BinTree seeking: a novel approach to mine both bi-sparse and cohesive modules in protein interaction networks

Modern science of networks has brought significant advances to our understanding of complex systems biology. As a representative model of systems biology, Protein Interaction Networks (PINs) are characterized by a remarkable modular structures, reflecting functional associations between their components. Many methods were proposed to capture cohesive modules so that there is a higher density of edges within modules than those across them. Recent studies reveal that cohesively interacting modules of proteins is not a universal organizing principle in PINs, which has opened up new avenues for revisiting functional modules in PINs. In this paper, functional clusters in PINs are found to be able to form unorthodox structures defined as bi-sparse module. In contrast to the traditional cohesive module, the nodes in the bi-sparse module are sparsely connected internally and densely connected with other bi-sparse or cohesive modules. We present a novel protocol called the BinTree Seeking (BTS) for mining both bi-sparse and cohesive modules in PINs based on Edge Density of Module (EDM) and matrix theory. BTS detects modules by depicting links and nodes rather than nodes alone and its derivation procedure is totally performed on adjacency matrix of networks. The number of modules in a PIN can be automatically determined in the proposed BTS approach. BTS is tested on three real PINs and the results demonstrate that functional modules in PINs are not dominantly cohesive but can be sparse. BTS software and the supporting information are available at: www.csbio.sjtu.edu.cn/bioinf/BTS/.     

Diverse arrangement of photosynthetic gene clusters in aerobic anoxygenic phototrophic bacteria

Background

Aerobic anoxygenic photototrophic (AAP) bacteria represent an important group of marine microorganisms inhabiting the euphotic zone of the ocean. They harvest light using bacteriochlorophyll (BChl) a and are thought to be important players in carbon cycling in the ocean.

Methodology/Principal Findings

Aerobic anoxygenic phototrophic (AAP) bacteria represent an important part of marine microbial communities. Their photosynthetic apparatus is encoded by a number of genes organized in a so-called photosynthetic gene cluster (PGC). In this study, the organization of PGCs was analyzed in ten AAP species belonging to the orders Rhodobacterales, Sphingomonadales and the NOR5/OM60 clade. Sphingomonadales contained comparatively smaller PGCs with an approximately size of 39 kb whereas the average size of PGCs in Rhodobacterales and NOR5/OM60 clade was about 45 kb. The distribution of four arrangements, based on the permutation and combination of the two conserved regions bchFNBHLM-LhaA-puhABC and crtF-bchCXYZ, does not correspond to the phylogenetic affiliation of individual AAP bacterial species. While PGCs of all analyzed species contained the same set of genes for bacteriochlorophyll synthesis and assembly of photosynthetic centers, they differed largely in the carotenoid biosynthetic genes. Spheroidenone, spirilloxanthin, and zeaxanthin biosynthetic pathways were found in each clade respectively. All of the carotenoid biosynthetic genes were found in the PGCs of Rhodobacterales, however Sphingomonadales and NOR5/OM60 strains contained some of the carotenoid biosynthetic pathway genes outside of the PGC.

Conclusions/Significance

Our investigations shed light on the evolution and functional implications in PGCs of marine aerobic anoxygenic phototrophs, and support the notion that AAP are a heterogenous physiological group phylogenetically scattered among Proteobacteria.     

Relationships between membrane binding, affinity and cell internalization efficacy of a cell-penetrating peptide: penetratin as a case study

Background

Penetratin is a positively charged cell-penetrating peptide (CPP) that has the ability to bind negatively charged membrane components, such as glycosaminoglycans and anionic lipids. Whether this primary interaction of penetratin with these cell surface components implies that the peptide will be further internalized is not clear.

Methodology

Using mass spectrometry, the amount of internalized and membrane bound penetratin remaining after washings, were quantified in three different cell lines: wild type (WT), glycosaminoglycans- (GAG^neg) and sialic acid-deficient (SA^neg) cells. Additionally, the affinity and kinetics of the interaction of penetratin to membrane models composed of pure lipids and membrane fragments from the referred cell lines was investigated, as well as the thermodynamics of such interactions using plasmon resonance and calorimetry.

Principal Findings

Penetratin internalized with the same efficacy in the three cell lines at 1 µM, but was better internalized at 10 µM in SA^neg>WT>GAG^neg. The heat released by the interaction of penetratin with these cells followed the ranking order of internalization efficiency. Penetratin had an affinity of 10 nM for WT cells and µM for SA^neg and GAG^neg cells and model membrane of phospholipids. The remaining membrane-bound penetratin after cells washings was similar in WT and GAG^neg cells, which suggested that these binding sites relied on membrane phospholipids. The interaction of penetratin with carbohydrates was more superficial and reversible while it was stronger with phospholipids, likely because the peptide can intercalate between the fatty acid chains.

Conclusion/Significance

These results show that accumulation and high-affinity binding of penetratin at the cell-surface do not reflect the internalization efficacy of the peptide. Altogether, these data further support translocation (membrane phospholipids interaction) as being the internalization pathway used by penetratin at low micromolecular concentration, while endocytosis is activated at higher concentration and requires accumulation of the peptide on GAG and GAG clustering.     

Increased activity imbalance in fronto-subcortical circuits in adolescents with major depression

Background

A functional discrepancy exists in adolescents between frontal and subcortical regions due to differential regional maturational trajectories. It remains unknown how this functional discrepancy alters and whether the influence from the subcortical to the frontal system plays a primacy role in medication naïve adolescent with major depressive disorder (MDD).

Methodology/Principal Findings

Eighteen MDD and 18 healthy adolescents were enrolled. Depression and anxiety severity was assessed by the Short Mood and Feeling Questionnaire (SMFQ) and Screen for Child Anxiety Related Emotional Disorders (SCARED) respectively. The functional discrepancy was measured by the amplitude of low-frequency fluctuations (ALFF) of resting-state functional MRI signal. Correlation analysis was carried out between ALFF values and SMFQ and SCARED scores. Resting brain activity levels measured by ALFF was higher in the frontal cortex than that in the subcortical system involving mainly (para) limbic-striatal regions in both HC and MDD adolescents. The difference of ALFF values between frontal and subcortical systems was increased in MDD adolescents as compared with the controls.

Conclusions/Significance

The present study identified an increased imbalance of resting-state brain activity between the frontal cognitive control system and the (para) limbic-striatal emotional processing system in MDD adolescents. The findings may provide insights into the neural correlates of adolescent MDD.     

Complete mitochondrial genome of Chilo suppressalis (Walker) (Lepidoptera: Crambidae)

The complete sequence of the mitochondrial genome (mitogenome) of the rice stem borer Chilo suppressalis (Walker) (Lepidoptera: Crambidae) was determined to be 15,465 bp. It contains 13 protein-coding genes (PCGs), 22 tRNA genes, the large and small rRNA genes, and an A+T-rich region. The nucleotide composition of the mitogenome of C. suppressalis is highly A+T biased, accounting for 79.70% in whole mitogenome, 77.74% in PCGs, 84.70% in tRNAs, 81.20% in rRNAs and 94.19% in A+T-rich region, respectively. The PCGs have typical ATN start codons, except for cox1, which contains the unusual CGA. The C. suppressalis A+T-rich region contains a conserved structure combining the motif ATAGA and a 19-bp poly-T stretch, but absence of the 9-bp poly-A element upstream trnM.     

Structural alterations from multiple displacement amplification of a human genome revealed by mate-pair sequencing

Comprehensive identification of the acquired mutations that cause common cancers will require genomic analyses of large sets of tumor samples. Typically, the tissue material available from tumor specimens is limited, which creates a demand for accurate template amplification. We therefore evaluated whether phi29-mediated whole genome amplification introduces false positive structural mutations by massive mate-pair sequencing of a normal human genome before and after such amplification. Multiple displacement amplification led to a decrease in clone coverage and an increase by two orders of magnitude in the prevalence of inversions, but did not increase the prevalence of translocations. While multiple strand displacement amplification may find uses in translocation analyses, it is likely that alternative amplification strategies need to be developed to meet the demands of cancer genomics.     

Differential expression of miR-195 in esophageal squamous cell carcinoma and miR-195 expression inhibits tumor cell proliferation and invasion by targeting of Cdc42

MicroRNAs (miRNA) have played an important role in carcinogenesis. In this study, Agilent miRNA microarray was used to identify differentially expressed miRNAs in esophageal squamous cell carcinoma (ESCC) tissues and miR-195 was downregulated in ESCC compared with normal esophageal tissues. Moreover, Cdc42 was confirmed as target gene of miR-195. Ectopic expression of miR-195 in ESCC cells significantly downregulated Cdc42 by directly binding its 3′ untranslated regions, and induced G1 cell cycle arrest, leading to a significant decrease in cell growth, migration, and invasion in vitro. Therefore, our findings demonstrated that miR-195 may act as a tumor suppressor in ESCC by targeting Cdc42.     

Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies

Cyclooxygenase 2 (COX)-2 is induced by bacterial and viral infections and has complex, poorly understood roles in anti-pathogen immunity. Here, we use a knock-in luciferase reporter model to image Cox2 expression across a range of tissues in mice following treatment with the either the prototypical bacterial pathogen-associated molecular pattern (PAMP), LPS, which activates Toll-like receptor (TLR)4, or with poly(I:C), a viral PAMP, which activates TLR3. LPS induced Cox2 expression in all tissues examined. In contrast, poly(I:C) elicited a milder response, limited to a subset of tissues. A panel of cytokines and interferons was measured in plasma of wild-type, Cox1^−/− and Cox2^−/− mice treated with LPS, poly(I:C), MALP2 (TLR2/6), Pam3CSK4 (TLR2/1), R-848 (TLR7/8) or CpG ODN (TLR9), to establish whether/how each COX isoform modulates specific PAMP/TLR responses. Only LPS induced notable loss of condition in mice (inactivity, hunching, piloerection). However, all TLR agonists produced cytokine responses, many of which were modulated in specific fashions by Cox1 or Cox2 gene deletion. Notably we observed opposing effects of Cox2 gene deletion on the responses to the bacterial PAMP, LPS, and the viral PAMP, poly(I:C), consistent with the differing abilities of the PAMPs to induce Cox2 expression. Cox2 gene deletion limited the plasma IL-1β and interferon-γ responses and hypothermia produced by LPS. In contrast, in response to poly(I:C), Cox2^−/− mice exhibited enhanced plasma interferon (IFNα,β,γ,λ) and related cytokine responses (IP-10, IL-12). These observations suggest that a COX-2 selective inhibitor, given early in infection, may enhance and/or prolong endogenous interferon responses, and thereby increase anti-viral immunity.