Despite the success of antiretroviral therapy (ART) to halt viral replication and slow disease progression, this treatment is not curative and there remains an urgent need to develop approaches to ...clear the latent HIV reservoir. The human IL-15 superagonist N-803 (formerly ALT-803) is a promising anti-cancer biologic with potent immunostimulatory properties that has been extended into the field of HIV as a potential "shock and kill" therapeutic for HIV cure. However, the ability of N-803 to reactivate latent virus and modulate anti-viral immunity in vivo under the cover of ART remains undefined. Here, we show that in ART-suppressed, simian-human immunodeficiency virus (SHIV)SF162P3-infected rhesus macaques, subcutaneous administration of N-803 activates and mobilizes both NK cells and SHIV-specific CD8+ T cells from the peripheral blood to lymph node B cell follicles, a sanctuary site for latent virus that normally excludes such effector cells. We observed minimal activation of memory CD4+ T cells and no increase in viral RNA content in lymph node resident CD4+ T cells post N-803 administration. Accordingly, we found no difference in the number or magnitude of plasma viremia timepoints between treated and untreated animals during the N-803 administration period, and no difference in the size of the viral DNA cell-associated reservoir post N-803 treatment. These results substantiate N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle during full ART suppression, and suggest N-803 must be paired with a bona fide latency reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir.
This paper examines the use of racial categories within the tabletop roleplaying game 'Dungeon's and Dragons' through the lens of racecraft as outlined by Karen and Barbara Fields. Examining D&D as ...an imaginary, I explore how its mechanics and fiction create categories of race through a process of profiling that produces sumptuary codes, perpetuates a racial hierarchy, invokes racialized accounts of biology, and constitutes a racialized gaze. Through stressing the continuity of this fictional account of race with real world racecraft, I analyze how the fiction of D&D fails to imagine beyond the condition of race. This fiction thereby operates as a mirror that reflects back to us the difficulties of thinking beyond such racial logics, reaffirming the need for continued critique and a reimagining of race.
The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including ...plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.
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•Distinct development trajectories of DC2 and DC3 underpin human cDC2 heterogeneity•pDC, cDC1, and DC2 (classical DCs) develop from LMPPs along a CD123+ IRF8high pathway•DC3 and monocytes develop from CD33+ GMPs along an IRF8low SIRPA+ pathway•IRF8 deficiency causes gene dose-dependent loss of IRF8high then IRF8low pathway DCs
Heterogeneity of human CD1c+ dendritic cells (cDC2s) is described, but how this arises is unknown. Cytlak and colleagues demonstrate that the cDC2 subsets, DC2 and DC3, develop along distinct hematopoietic trajectories, defined by differential IRF8 expression. DC2s develop from LMPPs along an IRF8hi pathway, while DC3 differentiation follows an IRF8low trajectory.
Herein we describe the use of dynamic combinatorial chemistry to self-assemble complex coiled coil motifs. We amide-coupled a series of peptides designed to form homodimeric coiled coils with ...3,5-dithiobenzoic acid (
B
) at the N-terminus and then allowed each
B
-peptide to undergo disulfide exchange. In the absence of peptide, monomer
B
forms cyclic trimers and tetramers, and thus we expected that addition of the peptide to monomer
B
would shift the equilibrium towards the tetramer to maximize coiled coil formation. Unexpectedly, we found that internal templation of the
B
-peptide through coiled coil formation shifts the equilibrium towards larger macrocycles up to 13
B
-peptide subunits, with a preference for 4, 7, and 10-membered macrocycles. These macrocyclic assemblies display greater helicity and thermal stability relative to intermolecular coiled coil homodimer controls. The preference for large macrocycles is driven by the strength of the coiled coil, as increasing the coiled coil affinity increases the fraction of larger macrocycles. This system represents a new approach towards the development of complex peptide and protein assemblies.
Combining two different driving forces in a dynamic combinatorial library - alpha-helical coiled coil dimer formation and covalent trimer and tetramer formation - leads to unexpected assembly of macrocycles up to 13 subunits.
When people use the phrase “personal relationship with Jesus,” how does one explain its significance? Normally attributed to evangelical Protestant Christians, use of the phrase “personal ...relationship with Jesus” is a complicated phenomenon, and an explanation of it requires drawing upon resources from across multiple disciplines rather than a single discipline only. Attempts to explain exactly what the phrase “personal relationship with Jesus” means frequently can be mystifying, on the one hand, or dismissive and simplistic, on the other hand. This article moves potentially toward a better context for understanding use of the phrase “personal relationship with Jesus” by drawing upon insights from multiple disciplines, including (1) rhetorical and cultural‐historical studies, (2) evolutionary and cognitive psychology, and (3) biological/behavioral and social/anthropological studies in order to set forth some basic lines of explanation for use of the phrase “personal relationship with Jesus.” The article concludes with some possible testable statements for future empirical studies.
The objective of this study was to evaluate the viability and performance of nitric oxide modified-atmosphere packaging (MAP) as a novel alternative to high oxygen and carbon monoxide MAP for ground ...beef. Packages of ground beef under high oxygen (HI-OX), carbon monoxide (CO), and nitric oxide (NO) atmospheres were evaluated for descriptive and instrumental color every 12 h during a 120 h display period. Surface myoglobin percentages, internal cooked color, thiobarbituric acid reactive substances (TBARS), and residual nitrite and nitrate were also evaluated. There were gas × time interactions for descriptive color, discoloration, a* values, b* values, deoxymyoglobin percentages, and metmyoglobin percentages (
< 0.05). There were also gas-type main effects for cooked color and TBARS (
< 0.05). Carbon monoxide maintained the most redness and least discoloration throughout the display period, while HI-OX started with a bright red color but rapidly browned (
< 0.05). Nitric oxide started as dark red to tannish-red but transitioned to a dull red (
< 0.05). However, NO had increased redness and a* values for internal cooked color (
< 0.05). Although CO outperformed NO packages, NO exhibited a unique color cycle warranting further research to optimize its use.
In Death in Documentaries: The Memento Mori Experience, Benjamin Bennett-Carpenter suggests that documentaries are an especially apt form of contemporary memento mori; that is, documentaries offer ...transformative experiences for a viewer to renew one's consciousness of mortality.
Clavicular fractures are common injuries that traditionally are managed nonsurgically without clinically significant sequelae. However, they may develop hypertrophic callus formation that compresses ...the brachial plexus. These cases may present months to years after initial injury with varying degrees of pain, paresthesia, and weakness on the affected side and usually are treated by surgical resection of the hypertrophic callus. We present a case of brachial plexopathy due to hypertrophic clavicular callus causing weakness and paresthesia. The plexopathy was confirmed with imaging and electrodiagnostic studies. This case was unusual in that resolution of symptoms was achieved nonsurgically.
Level of Evidence
V
Abstract Background Immunotherapy has demonstrated exciting curative potential in the treatment of lymphoid malignancies, but cancer cells have developed a variety of immune evasion mechanisms ...requiring targeted strategies. CXCR4 is a G-protein coupled receptor with crucial roles in homing, maintenance, and proliferation of a wide range of haematological cancers. We hypothesised that overexpression of CXCR4 in CD8 T cells (T-CXCR4) would improve homing to CXCL12-rich niches such as bone marrow, enhancing tumour killing. Methods We transduced murine CD8 T cells with a retroviral vector encoding either the Cxcr4 gene coupled to a GFP marker or a separate inducible vector encoding Cxcr4 and GFP under control of the Tet-On system. For allogeneic bone-marrow transplants, irradiated BALB/c recipient mice received intravenous B6 donor bone marrow and subcutaneous A20 lymphoma cells on day 0, and B6 T-CXCR4 or control T cells on day 2. For in-vivo imaging of T-cell accumulation, anaesthetised mice received luciferase-positive transduced T cells and luciferin. Transgenic OT-1 CD8 T cells expressing T-cell receptors specific for the SIINFEKL peptide were used in vaccination experiments. Findings In an allogeneic B-cell lymphoma model, T-CXCR4 were significantly better than control T cells at tumour control (p<0·0001, n=5 per group). In-vivo imaging did not demonstrate greater T-CXCR4 accumulation at the tumour site, suggesting superior per-cell function. In a vaccination model, OT-1 T-CXCR4 demonstrated substantially enhanced long-term persistence in bone marrow and spleen compared with control T cells (bone-marrow ratio 34 to 1, spleen 11 to 1; p<0·0001). T-CXCR4 express a distinctive CD62LHI CD122HI BCL2HI early memory phenotype post recall vaccination with increased effector cytokine production. This enhanced T-stem memory marker expression was not observed after in-vitro CXCL12 exposure and was specifically lost upon transfer to mice lacking interleukin 15 receptor α. Interpretation Coupled with gene expression data, these results suggest that heightened antitumour efficacy is mediated by successful homing and competition for cell-extrinsic niche-related factors, in particular interleukin 15 presentation by CXCL12-abundant reticular cells. Preferential generation of enhanced early memory T cells with therapeutic superiority to effector-type cells currently used in investigational protocols has great relevance for the design of next-generation immunotherapies. Funding Bloodwise.
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