Photoactivatable genetically encoded calcium indicators for targeted neuronal imaging.

Circuit mapping requires knowledge of both structural and functional connectivity between cells. Although optical tools have been made to assess either the morphology and projections of neurons or their activity and functional connections, few probes integrate this information. We have generated a family of photoactivatable genetically encoded Ca(2+) indicators that combines attributes of high-contrast photolabeling with high-sensitivity Ca(2+) detection in a single-color protein sensor. We demonstrated in cultured neurons and in fruit fly and zebrafish larvae how single cells could be selected out of dense populations for visualization of morphology and high signal-to-noise measurements of activity, synaptic transmission and connectivity. Our design strategy is transferrable to other sensors based on circularly permutated GFP (cpGFP)

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered

Analytic Behaviour of Competition among Three Species

We analyse the classical model of competition between three species studied by May and Leonard ({\it SIAM J Appl Math} \textbf{29} (1975) 243-256) with the approaches of singularity analysis and symmetry analysis to identify values of the parameters for which the system is integrable. We observe some striking relations between critical values arising from the approach of dynamical systems and the singularity and symmetry analyses.Comment: 14 pages, to appear in Journal of Nonlinear Mathematical Physic

On the mean-field spherical model

Exact solutions are obtained for the mean-field spherical model, with or without an external magnetic field, for any finite or infinite number N of degrees of freedom, both in the microcanonical and in the canonical ensemble. The canonical result allows for an exact discussion of the loci of the Fisher zeros of the canonical partition function. The microcanonical entropy is found to be nonanalytic for arbitrary finite N. The mean-field spherical model of finite size N is shown to be equivalent to a mixed isovector/isotensor sigma-model on a lattice of two sites. Partial equivalence of statistical ensembles is observed for the mean-field spherical model in the thermodynamic limit. A discussion of the topology of certain state space submanifolds yields insights into the relation of these topological quantities to the thermodynamic behavior of the system in the presence of ensemble nonequivalence.Comment: 21 pages, 5 figure

Search for microwave emission from ultrahigh energy cosmic rays

We present a search for microwave emission from air showers induced by ultrahigh energy cosmic rays with the microwave detection of air showers experiment. No events were found, ruling out a wide range of power flux and coherence of the putative emission, including those suggested by recent laboratory measurements.Comment: 5 pages, 3 figure

Relaxation and overlap probability function in the spherical and mean spherical model

The problem of the equivalence of the spherical and mean spherical models, which has been thoroughly studied and understood in equilibrium, is considered anew from the dynamical point of view during the time evolution following a quench from above to below the critical temperature. It is found that there exists a crossover time $t^* \sim V^{2/d}$ such that for $t < t^*$ the two models are equivalent, while for $t > t^*$ macroscopic discrepancies arise. The relation between the off equilibrium response function and the structure of the equilibrium state, which usually holds for phase ordering systems, is found to hold for the spherical model but not for the mean spherical one. The latter model offers an explicit example of a system which is not stochastically stable.Comment: 11 pages, 1 figure, references corrected, to appear in Phys.Rev.

Microtubule dynamics and glutathione metabolism in phagocytizing human polymorphonuclear leukocytes

Glutathione oxidants such as tertiary butyl hydroperoxide were shown previously to prevent microtubule assembly and cause breakdown of preassembled cytoplasmic microtubules in human polymorphonuclear leukocytes. The objectives of the present study were to determine the temporal relationship between the attachment and ingestion of phagocytic particles and the assembly of microtubules, and simultaneously to quantify the levels of reduced glutathione and products of its oxidation as potential physiological regulators of assembly. Polymorphonuclear leukocytes from human peripheral blood were induced to phagocytize opsonized zymosan at 30 degrees C. Microtubule assembly was assessed in the electron microscope by direct counts of microtubules in thin sections through centrioles. Acid extracts were assayed for reduced glutathione (GSH) and oxidized glutathione (GSSG), by the sensitive enzymatic procedure of Tietze. Washed protein pellets were assayed for free sulfhydryl groups and for mixed protein disulfides with glutathione (protein-SSG) after borohydride splitting of the disulfide bond. Resting cells have few assembled microtubules. Phagocytosis induces a cycle of rapid assembly followed by disassembly. Assembly is initiated by particle contact and is maximal by 3 min of phagocytosis. Disassembly after 5-9 min of phagocytosis is preceded by a slow rise in GSSG and coincides with a rapid rise in protein-SSG. Protein-SSG also increases under conditions in which butyl hydroperoxide inhibits the assembly of microtubules that normally follows binding of concanavalin A to leukocyte cell surface receptors. No evidence for direct involvement of GSH in the induction of assembly was obtained. The formation of protein-SSG, however, emerges as a possible regulatory mechanism for the inhibition of microtubule assembly and induction of their disassembly

The MIDAS experiment: A prototype for the microwave emission of Ultra-High Energy Cosmic Rays

Recent measurements suggest that extensive air showers initiated by ultra-high energy cosmic rays (UHECR) emit signals in the microwave band of the electromagnetic spectrum caused by the collisions of the free-electrons with the atmospheric neutral molecules in the plasma produced by the passage of the shower. Such emission is isotropic and could allow the detection of air showers with 100% duty cycle and a calorimetric-like energy measurement, a significant improvement over current detection techniques. We have built MIDAS (MIcrowave Detection of Air Showers), a prototype of microwave detector, which consists of a 4.5 m diameter antenna with a cluster of 53 feed-horns in the 4 GHz range. The details of the prototype and first results will be presented.Comment: To appear in the proceedings of 12th Topical Seminar on Innovative Particle and Radiation Detectors (IPRD10), Siena, Italy, 7 - 10 June 201