Oryzalin (ORY) is a dinitroaniline derivative that inhibits the microtubule polymerization in plants and parasitic protozoa by selectively binding to the α-tubulin subunit. This herbicidal agent ...exhibits good antiprotozoal activity against major human parasites, such as Toxoplasma gondii (toxoplasmosis), Leishmania mexicana (leishmaniasis), and Plasmodium falciparum (malaria). Previous chemical mutagenesis assays on T. gondii α-tubulin (TgAT) have identified key mutations that lead to ORY resistance. Herein, we employed alchemical free energy methods and molecular dynamics simulations to determine if the ORY resistance mutations either decrease the TgAT's affinity of the compound or increase the protein stability. Our results here suggest that L136F and V202F mutations significantly decrease the affinity of ORY to TgAT, while T239I and V252L mutations diminish TgAT's flexibility. On the other hand, protein stability predictors determined that R243S mutation reduces TgAT stability due to the loss of its salt bridge interaction with E27. Interestingly, molecular dynamics simulations confirm that the loss of this key interaction leads to ORY binding site closure. Our study provides a better insight into the TgAT-ORY interaction, further supporting our recently proposed ORY-binding site.
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•Toxoplasma gondii α-tubulin mutations alter either oryzalin affinity or tubulin stability.•L136F and V202F mutations affect ORY's affinity to T. gondii α-tubulin.•T239I and V252L mutations decrease T. gondii α-tubulin flexibility.•R243S mutation closes ORY-binding site by increasing the H7 kink angle.
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In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1–9 were tested in vitro using a set of three ...proteins recognized as important targets in diabetes and related diseases: PPARα, PPARγ, and GLUT-4. Compounds 1–3, 5, and 7 showed significant increases in the mRNA expression of PPARγ and GLUT-4, whereas compounds 1–3 did it over PPARα. Compounds 1–3 were identified as a dual PPAR α/γ modulators and were selected for evaluating the in vivo antidiabetic action at 100 mg/kg dose, being orally actives and decreasing blood glucose concentration in a hyperglycemic mice model, as well as reducing the triacylglycerides levels in normolipidemic rats. Docking and molecular dynamics studies were conducted to clarify the dual effect and binding mode of compounds 1–3 on both PPARs. Compounds 2 and 3 exhibited robust in vitro and in vivo efficacy and could be considered dual PPAR modulators with antidiabetic and antidyslipidemic effects.
Human epigenetic enzyme disruptor of telomeric silencing 1-like (DOT1L) is a key drug target for treating acute myeloid leukemia. Several nucleoside and non-nucleoside DOT1L inhibitors have been ...developed to inhibit its histone methyltransferase activity. Non-mechanism-based nucleoside DOT1L inhibitors have shown good inhibitory activity and high on-target residence times. Previous computational studies have explored the dynamic behavior of this group of molecules on DOT1L to design compounds with enhanced binding affinities. Nevertheless, it is well known that drug-target kinetics also plays a crucial role in the discovery of new drugs. Therefore, we performed
τ
-Random Acceleration Molecular Dynamics (
τ
RAMD) simulations to estimate the residence times of nucleoside DOT1L inhibitors. The high correlation between the calculated and experimental residence times suggested that the method can reliably estimate the residence time of nucleoside DOT1L inhibitors when modifications are made to those substituents that occupy the buried hydrophobic pocket of the active site, exhibit hydrophobic interactions with F245 or that form H-bonds with D161 and G163. Overall, this study will be a step toward understanding the binding kinetics of nucleoside DOT1L inhibitors for the treatment of acute myeloid leukemia.
Wild subspecies of
Olea europaea
constitute a source of genetic variability with huge potential for olive breeding to face global changes in Mediterranean-climate regions. We intend to identify wild ...olive genotypes with optimal adaptability to different environmental conditions to serve as a source of rootstocks and resistance genes for olive breeding. The SILVOLIVE collection includes 146 wild genotypes representative of the six
O. europaea
subspecies and early-generations hybrids. These genotypes came either from olive germplasm collections or from direct prospection in Spain, continental Africa and the Macaronesian archipelago. The collection was genotyped with plastid and nuclear markers, confirming the origin of the genotypes and their high genetic variability. Morphological and architectural parameters were quantified in 103 genotypes allowing the identification of three major groups of correlative traits including vigor, branching habits and the belowground-to-aboveground ratio. The occurrence of strong phenotypic variability in these traits within the germplasm collection has been shown. Furthermore, wild olive relatives are of great significance to be used as rootstocks for olive cultivation. Thus, as a proof of concept, different wild genotypes used as rootstocks were shown to regulate vigor parameters of the grafted cultivar “Picual” scion, which could improve the productivity of high-density hedgerow orchards.
The use of nanofertilizers has the potential to be used to enrich edible organs with nutrients (biofortification) and improve the biosynthesis of bioactive compounds and their antioxidant capacity. ...Therefore, the objective of this study was to evaluate the effect of biofortification with magnesium (Mg) nanofertilizer on the accumulation of bioactive compounds and antioxidant capacity in green bean cv. Strike compared to a conventional fertilizer (Mg sulfate). Two sources of Mg were applied via foliar: Nanofertilizer and Mg Sulfate at doses of 0, 50, 100, 200, and 300 mg/L of Mg. The accumulation of total polyphenols, flavonoids, anthocyanins, bioactive compounds, and antioxidant capacity was evaluated in pods. The results obtained in this research confirm the effect of green bean pods biofortified with Mg nanofertilizers on the production and accumulation of bioactive compounds and antioxidant capacity, improving the nutrition and nutraceutical quality of green beans. The 50 mg/L dose of Mg nanofertilizer was the most effective treatment to increase bioactive compounds and antioxidant capacity compared to high doses of Mg sulfate (300 mg/L). This is one of the first studies focused on biofortification with Mg nanofertilizers and their effect on the nutraceutical quality of green beans.
Immune thrombocytopenia (ITP) is a heterogeneous disease with an unpredictable course. Chronicity can develop in up to two-thirds of adults and 20–25% of children, representing a significant burden ...on patients' quality of life. Despite acceptable responses to treatment, precise etiology and pathophysiology phenomena driving evolution to chronicity remain undefined. We analyzed reported risk factors for chronic ITP and associated them with proposed underlying mechanisms in its pathogenesis, including bone marrow (BM) microenvironment disturbances, clinical features, and immunological markers. Their understanding has diagnostic implications, such as screening for the presence of specific antibodies or BM examination employing molecular tools, which could help predict prognosis and recognize main pathogenic pathways in each patient. Identifying these underlying mechanisms could guide the use of personalized therapies such as all-trans retinoic acid, mTor inhibitors, FcRn inhibitors, oseltamivir, and others. Further research should lead to tailored treatments and chronic course prevention, improving patients' quality of life.
The majority of emerging zoonoses originate in wildlife, and many are caused by viruses. However, there are no rigorous estimates of total viral diversity (here termed "virodiversity") for any ...wildlife species, despite the utility of this to future surveillance and control of emerging zoonoses. In this case study, we repeatedly sampled a mammalian wildlife host known to harbor emerging zoonotic pathogens (the Indian Flying Fox, Pteropus giganteus) and used PCR with degenerate viral family-level primers to discover and analyze the occurrence patterns of 55 viruses from nine viral families. We then adapted statistical techniques used to estimate biodiversity in vertebrates and plants and estimated the total viral richness of these nine families in P. giganteus to be 58 viruses. Our analyses demonstrate proof-of-concept of a strategy for estimating viral richness and provide the first statistically supported estimate of the number of undiscovered viruses in a mammalian host. We used a simple extrapolation to estimate that there are a minimum of 320,000 mammalian viruses awaiting discovery within these nine families, assuming all species harbor a similar number of viruses, with minimal turnover between host species. We estimate the cost of discovering these viruses to be ~$6.3 billion (or ~$1.4 billion for 85% of the total diversity), which if annualized over a 10-year study time frame would represent a small fraction of the cost of many pandemic zoonoses.
Recent years have seen a dramatic increase in viral discovery efforts. However, most lack rigorous systematic design, which limits our ability to understand viral diversity and its ecological drivers and reduces their value to public health intervention. Here, we present a new framework for the discovery of novel viruses in wildlife and use it to make the first-ever estimate of the number of viruses that exist in a mammalian host. As pathogens continue to emerge from wildlife, this estimate allows us to put preliminary bounds around the potential size of the total zoonotic pool and facilitates a better understanding of where best to allocate resources for the subsequent discovery of global viral diversity.
Thousands of people have died of COVID-19 in El Salvador. However, little is known about the mental health of those who are mourning the loss of a loved one to COVID-19. Therefore, the objective of ...this study was to examine the dysfunctional grief associated with COVID-19 death among Salvadoran adults. A sample of 435 Salvadorans (
M
= 29 years; SD = 8.75) who lost a family member or loved one to COVID-19 completed a digital survey using the Google Forms platform, during April 2 and 28, 2022. The results revealed that 35.1% reported clinically elevated symptoms of dysfunctional grief and among those mourners, and 25.1% also exhibited clinical levels of coronavirus anxiety. A binary logistic regression revealed that predictor variables such as COVID-19 anxiety (
p
= .003), depression (
p
= .021), and COVID-19 obsession (
p
= .032) were significant (
χ
2
= 84.31; Nagelkerke
R
2
= .242) and predict a 24.2% chance of dysfunctional bereavement.
The bacterium
is the etiologic agent of the European foulbrood (EFB), one of the most harmful bacterial diseases that causes the larvae of bees to have an intestinal infection. Although EFB has been ...known for more than a century and is practically present in all countries where beekeeping is practiced, the disease has been little studied compared to American foulbrood. Recently, great advances have been made to understand the disease and the interaction between the pathogen and its host. This review summarizes the research and advances to understand the disease. First, the morphological characteristics of
, the infection process and bacterial development in the gut of the larva are described. Also, the epidemiological distribution of EFB and factors that favor the development of the disease as well as the classification of
according its genomic and phenotype characteristics are reported. Finally, the new molecular tools for the study of
, possible virulence factors in its genome, the issue of current EFB control measures and possible alternatives to the use of antibiotics are addressed.
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