Hx, a novel fluorescent, minor groove and sequence specific recognition element: design, synthesis, and DNA binding properties of p-anisylbenzimidazole-imidazole/pyrrole-containing polyamides

With the aim of incorporating a recognition element that acts as a fluorescent probe upon binding to DNA, three novel pyrrole (P) and imidazole (I)-containing polyamides were synthesized. The compounds contain a p-anisylbenzimidazolecarboxamido (Hx) moiety attached to a PP, IP, or PI unit, giving compounds HxPP (2), HxIP (3), and HxPI (4), respectively. These fluorescent hybrids were tested against their complementary nonfluorescent, non-formamido tetraamide counterparts, namely, PPPP (5), PPIP (6), and PPPI (7) (cognate sequences 5'-AAATTT-3', 5'-ATCGAT-3', and 5'-ACATGT-3', respectively). The binding affinities for both series of polyamides for their cognate and noncognate sequences were ascertained by surface plasmon resonance (SPR) studies, which revealed that the Hx-containing polyamides gave binding constants in the 10(6) M(-1) range while little binding was observed for the noncognates. The binding data were further compared to the corresponding and previously reported formamido-triamides f-PPP (8), f-PIP (9), and f-PPI (10). DNase I footprinting studies provided additional evidence that the Hx moiety behaved similarly to two consecutive pyrroles (PP found in 5-7), which also behaved like a formamido-pyrrole (f-P) unit found in distamycin and many formamido-triamides, including 8-10. The biophysical characterization of polyamides 2-7 on their binding to the abovementioned DNA sequences was determined using thermal melts (ΔT(M)), circular dichroism (CD), and isothermal titration calorimetry (ITC) studies. Density functional calculations (B3LYP) provided a theoretical framework that explains the similarity between PP and Hx on the basis of molecular electrostatic surfaces and dipole moments. Furthermore, emission studies on polyamides 2 and 3 showed that upon excitation at 322 nm binding to their respective cognate sequences resulted in an increase in fluorescence at 370 nm. These low molecular weight polyamides show promise for use as probes for monitoring DNA recognition processes in cells.     

Description of a new species of the genus Awaous Valenciennes, 1837 (Gobiiformes: Oxudercidae) from the middle stretch of the Mahanadi River,Odisha, India,with comments on the Awaous species from India

A new species of the genus Awaous (Oxudercidae), Awaous motla sp. nov., is described based on 18 specimens collected from the Mahanadi River near Sonepur, Subarnapur District, and 3 specimens from the same river near Boudh bridge, Boudh District of Odisha, India. This species is distinct from its congeners by having a combination of characteristics: relatively small eyes, diameter of 6.6–8.4 in head length (LH); robust and long snout, 2.0–2.6 in LH; eye diameter 2.7–4.1 in snout length; cephalic sensory pore system interrupted with eight pores; predorsal scales 13–15; longitudinal scale series 55–58; gill rakers 2 + 1 + (6–7) on the first gill arch; teeth small, conical, and in a single row on the upper jaw and multiserial (2–3) on the lower jaw. This species is also differentiated from some of its congeners in the nucleotide composition of the cytochrome c oxidase I gene by 8.3%–13.8% Kimura two-parameter (K2P) distance and belongs to a separate cluster in the maximum likelihood tree analysis. This finding is also supported by the species delimitation analysis based on Assemble Species by Automatic Partitioning. The new species holds high commercial value in its locality and needs special conservation attention for sustainable utilization.     

Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors

Sarcomas represent a diverse group of malignancies with distinct molecular and pathological features. A better understanding of the alterations associated with specific sarcoma subtypes is critically important to improve sarcoma treatment. Renewed interest in the metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a therapeutic strategy. In this study, we have characterized key bioenergetic properties of human sarcoma cells in order to identify metabolic vulnerabilities between sarcoma subtypes. We have also investigated the effects of compounds that inhibit glycolysis or mitochondrial respiration, either alone or in combination, and examined relationships between bioenergetic parameters and sensitivity to metabolic inhibitors. Using 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glycolysis, oligomycin, an inhibitor of mitochondrial ATP synthase, and metformin, a widely used anti-diabetes drug and inhibitor of complex I of the mitochondrial respiratory chain, we evaluated the effects of metabolic inhibition on sarcoma cell growth and bioenergetic function. Inhibition of glycolysis by 2-DG effectively reduced the viability of alveolar rhabdomyosarcoma cells vs. embryonal rhabdomyosarcoma, osteosarcoma, and normal cells. Interestingly, inhibitors of mitochondrial respiration did not significantly affect viability, but were able to increase sensitivity of sarcomas to inhibition of glycolysis. Additionally, inhibition of glycolysis significantly reduced intracellular ATP levels, and sensitivity to 2-DG-induced growth inhibition was related to respiratory rates and glycolytic dependency. Our findings demonstrate novel relationships between sarcoma bioenergetics and sensitivity to metabolic inhibitors, and suggest that inhibition of metabolic pathways in sarcomas should be further investigated as a potential therapeutic strategy.     

Domain Compositions and Fullerene Aggregation Govern Charge Photogeneration in Polymer/Fullerene Solar Cells

The complex microstructure of organic semiconductor mixtures continues to obscure the connection between the active layer morphology and photovoltaic device performance. For example, the ubiquitous presence of mixed phases in the active layer of polymer/fullerene solar cells creates multiple morphologically distinct interfaces which are capable of exciton dissociation or charge recombination. Here, it is shown that domain compositions and fullerene aggregation can strongly modulate charge photogeneration at ultrafast timescales through studies of a model system, mixtures of a low band‐gap polymer, poly[(4,4′‐bis(2‐ethylhexyl)dithieno[3,2‐b:2′,3′‐d]germole)‐2,6‐diyl‐alt‐(2,1,3‐benzothia‐diazole)‐4,7‐diyl], and [6,6]‐phenyl‐C₇₁‐butyric acid methyl ester. Structural characterization using energy‐filtered transmission electron microscopy (EFTEM) and resonant soft X‐ray scattering shows similar microstructures even with changes in the overall film composition. Composition maps generated from EFTEM, however, demonstrate that compositions of mixed domains vary significantly with overall film composition. Furthermore, the amount of polymer in the mixed domains is inversely correlated with device performance. Photoinduced absorption studies using ultrafast infrared spectroscopy demonstrate that polaron concentrations are highest when mixed domains contain the least polymer. Grazing‐incidence X‐ray scattering results show that larger fullerene coherence lengths are correlated to higher polaron yields. Thus, the purity of the mixed domains is critical for efficient charge photogeneration because purity modulates fullerene aggregation and electron delocalization.     

Proton Beam Therapy for Localized Prostate Cancer 101: Basics,Controversies, and Facts

Proton beam therapy for prostate cancer has become a source of controversy in the urologic community, and the rapid dissemination and marketing of this technology has led to many patients inquiring about this therapy. Yet the complexity of the technology, the cost, and the conflicting messages in the literature have left many urologists ill equipped to counsel their patients regarding this option. This article reviews the basic science of the proton beam, examines the reasons for both the hype and the controversy surrounding this therapy, and, most importantly, examines the literature so that every urologist is able to comfortably discuss this option with inquiring patients.Key words: Prostate cancer, Proton beam therapy, External beam radiation therapy, Intensity modulated radiation therapyProton beam therapy (PBT) has become a source of controversy in the urologic community. It is not uncommon to hear mixed messages regarding the issue, from zealous advocates to cost-conscious skeptics, leaving many urologists unsure what to tell their patients with prostate cancer. What is clear, however, is that the technology is disseminating across the nation, and as our patients turn to the internet to learn more about their diagnosis, they are going to encounter increasingly more information about PBT, both scientific and promotional in nature. Hence, it is necessary for every urologist to understand the basics of PBT to help guide our patients through treatment options. This article reviews and compares the basic science of conventional external beam radiation therapy (EBRT) with PBT, examines the reasons for both the hype and the controversy surrounding this therapy, and, most importantly, examines the literature so that all urologists are adequately equipped to counsel their patients on this subject.     

High-Throughput Heterogeneous Integration of Diverse Nanomaterials on a Single Chip for Sensing Applications

There is a large variety of nanomaterials each with unique electronic, optical and sensing properties. However, there is currently no paradigm for integration of different nanomaterials on a single chip in a low-cost high-throughput manner. We present a high throughput integration approach based on spatially controlled dielectrophoresis executed sequentially for each nanomaterial type to realize a scalable array of individually addressable assemblies of graphene, carbon nanotubes, metal oxide nanowires and conductive polymers on a single chip. This is a first time where such a diversity of nanomaterials has been assembled on the same layer in a single chip. The resolution of assembly can range from mesoscale to microscale and is limited only by the size and spacing of the underlying electrodes on chip used for assembly. While many applications are possible, the utility of such an array is demonstrated with an example application of a chemical sensor array for detection of volatile organic compounds below parts-per-million sensitivity.     

Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis

Deleted in Breast Cancer 1 (DBC1) is an important metabolic sensor. Previous studies have implicated DBC1 in various cellular functions, notably cell proliferation, apoptosis, histone modification, and adipogenesis. However, current reports about the role of DBC1 in tumorigenesis are controversial and designate DBC1 alternatively as a tumor suppressor or a tumor promoter. In the present study, we report that polyoma small T antigen (PyST) associates with DBC1 in mammalian cells, and this interaction leads to the posttranslational downregulation of DBC1 protein levels. When coexpressed, DBC1 overcomes PyST-induced mitotic arrest and promotes the exit of cells from mitosis. Using both transient and stable modes of PyST expression, we also show that cellular DBC1 is subjected to degradation by LKB1, a tumor suppressor and cellular energy sensor kinase, in an AMP kinase-independent manner. Moreover, LKB1 negatively regulates the phosphorylation as well as activity of the prosurvival kinase AKT1 through DBC1 and its downstream pseudokinase substrate, Tribbles 3 (TRB3). Using both transient transfection and stable cell line approaches as well as soft agar assay, we demonstrate that DBC1 has oncogenic potential. In conclusion, our study provides insight into a novel signaling axis that connects LKB1, DBC1, TRB3, and AKT1. We propose that the LKB1–DBC1–AKT1 signaling paradigm may have an important role in the regulation of cell cycle and apoptosis and consequently tumorigenesis.     

Folate: Metabolism,genes, polymorphisms and the associated diseases

Folate being an important vitamin of B Complex group in our diet plays an important role not only in the synthesis of DNA but also in the maintenance of methylation reactions in the cells. Folate metabolism is influenced by several processes especially its dietary intake and the polymorphisms of the associated genes involved. Aberrant folate metabolism, therefore, affects both methylation as well as the DNA synthesis processes, both of which have been implicated in the development of various diseases. This paper reviews the current knowledge of the processes involved in folate metabolism and consequences of deviant folate metabolism, particular emphasis is given to the polymorphic genes which have been implicated in the development of various diseases in humans, like vascular diseases, Down's syndrome, neural tube defects, psychiatric disorders and cancers.