Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition.

Autophagy is a lysosomal degradation pathway that eliminates aggregated proteins and damaged organelles to maintain cellular homeostasis. A major route for activating autophagy involves inhibition of the mTORC1 kinase, but current mTORC1-targeting compounds do not allow complete and selective mTORC1 blockade. Here, we have coupled screening of a covalent ligand library with activity-based protein profiling to discover EN6, a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase, which activates mTORC1 via the Rag guanosine triphosphatases. EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling

Phase II study of TP300 in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma

Background: TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas. Methods: Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m2 with intra-patient escalation to 10 mg/m2 from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study. Results: In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 − 82), performance status ECOG 0/1, with GC [14] or GOJ carcinoma [6] were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m2 at cycle 2, 2 decreased to 6 mg/m2, and 3 continued on 8 mg/m2. There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 − 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI [1.6 − 4.9]), median time to progression (TTP) was 2.9 months (CI [1.4 − 4.2]). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders. Conclusions: This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response

The Nature of Blue Cores in Spheroids: a Possible Connection with AGN and Star Formation

We investigate the physical nature of blue cores in early-type galaxies through the first multi-wavelength analysis of a serendipitously discovered field blue-nucleated spheroid in the background of the deep ACS/WFC griz multicolor observations of the cluster Abell 1689. The resolved g-r, r-i and i-z color maps reveal a prominent blue core identifying this galaxy as a ``typical'' case study, exhibiting variations of 0.5-1.0 mag in color between the center and the outer regions, opposite to the expectations of reddened metallicity induced gradients in passively evolved ellipticals. From a Magellan-Clay spectrum we secure the galaxy redshift at $z=0.624$. We find a strong X-ray source coincident with the spheroid galaxy. Spectral features and a high X-ray luminosity indicate the presence of an AGN in the galaxy. However, a comparison of the X-ray luminosity to a sample derived from the Chandra Deep Field South displays Lx to be comparable to Type I/QSO galaxies while the optical flux is consistent with a normal star-forming galaxy. We conclude that the galaxy's non-thermal component dominates at high-energy wavelengths while we associate the spheroid blue light with the stellar spectrum of normal star-forming galaxies. We argue about a probable association between the presence of blue cores in spheroids and AGN activity.Comment: Accepted for publication in the Astrophysical Journal. 6 pages, 3 figures. Full resolution images available at http://acs.pha.jhu.edu/~felipe/e-print

Remembering what could have happened: Neural correlates of episodic counterfactual thinking

Recent evidence suggests that our capacities to remember the past and to imagine what might happen in the future largely depend on the same core brain network that includes the middle temporal lobe, the posterior cingulate/retrosplenial cortex, the inferior parietal lobe, the medial prefrontal cortex, and the lateral temporal cortex. However, the extent to which regions of this core brain network are also responsible for our capacity to think about what could have happened in our past, yet did not occur (i.e., episodic counterfactual thinking), is still unknown. The present study examined this issue. Using a variation of the experimental recombination paradigm (Addis, Pan, Vu, Laiser, & Schacter, 2009. Neuropsychologia. 47: 2222–2238), participants were asked both to remember personal past events and to envision alternative outcomes to such events while undergoing functional magnetic resonance imaging. Three sets of analyses were performed on the imaging data in order to investigate two related issues. First, a mean-centered spatiotemporal partial least square (PLS) analysis identified a pattern of brain activity across regions of the core network that was common to episodic memory and episodic counterfactual thinking. Second, a non-rotated PLS analysis identified two different patterns of brain activity for likely and unlikely episodic counterfactual thoughts, with the former showing significant overlap with the set of regions engaged during episodic recollection. Finally, a parametric modulation was conducted to explore the differential engagement of brain regions during counterfactual thinking, revealing that areas such as the parahippocampal gyrus and the right hippocampus were modulated by the subjective likelihood of counterfactual simulations. These results suggest that episodic counterfactual thinking engages regions that form the core brain network, and also that the subjective likelihood of our counterfactual thoughts modulates the engagement of different areas within this set of regions.Psycholog

U-Pb geochronology and global context of the Charnian Supergroup, UK: constraints on the age of key Ediacaran fossil assemblages

U-Pb (zircon) ages for key stratigraphic volcanic horizons within the ∼3200-m-thick Ediacaran-age Charnian Supergroup provide an improved age model for the included Avalonian assemblage macrofossils and, hence, temporal constraints essential for intercomparisons of the Charnian fossils with other Ediacaran fossil assemblages globally. The Ives Head Formation (Blackbrook Group), the oldest exposed part of the volcaniclastic Charnian Supergroup of the late Neoproterozoic Avalonian volcanic arc system of southern Britain, contains a bedding plane with an impoverished assemblage of ivesheadiomorphs that is constrained to between ca. 611 Ma and 569.1 ± 0.9 Ma (total uncertainty). Higher-diversity biotas, including the holotypes of Charnia, Charniodiscus, and Bradgatia, occupy the upper part of the volcaniclastic succession (Maplewell Group) and are dated at 561.9 ± 0.9 Ma (total uncertainty) and younger by zircons interpreted as coeval with eruption and deposition of the Park Breccia, Bradgate Formation. An ashy volcanic-pebble conglomerate in the Hanging Rocks Formation at the very top of the supergroup yielded two U-Pb zircon populations: an older detrital one at ca. 604 Ma, and a younger population at ca. 557 Ma, which is interpreted as the approximate depositional age. The temporal association of the fossiliferous Charnian Supergroup with comparable fossiliferous deep-water successions in Newfoundland, and the probable temporal overlap of the youngest Charnwood macrofossils with those from different paleoenvironmental settings, such as the Ediacaran White Sea macrofossils, indicate a primary role for ecological sensitivity in determining the composition of these late Neoproterozoic communities

Transit Timing Observations from Kepler: VI. Potentially interesting candidate systems from Fourier-based statistical tests

We analyze the deviations of transit times from a linear ephemeris for the Kepler Objects of Interest (KOI) through Quarter six (Q6) of science data. We conduct two statistical tests for all KOIs and a related statistical test for all pairs of KOIs in multi-transiting systems. These tests identify several systems which show potentially interesting transit timing variations (TTVs). Strong TTV systems have been valuable for the confirmation of planets and their mass measurements. Many of the systems identified in this study should prove fruitful for detailed TTV studies.Comment: 32 pages, 6 of text and one long table, Accepted to Ap

Pseudomonas aeruginosa Disrupts Caenorhabditis elegans Iron Homeostasis, Causing a Hypoxic Response and Death

SummaryThe opportunistic pathogen Pseudomonas aeruginosa causes serious human infections, but effective treatments and the mechanisms mediating pathogenesis remain elusive. Caenorhabditis elegans shares innate immune pathways with humans, making it invaluable to investigate infection. To determine how P. aeruginosa disrupts host biology, we studied how P. aeruginosa kills C. elegans in a liquid-based pathogenesis model. We found that P. aeruginosa-mediated killing does not require quorum-sensing pathways or host colonization. A chemical genetic screen revealed that iron chelators alleviate P. aeruginosa-mediated killing. Consistent with a role for iron in P. aeruginosa pathogenesis, the bacterial siderophore pyoverdin was required for virulence and was sufficient to induce a hypoxic response and death in the absence of bacteria. Loss of the C. elegans hypoxia-inducing factor HIF-1, which regulates iron homeostasis, exacerbated P. aeruginosa pathogenesis, further linking hypoxia and killing. As pyoverdin is indispensable for virulence in mice, pyoverdin-mediated hypoxia is likely to be relevant in human pathogenesis

Transit Timing Observations from Kepler: VII. Confirmation of 27 planets in 13 multiplanet systems via Transit Timing Variations and orbital stability

We confirm 27 planets in 13 planetary systems by showing the existence of statistically significant anti-correlated transit timing variations (TTVs), which demonstrates that the planet candidates are in the same system, and long-term dynamical stability, which places limits on the masses of the candidates---showing that they are planetary. %This overall method of planet confirmation was first applied to \kepler systems 23 through 32. All of these newly confirmed planetary systems have orbital periods that place them near first-order mean motion resonances (MMRs), including 6 systems near the 2:1 MMR, 5 near 3:2, and one each near 4:3, 5:4, and 6:5. In addition, several unconfirmed planet candidates exist in some systems (that cannot be confirmed with this method at this time). A few of these candidates would also be near first order MMRs with either the confirmed planets or with other candidates. One system of particular interest, Kepler-56 (KOI-1241), is a pair of planets orbiting a 12th magnitude, giant star with radius over three times that of the Sun and effective temperature of 4900 K---among the largest stars known to host a transiting exoplanetary system.Comment: 12 pages, 13 figures, 5 tables. Submitted to MNRA

Monte Carlo simulation of uncoupled continuous-time random walks yielding a stochastic solution of the space-time fractional diffusion equation

We present a numerical method for the Monte Carlo simulation of uncoupled continuous-time random walks with a Levy alpha-stable distribution of jumps in space and a Mittag-Leffler distribution of waiting times, and apply it to the stochastic solution of the Cauchy problem for a partial differential equation with fractional derivatives both in space and in time. The one-parameter Mittag-Leffler function is the natural survival probability leading to time-fractional diffusion equations. Transformation methods for Mittag-Leffler random variables were found later than the well-known transformation method by Chambers, Mallows, and Stuck for Levy alpha-stable random variables and so far have not received as much attention; nor have they been used together with the latter in spite of their mathematical relationship due to the geometric stability of the Mittag-Leffler distribution. Combining the two methods, we obtain an accurate approximation of space- and time-fractional diffusion processes almost as easy and fast to compute as for standard diffusion processes.Comment: 7 pages, 5 figures, 1 table. Presented at the Conference on Computing in Economics and Finance in Montreal, 14-16 June 2007; at the conference "Modelling anomalous diffusion and relaxation" in Jerusalem, 23-28 March 2008; et