Sensitization of tumour cells to lysis by virus-specific CTL using antibody-targeted MHC class I/peptide complexes

A number of cell surface molecules with specificity to tumour cells have been identified and monoclonal antibodies (mAb) to some of these antigens have been used for targeting tumour cells in vivo. We have sought to link the powerful effector mechanisms of cytotoxic T-cells with the specificity of mAb, by targeting recombinant HLA class I molecules to tumour cells using an antibody delivery system. Soluble recombinant MHC class I/peptide complexes including HLA-A2.1 refolded around an immunodominant peptide from the HIV gag protein (HLA-A2/gag) were synthesized, and the stability of these complexes at 37°C was confirmed by enzyme-linked immunosorbent assay using a conformation-specific antibody. MHC class I-negative lymphoma cells (Daudi) were labelled with a biotinylated mAb specific for a cell surface protein (anti-CD20) then linked to soluble biotinylated HLA-A2/gag complexes using an avidin bridge. Flow cytometry revealed strong labelling of lymphoma cells with HLA-A2/gag complexes (80-fold increase in mean channel fluorescence). CTL specific for HLA-A2/gag efficiently lysed complex-targeted cells, while control CTL (specific for an HLA-A2.1-restricted epitope of melan-A) did not. Similarly, SK-mel-29 melanoma cells were also efficiently lysed by HLA-A2/gag-specific CTL when HLA-A2/gag complexes were linked to their surface via the HMW-MAA specific anti-melanoma antibody 225.28s. With further consideration to the in vivo stability of the MHC class I/peptide complexes, this system could prove a new strategy for the immunological therapy of cancer. © 2000 Cancer Research Campaig

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Severe lung damage in COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways and genes present across the spectrum of histopathological damage in COVID-19 lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from areas of interest within well preserved post-mortem lung samples from three patients. Despite substantial inter-patient heterogeneity we discovered evidence for a common immune cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines including CXCL9, CXCL10 and CXCL11 which are known to promote the recruitment of CXCR3+ immune cells. The tumour necrosis factor (TNF) superfamily members BAFF ( TNFSF13B ) and TRAIL ( TNFSF10 ) were found to be consistently upregulated in the areas with severe tissue damage. We used published spatial and single cell SARS-CoV-2 datasets to confirm our findings in the lung tissue from additional cohorts of COVID-19 patients. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies. One Sentence Summary Spatial analysis identifies IFNγ response signatures as focal to severe alveolar damage in COVID-19 pneumonitis

Magnetic-field dependence of electron spin relaxation in n-type semiconductors

We present a theoretical investigation of the magnetic field dependence of the longitudinal ($T_1$) and transverse ($T_2$) spin relaxation times of conduction band electrons in n-type III-V semiconductors. In particular, we find that the interplay between the Dyakonov-Perel process and an additional spin relaxation channel, which originates from the electron wave vector dependence of the electron $g$-factor, yields a maximal $T_2$ at a finite magnetic field. We compare our results with existing experimental data on n-type GaAs and make specific additional predictions for the magnetic field dependence of electron spin lifetimes.Comment: accepted for publication in PRB, minor changes to previous manuscrip

Metallic Xenon, Molecular Condensates, and Superconductivity

A possibility of explaining the light absorption observed to occur under pressure-induced xenon metallization as due to the transition to the superconducting state is analyzed. The mechanism of the van der Waals bonding is discussed.Comment: LaTeX 2.09 (RevTeX), 4 pages, 4 PostScript figures included in tex

Elliptic Curves over Real Quadratic Fields are Modular

We prove that all elliptic curves defined over real quadratic fields are modular.Comment: 38 pages. Magma scripts available as ancillary files with this arXiv versio

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties

Measurement of the Bˉ→Dℓνˉ\bar{B}\to D\ell\bar{\nu} Partila Width and Form Factor Parameters

We have studied the decay $\bar{B} \to D\ell\bar{\nu}$, where $\ell=e or \mu$. From a fit to the differential decay rate $d\Gamma/dw$ we measure the rate normalization ${\cal F}_D(1)|V_{cb}|$ and form factor slope $\hat{\rho}^2_D$, and, using measured values of $\tau_B$, find $\Gamma(\bar{B} \to D\ell\bar{\nu}) = (12.0 \pm 0.9 \pm 2.1) ns^{-1}$. The resulting branching fractions are ${\cal B}(\bar{B}^0 \to D^+\ell^-\bar{\nu})=(1.87 \pm 0.15 \pm 0.32)$ and ${\cal B}(B^- \to D^0\ell^-\bar{\nu})=(1.94 \pm 0.15 \pm 0.34)$. The form factor parameters are in agreement with those measured in $\bar{B} \to D^*\ell\bar{\nu}$ decays, as predicted by heavy quark effective theory.Comment: 11 pages, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Flavor-Specific Inclusive B Decays to Charm

We have measured the branching fractions for B -> D_bar X, B -> D X, and B -> D_bar X \ell^+ \nu, where ``B'' is an average over B^0 and B^+, ``D'' is a sum over D^0 and D^+, and``D_bar'' is a sum over D^0_bar and D^-. From these results and some previously measured branching fractions, we obtain Br(b -> c c_bar s) = (21.9 $\pm$ 3.7)%, Br(b -> s g) K^- \pi^+) = (3.69 $\pm$ 0.20)%. Implications for the ``B semileptonic decay problem'' (measured branching fraction being below theoretical expectations) are discussed. The increase in the value of Br(b -> c c_bar s) due to $B -> D X$ eliminates 40% of the discrepancy.Comment: 12 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

A Measurement of the Decay Asymmetry Parameters in \Xi_{c}^{0}\to \X^{-}\pi^{+}

Using the CLEO II detector at the Cornell Electron Storage Ring we have measured the $\Xi_c^{0}$ decay asymmetry parameter in the decay $\Xi_c^{0} \to \Xi^{-} \pi^+$. We find $\alpha_{\Xi_c^{0}} \alpha_{\Xi} = 0.26 \pm 0.18{(stat)}^{+0.05}_{-0.04}{(syst)}$, using the world average value of $\alpha_{\Xi} = -0.456 \pm 0.014$ we obtain $\alpha_{\Xi_c^{0}} = -0.56 \pm 0.39{(stat)}^{+0.10}_{-0.09}{(syst)}$. The physically allowed range of a decay asymmetry parameter is $-1<\alpha<+1$. Our result prefers a negative value: $\alpha_{\Xi_c^{0}}$ is $<0.1$ at the 90% CL. The central value occupies the middle of the theoretically expected range but is not yet precise enough to choose between models.Comment: 10 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN