Revisiting Date and Party Hubs: Novel Approaches to Role Assignment in Protein Interaction Networks

The idea of 'date' and 'party' hubs has been influential in the study of protein-protein interaction networks. Date hubs display low co-expression with their partners, whilst party hubs have high co-expression. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. Here we show that the reported importance of date hubs to network connectivity can in fact be attributed to a tiny subset of them. Crucially, these few, extremely central, hubs do not display particularly low expression correlation, undermining the idea of a link between this quantity and hub function. The date/party distinction was originally motivated by an approximately bimodal distribution of hub co-expression; we show that this feature is not always robust to methodological changes. Additionally, topological properties of hubs do not in general correlate with co-expression. Thus, we suggest that a date/party dichotomy is not meaningful and it might be more useful to conceive of roles for protein-protein interactions rather than individual proteins. We find significant correlations between interaction centrality and the functional similarity of the interacting proteins.Comment: 27 pages, 5 main figures, 4 supplementary figure

Inferring topology from clustering coefficients in protein-protein interaction networks

BACKGROUND: Although protein-protein interaction networks determined with high-throughput methods are incomplete, they are commonly used to infer the topology of the complete interactome. These partial networks often show a scale-free behavior with only a few proteins having many and the majority having only a few connections. Recently, the possibility was suggested that this scale-free nature may not actually reflect the topology of the complete interactome but could also be due to the error proneness and incompleteness of large-scale experiments. RESULTS: In this paper, we investigate the effect of limited sampling on average clustering coefficients and how this can help to more confidently exclude possible topology models for the complete interactome. Both analytical and simulation results for different network topologies indicate that partial sampling alone lowers the clustering coefficient of all networks tremendously. Furthermore, we extend the original sampling model by also including spurious interactions via a preferential attachment process. Simulations of this extended model show that the effect of wrong interactions on clustering coefficients depends strongly on the skewness of the original topology and on the degree of randomness of clustering coefficients in the corresponding networks. CONCLUSION: Our findings suggest that the complete interactome is either highly skewed such as e.g. in scale-free networks or is at least highly clustered. Although the correct topology of the interactome may not be inferred beyond any reasonable doubt from the interaction networks available, a number of topologies can nevertheless be excluded with high confidence

Nicotine exposure and transgenerational impact: a prospective study on small regulatory microRNAs

Early developmental stages are highly sensitive to stress and it has been reported that pre-conditioning with tobacco smoking during adolescence predisposes those youngsters to become smokers as adults. However, the molecular mechanisms of nicotine-induced transgenerational consequences are unknown. In this study, we genome-widely investigated the impact of nicotine exposure on small regulatory microRNAs (miRNAs) and its implication on health disorders at a transgenerational aspect. Our results demonstrate that nicotine exposure, even at the low dose, affected the global expression profiles of miRNAs not only in the treated worms (F0 parent generation) but also in two subsequent generations (F1 and F2, children and grandchildren). Some miRNAs were commonly affected by nicotine across two or more generations while others were specific to one. The general miRNA patterns followed a “two-hit� model as a function of nicotine exposure and abstinence. Target prediction and pathway enrichment analyses showed daf-4, daf-1, fos-1, cmk-1, and unc-30 to be potential effectors of nicotine addiction. These genes are involved in physiological states and phenotypes that paralleled previously published nicotine induced behavior. Our study offered new insights and further awareness on the transgenerational effects of nicotine exposed during the vulnerable post-embryonic stages, and identified new biomarkers for nicotine addiction.ECU Open Access Publishing Support Fun

Phase II study of capecitabine and cisplatin as first-line combination therapy in patients with gastric cancer recurrent after fluoropyrimidine-based adjuvant chemotherapy

To evaluate the efficacy and safety of capecitabine and cisplatin in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant therapy. Patients with histologically confirmed and measurable advanced gastric cancer that had relapsed after fluoropyrimidine-based adjuvant chemotherapy received oral capecitabine (1250 mg m−2 twice daily, days 1–14) and intravenous cisplatin (60 mg m−2 over 1 h, day 1) every 3 weeks. In total, 32 patients were enrolled, of whom 30 were evaluable for efficacy and 32 for safety. A median of 5 cycles (range 1–10) was administered. One patient achieved a complete response and eight had partial responses, giving an overall response rate of 28% (95% CI, 13–44%). The median time to progression and median overall survival were 5.8 months (95% CI, 4.1–7.5 months) and 11.2 months (95% CI, 5.5–16.9 months), respectively. Grade 3 neutropenia and thrombocytopenia were observed in 38 and 6% of patients, respectively. Grade 2/3 nonhaematological toxicities included diarrhoea (19%), stomatitis (19%) and hand-foot syndrome (31%). No grade 4 toxicity, neutropenic fever or treatment-related deaths occurred. Capecitabine in combination with cisplatin was effective and well tolerated as first-line treatment in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant chemotherapy

Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium

Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous polyposis coli (APC) and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array data sets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the ‘triple negative’ phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumorigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of β-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with ‘squamoid’ ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt-driven mammary tumor model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis

High-throughput profiling of caenorhabditis elegans starvation-responsive microRNAs

MicroRNAs (miRNAs) are non-coding RNAs of ~22 nucleotides in length that regulate gene expression by interfering with the stability and translation of mRNAs. Their expression is regulated during development, under a wide variety of stress conditions and in several pathological processes. In nature, animals often face feast or famine conditions. We observed that subjecting early L4 larvae from Caenorhabditis elegans to a 12-hr starvation period produced worms that are thinner and shorter than well-fed animals, with a decreased lipid accumulation, diminished progeny, reduced gonad size, and an increased lifespan. Our objective was to identify which of the 302 known miRNAs of C. elegans changed their expression under starvation conditions as compared to well-fed worms by means of deep sequencing in early L4 larvae. Our results indicate that 13 miRNAs (miR-34-3p, the family of miR-35-3p to miR-41-3p, miR-39-5p, miR-41-5p, miR-240-5p, miR-246-3p and miR-4813-5p) were upregulated, while 2 miRNAs (let-7-3p and miR-85-5p) were downregulated in 12-hr starved vs. well-fed early L4 larvae. Some of the predicted targets of the miRNAs that changed their expression in starvation conditions are involved in metabolic or developmental process. In particular, miRNAs of the miR-35 family were upregulated 6-20 fold upon starvation. Additionally, we showed that the expression of gld-1, important in oogenesis, a validated target of miR-35-3p, was downregulated when the expression of miR-35-3p was upregulated. The expression of another reported target, the cell cycle regulator lin-23, was unchanged during starvation. This study represents a starting point for a more comprehensive understanding of the role of miRNAs during starvation in C. elegans

NaOCl produced by electrolysis of natural seawater as a potential method to control marine red-tide dinoflagellates

As part of the development of a method to control the outbreak and persistence of red tides using sodium hypochlorite (NaOCl), we investigated the effect of NaOCl on the survival of red-tide dinoflagellates, diatoms, heterotrophic protists, planktonic crustaceans, fin-fish, shellfish, and macroalgae. Because NaOCl introduced into natural waters would be subject to dilution, as well as breakdown in sunlight to NaCl, the survival of organisms was determined after 10 min exposure and 1 h exposure to NaOCl, and again after transfer to fresh seawater for 6 or 24 h. The lethal total residual chlorine (TRC) concentration that killed 50% of the test organisms (LC50) for the red-tide dinoflagellates Gymnodinium catenatum, Cochlodinium polykrikoides, Akashiwo sanguinea, Lingulodinium polyedrum, Prorocentrum micans, Alexandrium affine, and Gymnodinium impudicum ranged from 57 to 157 ppb for 10 min exposure and from 30 to 106 ppb for 1 h exposure. Complete mortality of all red-tide species occurred at TRC concentrations of similar to 500 ppb. The LC(50)s of the diatoms Skeletonema costatum and Thalassiosira rotula, 3083-3383 ppb for 10 min exposure and 3128-3433 ppb for 1 h exposure, were much higher than for red-tide dinoflagellates. But the LC50S of the heterotrophic dinoflagellates Polykrikos kofoidii and Oxyrrhis marina were similar to those of red-tide dinoflagellates. The ciliate Strombidinopsis sp. had LC(50)s of 306 ppb for. 10 min exposure and 119 ppb for 1 h exposure, which are higher than those for dinoflagellates. The LC(50)a of the calanoid copepods Acartia spp. and Pseudodiaptomus sp. were 1397-1493 ppb for 10 min exposure and 744-987 ppb for 1 h exposure, and those for larvae of the brine shrimp Artemia franciscana were 4905 ppb for 10 m exposure and 2814 ppb for 1 h exposure. The LC(50)s of juvenile gray mullet Mugil cephalus and juvenile black rockfish Sebastes schlegeli were 1234-1883 ppb for 10 min exposure and 1234-1440 ppb for 1 h exposure, whereas those of adult Manila clam Ruditapes philippinarum and spat of the abalone Nordotis discus were > 20,000 ppb. The LC(50)s of the macroalgae Griffithsia japonica (Rhodophyta) and Ulva pertusa (Chlorophyta) were 1519-12,365 ppb for 10 min exposure and 1085-12,558 ppb for 1 h exposure. The present study therefore suggests that, if NaOCl is introduced into waters containing red-tide organisms at TRC concentrations of 300-500 ppb for 10 min exposure and 200-400 ppb for 1 h exposure, red tides can be effectively controlled without serious harmful effects on other marine organisms, except heterotrophic dinoflagellates.N