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Background: CD8+ T cell responses develop rapidly during infection and are swiftly reduced during contraction, wherein .90% of primed CD8+ T cells are eliminated. The role of apoptotic mechanisms in controlling this rapid proliferation and contraction of CD8+ T cells remains unclear. Surprisingly, evidence has shown non-apoptotic activation of caspase-3 to occur during in vitro T-cell proliferation, but the relevance of these mechanisms to in vivo CD8+ T cell responses has yet to be examined. Methods and Findings: We have evaluated the activity of caspase-3, a key downstream inducer of apoptosis, throughout the entirety of a CD8+ T cell response. We utilized two infection models that differ in the intensity, onset and duration of antigen-presentation and inflammation. Expression of cleaved caspase-3 in antigen specific CD8+ T cells was coupled to the timing and strength of antigen presentation in lymphoid organs. We also observed coordinated activation of additional canonical apoptotic markers, including phosphatidylserine exposure. Limiting dilution analysis directly showed that in the presence of IL7, very little cell death occurred in both caspase-3hi and caspase-3low CD8+ T cells. The expression of active caspase-3 peaked before effector phenotype (CD62Llow) CD8+ T cells emerged, and was undetectable in effector-phenotype cells. In addition, OVA-specific CD8+ cells remained active caspase-3low throughout the contraction phase. Conclusions: Our results specifically implicate antigen and not inflammation in driving activation of apoptotic mechanisms without cell death in proliferating CD8+ T cells. Furthermore, the contraction of CD8+ T cell response following expansion is likely not mediated by the key downstream apoptosis inducer, caspase-3.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a virulent pathogen that induces rapid host death. Here we observed that host survival after infection with S. Typhimurium was enhanced in the absence of type I interferon signaling, with improved survival of mice deficient in the receptor for type I interferons (Ifnar1−/− mice) that was attributed to macrophages. Although there was no impairment in cytokine expression or inflammasome activation in Ifnar1−/− macrophages, they were highly resistant to S. Typhimurium–induced cell death. Specific inhibition of the kinase RIP1 or knockdown of the gene encoding the kinase RIP3 prevented the death of wild-type macrophages, which indicated that necroptosis was a mechanism of cell death. Finally, RIP3-deficient macrophages, which cannot undergo necroptosis, had similarly less death and enhanced control of S. Typhimurium in vivo. Thus, we propose that S. Typhimurium induces the production of type I interferon, which drives necroptosis of macrophages and allows them to evade the immune response.

CD8.sup.+ T cell responses develop rapidly during infection and are swiftly reduced during contraction, wherein >90% of primed CD8.sup.+ T cells are eliminated. The role of apoptotic mechanisms in controlling this rapid proliferation and contraction of CD8.sup.+ T cells remains unclear. Surprisingly, evidence has shown non-apoptotic activation of caspase-3 to occur during in vitro T-cell proliferation, but the relevance of these mechanisms to in vivo CD8.sup.+ T cell responses has yet to be examined. We have evaluated the activity of caspase-3, a key downstream inducer of apoptosis, throughout the entirety of a CD8.sup.+ T cell response. We utilized two infection models that differ in the intensity, onset and duration of antigen-presentation and inflammation. Expression of cleaved caspase-3 in antigen specific CD8.sup.+ T cells was coupled to the timing and strength of antigen presentation in lymphoid organs. We also observed coordinated activation of additional canonical apoptotic markers, including phosphatidylserine exposure. Limiting dilution analysis directly showed that in the presence of IL7, very little cell death occurred in both caspase-3.sup.hi and caspase-3.sup.low CD8.sup.+ T cells. The expression of active caspase-3 peaked before effector phenotype (CD62L.sup.low) CD8.sup.+ T cells emerged, and was undetectable in effector-phenotype cells. In addition, OVA-specific CD8.sup.+ cells remained active caspase-3.sup.low throughout the contraction phase. Our results specifically implicate antigen and not inflammation in driving activation of apoptotic mechanisms without cell death in proliferating CD8.sup.+ T cells. Furthermore, the contraction of CD8.sup.+ T cell response following expansion is likely not mediated by the key downstream apoptosis inducer, caspase-3.

Clothianidin, a synthetic neonicotinoid, is registered for pre-flood (to field soil) and post-flood (to field water) application to protect California rice fields against the rice seed midge, Criotopus sylvertis , and the rice water weevil, Lissoroptrus oryzophilus. Our objective was to characterize the individual mechanisms governing transport and degradation under conditions representative of California rice fields (20-36°C; UV irradiation< 1,350 μW cm-2 at 310 nm; pH 7-9; flooded soil redox potential Ehs between -123 and -217 mV). Clothianidin (pKa 11.0) is a neutral species within environmentally relevant pH ranges, has a low vapor pressure (3.8 x 10-11 Pa at 20°C), and is capable of strong absorbance of environmentally-relevant long (UV-A; 320 to 400 nm) and short (UV-B; 290 to 320 nm) UV irradiation. Based on these properties, we hypothesized that dissipation will be controlled by photolysis and microbial degradation under flooded conditions. Clothianidin was confirmed to be non-volatile (from water) via the gas-purge method, as no loss from the aqueous phase was observed at 22 and 37°C; an upper limit KH value was calculated at 2.9×10-11 Pa m3 mol-1 (20°C). Soil-water partitioning was determined by the batch equilibrium method using four soils collected from rice fields in the Sacramento Valley, and sorption affinity (Kd ), sorbent capacity, desorption and organic carbon-normalized distribution (Koc) were determined. Values for pH, cation exchange capacity, and organic matter content ranged between 4.5 to 6.6, 5.9 to 37.9, and 1.25 to 1.97%, respectively. Log Koc values (22 and 37°C) ranged between 2.6 to 2.7, while sorption capacity was low at 22°C and further decreased at 37°C. Hysteresis was observed in soils at both temperatures, suggesting that bound residues do not readily desorb. Photodegradation of clothianidin was characterized in deionized, Sacramento River, and rice field water samples. Pseudo first-order rate constants and DT50 values in rice field water (mean k = 0.0158 min-1; mean DT50 = 18.0 dequiv) were significantly slower than deionized (k = 0.0167 min -1; DT50 = 14.7 dequiv) and river water ( k = 0.0146 min-1; DT50 = 16.6 dequiv ) samples. Quantum yield C values demonstrate approximately 1% and 0.5% of the light energy absorbed results in photochemical transformation in pure and field water, respectively. Concentrations of the photodegradation product TZMU in aqueous photolysis samples were determined using LC-MS/MS analysis and accounted for ≤17% in deionized water and ≤8% in natural water. Microbial degradation of clothianidin was evaluated under flooded (anaerobic) and non-flooded (aerobic) microcosms. Clothianidin was recalcitrant to microbial degradation under aerobic conditions. First-order transformation rates and DT50 values of clothianidin in representative flooded soil at 35 ± 2°C (k = -7.16 x 10-2 ± 3.08 x 10-3 d-1, DT50 =9.7 d) were significantly faster than 25 ± 2°C microcosms °C ( k = -2.45 x 10-2 ± 1.59 x 10-3 d-1, DT50 = 28.3 d).

ObjectiveTo investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.MethodsEstablished patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.ResultsAlthough healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.ConclusionsIn two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.

Substance-use disorders are a public health crisis globally and carry with them significant morbidity and mortality. Stigma toward people who abuse these substances, as well as the internalization of that stigma by substance users, is widespread. In this review, we synthesized the available evidence for the role of perceived social stigma and self-stigma in people's willingness to seek treatment. While stigma may be frequently cited as a barrier to treatment in some samples, the degree of its impact on decision-making regarding treatment varied widely. More research needs to be done to standardize the definition and measurement of self- and perceived social stigma to fully determine the magnitude of their effect on treatment-seeking decisions.

The therapeutic potential of Wnt proteins has long been recognized but challenges associated with in vivo stability and delivery have hindered their development as drug candidates. By exploiting the hydrophobic nature of the protein we provide evidence that exogenous Wnt3a can be delivered in vivo if it is associated with a lipid vesicle. Recombinant Wnt3a associates with the external surface of the lipid membrane; this association stabilizes the protein and leads to prolonged activation of the Wnt pathway in primary cells. We demonstrate the consequences of Wnt pathway activation in vivo using a bone marrow engraftment assay. These data provide validation for the development of WNT3A as a therapeutic protein.

Sustaining the organisms, ecosystems and processes that underpin human wellbeing is necessary to achieve sustainable development. Here we define critical natural assets as the natural and semi-natural ecosystems that provide 90% of the total current magnitude of 14 types of nature’s contributions to people (NCP), and we map the global locations of these critical natural assets at 2 km resolution. Critical natural assets for maintaining local-scale NCP (12 of the 14 NCP) account for 30% of total global land area and 24% of national territorial waters, while 44% of land area is required to also maintain two global-scale NCP (carbon storage and moisture recycling). These areas overlap substantially with cultural diversity (areas containing 96% of global languages) and biodiversity (covering area requirements for 73% of birds and 66% of mammals). At least 87% of the world’s population live in the areas benefitting from critical natural assets for local-scale NCP, while only 16% live on the lands containing these assets. Many of the NCP mapped here are left out of international agreements focused on conserving species or mitigating climate change, yet this analysis shows that explicitly prioritizing critical natural assets and the NCP they provide could simultaneously advance development, climate and conservation goals. Bringing together multiple models and databases on nature’s contributions to people, the authors map these contributions globally and determine the critical areas where their magnitude is the highest and where they provide the highest potential human benefit.

Meeting global commitments to conservation, climate, and sustainable development requires consideration of synergies and tradeoffs among targets. We evaluate the spatial congruence of ecosystems providing globally high levels of nature’s contributions to people, biodiversity, and areas with high development potential across several sectors. We find that conserving approximately half of global land area through protection or sustainable management could provide 90% of the current levels of ten of nature’s contributions to people and meet minimum representation targets for 26,709 terrestrial vertebrate species. This finding supports recent commitments by national governments under the Global Biodiversity Framework to conserve at least 30% of global lands and waters, and proposals to conserve half of the Earth. More than one-third of areas required for conserving nature’s contributions to people and species are also highly suitable for agriculture, renewable energy, oil and gas, mining, or urban expansion. This indicates potential conflicts among conservation, climate and development goals. This study shows that conserving approximately half of global land area through protection or sustainable management could provide 90% of ten of nature’s contributions to people and could meet representation targets for 26,709 species of mammals, birds, amphibians, and reptiles. This finding supports recent commitments to conserve at least 30% of global lands and waters by 2030.