Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.
To identify genetic variants ...important for bronchodilator drug response (BDR) in racially diverse children.
We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.
We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10
) and suggestive (P < 7.06 × 10
) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.
The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.
The individual effects of protein deficiency and energy restriction on liver response to low-hexachlorobenzene (HCB) exposure were investigated in adult male Wistar rats. In rats fed either the ...low-protein or control diet, the only effect caused by HCB was a decrease in paralysis time following an ip injection of zoxazolamine. This decrease was similar for both groups. In the animals subjected to energy restriction, HCB induced a greater decrease in paralysis time, an increase in the size of centrilobular hepatocytes, a lower liver DNA content and an increased concentration of HCB in the adipose tissue, compared with the control and protein-deficient groups. Our data suggest that energy restriction increases liver response to HCB, while protein deficiency does not impair the hepatic reaction to small doses of HCB exposure.
Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification and transverse-tubule (T-tubule) remodeling. Our objective was to ...investigate whether microtubule densification contributes to T-tubule remodeling and excitation-contraction coupling dysfunction in heart disease.
In a mouse model of pressure overload-induced cardiomyopathy by transaortic banding, colchicine, a microtubule depolymerizer, significantly ameliorated T-tubule remodeling and cardiac dysfunction. In cultured cardiomyocytes, microtubule depolymerization with nocodazole or colchicine profoundly attenuated T-tubule impairment, whereas microtubule polymerization/stabilization with taxol accelerated T-tubule remodeling. In situ immunofluorescence of heart tissue sections demonstrated significant disorganization of junctophilin-2 (JP2), a protein that bridges the T-tubule and sarcoplasmic reticulum membranes, in transaortic banded hearts as well as in human failing hearts, whereas colchicine injection significantly preserved the distribution of JP2 in transaortic banded hearts. In isolated mouse cardiomyocytes, prolonged culture or treatment with taxol resulted in pronounced redistribution of JP2 from T-tubules to the peripheral plasma membrane, without changing total JP2 expression. Nocodazole treatment antagonized JP2 redistribution. Moreover, overexpression of a dominant-negative mutant of kinesin 1, a microtubule motor protein responsible for anterograde trafficking of proteins, protected against JP2 redistribution and T-tubule remodeling in culture. Finally, nocodazole treatment improved Ca(2+) handling in cultured myocytes by increasing the amplitude of Ca(2+) transients and reducing the frequency of Ca(2+) sparks.
Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation-contraction coupling, and heart failure.
To determine the prevalence of COVID-19-related discrimination among major US racial/ethnic groups and estimate associations between discrimination, race/ethnicity, and other sociodemographic ...characteristics.
We conducted a nationally representative online survey of 5500 American Indian/Alaska Native, Asian, Black/African American, Hawaiian/Pacific Islander, Latino (English and Spanish speaking), White, and multiracial adults from December 2020 to February 2021. Associations between sociodemographic characteristics and COVID-19-related discrimination were estimated via multinomial logistic regression.
A total of 22.1% of the participants reported experiencing discriminatory behaviors, and 42.7% reported that people acted afraid of them. All racial/ethnic minorities were more likely than White adults to experience COVID-19-related discrimination, with Asian and American Indian/Alaska Native adults being most likely to experience such discrimination (discriminatory behaviors: adjusted odd ratio AOR = 2.59; 95% confidence interval CI = 1.73, 3.89; and AOR = 2.67; 95% CI = 1.76, 4.04; people acting afraid: AOR = 1.54; 95% CI = 1.15, 2.07; and AOR = 1.84; 95% CI = 1.34, 2.51). Limited English proficiency, lower education, lower income, and residing in a big city or the East South Central census division also increased the prevalence of discrimination.
COVID-19-related discrimination is common, and it appears that the pandemic has exacerbated preexisting resentment against racial/ethnic minorities and marginalized communities. Efforts are needed to minimize and discredit racially driven language and discrimination around COVID-19 and future epidemics. (
. 2022;112(3):453-466. https://doi.org/10.2105/AJPH.2021.306594).
Several studies have investigated the antinociceptive, immunomodulatory and anti-inflammatory properties of compounds found in the lavender essential oil (LEO), however to date, there is still lack ...of substantial data. The objective of this study was to assess the antioxidant, anti-inflammatory and antinociceptive effects of lavender essential oil. The 1,1-diphenyl-2-picrylhydrazyl radical decolorization assay was used for antioxidant activity evaluation. The anti-inflammatory activity was tested using two models of acute inflammation: carrageenan-induced pleurisy and croton oil-induced ear edema. The antinociceptive activity was tested using the pain model induced by formalin. LEO has antioxidant activity, which is dose-dependent response. The inflammatory response evoked by carrageenan and by croton oil was reduced through the pre-treatment of animals with LEO. In the pleurisy model, the drug used as positive control, dexamethasone, was more efficacious. However, in the ear swelling, the antiedematogenic effect of the oil was similar to that observed for dexamethasone. In the formalin test, LEO consistently inhibited spontaneous nociception and presented a similar effect to that of tramadol. The results of this study reveal (in vivo) the analgesic and anti-inflammatory activities of LEO and demonstrates its important therapeutic potential.
The present study had the following objectives: to compare random regression models (RRM) considering the time-dependent (days in milk, DIM) and/or temperature × humidity-dependent (THI) covariate ...for genetic evaluation; to identify the effect of genotype by environment interaction (G×E) due to heat stress on milk yield; and to quantify the loss of milk yield due to heat stress across lactation of cows under tropical conditions. A total of 937,771 test-day records from 3603 first lactations of Brazilian Holstein cows obtained between 2007 and 2013 were analyzed. An important reduction in milk yield due to heat stress was observed for THI values above 66 (−0.23 kg/day/THI). Three phases of milk yield loss were identified during lactation, the most damaging one at the end of lactation (−0.27 kg/day/THI). Using the most complex RRM, the additive genetic variance could be altered simultaneously as a function of both DIM and THI values. This model could be recommended for the genetic evaluation taking into account the effect of G×E. The response to selection in the comfort zone (THI ≤ 66) is expected to be higher than that obtained in the heat stress zone (THI > 66) of the animals. The genetic correlations between milk yield in the comfort and heat stress zones were less than unity at opposite extremes of the environmental gradient. Thus, the best animals for milk yield in the comfort zone are not necessarily the best in the zone of heat stress and, therefore, G×E due to heat stress should not be neglected in the genetic evaluation.
The presence of fruits provokes significant modifications in plant water relations and leaf gas exchange. The underlying processes driving these modifications are still uncertain and likely depend on ...the water deficit level. Our objective was to explain and track the modification of leaf-water relations by the presence of fruits and water deficit. With this aim, net photosynthesis rate (AN), stomatal conductance (gs), leaf osmotic potential (Ψπ), leaf soluble sugars and daily changes in a variable related to leaf turgor (leaf patch pressure) were measured in olive trees with and without fruits at the same time, under well-watered (WW) and water stress (WS) conditions. Leaf gas exchange was increased by the presence of fruits, this effect being observed mainly in WW trees, likely because under severe water stress, the dominant process is the response of the plant to the water stress and the presence of fruits has less impact on the leaf gas exchange. Ψπ was also higher for WW trees with fruits than for WW trees without fruits. Moreover, leaves from trees without fruits presented higher concentrations of soluble sugars and starch than leaves from trees with fruits for both WW and WS, these differences matching those found in Ψπ. Thus, the sugar accumulation would have had a dual effect because on one hand, it decreased Ψπ, and on the other hand, it would have downregulated AN, and finally gs in WW trees. Interestingly, the modification of Ψπ by the presence of fruits affected turgor in WW trees, the change in which can be identified with leaf turgor sensors. We conclude that plant water relationships and leaf gas exchange are modified by the presence of fruits through their effect on the export of sugars from leaves to fruits. The possibility of automatically identifying the onset of sugar demand by the fruit through the use of sensors, in addition to the water stress produced by soil water deficit and atmosphere drought, could be of great help for fruit orchard management in the future.
Within the family Adeleidae, Adelina spp. belong to a group of arthropod pathogens. These parasites have been reported to have a wide geographic distribution, however, there are no reports of these ...protists in the Canary Islands, Spain. One of the peculiarities of the life cycle of Adelina spp. is the participation of a predator, because fecundation and sporulation occur inside the body cavity, and so necessitate destruction of the definitive host. The involvement therefore of a ‘dispersion host’, which eats the definitive host and spreads the oocysts through its faeces, is critical for the maintenance of certain Adelina spp. On the island of Gran Canaria, adeleid oocysts have been found in stool samples from four animals, three California kingsnakes (Lampropeltis californiae), and one feral cat. These animals were part of a larger coprological study of vertebrate parasites (117 snakes, 298 cats), where pseudoparasitic elements were also recorded. L. californiae and feral cats are invasive species which are widespread across the island and this novel finding of Adelina spp. oocysts in their faeces suggests that they could also serve as potential sentinel species for arthropod parasites.
PDF
