Gravitational Radiation from Post-Newtonian Sources and Inspiralling Compact Binaries

The article reviews the current status of a theoretical approach to the problem of the emission of gravitational waves by isolated systems in the context of general relativity. Part A of the article deals with general post-Newtonian sources. The exterior field of the source is investigated by means of a combination of analytic post-Minkowskian and multipolar approximations. The physical observables in the far-zone of the source are described by a specific set of radiative multipole moments. By matching the exterior solution to the metric of the post-Newtonian source in the near-zone we obtain the explicit expressions of the source multipole moments. The relationships between the radiative and source moments involve many non-linear multipole interactions, among them those associated with the tails (and tails-of-tails) of gravitational waves. Part B of the article is devoted to the application to compact binary systems. We present the equations of binary motion, and the associated Lagrangian and Hamiltonian, at the third post-Newtonian (3PN) order beyond the Newtonian acceleration. The gravitational-wave energy flux, taking consistently into account the relativistic corrections in the binary moments as well as the various tail effects, is derived through 3.5PN order with respect to the quadrupole formalism. The binary's orbital phase, whose prior knowledge is crucial for searching and analyzing the signals from inspiralling compact binaries, is deduced from an energy balance argument.Comment: 109 pages, 1 figure; this version is an update of the Living Review article originally published in 2002; available on-line at http://www.livingreviews.org

The Na+/H+ Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H+-Activated, Na+-Dependent Ionic Shift in Esophageal Cells

Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na+/H+ exchanger (NHE) and Na+ influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM -0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na+, subsequent loss of intracellular K+, an increase of Ca2+ and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na+, K+ and Ca2+ changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na+ levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na+ concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na+ influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis

Which Is the Most Suitable Classification for Colorectal Cancer, Log Odds, the Number or the Ratio of Positive Lymph Nodes?

Objective: The aim of the current study was to investigate which is the most suitable classification for colorectal cancer, log odds of positive lymph nodes (LODDS) classification or the classifications based on the number of positive lymph nodes (pN) and positive lymph node ratio(LNR) in a Chinese single institutional population. Design: Clinicopathologic and prognostic data of 1297 patients with colorectal cancer were retrospectively studied. The log-rank statistics, Cox’s proportional hazards model, the Nagelkerke R 2 index and a Harrell’s C statistic were used. Results: Univariate and three-step multivariate analyses identified that LNR was a significant prognostic factor and LNR classification was superior to both the pN and LODDS classifications. Moreover, the results of the Nagelkerke R 2 index (0.130) and a Harrell’s C statistic (0.707) of LNR showed that LNR and LODDS classifications were similar and LNR was a little better than the other two classifications. Furthermore, for patients in each LNR classification, prognosis was homologous between those in different pN or LODDS classifications. However, for patients in pN1a, pN1b, LODDS2 and LODDS3 classifications, significant differences in survival were observed among patients in different LNR classifications. Conclusions: For patients with colorectal cancer, the LNR classification is more suitable than pN and LODDS classification

An abrupt weakening of the subpolar gyre as trigger of Little Ice Age-type episodes

We investigate the mechanism of a decadal-scale weakening shift in the strength of the subpolar gyre (SPG) that is found in one among three last millennium simulations with a state-of-the-art Earth system model. The SPG shift triggers multicentennial anomalies in the North Atlantic climate driven by long-lasting internal feedbacks relating anomalous oceanic and atmospheric circulation, sea ice extent, and upper-ocean salinity in the Labrador Sea. Yet changes throughout or after the shift are not associated with a persistent weakening of the Atlantic Meridional Overturning Circulation or shifts in the North Atlantic Oscillation. The anomalous climate state of the North Atlantic simulated after the shift agrees well with climate reconstructions from within the area, which describe a transition between a stronger and weaker SPG during the relatively warm medieval climate and the cold Little Ice Age respectively. However, model and data differ in the timing of the onset. The simulated SPG shift is caused by a rapid increase in the freshwater export from the Arctic and associated freshening in the upper Labrador Sea. Such freshwater anomaly relates to prominent thickening of the Arctic sea ice, following the cluster of relatively small-magnitude volcanic eruptions by 1600 CE. Sensitivity experiments without volcanic forcing can nonetheless produce similar abrupt events; a necessary causal link between the volcanic cluster and the SPG shift can therefore be excluded. Instead, preconditioning by internal variability explains discrepancies in the timing between the simulated SPG shift and the reconstructed estimates for the Little Ice Age onset

IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function 1?4 . However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer?an aggressive malignancy that is refractory to standard treatments and current immunotherapies 5?8 ?induces endoplasmic reticulum stress and activates the IRE1α?XBP1 arm of the unfolded protein response 9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α?XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α?XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α?XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.Fil: Song, Minkyung. Weill Cornell Medicine; Estados UnidosFil: Sandoval, Tito A.. Weill Cornell Medicine; Estados UnidosFil: Chae, Chang-Suk. Weill Cornell Medicine; Estados UnidosFil: Chopra, Sahil. Weill Cornell Medicine; Estados UnidosFil: Tan, Chen. Weill Cornell Medicine; Estados UnidosFil: Rutkowski, Melanie R.. University of Virginia; Estados UnidosFil: Raundhal, Mahesh. Dana Farber Cancer Institute; Estados Unidos. Harvard Medical School; Estados UnidosFil: Chaurio, Ricardo A.. H. Lee Moffitt Cancer Center & Research Institute; Estados UnidosFil: Payne, Kyle K.. H. Lee Moffitt Cancer Center & Research Institute; Estados UnidosFil: Konrad, Csaba. Weill Cornell Medicine; Estados UnidosFil: Bettigole, Sarah E.. Quentis Therapeutics Inc.; Estados UnidosFil: Shin, Hee Rae. Quentis Therapeutics Inc.; Estados UnidosFil: Crowley, Michael J. P.. Weill Cornell Graduate School of Medical Sciences; Estados UnidosFil: Cerliani, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kossenkov, Andrew V.. The Wistar Institute; Estados UnidosFil: Motorykin, Ievgen. Weill Cornell Medicine,; Estados UnidosFil: Zhang, Sheng. Weill Cornell Medicine,; Estados UnidosFil: Manfredi, Giovanni. Weill Cornell Medicine,; Estados UnidosFil: Zamarin, Dmitriy. Memorial Sloan Kettering Cancer Center; Estados UnidosFil: Holcomb, Kevin. Weill Cornell Medicine,; Estados UnidosFil: Rodriguez, Paulo C.. H. Lee Moffitt Cancer Center & Research Institute; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Conejo Garcia, Jose R.. H. Lee Moffitt Cancer Center & Research Institute; Estados UnidosFil: Glimcher, Laurie H.. Dana Farber Cancer Institute; Estados Unidos. Harvard Medical School; Estados UnidosFil: Cubillos-Ruiz, Juan R.. Weill Graduate School Of Medical Sciences; Estados Unidos. Weill Graduate School Of Medical Sciences; Estados Unido

Chemical Genetics Reveals Bacterial and Host Cell Functions Critical for Type IV Effector Translocation by Legionella pneumophila

Delivery of effector proteins is a process widely used by bacterial pathogens to subvert host cell functions and cause disease. Effector delivery is achieved by elaborate injection devices and can often be triggered by environmental stimuli. However, effector export by the L. pneumophila Icm/Dot Type IVB secretion system cannot be detected until the bacterium encounters a target host cell. We used chemical genetics, a perturbation strategy that utilizes small molecule inhibitors, to determine the mechanisms critical for L. pneumophila Icm/Dot activity. From a collection of more than 2,500 annotated molecules we identified specific inhibitors of effector translocation. We found that L. pneumophila effector translocation in macrophages requires host cell factors known to be involved in phagocytosis such as phosphoinositide 3-kinases, actin and tubulin. Moreover, we found that L. pneumophila phagocytosis and effector translocation also specifically require the receptor protein tyrosine phosphate phosphatases CD45 and CD148. We further show that phagocytosis is required to trigger effector delivery unless intimate contact between the bacteria and the host is artificially generated. In addition, real-time analysis of effector translocation suggests that effector export is rate-limited by phagocytosis. We propose a model in which L. pneumophila utilizes phagocytosis to initiate an intimate contact event required for the translocation of pre-synthesized effector molecules. We discuss the need for host cell participation in the initial step of the infection and its implications in the L. pneumophila lifestyle. Chemical genetic screening provides a novel approach to probe the host cell functions and factors involved in host–pathogen interactions

Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Nck1 and Nck2 adaptor proteins are involved in signaling pathways mediating proliferation, cytoskeleton organization and integrated stress response. Overexpression of Nck1 in fibroblasts has been shown to be oncogenic. Through the years this concept has been challenged and the consensus is now that overexpression of either Nck cooperates with strong oncogenes to transform cells. Therefore, variations in Nck expression levels in transformed cells could endorse cancer progression.</p> <p>Methods</p> <p>Expression of Nck1 and Nck2 proteins in various cancer cell lines at different stages of progression were analyzed by western blots. We created human primary melanoma cell lines overexpressing GFP-Nck2 and investigated their ability to proliferate along with metastatic characteristics such as migration and invasion. By western blot analysis, we compared levels of proteins phosphorylated on tyrosine as well as cadherins and integrins in human melanoma cells overexpressing or not Nck2. Finally, in mice we assessed tumor growth rate of human melanoma cells expressing increasing levels of Nck2.</p> <p>Results</p> <p>We found that expression of Nck2 is consistently increased in various metastatic cancer cell lines compared with primary counterparts. Particularly, we observed significant higher levels of Nck2 protein and mRNA, as opposed to no change in Nck1, in human metastatic melanoma cell lines compared with non-metastatic melanoma and normal melanocytes. We demonstrated the involvement of Nck2 in proliferation, migration and invasion in human melanoma cells. Moreover, we discovered that Nck2 overexpression in human primary melanoma cells correlates with higher levels of proteins phosphorylated on tyrosine residues, assembly of Nck2-dependent pY-proteins-containing molecular complexes and downregulation of cadherins and integrins. Importantly, we uncovered that injection of Nck2-overexpressing human primary melanoma cells into mice increases melanoma-derived tumor growth rate.</p> <p>Conclusions</p> <p>Collectively, our data indicate that Nck2 effectively influences human melanoma phenotype progression. At the molecular level, we propose that Nck2 in human primary melanoma promotes the formation of molecular complexes regulating proliferation and actin cytoskeleton dynamics by modulating kinases or phosphatases activities that results in increased levels of proteins phosphorylated on tyrosine residues. This study provides new insights regarding cancer progression that could impact on the therapeutic strategies targeting cancer.</p

Role of Position 627 of PB2 and the Multibasic Cleavage Site of the Hemagglutinin in the Virulence of H5N1 Avian Influenza Virus in Chickens and Ducks

Highly pathogenic H5N1 avian influenza viruses have caused major disease outbreaks in domestic and free-living birds with transmission to humans resulting in 59% mortality amongst 564 cases. The mutation of the amino acid at position 627 of the viral polymerase basic-2 protein (PB2) from glutamic acid (E) in avian isolates to lysine (K) in human isolates is frequently found, but it is not known if this change affects the fitness and pathogenicity of the virus in birds. We show here that horizontal transmission of A/Vietnam/1203/2004 H5N1 (VN/1203) virus in chickens and ducks was not affected by the change of K to E at PB2-627. All chickens died between 21 to 48 hours post infection (pi), while 70% of the ducks survived infection. Virus replication was detected in chickens within 12 hours pi and reached peak titers in spleen, lung and brain between 18 to 24 hours for both viruses. Viral antigen in chickens was predominantly in the endothelium, while in ducks it was present in multiple cell types, including neurons, myocardium, skeletal muscle and connective tissues. Virus replicated to a high titer in chicken thrombocytes and caused upregulation of TLR3 and several cell adhesion molecules, which may explain the rapid virus dissemination and location of viral antigen in endothelium. Virus replication in ducks reached peak values between 2 and 4 days pi in spleen, lung and brain tissues and in contrast to infection in chickens, thrombocytes were not involved. In addition, infection of chickens with low pathogenic VN/1203 caused neuropathology, with E at position PB2-627 causing significantly higher infection rates than K, indicating that it enhances virulence in chickens