Although women appear to be more vulnerable to alcohol-induced pathophysiology than men, the neurobiological basis for sex differences is largely unknown, partially because most studies on alcohol ...drinking are conducted in male subjects only. The present study examined sex differences in alcohol consumption in two rat strains, Long Evans and Wistar, using multiple behavioral paradigms. The effects of the estrous cycle on alcohol consumption were monitored throughout the study. The results indicated that females drank more alcohol than males when given either continuous or intermittent access to alcohol (vs. water) in their home cages (voluntary drinking). Under operant conditions, no sex or strain differences were found in drinking prior to development of alcohol dependence. However, upon dependence induction by chronic, intermittent alcohol vapor exposure, Wistar rats of both sexes substantially escalated their alcohol intake compared with their nondependent drinking levels, whereas Long Evans rats only exhibited a moderate escalation of drinking. Under these conditions, the estrous cycle had no effect on alcohol drinking in any strain and drinking model. Thus, strain, sex, and drinking conditions interact to modulate nondependent and dependent alcohol drinking. The present results emphasize the importance of including sex and strain as biological variables in exploring individual differences in alcohol drinking and dependence.
•Most studies on alcohol drinking are conducted in male subjects only.•Wistar and Long Evans female rats voluntary drank more alcohol than male rats.•There were no sex or strain differences in drinking under operant conditions.•Alcohol dependent Wistar but not Long Evans rats escalated their alcohol intake.•The estrous cycle did not affect drinking in any strain or experimental condition.
Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, ...preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac LCPT) with a delayed absorption profile.
Randomized prospective crossover study.
50 African American maintenance kidney recipients on stable IR-Tac dosing.
Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose.
Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype.
CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles.
∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4).
This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes.
Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT.
Registered at ClinicalTrials.gov, with study number NCT01962922.
Exposure to air pollution is one of the major risk factors contributing to the occurrence and development of chronic obstructive pulmonary disease (COPD). However, few studies have investigated the ...susceptibility of patients with COPD to air pollution. Here, we provided a study protocol. A panel study of a total of 480 samples to compare the response to air pollution exposure between 60 patients with COPD and 60 healthy control subjects has been performed in Beijing (the COPDB study) since May 2016. The health assessment and exposure evaluation methods used in this COPDB study are summarized here. Throat, exhaled breath and condensate, urine, serum, plasma, and blood samples, as well as cardiopulmonary function indexes were repeatedly collected over four visits. Indicators of inflammation, oxidative stress, infection, metabolic changes, and genetic differences were then analyzed. Personal and ambient levels of fine particles and their components, as well as gaseous pollutants were monitored during the follow-up period. Linear mixed-effects models were used to evaluate the associations between changes in biomarkers and exposure to air pollution in both patients with COPD and healthy control subjects. Based on the COPDB study, the susceptibility of COPD patients and underlying mechanisms, involving difference in inflammatory, infection, metabolic, and genetic response to different air pollutants, were investigated. Our preliminary result shows that air pollution-associated changes in heart rate were higher in COPD patients than the healthy controls. More investigations of the underlying mechanisms of the susceptibility are ongoing. This study has been registered in ChiCTR with the number of ChiCTR1900023692.
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•The COPDB study utilized the nested case-control design to assess the susceptibility of COPD patients to air pollution.•Many indicators of cardiopulmonary functions, inflammation, metabolic and genetic changes were analyzed.•The associations between health indicators and air pollutant exposure were determined.•The preliminary result shows an enhanced air pollution-associated increase in heart rate in COPD patients.
I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored coauthored more than 600 ...publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (
a
) discovery and characterization of the AHR CYP1 axis, (
b
) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (
c
) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (
d
) discovery and characterization of the
SLC39A8
gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.
•Average age of incisor eruption varied by up to 2.5 months between sire groups.•Eruption was completed over 3 months for some sires but over 6 months for others.•Eruption occurred earlier for ...animals that were heavier at 12 months of age.•Age at eruption was influenced more by weaning weight than growth rate post weaning.•Knowing the pattern of eruption for a specific genotype can help optimise the sale value.
The eruption of the first permanent incisors in sheep determines the classification of lamb and hogget and impacts the sale value of animals in Australia. This study tested the hypothesis that the age of incisor eruption would differ between progeny from different Merino sires and would occur earlier for progeny that were heavier at 12 months of age. The study utilised wether progeny at a site in Western Australia from 29 sires born in 2016 (n = 347) or 2017 (n = 553), and ewe and wether (castrated male) progeny at a second site in New South Wales from 29 sires born in 2017 (n = 713 ewes and 343 wethers) or 2018 (n = 638 ewes and 457 wethers). Classing of incisor eruption commenced at 10–11 months of age and was recorded monthly until 19 or 20 months of age at the two sites. The average age of incisor eruption varied by up to 2.5 months between sire groups (P < 0.001) and incisor eruption was completed for all progeny within a sire group over three months for some sires but over 6 months for other sires. Incisor eruption occurred earlier for animals that were heavier at 12 months of age (P < 0.001). The period when animals gained weight up to 12 months also influenced incisor eruption, as differences in liveweight at weaning had twice the effect on age of incisor eruption compared with differences in liveweight gain post-weaning at both sites. Estimated stage of maturity at 12 months of age had minimal effects on subsequent age of incisor eruption, and regardless, the large variation in age of incisor eruption between sires were not accounted for by liveweight or stage of maturity at 12 months. In addition to selecting Merino sires that produce progeny that can be sold as lamb at an older age, farmers may also benefit from understanding the pattern of the first permanent incisors eruption specific to their genotype and monitoring liveweights and liveweight change to optimise the time and value of animals at sale.
Skin of color (SOC) populations include those who identify as Black/African, Hispanic/Latinx, Asian/Pacific Islander, American Indian/Native Alaskan, Indigenous Australian, Middle Eastern, ...biracial/multiracial, or non-White; this list is far from exhaustive and may vary between and within cultures. Recent genetic and immunological studies have suggested that cutaneous inflammatory disorders (atopic dermatitis, psoriasis, and hidradenitis suppurativa) and malignancies (melanoma, basal cell carcinoma, and cutaneous T-cell lymphoma) may have variations in their immunophenotype among SOC. Additionally, there is growing recognition of the substantial role social determinants of health play in driving health inequalities in SOC communities. It is critically important to understand that social determinants of health often play a larger role than biologic or genetic factors attributed to “race” in health care outcomes. Herein, we describe the structural, genetic, and immunological variations and the potential implications of these variations in populations with SOC. This article underscores the importance of increasing the number of large, robust genetic studies of cutaneous disorders in SOC to create more targeted, effective therapies for this often underserved and understudied population. Part II of this CME will highlight the clinical differences in the phenotypic presentation of and the health disparities associated with the aforementioned cutaneous disorders in SOC.
Rhizobia are capable of establishing compatible symbiosis with their hosts of origin and plants in the cross-nodulation group that the hosts of origin belonged to. However, different from the normal ...peanut
Bradyrhizobium
(Type I strains), the Type II strains showed incompatible symbiosis with
Vigna radiata
. Here, we employed transposon mutagenesis to identify the genetic loci related to this incompatibility in Type II strain CCBAU 53363. As results, seven Tn
5
transposon insertion mutants resulted in an increase in nodule number on
V. radiata
. By sequencing analysis of the sequence flanking Tn
5
insertion, six mutants were located in the chromosome of CCBAU 53363, respectively encoding acyltransferase (L265) and hypothetical protein (L615)—unique to CCBAU 53363, two hypothetical proteins (L4 and L82), tripartite tricarboxylate transporter substrate binding protein (L373), and sulfur oxidation c-type cytochrome SoxA (L646), while one mutant was in symbiotic plasmid encoding alanine dehydrogenase (L147). Significant differences were observed in L147 gene sequences and the deduced protein 3D structures between the Type II (in symbiotic plasmid) and Type I strains (in chromosome). Conversely, strains in both types shared high homologies in the chromosome genes L373 and L646 and in their protein 3D structures. These data indicated that the symbiotic plasmid gene in Type II strains might have directly affected their symbiosis incompatibility, whereas the chromosome genes might be indirectly involved in this process by regulating the plasmid symbiosis genes. The seven genes may initially explain the complication associated with symbiotic incompatibility.
Chimpanzees are the closest living relatives of humans. The divergence between human and chimpanzee ancestors dates to approximately 6,5-7,5 million years ago. Genetic features distinguishing us from ...chimpanzees and making us humans are still of a great interest. After divergence of their ancestor lineages, human and chimpanzee genomes underwent multiple changes including single nucleotide substitutions, deletions and duplications of DNA fragments of different size, insertion of transposable elements and chromosomal rearrangements. Human-specific single nucleotide alterations constituted 1.23% of human DNA, whereas more extended deletions and insertions cover ~ 3% of our genome. Moreover, much higher proportion is made by differential chromosomal inversions and translocations comprising several megabase-long regions or even whole chromosomes. However, despite of extensive knowledge of structural genomic changes accompanying human evolution we still cannot identify with certainty the causative genes of human identity. Most structural gene-influential changes happened at the level of expression regulation, which in turn provoked larger alterations of interactome gene regulation networks. In this review, we summarized the available information about genetic differences between humans and chimpanzees and their potential functional impacts on differential molecular, anatomical, physiological and cognitive peculiarities of these species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune escaping from host herd immunity has been related to changes in viral genomic sequences. The study aimed to understand the diverse immune responses to different subtypes or genotypes of human ...respiratory syncytial virus (RSV) in pediatric patients.
The genomic sequences of different subtypes or RSV genotypes, isolated from Beijing patients, were sequenced and systematically analyzed. Specifically, the antiviral effects of Palivizumab and the cross-reactivity of human sera from RSV-positive patients to different subtypes or genotypes of RSV were determined. Then, the level of 38 cytokines and chemokines in respiratory and serum samples from RSV-positive patients was evaluated.
The highest nucleotide and amino acid variations and the secondary and tertiary structure diversities among different subtypes or genotypes of RSV were found in G, especially for genotype ON1 with a 72bp-insertion compared to NA1 in subtype A, while more mutations of F protein were found in the NH-2 terminal, including the antigenic site II, the target of Palivizumab, containing one change N276S. Palivizumab inhibited subtype A with higher efficiency than subtype B and had stronger inhibitory effects on the reference strains than on isolated strains. However, RSV-positive sera had stronger inhibitory effects on the strains in the same subtypes or genotypes of RSV. The level of IFN-α2, IL-1α, and IL-1β in respiratory specimens from patients with NA1 was lower than those with ON1, while there were higher TNFα, IFNγ, IL-1α, and IL-1β in the first serum samples from patients with ON1 compared to those with BA9 of subtype B.
Diverse host immune responses were correlated with differential subtypes and genotypes of RSV in pediatric patients, demonstrating the impact of viral genetics on host immunity.
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