Hdac8 activates akt through upregulating plcb1 and suppressing desc1 expression in mek1/2 inhibition-resistant cells

Inhibition of the RAF-MEK1/2-ERK signaling pathway is an ideal strategy for treating cancers with NRAS or BRAF mutations. However, the development of resistance due to incomplete inhibition of the pathway and activation of compensatory cell proliferation pathways is a major impediment of the targeted therapy. The anthrax lethal toxin (LT), which cleaves and inactivates MEKs, is a modifiable biomolecule that can be delivered selectively to tumor cells and potently kills various tumor cells. However, resistance to LT and the mechanism involved are yet to be explored. Here, we show that LT, through inhibiting MEK1/2-ERK activation, inhibits the proliferation of cancer cells with NRAS/BRAF mutations. Among them, the human colorectal tumor HT-29 and murine melanoma B16-BL6 cells developed resistance to LT in 2 to 3 days of treatment. These resistant cells activated AKT through a histone deacetylase (HDAC) 8-dependent pathway. Using an Affymetrix microarray, followed by qPCR validation, we identified that the differential expression of the phos-pholipase C-β1 (PLCB1) and squamous cell carcinoma-1 (DESC1) played an important role in HDAC8-mediated AKT activation and resistance to MEK1/2-ERK inhibition. By using inhibitors, small interference RNAs and/or expression vectors, we found that the inhibition of HDAC8 suppressed PLCB1 expression and induced DESC1 expression in the resistant cells, which led to the inhibition of AKT and re-sensitization to LT and MEK1/2 inhibition. These results suggest that targeting PLCB1 and DESC1 is a novel strategy for inhibiting the resistance to MEK1/2 inhibition

The Web of Human Sexual Contacts

Many ``real-world'' networks are clearly defined while most ``social'' networks are to some extent subjective. Indeed, the accuracy of empirically-determined social networks is a question of some concern because individuals may have distinct perceptions of what constitutes a social link. One unambiguous type of connection is sexual contact. Here we analyze data on the sexual behavior of a random sample of individuals, and find that the cumulative distributions of the number of sexual partners during the twelve months prior to the survey decays as a power law with similar exponents $\alpha \approx 2.4$ for females and males. The scale-free nature of the web of human sexual contacts suggests that strategic interventions aimed at preventing the spread of sexually-transmitted diseases may be the most efficient approach.Comment: 7 pages with 2 eps figures. Latex file. For more details or for downloading the PDF file of the published article see http://polymer.bu.edu/~amaral/WebofContacts.html . For more results on teh structure of complex networks see http://polymer.bu.edu/~amaral/Networks.htm

Thermodynamics of spin chains of Haldane-Shastry type and one-dimensional vertex models

We study the thermodynamic properties of spin chains of Haldane-Shastry type associated with the A_{N-1} root system in the presence of a uniform external magnetic field. To this end, we exactly compute the partition function of these models for an arbitrary finite number of spins. We then show that these chains are equivalent to a suitable inhomogeneous classical Ising model in a spatially dependent magnetic field, generalizing the results of Basu-Mallick et al. for thezero magnetic field case. Using the standard transfer matrix approach, we are able to compute in closed form the free energy per site in the thermodynamic limit. We perform a detailed analysis of the chains' thermodynamics in a unified way, with special emphasis on the zero field and zero temperature limits. Finally, we provide a novel interpretation of the thermodynamic quantities of spin chains of Haldane-Shastry type as weighted averages of the analogous quantities over an ensemble of classical Ising models.Comment: LaTeX, 39 pages, 13 figure

The Songbird Neurogenomics (SoNG) Initiative: Community-based tools and strategies for study of brain gene function and evolution

BACKGROUND: Songbirds hold great promise for biomedical, environmental and evolutionary research. A complete draft sequence of the zebra finch genome is imminent, yet a need remains for application of genomic resources within a research community traditionally focused on ethology and neurobiological methods. In response, we developed a core set of genomic tools and a novel collaborative strategy to probe gene expression in diverse songbird species and natural contexts. RESULTS: We end-sequenced cDNAs from zebra finch brain and incorporated additional sequences from community sources into a database of 86,784 high quality reads. These assembled into 31,658 non-redundant contigs and singletons, which we annotated via BLAST search of chicken and human databases. The results are publicly available in the ESTIMA:Songbird database. We produced a spotted cDNA microarray with 20,160 addresses representing 17,214 non-redundant products of an estimated 11,500–15,000 genes, validating it by analysis of immediate-early gene (zenk) gene activation following song exposure and by demonstrating effective cross hybridization to genomic DNAs of other songbird species in the Passerida Parvorder. Our assembly was also used in the design of the "Lund-zfa" Affymetrix array representing ~22,000 non-redundant sequences. When the two arrays were hybridized to cDNAs from the same set of male and female zebra finch brain samples, both arrays detected a common set of regulated transcripts with a Pearson correlation coefficient of 0.895. To stimulate use of these resources by the songbird research community and to maintain consistent technical standards, we devised a "Community Collaboration" mechanism whereby individual birdsong researchers develop experiments and provide tissues, but a single individual in the community is responsible for all RNA extractions, labelling and microarray hybridizations. CONCLUSION: Immediately, these results set the foundation for a coordinated set of 25 planned experiments by 16 research groups probing fundamental links between genome, brain, evolution and behavior in songbirds. Energetic application of genomic resources to research using songbirds should help illuminate how complex neural and behavioral traits emerge and evolve

Ethanol Sclerotherapy for the Management of Craniofacial Venous Malformations: the Interim Results

Using data from the 2002–2003 Netherlands Kinship Panel Study and the Social Position and Provisions Ethnic Minorities Survey (N=2833) we describe patterns of intergenerational solidarity among five different ethnic groups in the Netherlands. We compare patterns of normative, associational and functional solidarity between various immigrant groups and the native Dutch, and question how and to what extent behavior is determined by filial norms, socio-demographic position or ethnic background. Results show that immigrant adult children show higher levels of normative (filial obligations) and associational (contact) solidarity. Functional solidarity (providing support) shows a more complex pattern. Immigrants are no more likely to provide counsel or advice than the Dutch but immigrant women are more likely to provide practical support than Dutch women

Gravitationally redshifted absorption lines in the X-ray burst spectra of a neutron star

The fundamental properties of neutron stars provide a direct test of the equation of state of cold nuclear matter, a relationship between pressure and density that is determined by the physics of the strong interactions between the particles that constitute the star. The most straightforward method of determining these properties is by measuring the gravitational redshift of spectral lines produced in the neutron star photosphere. The equation of state implies a mass-radius relation, while a measurement of the gravitational redshift at the surface of a neutron star provides a direct constraint on the mass-to-radius ratio. Here we report the discovery of signficant absorption lines in the spectra of 28 bursts of the low-mass X-ray binary EXO 0748-676. We identify the most signficant features with the Fe XXVI and XXV n=2-3 and O VIII n=1-2 transitions, all with a redshift of z=0.35, identical within small uncertainties for the respective transitions. For an astrophysically plausible range of masses (M ~ 1.3-2.0 M_solar), this value is completely consistent with models of neutron stars composed of normal nuclear matter, while it excludes some models in which the neutron stars are made of more exotic matter.Comment: Published in Nature (Nov 7, 2002

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD