Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates

There is a remarkable heterogeneity in the functional profile (quality) of T cell responses. Importantly, the magnitude and/or quality of a response required for protection may be different depending on the infection. Here, we assessed the capacity of different Toll like receptor (TLR)-binding compounds to influence T helper cell (Th)1 and CD8+ T cell responses when used as adjuvants in nonhuman primates (NHP) with HIV Gag as a model antigen. NHP were immunized with HIV Gag protein emulsified in Montanide ISA 51, an oil-based adjuvant, with or without a TLR7/8 agonist, a TLR8 agonist, or the TLR9 ligand cytosine phosphate guanosine oligodeoxynucleotides (CpG ODN), and boosted 12 wk later with a replication-defective adenovirus-expressing HIV-Gag (rAD-Gag). Animals vaccinated with HIV Gag protein/Montanide and CpG ODN or the TLR7/8 agonist had higher frequencies of Th1 responses after primary immunization compared to all other vaccine groups. Although the rAD-Gag boost did not elevate the frequency of Th1 memory cytokine responses, there was a striking increase in HIV Gag-specific CD8+ T cell responses after the boost in all animals that had received a primary immunization with any of the TLR adjuvants. Importantly, the presence and type of TLR adjuvant used during primary immunization conferred stability and dramatically influenced the magnitude and quality of the Th1 and CD8+ T cell responses after the rAD-Gag boost. These data provide insights for designing prime-boost immunization regimens to optimize Th1 and CD8+ T cell responses

Phase 1 Trial of Malaria Transmission Blocking Vaccine Candidates Pfs25 and Pvs25 Formulated with Montanide ISA 51

Pfs25 and Pvs25, surface proteins of mosquito stage of the malaria parasites P. falciparum and P. vivax, respectively, are leading candidates for vaccines preventing malaria transmission by mosquitoes. This single blinded, dose escalating, controlled Phase 1 study assessed the safety and immunogenicity of recombinant Pfs25 and Pvs25 formulated with Montanide ISA 51, a water-in-oil emulsion.The trial was conducted at The Johns Hopkins Center for Immunization Research, Washington DC, USA, between May 16, 2005-April 30, 2007. The trial was designed to enroll 72 healthy male and non-pregnant female volunteers into 1 group to receive adjuvant control and 6 groups to receive escalating doses of the vaccines. Due to unexpected reactogenicity, the vaccination was halted and only 36 volunteers were enrolled into 4 groups: 3 groups of 10 volunteers each were immunized with 5 microg of Pfs25/ISA 51, 5 microg of Pvs25/ISA 51, or 20 microg of Pvs25/ISA 51, respectively. A fourth group of 6 volunteers received adjuvant control (PBS/ISA 51). Frequent local reactogenicity was observed. Systemic adverse events included two cases of erythema nodosum considered to be probably related to the combination of the antigen and the adjuvant. Significant antibody responses were detected in volunteers who completed the lowest scheduled doses of Pfs25/ISA 51. Serum anti-Pfs25 levels correlated with transmission blocking activity.It is feasible to induce transmission blocking immunity in humans using the Pfs25/ISA 51 vaccine, but these vaccines are unexpectedly reactogenic for further development. This is the first report that the formulation is associated with systemic adverse events including erythema nodosum.ClinicalTrials.gov NCT00295581

Revisiting histories of anti-racist thought and activism

This piece reconsiders histories of anti-racist thought and practice, including the linkages between anti-racisms and other traditions of liberatory thought. We argue that anti-racism should be understood as a strand in radical thought linking internationalism, institutional critique and street activism, in the process interfeeding with other social movements. The traditions of anti-racist thought discussed in this special issue exemplify these cross-cutting influences

Children with Reading Disability Show Brain Differences in Effective Connectivity for Visual, but Not Auditory Word Comprehension

Background: Previous literature suggests that those with reading disability (RD) have more pronounced deficits during semantic processing in reading as compared to listening comprehension. This discrepancy has been supported by recent neuroimaging studies showing abnormal activity in RD during semantic processing in the visual but not in the auditory modality. Whether effective connectivity between brain regions in RD could also show this pattern of discrepancy has not been investigated. Methodology/Principal Findings: Children (8- to 14-year-olds) were given a semantic task in the visual and auditory modality that required an association judgment as to whether two sequentially presented words were associated. Effective connectivity was investigated using Dynamic Causal Modeling (DCM) on functional magnetic resonance imaging (fMRI) data. Bayesian Model Selection (BMS) was used separately for each modality to find a winning family of DCM models separately for typically developing (TD) and RD children. BMS yielded the same winning family with modulatory effects on bottom-up connections from the input regions to middle temporal gyrus (MTG) and inferior frontal gyrus(IFG) with inconclusive evidence regarding top-down modulations. Bayesian Model Averaging (BMA) was thus conducted across models in this winning family and compared across groups. The bottom-up effect from the fusiform gyrus (FG) to MTG rather than the top-down effect from IFG to MTG was stronger in TD compared to RD for the visual modality. The stronge

SKYSURF: Constraints on Zodiacal Light and Extragalactic Background Light through Panchromatic HST All-Sky Surface-Brightness Measurements: I. Survey Overview and Methods

We give an overview and describe the rationale, methods, and testing of the Hubble Space Telescope (HST) Archival Legacy project "SKYSURF." SKYSURF uses HST's unique capability as an absolute photometer to measure the ~0.2-1.7 $\mu$m sky surface brightness (SB) from 249,861 WFPC2, ACS, and WFC3 exposures in ~1400 independent HST fields. SKYSURF's panchromatic dataset is designed to constrain the discrete and diffuse UV to near-IR sky components: Zodiacal Light (ZL; inner Solar System), Kuiper Belt Objects (KBOs; outer Solar System), Diffuse Galactic Light (DGL), and the discrete plus diffuse Extragalactic Background Light (EBL). We outline SKYSURF's methods to: (1) measure sky-SB levels between its detected objects; (2) measure the integrated discrete EBL, most of which comes from AB$\simeq$17-22 mag galaxies; and (3) estimate how much diffuse light may exist in addition to the extrapolated discrete galaxy counts. Simulations of HST WFC3/IR images with known sky-values and gradients, realistic cosmic ray (CR) distributions, and star plus galaxy counts were processed with nine different algorithms to measure the "Lowest Estimated Sky-SB" (LES) in each image between the discrete objects. The best algorithms recover the inserted LES values within 0.2% when there are no image gradients, and within 0.2-0.4% when there are 5-10% gradients. SKYSURF requires non-standard re-processing of these HST images that includes restoring the lowest sky-level from each visit into each drizzled image. We provide a proof of concept of our methods from the WFC3/IR F125W images, where any residual diffuse light that HST sees in excess of the Kelsall et al. (1998) Zodiacal model prediction does not depend on the total object flux that each image contains. This enables us to present our first SKYSURF results on diffuse light in Carleton et al. (2022).Comment: Accepted to AJ; see accompanying paper Carleton et al. 2022: arXiv:2205.06347. Comments welcome

Phase 1 Study of Two Merozoite Surface Protein 1 (MSP1(42)) Vaccines for Plasmodium falciparum Malaria

OBJECTIVES: To assess the safety and immunogenicity of two vaccines, MSP1(42)-FVO/Alhydrogel and MSP1(42)-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites. DESIGN: A Phase 1 open-label, dose-escalating study. SETTING: Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005. PARTICIPANTS: Sixty healthy malaria-naïve volunteers 18–48 y of age. INTERVENTIONS: The C-terminal 42-kDa region of merozoite surface protein 1 (MSP1(42)) corresponding to the two allelic forms present in FVO and 3D7 P. falciparum lines were expressed in Escherichia coli, refolded, purified, and formulated on Alhydrogel (aluminum hydroxide). For each vaccine, volunteers in each of three dose cohorts (5, 20, and 80 μg) were vaccinated at 0, 28, and 180 d. Volunteers were followed for 1 y. OUTCOME MEASURES: The safety of MSP1(42)-FVO/Alhydrogel and MSP1(42)-3D7/Alhydrogel was assessed. The antibody response to each vaccine was measured by reactivity to homologous and heterologous MSP1(42), MSP1(19), and MSP1(33) recombinant proteins and recognition of FVO and 3D7 parasites. RESULTS: Anti-MSP1(42) antibodies were detected by ELISA in 20/27 (74%) and 22/27 (81%) volunteers receiving three vaccinations of MSP1(42)-FVO/Alhydrogel or MSP1(42)-3D7/Alhydrogel, respectively. Regardless of the vaccine, the antibodies were cross-reactive to both MSP1(42)-FVO and MSP1(42)-3D7 proteins. The majority of the antibody response targeted the C-terminal 19-kDa domain of MSP1(42), although low-level antibodies to the N-terminal 33-kDa domain of MSP1(42) were also detected. Immunofluorescence microscopy of sera from the volunteers demonstrated reactivity with both FVO and 3D7 P. falciparum schizonts and free merozoites. Minimal in vitro growth inhibition of FVO or 3D7 parasites by purified IgG from the sera of the vaccinees was observed. CONCLUSIONS: The MSP1(42)/Alhydrogel vaccines were safe and well tolerated but not sufficiently immunogenic to generate a biologic effect in vitro. Addition of immunostimulants to the Alhydrogel formulation to elicit higher vaccine-induced responses in humans may be required for an effective vaccine

Factors influencing overall survival rates for patients with pineocytoma

Given its rarity, appropriate treatment for pineocytoma remains variable. As the literature primarily contains case reports or studies involving a small series of patients, prognostic factors following treatment of pineocytoma remain unclear. We therefore compiled a systematic review of the literature concerning post-treatment outcomes for pineocytoma to better determine factors associated with overall survival among patients with pineocytoma. We performed a comprehensive search of the published English language literature to identify studies containing outcome data for patients undergoing treatment for pineocytoma. Kaplan–Meier analysis was utilized to determine overall survival rates. Our systematic review identified 168 total patients reported in 64 articles. Among these patients, 21% underwent biopsy, 38% underwent subtotal resection, 42% underwent gross total resection, and 29% underwent radiation therapy, either as mono- or adjuvant therapy. The 1 and 5 year overall survival rates for patients receiving gross total resection versus subtotal resection plus radiotherapy were 91 versus 88%, and 84 versus 17%, respectively. When compared to subtotal resection alone, subtotal resection plus radiation therapy did not offer a significant improvement in overall survival. Gross total resection is the most appropriate treatment for pineocytoma. The potential benefit of conventional radiotherapy for the treatment of these lesions is unproven, and little evidence supports its use at present

Genetic Dissection of Acute Ethanol Responsive Gene Networks in Prefrontal Cortex: Functional and Mechanistic Implications

Background Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol. Results Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol\u27s effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b,Gria1, Sncb and Nell2. Conclusions The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders