Biology of Bone Metastases in Prostate Cancer

Advanced-stage prostate cancer (PCa) patients are often diagnosed with bone metastases. Bone metastases remain incurable and therapies are palliative. PCa cells prevalently cause osteoblastic lesions, characterized by an excess of bone formation. The prevailing concept indicates that PCa cancer cell secrete an excess of paracrine factors stimulating osteoblasts directly or indirectly, thereby leading to an excess of bone formation. The exact mechanisms by which bone formation stimulates PCa cell growth are mostly elusive. In this review, the mechanisms of PCa cancer cell osteotropism, the cancer cell-induced response within the bone marrow/bone stroma, and therapeutic stromal targets will be summarized.

An integrated molecular biology and computational approach to CYP1A1 expression in human brain

The cytochromes P450 comprise a superfamily of heme-containing mono-oxygenases. These enzymes metabolize numerous xenobiotics, but also play a role in metabolism of endogenous compounds. The P450 1A1 enzyme generally metabolizes polycyclic aromatic hydrocarbons, and its expression can be induced by aryl hydrocarbon receptor (AhR) activation. CYP1A1 is an exception to the generality that the majority of CYPs demonstrate highest expression in liver; CYP1Al is present in numerous extrahepatic tissues, including brain. This P450 has been observed in two forms, wildtype (WT) and brain variant (BV), arising from alternatively spliced mRNA transcripts. The CYP1A1 BV mRNA presented an exon deletion and was detected in human brain but not liver tissue of the same individuals. ^ Quantitative PCR analyses were performed to determine CYP1A1 WT and BV transcript expression levels in normal, bipolar disorder or schizophrenic groups. In our samples, we show that CYP1A1 BV mRNA, when present, is found alongside the full-length form. Furthermore, we demonstrate a significant decrease in expression of CYP1A1 in patients with bipolar disorder or schizophrenia. The expression level was not influenced by post-mortem interval, tissue pH, age, tobacco use, or lifetime antipsychotic medication load. ^ There is no indication of increased brain CYP1A1 expression in normal smokers versus non-smokers in these samples. We observed slightly increased CYP1A1 expression only in bipolar and schizophrenic smokers versus non-smokers. This may be indicative of complex interactions between neuronal chemical environments and AhR-mediated CYP1A1 induction in brain. ^ Structural homology modeling demonstrated that P450 1A1 BV has several alterations to positions/orientations of substrate recognition site residues compared to the WT isoform. Automated substrate docking was employed to investigate the potential binding of neurological signaling molecules and neurotropic drugs, as well as to differentiate specificities of the two P450 1A1 isoforms. We consistently observed that the BV isoform produced energetically favorable substrate dockings in orientations not observed for the same substrate in the WT isoform. These results demonstrated that structural differences, namely an expanded substrate access channel and active site, confer greater capacity for unique compound docking positions suggesting a metabolic profile distinct from the wildtype form for these test compounds. ^

Systems Biology Approaches to Probe Gene Regulation in Bacteria

Mechanisms that allow pathogens to colonize the host are not the product of isolated genes, but instead emerge from the concerted operation of regulatory networks. Therefore, identifying components and the systemic behavior of networks is necessary to a better understanding of gene regulation and pathogenesis. To this end, I have developed systems biology approaches to study transcriptional and post-transcriptional gene regulation in bacteria, with an emphasis in the human pathogen Mycobacterium tuberculosis (Mtb). First, I developed a network response method to identify parts of the Mtb global transcriptional regulatory network utilized by the pathogen to counteract phagosomal stresses and survive within resting macrophages. As a result, the method unveiled transcriptional regulators and associated regulons utilized by Mtb to establish a successful infection of macrophages throughout the first 14 days of infection. Additionally, this network-based analysis identified the production of Fe-S proteins coupled to lipid metabolism through the alkane hydroxylase complex as a possible strategy employed by Mtb to survive in the host. Second, I developed a network inference method to infer the small non-coding RNA (sRNA) regulatory network in Mtb. The method identifies sRNA-mRNA interactions by integrating a priori knowledge of possible binding sites with structure-driven identification of binding sites. The reconstructed network was useful to predict functional roles for the multitude of sRNAs recently discovered in the pathogen, being that several sRNAs were postulated to be involved in virulence-related processes. Finally, I applied a combined experimental and computational approach to study post-transcriptional repression mediated by small non-coding RNAs in bacteria. Specifically, a probabilistic ranking methodology termed rank-conciliation was developed to infer sRNA-mRNA interactions based on multiple types of data. The method was shown to improve target prediction in Escherichia coli, and therefore is useful to prioritize candidate targets for experimental validation.

Biology community and bottom sediments in the West Bay of the Furugelm Island, Sea of Japan

An experiment was carried out on the soft bottom in the sublitoral zone of the Furugelm Island (Peter the Great Bay, Sea of Japan) to study formation of benthic communities. Boxes with defauned sediments were placed on depths of 4, 6 and 13 m and exposed during 60 days in the summer period. Half of them were covered with a net with mesh size 2 cm to prevent effect of large predators. It was found that spatial pattern of invertebrates' sinking in the bay conforms to distribution of benthic communities. Larvae of benthic invertebrates sinks in general in places inhabited by their adult species. The main factors responsible for recolonzation are: sediment type and local hydrodynamic conditions. Heart-shaped sea urchin Echinocardium cordatum is numerically dominated in the bay on depth 3-4.5 m, but its larvae sinks in the deeper area. Community structure is supported by mature specimen migration to places inhabited by species. Predators affect largely on the species.

Comparison of natural and forced amplification regimes in plasma-based soft-x-ray lasers seeded by high-order harmonic

The amplification of high-order harmonics (HOH) in a plasma-based amplifier is a multiscale, temporal phenomenon that couples plasma hydrodynamics, atomic processes, and HOH electromagnetic fields. We use a one-dimensional, time-dependent Maxwell-Bloch code to compare the natural amplification regime and another regime where plasma polarization is constantly forced by the HOH. In this regime, a 10-MW (i.e., 100 times higher than current seeded soft x-ray laser power), 1.5-μJ, 140-fs pulse free from the parasitic temporal structures appearing on the natural amplification regime can be obtained.

Self-validating technique for the measurement of the linewidth enhancement factor in semiconductor lasers

A new method for measuring the linewidth enhancement factor (α-parameter) of semiconductor lasers is proposed and discussed. The method itself provides an estimation of the measurement error, thus self-validating the entire procedure. The α-parameter is obtained from the temporal profile and the instantaneous frequency (chirp) of the pulses generated by gain switching. The time resolved chirp is measured with a polarization based optical differentiator. The accuracy of the obtained values of the α-parameter is estimated from the comparison between the directly measured pulse spectrum and the spectrum reconstructed from the chirp and the temporal profile of the pulse. The method is applied to a VCSEL and to a DFB laser emitting around 1550 nm at different temperatures, obtaining a measurement error lower than ± 8%.