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38; P = .005) and in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) (HR, 10.8; P = .003) after day +50 and lower in patients who received higher doses of CD34 cells (HR, .44; P = .006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning (HR, 1.69 P = .04) and in patients with acute GVHD (HR, 1.88; P = .02), and lower in those who received higher doses of CD34 cells (HR, .55; P = .01). In summary, we have shown that pretransplantation anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in HSCT. The use of high-dose cellular grafts, a modifiable risk factor, also protects against CMV reactivation.The purpose of this study was to investigate the effect of molecular mobility of water adsorbed by disintegrants on the hydrolytic degradation of active pharmaceutical ingredients (APIs). Fourteen different disintegrants were tested. First, powdered disintegrants were stored at conditions of 40 °C/75% relative humidity ("humid conditions") and their T2 relaxation times were measured by time-domain nuclear magnetic resonance for examination of the molecular mobility of water adsorbed by the disintegrant. From the observed T2 values, the water molecular mobility was fully characterized. In particular, the molecular mobility of water adsorbed by crospovidones was much higher than the molecular mobility of water adsorbed by the other test disintegrants because of longer T2 values. The next study examined the hydrolytic degradation of acetylsalicylic acid (ASA), a model moisture-sensitive API, stored under humid conditions. Physical mixtures of ASA and disintegrants or their model tablets were used as test samples, and they were stored for 7 d. The disintegrants contained in the samples clearly affected the ASA degradation the most significant ASA degradation was observed for the crospovidone-containing samples. Finally, we analyzed the effect of the molecular mobility of water adsorbed by disintegrants on the ASA degradation by the least absolute shrinkage and selection operator (Lasso) regression techniques. As in the T2 experiment, various properties of disintegrants (i.e., water content, pH, and water activity) were used in this experiment as the explanatory variables. From the Lasso analysis, we successfully showed that the higher molecular mobility of water adsorbed by disintegrants significantly enhanced ASA degradation. These findings provide profound insights into the chemical stability of moisture-sensitive APIs in tablets.4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is the second enzyme of the tyrosine catabolic pathway. Its physiological function is to catalyze the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, which displays different physiological effects in mammals and plants. Insights on the selective inhibition of human HPPD (hHPPD) by triketone inhibitors were furnished by the integrated application of molecular simulation and biological testing. The binding free energy of hHPPD and inhibitors was obtained through molecular dynamics (MD) simulations, and the result was in agreement with the inhibition experiment in vitro. The binding free energy contribution demonstrated that the formation of hHPPD-inhibitor complexes was mainly driven by van der Waals energy. Ser226, Asn241, Gln265, Phe336, Phe359 and Phe364 made great contributions to binding affinities of all the systems. Among the residues involved in the interaction between nitisinone (NTBC) and hHPPD, Tyr221 and Leu224, whose mutation into Ala caused significant decrease of NTBC binding ability, were two key residues in determining the selective binding affinity of inhibitor and hHPPD. This work provides valuable theoretical basis for rational design of highly selective inhibitors targeting hHPPD.The identification of substances that prevent or minimize the detrimental effects of ionizing radiation is an essential undertaking. The aim of this paper was to evaluate and compare the radioprotective potential of chlorophyllin, protoporphyrin and bilirubin, with amifostine®, an US Food & Drug Administration approved radioprotector Using the somatic mutation and recombination assay in the Drosophila melanogaster wing, it was found that pretreatment (1-9 h) with any of the porphyrins or amifostine® alone, did not affect the larva-adult viability or the basal frequency of mutation. However, they were associated with significant reductions in frequency of somatic mutation and recombination compared with the gamma-irradiated (20 Gy) control as follows bilirubin (69.3 %)> chlorophyllin (40.0 %)> protoporphyrin (39.0 %)> amifostine® (19.7 %). Bilirubin also caused a 16 % increase in larva-adult viability with 3 h of pretreatment respect to percentage induced in 20 Gy control group. Whilst amifostine® was associated with lower genetic damage after pre-treatment of 1 and 3 h, this did not attain significance. These findings suggest that the tested porphyrins may have some potential as radioprotectant agents.

This study aimed to combine in vitro phenotyping analysis and whole-genome-sequencing (WGS) to characterise the phenotype and genetic determinants associated with intrinsic resistance in 100 clinical and non-clinical Acinetobacter baumannii strains originating from Germany and Vietnam. Moreover, it aimed to assess whether powdered milk as a food source functions as a potential reservoir of antibiotic resistance and possesses similar antimicrobial resistance (AMR) genes as in clinical strains isolated from Germany.

Antimicrobial susceptibility testing was performed using the broth microdilution method and the minimum inhibitory concentration (MIC) was determined for 18 antibiotics. The WGS data from all isolates were mapped to intrinsic genes known to be associated with phenotypic AMR.

The highest resistance frequency was observed for chloramphenicol (100%), followed by fosfomycin (96%) and cefotaxime (95%). The lowest resistant rates were observed for colistin (3%), trimethoprim/sulfamethoxazole (17%), mases, multidrug efflux pumps and aminoglycoside-modifying enzymes.

The use of WGS for routine public health surveillance is a reliable method for the rapid detection of emerging AMR in A. baumannii isolates. Milk powder poses a risk to contain MDR Acinetobacter strains or resistance genes in Germany.

The use of WGS for routine public health surveillance is a reliable method for the rapid detection of emerging AMR in A. baumannii isolates. Milk powder poses a risk to contain MDR Acinetobacter strains or resistance genes in Germany.Loss of the blood-retinal barrier (BRB) integrity and subsequent damage to the neurovascular unit in the retina are the underlying reasons for diabetic retinopathy (DR). Damage to BRB eventually leads to severe visual impairment in the absence of prompt intervention. Diabetic macular edema and proliferative DR are the advanced stages of the disease where BRB integrity is altered. Primary mechanisms contributing to BRB dysfunction include loss of cell-cell barrier junctions, vascular endothelial growth factor, advanced glycation end products-induced damage, and oxidative stress. Although much is known about the involvement of adherens and tight-junction proteins in the regulation of vascular permeability in various diseases, there is a significant gap in our knowledge on the junctional proteins expressed in the BRB and how BRB function is modulated in the diabetic retina. In this review article, we present our current understanding of the molecular composition of BRB, the changes in the BRB junctional protein turnover in DR, and how BRB functional modulation affects vascular permeability and macular edema in the diabetic retina.The sigma-1 receptor (Sig1R) is a unique ligand-operated endoplasmic reticulum (ER) protein without any mammalian homolog. Dubermatinib It has long been a pharmacological target for intervention of psychiatric disorders, and recently garnered refreshed interest for its neuroprotective potential. Though reported to modulate various intracellular events, its influence on cell identity is little known. We explored a role for Sig1R in adipocyte differentiation. We induced adipogenic differentiation of mouse embryonic fibroblasts (MEFs) with a differentiation medium. MEFs were isolated from Sigmar1-/- and Sigmar1+/+ mice. The induced adipocyte-like phenotype was detected through Western blots of master transcription factors (PPARγ, CEBPA, SREBP1, SREBP2), lipogenic proteins (FABP4, ACC1, ACAT2), and Oil-Red-O staining of lipids. We found that the induced upregulation of these proteins and lipid accumulation were severely mitigated in Sigmar1-/- (vs Sigmar1+/+) MEFs. Sig1R activation with a selective agonist (PRE084) increased Sig1R protein and further enhanced the induced adipocyte-like phenotype in Sigmar1+/+ MEFs. We also determined mouse body weight gain induced by high-fat diet for 6 months, which was impeded in Sigmar1-/- (vs Sigmar1+/+) male mice. In summary, genetic ablation of Sig1R impairs, and agonist activation of Sig1R enhances adipocyte-like phenotype of induced MEFs. In vivo, Sig1R ablation impedes the body weight gain of male mice on high-fat diet. This study warrants further investigation of a previously unrecognized role for Sig1R in adipocyte differentiation.

Small cell carcinoma of ovary, hypercalcemia type (SCCOHT), also known as the malignant rhabdoid tumor of the ovary, is a rare and highly aggressive malignancy affecting younger women. The pathogenesis involves mutations in SWI/SNF-related, matrix-associated, actin-dependent regulator chromatin group A4 (SMARCA4)/Brahma-related gene 1 (BRG1) and/or SWI/SNF-related, matrix-associated, actin-dependent regulator chromatin group A2 (SMARCA2)/Brahma homolog (BRM).

A 10-year-old girl presented with lower abdominal pain and a mass for the past 2weeks. She underwent ultrasound-guided fine needle aspiration and core needle biopsy from the pelvic mass followed by surgery. On the basis of the characteristic morphologic and immunohistochemical features, a diagnosis of SCCOHT was rendered. Chemotherapy was started, however, she succumbed to the disease.

A 10-year-old girl presented with lower abdominal pain and a mass for the past 2 weeks. She underwent ultrasound-guided fine needle aspiration and core needle biopsy from the pelvic mass followed by surgery. On the basis of the characteristic morphologic and immunohistochemical features, a diagnosis of SCCOHT was rendered. Chemotherapy was started, however, she succumbed to the disease.Lipofection is a widely used molecular biology technique and one of the most promising non-viral gene therapy strategies. However, one of the main drawbacks of using cationic lipids-based lipoplexes in DNA/RNA delivery is serum-associated inhibition of transfection. We have addressed this issue using PTAI (trimethylpolyprenylammonium iodides)-based lipofection model. To overcome serum-sensitivity we used 100 different formulations based on different PTAI, various helper lipids compositions, lipoplex surface modifications with polyethylene glycol (PEG), and precondensation of DNA with poly-L-lysine (PLL). Multicomponent helper lipids compositions boosted serum resistance and largely improved long-term storage of PTAI-based reagents. This was observed, in particular, for PTAI with longer isoprenoid chains. Additionally, our PTAI-based carriers were efficient for DNA and RNA delivery and safe for human red blood cells (RBC). Moreover, a broad array of the modifications used resulted in an important observation - a diverse susceptibility of various cell types to different compositions was noted.