Structure and energetics of liquid water-hydroxyl layers on Pt(111).

The interactions between liquid water and hydroxyl species on Pt(111) surfaces have been intensely investigated due to their importance to fuel cell electrocatalysis. Here we present a molecular dynamics study of their structure and energetics using an ensemble of neural network potentials, which allow us to obtain unprecedented statistical sampling. We first study the energetics of hydroxyl formation, where we find a near-linear adsorption energy profile, which exhibits a soft and gradual increase in the differential adsorption energy at high hydroxyl coverages. This is strikingly different from the predictions of the conventional bilayer model, which displays a kink at 1/3ML OH coverage indicating a sizeable jump in differential adsorption energy, but within the statistical uncertainty of previously reported ab initio molecular dynamics studies. We then analyze the structure of the interface, where we provide evidence for the water-OH/Pt(111) interface being hydrophobic at high hydroxyl coverages. We furthermore explain the observed adsorption energetics by analyzing the hydrogen bonding in the water-hydroxyl adlayers, where we argue that the increase in differential adsorption energy at high OH coverage can be explained by a reduction in the number of hydrogen bonds from the adsorbed water molecules to the hydroxyls.

[Evaluation of Weaning Success in Long-Term Invasively Ventilated Patients at a Weaning Center]. / Ergebnisse der Re-Evaluation von Patienten aus der Intensivpflege in einem lokalen Weaning-Zentrum.

Despite the use of enormous personnel and other resources in German weaning centers, approximately 20 % of patients currently fail to get weaned from mechanical ventilation (MV) and need out-of-hospital ventilation.Between 03/2015 and 11/2019, we carried out a pilot project with 33 patients (48 % female, mean age 68 ±â€Š11 years at hospital admission) in order to re-evaluate their options of a possible weaning from MV. At this stage the patients had been invasively ventilated for 475 ±â€Š775 days. The mean stay in our weaning center was 26 ±â€Š19 days. 24/33 (73.53 %) patients were successfully weaned from MV. Of those, 11/24 (44 %) were discharged with non-invasive out-of-hospital ventilation. The completely weaned patients had a survival period of 3 or 12 months (92 % and 77 %), respectively. In those discharged with non-invasive ventilation, the survival period of 3 or months was 91 % and 81 %, respectively. In those discharged with invasive ventilation, this was 86 % and 71 %, respectively.The current results demonstrate that even those undergoing long-term out-of-hospital invasive ventilation can be successfully weaned from MV. Therefore, we suggest regular re-evaluations of weaning opportunities in invasively ventilated ambulatory patients.

[Prevalence and treatment of rheumatological adverse events due to immune checkpoint inhibitor therapy]. / Prävalenz und Therapie von rheumatologischen Nebenwirkungen bei Immun-Checkpoint-Inhibitor-Therapie.

BACKGROUND: Immune checkpoint inhibitors (ICI) have essentially improved the treatment options for various malignant diseases. They lead to an activation of the immune system and subsequent attack of tumor cells by affecting the immune system and preventing tumor cells from avoiding detection. In addition to this desired effect, immune-related adverse events (irAE) can occur in nearly all organ systems and therefore also rheumatological irAE (rh-irAE). OBJECTIVE: The occurrence of rh-irAE has been described in various publications and is specifically investigated in this review. The aim is to provide an overview on the prevalence, severity, treatment options and altered tumor response in patients with rh-irAE. MATERIAL AND METHODS: We conducted a literature search for studies and case reports on rh-irAE under ICI therapy in PubMed up to January 2020 using the PICO model. RESULTS: A total of 18 publications were included, most of which were clinical studies (n = 13) and the rest case reports (n = 5). Several rh-irAE can occur with a wide variety of manifestations of which arthralgia, arthritis and myositis were the most common. Other rheumatic diseases, such as vasculitis, connective tissue diseases and sarcoidosis were less frequently described. The published prevalence of rh-irAE varied with a prevalence between 2.3% and 6.6%. Treatment of rh-irAE depends on the severity and most patients receive nonsteroidal anti-inflammatory drugs and glucocorticosteroids. In some cases, conventional DMARDs, such as methotrexate and biological DMARDs, were administered. Patients with rh-irAE in general had a higher tumor response rate compared to patients without side effects. CONCLUSION: A close observation of patients and early detection of rh-irAE are important in order to treat these side effects in time. Further prospective studies are necessary to systematically investigate rh-irAE.

Optimized Ki-67 staining in murine cells: a tool to determine cell proliferation.

The reliable analysis of the cell cycle status has become increasingly relevant for scientific and clinical work, especially for the determination of tumor cell growth. One established method to characterize the proliferation activity of cells is the analysis of the Ki-67 protein. Ki-67 is expressed in the nucleus during the whole cell cycle except for the G0 phase. Several different protocols exist for the examination of the Ki-67 protein in tissue and cell culture, but most of them are defined for human cells. For the analysis of the Ki-67 protein in murine tissue and cell culture there is a variety of protocols existing which recommend different fixation and permeabilization reagents or special kits. In this study, we established a reliable protocol for Ki-67 staining in murine cells and tissue based on PFA fixation, which can be used not only for flow cytometry but also for immunofluorescence microscopy analysis. We tested our protocol successfully with three different Ki-67 anti-mouse antibodies in cell culture, regenerating liver tissue and mouse melanoma tumor to demonstrate the general applicability.

[Weaning Unit of the University Medicine Greifswald - Institutional Structure and Weaning Results from Prolonged Ventilation over 10 Years]. / Weaningzentrum Greifswald ­ Struktur und Ergebnisse bei der Entwöhnung von der Langzeitbeatmung über zehn Jahre.

The increasing importance of intensive care medicine including mechanical ventilation has been accompanied by the demand of weaning opportunities for patients undergoing prolonged mechanical ventilation. Consequently, specialised clinical institutions, focusing on the weaning from mechanical ventilation, have been established since the 1980 s.The present article illustrates the structural development and results of such a specialised institution at the University Medicine Greifswald, using data of 616 patients collected within the past ten years (2006 - 2015). Across the years, a shift in the underlying disease leading to mechanical ventilation can be found, with rising numbers of patients suffering from pneumonia/sepsis and declining numbers of patients who underwent cardiac surgery in advance. The days with mechanical ventilation outside (p = 0.004) and within the investigated institution (p = 0.02) are significantly declining. The percentage of successfully weaned patients increased from 62.7 % (2006 - 2010) to 77.3 % (2011 - 2015), p < 0.001. Consecutively, the percentage of patients who remained mechanically ventilated decreased from 16.4 % to 9.6 % (p < 0.001) and the share of in-hospital deceased patients significantly declined from 20.9 % to 13.0 % (p < 0.001). Furthermore, the one-year-survival after hospital discharge in successful weaned patients was 72 percent. The present data, collected at the University Medicine Greifswald are quite comparable to data of other German institutions that are specialised on weaning from mechanical ventilation.

Competition between Kondo Screening and Quantum Hall Edge Reconstruction.

We report on a Kondo correlated quantum dot connected to two-dimensional leads where we demonstrate the renormalization of the g factor in the pure Zeeman case. i.e., for magnetic fields parallel to the plane of the quantum dot. For the same system, we study the influence of orbital effects by investigating the quantum Hall regime; i.e., a perpendicular magnetic field is applied. In this case an unusual behavior of the suppression of the Kondo effect and of the split zero-bias anomaly is observed. The splitting decreases with magnetic field and shows discontinuous changes that are attributed to the intricate interplay between Kondo screening and the quantum Hall edge structure originating from electrostatic screening. This edge structure, made up of compressible and incompressible stripes, strongly affects the Kondo temperature of the quantum dot and thereby influences the renormalized g factor.

Decoupling strain and ligand effects in ternary nanoparticles for improved ORR electrocatalysis.

Ternary Pt-Au-M (M = 3d transition metal) nanoparticles show reduced OH adsorption energies and improved activity for the oxygen reduction reaction (ORR) compared to pure Pt nanoparticles, as obtained by density functional theory. The strain and ligand effects in nanoparticles are decoupled and correlated with the extended Pt(111) surface for benchmarking. The ternary metal in the core allows for tuning the catalytic activity through strain effects. Pt-Au-M for M = Cr, Mn, Co, Cu, Zn nanoparticles are of particular interest as they exhibit an optimal contribution of strain, ligand effects and stability. Good agreement is found with experimental studies showing increased activity of Pt-Au-Fe/Ni nanoparticles, and mid to late 3d transition metals are predicted to exhibit enhance activity and stability with respect to pure Pt nanoparticles.

A DFT-based genetic algorithm search for AuCu nanoalloy electrocatalysts for CO2 reduction.

Using a DFT-based genetic algorithm (GA) approach, we have determined the most stable structure and stoichiometry of a 309-atom icosahedral AuCu nanoalloy, for potential use as an electrocatalyst for CO2 reduction. The identified core-shell nano-particle consists of a copper core interspersed with gold atoms having only copper neighbors and a gold surface with a few copper atoms in the terraces. We also present an adsorbate-dependent correction scheme, which enables an accurate determination of adsorption energies using a computationally fast, localized LCAO-basis set. These show that it is possible to use the LCAO mode to obtain a realistic estimate of the molecular chemisorption energy for systems where the computation in normal grid mode is not computationally feasible. These corrections are employed when calculating adsorption energies on the Cu, Au and most stable mixed particles. This shows that the mixed Cu135@Au174 core-shell nanoalloy has a similar adsorption energy, for the most favorable site, as a pure gold nano-particle. Cu, however, has the effect of stabilizing the icosahedral structure because Au particles are easily distorted when adding adsorbates.

Elucidating the activity of stepped Pt single crystals for oxygen reduction.

The unexpectedly high measured activity of Pt[n(111) × (111)] and Pt[n(111) × (100)] stepped single crystal surfaces towards the oxygen reduction reaction (ORR) is explained utilizing the hydroxyl binding energy as the activity descriptor. Using this descriptor (estimated using experimental data obtained by different groups), a well-defined Sabatier-type volcano is observed for the activities measured for the Pt[n(111) × (111)] and Pt[n(111) × (100)] stepped single crystals, in remarkable agreement with earlier theoretical studies. We propose that the observed destabilisation of *OH species at these surfaces is due to the decreased solvation of the adsorbed hydroxyl intermediates on adjacent terrace sites.

Trends in electrochemical CO2 reduction activity for open and close-packed metal surfaces.

We present a theoretical analysis of trends in overpotentials for electrocatalytic CO2 reduction based on density functional theory calculations. The analysis is based on understanding variations in the free energy of intermediates and mapping out the potential at which different elementary steps are exergonic as a measure of the catalytic activity. We study different surface structures and introduce a simple model for including the effect of adsorbate-adsorbate interactions. We find that high coverages of CO under typical reaction conditions for the more reactive transition metals affect the catalytic activity towards the CO2 reduction reaction, but the ordering of metal activities is not changed. For the hydrogen evolution reaction, a high CO coverage shifts the maximum activity towards more reactive metals than Pt.

The effect of four different irrigation systems in the removal of a root canal sealer.

OBJECTIVES: The aim of this study was to compare the efficiency of sonic, ultrasonic, and hydrodynamic devices in the removal of a root canal sealer from the surface and from simulated irregularities of root canals. MATERIALS AND METHODS: Fifty-three root canals with two standardized grooves in the apical and coronal parts of longitudinally split roots were covered with AH Plus root canal sealer. Compared were the effects of (control) syringe irrigation, (1) CanalBrush, (2) passive ultrasonic irrigation, (3) EndoActivator, and (4) RinsEndo on the removal of the sealer. The specimens were divided into four groups (N = 12) and one control group (N = 5) via randomization. The amount of remaining sealer in the root canal irregularities was evaluated under a microscope using a 4-grade scoring system, whereas the remaining sealer on the root canal surface was evaluated with a 7-grade scoring system. RESULTS: Passive ultrasonic irrigation is more effective than the other tested irrigation systems or syringe irrigation in removing sealer from root canal walls (p < 0.01). None of the techniques had a significant effect on cleaning the lateral grooves. CONCLUSIONS: Within the limitations of this study protocol ultrasonic irrigation shows a superior effect on sealer removal from the root canal surface during endodontic retreatment. Cleaning of lateral grooves seems not to be possible with one of the techniques investigated. CLINICAL RELEVANCE: Incomplete removal of root canal sealer during re-treatment may cause treatment failure. Passive Ultrasonic irrigation seems to be the most effective system to remove sealer from a root canal.

Prevalence and prognostic impact of comorbidities in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive paralysis of striated muscles due to the loss of upper and lower motor neurons. The disease leads to death within 2-5 years, mainly due to respiratory failure. The pathogenesis of ALS is still unexplained for the most part. In this study, we aimed to determine the prevalence of different cardiovascular, metabolic, and neuropsychiatric comorbidities in a large ALS cohort and to evaluate their influence on the disease course. METHODS: A cohort of 514 patients with ALS of our ALS outpatient clinic was investigated retrospectively with reference to known prognostic factors and comorbidities. The prevalence of concomitant diseases was compared with the data from the German general population. Uni- and multivariate survival analyses were performed using the Cox proportional hazards model and Kaplan-Meier analysis. RESULTS: The prevalence of cardiovascular diseases and cardiovascular risk factors was significantly lower in patients with ALS compared to the German general population, whilst the prevalence of dementia, parkinsonism, and depressive symptoms was significantly higher in the ALS cohort. None of the investigated comorbidities had an influence on the disease course or on the survival of patients. CONCLUSIONS: Persons with cardiovascular diseases or risk factors seem to be at lower risk of ALS. Although these diseases are apparently somehow protective regarding ALS susceptibility, their presence did not modify disease progression and survival in patients with ALS. Our study further confirms the well-known continuum between ALS and dementia. It also suggests a link with other neurodegenerative diseases such as Parkinson's disease.

Modeling CO2 reduction on Pt(111).

Density functional theory was used to model the electrochemical reduction of CO2 on Pt(111) with an explicit solvation layer and the presence of extra hydrogen atoms to represent a negatively charged electrode. We focused on the electronic energy barriers for the first four lowest energy proton-electron transfer steps for reducing CO2 on Pt(111) beginning with adsorbed *CO2 and continuing with *COOH, *CO + H2O, *COH, and ending with *C + H2O. We find that simple elementary steps in which a proton is transferred to an adsorbate (such as the protonation of *CO to *COH) have small barriers on the order of 0.1 eV. Elementary steps in which a proton is transferred and a C-O bond is simultaneously cleaved show barriers on the order of 0.5 eV. All barriers calculated for these steps show no sign of being insurmountable at room temperature. To explain why these barriers are so small, we analyze the charge density and the density of states plots to see that first, the electron transfer is decoupled from the proton transfer so that in the initial state, the surface and adsorbate are already charged up and can easily accept the proton from solution. Also, we see that in the cases where barriers are on the order of 0.1 eV, electron density in the initial state localizes on the oxygen end of the adsorbate, while electron density is more spread out on the surface for initial states of the C-O bond cleaving elementary steps.

First principles investigation of zinc-anode dissolution in zinc-air batteries.

With surging interest in high energy density batteries, much attention has recently been devoted to metal-air batteries. The zinc-air battery has been known for more than a hundred years and is commercially available as a primary battery, but recharging has remained elusive, in part because the fundamental mechanisms still remain to be fully understood. Here, we present a density functional theory investigation of the zinc dissolution (oxidation) on the anode side in the zinc-air battery. Two models are envisaged, the most stable (0001) surface and a kink surface. The kink model proves to be more accurate as it brings about some important features of bulk dissolution and yields results in good agreement with experiments. From the adsorption energies of hydroxyl species and experimental values, we construct a free energy diagram and confirm that there is a small overpotential associated with the reaction. The applied methodology provides new insight into computational modelling and design of secondary metal-air batteries.

Prognostic marker for liver disease due to alpha1-antitrypsin deficiency.

BACKGROUND: Only some Alpha1-antitrypsin deficiency (A1ATD) PiZZ patients develop liver cirrhosis and portal hypertension. Aim of the study was to investigate the course of liver disease associated with PiZZ A1ATD and to determine prognostic factors. PATIENTS: We retrospectively reviewed the clinical and laboratory data of all PiZZ children up to 18 years of age admitted to our centre since 1978. 53 patients (age at first visit 2 days to 12 years) met our criteria. METHODS: The children were divided into 2 groups: group 1 'bad prognosis', meaning the patients which were on the waiting list for liver transplantation (LTx), had a liver transplantation or had died, and group 2 'good prognosis', containing the patients they were living with their own liver. We analysed family history including smoking, gestational age, maternal age at delivery, date of birth, sex, neonatal history, breast-feeding, symptoms at presentation, clinical and laboratory data and date of LTx and/or death. RESULTS: Various anamnesis parameters such as manifestation of neonatal cholestasis showed no prognostic significance. In contrast the laboratory parameters thrombocytes (p=0.008), bilirubin (p<0.001), prothrombin time (p<0.001), choline-sterase (p<0.001), gamma-GT (p=0.001) and GOT (p=0.002) showed a correlation with a liver transplantation and/or death. CONCLUSION: Prognosis is difficult to determine at an early stage of this disease, but various laboratory parameters can help to predict an outcome. Therefore a regular follow-up is necessary for the children.

Cation-induced changes in the inner- and outer-sphere mechanisms of electrocatalytic CO2 reduction.

The underlying mechanism of cation effects on CO2RR remains debated. Herein, we study cation effects by simulating both outer-sphere electron transfer (OS-ET) and inner-sphere electron transfer (IS-ET) pathways during CO2RR via constrained density functional theory molecular dynamics (cDFT-MD) and slow-growth DFT-MD (SG-DFT-MD), respectively. Our results show without any cations, only OS-ET is feasible with a barrier of 1.21 eV. In the presence of K+ (Li+), OS-ET shows a very high barrier of 2.93 eV (4.15 eV) thus being prohibited. However, cations promote CO2 activation through IS-ET with the barrier of only 0.61 eV (K+) and 0.91 eV (Li+), generating the key intermediate (adsorbed CO[Formula: see text]). Without cations, CO2-to-CO[Formula: see text](ads) conversion cannot proceed. Our findings reveal cation effects arise from short-range Coulomb interactions with reaction intermediates. These results disclose that cations modulate the inner- and outer-sphere pathways of CO2RR, offering substantial insights on the cation specificity in the initial CO2RR steps.

High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer.

For patients with metastatic breast cancer, we previously described that increased EZH2 expression levels were associated with an adverse outcome to tamoxifen therapy. Main objective of the present study is to investigate miR-26a and miR-101 levels, which both target EZH2, for their association with molecular pathways and with efficacy of tamoxifen as first-line monotherapy for metastatic breast cancer. Expression levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens of 235 estrogen receptor-α (ER)-positive patients. Pathway analysis was performed on microarray data available for 65 of these tumors. Logistic regression and Cox uni- and multivariate analysis were performed to relate expression levels with clinical benefit and time to progression (TTP). Increasing levels of miR-26a were significantly (P < 0.005) associated with both clinical benefit and prolonged TTP, whereas miR-101 was not. Cell cycle regulation and CCNE1 and CDC2 were the only significant overlapping pathway and genes differentially expressed between tumors with high and low levels of miR-26a and EZH2, respectively. In addition, increasing mRNA levels of CCNE1 (P < 0.05) and CDC2 (P < 0.001) were related to poor outcome. Multivariate analysis revealed miR-26a and CDC2 as an optimal set of markers associated with outcome on tamoxifen therapy, independently of traditional predictive factors. To summarize, only miR-26a levels are related with treatment outcome. Cell cycle regulation is the only overlapping pathway linked to miR-26a and EZH2 levels. Low mRNA levels of EZH2, CCNE1, and CDC2, and high levels of miR-26a are associated with favorable outcome on tamoxifen.

Solar hydrogen production with semiconductor metal oxides: new directions in experiment and theory.

An overview of a collaborative experimental and theoretical effort toward efficient hydrogen production via photoelectrochemical splitting of water into di-hydrogen and di-oxygen is presented here. We present state-of-the-art experimental studies using hematite and TiO(2) functionalized with gold nanoparticles as photoanode materials, and theoretical studies on electro and photo-catalysis of water on a range of metal oxide semiconductor materials, including recently developed implementation of self-interaction corrected energy functionals.

Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: binding of phosphonamidate to the S1'-pocket of thermolysin.

BACKGROUND: Prerequisite for the design of tight binding protein inhibitors and prediction of their properties is an in-depth understanding of the structural and thermodynamic details of the binding process. A series of closely related phosphonamidates was studied to elucidate the forces underlying their binding affinity to thermolysin. The investigated inhibitors are identical except for the parts penetrating into the hydrophobic S1'-pocket. METHODS: A correlation of structural, kinetic and thermodynamic data was carried out by X-ray crystallography, kinetic inhibition assay and isothermal titration calorimetry. RESULTS AND CONCLUSIONS: Binding affinity increases with larger ligand hydrophobic P1'-moieties accommodating the S1'-pocket. Surprisingly, larger P1'-side chain modifications are accompanied by an increase in the enthalpic contribution to binding. In agreement with other studies, it is suggested that the release of largely disordered waters from an imperfectly hydrated pocket results in an enthalpically favourable integration of these water molecules into bulk water upon inhibitor binding. This enthalpically favourable process contributes more strongly to the binding energetics than the entropy increase resulting from the release of water molecules from the S1'-pocket or the formation of apolar interactions between protein and inhibitor. GENERAL SIGNIFICANCE: Displacement of highly disordered water molecules from a rather imperfectly hydrated and hydrophobic specificity pocket can reveal an enthalpic signature of inhibitor binding.