15.2) over the course of the study. Latinx individuals had the highest odds ratio of SARS-CoV-2 exposure at 6.56 (95% CI, 4.66 to 9.44). Our findings aid in quantifying the degree of asymmetric SARS-CoV-2 exposure by ethnoracial grouping. We also find that 49% of a subset of seropositive individuals had detectable neutralizing antibodies, which was skewed toward those with recent respiratory infection symptoms

Updated guidance on the management of COVID-19:from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020)

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. METHODS: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. RESULTS: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. CONCLUSIONS: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.status: Published onlin