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Background and purpose: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late‐onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. Methods: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in‐person meeting, three rounds of discussion and voting to provide a consensus recommendation. Results: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient‐by‐patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion‐associated reactions. Switching of ERT should be discussed on a patient‐by‐patient shared‐decision basis. If there are severe, unmanageable infusion‐associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six‐monthly European Pompe Consortium muscle function assessments are recommended. Conclusions: The triple‐S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six‐monthly long‐term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT. [ABSTRACT FROM AUTHOR]

Subsurface drainage plays a crucial role in excess water removal through perforated pipes buried in the soil. The Red River Valley of eastern North Dakota and west central Minnesota often requires pumped drainage outlets due to its flat topography, with many modern systems incorporating variable frequency drives (VFD) for improved efficiency. VFDs adjust pump speeds to match drainage needs, but this dynamic operation complicates accurate flow rate estimation for edge-of-field monitoring. This project aimed to devise an automated method for calculating flow rate estimates from VFD pumping systems involving tank geometry, operational water levels, and pump duty cycling. Linear regressions with calibration data from a transit-time ultrasonic flowmeter produced mixed outcomes. Some linear regressions revealed errors in calculated versus measured flow rate of =14%, while other regressions showed errors nearing 40%. To address this, future efforts should explore methods incorporating the pump's electrical characteristics. This approach would provide a more accurate representation of the unstable and intricate pumping operations during transient conditions. [ABSTRACT FROM AUTHOR]

Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non‐invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium‐labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase‐encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non‐Cartesian spatial‐spectral sampling schemes for whole‐brain 2H FID‐MR Spectroscopic Imaging to assess time‐resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower‐resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6′]‐2H glucose. Time‐resolved whole brain 2H FID‐DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density‐weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal‐to‐noise ratios associated with smaller voxels, low‐rank denoising of the spatiotemporal data was performed during reconstruction. Sixty‐three minutes after oral tracer uptake three‐dimensional (3D) CRT‐DMI maps featured 19% higher (p =.006) deuterium‐labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p =.01) 2H‐Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low‐resolution PE‐DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM‐ and WM‐dominated areas for 2H‐Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p =.045), while no regional differences were observed for 2H‐Glx concentrations. In this study, we successfully implemented 3D FID‐MRSI with fast CRT encoding for dynamic whole‐brain DMI at 7 T with 2.5‐fold increased spatial resolution compared with conventional whole‐brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM‐ compared with WM‐dominated regions, which could not be reproduced using whole‐brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non‐invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications. [ABSTRACT FROM AUTHOR]

Objective: To assess the oncological and functional outcomes of focal high‐intensity focused ultrasound (HIFU) in treating localised prostate cancer (PCa), a 3‐year prospective study was undertaken using periodic post‐ablation saturation biopsies. Patients and Methods: Men with two or fewer lesions of grade group (GG) ≤3 PCa were eligible for participation. Additional criteria included a prostate‐specific antigen (PSA) level of ≤15 ng/mL, clinical T1c‐T2, and a life expectancy of ≥10 years. The primary endpoint was failure‐free survival (FFS), defined as absence of clinically significant PCa (csPCa) in‐ or out‐of‐field on protocol‐mandated saturation biopsy, no whole‐gland or systemic salvage treatment, PCa metastasis, or PCa‐related death. Results are reported using two distinct definitions of csPCa: (i) the presence of any GG ≥2 and (ii) any GG ≥3 or core involvement of ≥6 mm. Secondary endpoints were functional patient‐reported outcome measures addressing urinary, sexual, and bowel function. Results: A total of 91 patients were included: six (7%) with GG1 and 85 (93%) with GG ≥2. In all, 83 (91%) underwent at least one follow‐up biopsy. Biopsy attendance at 6, 12, and 36 months was 84%, 67%, and 51%, respectively. The FFS at these time points for any GG ≥2 PCa was 79% (95% confidence interval [CI] 80–88%), 57% (95% CI 48–69%) and 44% (95% CI 34–56%), respectively. Using the second definition, FFS were 88% (95% CI 81–95%), 70% (95% CI 61–81%) and 65% (95% CI 55–77%), respectively. The 3‐year cancer‐specific survival was 100%, and freedom from metastasis was 99%. Magnetic resonance imaging (MRI) (negative predictive value of up to 89%, 95% CI 84–93%) and relative decrease of PSA values (P = 0.4) performed poorly in detecting residual disease. Urinary and bowel assessment returned to baseline questionnaire scores within 3 months. In all, 17 (21%) patients reported meaningful worsening in erectile function. A significant decrease of PCa related anxiety was observed. Conclusions: Focal HIFU treatment for localised PCa shows excellent functional outcomes with half of the patients remaining cancer‐free after 3 years. Whole‐gland treatment was avoided in 81%. Early follow‐up biopsies are crucial to change or continue the treatment modality at the right time, while the use of MRI and PSA in detecting PCa recurrence is uncertain. [ABSTRACT FROM AUTHOR]

Based on the question of the representability of economy and economics in audiovisual media, developments on the financial markets have often been discussed as a depiction problem. The abstractness and complexity of economic interrelations seem to defy classical modes of storytelling and dramatization. Nevertheless, public opinion about economic changes and dependencies crucially relies on audiovisual media. But how can the public communicate in images, sounds, and words about forces that are out of sight and out of reach, and can supposedly only be adequately grasped by experts? In a case study on audiovisual images of the global financial crisis (2007–), this paper tracks and analyzes a recurring motif: the staging of expert knowledge as close‐ups of expressive faces vis‐à‐vis computer screens in television news, documentaries, as well as feature films. It draws on the use of digital tools for corpus exploration (reverse image search) and the visualization of video annotations. By relating and comparing different staging strategies by which these "broker faces" become embodiments of turbulent market dynamics, the paper proposes to not regard them as repeated instantiations of the same metaphor, but as a developing web of cinematic metaphors. Different perspectives (news of market developments or historical accounts of crisis developments) and affective stances toward the global financial crisis are expressed in these variations of the face‐screen constellation. The paper thus presents a selection of different appearances of "broker faces" as a medium for an audiovisual discourse of the global financial crisis. A concluding analysis of a scene from Margin Call focuses on its specific intertwining of expert and screen as an ambivalent movement figuration of staging insight. Between the feeling of discovery (of a potential future threat) and the sense of being haunted (by a menacing force), the film stages the emergence of a "broker face" in an atmospheric tension between suspense and melancholy. We argue that the film thereby reframes the motif and poses questions of agency, temporality, and expert knowledge. [ABSTRACT FROM AUTHOR]

Subsurface drainage plays a crucial role in excess water removal through perforated pipes buried in the soil. The Red River Valley of eastern North Dakota and west central Minnesota often requires pumped drainage outlets due to its flat topography, with many modern systems incorporating variable frequency drives (VFD) for improved efficiency. VFDs adjust pump speeds to match drainage needs, but this dynamic operation complicates accurate flow rate estimation for edge-of-field monitoring. This project aimed to devise an automated method for calculating flow rate estimates from VFD pumping systems involving tank geometry, operational water levels, and pump duty cycling. Linear regressions with calibration data from a transit-time ultrasonic flowmeter produced mixed outcomes. Some linear regressions revealed errors in calculated versus measured flow rate of ≤14%, while other regressions showed errors nearing 40%. To address this, future efforts should explore methods incorporating the pump’s electrical characteristics. This approach would provide a more accurate representation of the unstable and intricate pumping operations during transient conditions. [ABSTRACT FROM AUTHOR]

Context: Non-alcoholic fatty liver disease (NAFLD) is a leading causes of liver-related morbidity and mortality. While data on acromegaly, a state of chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess, suggest an inverse relationship with intrahepatic lipid (IHL) content, less is known about the impact of the GH/IGF-I axis on IHL, lipid composition, and phosphor metabolites in individuals without disorders of GH secretion. Objective: The aim was to investigate the relation between activity of the GH/IGF-I axis and IHL content and phosphor metabolism. Methods: We performed a cross-sectional study in 59 otherwise metabolically healthy individuals (30 females), of which 16 met the criteria of NAFLD with IHL of ≥5.6%. The GH/IGF-I axis was evaluated in a fasting state and during an oral glucose tolerance test (OGTT). Insulin sensitivity was estimated by validated indices. IHL, lipid composition (unsaturation index), and phosphate metabolites were analyzed by using 1 H/31P magnetic resonance spectroscopy. Results: In the overall cohort (40.6 ± 15 years; body mass index: 24.5 ± 3 kg/m2 ; IGF-I: 68.0 ± 17% upper limit of normal), fasting GH (R = −0.31; P = .02), GH during oral glucose tolerance test (R = −0.51; P < .01), and IGF-I (R = −0.28; P = .03) inversely correlated with IHL. GH levels during OGTT were significantly lower in NAFLD than in controls (47.7 [22; 143] ng/mL/min vs 16.8 [7; 32] ng/mL/min; P = .003). GH/IGF-I axis activity correlated with lipid composition and with phosphor metabolites. In multiple regression analysis, the GH/IGF-I axis activity was a strong predictor for IHL and lipid composition independent from insulin sensitivity. Conclusion: GH/IGF-I axis activity impacts hepatic lipid and phosphate metabolism in individuals without disorders in GH secretion. Lower GH axis activity is associated with higher IHL and an unfavorable lipid composition, probably mediated by changes in hepatic energy metabolism. [ABSTRACT FROM AUTHOR]

A 24-year-old man with diabetes mellitus presented with advanced kidney disease and severe proteinuria. Genetic testing revealed ABCC8-MODY12 (OMIM 600509), and a kidney biopsy showed nodular glomerulosclerosis. He commenced dialysis shortly thereafter, and glycemic control improved on treatment with a sulfonylurea. Diabetic end-stage kidney disease in patients with ABCC8-MODY12 has not been reported until now. Thus, our case highlights the risk for early-onset and severe diabetic kidney disease in patients with ABCC8-MODY12 and the importance of timely genetic diagnosis in unusual cases of diabetes to allow for proper treatment and prevention of late sequelae of diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with non-muscle invasive (NMI) urothelial bladder cancer (BC) are more likely to have a second cancer in the upper urinary tract (UTUC). During bladder cancer follow-up, UTUC can be detected early by regular imaging of the upper urinary tract. However, there is little evidence that this strategy is useful. We performed a retrospective analysis of patients with NMIBC treated at our center between 2003 and 2016. Our results show that regular imaging has a low detection rate and that UTUCs were only found in individuals who already had a high-risk disease, suggesting that only these individuals may require upper-tract surveillance. In the future, risk-adjusted follow-up strategies should be explored. Patients with non-muscle invasive (NMI) urothelial bladder cancer (BC) are at increased risk for the development of a secondary upper-urinary-tract urothelial carcinoma (UTUC). We aimed to assess the usefulness of routine upper-tract imaging surveillance during NMIBC follow-up in a patient cohort of a tertiary academic center. All routine upper-tract-imaging scans using computerized tomography urography (CTU) between 2003 and 2016 were assessed for UTUC detection. A total of 315 patients were analyzed. Initial tumor stage was Ta in 207 patients (65.7%), T1 in 98 patients (31.1%) and pure CIS in 10 patients (3.2%). A total of 149 (47.3%) presented with low-grade (LG), and 166 (52.7%) with high-grade (HG) disease. Median follow-up was 48 months (IQR: 55). Four patients (1.2%) were diagnosed with UTUC during follow-up. All four patients presented with initial Ta HG BC. Two of the patients (50%) were diagnosed by routine upper tract imaging. The other two patients were diagnosed after development of symptoms. The 5- and 10-year UTUC-free survival was 98.5% (standard error (SE) 0.9) and 97.6% (SE 1.3), respectively. UTUCs were detected exclusively in patients with initial HG disease, indicating that upper-tract surveillance might only be necessary in these patients. [ABSTRACT FROM AUTHOR]

A study was conducted at three sites in North Dakota to strengthen understanding of the usefulness of different proximal geophysical data types in agricultural contexts of varying pedology. This study hypothesizes that electromagnetic induction (EMI), gamma‐ray sensor (GRS), cosmic‐ray neutron sensor (CRNS), and elevation data layers are all useful in multiple linear regression (MLR) predictions of soil properties that meet expert criteria at three agricultural sites. In addition to geophysical data collection with vehicle‐mounted sensors, 15 soil samples were collected at each site and analyzed for nine soil properties of interest. A set of model training data was compiled by pairing the sampled soil property measurements with the nearest geophysical data. Eleven models passed expert‐defined uncertainty criteria at Site 1, 16 passed at Site 2, and 14 passed at Site 3. Electrical conductivity (EC), organic matter (OM), available water holding capacity, silt, and clay were predicted at Site 1 with an R‐squared of prediction (Rpred2)$(R_{pred}^2)$ >.50 and acceptable root mean square error of prediction (RMSEP). Bulk density (BD), OM, available water capacity, silt, and clay were predicted with Rpred2$R_{pred}^2$ >.50 and acceptable RMSEP at Site 2. At Site 3, no soil properties were predicted with acceptable RMSEP and an Rpred2$R_{pred}^2$ >.50. These results confirm feasibility of our method, and the authors recommend the prioritization of EMI data collection if geophysical data collection is limited to a single mapping effort and calibration soil samples are few. Core Ideas: Framework given to assess relationships between proximal sensing and soil properties.Correlations between sensing data and soil properties varied among three study sites.Electromagnetic induction was most consistently useful in soil property prediction. [ABSTRACT FROM AUTHOR]

Background: Biliary phosphatidylcholine (PtdC) concentration plays a role in the pathogenesis of bile duct diseases. In vivo phosphorus‐31 magnetic resonance spectroscopy (31P‐MRS) at 7 T offers the possibility to assess this concentration noninvasively with high spectral resolution and signal intensity. Purpose Comparison of PtdC levels of cholangiopathic patient groups to a control group using a measured T1 relaxation time of PtdC in healthy subjects. Study Type: Case control. Subjects: Two patient groups with primary sclerosing cholangitis (PSC, 2f/3 m; age: 43 ± 7 years) and primary biliary cholangitis (PBC, 4f/2 m; age: 57 ± 6 years), and a healthy control group (CON, 2f/3 m; age: 38 ± 7 years). Ten healthy subjects for the assessment of the T1 relaxation time of PtdC. Field Strength/Sequence: A 3D phase‐encoded pulse‐acquire 31P‐MRSI sequence for PtdC quantification and a 1D image‐selected in vivo 31P spectroscopy for T1 estimation at 7 T, and a T2‐weighted half‐Fourier single‐shot turbo spin echo MRI sequence for volumetry at 3 T. Assessment Calculation of gallbladder volumes and PtdC concentration in groups using hepatic gamma‐adenosine triphosphate signal as an internal reference and correction for insufficient relaxation of PtdC with a T1 value assessed in healthy subjects. Statistical Tests: Group comparison of PtdC content and gallbladder volumes of the PSC/PBC and CON group using Student's t‐tests with a significance level of 5%. Results: PtdC T1 value of 357 ± 85 msec in the gallbladder. Significant lower PtdC content for the PSC group, and for the female subgroup of the PBC group compared to the CON group (PSC/CON: 5.74 ± 0.73 mM vs. 9.64 ± 0.97 mM, PBC(f)/CON: 5.77 ± 1.44 mM vs. 9.64 ± 0.97 mM). Significant higher gallbladder volumes of the patient groups compared to the CON group (PSC/CON: 66.3 ± 15.8 mL vs. 20.9 ± 2.2 mL, PBC/CON: 49.8 ± 18.2 mL vs. 20.9 ± 2.2 mL). Data Conclusion: This study demonstrated the application of a 31P‐MRSI protocol for the quantification of PtdC in the human gallbladder at 7 T. Observed differences in PtdC concentration suggest that this metabolite could serve as a biomarker for specific hepatobiliary disorders. Level of Evidence: 2 Technical Efficacy Stage: 3 [ABSTRACT FROM AUTHOR]

Summary: Given the growing use of immune checkpoint inhibitor (ICI) therapy in oncology, the prevalence of endocrine side effects is rapidly increasing. As clinicians are nowadays frequently confronted with these side effects in routine clinical care, awareness, better knowledge of endocrine irAEs and their clinical presentation and diagnosis is crucial for an adequate management. In this short-review we give a compact overview of the recent recommendations for the management of endocrine irAE related to ICIs and highlight difficulties and uncertainties in current clinical practice. [ABSTRACT FROM AUTHOR]

This paper describes a case study of cold bent insulating glass units (IGUs) for use in facades or roofs using the example of a demonstrator called the "Twisted Tower". Modern designs often try to combine a curved shape with transparency. Cold bending IGUs is a cost efficient method to achieve both. In such applications the bending angles are often limited by the allowable deformations of the primary seal which ensures the gas tightness of the IGU. This investigation shows IGUs with much more acute bending angles than in standard applications were achieved using a flexible yet durable thermoplastic spacer ensuring superior gas tightness. This work investigates the geometry, the deformations and fixing options for the bent IGU form. The results demonstrate the advantages of using such spacer systems for these applications. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate whether the lack of signal transducer and activator of transcription 5 (STAT5) in mature adipocytes of obese mice (Stat5Adipoq mice) improves glucose and lipid metabolism as previously observed in lean mice. Male Stat5Adipoq mice and their wild type (WT) littermates were fed high-fat diet (HFD). Effects of adipocyte STAT5 deficiency on adiposity as well as on glucose and lipid metabolism were determined under ad libitum feeding and after weight loss induced by calorie restriction. Compared to WT mice, obese Stat5Adipoq mice showed modestly accelerated weight gain and blunted depletion of fat stores under calorie restriction (reduction in % body fat after 3 weeks: WT, -9.3±1.1, vs Stat5Adipoq, -5.9±0.8, p = 0.04). No differences were observed between Stat5Adipoq and WT mice with regard to parameters of glucose and lipid metabolism including basal glycaemia, glucose tolerance, and plasma triglycerides. In conclusion, STAT5 deficiency in the adipocyte of HFD-fed obese mice was associated with increased fat accumulation. In contrast to previous findings in lean mice, however, lipid accumulation was not associated with any improvement in glucose and lipid metabolism. Our results do not support adipocyte STAT5 as a promising target for the treatment of obesity-associated metabolic derangements. [ABSTRACT FROM AUTHOR]

Schon seit jeher besteht ein großes Interesse, das Verhalten von Bauwerken und Konstruktionen vorauszubestimmen. Zur Vorhersage des Verhaltens bedienen wir uns dabei neben experimentellen Versuchen zunehmend auch der meist zeit‐ und kostengünstigeren rechnerischen Simulationen. Die Finite‐Element‐Methode (FEM) ist ein Verfahren, welches sich dabei zunehmend durchgesetzt hat und seit Jahrzehnten im Flug‐ und Fahrzeugbau fest etabliert ist. In den letzten Jahren werden numerische Simulationen auch verstärkt zur Überprüfung von Klebeverbindungen eingesetzt. Speziell in der Fassade gewinnen polymere Werkstoffe wie bspw. Dichtstoffe oder thermoplastische Abstandhalter immer mehr an Bedeutung. Diese unterscheiden sich bzgl. ihres Dehnspannungsverhaltens stark vom klassisch linearen Verhalten etablierter Materialien wie Aluminium, Stahl oder Glas. Die vorliegende Arbeit verwendet nicht‐lineare Materialgesetze zur FEM‐Simulation und zeigt an diversen Projekten das Verhalten der Klebefuge in verschiedenen Belastungsszenarien. Nonlinear calculation methods for polymeric materials in structural glass construction – an overview. Since ever a strong interest in foreseeing the behavior of buildings and constructions exists. In order to predict the behavior, we use experiments as well as increasingly the usually more time‐ and cost‐effective computational simulations. The Finite Element Analysis (FEA) is a method that has become increasingly prevalent and has been firmly established in aviation and vehicle construction for decades. In recent years, numerical simulations are also increasingly used for the verification of adhesive bonds. Especially in the facade, polymeric materials such as sealants or thermoplastic spacers are becoming increasingly important. With regard to their expansion stress behavior, these differ strongly from the classic linear behavior of established materials such as aluminum, steel or glass. The present work uses non‐linear material laws for FEA and exhibits the behavior of the sealant joint in various load scenarios on several projects. [ABSTRACT FROM AUTHOR]

Although extensive research on brown adipose tissue (BAT) has stimulated optimism in the battle against obesity and diabetes, BAT physiology and organ crosstalk are not fully understood. Besides BAT, melanin-concentrating hormone (MCH) and its receptor (MCHR1) play an important role in energy homeostasis. Because of the link between hypothalamic MCH neurons and sympathetic BAT activation via ß-adrenoceptors, we investigated the expression and physiological role of the MCHR1 in BAT. MCHR1 was detected in rodent and human BAT with RT-qPCR and western blot analyses. In vivo imaging in rats used the glucose analog [18F]FDG and the MCHR1- tracer [11C]SNAP-7941. We found that the ß3-adrenoceptor (ADRB3) agonist CL316,243 increased [11C]SNAP- 7941 uptake in BAT. Additionally, a pharmacological concentration of SNAP-7941--a low-affinity ADRB3 ligand--stimulated [18F]FDGuptake, reflecting BAT activation. In cultured human adipocytes, CL316,243 inducedMCHR1 expression, further supporting a direct interaction between MCHR1 and ADRB3. These findings characterized MCHR1 expression in rodent and human BAT for the first time, including in vitro and in vivo data demonstrating a link betweenMCHR1 and the ß3-adrenergic system. The presence of MCHR1 in BAT emphasizes the role of BAT in energy homeostasis and may help uncover treatment approaches for obesity. [ABSTRACT FROM AUTHOR]

Neutral complexes [MII(C5Me5)(Q2−)(NO+)] with M=Ru or Os and the catecholates Q2− with 3,5‐di‐tert‐butyl (dtbc) or 3,4,5,6‐tetrachloro substituents (tcc) were identified with the oxidation and charge states indicated. Reversible electron transfer was analyzed spectroelectrochemically (EPR, UV‐vis‐NIR, IR), supported by DFT calculations. Reversible reduction was observed for [Ru(C5Me5)(tcc)(NO)] to occur on the nitrosyl ligand to yield the NO radical complex [RuII(C5Me5)(tcc2−)(NO.)]−, whereas the stepwise oxidation yielded o‐semiquinone cations, [MII(C5Me5)(Q.−)(NO+)]+, and dications. The metals remained in the stable low‐spin d6 states, RuII and OsII, respectively. Redox potentials were found to depend strongly on the donor or acceptor substitution pattern at Qn. [ABSTRACT FROM AUTHOR]

The potential impact of controlled drainage (CD), which limits drainage outflow, and subirrigation (SI), which provides supplemental water through drain tile, on surface water quality are not well known in the Red River Valley (RRV). In this study, water samples were collected and analyzed for chemical concentrations from a tile-drained field that also has controlled drainage and subirrigation modes in the RRV of southeastern North Dakota from 2012–2018. A decreasing trend in overall nutrient load loss was observed because of reduced drainage outflow, though some chemical concentrations were found to be above the recommended surface water quality standards in this region. For example, sulfate was recommended to be below 750 mg/L but was reported at a mean value of 1971 mg/L during spring free drainage. The chemical composition of the subirrigation water was shown to have an impact on drainage water and the soil, specifically on salinity-related parameters, and the impact varied between years. This variation largely depended on the amount of subirrigation applied, soil moisture, and soil properties. Overall, the results of this study show the benefits of controlled drainage on nutrient loss reduction from agricultural fields. [ABSTRACT FROM AUTHOR]

Objective: Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP).Research Design and Methods: Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90-180 min (MR1), and 300-390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques.Results: Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg-1 min-1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg-1 min-1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (-3.28 ± 0.49 vs. -2.53 ± 0.56 μmol kg-1 min-1; P = n.s.) or T2DM-P and T2DM-D (-0.74 ± 0.23 vs. -1.21 ± 0.33 μmol kg-1 min-1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg-1 min-1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed.Conclusions: The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin. [ABSTRACT FROM AUTHOR]

One of the main ways we try to understand the COVID-19 pandemic is through time series cross section counts of cases and deaths. Observational studies based on these kinds of data have concrete and well known methodological issues that suggest significant caution for both consumers and produces of COVID-19 knowledge. We briefly enumerate some of these issues in the areas of measurement, inference, and interpretation. [ABSTRACT FROM AUTHOR]

Aims: To investigate the mechanism of action of 55P0251, a novel multiflorine‐derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use. Materials and Methods: Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head‐to‐head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti‐hyperglycaemic multiflorine derivatives discovered in our programme. Results: 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P <.0001). For insulin release in vitro, this superiority became visible only under concomitant adrenergic background stimulation (glucose‐stimulated insulin release, fmol*islet−1*30 min−1: without α2‐adrenoceptor agonist: 500 μmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α2‐adrenoceptor agonist: 250 μmol/L 55P0251, 138 ± 9, vs 55P0250, 21 ± 6; P <.0001). Since receptor binding assays suggested antagonism at α2A‐adrenoceptors as a potential mechanism of action, we measured oxygen saturation in capillary blood from the tail as a surrogate of vasoconstriction, which supported α2‐antagonistic action in vivo (90 mg/kg 55P0251, 83 ± 3%, vs 55P0250, 57 ± 3%; P <.0001). Lack of association between glucose‐lowering activities and α2A‐adrenoceptor binding affinity arising from comparison of multiflorine derivatives was attributed to differences in their pharmacokinetic properties. Conclusions: Our findings suggest that 55P0251 and related multiflorine derivatives are to be categorized as α2‐adrenoceptor antagonists with potential to lower blood glucose by blocking α2A‐adrenoceptors on pancreatic β cells. [ABSTRACT FROM AUTHOR]

Background: The beneficial effects of exercise training for asthmatics might relate to repetitive airway stretching. Thus, a training with more pronounced airway stretch using isolated, volitional hyperpnea (HYP) might be similarly or more effective. However, in healthy subjects, a bout of HYP training is known to cause an acute FEV1 decline. Objective: The aim of the present study was therefore to test whether these changes are more pronounced in asthmatics, possibly putting them at risk with HYP training. Methods: Nine subjects with mild-moderate asthma (confirmed by mannitol challenge) and 11 healthy subjects performed six 5-min bouts (with 6-min breaks; HYP1) and one 30-min bout (HYP2) of normocapnic HYP at 60% of maximal voluntary ventilation using warm and humid air. FEV1 and airway resistance (R5) were measured before, in breaks (HYP1), and immediately after HYP, and during 60 min of recovery. Results: In both groups, a significant and similar decrease in FEV1 during HYP1 (asthmatics: –3 ± 3%; healthy subjects: –2 ± 3%), after HYP1 (asthmatics: –2 ± 5%; healthy subjects: –1 ± 4%), and after HYP2 (asthmatics: –4 ± 5%; healthy subjects: –3 ± 3%), and an increase in R5 during and after both HYPs were observed. Maximal changes in FEV1 and R5 did not correlate with baseline lung function or responsiveness to mannitol. Conclusions: A bout of HYP does not lead to relevant bronchoconstriction and the observed changes in lung function and airway resistance are neither of the magnitude of clinical relevance, nor do they differ from responses in healthy individuals. Thus, HYP training can safely be tested as an airway-specific exercise training alternative (or add-on) modality to regular aerobic exercise training. [ABSTRACT FROM AUTHOR]

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Core Ideas: Soil moisture is needed in defining well‐watered turfgrass condition in evapotranspiration measurement.Deep soil moisture supports turfgrass growth when surface soil moisture is not sufficient.The ETa can be estimated from 0.96 ETo using the ASCE‐EWRI standardized method for well‐watered turfgrass.The ASCE‐EWRI standardized reference ET equation can be used for water management of turfgrass in northern cool climates and during drought periods. Turfgrass actual evapotranspiration (ETa) measurements are critical for water management and irrigation scheduling. With no historical ETa measurements in eastern North Dakota, turfgrass ETa rates were measured with the residual method using eddy covariance instrumentation and two arrays of soil moisture sensors on unirrigated turfgrass under natural conditions in the 2011, 2012, and 2013 growing seasons. An on‐site weather station provided weather data to calculate the standardized grass‐based reference evapotranspiration (ETo) (Allen et al., 2005). The daily ETa/ETo ratios were screened using the criteria of soil moisture ≥50% of available water for the top 30 cm of the root zone, rain amounts ≤10 mm, and a recovering period after drought. The screened monthly average ETa/ETo ratios for the unirrigated turfgrass were 1.03, 0.98, 0.94, 0.90, 0.82, and 1.18 from May to October. The mean ETa/ETo ratio for the entire growing seasons was 0.96, implying that the American Society of Civil Engineering–Environmental and Water Resource Institute ETo method was valid for guiding the turfgrass ETa calculation even in unirrigated and cold climate conditions. Because this is the first reported study on ETa measurement of a turfgrass site, the limited data can provide a baseline on water management for turfgrass under various weather conditions in this region. The results indicated that a monthly refinement of ETa/ETo values might be required to maintain the landscape turfgrass quality more precisely in terms of water management. [ABSTRACT FROM AUTHOR]

The current European standard for dimensioning silicone adhesive joints in structural glazing applications is defined in the ETAG 002. Although there are several decades of field experience with this standard it still has some major limitations and mainly uses an empirical concept based on an average force by area engineering approach. In addition there are a number of other restrictions for example the limitation of specific substrates and rectangular shaped joints with defined aspect ratios as well as the exclusion of joints with non‐coplanar surfaces. The presented investigations are based on a combined numerical and experimental concept and demonstrate that appropriately designed elastic adhesive joints with complex geometries excluded by common standards can be evaluated and validated in a systematic and reliable way. The experimental test may easily be combined with well‐established and proven aging test schemes, for which long‐term reliable field experience is available. In addition any desired safety factor can be added. [ABSTRACT FROM AUTHOR]

Blood glucose and the prevalence of diabetes are lower in mountain than lowland dwellers, which could among other factors be due to reduced oxygen availability. To investigate metabolic adaptations to life under hypoxia, male mice on high fat diet (HFD) were continuously maintained at 10% O2. At variance to preceding studies, the protocol was designed to dissect direct metabolic effects from such mediated indirectly via hypoxia-induced reductions in appetite and weight gain. This was achieved by two separate control groups on normal air, one with free access to HFD, and one fed restrictedly in order to obtain a weight curve matching that of hypoxia-exposed mice. Comparable body weight in restrictedly fed and hypoxic mice was achieved by similar reductions in calorie intake (−22%) and was associated with parallel effects on body composition as well as on circulating insulin, leptin, FGF-21, and adiponectin. Whereas the effects of hypoxia on the above parameters could thus be attributed entirely to blunted weight gain, hypoxia improved glucose homeostasis in part independently of body weight (fasted blood glucose, mmol/l: freely fed control, 10.2 ± 0.7; weight-matched control, 8.0 ± 0.3; hypoxia, 6.8 ± 0.2; p < 0.007 each; AUC in the glucose tolerance test, mol/l*min: freely fed control, 2.54 ± 0.15; weight-matched control, 1.86 ± 0.08; hypoxia, 1.67 ± 0.05; p < 0.05 each). Although counterintuitive to lowering of glycemia, insulin sensitivity appeared to be impaired in animals adapted to hypoxia: In the insulin tolerance test, hypoxia-treated mice started off with lower glycaemia than their weight-matched controls (initial blood glucose, mmol/l: freely fed control, 11.5 ± 0.7; weight-matched control, 9.4 ± 0.3; hypoxia, 8.1 ± 0.2; p < 0.02 each), but showed a weaker response to insulin (final blood glucose, mmol/l: freely fed control, 7.0 ± 0.3; weight-matched control, 4.5 ± 0.2; hypoxia, 5.5 ± 0.3; p < 0.01 each). Furthermore, hypoxia weight-independently reduced hepatic steatosis as normalized to total body fat, suggesting a shift in the relative distribution of triglycerides from liver to fat (mg/g liver triglycerides per g total fat mass: freely fed control, 10.3 ± 0.6; weight-matched control, 5.6 ± 0.3; hypoxia, 4.0 ± 0.2; p < 0.0004 each). The results show that exposure of HFD-fed mice to continuous hypoxia leads to a unique metabolic phenotype characterized by improved glucose homeostasis along with evidence for impaired rather than enhanced insulin sensitivity. [ABSTRACT FROM AUTHOR]

The new redox-active complexes [RuH(CO)(EPh3)2(μ-Q2−)RuH(CO)(EPh3)2], E=P ( 1) and E=As ( 2) with the bis-chelate bridging ligand Q2−=1,4-dioxido-9,10-anthraquinone were prepared and characterised. The related compound [RuCl(CO)(PPh3)2(μ-Qx2−)RuCl(CO)(PPh3)2] ( 4) with E=P and Qx2−=5,8-dioxido-1,4-naphthoquinone 4 revealed trans-positioned PPh3 groups. The electrogenerated one-electron oxidised states 1+ and 2+ were examined using spectroelectrochemical techniques (EPR, IR and UV/Vis/NIR). In situ EPR studies gave spectra with 31P or 75As hyperfine splitting of about 16 Gauss, small 99, 101Ru coupling and small g-anisotropy in the frozen solution state. The 31P and 75As hyperfine values reflect axial positioning of the four Ru−E bonds relative to the plane of an anthrasemiquinone bridge. Single CO stretching bands around 1910 cm−1 of the precursors 1 and 2 shift by about 25 cm−1 to higher energies on oxidation. The direction, uniformity and the extent of the shifts confirm ligand bridge-based oxidation. Absorbance by the cations in the near infrared region is thus assigned to intra-ligand transitions of ruthenium(II)-bonded anthrasemiquinones and not to intervalence charge transfer of mixed-valent species. Ruthenium(II) stabilisation by CO and EPh3 is made responsible for the anthrasemiquinone formation instead of metal-centered oxidation. [ABSTRACT FROM AUTHOR]

The United States has long embraced calculated ambiguity over the conditions under which it might use nuclear weapons against adversaries, a trend that President Donald J. Trump has continued. This ambiguity could unsettle some observers, especially those who believe that the United States should declare a no-first-use (NFU) policy such that it would not be the first state to introduce nuclear weapons in either a crisis or an armed conflict. NFU advocates identify three potential pathways whereby a more ambiguous posture can lead to increased danger: downward spiral, accidental war, and use-it-or-lose-it. For evidence, they invoke Saddam Hussein’s risk-accepting decision to pre-delegate chemical-weapons use following US nuclear threats in the 1991 Gulf War. In analyzing the reasoning and evidence of these arguments, we argue that the alleged benefits of NFU may be overstated, at least for crisis stability in asymmetric crises, defined by one side’s overwhelming conventional military superiority. Each of the three foregoing pathways is logically inconsistent and the empirical case is misinterpreted. Nuclear ambiguity may not be so dangerous as NFU advocates claim. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from β-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice. [ABSTRACT FROM AUTHOR]

Whole-body warm-up exercises were shown to attenuate exercise-induced bronchoconstriction (EIB). Whether intense pre-exercise hyperpnea offers similar protection and whether this might negatively affect exercise performance is unknown. Nine subjects with EIB (25±5 yrs; forced expiratory volume in 1s [FEV1], 104±15% predicted) performed an exercise challenge (ECh) followed—after 30min—by a constant-load cycling test to exhaustion. The ECh was preceded by one of four conditions: by i) control warm-up (CON) or by 10min of normocapnic hyperpnea with partial rebreathing at either ii) 50% (WU50) or iii) variable intensity (8x 30s-80%/45s-30%; WU80/30), or at iv) 70% (WU70) of maximal voluntary ventilation. FEV1 was measured at baseline and in 5-min intervals until 15min after CON/warm-up and 30min after ECh. None of the warm-up conditions induced EIB. The maximal post-ECh decrease in FEV1 was -13.8±3.1% after CON, −9.3±5.0% after WU50 (p = 0.081 vs. CON), −8.6±7.5% after WU80/30 (p = 0.081 vs. CON) and −7.2±5.0% after WU70 (p = 0.006 vs. CON), and perception of respiratory exertion was significantly attenuated (all p≤0.048), with no difference between warm-up conditions. Only after CON, FEV1 remained significantly reduced up to the start of the cycling endurance test (−8.0±4.3%, p = 0.004). Cycling performance did not differ significantly between test days (CON: 13±7min; WU50: 14±9min; WU80/30: 13±9min; WU70: 14±7min; p = 0.582). These data indicate that intense hyperpnea warm-up is effective in attenuating EIB severity and accelerating lung function recovery while none of the warm-up condition do compromise cycling performance. [ABSTRACT FROM AUTHOR]

Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis. [ABSTRACT FROM AUTHOR]

Cerebral metabolic alterations during cardiac arrest, cardiopulmonary resuscitation (CPR) and extracorporeal cardiopulmonary life support (ECLS) are poorly explored. Markers are needed for a more personalized resuscitation and post—resuscitation care. Aim of this study was to investigate early metabolic changes in the hippocampal CA1 region during ventricular fibrillation cardiac arrest (VF-CA) and ECLS versus conventional CPR. Male Sprague-Dawley rats (350g) underwent 8min untreated VF-CA followed by ECLS (n = 8; bloodflow 100ml/kg), mechanical CPR (n = 18; 200/min) until return of spontaneous circulation (ROSC). Shams (n = 2) were included. Glucose, glutamate and lactate/pyruvate ratio were compared between treatment groups and animals with and without ROSC. Ten animals (39%) achieved ROSC (ECLS 5/8 vs. CPR 5/18; OR 4,3;CI:0.7–25;p = 0.189). During VF-CA central nervous glucose decreased (0.32±0.1mmol/l to 0.04±0.01mmol/l; p<0.001) and showed a significant rise (0.53±0.1;p<0.001) after resuscitation. Lactate/pyruvate (L/P) ratio showed a 5fold increase (31 to 164; p<0.001; maximum 8min post ROSC). Glutamate showed a 3.5-fold increase to (2.06±1.5 to 7.12±5.1μmol/L; p<0.001) after CA. All parameters normalized after ROSC with no significant differences between ECLS and CPR. Metabolic changes during ischemia and resuscitation can be displayed by cerebral microdialysis in our VF-CA CPR and ECLS rat model. We found similar microdialysate concentrations and patterns of normalization in both resuscitation methods used. Institutional Protocol Number: GZ0064.11/3b/2011 [ABSTRACT FROM AUTHOR]

Background: The melanin-concentrating hormone receptor 1 (MCHR1), which is highly expressed in the lateral hypothalamus, plays a key role in energy homeostasis, obesity and other endocrine diseases. Hence, there is a major interest in in vivo imaging of this receptor. A PET tracer would allow non-invasive in vivo visualization and quantification of the MCHR1. The aim of the study was the ex vivo evaluation of the MCHR1 ligand [F]FE@SNAP as a potential PET tracer for the MCHR1. Methods: [F]FE@SNAP was injected directly into the jugular vein of awake naïve rats for ex vivo brain autoradiography, biodistribution and additional blood metabolite analysis. Blocking experiments were conducted using the unlabeled MCHR1 ligand SNAP-7941. Results: A high uptake of [F]FE@SNAP was observed in the lateral hypothalamus and the ventricular system. Both regions were significantly blocked by SNAP-7941. Biodistribution evinced the highest uptake in the kidneys, adrenals, lung and duodenum. Specific blocking with SNAP-7941 led to a significant tracer reduction in the heart and adrenals. In plasma samples, 47.73 ± 6.1 % of a hydrophilic radioactive metabolite was found 45 min after tracer injection. Conclusions: Since [F]FE@SNAP uptake was significantly blocked in the lateral hypothalamus, there is strong evidence that [F]FE@SNAP is a highly suitable agent for specific MCHR1 imaging in the central nervous system. Additionally, this finding is supported by the specific blocking in the ventricular system, where the MCHR1 is expressed in the ependymal cells. These findings suggest that [F]FE@SNAP could serve as a useful imaging and therapy monitoring tool for MCHR1-related pathologies. [ABSTRACT FROM AUTHOR]

Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0±1.2 vs. 10.1±1.1; diabetic mice with 180 mg/kg 55P0110, 23.1±0.9 vs. 11.1±1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49±0.27; 55P0110, 2.99±0.35; gliclazide, 8.97±0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53±0.41; 55P0110, 3.80±0.46; gliclazide, 3.99±0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic substituted quinazolidines with an attractive pharmacological profile that recommends the structures for further evaluation as candidates for the treatment of diabetes mellitus. [ABSTRACT FROM AUTHOR]

A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1ΔE746A750-driven HCC827 NSCLCs and HERIwt-expressing MB231 triple negative breast cancers, but not by HERlow-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HERlow SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers. [ABSTRACT FROM AUTHOR]