Analytic Regularity and GPC Approximation for Control Problems Constrained by Linear Parametric Elliptic and Parabolic PDEs

This paper deals with linear-quadratic optimal control problems constrained by a parametric or stochastic elliptic or parabolic PDE. We address the (difficult) case that the state equation depends on a countable number of parameters i.e., on $\sigma_j$ with $j\in\N$, and that the PDE operator may depend non-affinely on the parameters. We consider tracking-type functionals and distributed as well as boundary controls. Building on recent results in [CDS1, CDS2], we show that the state and the control are analytic as functions depending on these parameters $\sigma_j$. We establish sparsity of generalized polynomial chaos (gpc) expansions of both, state and control, in terms of the stochastic coordinate sequence $\sigma = (\sigma_j)_{j\ge 1}$ of the random inputs, and prove convergence rates of best $N$-term truncations of these expansions. Such truncations are the key for subsequent computations since they do {\em not} assume that the stochastic input data has a finite expansion. In the follow-up paper [KS2], we explain two methods how such best $N$-term truncations can practically be computed, by greedy-type algorithms as in [SG, Gi1], or by multilevel Monte-Carlo methods as in [KSS]. The sparsity result allows in conjunction with adaptive wavelet Galerkin schemes for sparse, adaptive tensor discretizations of control problems constrained by linear elliptic and parabolic PDEs developed in [DK, GK, K], see [KS2]

Ion channels in control of pancreatic stellate cell migration

Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all “hallmarks of cancer” such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of K(Ca)3.1 channels in PSCs. K(Ca)3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of K(Ca)3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of K(Ca)3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2(+) concentration ([Ca(2+)](i)). K(Ca)3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca(2+)](i) and calpain activity. K(Ca)3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of K(Ca)3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology

A Novel NHE1-Centered Signaling Cassette Drives Epidermal Growth Factor Receptor–Dependent Pancreatic Tumor Metastasis and Is a Target for Combination Therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na+/H+ exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na +/H + exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na +/H + exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib

Worse glycemic control, higher rates of diabetic ketoacidosis, and more hospitalizations in children, adolescents, and young adults with type 1 diabetes and anxiety disorders

The aim of the study was to explore the metabolic characteristics and outcome parameters in youth with type 1 diabetes and anxiety disorders. HbA1c levels, rates of severe hypoglycemia, diabetic ketoacidosis (DKA), and hospital admission in children, adolescents, and young adults with type 1 diabetes and an anxiety disorder from 431 diabetes-care-centers participating in the nationwide German/Austrian/Swiss/Luxembourgian diabetes survey DPV were analyzed and compared with youth without anxiety disorders. Children, adolescents, and young adults with type 1 diabetes and anxiety disorders (n = 1325) had significantly higher HbA1c (8.5% vs. 8.2%), higher rates of DKA (4.2 vs. 2.5 per 100 patient-years), and higher hospital admission rates (63.6 vs. 40.0 per 100 patient-years) than youth without anxiety disorders (all p < 0.001). Rates of severe hypoglycemia did not differ. Individuals with anxiety disorders other than needle phobia (n = 771) had higher rates of DKA compared to those without anxiety disorders (4.2 vs. 2.5 per 100 patient-years, p = 0.003) whereas the rate of DKA in individuals with needle phobia (n = 555) was not significantly different compared to those without anxiety disorders. Children, adolescents, and young adults with anxiety disorders other than needle phobia had higher hospitalization rates (73.7 vs. 51.4 per 100 patient-years) and more inpatient days (13.2 vs. 10.1 days) compared to those with needle phobia (all p < 0.001). Children, adolescents, and young adults with type 1 diabetes and anxiety disorders had worse glycemic control, higher rates of DKA, and more hospitalizations compared to those without anxiety disorders. Because of the considerable consequences, clinicians should screen for comorbid anxiety disorders in youth with type 1 diabetes

Bone marrow haematopoiesis in patients with COVID-19

AIMS Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection broadly affects organ homeostasis, including the haematopoietic system. Autopsy studies are a crucial tool for investigation of organ-specific pathologies. Here we perform an in-depth analysis of the impact of severe coronavirus disease 2019 (COVID-19) on bone marrow haematopoiesis in correlation with clinical and laboratory parameters. METHODS AND RESULTS Twenty-eight autopsy cases and five controls from two academic centres were included in the study. We performed a comprehensive analysis of bone marrow pathology and microenvironment features with clinical and laboratory parameters and assessed SARS-CoV-2 infection of the bone marrow by quantitative polymerase chain reaction (qPCR) analysis. In COVID-19 patients, bone marrow specimens showed a left-shifted myelopoiesis (19 of 28, 64%), increased myeloid-erythroid ratio (eight of 28, 28%), increased megakaryopoiesis (six of 28, 21%) and lymphocytosis (four of 28, 14%). Strikingly, a high proportion of COVID-19 specimens showed erythrophagocytosis (15 of 28, 54%) and the presence of siderophages (11 of 15, 73%) compared to control cases (none of five, 0%). Clinically, erythrophagocytosis correlated with lower haemoglobin levels and was more frequently observed in patients from the second wave. Analysis of the immune environment showed a strong increase in CD68+ macrophages (16 of 28, 57%) and a borderline lymphocytosis (five of 28, 18%). The stromal microenvironment showed oedema (two of 28, 7%) and severe capillary congestion (one of 28, 4%) in isolated cases. No stromal fibrosis or microvascular thrombosis was found. While all cases had confirmed positive testing of SARS-CoV-2 in the respiratory system, SARS-CoV-2 was not detected in the bone marrow by high-sensitivity PCR, suggesting that SARS-CoV-2 does not commonly replicate in the haematopoietic microenvironment. CONCLUSIONS SARS-CoV-2 infection indirectly impacts the haematological compartment and the bone marrow immune environment. Erythrophagocytosis is frequent and associated with lower haemoglobin levels in patients with severe COVID-19

Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica

BACKGROUND Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patient

Innovating carbon-capture biotechnologies through ecosystem-inspired solutions

Rising atmospheric carbon concentrations affect global health, the economy, and overall quality of life. We are fast approaching climate tipping points that must be addressed, not only by reducing emissions but also through new innovation and action toward carbon capture for sequestration and utilization (CCSU). In this perspective, we delineate next-generation biotechnologies for CCSU supported by engineering design principles derived from ecological processes inspired by three major biomes (plant-soil, deep biosphere, and marine). These are to interface with existing industrial infrastructure and, in some cases, tap into the carbon sink potential of nature. To develop ecosystem-inspired biotechnology, it is important to identify accessible control points of CO2 and CH4 within a given system as well as value-chain opportunities that drive innovation. In essence, we must supplement natural biogeochemical carbon sinks with new bioengineering solutions

Initial State Dependence of the Breakup of Weakly Bound Carbon Isotopes

The one-neutron nuclear breakup from the Carbon isotopes $^{19}$C and $^{17}$C, is calculated as an example of application of the theory of transfer to the continuum reactions in the formulation which includes spin coupling. The effect of the energy sharing between the parallel and transverse neutron momentum distributions is taken into account thus resulting in a theory which is more general than sudden eikonal approaches. Both effects are necessary to understand properly the breakup from not too weakly bound $l_i>1$ orbitals. Breakup which leaves the core into an excited state below particle threshold is also considered. The core-target interaction is treated in the smooth cut-off approximation. By comparing to presently available experimental data we show how to make some hypothesis on the quantum numbers and occupancy of the neutron initial state. Possible ambiguities in the interpretation of inclusive cross sections are discussed.Comment: 22 RevTeX pages,3 ps figures. Phys. Rev. C, accepte

Climate control on terrestrial biospheric carbon turnover

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Eglinton, T. I., Galy, V. V., Hemingway, J. D., Feng, X., Bao, H., Blattmann, T. M., Dickens, A. F., Gies, H., Giosan, L., Haghipour, N., Hou, P., Lupker, M., McIntyre, C. P., Montluçon, D. B., Peucker-Ehrenbrink, B., Ponton, C., Schefuß, E., Schwab, M. S., Voss, B. M., Wacker, L., Wu, Y., & Zhao, M. Climate control on terrestrial biospheric carbon turnover. Proceedings of the National Academy of Sciences of the United States of America, 118(8), (2021): e2011585118, htps://doi.org/ 10.1073/pnas.2011585118.Terrestrial vegetation and soils hold three times more carbon than the atmosphere. Much debate concerns how anthropogenic activity will perturb these surface reservoirs, potentially exacerbating ongoing changes to the climate system. Uncertainties specifically persist in extrapolating point-source observations to ecosystem-scale budgets and fluxes, which require consideration of vertical and lateral processes on multiple temporal and spatial scales. To explore controls on organic carbon (OC) turnover at the river basin scale, we present radiocarbon (14C) ages on two groups of molecular tracers of plant-derived carbon—leaf-wax lipids and lignin phenols—from a globally distributed suite of rivers. We find significant negative relationships between the 14C age of these biomarkers and mean annual temperature and precipitation. Moreover, riverine biospheric-carbon ages scale proportionally with basin-wide soil carbon turnover times and soil 14C ages, implicating OC cycling within soils as a primary control on exported biomarker ages and revealing a broad distribution of soil OC reactivities. The ubiquitous occurrence of a long-lived soil OC pool suggests soil OC is globally vulnerable to perturbations by future temperature and precipitation increase. Scaling of riverine biospheric-carbon ages with soil OC turnover shows the former can constrain the sensitivity of carbon dynamics to environmental controls on broad spatial scales. Extracting this information from fluvially dominated sedimentary sequences may inform past variations in soil OC turnover in response to anthropogenic and/or climate perturbations. In turn, monitoring riverine OC composition may help detect future climate-change–induced perturbations of soil OC turnover and stocks.This work was supported by grants from the US NSF (OCE-0928582 to T.I.E. and V.V.G.; OCE-0851015 to B.P.-E., T.I.E., and V.V.G.; and EAR-1226818 to B.P.-E.), Swiss National Science Foundation (200021_140850, 200020_163162, and 200020_184865 to T.I.E.), and National Natural Science Foundation of China (41520104009 to M.Z.)