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Objective: Infiltration of adipocytes into the pancreatic parenchyma has been linked to impaired insulin secretion in individuals with increased genetic risk of T2D and prediabetic conditions. However, the study of this ectopic fat depot has been limited by the lack of suitable in vitro models. Methods: Here, we developed a novel 3D model of functionally mature human pancreatic adipose tissue organoids by aggregating human pancreatic adipose tissue-derived stromal vascular fraction (SVF) cells into organoids and differentiating them over 19 days. Results: These organoids carry biological properties of the in situ pancreatic fat, presenting levels of adipogenic markers comparable to native pancreatic adipocytes and improved lipolytic and anti-lipolytic response compared to conventional 2D cultures. The organoids harbour a small population of immune cells, mimicking in vivo adipose environment. Furthermore, they express GIPR, allowing investigation of incretin effects in pancreatic fat. In accordance, GIP and the dual GLP1R/GIPR agonist tirzepatide stimulate lipolysis but had distinct effects on the expression of proinflammatory cytokines. Conclusions: This novel adipose organoid model is a valuable tool to study the metabolic impact of incretin signalling in pancreatic adipose tissue, revealing potential therapeutic targets of incretins beyond islets. The donor-specific metabolic memory of these organoids enables examination of the pancreatic fat-islet crosstalk in a donor-related metabolic context.

An increasing number of climate model simulations is becoming available for the transition from the Last Glacial Maximum to the Holocene. Assessing the simulations' reliability requires benchmarking against environmental proxy records. To date, no established method exists to compare these two data sources in space and time over a period with changing background conditions. Here, we develop a new algorithm to rank simulations according to their deviation from reconstructed magnitudes and temporal patterns of orbital and millennial-scale temperature variations. The use of proxy forward modeling allows for accounting for non-climatic processes that affect the temperature reconstructions. It further avoids the need to reconstruct gridded fields or regional mean temperature time series from sparse and uncertain proxy data. First, we test the reliability and robustness of our algorithm in idealized experiments with prescribed deglacial temperature histories. We quantify the influence of limited temporal resolution, chronological uncertainties, and non-climatic processes by constructing noisy pseudo-proxies. While model–data comparison results become less reliable with increasing uncertainties, we find that the algorithm discriminates well between simulations under realistic non-climatic noise levels. To obtain reliable and robust rankings, we advise spatial averaging of the results for individual proxy records. Second, we demonstrate our method by quantifying the deviations between an ensemble of transient deglacial simulations and a global compilation of sea surface temperature reconstructions. The ranking of the simulations differs substantially between the considered regions and timescales, which suggests that optimizing for agreement with the temporal patterns of a small set of proxies might be insufficient for capturing the spatial structure of the deglacial temperature variability. We attribute the diversity in the rankings to more regionally confined temperature variations in reconstructions than in simulations, which could be the result of uncertainties in boundary conditions, shortcomings in models, or regionally varying characteristics of reconstructions such as recording seasons and depths. Future work towards disentangling these potential reasons can leverage the flexible design of our algorithm and its demonstrated ability to identify varying levels of model–data agreement. Additionally, the algorithm can be applied to variables like oxygen isotopes and climate transitions such as the penultimate deglaciation and the last glacial inception.

Modeling the long-term transient evolution of climate remains a technical and scientific challenge. However, understanding and improving modeling of the long-term behavior of the climate system increases confidence in projected changes in the mid- to long-term future. Energy balance models (EBMs) provide simplified and computationally efficient descriptions of long timescales and allow large ensemble runs by parameterizing energy fluxes. In this way, they can be used to pinpoint periods and phenomena of interest. Here, we present TransEBM, an extended version of the two-dimensional energy balance model by Zhuang et al. (2017a). Transient CO2, solar insolation, orbital configuration, fixed ice coverage, and land–sea distribution are implemented as effective radiative forcings at the land surface. We show that the model is most sensitive to changes in CO2 and ice distribution, but the obliquity and land–sea mask have significant influence on modeled temperatures as well. We tune TransEBM to reproduce the 1960–1989 CE global mean temperature and the Equator-to-pole and seasonal temperature gradients of ERA-20CM reanalysis (Hersbach et al., 2015). The resulting latitudinal and seasonal temperature distributions agree well with reanalysis and the general circulation model (GCM) HadCM3 for a simulation of the past millennium (Bühler et al., 2020). TransEBM does not represent the internal variability of the ocean–atmosphere system, but non-deterministic elements and nonlinearity can be introduced through model restarts and randomized forcing. As the model facilitates long transient simulations, we envisage its use in exploratory studies of stochastic forcing and perturbed parameterizations, thus complementing studies with comprehensive GCMs.

Dissolved organic matter (DOM) mobilized from the organic (O) horizons of forest soils is a temporally dynamic flux of carbon (C) and nutrients, and the fate of this DOM in downstream pools is dependent on the rate and pathways of water flow as well as its chemical composition. Here, we present observations of the composition of DOM mobilized weekly to monthly from O horizons in mature forest and adjacent harvested treatment plots. The study site was experimentally harvested, without replanting, 10-years prior to this study. Thus, the treatments differ significantly in terms of forest stand and soil properties, and they interact differently with the regional hydrometeorological conditions. This presented an opportunity to investigate the role of forest structure relative to environmental variation on soil DOM mobilization. On an annual basis, fluxes of total dissolved nitrogen (TDN) and dissolved organic nitrogen (DON) were largest from the warmer and thinner O horizons of the harvested (H) treatment compared to the forest (F) treatment; however, neither phosphate nor ammonium fluxes differed by treatment type. On a short-term basis in both H and F treatments, all fluxes were positively correlated to water input, and all concentrations were positively correlated to soil temperature and negatively correlated to water input. Soil moisture was negatively correlated to the C : N of DOM. These results suggest common seasonal controls on DOM mobilization regardless of harvesting treatment. Optical characterization of seasonally representative samples additionally supported a stronger control of season over harvesting. The chemical character of DOM mobilized during winter and snowmelt: lower C : N, higher specific ultraviolet absorbance and lower molecular weight of chromophoric DOM (CDOM; higher spectral slope ratio) were representative of relatively more decomposed DOM compared to that mobilized in summer and autumn. This shows that the decomposition of soil organic matter underneath a consistently deep snowpack is a key determinant of the composition of DOM mobilized from O horizons during winter and the hydrologically significant snowmelt period regardless of harvesting impact. Despite the higher proportion of aromatic DOM in the snowmelt samples, its lower molecular weight and rapid delivery from O to mineral horizons suggests that the snowmelt period is not likely to be a significant period of DOM sequestration by mineral soil. Rather, the higher-molecular-weight, high-C : N DOM mobilized during slow and relatively infrequent delivery during summer and rapid, frequent delivery during autumn are more likely to support periods of mineral soil sequestration and increased export of fresher terrestrial DOM, respectively. These observed seasonal dynamics in O horizon DOM suggest the predicted decreases in winter and spring snowfall and increasing autumn and winter rainfall with climate warming in this region will enhance mobilization of DOM that is more reactive to mineral interactions in deeper soil, but also more biological and photoreactive in the aquatic environment. Understanding the downstream consequences of this mobilized DOM in response to these shifts in precipitation timing and form can improve our ability to predict and manage forest C balance but requires understanding the response of landscape hydrology to these changing precipitation regimes.

One of the main sources of uncertainty in carbon budgets is that continental landscapes are made up of a heterogeneous mosaic of ecosystems. Here the authors put forward an integrative framework to improve estimates of land-atmosphere carbon exchange based on the accumulation of carbon in the landscape as constrained by its lateral export through rivers.

The fate of soil organic carbon (SOC) in boreal forests is dependent on the integrative ecosystem response to climate change. For example, boreal forest productivity is often nitrogen (N) limited, and climate warming can enhance N cycling and primary productivity. However, the net effect of this feedback on the SOC reservoir and its longevity with climate change remain unclear due to difficulty in detecting small differences between large and variable carbon (C) fluxes needed to determine net changes in soil reservoirs. The diagenetic state of SOC – resulting from the physicochemical and biological transformations that alter the original biomolecular composition of detrital inputs to soil over time – is useful for tracing the net response of SOC at the timescales relevant to climate change not usually discernible from fluxes and stocks alone. Here, we test two hypotheses using a mesic boreal forest climate transect: (1) the SOC diagenetic state is maintained across this climosequence, and (2) the maintenance of the SOC diagenetic state is a consequence of coupled soil C and N cycling, signifying the role of enhanced N cycling supporting SOC inputs that maintain SOC stocks within the warmer-climate forests. Shifts in nonvascular to vascular plant inputs with climate observed in these and other boreal forests highlighted the need to carefully separate biogeochemical indicators of SOC source from those signifying diagenetic alteration. We thus evaluated and applied lignin biomarkers to assess the diagenetic alteration of SOC in these boreal forest organic soils and directly compared the lignin diagenetic state with that of soil organic nitrogen (SON) assessed through amino acid composition. The lignin diagenetic state remained constant across the climate transect, indicating a balance between the input and removal of lignin in these mesic boreal forests. When combined with previous knowledge of these forest ecosystems, including the diagenetic state of SON and direct measures of C fluxes and stocks, the results indicate a coupled increase in C and N cycling with climate warming that supports forest productivity and maintains SOC stocks. This balance could markedly shift as other factors begin to limit forest productivity (e.g., trace nutrients, water) with further climate change or affect forest nutrient allocation (e.g., forest age or compositional change). Further application of the approach presented here could be used to detect the limits of this and other ecosystem–climate feedbacks, by providing a tractable and parameterizable index of the lignin state across large spatial scales, necessary for ecosystem-scale parameterizations.

BackgroundTo inform the development of an intervention, it is essential to have a well-developed theoretical understanding of how an intervention causes change, as stated in the UK Medical Research Council guidelines for developing complex interventions. Theoretical foundations are often ignored in the development of mobile health apps intended to support pain self-management for patients with cancer. ObjectiveThis study aims to systematically set a theory- and evidence-driven design for a pain self-management app and specify the app’s active features. MethodsThe Behavior Change Wheel (BCW) framework, a step-by-step theoretical approach to the development of interventions, was adopted to achieve the aim of this study. This started by understanding and identifying sources of behavior that could be targeted to support better pain management. Ultimately, the application of the BCW framework guided the identification of the active contents of the app, which were characterized using the Behavior Change Technique Taxonomy version 1. ResultsThe theoretical analysis revealed that patients may have deficits in their capability, opportunity, and motivation that prevent them from performing pain self-management. The app needs to use education, persuasion, training, and enablement intervention functions because, based on the analysis, they were found the most likely to address the specified factors. Eighteen behavior change techniques were selected to describe precisely how the intervention functions can be presented to induce the desired change regarding the intervention context. In other words, they were selected to form the active contents of the app, potentially reducing barriers and serving to support patients in the self-management of pain while using the app. ConclusionsThis study fully reports the design and development of a pain self-management app underpinned by theory and evidence and intended for patients with cancer. It provides a model example of the BCW framework application for health app development. The work presented in this study is the first systematic theory- and evidence-driven design for a pain app for patients with cancer. This systematic approach can support clarity in evaluating the intervention’s underlying mechanisms and support future replication.

Infections with hepatotropic viruses are associated with various immune phenomena. Hepatitis D virus (HDV) causes the most severe form of viral hepatitis. However, few recent data are available on non-disease-specific and non-organ-specific antibody (NOSA) titers and immunoglobulin G (IgG) levels in chronic hepatitis D (CHD) patients. Here, we examined the NOSA titers and IgG levels of 40 patients with CHD and different disease courses and compared them to 70 patients with chronic hepatitis B (CHB) infection. 43% of CHD patients had previously undergone treatment with pegylated interferon-α (IFN-α). The antibody display of 46 untreated patients diagnosed with autoimmune hepatitis (AIH) was used as a reference. The frequency of elevated NOSA titers (CHD 69% vs. CHB 43%, p

The crosstalk between NK cells and their surrounding environment is enabled through activating and inhibitory receptors, which tightly control NK cell activity. The co-inhibitory receptor TIGIT decreases NK cell cytotoxicity and is involved in NK cell exhaustion, but has also been associated with liver regeneration, highlighting that the contribution of human intrahepatic CD56bright NK cells in regulating tissue homeostasis remains incompletely understood. A targeted single-cell mRNA analysis revealed distinct transcriptional differences between matched human peripheral blood and intrahepatic CD56bright NK cells. Multiparameter flow cytometry identified a cluster of intrahepatic NK cells with overlapping high expression of CD56, CD69, CXCR6, TIGIT and CD96. Intrahepatic CD56bright NK cells also expressed significantly higher protein surface levels of TIGIT, and significantly lower levels of DNAM-1 compared to matched peripheral blood CD56bright NK cells. TIGIT+ CD56bright NK cells showed diminished degranulation and TNF-α production following stimulation. Co-incubation of peripheral blood CD56bright NK cells with human hepatoma cells or primary human hepatocyte organoids resulted in migration of NK cells into hepatocyte organoids and upregulation of TIGIT and downregulation of DNAM-1 expression, in line with the phenotype of intrahepatic CD56bright NK cells. Intrahepatic CD56bright NK cells represent a transcriptionally, phenotypically, and functionally distinct population of NK cells that expresses higher levels of TIGIT and lower levels of DNAM-1 than matched peripheral blood CD56bright NK cells. Increased expression of inhibitory receptors by NK cells within the liver environment can contribute to tissue homeostasis and reduction of liver inflammation.

Given America’s leading position in the global economy, the U.S. government has frequently leveraged that power to punish “rogue states”, discourage nuclear proliferation, promote democratization, and create pressure for regime change. Washington relied on economic incentives in relations with Russia after 1991, but since 2012 the United States has utilized a broad range of economic sanctions against Russian side, leading to a significant deterioration in what was already a troubled relationship. In contrast to earlier comprehensive sanctions like those imposed on Iraq and Haiti, the U.S. is now crafting “smart” or targeted sanctions designed to exert maximum pressure on selected Russian elites and firms. Rather than evaluating the effectiveness of these measures on changing Russian behavior, the author explores the neglected domestic dimension of the U.S. sanctions process to improve understanding of U.S. foreign policy. This article draws on primary sources in the form of Congressional legislation, executive orders, and official statements to analyze U.S. sanctions imposed on Russia, and develops three brief case studies - the Magnitsky Act, post-Ukraine sanctions, and the Countering America’s Adversaries Through Sanctions Act - to explicate the main issues and actors driving U.S. sanctions. The author argues that domestic factors, including Congressional pressures and interest group activity, are critical to understanding U.S. sanctions regimes. While President Donald Trump has frequently resisted congressionally imposed sanctions, expectations for a more conciliatory approach towards Russia under the Trump administration have not materialized.

The transcription factor promyelocytic leukemia zinc finger protein (PLZF) is involved in the development of natural killer (NK) cells and innate lymphoid cells, including liver‐resident NK cells in mice. In human NK cells, the role of PLZF in liver residency is still unknown. Expression of PLZF in matched human peripheral blood‐ and liver‐derived NK cells and the association of PLZF expression with surface molecules and transcription factors relevant for tissue residency were investigated using multiparameter flow cytometry and assessing single‐cell messenger RNA (mRNA) levels. Intrahepatic cluster of differentiation (CD)56bright NK cells expressed significantly higher levels of PLZF than peripheral blood CD56bright NK cells, which were predominantly PLZFlo. Expression of PLZF was highest within C‐X‐C motif chemokine receptor 6 (CXCR6)+CD69+ liver‐resident NK cells among intrahepatic CD56bright NK cell populations. Association of PLZF with liver‐residency markers was also reflected at mRNA levels. A small PLZFhiCD56bright NK cell population was identified in peripheral blood that also expressed the liver‐residency markers CXCR6 and CD69 and shared functional characteristics with liver‐resident NK cells. Conclusion: PLZF is implicated as part of a transcriptional network that promotes liver residency of human NK cells. Expression of liver‐homing markers on peripheral blood PLZFhiCD56bright NK cells identifies an intermediate population potentially contributing to the maintenance of liver‐resident NK cells.

Amines are important drivers in particle formation and growth, which have implications for Earth's climate. In this work, we developed an ion chromatographic (IC) method using sample cation-exchange preconcentration for separating and quantifying the nine most abundant atmospheric alkylamines (monomethylamine (MMAH+), dimethylamine (DMAH+), trimethylamine (TMAH+), monoethylamine (MEAH+), diethylamine (DEAH+), triethylamine (TEAH+), monopropylamine (MPAH+), isomonopropylamine (iMPAH+), and monobutylamine (MBAH+)) and two alkyl diamines (1, 4-diaminobutane (DABH+) and 1, 5-diaminopentane (DAPH+)). Further, the developed method separates the suite of amines from five common atmospheric inorganic cations (Na+, NH4+, K+, Mg2+, Ca2+). All 16 cations are greater than 95 % baseline resolved and elute in a runtime of 35 min. This paper describes the first successful separation of DEAH+ and TMAH+ by IC and achieves separation between three sets of structural isomers, providing specificity not possible by mass spectrometry. The method detection limits for the alkylamines are in the picogram per injection range and the method precision (±1σ) analyzed over 3 months was within 16 % for all the cations. The performance of the IC method for atmospheric application was tested with biomass-burning (BB) particle extracts collected from two forest fire plumes in Canada. In extracts of a size-resolved BB sample from an aged plume, we detected and quantified MMAH+, DMAH+, TMAH+, MEAH+, DEAH+, and TEAH+ in the presence of Na+, NH4+, and K+ at molar ratios of amine to inorganic cation ranging from 1 : 2 to 1 : 1000. Quantities of DEAH+ and DMAH+ of 0.2–200 and 3–1200 ng m−3, respectively, were present in the extracts and an unprecedented amine-to-ammonium molar ratio greater than 1 was observed in particles with diameters spanning 56–180 nm. Extracts of respirable fine-mode particles (PM2. 5) from a summer forest fire in British Columbia in 2015 were found to contain iMPAH+, TMAH+, DEAH+ and TEAH+ at molar ratios of 1 : 300 with the dominant cations. The amine-to-ammonium ratio in a time series of samples never exceeded 0.15 during the sampling of the plume. These results and an amine standard addition demonstrate the robustness and sensitivity of the developed method when applied to the complex matrix of BB particle samples. The detection of multiple alkylamines in the analyzed BB samples indicates that this speciation and quantitation approach can be used to constrain BB emission estimates and the biogeochemical cycling of these reduced nitrogen species.

The objective of early premature infant nutrition is to maintain, during the turbulent early days of life, a flow of nutrients that differs only minimally from that which would have prevailed had the infant remained in utero. Out of necessity, nutrients have at first to be provided mainly via the parenteral route. While that is going on, the feeding of small amounts of human milk (gut priming) is initiated as soon as practical. As mother's own milk is not available in sufficient quantity at this time, donor milk needs to be used temporarily. If not available, formula should be used. Gastric residuals are physiologic at this stage and are monitored to guide the increase of the size of feedings. As the volume of milk is gradually increased, nutrient fortification is initiated when the milk volume reaches around 20 ml/kg/day. There is no need to start with less than full-strength fortification. Fortification should employ one of the liquid fortifiers. Adjustable fortification may be employed but is labor-intensive and is not a necessity as long as full feeding volumes of around 170 ml/kg/day are maintained. As the infant grows beyond 1,500 g the level of fortification can be reduced gradually by omitting fortification first from one, and then from more feedings. After discharge there is still a need for fortification, which requires the mother to express some of her milk so it can be fortified. Nutrient supplementation directly to the infant would obviate the need for milk expression.