DPX: for the analysis of the protein core

Abstract Summary: In order to obtain an accurate description of the protein interior, we describe a simple and fast algorithm that measures the depth of each atom in a protein (dpx), defined as its distance (Å) from the closest solvent accessible atom. The program reads a PDB file containing the atomic solvent accessibility in the B-factor field, and writes a file in the same format, where the B-factor field now contains the dpx value. Output structure files can be thus directly displayed with molecular graphics programs like RASMOL, MOLMOL, Swiss-PDB View and colored according to dpx values. Availability: The algorithm is implemented in a standalone program written in C and its source is freely available at ftp.icgeb.trieste.it/pub/DPX or on request from the authors. Contact: [email protected]; [email protected]; [email protected] * To whom correspondence should be addressed

CX, DPX and PRIDE: WWW servers for the analysis and comparison of protein 3D structures

The WWW servers at are dedicated to the analysis of protein 3D structures submitted by the users as the Protein Data Bank (PDB) files. CX computes an atomic protrusion index that makes it possible to highlight the protruding atoms within a protein 3D structure. DPX calculates a depth index for the buried atoms and makes it possible to analyze the distribution of buried residues. CX and DPX return PDB files containing the calculated indices that can then be visualized using standard programs, such as Swiss-PDBviewer and Rasmol. PRIDE compares 3D structures using a fast algorithm based on the distribution of inter-atomic distances. The options include pairwise as well as multiple comparisons, and fold recognition based on searching the CATH fold database

Crystallographic Study of Mutant Lysl20Leu Xenopus laevis Cu,Zn Superoxide Dismutase

Theoretical calculations and experimental measurements on the Xenopus laevis Cu,Zn superoxide dismutase (XSODB) wild-type protein and on some of its engineered mutants showed that the electrostatic arrangement around the active site channel plays a fundamental role in determining the catalytic properties of the en-zyme. Lysl20, which lies on the lip of the active site channel, about 11 Å from the catalytic copper ion, influences the enzyme electrostatic environment and binding selectivity. Neutralization of this residue has the effect of decreasing the activity of the enzyme versus the negatively charged substrate. In order to get precise information about the mutated residue and its effects on the structure of the engineered protein, the crystal structure of single site Lysl20Leu mutant XSODB was determined at 2.0 Å resolution, and refined to an R-factor value of 0.181. The structure of Lysl20Leu mutant XSODB is little affected by the amino-acid substitution, suggesting that the main effect of the mutation is perturbation of the electrostatic properties of the SOD catalytic center

Convergent evolutionary trajectories uncover metastatic drivers in renal cancer

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348 Uric acid is associated with acute heart failure and cardiogenic shock at presentation in acute coronary syndrome patients

Abstract Aims we focused on the role of Uric Acid (UA) as a possible determinant of Heart Failure (HF) related issues in Acute Coronary Syndromes (ACS) patients. Main outcome were acute HF and cardiogenic shock at admission, secondary outcomes were the need of Non Invasive Ventilation (NIV) use and the admission Left Ventricular Ejection Fraction (LVEF). Methods and results we consecutively enrolled 1269 ACS patients admitted to the cardiological Intensive Care Unit of the Niguarda and San Paolo hospitals (Milan, Italy) from June 2016 to June 2019. Hyperuricaemia was defined as a value higher than 6 mg/dl for females and 7 mg/dl for males. All the evaluated outcomes occurred more frequently in the hyperuricemic subjects (n = 292): acute HF 35.8 vs. 11.1% (P < 0.0001), cardiogenic shock 10 vs. 3.1% (P < 0.0001), NIV 24.1 vs. 5.1% (P < 0.0001) with lower admission LVEF (42.9 ± 12.8 vs. 49.6 ± 9.9, P < 0.0001). By multivariable analyses, UA was confirmed to be significantly associated with all the outcomes with the following odds ratio (OR): acute HF OR = 1.119; 95% CI: 1.019–1.229; cardiogenic shock OR = 1.157; 95% CI: 1.001–1.337; NIV use OR = 1.208; 95% CI: 1.078–1.354; LVEF β = −0.999; 95% CI: −1.413 to − 0.586. Conclusions The main result of our study was the finding of a significant association between UA and acute HF, cardiogenic shock, NIV use and LVEF. Due to the cross-sectional nature of our study no definite answer on the direction of these relationship can be drawn and further longitudinal study on UA changes over time during an ACS hospitalization are needed

Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance

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DPY30 loss leads to DNA re-replication and immunoediting in pancreatic ductal adenocarcinoma

View full abstracthttps://openworks.mdanderson.org/leading-edge/1036/thumbnail.jp

Neddylation Inhibition Sensitises Renal Medullary Carcinoma Tumours to Platinum Chemotherapy

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC. METHODS: We evaluated the IC50 concentrations of the neddylation‐activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum‐based chemotherapy was evaluated in vivo in platinum‐naïve and platinum‐experienced patient‐derived xenograft (PDX) models of RMC. RESULTS: The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum‐based chemotherapy significantly inhibited tumour growth in both platinum‐naïve and platinum‐experienced PDX models of RMC (p \u3c .01). CONCLUSIONS: Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC

SMARCB1 regulates the hypoxic stress response in sickle cell trait during the pathogenesis of renal medullary carcinoma.

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