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Electrocatalytic and photocatalytic CO2 reduction by a heterobimetallic Cu/Fe–Mabiq complex were examined and compared to the monometallic [Fe(Mabiq)]+. The neighbouring Cu–Xantphos unit leads to marked changes in the electrocatalytic mechanism and enhanced photocatalytic performance. [ABSTRACT FROM AUTHOR]

Quantitative solid-state NMR distance measurements in strongly coupled spin systems are often complicated due to the simultaneous presence of multiple noncommuting spin interactions. In the case of zeroth-order homonuclear dipolar recoupling experiments, the recoupled dipolar interaction between distant spins is attenuated by the presence of stronger couplings to nearby spins, an effect known as dipolar truncation. In this article, we quantitatively investigate the effect of dipolar truncation on the polarization-transfer efficiency of various homonuclear recoupling experiments with analytical theory, numerical simulations, and experiments. In particular, using selectively 13C-labeled tripeptides, we compare the extent of dipolar truncation in model three-spin systems encountered in protein samples produced with uniform and alternating labeling. Our observations indicate that while the extent of dipolar truncation decreases in the absence of directly bonded nuclei, two-bond dipolar couplings can generate significant dipolar truncation of small, long-range couplings. Therefore, while alternating labeling alleviates the effects of dipolar truncation, and thus facilitates the application of recoupling experiments to large spin systems, it does not represent a complete solution to this outstanding problem. [ABSTRACT FROM AUTHOR]

The control of supramolecular complexes in living systems at the molecular level is an important goal in life-sciences. Spatiotemporal organization of molecular distribution & flow of such complexes are essential physicochemical processes in living cells and important for pharmaceutical processes. Membraneless organelles (MO) found in eukaryotic cells, formed by liquid-liquid phase-separation (LLPS) of intrinsically disordered proteins (IDPs) control and adjust intracellular organization. Artificially designed compartments based on LLPS open up a novel pathway to control chemical flux and partition in vitro and in vivo. We designed a library of chemically precisely defined block copolymer-like proteins based on elastin-like proteins (ELPs) with defined charge distribution and type, as well as polar and hydrophobic block domains. This enables the programmability of physicochemical properties and to control adjustable LLPS in vivo attaining control over intracellular partitioning and flux as role model for in vitro and in vivo applications. Tailor-made ELP-like block copolymer proteins exhibiting IDP-behavior enable LLPS formation in vitro and in vivo allowing the assembly of membrane-based and membraneless superstructures via protein phase-separation in E. coli. Subsequently, we demonstrate the responsiveness of protein phase-separated spaces (PPSSs) to environmental physicochemical triggers and their selective, charge-dependent and switchable interaction with DNA or extrinsic and intrinsic molecules enabling their selective shuttling across semipermeable phase boundaries including (cell)membranes. This paves the road for adjustable artificial PPSS-based storage and reaction spaces and the specific transport across phase boundaries for applications in pharmacy and synthetic biology. • An amphiphilic protein (aELP) library allows for adjustable compartments in vivo. • Extrinsic stimuli modulate protein-phase separated spaces (PPSS) in E. coli. • PPSS formed by charged aELPs direct DNA localization. • Charged aELP forming PPSS can control molecular flux of molecules in vivo. • Responsive PPSS can be used in pharmaceutical applications and synthetic biology. [ABSTRACT FROM AUTHOR]

This paper presents an improved mixed-integer model for the thermal unit commitment problem. By introducing new variables for the temperature of each thermal unit, the off-time-dependent start-up costs are modeled accurately and with a lower integrality gap than state-of-the-art formulations. This new approach significantly improves computational efficiency compared to existing formulations, even if they only model a rough approximation of the start-up costs. Our findings were validated on real-world test cases using CPLEX. [ABSTRACT FROM PUBLISHER]

The world's power systems are facing a structural change including liberalization of markets and integration of renewable energy sources. This paper describes the challenges that lie ahead in this process and points out avenues for overcoming different problems at different scopes, ranging from individual homes to international super-grids. We apply energy system models at those different scopes and find a trade-off between technical and social complexity. Small-scale systems would require technological breakthroughs, especially for storage, but individual agents can and do already start to build and operate such systems. In contrast, large-scale systems could potentially be more efficient from a techno-economic point of view. However, new political frameworks are required that enable long-term cooperation among sovereign entities through mutual trust. Which scope first achieves its breakthrough is not clear yet. [ABSTRACT FROM AUTHOR]

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%-12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition. [ABSTRACT FROM AUTHOR]

The electricity consumption in the ASEAN (Association of East Asian Nations) region is one of the fastest growing in the world and will lead to a dramatic increase in greenhouse gas emissions in the next decades. A decarbonization of the region's electricity supply is thus a very important measure when taking action on global climate change. This paper defines cost-optimal pathways towards a sustainable power system in the region by employing linear optimization. The proposed model simultaneously optimizes the required capacities and the hourly operation of generation, transmission, and storage. The obtained results show that all different kinds of renewable sources will have to be utilized, while none of them should have a share of more than one third. The findings give reason for setting up an ASEAN power grid, as it enables the transportation of electricity from the best sites to load centers and leads to a balancing of the fluctuations from wind and solar generation. We suggest fostering a diversified extension of renewables and to elaborate on political and technical solutions that enable the build up an transnational supergrid. [ABSTRACT FROM AUTHOR]

Purpose: Treatment with metamizole (dipyrone) has steadily increased in Germany over the last decade. The consequences of this increase for metamizole-induced agranulocytosis (MIA) are unclear. The present study addressed this topic using data from the Berlin Case-Control Surveillance Study. Methods: Adult patients (≥18 years of age) with acute nonchemotherapy-induced agranulocytosis were identified by active surveillance in all 51 Berlin hospitals between 2000 and 2010. Cases related to metamizole were ascertained applying the drug causality criteria of the World Health Organization. The incidence rate of MIA was calculated and standardised by age and sex based on the German standard population in 2010. Results: Twenty-six MIA cases out of 88 (30 %) patients with validated agranulocytosis were ascertained. The incidence of MIA was 0.96 (95 % confidence interval (CI) 0.95-0.97) cases per million per year. The median age of MIA cases was 50 years (quartile (Q)1 31 years; Q3 68 years) and 19 (73 %) of them were women. In 17 (65 %) cases, neutrophil granulocytes dropped below the value of 0.1 × 10 cells/L with three patients suffering from sepsis. Headache and postoperative pain were the most frequent indications for metamizole in outpatients ( n = 16) and inpatients ( n = 10), respectively. The median treatment duration was 6 days (Q1 4 days; Q3 19 days). Conclusions: MIA persists as a severe condition in current pharmacotherapy. The continuous increase of metamizole applications should be critically assessed, especially in regard to indications in the outpatient setting and with respect to metamizole treatment duration. [ABSTRACT FROM AUTHOR]

Nanoscale biological materials formed by the assembly of defined block-domain proteins control the formation of cellular compartments such as organelles. Here, we introduce an approach to intentionally 'program' the de novo synthesis and self-assembly of genetically encoded amphiphilic proteins to form cellular compartments, or organelles, in Escherichia coli. These proteins serve as building blocks for the formation of artificial compartments in vivo in a similar way to lipid-based organelles. We investigated the formation of these organelles using epifluorescence microscopy, total internal reflection fluorescence microscopy and transmission electron microscopy. The in vivo modification of these protein-based de novo organelles, by means of site-specific incorporation of unnatural amino acids, allows the introduction of artificial chemical functionalities. Co-localization of membrane proteins results in the formation of functionalized artificial organelles combining artificial and natural cellular function. Adding these protein structures to the cellular machinery may have consequences in nanobiotechnology, synthetic biology and materials science, including the constitution of artificial cells and bio-based metamaterials. [ABSTRACT FROM AUTHOR]

The access to defined protein-based material systems is a major challenge in bionanotechnology and regenerative medicine. Exact control over sequence composition and modification is an important requirement for the intentional design of structure and function. Herein structural- and matrix proteins provide a great potential, but their large repetitive sequences pose a major challenge in their assembly. Here we introduce an integrative "one-vector-toolbox-platform" (OVTP) approach which is fast, efficient and reliable. The OVTP allows for the assembly, multimerization, intentional arrangement and direct translation of defined molecular DNA-tecton libraries, in combination with the selective functionalization of the yielded protein-tecton libraries. The diversity of the generated tectons ranges from elastine-, resilin, silk- to epitope sequence elements. OVTP comprises the expandability of modular biohybrid-materials via the assembly of defined multi-block domain genes and genetically encoded unnatural amino acids (UAA) for site-selective chemical modification. Thus, allowing for the modular combination of the protein-tecton library components and their functional expansion with chemical libraries via UAA functional groups with bioorthogonal reactivity. OVTP enables access to multitudes of defined protein-based biohybrid-materials for self-assembled superstructures such as nanoreactors and nanobiomaterials, e.g. for approaches in biotechnology and individualized regenerative medicine. [ABSTRACT FROM AUTHOR]

Abstract: Flexibility is the ability of a power system to respond to changes in power demand and generation. Integrating large shares of variable renewable energy sources, in particular wind and solar, can lead to a strong increase of flexibility requirements for the complementary system, traditionally hydrothermal, which has to balance the fluctuations of variable generation. We quantify these flexibility requirements at the operational timescale of 1–12 hours and different spatial scales across Europe. Our results indicate that three major factors determine the ramping flexibility needed in future power systems: the penetration of variable renewables, their mix and the geographic system size. Compared to the variability of load, flexibility requirements increase strongly in systems with combined wind and PV (photovoltaics) contribution of more than 30% of total energy and a share of PV in the renewables mix above 20–30%. In terms of extreme ramps, the flexibility requirements of a geographically large, transnational power system are significantly lower than of smaller regional systems, especially at high wind penetration. [Copyright &y& Elsevier]

Purpose: Drug-induced agranulocytosis (DIAG) is a rare but serious adverse drug reaction. The Berlin Case-Control Surveillance Study (FAKOS) aimed to identify pharmaceuticals with an increased risk for this condition. Methods: Adult patients with acute non-chemotherapy-induced agranulocytosis, developed in hospital or in the outpatient setting, were ascertained by active surveillance in all 51 Berlin hospitals between the years 2000 and 2010. Applying the criteria of the World Health Organization, a standardized drug causality assessment was conducted for each agranulocytosis patient to determine possible drug aetiology. Drug risks were quantified in a case-control design with unconditional logistic regression analysis. Results: Sixty-three out of 88 validated cases of agranulocytosis were identified as being at least probably drug-related. Drug causality assessment resulted in 36 pharmaceuticals with a certain or probable relationship to agranulocytosis. Drugs involved in ≥ 3 cases with a probable or certain causality were metamizole (dipyrone) ( N = 10), clozapine ( N = 6), sulfasalazine ( N = 5), thiamazole ( N = 5), and carbamazepine ( N = 3). In case-control analysis, six drugs were identified with significant odds ratios for DIAG. The highest odds ratios were observed for clozapine, sulfasalazine, and thiamazole. Conclusions: Our findings are generally in agreement with those of earlier case-control studies. The spectrum of drugs causing acute agranulocytosis has not changed considerably over recent years, despite many newly marketed drugs. Evidence for induction of agranulocytosis by some new pharmaceuticals is supported. [ABSTRACT FROM AUTHOR]

: Treatment of hypertension in hemodialysis (HD) patients is characterised by lack of evidence for both the blood pressure (BP) target goal and the recommended drug class to use. Telmisartan, an Angiotensin receptor blocker (ARB) that is metabolised in the liver and not excreted via HD extracorporeal circuit might be particularly suitable for HD patients. We designed and conducted a randomised, placebo-controlled, double-blind and cross-over trial for treatment of dialysis–associated hypertension with telmisartan 80 mg once daily or placebo on top of standard antihypertensive treatment excluding other Renin-Angiotensin-System (RAS) blockers. In 29 patients after randomization we analysed BP after a treatment period of 8 weeks, while 13 started with telmisartan and 16 with placebo; after 8 weeks 11 continued with telmisartan and 12 with placebo after cross-over, respectively. Patients exhibited a significant reduction of systolic pre-HD BP from 141.9±21.8 before to 131.3±17.3 mmHg after the first treatment period with telmisartan or placebo. However, no average significant influence of telmisartan was observed compared to placebo. The latter may be due to a large inter-individual variability of BP responses reaching from a 40 mmHg decrease under placebo to 40 mmHg increase under telmisartan. Antihypertensive co-medication was changed for clinical reasons in 7 out of 21 patients with no significant difference between telmisartan and placebo groups. Our starting hypothesis, that telmisartan on top of standard therapy lowers systolic office BP in HD patients could not be confirmed. In conclusion, this small trial indicates that testing antihypertensive drug efficacy in HD patients is challenging due to complicated standardization of concomitant medication and other confounding factors, e.g. volume status, salt load and neurohormonal activation, that influence BP control in HD patients. Trial Registration: Clinicaltrialsregister.eu 2005-005021-60 [ABSTRACT FROM AUTHOR]

Background: Melatonin exerts multiple biological effects with potential impact on human diseases. This is underscored by genetic studies that demonstrated associations between melatonin receptor type 2 gene (MTNR1B) polymorphisms and characteristics of type 2 diabetes. We set out to test the hypothesis whether genetic variants at MTNR1B are also relevant for other disease phenotypes within the cardiovascular continuum. We thus investigated single nucleotide polymorphisms (SNPs) of MTNR1B in relation to blood pressure (BP) and cardiac parameters in hypertensive patients. Methods: Patients (n=605, mean age 56.2±9.4years, 82.3% male) with arterial hypertension and cardiac ejection fraction (EF) ≥40% were studied. Cardiac parameters were assessed by echocardiography. Results: The cohort comprised subjects with coronary heart disease (73.1%) and myocardial infarction (48.1%) with a mean EF of 63.7±8.9%. Analysis of SNPs rs10830962, rs4753426, rs12804291, rs10830963, and rs3781638 revealed two haplotypes 1 and 2 with frequencies of 0.402 and 0.277, respectively. Carriers with haplotype 1 (CTCCC) showed compared to non-carriers a higher mean 24-hour systolic BP (difference BP: 2.4mmHg, 95% confidence interval (CI): 0.3 to 4.5mmHg, p=0.023). Haplotype 2 (GCCGA) was significantly related to EF with an absolute increase of 1.8% (CI: 0.45 to 3.14%) in carriers versus non-carriers (p=0.009). Conclusion: Genetics of MTNR1B point to impact of the melatonin signalling pathway for BP and left ventricular function. This may support the importance of the melatonin system as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract: Nuclear fusion can be considered as a base-load power plant technology: High investment costs and limited operational flexibility require continuous operation. Wind and solar, on the other hand, as the putative main pillars of a future renewable energy system, are intermittent power sources. The resulting variations that occur on many different time scales require at first sight a rather flexible back-up system to balance this stochastic behavior. Fusion would appear not to be well suited for this task. The situation changes, however, if a large-scale renewable energy system is envisaged based on a transnational, or even transcontinental power grid. The present paper discusses a possible European power system in the year 2050 and beyond. A high percentage share of renewable energies and a strong power grid spanning the whole of Europe and involving neighboring countries, in particular those in North Africa, are assumed. The linear programming model URBS is used to describe the power system. The model optimizes the overall system costs and simulates power plant operation with an hourly resolution for one whole year. The geographical resolution is at least at the country level. The renewable technologies are modeled first on a more local level and then summed together at the country or regional level. The results indicate that the smoothing effects of the large-scale power grid transform the intermittent renewable supply, which is then more compatible with base-load power plants such as fusion reactors. [Copyright &y& Elsevier]

Background Glaucoma comprises age-related neurodegenerative diseases of retinal ganglion cells, the worldwide prevalence of which is increasing. Local pharmacotherapy is the primary treatment option, especially in the elderly. But this therapeutic approach may include risks for adverse drug effects and drug-drug interactions, of particular importance in frail nursing home resident populations. Objective The aim of the present study was to investigate anti-glaucoma pharmacotherapy in nursing home residents in the context of multi-morbidity and related systemic comedication. Methods Data for 8,685 nursing home residents with 88,695 drug prescriptions were analysed according to diagnosis and local or systemic pharmacotherapy. Data were provided in anonymous form by a German public health insurance company. Results The study cohort was characterized by a mean age of 83.6 ± 7.3 years (range: 65-106 years), 21 % of nursing home residents were at least 90 years old and 83.7 % were women. For each nursing home resident, an average of 6.0 ± 3.3 different drugs were registered. A diagnosis of glaucoma was recorded in 520 (6.0 %) nursing home residents; all subjects had co-existing medical conditions. Dementia was a frequent co-morbidity, diagnosed in 51.7 % of nursing home residents with glaucoma. Anti-glaucoma drugs contributed to 0.5 % of all prescriptions and were prescribed to 341 nursing home residents. The most frequently used anti-glaucoma ophthalmics were b-blockers (n = 219), followed by prostaglandin analogues (n = 101) and carbonic anhydrase inhibitors (n = 86). Local antiglaucoma therapy was co-prescribed with a systemic pharmacotherapy in 338 nursing home residents. An ophthalmic agent was, on average, combined with 6.5 ± 3.2 prescriptions for systemic agents. Thus, 71.9 % of nursing home residents were prescribed ophthalmic b-blockers and a concomitant antihypertensive medication; local and systemic b-blockers were combined in 20.2 %of these patients. Co-treatment with cardiac glycosides or calcium antagonists was found in 13 % of nursing home residents prescribed ophthalmic parasympathomimetics, and in 14 % of those prescribed ophthalmic b-blockers, with the potential for drug-drug interactions to influence cardiac function. Conclusions Anti-glaucoma pharmacotherapy in nursing home residents is frequently prescribed in the context of polypharmacy. This may modify the efficacy and safety of local and systemic therapies. Therefore, individualized pharmacotherapy that integrates anti-glaucoma drug therapy into the overall treatment rationale in nursing home residents is necessary. However, to realize this concept, further clinical research in nursing home residents is warranted. [ABSTRACT FROM AUTHOR]

Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9 ± 9.8 years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8 ± 21.0 g/H and 61.1 ± 9.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CI = 0.1% to 4.2%, p = 0.044) and an absolute increase in EF of 0.6% (CI = 0.1% to 1.1%, p = 0.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CI = 0.7% to 4.6%; p = 0.008, p = 0.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele −1.8%; CI = −2.8% to −0.7%; p = 0.002, p = 0.018; rs1151026, G allele −1.9%, CI = −3.0% to −0.8%; p < 0.001, p = 0.002) with the extension that a frequent haplotype in BICD1 showed an absolute −1.8% (CI = −3.0% to −0.7%; p = 0.002, p = 0.008) lower EF compared with those lacking this haplotype. Our results point to a role of genetic variants recently implicated in LTL for left ventricular function in hypertensive patients. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the levels of pigment epithelium-derived factor (PEDF), angiopoietin 2, vascular endothelial growth factor (VEGF), and soluble VEGF receptor 1 (sVEGFR-1) in vitreous samples of patients suffering from age-related macular degeneration with choroidal neovascularization or from proliferative diabetic retinopathy (PDR). Methods: Proteins in vitreous samples of 29 patients were quantified via enzyme-linked immunosorbent assays. Results: Vitreous levels of sVEGFR-1 were significantly higher in age-related macular degeneration with choroidal neovascularization (p = 0.005) and in PDR (p = 0.003) versus controls. In analogue comparisons, PEDF was significantly decreased (p < 0.01). PDR was associated with significantly increased angiopoietin 2 and VEGF levels (p = 0.001 for both). Conclusion: The vitreous in retinal or choroidal neovascularization revealed a pro-angiogenic potential indicated by decreased PEDF or increased angiopoietin 2 levels compared to controls. However, higher amounts of sVEGFR-1 were concomitant, pointing to activation of an endogenous anti-angiogenic system in the protein network. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Partial deuteration is a powerful tool to increase coherence life times and spectral resolution in proton solid-state NMR. The J coupling to deuterium needs, however, to be decoupled to maintain the good resolution in the (usually indirect) 13C dimension(s). We present a simple and reversible way to expand a commercial 1.3mm HCN MAS probe with a 2H channel with sufficient field strength for J-decoupling of deuterium, namely 2–3kHz. The coil is placed at the outside of the stator and requires no significant modifications to the probe. The performance and the realizable gains in sensitivity and resolution are demonstrated using perdeuterated ubiquitin, with selectively CHD2-labeled methyl groups. [Copyright &y& Elsevier]

The aim of this study was to investigate any influence on olmesartan plasma pharmacokinetics from amlodipine or atenolol. We analysed pharmacokinetics and safety of olmesartan medoxomil in combination with either amlodipine or atenolol compared to respective monotherapies in two separate studies. In one study, 18 subjects received once daily treatment for 7 days with olmesartan medoxomil 20 mg alone or with amlodipine 5 mg or amlodipine 5 mg alone. In the other study, atenolol 50 mg once daily replaced amlodipine. Concentration vs. time profiles for olmesartan monotherapy were similar to combination therapy. Mean olmesartan AUCss,τ for olmesartan alone and with amlodipine were 2439 and 2388 ng h/mL and for olmesartan alone and with atenolol were 2340 and 2247 ng h/mL. Corresponding olmesartan Css,max values were 465.7 and 439.5 ng/mL for amlodipine, and 447.4 and 423.8 ng/mL for atenolol. Median tmax values for olmesartan were 1.5 h for each group in each study. Bioequivalence was established for all pharmacokinetic parameters. Lack of significant pharmacokinetic interactions between olmesartan and amlodipine or atenolol provides a basis for combination therapy. [ABSTRACT FROM AUTHOR]

Abstract: We introduce a second-order dipolar recoupling condition for magic-angle spinning NMR where the isotropic chemical-shift difference of two homonuclear S spins is matched by the rf-irradiation amplitude, or, alternatively, phase-modulation frequency, on a heteronuclear spin. The experiment can be looked at as a mixed rotational and rotary-resonance condition (MIRROR). The effective MIRROR Hamiltonian promotes homonuclear zero-quantum polarization transfer and heteronuclear zero-quantum and double-quantum polarization transfer. The MIRROR recoupling condition is applied to obtain enhanced polarization transfer through spin diffusion (MIRROR-SD) and to establish through-space neighborhood of spins at high MAS frequencies. [Copyright &y& Elsevier]

We consider atoms with closed shells, i.e. the electron number N is 2, 8, 10,..., and weak electron-electron interaction. Then there exists a unique solution γ of the Dirac–Fock equations $$[D_{g,\alpha}^{(\gamma)},\gamma]=0$$ with the additional property that γ is the orthogonal projector onto the first N positive eigenvalues of the Dirac–Fock operator $$D_{g,\alpha}^{(\gamma)}$$ . Moreover, γ minimizes the energy of the relativistic electron-positron field in Hartree–Fock approximation, if the splitting of $$\mathfrak{H}:=L^2(\mathbb{R}^3)\otimes \mathbb{C}^4$$ into electron and positron subspace is chosen self-consistently, i.e. the projection onto the electron-subspace is given by the positive spectral projection of $$D_{g,\alpha}^{(\gamma)}$$ . For fixed electron-nucleus coupling constant g:=α Z we give quantitative estimates on the maximal value of the fine structure constant α for which the existence can be guaranteed. [ABSTRACT FROM AUTHOR]

Recently the block-diagonalization of Dirac-operators was investigated from a mathematical point of view in the one-particle case [14]. We extend this result to the N-particle case. This leads to a perturbative realization of the Furry picture in the N-particle two-spinor space. [ABSTRACT FROM AUTHOR]

Objective. To investigate the pharmacokinetic interactions, safety, and tolerability of the combination of olmesartan medoxomil with glibenclamide. Methods. In an open, three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered, seven-day treatment periods. The three treatments comprised once daily administration of (1) olmesartan 20 mg, (2) olmesartan 20 mg plus glibenclamide 3.5 mg, or (3) glibenclamide 3.5 mg. Results. The combination of olmesartan with glibenclamide did not influence the bioequivalence of the area under the plasma-concentration time curve at steady state during one dosing interval 0 to τ = 24 hours (AUCss,τ) or the maximum steady-state concentration (Css,max) of both substances. Mean AUCss,τ values for olmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combination with glibenclamide; the corresponding Css,max values were 479.3 ng/ml and 462.7 ng/ml, respectively. For glibenclamide, the mean AUCss,τ values were 525.7 ng·h/ml for monotherapy and 518.7 ng·h/ml for its combination with olmesartan. The median time to reach Css,max (tmax) for glibenclamide was shifted from 2.0 h to 1.0 h when combined with olmesartan, whereas the median tmax values for olmesartan remained unchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide, no adverse event occurred, and the medications were well tolerated. Conclusion. With the exception of a slight shift of tmax values for glibenclamide, the concomitant administration of olmesartan medoxomil with glibenclamide had no significant effects on the steady-state pharmacokinetics of either agent. This provides the pharmacokinetic rationale for clinical studies to test the combination therapy of patients with hypertension and type-2 diabetes mellitus with both compounds. [ABSTRACT FROM AUTHOR]

Abstract: Background: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. Objective: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. Materials and methods: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. Results and discussion: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158–189%, intraindividual range of CV of plasma Mtx levels 35–64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r =−0.7), which reflects their largely common elimination from CSF. Conclusion: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy. [Copyright &y& Elsevier]

Objective: Evaluation of the benefits of a virtual reality (VR) environment with a head-mounted display (HMD) for decision-making in liver surgery. Background: Training in liver surgery involves appraising radiologic images and considering the patient's clinical information. Accurate assessment of 2D-tomography images is complex and requires considerable experience, and often the images are divorced from the clinical information. We present a comprehensive and interactive tool for visualizing operation planning data in a VR environment using a head-mounted-display and compare it to 3D visualization and 2D-tomography. Methods: Ninety medical students were randomized into three groups (1:1:1 ratio). All participants analyzed three liver surgery patient cases with increasing difficulty. The cases were analyzed using 2D-tomography data (group "2D"), a 3D visualization on a 2D display (group "3D") or within a VR environment (group "VR"). The VR environment was displayed using the "Oculus Rift ™" HMD technology. Participants answered 11 questions on anatomy, tumor involvement and surgical decision-making and 18 evaluative questions (Likert scale). Results: Sum of correct answers were significantly higher in the 3D (7.1 ± 1.4, p < 0.001) and VR (7.1 ± 1.4, p < 0.001) groups than the 2D group (5.4 ± 1.4) while there was no difference between 3D and VR (p = 0.987). Times to answer in the 3D (6:44 ± 02:22 min, p < 0.001) and VR (6:24 ± 02:43 min, p < 0.001) groups were significantly faster than the 2D group (09:13 ± 03:10 min) while there was no difference between 3D and VR (p = 0.419). The VR environment was evaluated as most useful for identification of anatomic anomalies, risk and target structures and for the transfer of anatomical and pathological information to the intraoperative situation in the questionnaire. Conclusions: A VR environment with 3D visualization using a HMD is useful as a surgical training tool to accurately and quickly determine liver anatomy and tumor involvement in surgery. [ABSTRACT FROM AUTHOR]

Since the beginning of the industrial revolution, atmospheric carbon dioxide (CO 2) concentrations have risen steadily and have induced a decrease of the averaged surface ocean pH by 0.1 units, corresponding to an increase in ocean acidity of about 30 %. In addition to ocean warming, ocean acidification poses a tremendous challenge to some marine organisms, especially calcifiers. The need for long-term oceanic observations of pH and temperature is a key element to assess the vulnerability of marine communities and ecosystems to these pressures. Nearshore productive environments, where a large majority of shellfish farming activities are conducted, are known to present pH levels as well as amplitudes of daily and seasonal variations that are much larger than those observed in the open ocean. Yet, to date, there are very few coastal observation sites where these parameters are measured simultaneously and at high frequency. To bridge this gap, an observation network was initiated in 2021 in the framework of the CocoriCO 2 project. Six sites were selected along the French Atlantic and Mediterranean coastlines based on their importance in terms of shellfish production and the presence of high- and low-frequency monitoring activities. At each site, autonomous pH sensors were deployed, both inside and outside shellfish production areas, next to high-frequency CTD (conductivity–temperature–depth) probes operated through two operating monitoring networks. pH sensors were set to an acquisition rate of 15 min, and discrete seawater samples were collected biweekly in order to control the quality of pH data (laboratory spectrophotometric measurements) as well as to measure total alkalinity and dissolved inorganic carbon concentrations for full characterization of the carbonate system. While this network has been up and running for more than 2 years, the acquired dataset has already revealed important differences in terms of pH variations between monitored sites related to the influence of diverse processes (freshwater inputs, tides, temperature, biological processes). Data are available at 10.17882/96982 (Petton et al., 2023a). [ABSTRACT FROM AUTHOR]

Since the beginning of the industrial revolution, atmospheric carbon dioxide (CO2) concentrations have risen steadily and have induced a decrease of the averaged surface ocean pH by 0.1 units, corresponding to an increase in ocean acidity of about 30 %. In addition to ocean warming, ocean acidification poses a tremendous challenge to some marine organisms, especially calcifiers. The need for long-term oceanic observations of pH and temperature is a key element to assess the vulnerability of marine communities and ecosystems to these pressures. Nearshore productive environments, where a large majority of shellfish farming activities are conducted, are known to present pH levels as well as amplitudes of daily and seasonal variations that are much larger than those observed in the open ocean. Yet, to date, there are very few coastal observation sites where these parameters are measured simultaneously and at high frequency. To bridge this gap, an observation network was initiated in 2021 in the framework of the CocoriCO2 project. Six sites were selected along the French Atlantic and Mediterranean coastlines based on their importance in terms of shellfish production and the presence of high- and low-frequency monitoring activities. At each site, autonomous pH sensors were deployed both inside and outside shellfish production areas, next to high-frequency CTD (conductivity- temperature-depth) probes operated through two operating monitoring networks. pH sensors were set to an acquisition rate of 15 min and discrete seawater samples were collected biweekly in order to control the quality of pH data (laboratory spectrophotometric measurements) as well as to measure total alkalinity and dissolved inorganic carbon concentrations for full characterization of the carbonate system. While this network has been up and running for more than two years, the acquired dataset has already revealed important differences in terms of pH variations between monitored sites related to the influence of diverse processes (freshwater inputs, tides, temperature, biological processes). [ABSTRACT FROM AUTHOR]

Abstract We characterized visual system defects in two recessive zebrafish mutants oval and elipsa . These mutants share the syndromic phenotype of outer retinal dystrophy in conjunction with cystic renal disorder. We tested the function of the larval visual system in a behavioural assay, eliciting optokinetic eye movements by high-contrast motion stimulation while recording eye movements in parallel. Visual stimulation did not elicit eye movements in mutant larvae, while spontaneous eye movements could be observed. The retina proved to be unresponsive to light using electroretinography, indicative of a defect in the outer retina. Histological analysis of mutant retinas revealed progressive degeneration of photoreceptors, initiated in central retinal locations and spreading to more peripheral regions with increasing age. The inner retina remains unaffected by the mutation. Photoreceptors display cell type-specific immunoreactivity prior to apoptotic cell death, arguing for a dystrophic defect. Genomic mapping employing simple sequence-length polymorphisms located both mutations on different regions of zebrafish linkage group 9. These mutants may serve as accessible animal models of human outer retinal dystrophies, including oculo-renal diseases, and show the general usefulness of a behavioural genetic approach to study visual system development in the model vertebrate zebrafish. [ABSTRACT FROM AUTHOR]

Despite its central importance for understanding the molecular basis of Alzheimer's disease (AD), high-resolution structural information on amyloid β-peptide (Aβ) fibrils, which are intimately linked with AD, is scarce. We report an atomic-resolution fibril structure of the Aβ1-40 peptide with the Osaka mutation (E22Δ), associated with early-onset AD. The structure, which differs substantially from all previously proposed models, is based on a large number of unambiguous intra- and intermolecular solid-state NMR distance restraints. [ABSTRACT FROM AUTHOR]

Trotz der zentralen Bedeutung für das Verständnis der molekularen Grundlage der Alzheimer ‐ Krankheit (AK), gibt es bisher wenig Wissen über die hochaufgelösten Strukturen von Fibrillen des Amyloid ‐ β(Aβ) ‐ Peptids. Wir präsentieren hier eine atomar aufgelöste Struktur von Fibrillen des Aβ1 ‐ 40 ‐ Peptids mit der Osaka ‐ Mutation (E22Δ), die mit früh auftretender AK in Zusammenhang steht. Die Struktur, die sich grundlegend von allen bisher vorgestellten Aβ ‐ Modellen unterscheidet, basiert auf einer großen Anzahl eindeutiger intra ‐ und intermolekularer Abstandsbeschränkungen (“distance restraints”). Die Fibrillenstruktur des Aβ1 ‐ 40 ‐ Peptids mit der Osaka ‐ Mutation (E22Δ), die mit früh auftretender Alzheimer ‐ Erkrankung in Zusammenhang steht, wurde in atomarer Auflösung erhalten und unterscheidet sich grundlegend von allen bisher vorgeschlagenen Aβ ‐ Modellen: Sie ist komplex geordnet, wobei sich die Deletionsmutation in einer β ‐ Schleife der Struktur befindet. [ABSTRACT FROM AUTHOR]

Elastin‐like proteins (ELPs) are biologically important proteins and models for intrinsically disordered proteins (IDPs) and dynamic structural transitions associated with coacervates and liquid–liquid phase transitions. However, the conformational status below and above coacervation temperature and its role in the phase separation process is still elusive. Employing matrix least‐squares global Boltzmann fitting of the circular dichroism spectra of the ELPs (VPGVG)20, (VPGVG)40, and (VPGVG)60, we found that coacervation occurs sharply when a certain number of repeat units has acquired β‐turn conformation (in our sequence setting a threshold of approx. 20 repeat units). The character of the differential scattering of the coacervate suspensions indicated that this fraction of β‐turn structure is still retained after polypeptide assembly. Such conformational thresholds may also have a role in other protein assembly processes with implications for the design of protein‐based smart materials. [ABSTRACT FROM AUTHOR]

Elastin‐artige Proteine (ELPs) haben neben ihrer biologischen Funktion auch Bedeutung als Modelle für intrinsisch ungeordnete Proteine und dynamische Strukturübergänge, die mit Koazervation und Flüssig‐flüssig‐Phasenübergängen einhergehen. Über den Konformerenzustand direkt unter‐ und oberhalb der Koazervationstemperatur und dessen Rolle im Phasentrennprozess ist allerdings nach wie vor wenig bekannt. Durch globales Matrix‐kleinste‐Quadrate‐Boltzmann‐Fitting der Zirkulardichroismus‐Spektren dreier ELPs deckten wir auf, dass es unmittelbar zur Koazervation kommt, wenn eine bestimmte Anzahl von Wiederholungseinheiten β‐Turn‐Konformation angenommen hat (hier etwa 20 Wiederholungseinheiten). Der Charakter der differenziellen Streuung der Koazervat‐Suspensionen wies darauf hin, dass dieser Anteil an β‐Turn‐Struktur auch nach der Zusammenlagerung der Polypeptide erhalten bleibt. Möglicherweise spielen derartige "Konformationsschwellenwerte" auch in anderen Protein‐Zusammenlagerungsprozessen eine Rolle. [ABSTRACT FROM AUTHOR]

Background: Virtual reality (VR) with head-mounted displays (HMD) may improve medical training and patient care by improving display and integration of different types of information. The aim of this study was to evaluate among different healthcare professions the potential of an interactive and immersive VR environment for liver surgery that integrates all relevant patient data from different sources needed for planning and training of procedures. Methods: 3D-models of the liver, other abdominal organs, vessels, and tumors of a sample patient with multiple hepatic masses were created. 3D-models, clinical patient data, and other imaging data were visualized in a dedicated VR environment with an HMD (IMHOTEP). Users could interact with the data using head movements and a computer mouse. Structures of interest could be selected and viewed individually or grouped. IMHOTEP was evaluated in the context of preoperative planning and training of liver surgery and for the potential of broader surgical application. A standardized questionnaire was voluntarily answered by four groups (students, nurses, resident and attending surgeons). Results: In the evaluation by 158 participants (57 medical students, 35 resident surgeons, 13 attending surgeons and 53 nurses), 89.9% found the VR system agreeable to work with. Participants generally agreed that complex cases in particular could be assessed better (94.3%) and faster (84.8%) with VR than with traditional 2D display methods. The highest potential was seen in student training (87.3%), resident training (84.6%), and clinical routine use (80.3%). Least potential was seen in nursing training (54.8%). Conclusions: The present study demonstrates that using VR with HMD to integrate all available patient data for the preoperative planning of hepatic resections is a viable concept. VR with HMD promises great potential to improve medical training and operation planning and thereby to achieve improvement in patient care. [ABSTRACT FROM AUTHOR]

Abstract: We present a de novo high-resolution structure of the peptide Alanyl-Prolyl-Glycine using a combination of sensitive solid-state NMR techniques that each yield precise structural constraints. High-quality 13C–13C distance constraints are extracted by fitting rotational resonance width (R2W) experiments using Multimode Multipole Floquet Theory and experimental chemical shift anisotropy (CSA) orientations. In this strategy, a structure is first calculated using DANTE-REDOR and torsion angle measurements and the resulting relative CSA orientations are used as an input parameter in the 13C–13C distance calculations. Finally, a refined structure is calculated using all the constraints. We investigate the effect of different structural constraints on structure quality, as determined by comparison to the crystal structure and also self-consistency of the calculated structures. Inclusion of all or subsets of these constraints into CNS calculations resulted in high-quality structures (0.02Å backbone RMSD using all 11 constraints). [Copyright &y& Elsevier]

BACKGROUND: Hypertension treatment guidelines recommend combination therapy with diuretics and other antihypertensive agents, including angiotensin II type 1 (AT1) receptor antagonists. This trial investigated the possibility of pharmacokinetic interactions between the AT1 receptor antagonist olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide in healthy subjects. METHODS: Twenty-four healthy normotensive adult male subjects underwent three consecutive 7-day treatment periods (A, B and C, respectively) during which they were randomised to receive: olmesartan medoxomil 20mg once daily (regimen A), hydrochlorothiazide 25mg once daily (regimen B), or olmesartan medoxomil 20mg once daily plus hydrochlorothiazide 25mg once daily (regimen C). Treatment periods were separated by washouts of 7-14 days. The primary pharmacokinetic parameters evaluated were: the area under the plasma concentration versus time curve at steady state (AUCss,τ), the maximum plasma concentration at steady state (Css,max), and the time at which Css,max occurred (tmax). RESULTS: Complete data sets from 17 subjects were available for pharmacokinetic analyses. Mean concentration versus time profiles were similar for monotherapy and combination treatment for both olmesartan (the active metabolite of olmesartan medoxomil) and hydrochlorothiazide. For olmesartan, comparison of-monotherapy with combination therapy showed that for AUCss,τ and Css,max point-estimates were close to unity, demonstrating bioequivalence. For hydrochlorothiazide, combination therapy resulted in decreases in AUCss,τ and Css,max of approximately 10% versus monotherapy; nevertheless, since 90% CIs were within the acceptance range, bioequivalence was proven. Median tmax values for olmesartan and hydrochlorothiazide for periods A, B and C were identical, indicating bioequivalence. Both olmesartan medoxomil and hydrochlorothiazide were well tolerated. CONCLUSION: These results show that there is little or no potential for a clinically relevant pharmacokinetic interaction between olmesartan medoxomil 20mg and hydrochlorothiazide 25mg, and therefore dosage adjustment should not be necessary when they are co-administered. [ABSTRACT FROM AUTHOR]

• Strain-specific toxicities of Alexandrium minutum upon early-larval development were observed. • Among oyster free-living stages, embryos are the most sensitive stage to A. minutum. • A non-PST-producing strain altered larval feeding, growth, survival, and settlement. • Oyster larvae fed with toxic A. minutum accumulated PST. The dinoflagellate genus Alexandrium comprises species that produce highly potent neurotoxins known as paralytic shellfish toxins (PST), and bioactive extracellular compounds (BEC) of unknown structure and ecological significance. The toxic bloom-forming species, Alexandrium minutum , is distributed worldwide and adversely affects many bivalves including the commercially and ecologically important Pacific oyster, Crassostrea gigas. In France, recurrent A. minutum blooms can co-occur with C. gigas spawning and larval development, and may endanger recruitment and population renewal. The present study explores how A. minutum affects oyster early development by exposing embryos and larvae, under controlled laboratory conditions, to two strains of A. minutum , producing only BEC or both PST and BEC. Results highlight the major role of BEC in A. minutum toxicity upon oyster development. The BEC strain caused lysis of embryos, the most sensitive stage to A. minutum toxicity among planktonic life stages. In addition, the non-PST-producing A. minutum strain inhibited hatching, disrupted larval swimming behavior, feeding, growth, and induced drastic decreases in survival and settlement of umbonate and eyed larvae (9 and 68 %, respectively). The findings indicated PST accumulation in oyster larvae (e.g. umbonate stages), possibly impairing development and settlement of larvae in response to the PST-producing strain. This work provides evidences that A. minutum blooms could hamper settlement of shellfish. [ABSTRACT FROM AUTHOR]

Abstract: Immune-mediated heparin-induced thrombocytopenia (HIT) is the clinically most important adverse drug reaction (ADR) in response to heparin therapy characterized by a prothrombotic state despite a decrease in platelet count. We conducted a genome-wide association study in 96 suspected HIT cases and 96 controls to explore the genetic predisposition for HIT within a case-control pharmacovigilance study followed by replication in additional 86 cases and 86 controls from the same study. One single nucleotide polymorphism (SNP, rs1433265, P = 6.5 × 10−5, odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 × 10−4, OR 2.77; combined data set P = 2.7 × 10−8, OR 2.77) and remained the most strongly associated SNP after imputing locus genotypes. Fine mapping revealed a significantly associated risk-conferring haplotype (P = 4.9 × 10−6, OR 2.41). In order to find rare variants contributing to the association signals, we applied a targeted resequencing approach in a subgroup of 73 HIT patients and 23 controls for the regions with the 16 most strongly HIT-associated SNPs. C-alpha testing was applied to test for the impact of rare variants and we detected two candidate genes, the discoidin domain receptor tyrosine kinase 1 (DDR1, P = 3.6 × 10−2) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 × 10−2). For the genes interactor of little elongation complex ELL subunit 1 (ICE1) and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 16 (ADAMTS16) nearby rs1433265, we identified several missense variants. Although replication in an independent population is warranted, these findings provide a basis for future studies aiming to identify and characterize genetic susceptibility factors for HIT.Key messages: We identified and validated a HIT-associated locus on chromosome 5.Targeted NGS analysis for rare variants identifies DDR1 and MCTP2 as novel candidates.In addition, missense variants for ADAMTS16 and ICE1 were identified in the locus. [ABSTRACT FROM AUTHOR]

Inflammasomes are multiprotein complexes that control the innate immune response by activating caspase-1, thus promoting the secretion of cytokines in response to invading pathogens and endogenous triggers. Assembly of inflammasomes is induced by activation of a receptor protein. Many inflammasome receptors require the adapter protein ASC [apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD)], which consists of two domains, the N-terminal pyrin domain (PYD) and the C-terminal CARD. Upon activation, ASC forms large oligomeric filaments, which facilitate procaspase-1 recruitment. Here, we characterize the structure and filament formation of mouse ASC in vitro at atomic resolution. Information from cryo-electron microscopy and solid-state NMR spectroscopy is combined in a single structure calculation to obtain the atomic-resolution structure of the ASC filament. Perturbations of NMR resonances upon filament formation monitor the specific binding interfaces of ASC-PYD association. Importantly, NMR experiments show the rigidity of the PYD forming the core of the filament as well as the high mobility of the CARD relative to this core. The findings are validated by structure-based mutagenesis experiments in cultured macrophages. The 3D structure of the mouse ASC-PYD filament is highly similar to the recently determined human ASC-PYD filament, suggesting evolutionary conservation of ASC-dependent inflammasome mechanisms. [ABSTRACT FROM AUTHOR]

A major quantitative trait locus (QTL) on rat chromosome (RNO)6 was linked to albuminuria in Munich Wistar Frömter rats (MWF). We tested whether transfer of MWF RNO6 into the background of albuminuria-resistant spontaneously hypertensive rats (SHR) induces albuminuria in consomic SHR-6MWF animals. Male MWF, SHR, and SHR-6MWF were sham operated and treated between 6 and 24 wk of age with normal water (Sham) or with water containing 20 mg/l NG-nitro-L-arginine methyl ester (L-NAME) or unilaterally nephrectomized (Nx). Compared with SHR albuminuria was not increased in SHR-6MWF in both Sham and Nx groups. All animals survived the observation period in Sham and Nx groups, while premature mortality occurred from 12-14 wk on in L-NAME-treated SHR and SHR-6MWF compared with MWF L-NAME animals, in which survival was not affected (P < 0.005, respectively). Subsequent further analysis of L-NAME-treated animals at 12 wk of age showed significantly increased arterial blood pressures in both SHR and SHR-6MWF compared with control (P < 0.05), with higher levels in SHR compared with consomics (P < 0.05). However, L-NAME-treated consomic animals demonstrated increased albuminuria compared with SHR (12.7 ± 3.5 vs. 0.8 ± 0.2 mg/24 h; P < 0.05) and an induction of tubulointerstitial structural injury and expression of neutrophil gelatinase- associated lipocalin mRNA (P < 0.05 vs. other strains). Our study demonstrates that isolation of the RNO6 albuminuria QTL from the MWF background and transfer into SHR fails to induce an albuminuria phenotype during normal conditions or after nephron reduction. Moreover, our data indicate that genes on RNO6 contribute to the development of L-NAME-induced renal damage in the SHR strain. [ABSTRACT FROM AUTHOR]

We have studied two different β-peptides in methanol using explicit solvent molecular dynamics simulations and the GROMOS 53A6 force field: a heptapeptide (peptide 1) expected to form a left-handed 314-helix, and a hexapeptide (peptide 2) expected to form a β-hairpin in solution. Our analysis has focused on identifying and analyzing the stability of the dominant secondary structure conformations adopted by the peptides, as well as on comparing the experimental NOE distance upper bounds and 3J-coupling values with their counterparts calculated on the basis of the simulated ensembles. Moreover, we have critically compared the present results with the analogous results obtained with the GROMOS 45A3 (peptide 1) and 43A1 (peptide 2) force fields. We conclude that within the limits of conformational sampling employed here, the GROMOS 53A6 force field satisfactorily reproduces experimental findings regarding the behavior of short β-peptides, with accuracy that is comparable to but not exceeding that of the previous versions of the force field.[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Background: Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. Results: We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. Conclusion: By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations. [ABSTRACT FROM AUTHOR]

Recent experimental work indicates that the hyperglycemia-induced increase in mesangial matrix production, which is a hallmark in the development of diabetic nephropathy, is mediated by increased expression of GLUT1. Mesangial cells stably transfected with human GLUT1 mimic the effect of hyperglycemia on the production of the extracellular matrix proteins, particularly fibronectin, when cultured under normoglycemic conditions. Our investigation of the molecular mechanism of this effect has revealed that the enhanced fibronectin production was not mediated by the prosclerotic cytokine transforming growth factor (TGF)-beta1. We found markedly increased nuclear content in Jun proteins, leading to enhanced DNA-binding activity of activating protein 1 (AP-1). AP-1 inhibition reduced fibronectin production in a dosage-dependent manner. Moreover, inhibition of classic protein kinase C (PKC) isoforms prevented both the activation of AP-1 and the enhanced fibronectin production. In contrast to mesangial cells exposed to high glucose, no activation of the hexosamine biosynthetic, p38, or extracellular signal-related kinase 1 and 2 mitogen-activated protein kinase pathways nor any increase in TGF-beta1 synthesis could be detected, which could be explained by the absence of oxidative stress in cells transfected with the human GLUT1 gene. Our data indicate that increased glucose uptake and metabolism induce PKC-dependent AP-1 activation that is sufficient for enhanced fibronectin production, but not for increased TGF-beta1 expression. [ABSTRACT FROM AUTHOR]

Recent experimental work indicates that the hyperglycemia-induced increase in mesangial matrix production, which is a hallmark in the development of diabetic nephropathy, is mediated by increased expression of GLUTI. Mesangial cells stably transfected with human GLUT1 mimic the effect of hyperglycemia on the production of the extracellular matrix proteins, particularly fibronectin, when cultured under normoglycemic conditions. Our investigation of the molecular mechanism of this effect has revealed that the enhanced fibronectin production was not mediated by the prosclerotic cytokine transforming growth factor (TGF)-β1. We found markedly increased nuclear content in Jun proteins, leading to enhanced DNA-binding activity of activating protein 1 (AP-1). AP-1 inhibition reduced fibronectin production in a dosage-dependent manner. Moreover, inhibition of classic protein kinase C (PKC) isoforms prevented both the activation of AP-1 and the enhanced fibronectin production. In contrast to mesangial cells exposed to high glucose, no activation of the hexosamine biosynthetic, p38, or extracellular signal-related kinase 1 and 2 mitogen-activated protein kinase pathways nor any increase in TGF-β1 synthesis could be detected, which could be explained by the absence of oxidative stress in cells transfected with the human GLUT1 gene. Our data indicate that increased glucose uptake and metabolism induce PKC-dependent AP-1 activation that is sufficient for enhanced fibronectin production, but not for increased TGF-β1 expression. [ABSTRACT FROM AUTHOR]

• Archetypes to summarize countries globally regarding their energy system. • Framework to define, model and validate these archetypes. • Archetype classification 44% better than simple geographic grouping. • Photovoltaics and flexibility are identified and quantified as global challenges by the archetype modeling. • Country modeling validates archetype approach with few outliers. Energy system models help to find the optimal technology mixes for decarbonization strategies in countries worldwide. To reduce the modeling effort and analyze as many countries as possible, this paper proposes a novel approach of energy system archetypes which can be directly evaluated. These archetypes classify similar countries worldwide independently from their geographic location. Advantages of this idea are the setup of a transferable global database allowing for data reconstruction between countries, market size estimations, and the ability to compare peer countries facing similar challenges. To enable such modeling, a framework is developed in which the archetypes are defined, standardized modeling rules are developed, and the results are evaluated for validation. In a benchmark against simple geographic classifications, the presented clustering approach, which results in 15 archetypes, improves the variance between all countries and their corresponding archetypes by 44% compared to the variance between the countries and their geographic sub-regions. The model results of these archetypes state the need of balancing technologies for the daily cycle of photovoltaic generation and the general importance of flexibility in future decarbonized energy systems. Overall, the results confirm that archetypes are an adequate approach to derive the set of solutions for the decarbonization of worldwide countries. [ABSTRACT FROM AUTHOR]

Pathways leading to a carbon neutral future for the German energy system have to deal with the expected phase-out of coal-fired power generation, in addition to the shutdown of nuclear power plants and the rapid ramp-up of photovoltaics and wind power generation. An analysis of the expected impact on electricity market, security of supply, and system stability must consider the European context because of the strong coupling—both from an economic and a system operation point of view—through the cross-border power exchange of Germany with its neighbors. This analysis, complemented by options to improve the existing development plans, is the purpose of this paper. We propose a multilevel energy system modeling, including electricity market, network congestion management, and system stability, to identify challenges for the years 2023 and 2035. Out of the results, we would like to highlight the positive role of innovative combined heat and power (CHP) solutions securing power and heat supply, the importance of a network congestion management utilizing flexibility from sector coupling, and the essential network extension plans. Network congestion and reduced security margins will become the new normal. We conclude that future energy systems require expanded flexibilities in combination with forward planning of operation. [ABSTRACT FROM AUTHOR]

The decarbonization of energy systems has led to a fundamental change in their topology since generation is shifted to locations with favorable renewable conditions. In planning, this change is reflected by applying optimization models to regions within a country to optimize the distribution of generation units and to evaluate the resulting impact on the grid topology. This paper proposes a globally applicable framework to find a suitable regionalization for energy system models with a data-driven approach. Based on a global, spatially resolved database of demand, generation, and renewable profiles, hierarchical clustering with fine-tuning is performed. This regionalization approach is applied by modeling the resulting regions in an optimization model including a synthesized grid. In an exemplary case study, South Africa's energy system is examined. The results show that the data-driven regionalization is beneficial compared to the common approach of using political regions. Furthermore, the results of a modeled 80% decarbonization until 2045 demonstrate that the integration of renewable energy sources fundamentally changes the role of regions within South Africa's energy system. Thereby, the electricity exchange between regions is also impacted, leading to a different grid topology. Using clustered regions improves the understanding and analysis of regional transformations in the decarbonization process. [ABSTRACT FROM AUTHOR]