An unfolded protein-induced conformational switch activates mammalian IRE1.

The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α's ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization

Relativistic Hartree-Fock-Bogoliubov theory with Density Dependent Meson-Nucleon Couplings

Relativistic Hartree-Fock-Bogoliubov (RHFB) theory with density-dependent meson-nucleon couplings is presented. The integro-differential RHFB equations are solved by expanding the different components of the quasi-particle spinors in the complete set of eigen-solutions of the Dirac equations with Woods-Saxon potentials. Using the finite-range Gogny force D1S as an effective interaction in the pairing channel, systematic RHFB calculations are performed for Sn isotopes and N=82 isotones. It is demonstrated that an appropriate description of both mean field and pairing effects can be obtained within RHFB theory with finite range Gogny pairing forces. Better systematics are also found in the regions from the stable to the neutron-rich side with the inclusion of Fock terms, especially in the presence of $\rho$-tensor couplings.Comment: 11 pages, 2 tables and 4 figure

Superpixel-based segmentation of muscle fibers in multi-channel microscopy

Background Confetti fluorescence and other multi-color genetic labelling strategies are useful for observing stem cell regeneration and for other problems of cell lineage tracing. One difficulty of such strategies is segmenting the cell boundaries, which is a very different problem from segmenting color images from the real world. This paper addresses the difficulties and presents a superpixel-based framework for segmentation of regenerated muscle fibers in mice. Results We propose to integrate an edge detector into a superpixel algorithm and customize the method for multi-channel images. The enhanced superpixel method outperforms the original and another advanced superpixel algorithm in terms of both boundary recall and under-segmentation error. Our framework was applied to cross-section and lateral section images of regenerated muscle fibers from confetti-fluorescent mice. Compared with “ground-truth” segmentations, our framework yielded median Dice similarity coefficients of 0.92 and higher. Conclusion Our segmentation framework is flexible and provides very good segmentations of multi-color muscle fibers. We anticipate our methods will be useful for segmenting a variety of tissues in confetti fluorecent mice and in mice with similar multi-color labels.National University of Singapore (Duke-NUS SRP Phase 2 Research Block Grant)Singapore. National Research Foundation (CREATE programme)Singapore-MIT Alliance for Research and Technology (SMART

Inositol Acylation of Phosphatidylinositol Mannosides: A Rapid Mass Response to Membrane Fluidization in Mycobacteria

Mycobacteria share an unusually complex, multilayered cell envelope, which contributes to adaptation to changing environments. The plasma membrane is the deepest layer of the cell envelope and acts as the final permeability barrier against outside molecules. There is an obvious need to maintain the plasma membrane integrity, but the adaptive responses of the plasma membrane to stress exposure remain poorly understood. Using chemical treatment and heat stress to fluidize the membrane, we show here that phosphatidylinositol (PI)-anchored plasma membrane glycolipids known as PI mannosides (PIMs) are rapidly remodeled upon membrane fluidization in Mycobacterium smegmatis. Without membrane stress, PIMs are predominantly in a triacylated form: two acyl chains of the PI moiety plus one acyl chain modified at one of the mannose residues. Upon membrane fluidization, we determined the fourth fatty acid is added to the inositol moiety of PIMs, making them tetra-acylated variants. Additionally, we show that PIM inositol acylation is a rapid response independent of de novo protein synthesis, representing one of the fastest mass conversions of lipid molecules found in nature. Strikingly, we found that M. smegmatis is more resistant to the bactericidal effect of a cationic detergent after benzyl alcohol pre-exposure. We further demonstrate that fluidization-induced PIM inositol acylation is conserved in pathogens such as Mycobacterium tuberculosis and Mycobacterium abscessus. Our results demonstrate that mycobacteria possess a mechanism to sense plasma membrane fluidity change. We suggest that inositol acylation of PIMs is a novel membrane stress response that enables mycobacterial cells to resist membrane fluidization

Comprehensive User Engagement Sites (CUES) in Philadelphia: A Constructive Proposal

This paper is a study about Philadelphia’s comprehensive user engagement sites (CUESs) as the authors address and examine issues related to the upcoming implementation of a CUES while seeking solutions for its disputed questions and plans. Beginning with the federal drug schedules, the authors visit some of the medical and public health issues vis-à-vis safe injection facilities (SIFs). Insite, a successful Canadian SIF, has been thoroughly researched as it represents a paradigm for which a Philadelphia CUES can expand upon. Also, the existing criticisms against SIFs are revisited while critically unpackaged and responded to in favor of the establishment. In the main section, the authors propose the layout and services of the upcoming CUES, much of which would be in congruent to Vancouver’s Insite. On the other hand, the CUES would be distinct from Insite, as the authors emphasize, in that it will offer an information center run by individuals in recovery and place additional emphasis on early education for young healthcare professionals by providing them a platform to work at the site. The paper will also briefly investigate the implementation of a CUES site under an ethical scope of the Harm Reduction Theory. Lastly, the authors recommend some strategic plans that the Philadelphia City government may consider employing at this crucial stage

HST Imaging Polarimetry of the Gravitational Lens FSC10214+4724

We present imaging polarimetry of the extremely luminous, redshift 2.3 IRAS source FSC10214+4724. The observations were obtained with HST's Faint Object Camera in the F437M filter, which is free of strong emission lines. The 0.7 arcsec long arc is unresolved to 0.04 arcsec FWHM in the transverse direction, and has an integrated polarization of 28 +/- 3 percent, in good agreement with ground-based observations. The polarization position angle varies along the arc by up to 35 deg. The overall position angle is 62 +/- 3 deg east of north. No counterimage is detected to B = 27.5 mag ($3\sigma$), giving an observed arc to counterimage flux ratio greater than 250, considerably greater than the flux ratio of 100 measured previously in the I-band. This implies that the configuration of the object in the source plane at the B-band is different from that at I-band, and/or that the lensing galaxy is dusty.Comment: 17 pages, 3 figures. Accepted for publication in Astronomical Journal, February 199

Forages Improve Livelihoods of Smallholder Farmers with Beef Cattle in South Central Coastal Vietnam

In South Central Coastal Vietnam, on-farm research and farmer experience demonstrated the benefits of growing improved forages as a means of improving the year round quantity and quality of feed available for beef cattle. In Binh Dinh, Phu Yen and Ninh Thuan provinces, five new forage species (Panicum maximum, cv. TD58, Brachiaria hybrid cv. Mulato II, Pennisetum purpureum cv.VA06, Paspalum atratum cv. Terenos and Stylosanthes guianensis cv. CIAT 184) were evaluated for yield and crude protein concentration. There was not a consistent yield difference between locations for the forage grasses, but in Binh Dinh province P. maximum TD58 produced the highest yield. The grasses were comparable in crude protein concentration. Stylo CIAT 184 performed relatively well and had the highest crude protein concentration. All species have potential use, depending on the circumstances and site factors such as fertility, drainage and availability of irrigation. This work was expanded to a total of 45 farmers to gain feedback on farmer experience in growing different forages. The percentage of farmers who “liked” the introduced forages was Mulato II, 92%; TD58, 85%; VA06, 82%; Paspalum, 46%; and Stylo, 36%. By far the most important early socio-economic impact of developing perennial forage plots close to households was an average 50% reduction in the amount of labour and time that farmers spend supplying cut and carry forage to their animals. In addition, the growing of forages can meaningfully reduce the grazing pressure on common grazing lands, thereby lowering the potential for environmental degradation

Aluminum-, Calcium- And Titanium-Rich Oxide Stardust In Ordinary Chondrite Meteorites

We report isotopic data for a total of 96 presolar oxide grains found in residues of several unequilibrated ordinary chondrite meteorites. Identified grain types include Al2O3, MgAl2O4, hibonite (CaAl12O19) and Ti oxide. This work greatly increases the presolar hibonite database, and is the first report of presolar Ti oxide. O-isotopic compositions of the grains span previously observed ranges and indicate an origin in red giant and asymptotic giant branch (AGB) stars of low mass (<2.5 MSun) for most grains. Cool bottom processing in the parent AGB stars is required to explain isotopic compositions of many grains. Potassium-41 enrichments in hibonite grains are attributable to in situ decay of now-extinct 41Ca. Inferred initial 41Ca/40Ca ratios are in good agreement with model predictions for low-mass AGB star envelopes, provided that ionization suppresses 41Ca decay. Stable Mg and Ca isotopic ratios of most of the hibonite grains reflect primarily the initial compositions of the parent stars and are generally consistent with expectations for Galactic chemical evolution, but require some local interstellar chemical inhomogeneity. Very high 17O/16O or 25Mg/24Mg ratios suggest an origin for some grains in binary star systems where mass transfer from an evolved companion has altered the parent star compositions. A supernova origin for the hitherto enigmatic 18O-rich Group 4 grains is strongly supported by multi-element isotopic data for two grains. The Group 4 data are consistent with an origin in a single supernova in which variable amounts of material from the deep 16O-rich interior mixed with a unique end-member mixture of the outer layers. The Ti oxide grains primarily formed in low-mass AGB stars. They are smaller and rarer than presolar Al2O3, reflecting the lower abundance of Ti than Al in AGB envelopes.Comment: Accepted for publication in ApJ; 47 pages, 13 figure

KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS

Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Krüppel-like transcription factors (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rats of both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is critical for KLF9\u27s axon-growth-suppressive activity. Interfering with a JNK3-binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 and Ser110, effectively abolished KLF9\u27s neurite growth suppression in vitro and promoted axon regeneration in vivo. These findings demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in regenerative failure in the optic nerve and suggest new therapeutic strategies to promote axon regeneration in the adult CNS