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Respiratory Medicine Case Reports 2024Metastatic pulmonary calcification (MPC) is a metabolic disorder characterized by an ectopic deposition of calcium in the lung parenchyma, prevalent in patients with...
Metastatic pulmonary calcification (MPC) is a metabolic disorder characterized by an ectopic deposition of calcium in the lung parenchyma, prevalent in patients with chronic kidney disease. A combination of parenchymal lung abnormalities on high resolution chest computed tomography (CT) and pulmonary radiotracer uptake in Tc-methyl diphosphate (MDP) bone scintigraphy can establish diagnosis of MPC. We herein present a case of MPC with documented stability of chest CT abnormalities after renal transplant. We also describe novel findings of diffuse pulmonary uptake of F-sodium fluoride, a calcium-avid radiotracer, in positron emission tomography (PET)/CT performed in the same patient.
PubMed: 38872935
DOI: 10.1016/j.rmcr.2024.102043 -
Journal of Agricultural and Food... Jun 2024The addition of the -linked -acetylglucosamine (-GlcNAc) is a significant modification for active molecules, such as proteins, carbohydrates, and natural products....
The addition of the -linked -acetylglucosamine (-GlcNAc) is a significant modification for active molecules, such as proteins, carbohydrates, and natural products. However, the synthesis of terpenoid glycoside derivatives decorated with GlcNAc remains a challenging task due to the absence of glycosyltransferases, key enzymes for catalyzing the transfer of GlcNAc to terpenoids. In this study, we demonstrated that the enzyme mutant UGT74AC1 efficiently transferred GlcNAc from uridine diphosphate (UDP)-GlcNAc to a variety of terpenoids. This powerful enzyme was employed to synthesize GlcNAc-decorated derivatives of terpenoids, including mogrol, steviol, andrographolide, protopanaxadiol, glycyrrhetinic acid, ursolic acid, and betulinic acid for the first time. To unravel the mechanism of UDP-GlcNAc recognition, we determined the X-ray crystal structure of the inactivated mutant UGT74AC1 in complex with UDP-GlcNAc at a resolution of 1.66 Å. Through molecular dynamic simulation and activity analysis, we revealed the molecular mechanism and catalytically important amino acids directly involved in the recognition of UDP-GlcNAc. Overall, this study not only provided a potent biocatalyst capable of glycodiversifying natural products but also elucidated the structural basis for UDP-GlcNAc recognition by glycosyltransferases.
Topics: Acetylglucosamine; Glycosides; Glycosyltransferases; Terpenes; Plant Proteins; Biocatalysis
PubMed: 38867497
DOI: 10.1021/acs.jafc.4c02832 -
British Journal of Clinical Pharmacology Jun 2024Transgender persons face a greater burden of HIV compared to cisgender counterparts. Concerns around drug-drug interactions (DDIs) have been cited as reasons for lower... (Review)
Review
Transgender persons face a greater burden of HIV compared to cisgender counterparts. Concerns around drug-drug interactions (DDIs) have been cited as reasons for lower engagement in HIV care and lower pre-exposure prophylaxis (PrEP) uptake among transgender populations. It is therefore imperative for hormone therapy, PrEP and antiretroviral therapy providers to understand the DDI potential between these therapies. Studies of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) PrEP with feminizing hormone therapies (FHTs) show reduced plasma tenofovir concentrations, but intracellular concentrations of tenofovir-diphosphate are not reduced. Efficacy of PrEP is expected to be maintained despite this interaction. Masculinizing hormone therapies have no effect on tenofovir concentrations but may increase FTC to a nonclinically relevant extent. No interactions between FHT and cabotegravir or tenofovir alafenamide have been demonstrated. Administration of TDF/FTC PrEP has no effect on hormone levels in transmen or transwomen. PrEP is expected to be effective and safe in transpersons and should be provided to high-risk individuals regardless of gender affirming hormone use. Enzyme inducing/inhibiting antiretroviral therapy may decrease or increase, respectively, the concentrations of FHT and masculinizing hormone therapy. Unboosted integrase inhibitors or enzyme neutral non-nucleoside reverse transcriptase inhibitors are not expected to affect and are not affected by gender affirming hormones and can be considered in transmen and transwomen. Overlapping toxicities including weight gain, dyslipidaemia, cardiovascular disease and bone density effects should be considered, and antiretroviral modifications can be made to minimize toxicities. Interactions between supportive care medications should be assessed to avoid chelation interactions and hyperkalaemia.
PubMed: 38866600
DOI: 10.1111/bcp.16097 -
The Plant Cell Jun 2024Pyrimidine nucleotide monophosphate biosynthesis ends in the cytosol with uridine monophosphate (UMP). UMP phosphorylation to uridine diphosphate (UDP) by UMP KINASEs...
Pyrimidine nucleotide monophosphate biosynthesis ends in the cytosol with uridine monophosphate (UMP). UMP phosphorylation to uridine diphosphate (UDP) by UMP KINASEs (UMKs) is required for the generation of all pyrimidine (deoxy)nucleoside triphosphates as building blocks for nucleic acids and central metabolites like UDP-glucose. The Arabidopsis (Arabidopsis thaliana) genome encodes five UMKs and three belong to the AMP KINASE (AMK)-like UMKs, which were characterized to elucidate their contribution to pyrimidine metabolism. Mitochondrial UMK2 and cytosolic UMK3 are evolutionarily conserved, whereas cytosolic UMK1 is specific to the Brassicaceae. In vitro, all UMKs can phosphorylate UMP, cytidine monophosphate (CMP) and deoxycytidine monophosphate (dCMP), but with different efficiencies. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9)-induced null mutants were generated for UMK1 and UMK2, but not for UMK3, since frameshift alleles were lethal for germline cells. However, a mutant with diminished UMK3 activity showing reduced growth was obtained. Metabolome analyses of germinating seeds and adult plants of single and higher-order mutants revealed that UMK3 plays an indispensable role in the biosynthesis of all pyrimidine (deoxy)nucleotides and UDP-sugars, while UMK2 is important for dCMP recycling that contributes to mitochondrial DNA stability. UMK1 is primarily involved in CMP recycling. We discuss the specific roles of these UMKs referring also to the regulation of pyrimidine nucleoside triphosphate synthesis.
PubMed: 38865437
DOI: 10.1093/plcell/koae170 -
Journal of Agricultural and Food... Jun 2024The cotton aphid, , is a polyphagous pest that stunts host plant growth via direct feeding or transmitting plant virus. Due to the long-term application of insecticides,...
The cotton aphid, , is a polyphagous pest that stunts host plant growth via direct feeding or transmitting plant virus. Due to the long-term application of insecticides, has developed different levels of resistance to numerous insecticides. We found that five field populations had evolved multiple resistances to neonicotinoids. To explore the resistance mechanism mediated by uridine diphosphate glycosyltransferases (UGTs), two upregulated UGT genes in these five strains, and , were selected for functional analysis of their roles in neonicotinoid detoxification. Transgenic bioassay results indicated that compared with the control lines, the and overexpression lines were more tolerant to thiamethoxam, imidacloprid, and dinotefuran. Knockdown of and significantly increased sensitivity to thiamethoxam, imidacloprid, and dinotefuran. Molecular docking analysis demonstrated that these neonicotinoids could bind to the active pockets of UGT350C3 and UGT344L7. This study provides functional evidence of neonicotinoid detoxification mediated by UGTs and will facilitate further work to identify strategies for preventing the development of neonicotinoid resistance in insects.
Topics: Animals; Aphids; Neonicotinoids; Insecticides; Insecticide Resistance; Glycosyltransferases; Nitro Compounds; Molecular Docking Simulation; Insect Proteins; Thiamethoxam; Drosophila; Guanidines
PubMed: 38864686
DOI: 10.1021/acs.jafc.4c02682 -
BMC Plant Biology Jun 2024This study examines the impact of titanium dioxide nanoparticles (TiONPs) on gene expression associated with menthol biosynthesis and selected biochemical parameters in...
Studying the impact of titanium dioxide nanoparticles on the expression of pivotal genes related to menthol biosynthesis and certain biochemical parameters in peppermint plants (Mentha Piperita L.).
BACKGROUND
This study examines the impact of titanium dioxide nanoparticles (TiONPs) on gene expression associated with menthol biosynthesis and selected biochemical parameters in peppermint plants (Mentha piperita L.). Menthol, the active ingredient in peppermint, is synthesized through various pathways involving key genes like geranyl diphosphate synthase, menthone reductase, and menthofuran synthase. Seedlings were treated with different concentrations of TiONPs (50, 100, 200, and 300 ppm) via foliar spray. After three weeks of treatment, leaf samples were gathered and kept at -70 °C for analysis.
RESULTS
According to our findings, there was a significant elevation (P ≤ 0.05) in proline content at concentrations of 200 and 300 ppm in comparison with the control. Specifically, the highest proline level was registered at 200 ppm, reaching 259.64 ± 33.33 µg/g FW. Additionally, hydrogen peroxide and malondialdehyde content exhibited a decreasing trend following nanoparticle treatments. Catalase activity was notably affected by varying TiONP concentrations, with a significant decrease observed at 200 and 300 ppm compared to the control (P ≤ 0.05). Conversely, at 100 ppm, catalase activity significantly increased (11.035 ± 1.12 units/mg of protein/min). Guaiacol peroxidase activity decreased across all nanoparticle concentrations. Furthermore, RT-qPCR analysis indicated increased expression of the studied genes at 300 ppm concentration.
CONCLUSIONS
Hence, it can be inferred that at the transcript level, this nanoparticle exhibited efficacy in influencing the biosynthetic pathway of menthol.
Topics: Titanium; Mentha piperita; Menthol; Nanoparticles; Gene Expression Regulation, Plant; Plant Proteins; Plant Leaves; Metal Nanoparticles; Genes, Plant; Hydrogen Peroxide
PubMed: 38862885
DOI: 10.1186/s12870-024-05228-9 -
Nature Communications Jun 2024Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well...
Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well understood. Here, we use recombinant focal adhesion proteins to reconstitute the core structural machinery in vitro. We observe liquid-liquid phase separation of the core focal adhesion proteins talin and vinculin for a spectrum of conditions and interaction partners. Intriguingly, we show that binding to PI(4,5)P-containing membranes triggers phase separation of these proteins on the membrane surface, which in turn induces the enrichment of integrin in the clusters. We suggest a mechanism by which 2-dimensional biomolecular condensates assemble on membranes from soluble proteins in the cytoplasm: lipid-binding triggers protein activation and thus, liquid-liquid phase separation of these membrane-bound proteins. This could explain how early focal adhesions maintain a structured and force-resistant organization into the cytoplasm, while still being highly dynamic and able to quickly assemble and disassemble.
Topics: Talin; Focal Adhesions; Cell Membrane; Vinculin; Humans; Animals; Phosphatidylinositol 4,5-Diphosphate; Integrins; Cytoplasm; Protein Binding; Phase Separation
PubMed: 38862544
DOI: 10.1038/s41467-024-49222-z -
Proceedings of the National Academy of... Jun 2024causes life-threatening wound and gastrointestinal infections, mediated primarily by the production of a Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin....
causes life-threatening wound and gastrointestinal infections, mediated primarily by the production of a Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The most commonly present MARTX effector domain, the Makes Caterpillars Floppy-like (MCF) toxin, is a cysteine protease stimulated by host adenosine diphosphate (ADP) ribosylation factors (ARFs) to autoprocess. Here, we show processed MCF then binds and cleaves host s-related proteins in rain (Rab) guanosine triphosphatases within their C-terminal tails resulting in Rab degradation. We demonstrate MCF binds Rabs at the same interface occupied by ARFs. Moreover, we show MCF preferentially binds to ARF1 prior to autoprocessing and is active to cleave Rabs only subsequent to autoprocessing. We then use structure prediction algorithms to demonstrate that structural composition, rather than sequence, determines Rab target specificity. We further determine a crystal structure of aMCF as a swapped dimer, revealing an alternative conformation we suggest represents the open, activated state of MCF with reorganized active site residues. The cleavage of Rabs results in Rab1B dispersal within cells and loss of Rab1B density in the intestinal tissue of infected mice. Collectively, our work describes an extracellular bacterial mechanism whereby MCF is activated by ARFs and subsequently induces the degradation of another small host guanosine triphosphatase (GTPase), Rabs, to drive organelle damage, cell death, and promote pathogenesis of these rapidly fatal infections.
Topics: Animals; Female; Humans; Mice; ADP-Ribosylation Factors; Bacterial Toxins; HEK293 Cells; Mice, Inbred ICR; Proteolysis; rab GTP-Binding Proteins; Vibrio Infections; Vibrio vulnificus
PubMed: 38861595
DOI: 10.1073/pnas.2316143121 -
Annals of Surgery Jun 2024The aim of this prospective study was to 1) objectively quantify the impact of sex on platelet function in patients with PAD taking antiplatelet and anticoagulant...
OBJECTIVE
The aim of this prospective study was to 1) objectively quantify the impact of sex on platelet function in patients with PAD taking antiplatelet and anticoagulant medications and 2) to develop and test a personalized, iterative algorithm which personalizes thromboprophylaxis that incorporates platelet function testing.
SUMMARY BACKGROUND DATA
Women with Peripheral Artery Disease (PAD) have worse outcomes as compared to their male counterparts in spite of having lower risk factors. This health disparity may be mitigated by personalizing thromboprophylaxis regimens.
METHODS
Patients undergoing revascularization were enrolled. Serial thromboelastography (TEG) and TEG with Platelet Mapping (TEG-PM) was performed up to 6-months post-operatively to determine objective coagulation profiles. In a subset of patients, the Antiplatelet Coagulation Exactness (ACE) algorithm was implemented where patients were iteratively evaluated with TEG and given antiplatelet medications to maintain platelet inhibition at >29%. Statistical analysis was performed using unpaired t-test, ANOVA and Fisher's exact test.
RESULTS
One hundred and eighty-one patients met study criteria. 58(32%) patients were females and 123(68%) were males. In the Aspirin cohort, females showed significantly greater clot strength as Maximum Amplitude - Arachidonic Acid (MAAA) and significantly lower platelet inhibition than males: [37.26 vs.32.38, P<0.01] and [52.95% vs.61.65%, P<0.05], respectively. In the Clopidogrel cohort, females showed higher Maximum Amplitude - Adenosine Diphosphate (MAADP) [42.58 vs.40.35, P=NS] compared to males. Females on dual antiplatelet therapy had higher MAADP [39.74 vs.35.07, P=NS] and lower platelet inhibition [45.25% vs.54.99%, P=NS] than males. The incidence of thrombosis of the revascularized segment, defined as thrombotic event, was objectively identified on an arterial duplex. Women showed significantly higher thrombotic events than men [22.95% vs.10.57%, P<0.05] on the same medication. In our pilot study, implementation of the ACE algorithm led to a significant decrease in the thrombosis rate (3%), including non-thrombotic events for females, vs. the historic thrombotic rate (22%) from our institution.
CONCLUSIONS
Women with PAD exhibited higher platelet reactivity, clot strength, and reduced platelet inhibition in response to antiplatelet therapy. The use of the ACE algorithm to tailor antiplatelet medication in patients with PAD post-revascularization, resulted in a significant decrease in thrombotic event rates. This may serve as an opportune way to mitigate outcome sex-specific disparities caused by inadequate thromboprophylaxis in women.
PubMed: 38860382
DOI: 10.1097/SLA.0000000000006375 -
Global Medical Genetics Jun 2024Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological...
Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological characteristics of megakaryocytes (MKs) in MDS patients with gene mutation are not well established. Bone marrow MK specimens from 104 patients with primary MDS were evaluated, and all patients were distributed into two groups according to gene mutation associated with functional MKs. The morphologic and cellular characteristics of MKs and platelets were recorded and compared. The more frequently mutated genes in MDS patients were (11.54%), (8.65%), (5.77%), and the most common point mutation was p.(R307H) and p.(Q43P). Patients with MK mutation showed a decrease in adenosine diphosphate-induced platelet aggregation, high proportion of CD34 CD61 MKs (10.00 vs. 4.00%, = 0.012), and short overall survival (33.15 vs. 40.50 months, = 0.013). Further, patients with a higher percent of CD34 CD61 MKs (≧20.00%) had lower platelet counts (36.00 × 10 /L vs. 88.50 × 10 /L, = 0.015) and more profound emperipolesis ( = 0.001). By analyzing RNA-sequencing of MKs, differentially expressed mRNA was involved in physiological processes including platelet function and platelet activation, especially for MDS patients with high percent of CD34 CD61 MKs. The high levels of expression of CD62P, CXCL10, and S100A9 mRNA, shown by RNA sequencing, were validated by PCR assay. High proportion of CD34 CD61 MKs was a poor prognostic factor in MDS patients with MK mutation. CD62P, CXCL10, and S100A9 may be the potential targets to evaluate the molecular link between gene defects and platelet function.
PubMed: 38860162
DOI: 10.1055/s-0044-1787752