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Viruses Jun 2024The Omicron variant and its sub-lineages are the only current circulating SARS-CoV-2 viruses worldwide. In this study, the conformational stability of the isolated...
The Omicron variant and its sub-lineages are the only current circulating SARS-CoV-2 viruses worldwide. In this study, the conformational stability of the isolated Receptor Binding Domain (RBD) of Omicron's spike protein is examined in detail. The parent Omicron lineage has over ten mutations in the ACE2 binding region of the RBD that are specifically associated with its β hairpin loop domain. It is demonstrated through biophysical molecular computations that the mutations in the β hairpin loop domain significantly increase the intra-protein interaction energies of intra-loop and loop-RBD interactions. The interaction energy increases include the formation of new hydrogen bonds in the β hairpin loop domain that help stabilize this critical ACE2 binding region. Our results also agree with recent experiments on the stability of Omicron's core β barrel domain, outside of its loop domain, and help demonstrate the overall conformational stability of the Omicron RBD. It is further shown here through dynamic simulations that the unbound state of the Omicron RBD remains closely aligned with the bound state configuration, which was not observed for the wild-type RBD. Overall, these studies demonstrate the significantly increased conformational stability of Omicron over its wild-type configuration and raise a number of questions on whether conformational stability could be a positive selection feature of SARS-CoV-2 viral mutational changes.
Topics: Spike Glycoprotein, Coronavirus; SARS-CoV-2; Mutation; Protein Binding; Humans; Molecular Dynamics Simulation; Angiotensin-Converting Enzyme 2; Protein Conformation; Protein Domains; Protein Stability; COVID-19; Binding Sites
PubMed: 38932204
DOI: 10.3390/v16060912 -
Viruses May 2024Papaya ringspot virus (PRSV) limits papaya production worldwide. Previously, we generated transgenic lines of hybrid Tainung No.2 (TN-2) carrying the coat protein (CP)...
Papaya ringspot virus (PRSV) limits papaya production worldwide. Previously, we generated transgenic lines of hybrid Tainung No.2 (TN-2) carrying the coat protein (CP) gene of PRSV with broad resistance to PRSV strains. Unfortunately, all of them were female, unacceptable for growers and consumers in practical applications. With our reported flanking sequences and the newly released papaya genomic information, the CP-transgene insert was identified at a non-coding region in chromosome 3 of the papaya genome, and the flanking sequences were verified and extended. The female transgenic line 16-0-1 was first used for backcrossing with the parental Sunrise cultivar six times and then followed by selfing three times. With multi-level molecular markers developed from the PRSV CP transgene and the genomic flanking sequences, the presence and zygosity of the CP transgene were characterized at the seedling stage. Meanwhile, hermaphrodite genotype was identified by a sex-linked marker. With homozygotic transgene and horticultural properties of Sunrise, a selected hermaphrodite individual was propagated by tissue culture (TC) and used as maternal progenitor to cross with non-transgenic parental cultivar Thailand to generate a new hybrid cultivar TN-2 with a hemizygotic CP-transgene. Three selected hermaphrodite individuals of transgenic TN were micropropagated by TC, and they showed broad-spectrum resistance to different PRSV strains from Taiwan, Hawaii, Thailand, and Mexico under greenhouse conditions. The selected clone TN-2 #1, with excellent horticultural traits, also showed complete resistance to PRSV under field conditions. These selected TC clones of hermaphrodite transgenic TN-2 provide a novel cultivation system in Taiwan and elsewhere.
Topics: Carica; Potyvirus; Plants, Genetically Modified; Disease Resistance; Plant Diseases; Transgenes; Capsid Proteins; Genome, Plant; Chromosome Mapping
PubMed: 38932116
DOI: 10.3390/v16060823 -
Pharmaceutics May 2024Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of...
Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine's Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes.
Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ's nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent-metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus. The model was utilized for Drug-Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ's nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUC ratio was 0.49 (slightly outside of the two-fold range). CBZ's nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer.
PubMed: 38931859
DOI: 10.3390/pharmaceutics16060737 -
Pharmaceutics May 2024We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence...
We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence (Q/D)-(R/K)-X-X-A-(Gln/Asp)-(Arg/Lys)-AA-AA-Ala-based on a motif called "shared epitope (SE)", specifically present in specific alleles of the gene. This SE binds to a particular site within the proline reach domain (P-domain) of the cell surface-calreticulin (CS-CRT). CS-CRT is a multifunctional endoplasmic reticulum (ER) calcium-binding protein that is located on the cell surface of T cells and triggers innate immune signaling, leading to the development of inflammatory autoimmune diseases. The development of Clarstatin was based on the parent peptide W-G-D-K-S-G-A- derived from the active region of the SE. Following the design based on the cycloscan method, the synthesis of Clarstatin was performed by the Fmoc solid phase peptide synthesis (SPPS) method, purified by HPLC to 96% homogeneity, and its structure was confirmed by LC-MS. Clarstatin reduced calcium levels in Jurkat lymphocyte cultures, ameliorated uveitis in vivo in the experimental autoimmune uveitis (EAU) mice model, and was safe upon acute toxicity evaluation. These findings identify Clarstatin as a promising lead compound for future drug development as a novel class of therapeutic agents in the therapy of uveitis.
PubMed: 38931845
DOI: 10.3390/pharmaceutics16060723 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances... (Review)
Review
Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.
PubMed: 38931425
DOI: 10.3390/ph17060758 -
Pharmaceuticals (Basel, Switzerland) May 2024Autism Spectrum Disorder (ASD) encompasses a wide range of neurodevelopmental conditions characterized by deficits in social interaction, communication and behavior....
Clinical and Family Implications of Cannabidiol (CBD)-Dominant Full-Spectrum Phytocannabinoid Extract in Children and Adolescents with Moderate to Severe Non-Syndromic Autism Spectrum Disorder (ASD): An Observational Study on Neurobehavioral Management.
Autism Spectrum Disorder (ASD) encompasses a wide range of neurodevelopmental conditions characterized by deficits in social interaction, communication and behavior. Current pharmacological options are limited and feature significant side effects. In this study, we conducted a retrospective, observational, and cross-sectional cohort study to evaluate the effects of Cannabidiol (CBD)-dominant, full-spectrum cannabis extract, containing Tetrahydrocannabinol (THC) in a ratio of 33:1 (CBD:THC), on non-syndromic children and adolescents (5-18 years old) with moderate to severe ASD. Thirty volunteers were recruited, underwent neuropsychological evaluations and were treated with individualized doses of CBD-dominant extract. Clinical assessments were conducted by the designated clinician. Additionally, parents or caregivers were independently interviewed to assess perceived treatment effects. We found significant improvements in various symptomatic and non-symptomatic aspects of ASD, with minimal untoward effects, as reported by both clinical assessments and parental perceptions. The observed improvements included increased communicative skills, attention, learning, eye contact, diminished aggression and irritability, and an overall increase in both the patient's and family's quality of life. Despite its limitations, our findings suggest that treatment with full-spectrum CBD-dominant extract may be a safe and effective option for core and comorbid symptoms of ASD, and it may also increase overall quality of life for individuals with ASD and their families.
PubMed: 38931353
DOI: 10.3390/ph17060686 -
Nutrients Jun 2024Malnutrition among adolescents is a major public health issue. This problem is particularly pressing in Sudan, an African country where there is scarce published data on...
BACKGROUND
Malnutrition among adolescents is a major public health issue. This problem is particularly pressing in Sudan, an African country where there is scarce published data on the nutritional status of adolescents. In this study, we aimed to assess the nutritional status of adolescents in eastern Sudan.
METHODS
A community-based cross-sectional survey was carried out in Gadarif, eastern Sudan. A questionnaire was used to collect sociodemographic data, and the anthropometric measurements (weight and height) of adolescent participants were recorded. Height-for-age and body mass index-for-age Z-scores were calculated using the WHO anthropometric standards. Binary and multivariate multinomial regression analyses were performed.
RESULTS
A total of 388 adolescents were included in this survey, 207 (53.4%) were female, and 181 (46.6%) were male. The median (interquartile) age was 13.9 (12.0-16.0) years. The results showed that a total of 29 (7.5%), 93 (24.0%), 33 (8.5%), and 16 (4.1%) adolescents were stunted, thin, overweight, and obese, respectively. None of the investigated factors (age, sex, parents' education levels, and occupation) were associated with stunting. In the multivariate multinomial analysis, the male sex was associated with thinness (OR = 2.41, 95.0% CI = 1.47-3.94). Moreover, adolescents whose mothers had an education lower than secondary level were at a lower risk of overweight/obesity (OR = 0. 0.35, 95.0% CI = 0. 0.35).
CONCLUSIONS
While both undernutrition and overnutrition exist in eastern Sudan, undernutrition is more common. Male sex and mothers' education levels are associated with malnutrition.
Topics: Humans; Sudan; Female; Male; Adolescent; Cross-Sectional Studies; Nutritional Status; Child; Thinness; Malnutrition; Body Mass Index; Growth Disorders; Overweight
PubMed: 38931290
DOI: 10.3390/nu16121936 -
Nutrients Jun 2024The purpose of this research was to assess the growth, tolerance, and compliance outcomes associated with the consumption of a hydrolyzed rice infant formula (HRF)...
BACKGROUND
The purpose of this research was to assess the growth, tolerance, and compliance outcomes associated with the consumption of a hydrolyzed rice infant formula (HRF) enriched with 2'-Fucosyllactose (2'-FL) a Human Milk Oligosaccharide (HMO), and nucleotides in an intended population of infants.
METHODS
This was a non-randomized single-group, multicenter study. The study formula was a hypoallergenic HRF with 2'-FL, Docosahexaenoic acid (DHA), Arachidonic acid (ARA), and nucleotides. Infants 0-90 days of age who were formula fed and experiencing persistent feeding intolerance symptoms, symptoms of suspected food protein (milk and/or soy) allergy, or other conditions where an extensively hydrolyzed infant formula was deemed an appropriate feeding option were recruited by pediatricians from their local populations. The primary outcome was maintenance of weight-for-age z-score. Weight, length, head circumference, formula intake, tolerance measures, clinical symptoms and questionnaires were collected. Thirty-three infants were enrolled, and 27 completed the study, on study product.
RESULTS
Weight-for-age z-scores of infants showed a statistically significant improvement from Visit 1 to Visit 4 ( = 0.0331). There was an adequate daily volume intake of 762 ± 28 mL/day, average daily number of stools of 2.1 ± 0.3, and mean rank stool consistency of 2.38 ± 0.18. After 28 days of switching to a HRF, 86.8 ± 5.9% of the symptoms resolved or got better by Visit 4 as reported by parents.
CONCLUSIONS
HRF with 2'-FL HMO was safe, well tolerated, and supported weight gain in infants with suspected cow's milk allergy or persistent feeding intolerance.
Topics: Humans; Infant Formula; Trisaccharides; Infant; Milk, Human; Oryza; Female; Male; Oligosaccharides; Infant, Newborn; Infant Nutritional Physiological Phenomena
PubMed: 38931218
DOI: 10.3390/nu16121863 -
Nutrients Jun 2024Low levels of vitamin D in maternal and cord blood have been associated with neonatal sepsis. This study assessed the association of vitamin D metabolites (25(OH)D,...
Low levels of vitamin D in maternal and cord blood have been associated with neonatal sepsis. This study assessed the association of vitamin D metabolites (25(OH)D, 3-epi-25(OH)D, and 24,25(OH)D) levels in maternal and cord blood with newborn sepsis evaluation in Nigerian mother-infant dyads. Maternal and cord blood from 534 mothers and 536 newborns were processed using liquid chromatography-tandem mass spectrometry. Spearman correlation was used to compare continuous variables, Mann-Whitney for dichotomous variables, and Kruskal-Wallis for two or more groups. High cord percent 3-epi-25(OH)D levels were positively associated with newborn evaluation for sepsis ( = 0.036), while maternal and cord 25(OH)D and 24,25(OH)D levels were not. Being employed was positively associated with maternal and newborn 3-epi-25(OH)D concentrations ( = 0.007 and = 0.005, respectively). The maternal 3-epi-25(OH)D and percent 3-epi-25(OH)D were positively associated with vaginal delivery ( = 0.013 and = 0.012, respectively). Having a weight-for-age Z-score ≤ -2 was positively associated with newborn percent 3-epi-25(OH)D levels ( = 0.004), while a weight-for-length Z-score ≤ -3 was positively associated with maternal and newborn percent 3-epi-25(OH)D levels ( = 0.044 and = 0.022, respectively). Our study highlights the need to further investigate the biological role of 3-epi-25(OH)D and its clinical significance in fetal growth and newborn outcome.
Topics: Humans; Female; Nigeria; Infant, Newborn; Adult; Fetal Blood; Vitamin D; Pregnancy; Vitamin D Deficiency; Young Adult; Neonatal Sepsis; Mothers; Male; Tandem Mass Spectrometry
PubMed: 38931212
DOI: 10.3390/nu16121857 -
Nutrients Jun 2024Growing evidence indicates that human milk oligosaccharides (HMOs) are important bioactive compounds that enhance health and developmental outcomes in breastfed babies....
Growing evidence indicates that human milk oligosaccharides (HMOs) are important bioactive compounds that enhance health and developmental outcomes in breastfed babies. Maternal dietary intake likely contributes to variation in HMO composition, but studies identifying diet-HMO relationships are few and inconsistent. This study aimed to investigate how the maternal intake of macronutrients and micronutrients-specifically proteins, fats, vitamins, and minerals-associated with HMOs at 1 month (n = 210), 6 months (n = 131), and 12 months postpartum (n = 84). Several associations between maternal dietary factors and HMO profiles were identified utilizing partial correlation analysis. For example, maternal free sugar (rho = -0.02, < 0.01), added sugar (rho = -0.22, < 0.01), and sugary sweetened beverage (rho = -0.22, < 0.01) intake were negatively correlated with the most abundant HMO, 2'-fucosyllactose (2'-FL), at 1 month, suggesting that higher sugar consumption was associated with reduced levels of 2'-FL. Further, vitamins D, C, K, and the minerals zinc and potassium were positively correlated with 2'-FL at 1 month (p < 0.05). For the longitudinal analysis, a mixed-effects linear regression model revealed significant associations between maternal vitamin intake and HMO profiles over time. For example, for each unit increase in niacin intake, there was a 31.355 nmol/mL increase in 2'-FL concentration ( = 0.03). Overall, the results provide additional evidence supporting a role for maternal nutrition in shaping HMO profiles, which may inform future intervention strategies with the potential of improving infant growth and development through optimal HMO levels in mothers' milk.
Topics: Humans; Milk, Human; Female; Oligosaccharides; Adult; Maternal Nutritional Physiological Phenomena; Hispanic or Latino; Diet; Young Adult; Infant; Breast Feeding; Trisaccharides; Vitamins; Longitudinal Studies; Mothers
PubMed: 38931150
DOI: 10.3390/nu16121795