Evaluation of QuantiFERON SARS-CoV-2 interferon-γ release assay following SARS-CoV-2 infection and vaccination.

T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines. Forty-eight participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established 'Protective Immunity from T Cells in Healthcare workers' (PITCH) ELISpot, which can evaluate spike-specific T-cell responses. The primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared with the PITCH ELISpot. The QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12-21 days post positive PCR) from naïve individuals (P < 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172-444 days post positive test) and was inferior to the PITCH ELISpot (75%). Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55-166 days since second vaccination), the latter also had reduced sensitivity (44.4%) compared to the PITCH ELISpot (66.6%). The QuantiFERON SARS-CoV-2 assay showed potential as a T- cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.

The development of diphenyleneiodonium analogs as GPR3 agonists.

G protein-coupled receptor 3 (GPR3) is an orphan receptor potentially involved in many important physiological processes such as drug abuse, neuropathic pain, and anxiety and depression related disorders. Pharmacological studies of GPR3 have been limited due to the restricted number of known agonists and inverse agonists for this constitutively active receptor. In this medicinal chemistry study, we report the discovery of GPR3 agonists based off the diphenyleneiodonium (DPI) scaffold. The most potent full agonist was the 3-trifluoromethoxy analog (32) with an EC50 of 260 nM and 90% efficacy compared to DPI. Investigation of a homology model of GPR3 from multiple sequence alignment resulted in the finding of a binding site rich in potential π-π and π-cation interactions stabilizing DPI-scaffold agonists. MMGBSA free energy analysis showed a good correlation with trends in observed EC50s. DPI analogs retained the same high receptor selectivity for GPR3 over GPR6 and GPR12 as observed with DPI. Collectively, the DPI analog series shows that order of magnitude improvements in potency with the scaffold were attainable; however, attempts to replace the iodonium ion to make the scaffold more druggable failed.

The Creation of a Multidomain Neighborhood Environmental Vulnerability Index Across New York City.

Compared to previous studies commonly using a single summary score, we aimed to construct a multidomain neighborhood environmental vulnerability index (NEVI) to characterize the magnitude and variability of area-level factors with the potential to modify the association between environmental pollutants and health effects. Using the Toxicological Prioritization Index framework and data from the 2015-2019 U.S. Census American Community Survey and the 2020 CDC PLACES Project, we quantified census tract-level vulnerability overall and in 4 primary domains (demographic, economic, residential, and health status), 24 subdomains, and 54 distinct area-level features for New York City (NYC). Overall and domain-specific indices were calculated by summing standardized feature values within the subdomains and then aggregating and weighting based on the number of features within each subdomain within equally-weighted primary domains. In citywide comparisons, NEVI was correlated with multiple existing indices, including the Neighborhood Deprivation Index (r = 0.91) and Social Vulnerability Index (r = 0.87) but provided additional information on features contributing to vulnerability. Vulnerability varied spatially across NYC, and hierarchical cluster analysis using subdomain scores revealed six patterns of vulnerability across domains: 1) low in all, 2) primarily low except residential, 3) medium in all, 4) high demographic, economic, and residential 5) high economic, residential, and health status, and 6) high demographic, economic and health status. Created using methods that offer flexibility for theory-based construction, NEVI provided detailed vulnerability metrics across domains that can inform targeted research and public health interventions aimed at reducing the health impacts from environmental exposures across urban centers.

Reference genome for the Mojave poppy bee (Perdita meconis), a specialist pollinator of conservation concern.

The Mojave poppy bee, Perdita meconis Griswold (Hymenoptera: Anthophila: Andrenidae), is a species of conservation concern that is restricted to the eastern Mojave Desert of North America. It is a specialist pollinator of two poppy genera, Arctomecon and Argemone (Papaveraceae), and is being considered for listing under the US Endangered Species Act along with one of its pollinator hosts, the Las Vegas bearpoppy (Arctomecon californica). Here, we present a near chromosome-level genome of the Mojave poppy bee to provide a genomic resource that will aid conservation efforts and future research. We isolated DNA from a single, small (<7 mm), male specimen collected using non-ideal preservation methods then performed whole-genome sequencing using PacBio HiFi technology. After quality and contaminant filtering, the final draft genome assembly is 327 Mb, with an N50 length of 17.5 Mb. Annotated repetitive elements compose 37.3% of the genome, although a large proportion (24.87%) of those are unclassified repeats. Additionally, we annotated 18,245 protein-coding genes and 19,433 transcripts. This genome represents one of only a few genomes from the large bee family Andrenidae and one of only a few genomes for pollinator specialists. We highlight both the potential of this genome as a resource for future research, and how high-quality genomes generated from small, non-ideal (in terms of preservation) specimens could facilitate biodiversity genomics.

Resilience in development: Neighborhood context, experiences of discrimination, and children's mental health.

An understanding of child psychopathology and resilience requires attention to the nested and interconnected systems and contexts that shape children's experiences and health outcomes. In this study, we draw on data from the National Survey of Children's Health, 2016 to 2021 (n = 182,375 children, ages 3- to 17 years) to examine associations between community social capital and neighborhood resources and children's internalizing and externalizing problems, and whether these associations were moderated by experiences of racial discrimination. Study outcomes were caregiver-report of current internalizing and externalizing problems. Using logistic regression models adjusted for sociodemographic characteristics of the child and household, higher levels of community social capital were associated with a lower risk of children's depression, anxiety, and behaviors. Notably, we observed similar associations between neighborhood resources and child mental health for depression only. In models stratified by the child's experience of racial/ethnic discrimination, the protective benefits of community social capital were specific to those children who did not experience racial discrimination. Our results illustrate heterogeneous associations between community social capital and children's mental health that differ based on interpersonal experiences of racial/ethnic discrimination, illustrating the importance of a multilevel framework to promote child wellbeing.

Adoptive T Cell Therapy with IL-12-Preconditioned Low-Avidity T Cells Prevents Exhaustion and Results in Enhanced T Cell Activation, Enhanced Tumor Clearance, and Decreased Risk for Autoimmunity.

Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield T cells able to home to tumors and effectively kill them. Our previous study demonstrated ex vivo activation in the presence of IL-12-induced optimal CD8+ T cell expansion and melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due to transfer of high-avidity self-specific T cells. In this study, we compared mouse low- and high-avidity T cells targeting the tumor Ag tyrosinase-related protein 2 (TRP2). Not surprisingly, high-avidity T cells provide superior tumor control, yet low-avidity T cells can promote tumor regression. The addition of IL-12 during in vitro expansion boosts low-avidity T cell responsiveness, tumor regression, and prevents T cell exhaustion. In this study, we demonstrate that IL-12-primed T cells are resistant to PD-1/PD-L1-mediated suppression and retain effector function. Importantly, IL-12 preconditioning prevented exhaustion as LAG-3, PD-1, and TOX were decreased while simultaneously increasing KLRG1. Using intravital imaging, we also determined that high-avidity T cells have sustained contacts with intratumoral dendritic cells and tumor targets compared with low-avidity T cells. However, with Ag overexpression, this defect is overcome, and low-avidity T cells control tumor growth. Taken together, these data illustrate that low-avidity T cells can be therapeutically beneficial if cocultured with IL-12 cytokine during in vitro expansion and highly effective in vivo if Ag is not limiting. Clinically, low-avidity T cells provide a safer alternative to high-avidity, TCR-engineered T cells, as IL-12-primed, low-avidity T cells cause less autoimmune vitiligo.

Programmed Death-1 Restrains the Germinal Center in Type 1 Diabetes.

Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, and although numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production. PD-1 inhibition accelerates autoimmunity in mice, but its role in regulating germinal centers (GC) is controversial. To address the role of PD-1 in the GC reaction in type 1 diabetes, we used tetramers to phenotype insulin-specific CD4+ T and B cells in NOD mice. PD-1 or PD-L1 deficiency, and PD-1 but not PD-L2 blockade, unleashed insulin-specific T follicular helper CD4+ T cells and enhanced their survival. This was concomitant with an increase in GC B cells and augmented insulin autoantibody production. The effect of PD-1 blockade on the GC was reduced when mice were treated with a mAb targeting the insulin peptide:MHC class II complex. This work provides an explanation for autoimmune side effects following PD-1 pathway inhibition and suggests that targeting the self-peptide:MHC class II complex might limit autoimmunity arising from checkpoint blockade.

Framing the past (and future): Effects of generic photos on autobiographical judgments.

Do the images we see every day influence how we remember our lives? Research on this matter often concerns how entire memories of events can be created or shaped through the use of doctored photographs of personal (Wade et al., Psychonomic bulletin & review, 9 (3), 597-603, 2002) and public events (Sacchi et al., Applied Cognitive Psychology, 21 (8), 1005-1022, 2007). Although this paradigm has yielded insights into false memory production, it may underestimate the extent to which photographs can bias or distort memory in a subtler manner (i.e., without the use of doctored photographs or suggestion). In Experiments 1 (N = 95) and 2 (N = 186) of the present study, we examined whether the mere presence of generic images, typical of stock photography, could influence aspects of our memories. Given the parallel between autobiographical remembering and forecasting (Berntsen & Bohn, Memory & Cognition, 38(3), 265-278, 2010), we also examined (Experiment 3: N=204) how such images would influence future autobiographical judgments. Specifically, three experiments investigated whether photographs would bias autobiographical judgments for either quantitative (e.g., How many movies have you seen in the past year?) or affective (e.g., How enjoyable do you think your next date will be?) aspects of events in everyday life. We found that photographs reliably influenced judgments related to quantitative aspects of autobiographical events. Moreover, though less robustly, there was an indication that these photos could bias our affective construal of such events as well. Overall, we conclude that the mere presence of generic photographs may exert an influence on the way we think about our lives to an extent previously under-recognized.

Thistledown velvet ants in the Desert Mimicry Ring and the evolution of white coloration: Müllerian mimicry, camouflage and thermal ecology.

Adaptive coloration among animals is one of the most recognizable outcomes of natural selection. Here, we investigate evolutionary drivers of white coloration in velvet ants (Hymenoptera: Mutillidae), which has previously been considered camouflage with the fruit of creosote bush (Larrea tridentata). Our analyses indicate instead that velvet ants evolved white coloration millions of years before creosote bush was widespread in North America's hot deserts. Furthermore, velvet ants and the creosote fruit exhibit different spectral reflectance patterns, which appear distinct to potential insectivorous predators. While the white coloration in velvet ants likely did not evolve as camouflage, we find that white-coloured species remain cooler than their red/orange relatives, and therefore we infer the white coloration likely evolved in response to Neogene desertification. This study shows the importance of cross-disciplinary investigation and of testing multiple hypotheses when investigating evolutionary drivers of adaptive coloration.

The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

Picture (im)perfect: Illusions of recognition memory produced by photographs at test.

Photographs have been found to affect a variety of psychological judgments. For example, nonprobative but semantically related photographs may increase beliefs in the truth of general knowledge statements (Newman, Garry, Bernstein, Kantner, & Lindsay, Psychonomic Bulletin & Review, 19(5), 969-974, 2012; Newman et al., Journal of Experimental Psychology: Learning, Memory, and Cognition, 41(5), 1337-1348, 2015). Photographs can also create illusions of memory (Cardwell, Henkel, Garry, Newman, & Foster, Memory & Cognition, 44(6), 883-896, 2016; Henkel, Applied Cognitive Psychology, 25(1), 78-86, 2011; Henkel & Carbuto, 2008). A candidate mechanism for these effects is that a photograph increases the fluency with which a statement or an event is processed. The present study was conducted to determine whether photos at test can induce illusions of recognition memory and to test the viability of a conceptual fluency explanation of these effects. The results of the present study suggest that photographs enhance the fluency of related words (Experiment 1), that false memories can be produced by the mere presence of a related photo on a recognition memory test for words (Experiments 2 & 3), and that these effects appear to be limited to conceptually based recognition tests (Experiments 4 & 5). The results support the notion that photograph-based illusions of memory stem from the ability of related photographs to increase the speed and ease of conceptual processing.

Interobserver and intraobserver reliability of radiographic classification of acromioclavicular joint dislocations.

HYPOTHESIS AND BACKGROUND: The classification and treatment of acromioclavicular (AC) joint dislocations remain controversial. The purpose of this study was to determine the interobserver and intraobserver reliability of the Rockwood classification system. We hypothesized poor interobserver and intraobserver reliability, limiting the role of the Rockwood classification system in determining severity of AC joint dislocations and accurately guiding treatment decisions. METHODS: We identified 200 patients with AC joint injuries using the International Classification of Diseases, Ninth Revision code 831.04. Fifty patients met inclusion criteria. Deidentified radiographs were compiled and presented to 6 fellowship-trained upper extremity orthopedic surgeons. The surgeons classified each patient into 1 of the 6 classification types described by Rockwood. A second review was performed several months later by 2 surgeons. A κ value was calculated to determine the interobserver and intraobserver reliability. RESULTS: The interobserver and intraobserver κ values were fair (κ = 0.278) and moderate (κ = 0.468), respectively. Interobserver results showed that 4 of the 50 radiographic images had a unanimous classification. Intraobserver results for the 2 surgeons showed that 18 of the 50 images were rated the same on second review by the first surgeon and 38 of the 50 images were rated the same on second review by the second surgeon. CONCLUSION: We found that the Rockwood classification system has limited interobserver and intraobserver reliability. We believe that unreliable classification may account for some of the inconsistent treatment outcomes among patients with similarly classified injuries. We suggest that a better classification system is needed to use radiographic imaging for diagnosis and treatment of AC joint dislocations.

Smoking Urges During Treatment and Long-Term Cessation among Low-Income African Americans.

Objective: The urge to smoke is a predictor of smoking relapse. Little research has focused on the impact of acute urges during treatment among African Americans. This study examined the relationship between smoking urges and long-term abstinence among treatment seekers. Design: Longitudinal prospective investigation. Urges to smoke were assessed at the initial (session 1) and final (session 8) sessions among adult smokers (N=308) enrolled in a 4-week group intervention trial. Nicotine patch use was assessed over 30 days. Main Outcome Measures: Biochemically verified 7-day point prevalence abstinence (7-day ppa) was assessed immediately post-intervention, and at 3-, 6-, and 12-month follow-ups. Hierarchical logistic regressions tested associations between session 1 and session 8 urges and 7-day ppa at each smoking status assessment. Results: There was a significant overall decrease in smoking urges (M=29, SD=15 at session 1; M=17, SD=11 at session 8). After controlling for covariates, urges to smoke at session 1 were unrelated to 7-day ppa at any of the assessment points. However, session 8 urges were inversely associated with 7-day ppa post-intervention (AOR=.94, CI:.92-.97), at 3-months (AOR=.93, CI: .89-.97), 6-months (AOR=.93, CI: .90-.97), and 12-months (AOR=.96, CI: .96-.99). Nicotine patch use was positively associated with 7-day ppa at each assessment. Conclusions: The most robust predictors of abstinence through 12-months post-intervention were decreased urges over the 4-week, 8-session group intervention and the frequency of nicotine patch use. Interventions aimed at addressing the needs of African American smokers should address urges and encourage nicotine replacement adherence to increase abstinence rates.

Intraspecific phytochemical variation shapes community and population structure for specialist caterpillars.

Chemically mediated plant-herbivore interactions contribute to the diversity of terrestrial communities and the diversification of plants and insects. While our understanding of the processes affecting community structure and evolutionary diversification has grown, few studies have investigated how trait variation shapes genetic and species diversity simultaneously in a tropical ecosystem. We investigated secondary metabolite variation among subpopulations of a single plant species, Piper kelleyi (Piperaceae), using high-performance liquid chromatography (HPLC), to understand associations between plant phytochemistry and host-specialized caterpillars in the genus Eois (Geometridae: Larentiinae) and associated parasitoid wasps and flies. In addition, we used a genotyping-by-sequencing approach to examine the genetic structure of one abundant caterpillar species, Eois encina, in relation to host phytochemical variation. We found substantive concentration differences among three major secondary metabolites, and these differences in chemistry predicted caterpillar and parasitoid community structure among host plant populations. Furthermore, E. encina populations located at high elevations were genetically different from other populations. They fed on plants containing high concentrations of prenylated benzoic acid. Thus, phytochemistry potentially shapes caterpillar and wasp community composition and geographic variation in species interactions, both of which can contribute to diversification of plants and insects.

Emotion Dysregulation and Inflammation in African-American Women with Type 2 Diabetes.

C-reactive protein (CRP), a marker of systemic inflammation, has been associated with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state. The objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus (T2DM). We examined associations between trauma exposure, MDD, PTSD, emotion dysregulation, and CRP among 40 African-American women with T2DM recruited from an urban hospital. Emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale. PTSD and MDD were measured with structured clinical interviews. Child abuse and lifetime trauma load were also assessed. Analyses showed that both emotion dysregulation and current MDD were significantly associated with higher levels of CRP (p < 0.01). Current PTSD was not significantly related to CRP. In a regression model, emotion dysregulation was significantly associated with higher CRP (p < 0.001) independent of body mass index, trauma exposure, and MDD diagnosis. These findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with T2DM, though a causal relationship cannot be determined from this study.

The evolution of novel host use is unlikely to be constrained by trade-offs or a lack of genetic variation.

The genetic and ecological factors that shape the evolution of animal diets remain poorly understood. For herbivorous insects, the expectation has been that trade-offs exist, such that adaptation to one host plant reduces performance on other potential hosts. We investigated the genetic architecture of alternative host use by rearing individual Lycaeides melissa butterflies from two wild populations in a crossed design on two hosts (one native and one introduced) and analysing the genetic basis of differences in performance using genomic approaches. Survival during the experiment was highest when butterfly larvae were reared on their natal host plant, consistent with local adaptation. However, cross-host correlations in performance among families (within populations) were not different from zero. We found that L. melissa populations possess genetic variation for larval performance and variation in performance had a polygenic basis. We documented very few genetic variants with trade-offs that would inherently constrain diet breadth by preventing the optimization of performance across hosts. Instead, most genetic variants that affected performance on one host had little to no effect on the other host. In total, these results suggest that genetic trade-offs are not the primary cause of dietary specialization in L. melissa butterflies.

The evolution of Batesian mimicry within the North American Asidini (Coleoptera: Tenebrionidae).

The asidine darkling beetles (Coleoptera: Tenebrionidae: Asidini) are a diverse tribe of flightless tenebrionids found in many arid and sub-arid habitats around the world. The 263 currently described North American species are contained in ten genera, all of which are restricted to the western half of the continent. The Asidini, like all members of the subfamily Pimeliinae, lack defensive glands. Instead, several phenotypic traits occur within the tribe that may help limit predation. These include the contrasting defensive strategies of crypsis, through either background matching or pattern disruption, and Batesian mimicry of the chemically defended genus Eleodes. Dorsal elytral morphology was assessed between 53 North American asidine species and 13 common Eleodes model species using multiple methodologies to assess similarities between species in the two groups that might indicate mimetic relationships. A phylogeny of the North American asidines is used to map the occurrence of differing defensive strategies within the tribe. Crypsis is reconstructed as the ancestral state, with two origins for Batesian mimicry and multiple reversals. The combination of strongly to weakly cryptic species and varying levels of mimetic fidelity to Eleodes model species make the asidines a promising lineage upon which to further explore the evolution of defensive phenotypes.

Morphological outcomes of gynandromorphism in Lycaeides butterflies (Lepidoptera: Lycaenidae).

The genitalia of male insects have been widely used in taxonomic identification and systematics and are potentially involved in maintaining reproductive isolation between species. Although sexual selection has been invoked to explain patterns of morphological variation in genitalia among populations and species, developmental plasticity in genitalia likely contributes to observed variation but has been rarely examined, particularly in wild populations. Bilateral gynandromorphs are individuals that are genetically male on one side of the midline and genetically female on the other, while mosaic gynandromorphs have only a portion of their body developing as the opposite sex. Gynandromorphs might offer unique insights into developmental plasticity because individuals experience abnormal cellular interactions at the genitalic midline. In this study, we compare the genitalia and wing patterns of gynandromorphic Anna and Melissa blue butterflies, Lycaeides anna (Edwards) (formerly L. idas anna) and L. melissa (Edwards) (Lepidoptera: Lycaenidae), to the morphology of normal individuals from the same populations. Gynandromorph wing markings all fell within the range of variation of normal butterflies; however, a number of genitalic measurements were outliers when compared with normal individuals. From these results, we conclude that the gynandromorphs' genitalia, but not wing patterns, can be abnormal when compared with normal individuals and that the gynandromorphic genitalia do not deviate developmentally in a consistent pattern across individuals. Finally, genetic mechanisms are considered for the development of gynandromorphism in Lycaeides butterflies.