A circumpolar study unveils a positive non-linear effect of temperature on arctic arthropod availability that may reduce the risk of warming-induced trophic mismatch for breeding shorebirds.

Seasonally abundant arthropods are a crucial food source for many migratory birds that breed in the Arctic. In cold environments, the growth and emergence of arthropods are particularly tied to temperature. Thus, the phenology of arthropods is anticipated to undergo a rapid change in response to a warming climate, potentially leading to a trophic mismatch between migratory insectivorous birds and their prey. Using data from 19 sites spanning a wide temperature gradient from the Subarctic to the High Arctic, we investigated the effects of temperature on the phenology and biomass of arthropods available to shorebirds during their short breeding season at high latitudes. We hypothesized that prolonged exposure to warmer summer temperatures would generate earlier peaks in arthropod biomass, as well as higher peak and seasonal biomass. Across the temperature gradient encompassed by our study sites (>10°C in average summer temperatures), we found a 3-day shift in average peak date for every increment of 80 cumulative thawing degree-days. Interestingly, we found a linear relationship between temperature and arthropod biomass only below temperature thresholds. Higher temperatures were associated with higher peak and seasonal biomass below 106 and 177 cumulative thawing degree-days, respectively, between June 5 and July 15. Beyond these thresholds, no relationship was observed between temperature and arthropod biomass. Our results suggest that prolonged exposure to elevated temperatures can positively influence prey availability for some arctic birds. This positive effect could, in part, stem from changes in arthropod assemblages and may reduce the risk of trophic mismatch.

Why do avian responses to change in Arctic green-up vary?

Global climate change has altered the timing of seasonal events (i.e., phenology) for a diverse range of biota. Within and among species, however, the degree to which alterations in phenology match climate variability differ substantially. To better understand factors driving these differences, we evaluated variation in timing of nesting of eight Arctic-breeding shorebird species at 18 sites over a 23-year period. We used the Normalized Difference Vegetation Index as a proxy to determine the start of spring (SOS) growing season and quantified relationships between SOS and nest initiation dates as a measure of phenological responsiveness. Among species, we tested four life history traits (migration distance, seasonal timing of breeding, female body mass, expected female reproductive effort) as species-level predictors of responsiveness. For one species (Semipalmated Sandpiper), we also evaluated whether responsiveness varied across sites. Although no species in our study completely tracked annual variation in SOS, phenological responses were strongest for Western Sandpipers, Pectoral Sandpipers, and Red Phalaropes. Migration distance was the strongest additional predictor of responsiveness, with longer-distance migrant species generally tracking variation in SOS more closely than species that migrate shorter distances. Semipalmated Sandpipers are a widely distributed species, but adjustments in timing of nesting relative to variability in SOS did not vary across sites, suggesting that different breeding populations of this species were equally responsive to climate cues despite differing migration strategies. Our results unexpectedly show that long-distance migrants are more sensitive to local environmental conditions, which may help them to adapt to ongoing changes in climate.

Astringency and its sub-qualities: a review of astringency mechanisms and methods for measuring saliva lubrication.

Astringency is an important mouthfeel attribute that influences the sensory experiences of many food and beverage products. While salivary lubricity loss and increased oral friction were previously believed to be the only astringency mechanisms, recent research has demonstrated that nontactile oral receptors can trigger astringency by responding to astringents without mechanical stimulation. Various human factors have also been identified that affect individual responses to astringents. This article presents a critical review of the key research milestones contributing to the current understanding of astringency mechanisms and the instrumental approaches used to quantify perceived astringency intensity. Although various chemical assays or physical measures mimic in-mouth processes involved in astringent mouthfeel, this review highlights how one chemical or physical approach can only provide a single measure of astringency determined by a specific mechanism. Subsequently, using a single measurement to predict astringency perception is overly idealistic. Astringency has not been quantified beyond the loss of saliva lubrication; therefore, nontactile receptor-based responses must also be explored. An important question remains about whether astringency is a single perception or involves distinct sub-qualities such as pucker, drying, and roughness. Although these sub-quality lexicons have been frequently cited, most studies currently view astringency as a single perception rather than dividing it into sub-qualities and investigating the potentially independent mechanisms of each. Addressing these knowledge gaps should be an important priority for future research.

Sex and age affect depot expression of Ca2+ channels in rat white fat adipocytes.

White adipose tissue (WAT) requires extracellular Ca2+ influx for lipolysis, differentiation, and expansion. This partly occurs via plasma membrane Ca2+ voltage-dependent channels (CaVs). However, WFA exists in different depots whose function varies with age, sex, and location. To explore whether their CaV expression profiles also differ we used RNAseq and qPCR on gonadal, mesenteric, retroperitoneal, and inguinal subcutaneous fat depots from rats of different ages and sex. CaV expression was found dependent on age, sex, and WFA location. In the gonadal depots of both sexes a significantly lower expression of CaV1.2 and CaV1.3 was seen for adults compared to pre-pubescent juveniles. A lower level of expression was also seen for CaV3.1 in adult male but not female gonadal WFA, the latter of whose expression remained unchanged with age. Relatively little expression of CaV3.2 and 3.2 was observed. In post-pubescent inguinal subcutaneous fat, where the third and fourth mammary glands are located, CaV3.1 was decreased in males but increased in females - thus suggesting that this channel is associated with mammogenesis; however, no difference in intracellular Ca2+ levels or adipocyte size were noted. For all adult depots, CaV3.1 expression was larger in females than males - a difference not seen in pre-pubescent rats. These observations are consistent with the changes of CaV3.1 expression seen in 3T3-L1 cell differentiation and the ability of selective CaV3.1 antagonists to inhibit adipogensis. Our results show that changes in CaV expression patterns occur in fat depots related to sexual dimorphism: reproductive tracts and mammogenesis.

Taking the beat of the Arctic: are lemming population cycles changing due to winter climate?

Reports of fading vole and lemming population cycles and persisting low populations in some parts of the Arctic have raised concerns about the spread of these fundamental changes to tundra food web dynamics. By compiling 24 unique time series of lemming population fluctuations across the circumpolar region, we show that virtually all populations displayed alternating periods of cyclic/non-cyclic fluctuations over the past four decades. Cyclic patterns were detected 55% of the time (n = 649 years pooled across sites) with a median periodicity of 3.7 years, and non-cyclic periods were not more frequent in recent years. Overall, there was an indication for a negative effect of warm spells occurring during the snow onset period of the preceding year on lemming abundance. However, winter duration or early winter climatic conditions did not differ on average between cyclic and non-cyclic periods. Analysis of the time series shows that there is presently no Arctic-wide collapse of lemming cycles, even though cycles have been sporadic at most sites during the last decades. Although non-stationary dynamics appears a common feature of lemming populations also in the past, continued warming in early winter may decrease the frequency of periodic irruptions with negative consequences for tundra ecosystems.

Review of terrestrial temporarily conserved areas in Canada, the United States, and Mexico.

The establishment of protected areas is a cornerstone of conservation, but permanent protection could be inefficient or even impossible in some situations. We synthesized the literature on temporarily conserved areas (TCAs) across Canada, the United States, and Mexico. We used a comprehensive search string to retrieve peer-reviewed articles published from 2000 to 2021 from the Web of Science. We identified 27 relevant peer-reviewed articles that examined the potential benefits of TCAs in the study area, indicating TCA is a relatively understudied area of research in the peer-reviewed literature. The TCA studies were highly clustered; 77% of studies focused on protecting a single life stage of migratory species and 61% of studies related to temporary conservation of breeding or staging habitats for migratory birds. Ninety-three percent of studies focused on preventing human-driven threats, mainly on public lands of coastal areas, the Great Plains, and the Mississippi Valley in the central United States. Short-term and experimental studies were the dominant study types. TCAs have the potential to complement permanently protected areas and provide protection when permanent protection is difficult. Some included studies examined their conservation value, but the ecological, social, and economic outcomes of TCAs are unclear. More TCA research is needed to determine the role they could play in conservation worldwide. Embracing the concept of TCAs as conservation tool could lead to more comprehensive and consistent reporting of the outcomes of temporary area-based conservation measures. However, a global review and analysis of effectiveness of TCAs will be required if they are to play a formal role in meeting international targets for biodiversity conservation.

Revisión de áreas terrestres conservadas temporalmente en Canadá, Estados Unidos y México Resumen La creación de áreas protegidas es una piedra angular de la conservación, aunque en algunos casos la protección permanente podría ser ineficiente o incluso imposible. Condensamos la literatura sobre las áreas de conservación temporal (ACT) en Canadá, Estados Unidos y México. Usamos una cadena completa de búsqueda para obtener artículos revisados por pares publicados del 2000 al 2021 en Web of Science. Identificamos 27 artículos relevantes que analizaban el potencial de las ACT en el área de estudio, lo que indica que las ACT es un área poco estudiada en la literatura revisada por pares. Los estudios sobre ACT estaban muy agrupados: el 77% se enfocaban en la protección de un solo estadio de vida de las especies migratorias y el 61% se relacionaban con la conservación temporal de los hábitats de reproducción o de descanso de las aves migratorias. El 93% de los estudios se enfocó en la prevención de amenazas causadas por humanos, principalmente en los terrenos públicos de las áreas costeras, las Grandes Llanuras y el valle del Mississippi en el centro de los Estados Unidos. Los estudios experimentales y a corto plazo fueron el tipo de estudio dominante. Las áreas de conservación temporal tienen el potencial para complementar las áreas de protección permanente y proporcionar protección cuando es complicado proporcionarla permanentemente. Algunos de los estudios incluidos analizaron el valor para la conservación de las ACT, pero aún no están claros sus resultados ecológicos, sociales y económicos. Se necesita más investigación sobre las ACT para determinar el papel que podrían tener en la conservación mundial. Si se acepta el concepto de ACT como una herramienta de conservación, se podrían reportar los resultados de las medidas de conservación basadas en las ACT de forma más completa y consistente. Sin embargo, se requerirá una revisión y análisis global de la eficiencia de las ACT si se espera que tengan un papel formal en el cumplimiento de los objetivos internacionales de la conservación de la biodiversidad.

Factors influencing mercury exposure in Arctic-breeding shorebirds.

Mercury (Hg) pollution remains a concern to Arctic ecosystems, due to long-range transport from southern industrial regions and melting permafrost and glaciers. The objective of this study was to identify intrinsic, extrinsic, and temporal factors influencing Hg concentrations in Arctic-breeding shorebirds and highlight regions and species at greatest risk of Hg exposure. We analyzed 1094 blood and 1384 feather samples from 12 shorebird species breeding at nine sites across the North American Arctic during 2012 and 2013. Blood Hg concentrations, which reflect Hg exposure in the local area in individual shorebirds: 1) ranged from 0.01-3.52 µg/g ww, with an overall mean of 0.30 ± 0.27 µg/g ww; 2) were influenced by species and study site, but not sampling year, with birds sampled near Utqiagvik, AK, having the highest concentrations; and 3) were influenced by foraging habitat at some sites. Feather Hg concentrations, which reflected Hg exposure from the wintering grounds: 1) ranged from 0.07-12.14 µg/g fw in individuals, with an overall mean of 1.14 ± 1.18 µg/g fw; and 2) were influenced by species and year. Most Arctic-breeding shorebirds had blood and feather Hg concentrations at levels where no adverse effects of exposure were predicted, though some individuals sampled near Utqiagvik had Hg levels that would be considered of concern. Overall, these data increase our understanding of how Hg is distributed in the various shorebird breeding areas of the Arctic, what factors predispose Arctic-breeding shorebirds to Hg exposure, and lay the foundation for future monitoring efforts.

Preclinical immunological characterization of rademikibart (CBP-201), a next-generation human monoclonal antibody targeting IL-4Rα, for the treatment of Th2 inflammatory diseases.

Rademikibart (CBP-201) is a next-generation human monoclonal antibody targeting IL-4Rα, undergoing evaluation in Phase 2 clinical trials for the treatment of moderate-to-severe Th2 inflammatory diseases. We report the immunological characterization of rademikibart. Rademikibart and dupilumab were associated with KD of 20.7 pM and 45.8 pM, respectively, when binding to distinct human IL-4Rα epitopes. Rademikibart did not bind to IL-4Rα from other species. Rademikibart inhibited IL-4 and IL-13-mediated STAT6 signaling (mean ± SD IC50: 7.0 ± 2.5 and 6.6 ± 1.5 ng/mL, respectively), TF-1 cell proliferation (IC50: 8.0 ± 1.6 and 9.7 ± 0.8 ng/mL, respectively) and TARC production in PBMCs (IC50: 59.2 ± 3.9 and 13.5 ± 0.2 ng/mL, respectively). Rademikibart versus dupilumab was more potent in the STAT6 assays (IL-4, p < 0.01; IL-13, p = 0.03), with non-significant trends towards greater potency in the TF-1 cell assays (IL-4, p = 0.09; IL-13, p = 0.20), and similar potency in the TARC assays. In experiments with mice expressing human IL-4Rα and IL-4, rademikibart and dupilumab demonstrated similar potency; both monoclonal antibodies eliminated IL-4 (p < 0.0001) and IL-13 (p < 0.05) mediated B cell activation in vitro and ovalbumin-induced IgE (p < 0.01) and eosinophilic lung infiltration (p < 0.0001) in vivo. In Th2-stimulated human skin explants, rademikibart rapidly downregulated IL-4, IL-13, and TARC gene expression, with greater effectiveness than dupilumab for IL-4 (p < 0.01) and a non-significant trend towards superiority for IL-13. In summary, rademikibart bound to a distinct IL-4Rα epitope with high affinity and demonstrated reductions in Th2 inflammatory biomarkers with at least similar and potentially superior potency to dupilumab.

ArcticBirdSounds: An open-access, multiyear, and detailed annotated dataset of bird songs and calls.

Tracking biodiversity shifts is central to understanding past, present, and future global changes. Recent advances in bioacoustics and the low cost of high-quality automatic recorders are revolutionizing studies in biogeography and community and behavioral ecology with a robust assessment of phenology, species occurrence, and individual activity. This large volume of acoustic recordings has recently generated a plethora of datasets that can now be handled automatically, mostly via big data methods such as deep learning. These approaches need high-quality annotations to classify and detect recorded sounds efficiently. However, very few strongly annotated datasets-that is, with detailed information on start and end time of each vocalization-are openly accessible to the public. Moreover, these datasets mostly cover temperate species and are usually limited to a single year of recordings. Here, we present ArcticBirdSounds, the first open-access, multisite, and multiyear strongly annotated dataset of arctic bird vocalizations. ArcticBirdSounds offers 20 h of annotated recordings over 2 years (2018, 2019), taken from 15 distinct plots within six locations across the Arctic, from Alaska to Greenland. Recordings cover the arctic vertebrates' breeding period and are evenly spaced during the day; they capture most species breeding there with 12,933 temporal annotations in 49 classes of sounds. While these data can be used for many pressing ecological questions, it is also a unique resource for methodological development to help meet the challenges of fast ecosystem transformations such as those happening in the Arctic. All data, including audio files, annotation files, and companion spreadsheets, are available in an Open Science Framework repository published under a CC BY 4.0 License.

Applied winter biology: threats, conservation and management of biological resources during winter in cold climate regions.

Winter at high latitudes is characterized by low temperatures, dampened light levels and short photoperiods which shape ecological and evolutionary outcomes from cells to populations to ecosystems. Advances in our understanding of winter biological processes (spanning physiology, behaviour and ecology) highlight that biodiversity threats (e.g. climate change driven shifts in reproductive windows) may interact with winter conditions, leading to greater ecological impacts. As such, conservation and management strategies that consider winter processes and their consequences on biological mechanisms may lead to greater resilience of high altitude and latitude ecosystems. Here, we use well-established threat and action taxonomies produced by the International Union of Conservation of Nature-Conservation Measures Partnership (IUCN-CMP) to synthesize current threats to biota that emerge during, or as the result of, winter processes then discuss targeted management approaches for winter-based conservation. We demonstrate the importance of considering winter when identifying threats to biodiversity and deciding on appropriate management strategies across species and ecosystems. We confirm our expectation that threats are prevalent during the winter and are especially important considering the physiologically challenging conditions that winter presents. Moreover, our findings emphasize that climate change and winter-related constraints on organisms will intersect with other stressors to potentially magnify threats and further complicate management. Though conservation and management practices are less commonly considered during the winter season, we identified several potential or already realized applications relevant to winter that could be beneficial. Many of the examples are quite recent, suggesting a potential turning point for applied winter biology. This growing body of literature is promising but we submit that more research is needed to identify and address threats to wintering biota for targeted and proactive conservation. We suggest that management decisions consider the importance of winter and incorporate winter specific strategies for holistic and mechanistic conservation and resource management.

Climate variables are not the dominant predictor of Arctic shorebird distributions.

Competing theoretical perspectives about whether or not climate is the dominant factor influencing species' distributions at large spatial scales have important consequences when habitat suitability models are used to address conservation problems. In this study, we tested how much variables in addition to climate help to explain habitat suitability for Arctic-breeding shorebirds. To do this we model species occupancy using path analyses, which allow us to estimate the indirect effects of climate on other predictor variables, such as land cover. We also use deviance partitioning to quantify the total relative importance of climate versus additional predictors in explaining species occupancy. We found that individual land cover variables are often stronger predictors than the direct and indirect effects of climate combined. In models with both climate and additional variables, on average the additional variables accounted for 57% of the explained deviance, independent of shared effects with the climate variables. Our results support the idea that climate-only models may offer incomplete descriptions of current and future habitat suitability and can lead to incorrect conclusions about the size and location of suitable habitat. These conclusions could have important management implications for designating protected areas and assessing threats like climate change and human development.

Climate-related range shifts in Arctic-breeding shorebirds.

Aim: To test whether the occupancy of shorebirds has changed in the eastern Canadian Arctic, and whether these changes could indicate that shorebird distributions are shifting in response to long-term climate change. Location: Foxe Basin and Rasmussen Lowlands, Nunavut, Canada. Methods: We used a unique set of observations, made 25 years apart, using general linear models to test if there was a relationship between changes in shorebird species' occupancy and their species temperature Index, a simple version of a species climate envelope. Results: Changes in occupancy and density varied widely across species, with some increasing and some decreasing. This is despite that overall population trends are known to be negative for all of these species based on surveys during migration. The changes in occupancy that we observed were positively related to the species temperature index, such that the warmer-breeding species appear to be moving into these regions, while colder-breeding species appear to be shifting out of the regions, likely northward. Main Conclusions: Our results suggest that we should be concerned about declining breeding habitat availability for bird species whose current breeding ranges are centered on higher and colder latitudes.

Habitat alteration and fecal deposition by geese alter tundra invertebrate communities: Implications for diets of sympatric birds.

Over the last 60 years, Arctic goose populations have increased while many sympatric tundra nesting bird populations have declined. Hyperabundant geese have well-documented effects on tundra habitats, which can alter habitat use by sympatric bird species. These habitat changes may also alter invertebrate communities and abundances, with potentially important, but as of yet, undocumented effects on insectivorous birds such as shorebirds. Here, we determined the effects of goose-induced habitat alteration on invertebrate communities and relate the observed changes to shorebird diet. At sites and habitat types representing a gradient of goose influence, we identified goose-related changes in ground cover and linked these factors to variation in invertebrate communities. We then used DNA metabarcoding to characterize the diet of six shorebird species across sites and identify inter-site variation in abundance, biomass, and timing of emergence of dominant shorebird prey items. Invertebrate diversity and richness did not vary either among sites or habitat types. However, for prey items identified as part of the shorebird diet, we found significantly higher abundances and biomasses at a moderately goose-influenced site than at either low or high goose-influenced sites. Biomass of Tipulidae, the dominant prey taxon for shorebirds at the study sites, was 7.5 times higher at the moderately goose-influenced site compared to the site where goose influence was minor. We attribute this enhancement of prey biomass to both the fertilizing effect of goose fecal pellets and the moderate grazing pressure. Many studies have documented adverse effects of overabundant geese, but here we show that a moderate degree of goose grazing can lead to enhanced biomass of invertebrates, with the potential for improved shorebird foraging success and chick growth. These benefits, however, might be outweighed by negative effects of goose-induced habitat alteration and predation pressure.

Drought at a coastal wetland affects refuelling and migration strategies of shorebirds.

Droughts can affect invertebrate communities in wetlands, which can have bottom-up effects on the condition and survival of top predators. Shorebirds, key predators at coastal wetlands, have experienced widespread population declines and could be negatively affected by droughts. We explored, in detail, the effects of drought on multiple aspects of shorebird stopover and migration ecology by contrasting a year with average wet/dry conditions (2016) with a year with moderate drought (2017) at a major subarctic stopover site on southbound migration. We also examined the effects of drought on shorebird body mass during stopover across 14 years (historical: 1974-1982 and present-day: 2014-2018). For the detailed comparison of two years, in the year with moderate drought we documented lower invertebrate abundance at some sites, higher prey family richness in shorebird faecal samples, lower shorebird refuelling rates, shorter stopover durations for juveniles, and, for most species, a higher probability of making a subsequent stopover in North America after departing the subarctic, compared to the year with average wet/dry conditions. In the 14-year dataset, shorebird body mass tended to be lower in drier years. We show that even short-term, moderate drought conditions can negatively affect shorebird refuelling performance at coastal wetlands, which may carry-over to affect subsequent stopover decisions. Given shorebird population declines and predicted changes in the severity and duration of droughts with climate change, researchers should prioritize a better understanding of how droughts affect shorebird refuelling performance and survival.

The PI3Kδ inhibitor parsaclisib ameliorates pathology and reduces autoantibody formation in preclinical models of systemic lupus erythematosus and Sjӧgren's syndrome.

Dysregulation of phosphoinositide 3-kinase δ (PI3Kδ) signaling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases. Parsaclisib (INCB050465) represents a potent and selective PI3Kδ inhibitor, which is being clinically investigated for treatment of autoimmune hemolytic anemia and hematological malignancies. We characterized the potential of parsaclisib to ameliorate autoimmune mechanisms implicated in the pathophysiology of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Spontaneous mouse models of SLE and SS were utilized to elucidate the efficacy of orally administered parsaclisib on autoreactive B-cell-mediated antibody-driven disease. Parsaclisib significantly reduced disease symptoms and pathology in three distinct mouse models of SLE. Parsaclisib effectively preserved renal function as measured by glomerular filtration rate, abrogated histopathological evidence of nephritis, modulated discrete immune cell subsets, and decreased anti-dsDNA antibody level. Furthermore, parsaclisib demonstrated efficacy in two spontaneous mouse models of SS. Oral parsaclisib treatment ameliorated the severity of salivary gland inflammation and reduced circulating levels of autoantibodies. Parsaclisib mediated improvement of salivary gland inflammation coincided with reduced B-cell activating cytokine (BAFF) in saliva. Transcriptomic analysis of kidney and salivary gland tissues revealed a downregulation in inflammatory gene expression consistent with PI3Kδ pathway inhibition. Parsaclisib reduced autoreactive B-cells and autoantibody levels, and significantly improved nephritis and salivary gland inflammation. These data provide the scientific rationale for PI3Kδ inhibition as a therapeutic strategy for treatment of B-cell-mediated antibody-driven autoimmune diseases.

Ruxolitinib, a JAK1/2 Inhibitor, Ameliorates Cytokine Storm in Experimental Models of Hyperinflammation Syndrome.

Hyperinflammatory syndromes comprise a heterogeneous group of disorders characterized by severe inflammation, multiple organ dysfunction, and potentially death. In response to antigenic stimulus (e.g., SARS-CoV-2 infection), overactivated CD8+ T-cells and macrophages produce high levels of proinflammatory cytokines, such as IFN-γ, TNF-α, IL-6, and IL-12. Multiple inflammatory mediators implicated in hyperinflammatory syndromes utilize the Janus kinase-signal transducers and activators of transcription (JAK-STAT) cascade to propagate their biological function. Our findings demonstrate that oral ruxolitinib dosing designed to mimic clinically relevant JAK-STAT pathway inhibition significantly reduces the harmful consequences of immune overactivation in multiple hyperinflammatory models. In contrast to monoclonal antibody therapies targeting a single cytokine, ruxolitinib effectively downregulates the functional effect of multiple cytokines implicated in hyperinflammatory states, without broad immunosuppression.

Precipitation of Tannin-Anthocyanin Derivatives in Wine is Influenced by Acetaldehyde Concentration and Tannin Molecular Mass with Implications for the Development of Nonbleachable Pigments.

This study aimed to assess the effect of tannin molecular mass on nonbleachable pigment formation and subsequent stability under wine-like conditions. Tannin fractions of a defined molecular mass range were prepared from grape skins and seeds and reacted with malvidin-3-glucoside for 120 days in three media types: chemically defined wine media with or without acetaldehyde addition or model wine without acetaldehyde. Precipitation was observed after the reaction period and increased in response to both higher tannin molecular mass and acetaldehyde concentration. To confirm whether acetaldehyde-mediated condensation of tannin and anthocyanin modified the solubility of the nonbleachable pigments formed, HPLC-MS was used for the semiquantitative identification of vinyl derivatives and ethyl-linked adducts in soluble and precipitated materials. It was found that the proportion of vinyl derivatives and ethyl-linked anthocyanin was elevated in tannin precipitates relative to soluble pigmented material. Despite substantial losses of tannin due to precipitation, the resulting nonbleachable pigment concentration and color intensity were higher in wine media containing elevated acetaldehyde, when each tannin size category was considered independently. The results of this study indicated that the development of nonbleachable pigments from larger tannins may be limited when acetaldehyde-mediated condensation with anthocyanin predominates in wine, concomitant with precipitation.

Effect of mitochondrial complex III inhibitors on the regulation of vascular tone in porcine coronary artery.

In order to gain insight into the regulation of vascular tone by mitochondria, the effects of mitochondrial complex III inhibitors on contractile responses in porcine isolated coronary arteries were investigated. Segments of porcine coronary arteries were set up for isometric tension recording and concentration response curves to contractile agents were carried out in the absence or presence of the complex III inhibitors antimycin A or myxothiazol. Activity of AMP kinase was determined by measuring changes in phosphorylation of AMP kinase at Thr172. Pre-incubation with 10 µM antimycin A (Qi site inhibitor), or myxothiazol (Qo site inhibitor) led to inhibition of the contraction to the thromboxane receptor agonist U46619. Similar effects were seen on contractile responses to extracellular calcium, and the L-type calcium channel opener BAY K 8644, suggesting that both antimycin A and myxothiazol inhibit calcium-dependent contractions. The inhibitory effect of antimycin A was still seen in the absence of extracellular calcium, indicating an additional effect on a calcium independent pathway. The AMP kinase inhibitor dorsomorphin (10 µM) prevented the inhibitory of antimycin A but not myxothiazol. Furthermore, antimycin A increased the phosphorylation of AMP kinase, indicating an increase in activity, suggesting that antimycin A also acts through this pathway. These data indicate that inhibition of complex III attenuates contractile responses through inhibition of calcium influx. However, inhibition of the Qi site can also inhibit the contractile response through activation of AMP kinase.

Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy.

PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including IFNγ and IL6. EXPERIMENTAL DESIGN: Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor activity, and cytokine levels in in vitro and in vivo models. RESULTS: We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T cells adoptively transferred into CD19+ tumor-bearing immunodeficient animals was unabated by oral itacitinib treatment. CONCLUSIONS: Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T cell-induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).

Half of resources in threatened species conservation plans are allocated to research and monitoring.

Funds to combat biodiversity loss are insufficient, requiring conservation managers to make trade-offs between costs for actions to avoid further loss and costs for research and monitoring to guide effective actions. Using species' management plans for 2328 listed species from three countries we show that 50% of species' proposed recovery plan budgets are allocated to research and monitoring. The proportion of budgets allocated to research and monitoring vary among jurisdictions and taxa, but overall, species with higher proportions of budgets allocated to research and monitoring have poorer recovery outcomes. The proportion allocated to research and monitoring is lower for more recent recovery plans, but for some species, plans have allocated the majority of funds to information gathering for decades. We provide recommendations for careful examination of the value of collecting new information in recovery planning to ensure that conservation programs emphasize action or research and monitoring that directly informs action.