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Two new steroidal saponins (1 and 2) were isolated from the dried bulbs of Allium macrostemon Bunge. Their structures were elucidated by the spectral data as 26-O- β-D-glucopyranosyl-5α-furost-25 (27)-ene-3β, 12β, 22, 26-tetraol-3-O-β-Dglucopyranosyl (1→2) [β-D-glucopyranosyl (1→3)]-β-D-glucopyranosyl (1→4)-β-Dgalactopyranoside (1) and 26-O-β-D-glucopyranosyl-5β-furost-20 (22)-25 (27)-dien-3β, 12β, 26-triol-3-O-β-D-glucopyranosyl (1→2)-β-D-galactopyranoside (2), respectively. Their cytotoxic activities on several cancer cell lines (MCF-7, NCI-H460, SF-268 and HepG2) were tested. 1 showed special cytotoxity on SF-268, while 2 showed cytotoxity on NCI-H460 and SF-268 cell lines, respectively. [ABSTRACT FROM AUTHOR]

In a previously made cross Brassica napus cv. Oro (2 n = 38) × Capsella bursa-pastoris (2 n = 4 x = 32), one F1 hybrid with 2 n = 38 was totally male sterile. The hybrid contained no complete chromosomes from C. bursa-pastoris, but some specific AFLP (amplified fragment length polymorphism) bands of C. bursa- pastoris were detected. The hybrid was morphologically quite similar to ‘Oro’ except for smaller flowers with rudimentary stamens but normal pistils, and showed good seed-set after pollination by ‘Oro’ and other B. napus cultivars. The fertility segregation ratios (3:1, 1:1) in its progenies indicated that the male sterility was controlled by a single recessive gene. In the pollen mother cells of the male sterile hybrid, chromosome pairing and segregation were normal. Histological sectioning of its anthers showed that the tapetum was multiple layers and was hypertrophic from the stage of sporogenic cells, and that the tetrads were compressed by the vacuolated and disaggregated tapetum and no mature pollen grains were formed in anther sacs, thus resulting in male sterility. The possible mechanisms for the production of the male sterile hybrid and its potential in breeding are discussed. [ABSTRACT FROM AUTHOR]

Abstract   Capsella bursa-pastoris (L.) Medic (2n = 4x = 32) is a natural double-low (erucic acid Sclerotinia sclerotiorum. Hybridizations were carried out between two Brassica species viz. B. rapa (2n = 20) and B. napus (2n = 38) as female and C. bursa-pastoris as male parent to introduce these desirable traits into cultivated Brassica species. Majority of F1 plants resembled female parents in morphology and only a few expressed some characters of male parent, including the white petals. Based on cytological observation of somatic cells, the F1 plants were classified into five types: two types from the cross with B. rapa, type I had 2n = 27–29; type II had 2n = 20; three types from the crosses with B. napus, type III was haploids with 2n = 19; type IV had 2n = 29; type V had 2n = 38. One to two chromosomes of C. bursa-pastoris were detected in pollen mother cells (PMCs) of type I plant by genomic in situ hybridization (GISH), together with chromosomal segments in ovary cells and PMCs of some F1 plants. Amplified fragment length polymorphism (AFLP) bands specific for the male parent, novel for two parents and absent bands in Brassica parents were generated in majority of F1 plants, even in Brassica-types and haploids, indicating the introgressions at various levels from C. bursa-pastoris and genomic alterations following hybridization. Some Brassica-type progeny plants had reduced contents of erucic acid and glucosinolates associated with improved resistance to S. sclerotiorum. The cytological and molecular mechanisms behind these results are discussed. [ABSTRACT FROM AUTHOR]

The MDM2 N-terminal domain can bind to the transactivation domain of p53 and downregulate its ability to activate transcription. It was found that binding with p53 stabilizes the MDM2 N-terminal domain. Thus the coupling between binding and folding is essential in the normal functional interactions between p53 and MDM2. We have performed explicit-solvent molecular dynamics simulations (MD) for both bound MDM2N and apo-MDM2 to study the interdependence of binding and folding in the p53-MDM2 complex. Kinetic analysis of high-temperature MD simulations shows that both bound MDM2N and apo-MDM2 unfold via a two-state process. Both kinetics and free energy landscape analyses indicate that bound MDM2 unfolds in the order of p53 unbinding, tertiary unfolding, and finally secondary structure unfolding. Our data show that the unfolding pathways are different between bound MDM2N and apo-MDM2: the unfolding order of unstable helices and tertiary contacts is reversed. Transition state analysis shows that the transition state of bound MDM2 is more nativelike and more heterogeneous than that of apo-MDM2. The predicted Φ-values suggest that the stable helices are more nativelike than other regions in both bound MDM2N and apo-MDM2. Within the stable helices, helix II in bound MDM2 is more nativelike than that in apo-MDM2. However, helix I and IV in bound MDM2 are less nativelike than those in apo-MDM2. [ABSTRACT FROM AUTHOR]

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 μM. The rationality of the method was validated by experimental results. [ABSTRACT FROM AUTHOR]

Abstract Background Wound infection after inguinal hernia surgery is not uncommon in the clinical setting. The common microbial aetiology of postoperative inguinal hernia wound infection is Gram-positive bacteria. Staphylococcus aureus is a common pathogen causing wound infection while Staphylococcus epidermidis and Pseudomonas are rare. Staphylococcus epidermidis as a cause of severe wound infection is rarely described in literature. We herein present a case of a 79-year-old man with a rare wound infection after bilateral inguinal herniorrhaphy caused by MRCNS (Methicillin Resistant Coagulase Negative Staphylococcus). Case presentation We present a case of wound infection accompanied by fever with a temperature of 38.8 °C after bilateral inguinal herniorrhaphy in a 79-year-old man. Bilateral inguinal wounds were marked by redness and swelling, with skin necrosis. In addition, an abscess of approximately 1.5 cm × 1.5 cm was seen on the left wrist. A small amount of gas under the skin in the wound area was observed after pelvic computed tomography (CT) scans. No bacteria were cultured from the inguinal wound discharge, while blood culture detected MRCNS, and Acinetobacter lwoffi was cultured from the pus in the left wrist. We chose appropriate antibiotics based on the results of the bacterial culture and the drug susceptibility results. Vacuum assisted closure (VAC) therapy was used after debridement. The patient was discharged after the wounds improved. He was followed up for ten months and showed no signs of complications. We are sharing our experience along with literature review. Conclusions We are presenting a rare case of MRCNS wound infection following open inguinal hernia surgery. Although a rarity, clinicians performing inguinal hernia surgery must consider this entity in an infected wound and follow up the patient for complications of MRCNS.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1-G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1-G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7-G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9-G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia. [ABSTRACT FROM AUTHOR]

TIS11d tandem zinc finger (TZF) domain can bind the class II AU-rich element of target mRNA and regulate mRNA turnover by promoting or inhibiting degradation. NMR spectra show that TIS11dTZF undergoes a transition from disordered to well folded upon binding to Zn and mRNA. To gain an insight into the mechanism, we have performed explicit-solvent molecular dynamics simulations (MD) for both bound and apo-TIS11dTZF to study the interdependence of binding and folding in the mRNA-TIS11dTZF complex. These results are in qualitative agreement with NMR experiment. Furthermore, this method could be used to other study about protein folding upon ligand binding. [ABSTRACT FROM AUTHOR]

Four new metabolites, including three new oblongolides named C1, P1, and X1 (1-3) and 6-hydroxyphomodiol (10), along with eight known compounds – oblongolides B (4), C (5), D (6), O (7), P (8) and U (9), (3R,4aR,5S,6R)-6-hydroxy-5-methylramulosin (11), and (3R)-5-methylmellein (12) – were isolated from the endophytic fungal strain Phomopsis sp. XZ-01 of Camptotheca acuminate. Their structures were elucidated by spectroscopic analyses, including 1H- and 13C-NMR, 2D NMR (HSQC, HMBC, 1H-1H COSY and NOESY) and HR-FT-MS. Cytotoxic activities of these compounds were evaluated. Some of them showed weak selective activities.

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α-mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNFα activation of AKT by inhibiting TNF-α-induced tRXR-α interaction with the p85a regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells. [ABSTRACT FROM AUTHOR]

The phosphotriesterase-like lactonase (PLL) enzymes in the amidohydrolase superfamily hydrolyze various lactones and exhibit latent phosphotriesterase activities. These enzymes serve as attractive templates for in vitro evolution of neurotoxic organophos-phates (OPs) with hydrolytic capabilities that can be used as bioremediation tools. Here, a thermostable PLL from Geobacillus kaustophilus HTA426 (GkaP) was targeted for joint laboratory evolution with the aim of enhancing its catalytic efficiency against OP pesticides. By a combination of site saturation mutagenesis and whole-gene error-prone PCR approaches, several improved variants were isolated. The most active variant, 26A8C, accumulated eight amino acid substitutions and demonstrated a 232-fold improvement over the wild-type enzyme in reactivity (Kcat/Km) for the OP pesticide ethyl-paraoxon. Concomitantly, this variant showed a 767-fold decrease in lactonase activity with δ-decanolactone, imparting a specificity switch of 1.8 x 105-fold. 26A8C also exhibited high hydrolytic activities (19- to 497-fold) for several OP pesticides, including parathion, diazinon, and chlorpyri-fos. Analysis of the mutagenesis sites on the GkaP structure revealed that most mutations are located in loop 8, which determines substrate specificity in the amidohydrolase superfamily. Molecular dynamics simulation shed light on why 26A8C lost its native lactonase activity and improved the promiscuous phosphotriesterase activity. These results permit us to obtain further insights into the divergent evolution of promiscuous enzymes and suggest that laboratory evolution of GkaP may lead to potential biological solutions for the efficient decontamination of neurotoxic OP compounds. [ABSTRACT FROM AUTHOR]