Exploding the necroptotic bubble

The apoptotic death of cells is accompanied by the exposure of “eat-me” signals that serve to prevent necrotic degradation of apoptotic cells, and thereby prevent inflammation, promote resolution of immune responses, and stimulate tissue repair. These “eat-me” signals include the exposure of phosphatidylserine (PS) on the outer plasma membrane during the early stages of apoptosis as well as on the surface of apoptotic bodies, plasma membrane vesicles that are shed during the later stages of cell death. In our recent publication (PLoS Biol. 15(6):e2002711), we describe similar ‘eat-me’ and ‘find-me’ signals present during necroptosis, challenging some of our common assumptions about regulated forms of lytic death

DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes

Eukaryotic cells store their chromosomes in a single nucleus. This is important to maintain genomic integrity, as chromosomes packaged into separate nuclei (micronuclei) are prone to massive DNA damage. During mitosis, higher eukaryotes disassemble their nucleus and release individualized chromosomes for segregation. How numerous chromosomes subsequently reform a single nucleus has remained unclear. Using image-based screening of human cells, we identified barrier-to-autointegration factor (BAF) as a key factor guiding membranes to form a single nucleus. Unexpectedly, nuclear assembly does not require BAF?s association with inner nuclear membrane proteins but instead relies on BAF?s ability to bridge distant DNA sites. Live-cell imaging and in vitro reconstitution showed that BAF enriches around the mitotic chromosome ensemble to induce a densely cross-bridged chromatin layer that is mechanically stiff and limits membranes to the surface. Our study reveals that BAF-mediated changes in chromosome mechanics underlie nuclear assembly with broad implications for proper genome function

Deep Hole States in Medium Mass Nuclei

Supported by the National Science Foundation and Indiana Universit

Linear Protection Schemes Analysis in Scattered Placement Fiber-To-The Home-Passive Optical Network Using Customer Access Protection Unit Solution

<STRONG>Problem statement:</STRONG> This study highlights on restoration scheme proposed against failure in working line at the drop region for Fiber-To-The Home (FTTH) with a Passive Optical Network (PON). Whereas PON is a system that brings optical fiber cable and signals all or most of the way to the end user.<STRONG> Approach:</STRONG> Survivability scheme against failure is focused on scattered residence architectures and it is applied in the ring and tree topology respectively by means of Customer Access Protection Unit (CAPU). CAPU will be installed before the ONU and ensure the signal will find the alternative path when failure occurs at the specific line. Our proposal scheme is low cost and applicable to any residence architecture. The advantage of this scheme is the failure at fiber line can be recovered until three levels to make sure the optic signal flow continuously to avoid any application disturbance. Two type of restoration scheme is proposed by means of linear protection (tree) and migrated protection (ring). FTTH based network design is simulated by using Opti System 7.0 in order to investigate the power output and BER performance at each node in the tree and ring protection scheme in scattered placement. This study we perform an analysis on linear protection scheme that consisting of two model a) Line to Line (L2L) protection and CAPU to CAPU (C2C) or Shared protection. However the migration of tree to ring topology to enable the signal flow continuously in the case of failure occurs specifically in random or scattered placement topology has been highlighted in our previous publication. <STRONG>Results:</STRONG> The signal will be divided into section; drop and pass through and the ratio is significant to determine the number of user allowed and achievable distance. Output power for optical nodes could be slightly improved by varying the pass through and drop signal ratio. <STRONG>Conclusion:</STRONG> Our proposal is the first reported up to this time in which the upstream signal flows in anticlockwise in ring topology when the restoration scheme activated

Discovery and Characterization of 2-Aminobenzimidazole Derivatives as Selective NOD1 Inhibitors

SummaryNLR family proteins play important roles in innate immune response. NOD1 (NLRC1) activates various signaling pathways including NF-κB in response to bacterial ligands. Hereditary polymorphisms in the NOD1 gene are associated with asthma, inflammatory bowel disease, and other disorders. Using a high throughput screening (HTS) assay measuring NOD1-induced NF-κB reporter gene activity, followed by multiple downstream counter screens that eliminated compounds impacting other NF-κB effectors, 2-aminobenzimidazole compounds were identified that selectively inhibit NOD1. Mechanistic studies of a prototypical compound, Nodinitib-1 (ML130; CID-1088438), suggest that these small molecules cause conformational changes of NOD1 in vitro and alter NOD1 subcellular targeting in cells. Altogether, this inaugural class of inhibitors provides chemical probes for interrogating mechanisms regulating NOD1 activity and tools for exploring the roles of NOD1 in various infectious and inflammatory diseases

Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis

Response of CsI(Tl) scintillators over a large range in energy and atomic number of ions (Part I): recombination and delta -- electrons

A simple formalism describing the light response of CsI(Tl) to heavy ions, which quantifies the luminescence and the quenching in terms of the competition between radiative transitions following the carrier trapping at the Tl activator sites and the electron-hole recombination, is proposed. The effect of the delta rays on the scintillation efficiency is for the first time quantitatively included in a fully consistent way. The light output expression depends on four parameters determined by a procedure of global fit to experimental data.Comment: 28 pages, 6 figures, submitted to Nucl. Inst. Meth.

Multifragmentation process for different mass asymmetry in the entrance channel around the Fermi energy

The influence of the entrance channel asymmetry upon the fragmentation process is addressed by studying heavy-ion induced reactions around the Fermi energy. The data have been recorded with the INDRA 4pi array. An event selection method called the Principal Component Analysis is presented and discussed. It is applied for the selection of central events and furthermore to multifragmentation of single source events. The selected subsets of data are compared to the Statistical Multifragmentation Model (SMM) to check the equilibrium hypothesis and get the source characteristics. Experimental comparisons show the evidence of a decoupling between thermal and compresional (radial flow) degrees of freedom in such nuclear systems.Comment: 28 pages, 15 figures, article sumitted to Nuclear Physics

Multifragmentation in Xe(50A MeV)+Sn Confrontation of theory and data

We compare in detail central collisions Xe(50A MeV) + Sn, recently measured by the INDRA collaboration, with the Quantum Molecular Dynamics (QMD) model in order to identify the reaction mechanism which leads to multifragmentation. We find that QMD describes the data quite well, in the projectile/target region as well as in the midrapidity zone where also statistical models can be and have been employed. The agreement between QMD and data allows to use this dynamical model to investigate the reaction in detail. We arrive at the following observations: a) the in medium nucleon nucleon cross section is not significantly different from the free cross section, b) even the most central collisions have a binary character, c) most of the fragments are produced in the central collisions and d) the simulations as well as the data show a strong attractive in-plane flow resembling deep inelastic collisions e) at midrapidity the results from QMD and those from statistical model calculations agree for almost all observables with the exception of ${d^2 \sigma \over dZdE}$. This renders it difficult to extract the reaction mechanism from midrapidity fragments only. According to the simulations the reaction shows a very early formation of fragments, even in central collisions, which pass through the reaction zone without being destroyed. The final transverse momentum of the fragments is very close to the initial one and due to the Fermi motion. A heating up of the systems is not observed and hence a thermal origin of the spectra cannot be confirmed.Comment: figures 1 and 2 changed (no more ps -errors

Effect of the intermediate velocity emissions on the quasi-projectile properties for the Ar+Ni system at 95 A.MeV

The quasi-projectile (QP) properties are investigated in the Ar+Ni collisions at 95 A.MeV taking into account the intermediate velocity emission. Indeed, in this reaction, between 52 and 95 A.MeV bombarding energies, the number of particles emitted in the intermediate velocity region is related to the overlap volume between projectile and target. Mean transverse energies of these particles are found particularly high. In this context, the mass of the QP decreases linearly with the impact parameter from peripheral to central collisions whereas its excitation energy increases up to 8 A.MeV. These results are compared to previous analyses assuming a pure binary scenario