Dirhodium C-H Functionalization of Hole-Transport Materials.

Hole-transport materials (HTMs) based on triarylamine derivatives play important roles in organic electronics applications including organic light-emitting diodes and perovskite solar cells. For some applications, triarylamine derivatives bearing appropriate binding groups have been used to functionalize surfaces, while others have been incorporated as side chains into polymers to manipulate the processibility of HTMs for device applications. However, only a few approaches have been used to incorporate a single surface-binding group or polymerizable group into triarylamine materials. Here, we report that Rh-carbenoid chemistry can be used to insert carboxylic esters and norbornene functional groups into sp2 C-H bonds of a simple triarylamine and a 4,4'-bis(diarylamino)biphenyl, respectively. The norbenene-functionalized monomer was polymerized by ring-opening metathesis; the electrochemical, optical, and charge-transport properties of these materials were similar to those of related materials synthesized by conventional means. This method potentially offers straightforward access to a diverse range of HTMs with different functional groups.

COMBREX-DB: an experiment centered database of protein function: knowledge, predictions and knowledge gaps.

The COMBREX database (COMBREX-DB; combrex.bu.edu) is an online repository of information related to (i) experimentally determined protein function, (ii) predicted protein function, (iii) relationships among proteins of unknown function and various types of experimental data, including molecular function, protein structure, and associated phenotypes. The database was created as part of the novel COMBREX (COMputational BRidges to EXperiments) effort aimed at accelerating the rate of gene function validation. It currently holds information on ∼ 3.3 million known and predicted proteins from over 1000 completely sequenced bacterial and archaeal genomes. The database also contains a prototype recommendation system for helping users identify those proteins whose experimental determination of function would be most informative for predicting function for other proteins within protein families. The emphasis on documenting experimental evidence for function predictions, and the prioritization of uncharacterized proteins for experimental testing distinguish COMBREX from other publicly available microbial genomics resources. This article describes updates to COMBREX-DB since an initial description in the 2011 NAR Database Issue.

Upregulation of RPA2 promotes NF-κB activation in breast cancer by relieving the antagonistic function of menin on NF-κB-regulated transcription.

RPA2, a subunit of the heterotrimeric replication protein A (RPA) complex, is overexpressed in various cancers. In this study, we showed a significant RPA2 upregulation in breast cancer tissues and cell lines. Ectopic expression of RPA2 in MCF7 and MDA-MB-231 cells promoted cell proliferation, adhesion, migration and invasion, and induced epithelial-mesenchymal transition (EMT) of MCF7 cells. Ablation of RPA2 in MDA-MB-231 cells induced apoptosis and suppressed colony formation, EMT and invasion. Binding assays indicated that menin, the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene product, interacted with RPA2. Ectopic expression of RPA2 inhibited the formation of the menin-NK-κB p65 complex and repressed the inhibitory effect of menin on expression of NF-κB-regulated genes that contribute to tumor progression. Conversely, knockdown of RPA2 promoted formation of the menin-p65 complex and repressed the expression of NF-κB-mediated genes. RPA2 expression was induced via an E2F1-dependent mechanism in MCF7 and MDA-MB-231 cells treated with NF-κB activators, TNF-alpha or lipopolysaccharide (LPS). These results suggested that RPA2-dependent tumorigenicity was mediated via enhancement of NF-κB activity by relieving the antagonistic function of menin on NF-κB-regulated transcription in breast cancer cells.

Visualization of Metabolic Interaction Networks in Microbial Communities Using VisANT 5.0.

The complexity of metabolic networks in microbial communities poses an unresolved visualization and interpretation challenge. We address this challenge in the newly expanded version of a software tool for the analysis of biological networks, VisANT 5.0. We focus in particular on facilitating the visual exploration of metabolic interaction between microbes in a community, e.g. as predicted by COMETS (Computation of Microbial Ecosystems in Time and Space), a dynamic stoichiometric modeling framework. Using VisANT's unique metagraph implementation, we show how one can use VisANT 5.0 to explore different time-dependent ecosystem-level metabolic networks. In particular, we analyze the metabolic interaction network between two bacteria previously shown to display an obligate cross-feeding interdependency. In addition, we illustrate how a putative minimal gut microbiome community could be represented in our framework, making it possible to highlight interactions across multiple coexisting species. We envisage that the "symbiotic layout" of VisANT can be employed as a general tool for the analysis of metabolism in complex microbial communities as well as heterogeneous human tissues. VisANT is freely available at: http://visant.bu.edu and COMETS at http://comets.bu.edu.

VisANT 4.0: Integrative network platform to connect genes, drugs, diseases and therapies.

With the rapid accumulation of our knowledge on diseases, disease-related genes and drug targets, network-based analysis plays an increasingly important role in systems biology, systems pharmacology and translational science. The new release of VisANT aims to provide new functions to facilitate the convenient network analysis of diseases, therapies, genes and drugs. With improved understanding of the mechanisms of complex diseases and drug actions through network analysis, novel drug methods (e.g., drug repositioning, multi-target drug and combination therapy) can be designed. More specifically, the new update includes (i) integrated search and navigation of disease and drug hierarchies; (ii) integrated disease-gene, therapy-drug and drug-target association to aid the network construction and filtering; (iii) annotation of genes/drugs using disease/therapy information; (iv) prediction of associated diseases/therapies for a given set of genes/drugs using enrichment analysis; (v) network transformation to support construction of versatile network of drugs, genes, diseases and therapies; (vi) enhanced user interface using docking windows to allow easy customization of node and edge properties with build-in legend node to distinguish different node type. VisANT is freely available at: http://visant.bu.edu.

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

COMBREX: a project to accelerate the functional annotation of prokaryotic genomes.

COMBREX (http://combrex.bu.edu) is a project to increase the speed of the functional annotation of new bacterial and archaeal genomes. It consists of a database of functional predictions produced by computational biologists and a mechanism for experimental biochemists to bid for the validation of those predictions. Small grants are available to support successful bids.

Thermal Insolubilization of Electrically n-Doped Films Achieved Using 7-Alkoxy-Benzocyclobutene-Substituted Fullerene and Dopant Molecules.

Insoluble electrically n-doped fullerene-containing films have been obtained by thermal annealing of a fullerene compound and a 1,3-dimethyl-2,3-dihydro-1H-benzo[d]imidazole n-dopant moiety, both of which are functionalized with a 7-butoxybenzocyclobutene group. The covalent tethering and electrical doping reactions are studied by mass spectrometry as well as electron paramagnetic resonance. Optical absorption spectra on BBCB-N-DMBI-H-doped BBCBP indicate films heated at 150 °C for 10 min are unaffected by immersion for 10 min in ortho-dichlorobenzene. Although films containing a 10 mol % loading of the dopant showed electrical conductivity values of 1.1 × 10-5 ± 3.4 × 10-7 S cm-1 prior to heating, the thermal insolubilization process led to values around two orders-of-magnitude lower. However, the thermal insolubilization also leads to immobilization of the dopant molecule and the corresponding cation, reducing their ability to diffuse into an adjacent layer of a stronger electron acceptor.

VisANT 3.5: multi-scale network visualization, analysis and inference based on the gene ontology.

Despite its wide usage in biological databases and applications, the role of the gene ontology (GO) in network analysis is usually limited to functional annotation of genes or gene sets with auxiliary information on correlations ignored. Here, we report on new capabilities of VisANT--an integrative software platform for the visualization, mining, analysis and modeling of the biological networks--which extend the application of GO in network visualization, analysis and inference. The new VisANT functions can be classified into three categories. (i) Visualization: a new tree-based browser allows visualization of GO hierarchies. GO terms can be easily dropped into the network to group genes annotated under the term, thereby integrating the hierarchical ontology with the network. This facilitates multi-scale visualization and analysis. (ii) Flexible annotation schema: in addition to conventional methods for annotating network nodes with the most specific functional descriptions available, VisANT also provides functions to annotate genes at any customized level of abstraction. (iii) Finding over-represented GO terms and expression-enriched GO modules: two new algorithms have been implemented as VisANT plugins. One detects over-represented GO annotations in any given sub-network and the other finds the GO categories that are enriched in a specified phenotype or perturbed dataset. Both algorithms take account of network topology (i.e. correlations between genes based on various sources of evidence). VisANT is freely available at http://visant.bu.edu.

Increasing Volume in Conjugated Polymers to Facilitate Electrical Doping with Phosphomolybdic Acid.

Molecular p-type electrical dopants have been proven useful to fine-tune the optoelectronic properties of bulk organic semiconductors and their interfaces. Here, the volume in polymer films and its role in solution-based electrical p-type doping using phosphomolybdic acid (PMA) are studied. The polymer film volume was controlled using two approaches. One is based on heating both the PMA solution and the film prior to immersion. The second is based on coating the polymer film with a liquid blend that contains the PMA solution and a swelling solvent. 31P NMR and FTIR experiments indicate that the Keggin structure appears to be preserved throughout the doping process. Results show that increasing the polymer volume facilitates the infiltration of the PMA Keggin structure, which results in an increased electrical p-type doping level.

Resveratrol induced premature senescence and inhibited epithelial-mesenchymal transition of cancer cells via induction of tumor suppressor Rad9.

Resveratrol (RSV) has been reported to influence many biological processes, including the stimulation of cellular senescence and inhibition of epithelial-mesenchymal transition (EMT). In this research, we explored the mechanisms of RSV on EMT and cellular senescence through the expression of a DNA damage response (DDR) protein, Rad9, in breast and lung cancer cell lines. Upon treating breast and lung cancer cell lines with RSV at the concentrations of 10-50 µM, Rad9 expression was increased at both transcriptional and translational levels. The results indicated that RSV-induced Rad9 expression, mediated by DNA damage and ROS, can significantly suppress proliferation by activating cellular senescence, and diminishing the expression of EMT markers with concomitant downregulation of Slug in breast and lung cancer cell lines. By using a siRNA approach, RSV was shown to mediate cellular senescence and EMT through a Rad9-dependent mechanism. The treatment with RSV can inhibit the proliferation, EMT, and increase cellular senescence of breast and lung cancer cell lines by activating Rad9. Our results suggest that the breast and lung tumor suppressive activities of RSV are, at least in part, mediated by the upregulation of Rad9.

Isolated traumatic phrenic nerve injury treated with video-assisted thoracoscopic diaphragmatic plication-a case report.

Isolated traumatic phrenic nerve injury resulting from a stab wound to the neck is very rare. Herein, we report the case of a patient who was accidentally stabbed with garden shears that pierced her neck and penetrated the spinal canal. She sustained a right phrenic nerve injury complicated by diaphragm palsy and subsequent respiratory distress. We successfully treated the patient with video-assisted thoracoscopic diaphragm plication.

Localization of thoracic duct using heavily T2W MRI for intractable post-esophagectomy chylothorax-a case report.

Post-esophagectomy chylothorax is a rare yet serious complication. Herein we report the case of a patient with intractable post-esophagectomy chylothorax despite medical treatment with total parenteral nutrition and octreotide, as well as prophylactic and repeated thoracic duct mass ligation. The patient was eventually treated with localization of thoracic duct using T2-weighted magnetic resonance imaging (T2W MRI), followed by video-assisted thoracoscopic thoracic duct ligation.

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program.

A shift of the delicate balance between apoptosis and survival-inducing signals determines the fate of neurons during the development of the central nervous system and its homeostasis throughout adulthood. Both pathways, promoting or protecting from apoptosis, trigger a transcriptional program. We conducted whole-genome expression profiling to decipher the transcriptional regulatory elements controlling the apoptotic/survival switch in cerebellar granule neurons following the induction of apoptosis by serum and potassium deprivation or their rescue by either insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase-activating polypeptide (Pacap). Although depending on different upstream signaling pathways, the survival effects of Igf1 and Pacap converged into common transcriptional cascades, thus suggesting the existence of a general transcriptional program underlying neuronal survival.

GCIP functions as a tumor suppressor in non-small cell lung cancer by suppressing Id1-mediated tumor promotion.

Grap2 and cyclin D1 interacting protein (GCIP) has been recognized as a putative tumor suppressor, but the molecular mechanisms underlying its anti-tumor properties remain undefined. Here, we report that GCIP is frequently downregulated in non-small cell lung cancer (NSCLC) tissues. Binding assays indicated that inhibitor of DNA binding/differentiation 1 (Id1) interacts with GCIP in the nucleus. Ectopic GCIP expression in the highly invasive NSCLC cell line, H1299, inhibited proliferation, colony formation, invasion and migration, and increased susceptibility to anticancer drugs. Conversely, silencing GCIP expression in the minimally invasive NSCLS cell line, A549, increased proliferation, colony formation, invasion, and migration in vitro, and increased survival and resistance to anticancer drugs. GCIP also suppresses tumorigenicity of NSCLC cells in vivo and GCIP suppresses NSCLC progression is mediated in part by interfering with Id1 signaling, which was confirmed in conditionally induced stable cell lines. In addition, GCIP downregulates the expression of Id1, and GCIP and Id1 are inversely expressed in NSCLC cell lines and specimens. Taken together, these results suggest that GCIP is a potential tumor suppressor in NSCLC and that suppression of Id1-mediated oncogenic properties may be a key mechanism by which GCIP can potently suppress NSCLC tumor progression.

Thousands of missed genes found in bacterial genomes and their analysis with COMBREX.

BACKGROUND: The dramatic reduction in the cost of sequencing has allowed many researchers to join in the effort of sequencing and annotating prokaryotic genomes. Annotation methods vary considerably and may fail to identify some genes. Here we draw attention to a large number of likely genes missing from annotations using common tools such as Glimmer and BLAST. RESULTS: By analyzing 1,474 prokaryotic genome annotations in GenBank, we identify 13,602 likely missed genes that are homologs to non-hypothetical proteins, and 11,792 likely missed genes that are homologs only to hypothetical proteins, yet have supporting evidence of their protein-coding nature from COMBREX, a newly created gene function database. We also estimate the likelihood that each potential missing gene found is a genuine protein-coding gene using COMBREX. CONCLUSIONS: Our analysis of the causes of missed genes suggests that larger annotation centers tend to produce annotations with fewer missed genes than smaller centers, and many of the missed genes are short genes <300 bp. Over 1,000 of the likely missed genes could be associated with phenotype information available in COMBREX. 359 of these genes, found in pathogenic organisms, may be potential targets for pharmaceutical research. The newly identified genes are available on COMBREX's website. REVIEWERS: This article was reviewed by Daniel Haft, Arcady Mushegian, and M. Pilar Francino (nominated by David Ardell).

Deep sequencing of the oral microbiome reveals signatures of periodontal disease.

The oral microbiome, the complex ecosystem of microbes inhabiting the human mouth, harbors several thousands of bacterial types. The proliferation of pathogenic bacteria within the mouth gives rise to periodontitis, an inflammatory disease known to also constitute a risk factor for cardiovascular disease. While much is known about individual species associated with pathogenesis, the system-level mechanisms underlying the transition from health to disease are still poorly understood. Through the sequencing of the 16S rRNA gene and of whole community DNA we provide a glimpse at the global genetic, metabolic, and ecological changes associated with periodontitis in 15 subgingival plaque samples, four from each of two periodontitis patients, and the remaining samples from three healthy individuals. We also demonstrate the power of whole-metagenome sequencing approaches in characterizing the genomes of key players in the oral microbiome, including an unculturable TM7 organism. We reveal the disease microbiome to be enriched in virulence factors, and adapted to a parasitic lifestyle that takes advantage of the disrupted host homeostasis. Furthermore, diseased samples share a common structure that was not found in completely healthy samples, suggesting that the disease state may occupy a narrow region within the space of possible configurations of the oral microbiome. Our pilot study demonstrates the power of high-throughput sequencing as a tool for understanding the role of the oral microbiome in periodontal disease. Despite a modest level of sequencing (~2 lanes Illumina 76 bp PE) and high human DNA contamination (up to ~90%) we were able to partially reconstruct several oral microbes and to preliminarily characterize some systems-level differences between the healthy and diseased oral microbiomes.