The holographic principle

There is strong evidence that the area of any surface limits the information content of adjacent spacetime regions, at 10^(69) bits per square meter. We review the developments that have led to the recognition of this entropy bound, placing special emphasis on the quantum properties of black holes. The construction of light-sheets, which associate relevant spacetime regions to any given surface, is discussed in detail. We explain how the bound is tested and demonstrate its validity in a wide range of examples. A universal relation between geometry and information is thus uncovered. It has yet to be explained. The holographic principle asserts that its origin must lie in the number of fundamental degrees of freedom involved in a unified description of spacetime and matter. It must be manifest in an underlying quantum theory of gravity. We survey some successes and challenges in implementing the holographic principle.Comment: 52 pages, 10 figures, invited review for Rev. Mod. Phys; v2: reference adde

Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells

Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs

The entropy of black holes: a primer

After recalling the definition of black holes, and reviewing their energetics and their classical thermodynamics, one expounds the conjecture of Bekenstein, attributing an entropy to black holes, and the calculation by Hawking of the semi-classical radiation spectrum of a black hole, involving a thermal (Planckian) factor. One then discusses the attempts to interpret the black-hole entropy as the logarithm of the number of quantum micro-states of a macroscopic black hole, with particular emphasis on results obtained within string theory. After mentioning the (technically cleaner, but conceptually more intricate) case of supersymmetric (BPS) black holes and the corresponding counting of the degeneracy of Dirichlet-brane systems, one discusses in some detail the ``correspondence'' between massive string states and non-supersymmetric Schwarzschild black holes.Comment: 51 pages, 4 figures, talk given at the "Poincare seminar" (Paris, 6 December 2003), to appear in Poincare Seminar 2003 (Birkhauser

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Dynamics of direct inter-pack encounters in endangered African wild dogs

Aggressive encounters may have important life history consequences due to the potential for injury and death, disease transmission, dispersal opportunities or exclusion from key areas of the home range. Despite this, little is known of their detailed dynamics, mainly due to the difficulties of directly observing encounters in detail. Here, we describe detailed spatial dynamics of inter-pack encounters in African wild dogs (Lycaon pictus), using data from custom-built high-resolution GPS collars in 11 free-ranging packs. On average, each pack encountered another pack approximately every 7 weeks and met each neighbour twice each year. Surprisingly, intruders were more likely to win encounters (winning 78.6% of encounters by remaining closer to the site in the short term). However, intruders did tend to move farther than residents toward their own range core in the short-term (1 h) post-encounter, and if this were used to indicate losing an encounter, then the majority (73.3%) of encounters were won by residents. Surprisingly, relative pack size had little effect on encounter outcome, and injuries were rare (<15% of encounters). These results highlight the difficulty of remotely scoring encounters involving mobile participants away from static defendable food resources. Although inter-pack range overlap was reduced following an encounter, encounter outcome did not seem to drive this, as both packs shifted their ranges post-encounter. Our results indicate that inter-pack encounters may be lower risk than previously suggested and do not appear to influence long-term movement and ranging

A mammalian functional-genetic approach to characterizing cancer therapeutics

Supplementary information is available online at http://www.nature.com/naturechemicalbiology/. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/.Identifying mechanisms of drug action remains a fundamental impediment to the development and effective use of chemotherapeutics. Here we describe an RNA interference (RNAi)–based strategy to characterize small-molecule function in mammalian cells. By examining the response of cells expressing short hairpin RNAs (shRNAs) to a diverse selection of chemotherapeutics, we could generate a functional shRNA signature that was able to accurately group drugs into established biochemical modes of action. This, in turn, provided a diversely sampled reference set for high-resolution prediction of mechanisms of action for poorly characterized small molecules. We could further reduce the predictive shRNA target set to as few as eight genes and, by using a newly derived probability-based nearest-neighbors approach, could extend the predictive power of this shRNA set to characterize additional drug categories. Thus, a focused shRNA phenotypic signature can provide a highly sensitive and tractable approach for characterizing new anticancer drugs.National Institute of Mental Health (U.S.) (grant RO1 CA128803-03)American Association for Cancer ResearchMassachusetts Institute of Technology. Dept. of BiologyNational Cancer Institute (U.S.). Integrative Cancer Biology Program (grant 1-U54-CA112967

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence(1,2). Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies(3). To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma(4,5). We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth

Derivation of Suitability Metrics for Remote Access Mode Experiments

When considering the possible use of an online mode of experimentation it is important to evaluate the suitability of the remote access mode to a particular learning exercise. Within a large and diverse set of possible experiment-oriented learning exercises, it follows that not all laboratory experiments are well-suited for conversion to the remote access mode. In this paper we consider a range of factors that should be considered before the decision is taken to implement a remote laboratory. These factors fit broadly into four categories: learning factors, equipment factors, cohort factors and accreditation factors. Some of the factors may demonstrate a tendency to belong to more than one category, and some may present with a more significant weighting than others, but the categorical organization of the factors adds an ability to apply an objective assessment to remote access mode suitability

Morphine activation of mu opioid receptors causes disinhibition of neurons in the ventral tegmental area mediated by β-arrestin2 and c-Src

Abstract The tyrosine kinase, c-Src, participates in mu opioid receptor (MOP) mediated inhibition in sensory neurons in which β-arrestin2 (β-arr2) is implicated in its recruitment. Mice lacking β-arr2 exhibit increased sensitivity to morphine reinforcement; however, whether β-arr2 and/or c-Src participate in the actions of opioids in neurons within the reward pathway is unknown. It is also unclear whether morphine acts exclusively through MOPs, or involves delta opioid receptors (DOPs). We examined the involvement of MOPs, DOPs, β-arr2 and c-Src in the inhibition by morphine of GABAergic inhibitory postsynaptic currents (IPSCs) recorded from neurons in the mouse ventral tegmental area. Morphine inhibited spontaneous IPSC frequency, mainly through MOPs, with only a negligible effect remaining in MOP−/− neurons. However, a reduction in the inhibition by morphine for DOP−/− c.f. WT neurons and a DPDPE-induced decrease of IPSC frequency revealed a role for DOPs. The application of the c-Src inhibitor, PP2, to WT neurons also reduced inhibition by morphine, while the inactive PP3, and the MEK inhibitor, SL327, had no effect. Inhibition of IPSC frequency by morphine was also reduced in β-arr2−/− neurons in which PP2 caused no further reduction. These data suggest that inhibition of IPSCs by morphine involves a β-arr2/c-Src mediated mechanism

Comments on black holes I: The possibility of complementarity

We comment on a recent paper of Almheiri, Marolf, Polchinski and Sully who argue against black hole complementarity based on the claim that an infalling observer 'burns' as he approaches the horizon. We show that in fact measurements made by an infalling observer outside the horizon are statistically identical for the cases of vacuum at the horizon and radiation emerging from a stretched horizon. This forces us to follow the dynamics all the way to the horizon, where we need to know the details of Planck scale physics. We note that in string theory the fuzzball structure of microstates does not give any place to 'continue through' this Planck regime. AMPS argue that interactions near the horizon preclude traditional complementarity. But the conjecture of 'fuzzball complementarity' works in the opposite way: the infalling quantum is absorbed by the fuzzball surface, and it is the resulting dynamics that is conjectured to admit a complementary description.Comment: 34 pages, 6 figures, v3: clarifications & references adde