Mitochondrial ATP synthase inhibition and nitric oxide are involved in muscle weakness that occurs in acute exposure of rats to monocrotophos

Organophosphate poisoning in the context of self-harm is a common medical emergency in Asia. Prolonged muscle weakness is an important but poorly understood cause of morbidity and mortality of the poisoning. This study examined mitochondrial function and its modulation by nitric oxide in muscle weakness of rats exposed to an acute, oral (0.8LD50) dose of monocrotophos. Muscle mitochondrial ATP synthase activity was inhibited in the rat in acute exposure to monocrotophos while respiration per se was not affected. This was accompanied by decreased mitochondrial uptake of calcium and increased levels of nitric oxide. Reactive cysteine groups of ATP synthase subunits were reduced in number, which may contribute to decreased enzyme activity. The decrease in ATP synthase activity and reactive cysteine groups of ATP synthase subunits was prevented by treatment of animals with the nitric oxide synthase inhibitor, L-NG Nitroarginine methyl ester, at 12 mg/kg body weight for 9 days in drinking water, prior to monocrotophos exposure. This indicated a role for nitric oxide in the process. The alterations in mitochondrial calcium uptake may influence cytosolic calcium levels and contribute to muscle weakness of acute organophosphate exposure

Participatory instructional redesign by students and teachers in secondary education: effects on perceptions of instruction

Könings, K. D., Brand-Gruwel, S., & Van Merriënboer, J. J. G. (2011). Participatory instructional redesign by students and teachers in secondary education: effects on perceptions of instruction. Instructional Science, 39(5), 737–762.Students’ perceptions of instruction are important because they direct the learning of students. The fact that teachers have only limited knowledge of these perceptions is likely to threaten the effectiveness of learning, because congruence between interpretations of an instructional intervention is necesarry for its optimal use. This study examines participatory design as a strategy for taking student perceptions into account in instructional re/design. Participatory design meetings of groups of teachers and seven co-designing students in a secondary education setting identified changes to improve the regular education process. The results on changes in student perceptions, perceived-desired discrepancy, and teacher-student disagreement showed some improvement for the co-designers but, unexpectedly, limited or even negative effects for the non-co-designing students. Possible causes are discussed. Participatory design seems to have potential for improving education, but further research is needed

Dynamic Nuclear Polarization NMR Spectroscopy Allows High-Throughput Characterization of Microporous Organic Polymers

Dynamic nuclear polarization (DNP) solid-state NMR was used to obtain natural abundance 13C and 15N CP MAS NMR spectra of microporous organic polymers with excellent signal-to-noise ratio, allowing for unprecedented details in the molecular structure to be determined for these complex polymer networks. Sensitivity enhancements larger than 10 were obtained with bis-nitroxide radical at 14.1 T and low temperature (∼105 K). This DNP MAS NMR approach allows efficient, high-throughput characterization of libraries of porous polymers prepared by combinatorial chemistry methods

Treatment- and Population-Dependent Activity Patterns of Behavioral and Expression QTLs

Genetic control of gene expression and higher-order phenotypes is almost invariably dependent on environment and experimental conditions. We use two families of recombinant inbred strains of mice (LXS and BXD) to study treatment- and genotype-dependent control of hippocampal gene expression and behavioral phenotypes. We analyzed responses to all combinations of two experimental perturbations, ethanol and restraint stress, in both families, allowing for comparisons across 8 combinations of treatment and population. We introduce the concept of QTL activity patterns to characterize how associations between genomic loci and traits vary across treatments. We identified several significant behavioral QTLs and many expression QTLs (eQTLs). The behavioral QTLs are highly dependent on treatment and population. We classified eQTLs into three groups: cis-eQTLs (expression variation that maps to within 5 Mb of the cognate gene), syntenic trans-eQTLs (the gene and the QTL are on the same chromosome but not within 5 Mb), and non-syntenic trans-eQTLs (the gene and the QTL are on different chromosomes). We found that most non-syntenic trans-eQTLs were treatment-specific whereas both classes of syntenic eQTLs were more conserved across treatments. We also found there was a correlation between regions along the genome enriched for eQTLs and SNPs that were conserved across the LXS and BXD families. Genes with eQTLs that co-localized with the behavioral QTLs and displayed similar QTL activity patterns were identified as potential candidate genes associated with the phenotypes, yielding identification of novel genes as well as genes that have been previously associated with responses to ethanol

Isolation, Characterization, and Stability of Discretely-Sized Nanolipoprotein Particles Assembled with Apolipophorin-III

Background: Nanolipoprotein particles (NLPs) are discoidal, nanometer-sized particles comprised of self-assembled phospholipid membranes and apolipoproteins. NLPs assembled with human apolipoproteins have been used for myriad biotechnology applications, including membrane protein solubilization, drug delivery, and diagnostic imaging. To expand the repertoire of lipoproteins for these applications, insect apolipophorin-III (apoLp-III) was evaluated for the ability to form discretely-sized, homogeneous, and stable NLPs. Methodology: Four NLP populations distinct with regards to particle diameters (ranging in size from 10 nm to.25 nm) and lipid-to-apoLp-III ratios were readily isolated to high purity by size exclusion chromatography. Remodeling of the purified NLP species over time at 4uC was monitored by native gel electrophoresis, size exclusion chromatography, and atomic force microscopy. Purified 20 nm NLPs displayed no remodeling and remained stable for over 1 year. Purified NLPs with 10 nm and 15 nm diameters ultimately remodeled into 20 nm NLPs over a period of months. Intra-particle chemical cross-linking of apoLp-III stabilized NLPs of all sizes. Conclusions: ApoLp-III-based NLPs can be readily prepared, purified, characterized, and stabilized, suggesting their utilit

Identification of a potent herbal molecule for the treatment of breast cancer

<p>Abstract</p> <p>Background</p> <p>Breast cancer (BCa)-related mortality still remains the second leading cause of cancer-related deaths worldwide. Patients with BCa have increasingly shown resistance and high toxicity to current chemotherapeutic drugs for which identification of novel targeted therapies are required.</p> <p>Methods</p> <p>To determine the effect of PDBD on BCa cells, estrogen-receptor positive (ER⁺)-MCF-7 and estrogen-receptor negative (ER^-)-MDA 231 cells were treated with PDBD and the cell viability, apoptotic, cell cycle, Western blot and Promoter assays were performed.</p> <p>Results</p> <p>PDBD inhibits cell viability of ER⁺and ER^-BCa cells by inducing apoptosis without causing significant toxicity in normal breast epithelial cells. While dissecting the mechanism of action of PDBD on BCa, we found that PDBD inhibits Akt signaling and its downstream targets such as NF-κB activation, IAP proteins and Bcl-2 expression. On the other hand, activation of JNK/p38 MAPK-mediated pro-apoptotic signaling was observed in both ER⁺and ER^-BCa cells.</p> <p>Conclusion</p> <p>These findings suggest that PDBD may have wide therapeutic application in the treatment of BCa.</p

Analysis and prediction of cancerlectins using evolutionary and domain information

<p>Abstract</p> <p>Background</p> <p>Predicting the function of a protein is one of the major challenges in the post-genomic era where a large number of protein sequences of unknown function are accumulating rapidly. Lectins are the proteins that specifically recognize and bind to carbohydrate moieties present on either proteins or lipids. Cancerlectins are those lectins that play various important roles in tumor cell differentiation and metastasis. Although the two types of proteins are linked, still there is no computational method available that can distinguish cancerlectins from the large pool of non-cancerlectins. Hence, it is imperative to develop a method that can distinguish between cancer and non-cancerlectins.</p> <p>Results</p> <p>All the models developed in this study are based on a non-redundant dataset containing 178 cancerlectins and 226 non-cancerlectins in which no two sequences have more than 50% sequence similarity. We have applied the similarity search based technique, i.e. BLAST, and achieved a maximum accuracy of 43.25%. The amino acids compositional analysis have shown that certain residues (e.g. Leucine, Proline) were preferred in cancerlectins whereas some other (e.g. Asparatic acid, Asparagine) were preferred in non-cancerlectins. It has been found that the PROSITE domain "Crystalline beta gamma" was abundant in cancerlectins whereas domains like "SUEL-type lectin domain" were found mainly in non-cancerlectins. An SVM-based model has been developed to differentiate between the cancer and non-cancerlectins which achieved a maximum Matthew's correlation coefficient (MCC) value of 0.32 with an accuracy of 64.84%, using amino acid compositions. We have developed a model based on dipeptide compositions which achieved an MCC value of 0.30 with an accuracy of 64.84%. Thereafter, we have developed models based on split compositions (2 and 4 parts) and achieved an MCC value of 0.31, 0.32 with accuracies of 65.10% and 66.09%, respectively. An SVM model based on Position Specific Scoring Matrix (PSSM), generated by PSI-BLAST, was developed and achieved an MCC value of 0.36 with an accuracy of 68.34%. Finally, we have integrated the PROSITE domain information with PSSM and developed an SVM model that has achieved an MCC value of 0.38 with 69.09% accuracy.</p> <p>Conclusion</p> <p>BLAST has been found inefficient to distinguish between cancer and non-cancerlectins. We analyzed the protein sequences of cancer and non-cancerlectins and identified interesting patterns. We have been able to identify PROSITE domains that are preferred in cancer and non-cancerlectins and thus provided interesting insights into the two types of proteins. The method developed in this study will be useful for researchers studying cancerlectins, lectins and cancer biology. The web-server based on the above study, is available at <url>http://www.imtech.res.in/raghava/cancer_pred/</url></p

A Project Portfolio Management Approach to Tacklingthe Exploration/Exploitation Trade-off

Organizational ambidexterity (OA) is an essen-tial capability for surviving in dynamic business environ-ments that advocates the simultaneous engagement inexploration and exploitation. Over the last decades,knowledge on OA has substantially matured, coveringinsights into antecedents, outcomes, and moderators of OA.However, there is little prescriptive knowledge that offersguidance on how to put OA into practice and to tackle thetrade-off between exploration and exploitation. To addressthis gap, the authors adopt the design science researchparadigm and propose an economic decision model asartifact. The decision model assists organizations inselecting and scheduling exploration and exploitation pro-jects to become ambidextrous in an economically reason-able manner. As for justificatory knowledge, the decisionmodel draws from prescriptive knowledge on projectportfolio management and value-based management, andfrom descriptive knowledge related to OA to structure thefield of action. To evaluate the decision model, its designspecification is discussed against theory-backed designobjectives and with industry experts. The paper alsoinstantiates the decision model as a software prototype andapplies the prototype to a case based on real-world data