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Abstract: Human immunodeficiency virus type 1 (HIV-1) canarypox vaccines are safe but poorly immunogenic. CD40 ligand (CD40L), a member of the tumor necrosis factor superfamily (TNFSF), is a pivotal costimulatory molecule for immune responses. To explore whether CD40L can be used as an adjuvant for HIV-1 canarypox vaccine, we constructed recombinant canarypox viruses expressing CD40L. Co-immunization of mice with CD40L expressing canarypox and the canarypox vaccine expressing HIV-1 proteins, vCP1452, augmented HIV-1 specific cytotoxic T lymphocyte (CTL) responses in terms of frequency, polyfunctionality and interleukin (IL)-7 receptor α chain (IL-7Rα, CD127) expression. In addition, CD40L expressed from canarypox virus could significantly augment CD4+ T cell responses against HIV-1 in mice. CD40L expressed from canarypox virus matured human monocyte-derived dendritic cells (MDDCs) in a tumor necrosis factor-α (TNF-α) independent manner, which underwent less apoptosis, and could expand ex vivo Epstein–Barr virus (EBV)-specific CTL responses from healthy human individuals and ex vivo HIV-1-specific CTL responses from HIV-1-infected individuals in the presence or absence of CD4+ T cells. Taken together, our results suggest that CD40L incorporation into poxvirus vectors could be used as a strategy to enhance their immunogenicity. [Copyright &y& Elsevier]

The intermediate polar FO Aquarii (FO Aqr) experienced its first reported low-accretion states in 2016, 2017, and 2018, and, using newly available photographic plates, we identify prediscovery low states in 1965, 1966, and 1974. The primary focus of our analysis, however, is an extensive set of time-series photometry obtained between 2002 and 2018, with particularly intensive coverage of the 2016–2018 low states. After computing an updated spin ephemeris for the white dwarf (WD), we show that its spin period began to increase in 2014 after having spent 27 yr decreasing; no other intermediate polar has experienced a sign change of its period derivative, but FO Aqr has now done so twice. Our central finding is that the recent low states all occurred shortly after the WD began to spin down, even though no low states were reported in the preceding quarter-century, when it was spinning up. Additionally, the system's mode of accretion is extremely sensitive to the mass-transfer rate, with accretion being almost exclusively disk-fed when FO Aqr is brighter than V ∼ 14 and substantially stream-fed when it is not. Even in the low states, a grazing eclipse remains detectable, confirming the presence of a disklike structure (but not necessarily a Keplerian accretion disk). We relate these various observations to theoretical predictions that during the low state, the system's accretion disk dissipates into a non-Keplerian ring of diamagnetic blobs. Finally, a new XMM-Newton observation from a high state in 2017 reveals an anomalously soft X-ray spectrum and diminished X-ray luminosity compared to pre-2016 observations. [ABSTRACT FROM AUTHOR]

Highlights • Light curves of the dwarf nova AT Cnc during two standstills are analyzed. • For the first time orbital variations are detected permitting to refine the period. • A hitherto unobserved coherent variation with a period of 27.6 min is detected. • The 27.6 min variation indicates an intermediate polar nature of AT Cnc. Abstract Light curves of the Z Cam type dwarf nova AT Cnc observed during standstill in 2016 and 2018 are analyzed. On the time scale of hours, previous reports on periodicities, in particular the presence of negative superhumps, could not be confirmed. Instead, a modulation with a period equal to the spectroscopic orbital period was detected which we thus interpret as a manifestations of the binary revolution. It enables us to derive a more accurate value of 0.201634 ± 0.000005 days (or its alias of 0.021580 days) for the period. AT Cnc also exhibits a hitherto unreported modulation of 25.731 ± 0.005 min, stable in period but not in amplitude over the entire time base of two years of the observations. We tentatively interpret this modulation in the context of an intermediate polar model for the system. [ABSTRACT FROM AUTHOR]

An obituary for attorney and former white house counsel, Abner J. Mikva is presented.

Vaccination with tumor-associated antigens can induce cancer-specific CD8+ T cells. A recent improvement has been the targeting of antigen to dendritic cells (DC) using antibodies that bind DC surface molecules. This study explored the use of multi-trimers of CD40L to target the gp100 melanoma tumor antigen to DC. The spontaneously-multimerizing gene Surfactant Protein D (SPD) was used to fuse gp100 tumor antigen and CD40L, creating the recombinant protein SPD-gp100-CD40L. This “third generation” DC-targeting vaccine was designed to both target antigen to DC and optimally activate dendritic cells by aggregating CD40 trimers on the DC membrane surface. SPD-gp100-CD40L expressed as a 110 kDa protein. Analytical light scattering analysis gave elution data corresponding to 4-trimer and multi-trimer SPD-gp100-CD40L oligomers. The protein was biologically active on dendritic cells and induced CD40-mediated NF-κB signaling. DNA vaccination with SPD-gp100-CD40L plasmid, together with plasmids encoding IL-12p70 and GM-CSF, significantly enhanced survival and inhibited tumor growth in a B16-F10 melanoma model. Expression of gp100 and SPD-CD40L as separate molecules did not enhance survival, highlighting the requirement to encode gp100 within SPD-CD40L for optimal vaccine activity. These data support a model where DNA vaccination with SPD-gp100-CD40L targets gp100 to DC in situ, induces activation of these DC, and generates a protective anti-tumor response when given in combination with IL-12p70 and GM-CSF plasmids. [ABSTRACT FROM AUTHOR]

CD40 ligand (CD40L, CD154) is a membrane protein that is important for the activation of dendritic cells (DCs) and DC-induced CD8+ T cell responses. To be active, CD40L must cluster CD40 receptors on responding cells. To produce a soluble form of CD40L that clusters CD40 receptors necessitates the use of a multitrimer construct. With this in mind, a tripartite fusion protein was made from surfactant protein D (SPD), HIV-1 Gag as a test antigen, and CD40L, where SPD serves as a scaffold for the multitrimer protein complex. This SPD-Gag-CD40L protein activated CD40-bearing cells and bone marrow-derived DCs in vitro. Compared to a plasmid for Gag antigen alone (pGag), DNA vaccination of mice with pSPD-Gag-CD40L induced an increased number of Gag-specific CD8+ T cells with increased avidity for major histocompatibility complex class I-restricted Gag peptide and improved vaccine-induced protection from challenge by vaccinia-Gag virus. The importance of the multitrimeric nature of the complex was shown using a plasmid lacking the N terminus of SPD that produced a single trimer fusion protein. This plasmid, pTrimer-Gag-CD40L, was only weakly active on CD40-bearing cells and did not elicit strong CD8+ T cell responses or improve protection from vaccinia-Gag challenge. An adenovirus 5 (Ad5) vaccine incorporating SPD-Gag-CD40L was much stronger than Ad5 expressing Gag alone (Ad5-Gag) and induced complete protection (i.e., sterilizing immunity) from vaccinia- Gag challenge. Overall, these results show the potential of a new vaccine design in which antigen is introduced into a construct that expresses a multitrimer soluble form of CD40L, leading to strongly protective CD8+ T cell responses. [ABSTRACT FROM AUTHOR]

The article presents an obituary for David P. Currie, former professor at the University of Chicago, is presented.

The article presents a letter dated February 2, 2006 from scholars and former government officials to Congressional leadership in response to the U.S. Justice Department Whitepaper dated January 19, 2006. The letter highlights the National Security Agency spying program of the Justice Department.

The article presents a letter dated January 9, 2006 from scholars and former government officials to Congressional leadership in response to the December 22, 2005 U.S. Justice Department letter. The regulations of the Foreign Intelligence Surveillance Act (FISA) are described. The letter asserts mentions the acknowledgment by the Justice Department that the National Security Agency program was not authorized by any of the FISA provisions.

Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment., (©2024 American Association for Cancer Research.)

Purpose: To determine whether the critical shoulder angle (CSA) in acute, traumatic rotator cuff tears (RCTs) is consistent with the previously described CSA in chronic degenerative RCTs., Methods: We performed a multicenter retrospective analysis of 134 patients presenting to 5 surgeons fellowship trained in shoulder and elbow or sports. Preoperative imaging was used to measure the CSA and tear characteristics. Patients were included if they had acute, traumatic full-thickness RCTs documented on advanced imaging and had preoperative Grashey radiographs. Patients were excluded if they had any history of shoulder pain, injury, surgery, or treatment prior to the current episode; were overhead athletes; or had fatty infiltration greater than Goutallier grade 1 on imaging., Results: The mean CSA was 33.5° (standard deviation, 4.1°), and 60% of tears had a CSA of less than 35°, much below the mean of 38.0° and the threshold of greater than 35° in degenerative RCTs. The mean age was 58 years, and 70% of patients were men. Overall, 60% of tears involved the subscapularis, 49% of tears occurred in patients aged 60 years or older, and 18% of patients sustained a dislocation. Older age (β = 0.316, P = .003) and male sex (β = 5.532, P = .025) were predictive of tear size, and older age (β = 0.229, P = .011) and biceps avulsion (β = 8.822, P = .012) were predictive of tear retraction., Conclusions: Acute, traumatic RCTs have CSAs that are 5° smaller than those of degenerative tears, and the majority (60%) have CSAs that are below the threshold consistent with degenerative RCTs. The majority of traumatic tears (60%) involve the subscapularis., Clinical Relevance: The study findings suggest that a traumatic tear is not simply the acute failure of a degenerative tendon and that it represents a distinct pathologic entity. These findings support current practice of treating traumatic RCTs differently than degenerative RCTs., (Copyright © 2022 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

HIV infection is characterized by chronic immune activation and the establishment of a pool of latently infected cells. Antiretroviral therapy (ART) can suppress viral load to undetectable levels in peripheral blood by standard measure, however immune activation/chronic inflammation and latent infection persist and affect quality of life. We have now shown that a novel therapeutic HIV vaccine consisting of replication-defective HIV (HIVAX), given in the context of viral suppression under ART, can reduce both immune activation/chronic inflammation and latent infection. Immune activation, as measured by percent of CD8 + HLA-DR + CD38 + T cells, approached levels of healthy controls at week 16 following vaccination. Reduced immune activation was accompanied by a reduction in pro-inflammatory cytokines and peripheral α4β7 + plasmacytoid DC (a marker of mucosal immune activation). Levels of both HIV-1 DNA and 2-LTR circles were reduced at week 16 following vaccination, suggesting HIVAX can impact HIV-1 latency and reduce viral replication. Surprisingly, reduced immune activation/chronic inflammation was accompanied by an increase in the percent of memory CD4 + T cells expressing markers PD-1 and TIM-3. In addition, evaluation of HIV-1 Gag-specific CD4 + T cells for expression of 96 T cell related genes pre- and post-therapy revealed increased expression of a number of genes involved in the regulation of immune activation, T cell activation, and antiviral responses. Overall this study provides evidence that vaccination with HIVAX in subjects under long term antiviral suppression can reduce immune activation/chronic inflammation and latent infection (Clinicaltrials.gov, identifier NCT01428596)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: Frank Y. Tung is an employee of GeneCure Biotechnologies. The remaining authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The treatment of periprosthetic joint infection is a difficult challenge in shoulder arthroplasty. This study investigated 1-stage modular component exchange vs. 1-stage complete removal and reimplantation (CRR) vs. 2-stage revision arthroplasty for periprosthetic joint infection., Methods: Between January 1, 2004, and December 31, 2012, 79 patients received a component exchange (n = 15), CRR (n = 45), or a 2-stage (n = 19) revision for infection. A binary logistic regression analysis was performed to determine factors presenting the greatest risk of reinfection. Complications and functional outcomes were also evaluated., Results: Overall, 4 of 15 (27%) component exchanges, 2 of 45 (4%) CRRs, and 4 of 19 (21%) 2-stage procedures required a reoperation for infection with a minimum of 1 year of follow-up. The difference between the CRR group and exchange group was significant (P = .030); however, the difference between the CRR group and 2-stage group did not reach statistical significance (P = .059). No preoperative and intraoperative selection bias between the groups was found. Binary logistic regression predicted that reinfection was highest in patients whose cultures grew Staphylococcus aureus (P = .004) or coagulase-negative Staphylococcus species (P = .041) or those treated with a component exchange (P = .015). The difference between groups for noninfection-related complications was not significant (P = .703). All procedures provided improved functional outcomes and pain relief., Conclusion: Patients with infection caused by Staphylococcus aureus or coagulase-negative Staphylococcus species may require additional operations to treat the infection. Although effective in some cases, component exchange presents an increased risk for reinfection. A 1-stage CRR procedure had similar reinfection rates as a 2-stage procedure in our patient population., (Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Unlabelled: In this study, we examined the peripheral blood (PB) central memory (TCM) CD4(+) T cell subsets designated peripheral T follicular helper cells (pTfh cells) and non-pTfh cells to assess HIV permissiveness and persistence. Purified pTfh and non-pTfh cells from healthy HIV-negative donors were tested for HIV permissiveness using green fluorescent protein (GFP)-expressing HIV-1NL4-3/Ba-L, followed by viral reactivation using beads coated with anti-CD3/anti-CD28 monoclonal antibodies. The role of pTfh cells in HIV persistence was analyzed in 12 chronically HIV-1 infected patients before and 48 weeks after initiation of raltegravir-containing combination antiretroviral therapy (cART). Total cellular HIV-1 DNA and episomes containing two copies of the viral long terminal repeat (2LTR circles) were analyzed in using droplet digital PCR in the purified pTfh and non-pTfh cells. Activation-inducible HIV p24 expression was determined by flow cytometry. Results indicate that pTfh cells, in particular PD1(+) pTfh cells, showed greater permissiveness for HIV infection than non-pTfh cells. At week 48 on cART, HIV DNA levels were unchanged from pre-cART levels, although a significant decrease in 2LTR circles was observed in both cell subsets. Inducible HIV p24 expression was higher in pTfh cells than in non-pTfh cells, with the highest frequencies in the PD1(+) CXCR3(-) pTfh cell subset. Frequencies of HLADR(+) CD38(+) activated CD4 T cells correlated with 2LTR circles in pTfh and non-pTfh cells at both time points and with p24(+) cells at entry. In conclusion, among CD4 TCM cells in PB of aviremic patients on cART, pTfh cells, in particular the PD1(+) CXCR3(-) subset, constitute a major HIV reservoir that is sustained by ongoing residual immune activation. The inducible HIV p24 assay is useful for monitoring HIV reservoirs in defined CD4 T cell subsets., Importance: Identification of the type and nature of the cellular compartments of circulating HIV reservoirs is important for targeting of HIV cure strategies. In lymph nodes (LN), a subset of CD4 T cells called T follicular helper (Tfh) cells are preferentially infected by HIV. Central memory (TCM) CD4 T cells are the major cellular reservoir for HIV in peripheral blood and contain a subset of CD4 TCM cells expressing chemokine receptor CXCR5 similar in function to LN Tfh cells termed peripheral Tfh (pTfh) cells. We found that the circulating pTfh cells are highly susceptible to HIV infection and that in HIV-infected patients, HIV persists in these cells following plasma virus suppression with potent cART. These pTfh cells, which constitute a subset of TCM CD4 T cells, can be readily monitored in peripheral blood to assess HIV persistence., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Distal humerus fractures are challenging injuries for the upper extremity surgeon. However, recent techniques in open reduction internal fixation have been powerful tools in getting positive outcomes. To get such results, the surgeon must be aware of how to properly use these techniques in their respective practices. The method of fixation depends on the fracture, taking the degree of comminution and the restoration of the columns and articular surface into account. This article helps surgeons understand the concepts behind open reduction internal fixation of the distal humerus and makes them aware of pitfalls that may lead to negative results., (Copyright © 2015 Elsevier Inc. All rights reserved.)

CD40 ligand (CD40L, CD154) is a membrane protein that is important for the activation of dendritic cells (DCs) and DC-induced CD8(+) T cell responses. To be active, CD40L must cluster CD40 receptors on responding cells. To produce a soluble form of CD40L that clusters CD40 receptors necessitates the use of a multitrimer construct. With this in mind, a tripartite fusion protein was made from surfactant protein D (SPD), HIV-1 Gag as a test antigen, and CD40L, where SPD serves as a scaffold for the multitrimer protein complex. This SPD-Gag-CD40L protein activated CD40-bearing cells and bone marrow-derived DCs in vitro. Compared to a plasmid for Gag antigen alone (pGag), DNA vaccination of mice with pSPD-Gag-CD40L induced an increased number of Gag-specific CD8(+) T cells with increased avidity for major histocompatibility complex class I-restricted Gag peptide and improved vaccine-induced protection from challenge by vaccinia-Gag virus. The importance of the multitrimeric nature of the complex was shown using a plasmid lacking the N terminus of SPD that produced a single trimer fusion protein. This plasmid, pTrimer-Gag-CD40L, was only weakly active on CD40-bearing cells and did not elicit strong CD8(+) T cell responses or improve protection from vaccinia-Gag challenge. An adenovirus 5 (Ad5) vaccine incorporating SPD-Gag-CD40L was much stronger than Ad5 expressing Gag alone (Ad5-Gag) and induced complete protection (i.e., sterilizing immunity) from vaccinia-Gag challenge. Overall, these results show the potential of a new vaccine design in which antigen is introduced into a construct that expresses a multitrimer soluble form of CD40L, leading to strongly protective CD8(+) T cell responses.

Background: Targeting of protein antigens to dendritic cells (DC) via the DEC205 receptor enhances presentation of antigen-derived peptides on MHC-I and MHC-II molecules and, in the presence of costimulatory signals, antigen-specific immune responses. The immunogenicity and efficacy of DNA vaccination can also be enhanced by fusing the encoded antigen to single chain antibodies directed against DEC205. To further improve this strategy, we evaluated different toll-like receptor ligands (TLR) and CD40 ligands (CD40L) as adjuvants for DNA vaccines encoding a DEC205-single-chain antibody fused to the ovalbumin model antigen or HIV-1 Gag and assessed the priming efficacy of DNA in a DNA prime adenoviral vector boost immunization regimen., Results: Mice were primed with the adjuvanted DEC-205 targeted DNA vaccines and boosted with adenoviral vectors encoding the same antigens. CD8+ T cell responses were determined after the adenoviral booster immunization, to determine how well the different DNA immunization regimens prime for the adenoviral boost. In the absence of adjuvants, targeting of DNA-encoded ovalbumin to DCs suppressed CD8+ T-cell responses after the adenoviral booster immunization. CD8+ T-cell responses to the DEC205 targeted DNA vaccines increased only slightly by adding either the TLR-9 ligand CpG, the TLR-3 ligand Poly I:C, or CD40 ligand expression plasmids. However, the combination of both TLR-ligands led to a strong enhancement of CD8+ T-cell responses compared to a non-targeted DNA vaccine. This finding was confirmed using HIV Gag as antigen., Conclusion: Although DNA prime adenoviral vector boost immunizations belong to the strongest inducers of cytotoxic T cell responses in different animal models and humans, the CD8+ T cell responses can be further improved by targeting the DNA encoded antigen to DEC205 in the presence of synergistic TLR ligands CpG and Poly I:C.

Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compounds, NB2001 and NB2030, contain a cephalosporin with a thienyl (NB2001) or a tetrazole (NB2030) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compounds exploit beta-lactamases to release triclosan through hydrolysis of the beta-lactam ring. Like cephalothin, NB2001 and NB2030 were hydrolyzed by class A beta-lactamases (Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C beta-lactamases (Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies (k(cat)/K(m)). They also bound to the penicillin-binding proteins of S. aureus and E. coli, but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphology in E. coli consistent with the toxophore rather than the beta-lactam being responsible for antibacterial activity. In biochemical assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concentrations being markedly reduced relative to that of free triclosan. The transport of NB2001, NB2030, and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli. Taken together, the results suggest that NB2001 and NB2030 act primarily as triclosan prodrugs in S. aureus and E. coli.