Comparative Structural Analysis of Lipid Binding START Domains

Steroidogenic acute regulatory (StAR) protein related lipid transfer (START) domains are small globular modules that form a cavity where lipids and lipid hormones bind. These domains can transport ligands to facilitate lipid exchange between biological membranes, and they have been postulated to modulate the activity of other domains of the protein in response to ligand binding. More than a dozen human genes encode START domains, and several of them are implicated in a disease.We report crystal structures of the human STARD1, STARD5, STARD13 and STARD14 lipid transfer domains. These represent four of the six functional classes of START domains.Sequence alignments based on these and previously reported crystal structures define the structural determinants of human START domains, both those related to structural framework and those involved in ligand specificity.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Conformational dynamics of alpha-synuclein:insights from mass spectrometry

The aggregation and deposition of alpha-synuclein in Lewy bodies is associated with the progression of Parkinson's disease. Here, Mass Spectrometry (MS) is used in combination with Ion Mobility (IM), chemical crosslinking and Electron Capture Dissociation (ECD) to probe transient structural elements of alpha-synuclein and its oligomers. Each of these reveals different aspects of the conformational heterogeneity of this 14 kDa protein. IM-MS analysis indicates that this protein is highly disordered, presenting in positive ionisation mode with a charge state range of 5 <= z <= 21 for the monomer, along with a collision cross section range of similar to 1600 angstrom(2)). Chemical crosslinking applied in conjunction with IM-MS captures solution phase conformational families enabling comparison with those exhibited in the gas phase. Crosslinking IM-MS identifies 3 distinct conformational families, Compact (similar to 1200 angstrom(2)), Extended (similar to 1500 angstrom(2)) and Unfolded (similar to 2350 angstrom(2)) which correlate with those observed in solution. ECD-Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry (ECD-FT-ICR MS) highlights the effect of pH on alpha-synuclein structure, identifying the conformational flexibility of the N and C termini as well as providing evidence for structure in the core and at times the C terminus. A hypothesis is proposed for the variability displayed in the structural rearrangement of alpha-synuclein following changes in solution pH. Following a 120 h aggregation time course, we observe an increase in the ratio of dimer to monomer, but no gross conformational changes in either, beyond the significant variations that are observed day-to-day from this conformationally dynamic protein

Using goal programming method to solve DEA problems with value judgments

Data envelopment analysis (DEA) is a linear programming approach for measuring relative efficiency of peer decision making units that have multiple inputs and outputs. DEA was developed without consideration of the decision maker’s preference structures. DEA and multiple objective linear programming are tools that can be used in management control and planning. This paper shows how a data envelopment analysis problem can be solved by transforming it into MOLP formulation. We use the goal programming method to reflect the decision making preferences in the process of assessing efficiency, such that the value judgments of the decision maker are considered. Therefore, the proposed method can find a solution that satisfies the decision maker’s goal levels. A case study is provided to illustrate how data envelopment oriented efficiency analysis can be conducted by using goal programming method

An Interactive Procedure to Solve Multi-Objective Decision-Making Problem: An Improvment to STEM Method

Decisions in the real-world contexts are often made in the presence of multiple, conflicting, and incommensurate criteria. Multiobjective programming methods such as multiple objective linear programming (MOLP) are techniques used to solve such multiple-criteria decision-making (MCDM) problems. One of the first interactive procedures to solve MOLP is STEM method. In this paper we try to improve STEM method in a way that we search a point in reduced feasible region whose criterion vector is closest to positive ideal criterion vector and furthest to negative ideal criterion vector. Therefore the presented method tries to increase the rate of satisfactoriness of the obtained solution. Finally, a numerical example for illustration of the new method is given to clarify the main results developed in this paper

Antioxidative Effect of Hydroalcoholic Extracts of Fruit and Pit of Elaeagnud Angosifolia Against Oxidative Stress Markers in Benign Prostatic Hyperplasia

Background & aim: The use of medicinal plants has been common among people since ancient times, and in recent years special attention has been paid to their therapeutic consumption. As oxidative stress is one of the possible causes of benign prostatic hyperplasia, the aim of the present study was to determine and compare the antioxidative effect of hydroalcoholic extracts of fruit and pit of Elaeagnud angosifolia against oxidative stress markers in benign prostatic hyperplasia. Methods: In the present semi-experimental study conducted in 2021 at Yasuj University of Medical Sciences, 96 patients over 45 years of age with benign prostatic hyperplasia with International Prostate Symptoms Score (IPSS) below 20 were randomly assigned to two groups receiving placebo (600 mg of white wheat flour for one month) and drug (600 mg of hydroalcoholic extract of elderberry for one month). Blood samples were taken from each patient before and after the study to check the level of oxidative stress factors, including total thiol (TSH), total plasma antioxidant capacity (FRAP), malondialdehyde (MDA) and nitric oxide (NO) metabolites, and at the end of the study, was evaluated. The collected data were analyzed using t-test, Will-Coxon and Mann-Whitney tests. Results: The results of the present study indicated that the hydroalcoholic extract of elderberry kernel and fruit increased the MDA level in the group receiving the extract (480.7±65 vs. 457.8±51) compared to the placebo group (454.8±50 vs. 36±36). 447/3) decreased, however, this decrease was not significant. Also, the amount of NO metabolites in the group receiving the hydroalcoholic extract of elderberry kernel and fruit (6.7±7.8 to 15.7±9) compared to the placebo group (5.5±3 versus 16.6±9) indicated a lower increase. This increase was correspondingly not significant. In addition, there was no statistically significant difference in the amount of FRAP and TSH between the drug and placebo groups (p<0.05). Conclusion: It appeared that the consumption of hydroalcoholic extract of elderberry fruit and kernel could be able to reduce the amount of oxidative stress in benign prostatic hyperplasia patients by reducing lipid peroxidation and also inhibiting NO production

Data mining the Protein Data Bank to identify and characterise chameleon coil sequences that form symmetric homodimer β-sheet interfaces

A protein’s environment may affect its secondary structure. In this study, the focus is on homodimers with symmetric β-sheet interfaces resulting from the conversion of coil sequences into β-strands. All homodimers in the Protein Data Bank relying on those chameleon sequences have been identified. Initial analysis based on sequential and structural features has revealed that many of those dimers display specific properties which could contribute to their detection. Such result is important since it could provide some insight on dimerisation and possibly aggregation mechanisms