The lysosomal trafficking regulator “LYST”: an 80-year traffic jam

Lysosomes and lysosome related organelles (LROs) are dynamic organelles at the intersection of various pathways involved in maintaining cellular hemostasis and regulating cellular functions. Vesicle trafficking of lysosomes and LROs are critical to maintain their functions. The lysosomal trafficking regulator (LYST) is an elusive protein important for the regulation of membrane dynamics and intracellular trafficking of lysosomes and LROs. Mutations to the LYST gene result in Chédiak-Higashi syndrome, an autosomal recessive immunodeficiency characterized by defective granule exocytosis, cytotoxicity, etc. Despite eight decades passing since its initial discovery, a comprehensive understanding of LYST’s function in cellular biology remains unresolved. Accumulating evidence suggests that dysregulation of LYST function also manifests in other disease states. Here, we review the available literature to consolidate available scientific endeavors in relation to LYST and discuss its relevance for immunomodulatory therapies, regenerative medicine and cancer applications

A survey of ex vivo/in vitro transduction efficiency of mammalian primary cells and cell lines with Nine natural adeno-associated virus (AAV1-9) and one engineered adeno-associated virus serotype

Abstract: Background: The ability to deliver a gene of interest into a specific cell type is an essential aspect of biomedical research. Viruses can be a useful tool for this delivery, particularly in difficult to transfect cell types. Adeno-associated virus (AAV) is a useful gene transfer vector because of its ability to mediate efficient gene transduction in numerous dividing and quiescent cell types, without inducing any known pathogenicity. There are now a number of natural for that designed AAV serotypes that each has a differential ability to infect a variety of cell types. Although transduction studies have been completed, the bulk of the studies have been done in vivo, and there has never been a comprehensive study of transduction ex vivo/in vitro. Methods: Each cell type was infected with each serotype at a multiplicity of infection of 100,000 viral genomes/cell and transduction was analyzed by flow cytometry + . Results: We found that AAV1 and AAV6 have the greatest ability to transduce a wide range of cell types, however, for particular cell types, there are specific serotypes that provide optimal transduction. Conclusions: In this work, we describe the transduction efficiency of ten different AAV serotypes in thirty-four different mammalian cell lines and primary cell types. Although these results may not be universal due to numerous factors such as, culture conditions and/ or cell growth rates and cell heterogeneity, these results provide an important and unique resource for investigators who use AAV as an ex vivo gene delivery vector or who work with cells that are difficult to transfect

Precession of the Super-Massive Black Hole in NGC 1275 (3C 84)?

The X-ray holes at the centre of the Perseus Cluster of galaxies are not all at the same position angle with respect to the centre of the cluster. This configuration would result if the jet inflating the bubbles is precessing, or moving around, and the bubbles detach at different times. The orientations which best fit the observed travel directions are an inclination of the precession axis to the line of sight of 120 degrees and an opening angle of 50 degrees. From the timescales for the bubbles seen in the cluster, the precession timescale, t_prec, is around 3.3x10^7 yrs. The bubbles rising up through different parts of the cluster may have interacted with the central cool gas, forming the whorl of cool gas observed in the temperature structure of the cluster. The dynamics of bubbles rising in fluids is discussed. The conditions present in the cluster are such that oscillatory motion, observed for bubbles rising in fluids on Earth, should take place. However the timescale for this motion is longer than that taken for the bubbles to evolve into spherical cap bubbles, which do not undergo a path instability, so such motion is not expected to occur.Comment: 9 pages, accepted for publication in MNRA

Crop Updates 2002 - Lupins

This session covers twenty four papers from different authors: LUPIN INDUSTRY ISSUES AND RESEARCH DIRECTIONS ACKNOWLEDGMENTS Amelia McLarty LUPIN CONVENOR DEPARTMENT OF AGRICULTURE VARIETIES 1. Evaluation of lupinus mutabilis in Western Australia, Bob French, Laurie Wahlsten and Martin Harries, Department of Agriculture 2. Adaption of restricted-branching lupins in short-growing season environments, Bob French, Laurie Wahlsten, Department of Agriculture ESTABLISHMENT 3. Moisture delving for better lupin establishment, Dr Paul Blackwell, Department of Agriculture 4. Lupins, tramlines, 600mm rows, rolling and shield spraying … a good result in a dry season! Paul Blackwell and Mike Collins, Department of Agriculture 5. Lupin wider row spacing data and observations, Bill CrabtreeA, Geoff FosberyB, Angie RoeB, Mike CollinsCand Matt BeckettA,AWANTFA, BFarm Focus Consultants and CDepartment of Agriculture NUTRITION 6. Lupin genotypes respond differently to potash, Bob French and Laurie Wahlsten, Department of Agriculture 7. Consequence of radish competition on lupin nutrients in a wheat-lupin rotation, Abul Hashem and Nerys Wilkins, Department of Agriculture 8. Consequence of ryegrass competition on lupin nutrients in a wheat-lupin rotation, Abul Hashem and Nerys Wilkins, Department of Agriculture PESTS AND DISEASES 9. Fungicide sprays for control of lupin anthracnose, Geoff Thomas and Ken Adcock, Department of Agriculture 10. Estimated yield losses in lupin varieties from sowing anthracnose infected seed, Geoff Thomas, Department of Agriculture 11. Effect of variety and environment (northern and southern wheatbelt) on yield losses in lupins due to anthracnose, Geoff Thomas and Ken Adcock, Department of Agriculture, 12. A decision support system for the control of aphids and CMV in lupin crops, Debbie Thackray, Jenny Hawkes and Roger Jones, Centre for Legumes in Mediterranean Agriculture and Department of Agriculture 13. Integrated management strategies for virus diseases of lupin, Roger Jones, Crop Improvement Institute, Department of Agriculture, and Centre for Legumes in Mediterranean Agriculture, University of WA 14. Quantifying yield losses caused by the non-necrotic strain of BYMV in lupin, Roger Jones and Brenda Coutts, Department of Agriculture, and Centre for Legumes in Mediterranean Agriculture 15. Screening for pod resistance to phomopsis in various lupin species, Manisha Shankar1, Mark Sweetingham1&2and Bevan Buirchell2 1Co-operative Research Centre for Legumes in Mediterranean Agriculture, The University of Western Australia, 2 Department of Agriculture 16. Lupin disease diagnostics, Nichole Burges and Dominie Wright, Department of Agriculture QUALITY AND MARKET DEVELOPMENT 17. To GM or not to GM pulses – that is the question, Dr Susan J. Barker, The University of Western Australia 18. Towards a management package for grain protein in lupins, Bob French, Senior Research Officer, Department of Agriculture 19. Yield and seed protein response to foliar application of N among lupin genotypes, Jairo A Palta1&2, Bob French2&3and Neil C Turner1&2 , 1 CSIRO Plant Industry, Floreat Park, 2 CLIMA, University of Western Australia,3Department of Agriculture 20. Foliar nitrogen application to improve protein content in narrow-leafed lupin, Martin Harries, Bob French, Laurie Wahlsten, Department of Agriculture, Matt Evans, CSBP 21. Effect of time of swathing of lupins on grain protein content, Martin Harries, Department of Agriculture 22. Putting a value on protein premiums for the animal feed industries: Aquaculture, Brett Glencross and John Curnow, Department of Fisheries, Wayne Hawkins, Department of Agriculture 23. Progress in selecting for reduced seed hull and pod wall in lupin, Jon C. Clements, CLIMA, University of Western Australia 24. Contact details for principal author

Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson’s disease, STEM-PD

Cell replacement therapies for Parkinson’s disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome

Climate variability of southern Chile since the Last Glacial Maximum : a continuous sedimentological record from Lago Puyehue (40°S)

Author Posting. © Springer, 2007. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Paleolimnology 39 (2008): 179-195, doi:10.1007/s10933-007-9117-y.This paper presents a multi-proxy climate record of an 11 m long core collected in Lago Puyehue (southern Chile, 40°S) and extending back to 18,000 cal yr BP. The multi-proxy analyses include sedimentology, mineralogy, grain size, geochemistry, loss-on-ignition, magnetic susceptibility and radiocarbon datings. Results demonstrate that sediment grain size is positively correlated with the biogenic sediment content and can be used as a proxy for lake paleoproductivity. On the other hand, the magnetic susceptibility signal is correlated with the aluminium and titanium concentrations and can be used as a proxy for the terrigenous supply. Temporal variations of sediment composition evidence that, since the last glacial maximum, the Chilean Lake District was characterized by 3 abrupt climate changes superimposed on a long-term climate evolution. These rapid climate changes are: (1) an abrupt warming at the end of the last glacial maximum at 17,300 cal yr BP; (2) a 13,100-12,300 cal yr BP cold event, ending rapidly and interpreted as the local counter part of the Younger Dryas cold period, and (3) a 3400-2900 cal yr BP climatic instability synchronous with a period of low solar activity. The timing of the 13,100-12,300 cold event is compared with similar records in both hemispheres and demonstrates that this southern hemisphere climate change lags behind the northern hemisphere Younger Dryas cold period by 500 to 1000 years.This research is supported by the Belgian OSTC project EV/12/10B "A continuous Holocene record of ENSO variability in southern Chile"

Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal

The canonical Wnt/β-catenin signaling pathway governs diverse developmental, homeostatic and pathologic processes. Palmitoylated Wnt ligands engage cell surface Frizzled (Fzd) receptors and Lrp5/6 co-receptors enabling β-catenin nuclear translocation and Tcf/Lef-dependent gene transactivation1–3. Mutations in Wnt downstream signaling components have revealed diverse functions presumptively attributed to Wnt ligands themselves, although direct attribution remains elusive, as complicated by redundancy between 19 mammalian Wnts and 10 Fzds1 and Wnt hydrophobicity2,3. For example, individual Wnt ligand mutations have not revealed homeostatic phenotypes in the intestinal epithelium4, an archetypal canonical Wnt pathway-dependent rapidly self-renewing tissue whose regeneration is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs)5–9. R-spondin ligands (Rspo1–4) engage distinct Lgr4-6 and Rnf43/Znrf3 receptor classes10–13, markedly potentiate canonical Wnt/β-catenin signaling and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo8,14–17. However, the interchangeability, functional cooperation and relative contributions of Wnt versus Rspo ligands to in vivo canonical Wnt signaling and ISC biology remain unknown. Here, we deconstructed functional roles of Wnt versus Rspo ligands in the intestinal crypt stem cell niche. We demonstrate that the default fate of Lgr5+ ISCs is lineage commitment, escape from which requires both Rspo and Wnt ligands. However, gain-of-function studies using Rspo versus a novel non-lipidated Wnt analog reveal qualitatively distinct, non-interchangeable roles for these ligands in ISCs. Wnts are insufficient to induce Lgr5+ ISC self-renewal, but rather confer a basal competency by maintaining Rspo receptor expression that enables Rspo to actively drive and specify the extent of stem cell expansion. This functionally non-equivalent yet cooperative interplay between Wnt and Rspo ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precision control of tissue regeneration