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Mitochondria play a critical role in the generation of metabolic energy and are crucial for eukaryotic cell survival and proliferation. In most sexual eukaryotes, mitochondrial DNA (mtDNA) is inherited from only one parent in non-Mendelian inheritance in contrast to the inheritance of nuclear DNA. The model organism Saccharomyces cerevisiae is commonly used to study mitochondrial biology. It has two mating types: MATa and MATα. Previous studies have suggested that the mtDNA inheritance patterns in hybrid diploid cells depend on the genetic background of parental strains. However, the underlying mechanisms remain unclear. To elucidate the mechanisms, we examined the effects of environmental factors on the mtDNA inheritance patterns in hybrids obtained by crossing S. cerevisiae with its close relative S. paradoxus. The results demonstrated that environmental factors can influence mtDNA transmission in hybrid diploids, and that the inheritance patterns are strain dependent. The fitness competition assay results showed that the fitness differences can explain the mtDNA inheritance patterns under specific conditions. However, in this study, we found that fitness differences cannot fully be explained by mitochondrial activity in hybrids under stress conditions. [ABSTRACT FROM AUTHOR]

Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling through amplifications, mutations, and gene fusions has been implicated in a broad array of cancers (e.g. liver, gastric, ovarian, endometrial, and bladder). ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR addicted cell lines and tumors. Biochemically, ARQ 087 exhibited IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2α, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions. ARQ 087 is currently being studied in a phase 1/2 clinical trial that includes a sub cohort for intrahepatic cholangiocarcinoma patients with confirmed FGFR2 gene fusions (NCT01752920). [ABSTRACT FROM AUTHOR]

Identifying similar diseases could potentially provide deeper understanding of their underlying causes, and may even hint at possible treatments. For this purpose, it is necessary to have a similarity measure that reflects the underpinning molecular interactions and biological pathways. We have thus devised a network-based measure that can partially fulfill this goal. Our method assigns weights to all proteins (and consequently their encoding genes) by using information flow from a disease to the protein interaction network and back. Similarity between two diseases is then defined as the cosine of the angle between their corresponding weight vectors. The proposed method also provides a way to suggest disease-pathway associations by using the weights assigned to the genes to perform enrichment analysis for each disease. By calculating pairwise similarities between 2534 diseases, we show that our disease similarity measure is strongly correlated with the probability of finding the diseases in the same disease family and, more importantly, sharing biological pathways. We have also compared our results to those of MimMiner, a text-mining method that assigns pairwise similarity scores to diseases. We find the results of the two methods to be complementary. It is also shown that clustering diseases based on their similarities and performing enrichment analysis for the cluster centers significantly increases the term association rate, suggesting that the cluster centers are better representatives for biological pathways than the diseases themselves. This lends support to the view that our similarity measure is a good indicator of relatedness of biological processes involved in causing the diseases. Although not needed for understanding this paper, the raw results are available for download for further study at . [ABSTRACT FROM AUTHOR]

Organizing experimentally determined protein associations as a hierarchy can be a good approach to elucidating the content of protein complexes and the modularity of subcomplexes. Several challenges exist. First, intrinsically sticky proteins, such as chaperones, are often falsely assigned to many functionally unrelated complexes. Second, the reported collections of proteins may not be true “complexes” in the sense that they bind together and perform a joint cellular function. Third, due to imperfect sensitivity of protein detection methods, both false positive and false negative assignments of a protein to complexes may occur. We mitigate the first issue by down-weighting sticky proteins by their occurrence frequencies. We approach the other two problems by merging nearly identical complexes and by constructing a directed acyclic graph (DAG) based on the relationship of partial inclusion. The constructed DAG, within which smaller complexes form parts of the larger, can reveal how different complexes are joined. By merging almost identical complexes one can deemphasize the influence of false positives, while allowing false negatives to be rescued by other nearly identical association data. We investigate several protein weighting schemes and compare their corresponding DAGs using yeast and human complexes. We find that the scheme incorporating weights based on information flow in the network of direct protein–protein interactions produces biologically most meaningful DAGs. In either yeast or human, isolated nodes form a large proportion of the final hierarchy. While most connected components encompass very few nodes, the largest one for each species contains a sizable portion of all nodes. By considering examples of subgraphs composed of nodes containing a specified protein, we illustrate that the graphs' topological features can correctly suggest the biological roles of protein complexes. The input data, final results and the source code are available at ftp://ftp.ncbi.nlm.nih.gov/pub/qmbpmn/ProteinComplexDAG/. [ABSTRACT FROM AUTHOR]

TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs), another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes. [ABSTRACT FROM AUTHOR]

Cancer is one of the most troublesome diseases and a leading cause of death worldwide. Recently, novel treatments have been continuously developed to improve the disadvantages of conventional therapies, such as prodigious expenses, unwanted side effects, and tumor recurrence. Here, we provide the first non-invasive treatment that has combined epigallocatechin gallate (EGCG), the most abundant catechin in green tea, with a low strength pulsed electric field (PEF) and a low energy ultrasound (US). It has been observed that the cell viability of human pancreatic cancer PANC-1 was decreased approximately to 20% of the control after this combination treatment for 72 h. Besides, the combined triple treatment significantly reduced the high tolerance of HepG2 cells to the EGCG-induced cytotoxicity and similarly exhibited compelling proliferation-inhibitory effects. We also found the combined triple treatment increased the intracellular reactive oxygen species (ROS) and acidic vesicles, and the EGCG-induced inhibition of Akt phosphorylation was dramatically intensified. In this study, the apoptosis inhibitor Z-VAD-FMK and the autophagy inhibitor 3-MA were, respectively, shown to attenuate the anticancer effects of the triple treatment. This indicates that the triple treatment-induced autophagy was switched from cytoprotective to cytotoxic, and hence, cooperatively caused cell death with the apoptosis. Since the EGCG is easily accessible from the green tea and mild for a long-term treatment, and the non-invasive physical stimulations could be modified to focus on a specific location, this combined triple treatment may serve as a promising strategy for anticancer therapy. [ABSTRACT FROM AUTHOR]

Hyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a unique strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first in vitro thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential of the TC-HT as an alternative strategy in thermal treatment. [ABSTRACT FROM AUTHOR]

Daily urine protein (UP) loss is a cumbersome but important measurement to guide diagnosis and treatment of renal disease. Spot urine protein-creatinine ratio (UPCR) can been applied to estimate daily proteinuria. However, the correlations between spot and 24h proteinuria remain controversial. In this cross-sectional study, simultaneous collection of 24h and spot urines were performed from 1,039 (derivation cohort) and 204 CKD patients (validation cohort) of Chang Gung Memorial Hospital, from 2007 to 2017. The correlations between spot UPCR and 24h proteinuria were compared. The mean age of patients of derivation and validation cohort was 63 and 55 years and the mean estimated glomerular filtration rate was 62 ± 35 and 59 ± 36 mL/min/m2, respectively. The correlation coefficient was 0.819 between UPCR and 24hUP. Prediction equation was derived as: Log1024hUP (g) = 0.814 x Log10UPCR (mg/mg) + 0.110 x Gender– 0.004 x Age + 0.004 x Body weight (kg) + 0.002 x CKD stage coefficient– 0.018, where CKD stage coefficient: CKD stage G1 = 1, G2 = 2, G3a = 3.1, G3b = 3.2, G4 = 4, G5 = 5. Correlation coefficient between measured and predicted 24hUP among derivation group and validation group is 0.866 and 0.915, respectively. However, the agreement of spot and daily estimates was less pronounced with proteinuria > 3g than lower values in Bland-Altman analysis. Spot UPCR can accurately predict 24hUP in patients with daily proteinuria below 3g. The development of this equation may facilitate estimation of 24hUP in the clinical practice. [ABSTRACT FROM AUTHOR]

Bradysia odoriphaga (Diptera: Sciaridae) is the most important pest of Chinese chive (Allium tuberosum) in Asia; however, the molecular genetics are poorly understood. To explore the molecular biological mechanism of development, Illumina sequencing and de novo assembly were performed in the third-instar, fourth-instar, and pupal B. odoriphaga. The study resulted in 16.2 Gb of clean data and 47,578 unigenes (≥125bp) contained in 7,632,430contigs, 46.21% of which were annotated from non-redundant protein (NR), Gene Ontology (GO), Clusters of Orthologous Groups (COG), Eukaryotic Orthologous Groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. It was found that 19.67% of unigenes matched the homologous species mainly, including Aedes aegypti, Culex quinquefasciatus, Ceratitis capitata, and Anopheles gambiae. According to differentially expressed gene (DEG) analysis, 143, 490, and 309 DEGs were annotated as involved in the developmental process in the GO database respectively, in the comparisons of third-instar and fourth-instar larvae, third-instar larvae and pupae, and fourth-instar larvae and pupae. Twenty-five genes were closely related to these processes, including developmental process, reproduction process, and reproductive organs development and programmed cell death (PCD). The information of unigenes assembled in B. odoriphaga through transcriptome and DEG analyses could provide a detailed genetic basis and regulated information for elaborating the developmental mechanism from the larval, pre-pupal to pupal stages of B. odoriphaga. [ABSTRACT FROM AUTHOR]

In biosynthesis of natural products, potential intermediates or analogs of a particular compound in the crude extracts are commonly overlooked in routine assays due to their low concentration, limited structural information, or because of their insignificant bio-activities. This may lead into an incomplete and even an incorrect biosynthetic pathway for the target molecule. Here we applied multiple compound mining approaches, including genome scanning and precursor ion scan-directed mass spectrometry, to identify potential pyrrolamide compounds in the fermentation culture of Streptomyces netropsis. Several novel congocidine and distamycin analogs were thus detected and characterized. A more reasonable route for the biosynthesis of pyrrolamides was proposed based on the structures of these newly discovered compounds, as well as the functional characterization of several key biosynthetic genes of pyrrolamides. Collectively, our results implied an unusual “iterative strategy” underlying the pyrrole polymerization in the biosynthesis of pyrrolamide antibiotics. [ABSTRACT FROM AUTHOR]