Fiber absorption measurement errors resulting from re-emission of radiation

We show that errors in the absorption measured in rare-earth-doped fibers can exceed 50% and severely distort the spectral shape. This is a result of re-emission in fibers with overlapping absorption and emission spectra

Infection-generated electric field in gut epithelium drives bidirectional migration of macrophages.

Many bacterial pathogens hijack macrophages to egress from the port of entry to the lymphatic drainage and/or bloodstream, causing dissemination of life-threatening infections. However, the underlying mechanisms are not well understood. Here, we report that Salmonella infection generates directional electric fields (EFs) in the follicle-associated epithelium of mouse cecum. In vitro application of an EF, mimicking the infection-generated electric field (IGEF), induces directional migration of primary mouse macrophages to the anode, which is reversed to the cathode upon Salmonella infection. This infection-dependent directional switch is independent of the Salmonella pathogenicity island 1 (SPI-1) type III secretion system. The switch is accompanied by a reduction of sialic acids on glycosylated surface components during phagocytosis of bacteria, which is absent in macrophages challenged by microspheres. Moreover, enzymatic cleavage of terminally exposed sialic acids reduces macrophage surface negativity and severely impairs directional migration of macrophages in response to an EF. Based on these findings, we propose that macrophages are attracted to the site of infection by a combination of chemotaxis and galvanotaxis; after phagocytosis of bacteria, surface electrical properties of the macrophage change, and galvanotaxis directs the cells away from the site of infection

Frequency and Outcomes of Abnormal Imaging in Patients With Cirrhosis Enrolled in a Hepatocellular Carcinoma Surveillance Program

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148235/1/lt25398_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148235/2/lt25398.pd

A novel auxiliary subunit critical to BK channel function in caenorhabditis elegans

The BK channel is a Ca(2+)- and voltage-gated potassium channel with many important physiological functions. To identify proteins important to its function in vivo, we screened for C. elegans mutants that suppressed a lethargic phenotype caused by expressing a gain-of-function (gf) isoform of the BK channel α-subunit SLO-1. BKIP-1, a small peptide with no significant homology to any previously characterized molecules was thus identified. BKIP-1 and SLO-1 showed similar expression and subcellular localization patterns, and appeared to interact physically through discrete domains. bkip-1 loss-of-function (lf) mutants phenocopied slo-1(lf) mutants in behavior and synaptic transmission, and suppressed the lethargy, egg-laying defect, and deficient neurotransmitter release caused by SLO-1(gf). In heterologous expression systems, BKIP-1 decreased the activation rate and shifted the conductance-voltage (G-V) relationship of SLO-1 in a Ca(2+)-dependent manner, and increased SLO-1 surface expression. Thus, BKIP-1 is a novel auxiliary subunit critical to SLO-1 function in vivo

Immunological Conversion of Solid Tumours Using a Bispecific Nanobioconjugate for Cancer Immunotherapy

Solid tumours display a limited response to immunotherapies. By contrast, haematological malignancies exhibit significantly higher response rates to immunotherapies as compared with solid tumours. Among several microenvironmental and biological disparities, the differential expression of unique immune regulatory molecules contributes significantly to the interaction of blood cancer cells with immune cells. The self-ligand receptor of the signalling lymphocytic activation molecule family member 7 (SLAMF7), a molecule that is critical in promoting the body\u27s innate immune cells to detect and engulf cancer cells, is expressed nearly exclusively on the cell surface of haematologic tumours, but not on solid ones. Here we show that a bispecific nanobioconjugate that enables the decoration of SLAMF7 on the surface of solid tumours induces robust phagocytosis and activates the phagocyte cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, sensitizing the tumours to immune checkpoint blockade. Our findings support an immunological conversion strategy that uses nano-adjuvants to improve the effectiveness of immunotherapies for solid tumours

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR V beta sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses

Comparison of heavy-ion transport simulations: Collision integral with pions and Δ resonances in a box

We compare ten transport codes for a system confined in a box, aiming at improved handling of the production of $\Delta$ resonances and pions, which is indispensable for constraining high-density symmetry energy from observables such as the $\pi^-/\pi^+$ yield ratio in heavy-ion collisions. The system in a box is initialized with nucleons at saturation density and at 60 MeV temperature. The reactions $NN\leftrightarrow N\Delta$ and $\Delta\leftrightarrow N\pi$ are implemented, but the Pauli blocking and the mean-field potential are deactivated in the present comparison. Results are compared to those from the two reference cases of a chemically equilibrated ideal gas mixture and of the rate equation. In the results of the numbers of $\Delta$ and $\pi$, deviations from the reference values are observed in many codes, and they depend significantly on the size of the time step. These deviations are tied to different ways in ordering the sequence of collisions and decays, that take place in the same time step. Better agreements are seen in the reaction rates and the number ratios among the isospin species of $\Delta$ and $\pi$. These are, however, affected by the correlations, which are absent in the Boltzmann equation, but are induced by the way particle scatterings are treated in transport calculations. The uncertainty in the transport-code predictions of the $\pi^-/\pi^+$ ratio for the system initialized at n/p = 1.5, after letting the existing $\Delta$ resonances decay, is found to be within a few percent, which is sufficiently small so that it does not strongly impact constraining the high-density symmetry energy from heavy-ion collisions. Most of the sources of uncertainties have been understood, and individual codes may be further improved. This investigation will be extended in the future to heavy-ion collisions to ensure the problems identified here remain under control.Comment: 36 pages, 27 figures; a new Fig. 21 and revised results from some codes, achieving improved and consistent understandin

Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling

SummaryMany signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming

Adaptive Design of mRNA-Loaded Extracellular Vesicles for Targeted Immunotherapy of Cancer

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications