Belle II grid-based user analysis Bennett, J V; Guilliams, J; M Hernandez Villanueva ...
arXiv (Cornell University),
03/2022
Paper, Journal Article
Open access
The Belle II experiment at the SuperKEKB accelerator is a next-generation B-factory aiming to collect 50 ab\(^{-1}\), about 50 times the data collected at Belle, to study rare processes and make ...precision measurements that may expose physics beyond the Standard Model. Corresponding to roughly 100 PB of storage for raw data, plus dozens of PBs per year for Monte Carlo (MC) and analysis data, these massive samples require careful planning for the storage, processing, and analysis of data. This white paper notes some of the challenges that await grid-based user-analysis at the intensity frontier and invites further discussion and exploration to improve the tools and techniques necessary to leverage the massive data samples that will be available at Belle II as part of the Snowmass process.
Upgrading the SuperKEKB electron-positron collider with polarized electron beams opens a new program of precision physics at a center-of-mass energy of 10.58 GeV. This white paper describes the ...physics potential of this `Chiral Belle' program. It includes projections for precision measurements of \(\sin^2\theta_W\) that can be obtained from independent left-right asymmetry measurements of \(e^+e^-\) transitions to pairs of electrons, muons, taus, charm and b-quarks. The \(\sin^2\theta_W\) precision obtainable at SuperKEKB will match that of the LEP/SLC world average, but at the centre-of-mass energy of 10.58 GeV. Measurements of the couplings for muons, charm, and \(b\)-quarks will be substantially improved and the existing \(3\sigma\) discrepancy between the SLC \(A_{LR}\) and LEP \(A_{FB}^b\) measurements will be addressed. Precision measurements of neutral current universality will be more than an order of magnitude more precise than currently available. As the energy scale is well away from the \(Z^0\)-pole, the precision measurements will have sensitivity to the presence of a parity-violating dark sector gauge boson, \(Z_{\rm dark}\). The program also enables the measurement of the anomalous magnetic moment \(g-2\) form factor of the \(\tau\) to be made at an unprecedented level of precision. A precision of \(10^{-5}\) level is accessible with 40~ab\(^{-1}\) and with more data it would start to approach the \(10^{-6}\) level. This technique would provide the most precise information from the third generation about potential new physics explanations of the muon \(g-2\) \(4\sigma\) anomaly. Additional \(\tau\) and QCD physics programs enabled or enhanced with having polarized electron beams are also discussed in this White Paper. This paper includes a summary of the path forward in R&D and next steps required to implement this upgrade and access its exciting discovery potential.
Belle II Executive Summary Asner, D M; Atmacan, H; Banerjee, Sw ...
arXiv (Cornell University),
03/2022
Paper, Journal Article
Open access
Belle II is a Super \(B\) Factory experiment, expected to record 50 ab\(^{-1}\) of \(e^+e^-\) collisions at the SuperKEKB accelerator over the next decade. The large samples of \(B\) mesons, charm ...hadrons, and tau leptons produced in the clean experimental environment of \(e^+e^-\) collisions will provide the basis of a broad and unique flavor-physics program. Belle II will pursue physics beyond the Standard Model in many ways, for example: improving the precision of weak interaction parameters, particularly Cabibbo-Kobayashi-Maskawa (CKM) matrix elements and phases, and thus more rigorously test the CKM paradigm, measuring lepton-flavor-violating parameters, and performing unique searches for missing-mass dark matter events. Many key measurements will be made with world-leading precision.
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is ...under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
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•Type I interferon drives differentiation of inf-cDC2s that closely resemble MCs•Inf-cDC2s prime CD4+ and CD8+ T cells, whereas MCs lack APC function•Inf-cDC2s internalize antibody-complexed antigen via Fc receptors•IRF8 controls maturation gene module in inf-cDC2s
The dichotomy between type 1 and 2 conventional DCs under steady-state conditions is well defined. Bosteels et al. demonstrate that, upon inflammation, cDC2s acquire a hybrid inf-cDC2 phenotype, sharing phenotype, gene expression, and function with cDC1s and monocyte-derived cells, to optimally boost CD4 and CD8 immunity via Fc receptors.
The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining ...single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.
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•Spatial proteogenomic single-cell atlas of healthy and obese murine and human liver•Validated flow cytometry and microscopy panels for all hepatic cells•LAMs are differentially located in the lean and obese liver•Evolutionary conserved BMP9/10-ALK1 axis is essential for KC development
By combining single-cell and -nucleus sequencing with spatial mapping of RNA and proteins, this vast spatial proteogenomic atlas of healthy and obese human and mouse livers presents methods to identify and localize all hepatic cells and provides insights into hepatic myeloid cells, including identification of reliable surface markers for isolation and localization of hepatic macrophages, characterization of lipid-associated macrophages in both healthy and steatotic livers, determination of a key regulatory axis of Kupffer cell development, and identification of a conserved core gene expression signature of Kupffer cells across 7 species, including chickens and zebrafish.
Cloneable inorganic nanoparticles Hendricks, Alexander R; Guilliams, Bradley F; Cohen, Rachel S ...
Chemical communications (Cambridge, England),
07/2023, Volume:
59, Issue:
56
Journal Article
Peer reviewed
Open access
When a defined protein/peptide (or combinations thereof) control and define the synthesis of an inorganic nanoparticle, the result is a cloneable NanoParticle (cNP). This is because the protein ...sequence/structure/function is encoded in DNA, and therefore the physicochemical properties of the nanoparticle are also encoded in DNA. Thus the cloneable nanoparticle paradigm can be considered as an extension of the central dogma of molecular biology (
DNA → mRNA → protein → cNP); modifications to the DNA encoding a cNP can modify the resulting properties of the cNP. Inorganic ion oxidoreductases (
, mercuric reductase, tellurite reductase,
) can select and reduce specific inorganic oxyanions and coordination complexes, creating zerovalent precipitates. Other proteins/peptides (often genetically concatenated to the parent oxidoreductase) serve as ligands, directing the size, shape, crystal structure and other properties of the nanoparticle. The DNA encoding a cNP can be recombinantly transferred into any organism. Ideally, this enables recombinant production of cNPs with the same defined physiochemical properties. Such cNPs are of interest for applications ranging from molecular imaging, bio-remediation, catalysis, and biomining. In this Feature Article we detail and define the cNP concept, and retrace the story of our creation of a cloneable Se NanoParticle (cSeNP). We also describe our more preliminary work that we expect to result in cloneable semiconductor quantum dots, cloneable Te nanoparticles, and other cNP formulations. We highlight the application of cNPs in cellular electron microscopy and compare this approach to other cloneable imaging contrast approaches.
Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are ...controversial. Here we show resident F4/80(hi)GATA6(+) macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C(+) monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80(lo)MHCII(+) cells that act, in part, as precursors of F4/80(hi)GATA6(+) macrophages. Notably, monocyte-derived F4/80(hi) macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.
Significance Certain oligomeric species generated during the self-assembly of specific proteins into ordered fibrillar aggregates are likely to be key players in the initiation and spreading of ...neurodegenerative diseases. We have purified stable toxic oligomeric species of α-synuclein and defined and minimized their degree of heterogeneity, which has allowed us to identify distinct subgroups of oligomers and determine their structural properties and three-dimensional molecular architectures. All the oligomeric subgroups possess approximately cylindrical architectures with marked similarities to amyloid fibrils, suggesting that these types of oligomers are kinetically trapped during protein self-assembly. The relative stabilities and inherent pathological roles of different amyloid oligomers are likely to result from the multiplicity of pathways of the misfolding process and the remarkably slow rates of structural conversions.
We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of β-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their β-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the β-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species.
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