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Interfacial engineering has fueled recent development of p-i-n perovskite solar cells (PSCs), with self-assembled monolayer-based hole-transport layers (SAM-HTLs) enabling almost lossless contacts for solution-processed PSCs, resulting in the highest achieved power conversion efficiency (PCE) to date. Substrate interfaces are particularly crucial for the growth and quality of co-evaporated PSCs. However, adoption of SAM-HTLs for co-evaporated perovskite absorbers is complicated by the underexplored interaction of such perovskites with phosphonic acid functional groups. In this work, we highlight how exposed phosphonic acid functional groups impact the initial phase and final bulk crystal structures of co-evaporated perovskites and their resultant PCE. The explored surface interaction is mediated by hydrogen bonding with interfacial iodine, leading to increased formamidinium iodide adsorption, persistent changes in perovskite structure, and stabilization of bulk α-FAPbI3, hypothesized as being due to kinetic trapping. Our results highlight the potential of exploiting substrates to increase control of co-evaporated perovskite growth.

Environmental conditions for trees that established in central Fennoscandia shortly after the final retreat of the Weichselian ice sheet remain poorly understood. In this study we examine tree rings of five well-preserved Pinus sylvestris(Scots pines) that grew in the area in front of the retreating ice sheet in northern Sweden. They became buried in flood sediments deposited by a glacial outburst flood (jökulhlaup) about 9.5–9.9 kyr cal bpand the aim of our study was to search for information regarding damage from fires and bioclimatic conditions in their ancient tree ring records. Our analysis, providing a glimpse into the local early Holocene environment in north-central Sweden, suggests that: 1, there were repeated fires (four fire events detected) during the early Holocene; and 2, bioclimatic conditions when the ancient pines were growing resembled those of modern sub-alpine pine woods. The latter is indicated by their patterns of tree ring growth (growth rate and variation), which were statistically similar to those of pines growing in sub-alpine woods with an open canopy, but different from pines in protected and managed boreal forests. Lower δ13C for the ancient latewood in comparison to pine wood from trees growing near the Scandinavian mountains before the 1850s were probably caused both by stomata fractionation due to lower atmospheric CO2during the early Holocene and by the moist local environment created by the nearby ancient Ancylus lake, which preceded the Baltic Sea. Periods with cloudy and cold summers were also indicated by the occurrence of ‘false rings’. Finds of charred fragments of Calluna vulgaris(heather, ling), an understory shrub that can burn even with a relatively high moisture content, suggest that heath vegetation was crucial to make fire a reoccurring ecological factor in the area during the early Holocene.

Formamidinium lead iodide (FAPbI3) has emerged as one of the most promising perovskite semiconductors for perovskite solar cells (PSCs), demonstrating high power conversion efficiency (PCE) and good stability. However, only a few reports address the scalable processing and fabrication of FAPbI3perovskite solar modules. Here, we report a void-free perovskite-buried interface in p-i-n-based PSCs, which enables us to upscale lab-scale solar cells (<1 cm2) to mini-module dimensions (>10 cm2). An innovative combination of a moderate N2flow during vacuum-assisted growth (VAG) control of the perovskite thin films as well as the employment of MACl as an additive eliminates interfacial voids in blade-coated large-area FAPbI3layers, enabling respective PCEs of 20.0% and 18.3% in blade-coated PSCs (0.105 cm2) and fully scalable modules (aperture area of 12.25 cm2and geometric fill factor of 96.3%). This is a remarkable advance in upscaling FAPbI3-based perovskite photovoltaics.

One of the great challenges of hybrid organic–inorganic perovskite photovoltaics is the material’s stability at elevated temperatures. Over the past years, significant progress has been achieved in the field by compositional engineering of perovskite semiconductors, e.g., using multiple-cation perovskites. However, given the large variety of device architectures and nonstandardized measurement protocols, a conclusive comparison of the intrinsic thermal stability of different perovskite compositions is missing. In this work, we systematically investigate the role of cation composition on the thermal stability of perovskite thin films. The cations in focus of this study are methylammonium (MA), formamidinium (FA), cesium, and the most common mixtures thereof. We compare the thermal degradation of these perovskite thin films in terms of decomposition, optical losses, and optoelectronic changes when stressed at 85 °C for a prolonged time. Finally, we demonstrate the effect of thermal stress on perovskite thin films with respect to their performance in solar cells. We show that all investigated perovskite thin films show signs of degradation under thermal stress, though the decomposition is more pronounced in methylammonium-based perovskite thin films, whereas the stoichiometry in methylammonium-free formamidinium lead iodide (FAPbI3) and formamidinium cesium lead iodide (FACsPbI3) thin films is much more stable. We identify compositions of formamidinium and cesium to result in the most stable perovskite compositions with respect to thermal stress, demonstrating remarkable stability with no decline in power conversion efficiency when stressed at 85 °C for 1000 h. Thereby, our study contributes to the ongoing quest of identifying the most stable perovskite compositions for commercial application.

The internal luminescence quantum efficiency (Qilum) provides an excellent assessment of the optoelectronic quality of semiconductors. To determine Qilumfrom the experimentally accessible external luminescence quantum efficiency (Qelum), it is essential to account for photon recycling, and this requires knowledge of the photon escape probability (p¯e). Here, we establish an analysis procedure based on a curve-fitting model that accurately determines p¯eof perovskite films from photoluminescence (PL) spectra measured with a confocal microscope and an integrating sphere setup. We show that scattering-induced outcoupling of initially trapped PL explains commonly observed red-shifted and broadened PL spectral shapes and leads to p¯ebeing more than a factor of two higher compared with earlier assumptions. Applying our model to CH3NH3PbI3films with exceptionally high Qelumup to 47.4% corrects previous estimates for Qilumof ∼90% to a real benchmark of 78.0% ± 0.5%. Thereby, our study reveals there is beyond a factor of two more scope for reducing non-radiative recombination in perovskite films than previously thought.

ABSTRACTBasal-like triple-negative breast cancers frequently express high levels of c-Myc. This oncoprotein signals to the core cell cycle machinery by impinging on cyclin E. High levels of E-type cyclins (E1 and E2) are often seen in human triple-negative breast tumors. In the current study, we examined the requirement for E-type cyclins in the c-Myc-driven mouse model of breast cancer (MMTV-c-Myc mice). To do so, we crossed cyclin E1- (E1-/-) and E2- (E2-/-) deficient mice with MMTV-c-Myc animals, and observed the resulting cyclin E1-/-/MMTV-c-Myc and cyclin E2-/-/MMTV-c-Myc females for breast cancer incidence. We found that mice lacking cyclins E1 or E2 developed breast cancers like their cyclin Ewild-type counterparts. In contrast, further reduction of the dosage of E-cyclins in cyclin E1-/-E2+/-/MMTV-c-Myc and cyclin E1+/-E2-/-/MMTV-c-Myc animals significantly decreased the incidence of mammary carcinomas, revealing arole for E-cyclins in tumor initiation. We also observed that depletion of E-cyclins in human triple-negative breast cancer cell lines halted cell cycle progression, indicating that E-cyclins are essential for tumor cell proliferation. In contrast, we found that the catalytic partner of E-cyclins, the cyclin-dependent kinase 2 (CDK2), is dispensable for the proliferation of these cells. These results indicate that E-cyclins, but not CDK2, play essential and rate-limiting roles in driving the proliferation of c-Myc overexpressing breast cancer cells.

Unfractionated heparin is the mainstay of anticoagulation during cardiac surgery on cardiopulmonary bypass (CPB) due to its low cost, quick onset, and ease of reversal. Since over 30 years, the activated clotting time (ACT) has been used to assess the level of heparin activity both before and after CPB. We compared two different methods of measuring the ACT: i-STAT, which uses amperometric detection of thrombin cleavage, and Hemochron Jr, which is based on detecting viscoelastic changes in blood. We included 402 patients from three institutions (Papworth Hospital, Cambridge, UK; Groote Schuur, Cape Town, South Africa; University Hospital Basel, Basel, Switzerland) undergoing elective cardiac surgery on CPB in our study. We analyzed duplicate samples on both devices at all standard measuring points during the procedure. The correlation coefficient between two Hemochron and two i-STAT devices was .9165 and .9857, respectively. The within-subject coefficient of variation (WSCV) ranged from 8.2 to 13.6% for the Hemochron and from 4.1 to 9.1% for the i-STAT. We found that the number of occasions where one of the duplicate readings was >1,000 seconds while the other was below or close to the clinically significant threshold of 400 seconds were higher for the Hemochron. We found the i-STAT to systematically return higher measurements. We conclude that the i-STAT provides a more reliable test for heparin activity and assesses safe anticoagulation during cardiac surgery on pump. The fact the that the i-STAT reads higher than the Hemochron leads to the recommendation to validate the methods against each other before changing devices.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.

In this work, we examine the effect of microstructure on ion-migration-induced photoluminescence (PL) quenching in methylammonium lead iodide perovskite films. Thin films were fabricated by two methods: spin-coating, which results in randomly oriented perovskite grains, and zone-casting, which results in aligned grains. As an external bias is applied to these films, migration of ions causes a quenching of the PL signal in the vicinity of the anode. The evolution of this PL-quenched zone is less uniform in the spin-coated devices than in the zone-cast ones, suggesting that the relative orientation of the crystal grains plays a significant role in the migration of ions within polycrystalline perovskite. We simulate this effect via a simple Ising model of ionic motion across grains in the perovskite thin film. The results of this simulation align closely with the observed experimental results, further solidifying the correlation between crystal grain orientation and the rate of ionic transport.

Supplemental Digital Content is available in the text.Published ahead of print May 19, 2017.

Enhancing production of the anti-inflammatory cytokine interleukin-10 (IL-10) is a promising strategy to suppress pathogenic inflammation. To identify new mechanisms regulating IL-10 production, we conducted a phenotypic screen for small molecules that enhance IL-10 secretion from activated dendritic cells. Mechanism-of-action studies using a prioritized hit from the screen, BRD6989, identified the Mediator-associated kinase CDK8, and its paralog CDK19, as negative regulators of IL-10 production during innate immune activation. The ability of BRD6989 to upregulate IL-10 is recapitulated by multiple, structurally differentiated CDK8 and CDK19 inhibitors and requires an intact cyclin C–CDK8 complex. Using a highly parallel pathway reporter assay, we identified a role for enhanced AP-1 activity in IL-10 potentiation following CDK8 and CDK19 inhibition, an effect associated with reduced phosphorylation of a negative regulatory site on c-Jun. These findings identify a function for CDK8 and CDK19 in regulating innate immune activation and suggest that these kinases may warrant consideration as therapeutic targets for inflammatory disorders.

ZnO as electron extraction layer in photovoltaic devices has many advantages, including high mobility and low processing temperature. However, it has been underutilized in perovskite solar cells due to the reported instabilities of perovskite layers deposited on ZnO resulting in poor device performance. Herein, we modify the ZnO layer by incorporating Cs or Li dopants in its bulk and depositing a self-assembled monolayer on its surface. This combined approach of engineering both the bulk and surface properties of ZnO results in significant improvements in the performance of planar MAPbI3perovskite solar cells with a maximum power conversion efficiency of 18%, accompanied by a reduction in hysteresis and a significant enhancement of the device stability. Our work makes engineered solution-processed ZnO layers a practical alternative to TiO2as electron extraction layers in perovskite solar cells, while also eliminating the need for high temperature sintering steps from the device fabrication.

Supplemental Digital Content is available in the text.

Zusammenfassung.Perioperative kardiovaskuläre Komplikationen sind häufig und haben eine hohe Mortalität. Die präoperative hausärztliche und anästhesiologische Beurteilung des kardiovaskulären Risikos eines Patienten ist wichtig für die Risiko-Nutzen Analyse einer Operation und kann zur risikomindernden Massnahmen führen. Die Basis der Risikobeurteilung ist die Anamnese mit Erfragen von relevanten kardiovaskulären Vorerkrankungen sowie der körperlichen Leistungsfähigkeit. Je nach dieser Einschätzung und dem Operationsrisiko des jeweiligen Eingriffs (niedrig / mittel / hoch) wird dann entschieden, welche zusätzlichen Abklärungen nötig und sinnvoll sind. Dabei gilt als Grundregel, dass nur Abklärungen durchgeführt werden, welche bei dem entsprechenden Patienten auch ohne die anstehende Operation indiziert sind. Ausserdem wird aufgrund der präoperativen Risikobeurteilung, das anästhesiologische Management und das Level der postoperativen Überwachung festgelegt. Bei erhöhtem Risiko muss der Patient präoperativ medikamentös optimal eingestellt werden. Durch ein perioperatives Troponinscreening bei gefährdeten Patienten können die Detektionsrate von häufig asymptomatischen perioperativen Myokardinfarkten erhöht- und therapeutische Massnahmen frühzeitig eingeleitet werden.

Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis.

Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14−/−mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation.

Objective We present the post-CE(Conformité Européenne)-mark single-center implantation experience and short-term outcome with the second-generation transapical JenaValve transcatheter aortic valve implantation system.Methods Patients [N = 27; 9 women; mean (SD) age, 80.3 (5.5) years] were operated on between November 2011 and August 2012. Via a transapical approach, the valve was positioned, in some cases, repositioned, and finally implanted. All data were collected during the hospital stay.Results The implantation success rate was 100%; the mean (SD) operation time was 124.7 (43.2) minutes; and the size of the implanted prosthesis was 23 mm (n = 6), 25 mm (n = 14), and 27 mm (n = 7). The in-hospital major adverse cardiac and cerebrovascular events were as follows: intraoperative resuscitation with subsequent aortic rupture (n = 1), postoperative hemorrhage needing revision (n = 1), myocardial infarction (n = 1), atrioventricular block needing a definitive pacemaker (n = 1), new-onset renal failure needing hemodialysis (n = 1), and stroke (n = 1). The 30-day mortality was 11.1% (n = 3). The mean (SD) intensive care unit/total stay was 2.2 (1.7)/11.7 (7.9) days. Postoperative echocardiography [day 6.7 (4.8)] revealed residual para-valvular leakage of trace to grade 1 in 12 patients (44.5%) and no leakage in 15 patients, with a mean (SD) transvalvular pressure gradient of 11.6 (5.6) mm Hg with significant reduction by 36.0 (17.7) mm Hg (P= 0.0001, Wilcoxon signed rank test).Conclusions This second-generation repositionable transcatheter aortic valve implantation device could safely and successfully be implanted with a fast learning curve, significant reduction in pressure gradients, overall clinical improvement at discharge, as well as an acceptable morbidity and mortality rate in this highest-risk patient cohort.

Objective We present the post-CE(Conformité Européenne)-mark single-center implantation experience and short-term outcome with the second-generation transapical JenaValve transcatheter aortic valve implantation system.Methods Patients [N = 27; 9 women; mean (SD) age, 80.3 (5.5) years] were operated on between November 2011 and August 2012. Via a transapical approach, the valve was positioned, in some cases, repositioned, and finally implanted. All data were collected during the hospital stay.Results The implantation success rate was 100%; the mean (SD) operation time was 124.7 (43.2) minutes; and the size of the implanted prosthesis was 23 mm (n = 6), 25 mm (n = 14), and 27 mm (n = 7). The in-hospital major adverse cardiac and cerebrovascular events were as follows: intraoperative resuscitation with subsequent aortic rupture (n = 1), postoperative hemorrhage needing revision (n = 1), myocardial infarction (n = 1), atrioventricular block needing a definitive pacemaker (n = 1), new-onset renal failure needing hemodialysis (n = 1), and stroke (n = 1). The 30-day mortality was 11.1% (n = 3). The mean (SD) intensive care unit/total stay was 2.2 (1.7)/11.7 (7.9) days. Postoperative echocardiography [day 6.7 (4.8)] revealed residual para-valvular leakage of trace to grade 1 in 12 patients (44.5%) and no leakage in 15 patients, with a mean (SD) transvalvular pressure gradient of 11.6 (5.6) mm Hg with significant reduction by 36.0 (17.7) mm Hg (P= 0.0001, Wilcoxon signed rank test).Conclusions This second-generation repositionable transcatheter aortic valve implantation device could safely and successfully be implanted with a fast learning curve, significant reduction in pressure gradients, overall clinical improvement at discharge, as well as an acceptable morbidity and mortality rate in this highest-risk patient cohort.

Volatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery.

We describe the transcranial Doppler pattern during a period of cardiopulmonary resuscitation in a patient undergoing a transcatheter off-pump aortic valve implantation. Transcranial Doppler of the middle cerebral artery flow was measured as a part of a separate ongoing study. The patient developed a cardiac arrest during deployment of the valve prosthesis. The incidental presence of the transcranial Doppler allowed us to assess middle cerebral artery flow during cardiopulmonary resuscitation in real time. An initial lack of a diastolic flow pattern seen with transcranial Doppler at the beginning of cardiopulmonary resuscitation led to volume loading and optimisation of the resuscitation technique. After increasing the depth of external cardiac massage, the cerebral flow pattern improved to produce sufficient diastolic flow. The transcranial Doppler provided additional information during cardiopulmonary resuscitation, which was helpful in clinical management. The use of transcranial Doppler may be helpful for other cardiac procedures where cerebral malperfusion may occur.

To confirm the reliability and applicability of the Polymyalgia Rheumatica Disease Activity Score (PMR‐AS), and to establish a threshold for remission.First, 78 patients with PMR (50 women/28 men, mean age 65.97 years) were enrolled in a cross‐sectional evaluation. The PMR‐AS, patient's satisfaction with disease status (PATSAT; range 1–5), erythrocyte sedimentation rate (ESR; first hour), and a visual analog scale of patients' general health assessment (VAS patient global; range 0–100) were recorded. Subsequently, another 39 PMR patients (24 women/15 men, mean age 68.12 years) were followed longitudinally. Relationships between the PMR‐AS, PATSAT, ESR, and VAS patient global were analyzed by the Kruskal‐Wallis test, Spearman's rank correlation, and kappa statistics. PMR‐AS values in patients with a PATSAT score of 1 and a VAS patient global <10 formed the basis to establish a remission threshold.PMR‐AS values were significantly related to PATSAT (P < 0.001), VAS patient global (P < 0.001), and ESR (P < 0.01). PATSAT and VAS patient global were reasonably different (κ = 0.226). The median PMR‐AS score in patients with PATSAT score 1 and VAS patient global <10 was 0.7 (range 0–3.3), and the respective 75th percentile was 1.3. To enhance applicability, a range from 0 to 1.5 was proposed to define remission in PMR. The median ESR in these patients was 10 mm/hour (range 3–28), indicating external validity.We demonstrated the reliability, validity, and applicability of the PMR‐AS in daily routine. Moreover, we proposed a remission threshold (0–1.5) founded on patient‐dependent parameters.

To assess the factorial structure of the Disease Activity Score including a 28‐joint count (DAS28) if applied in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA).DAS28 values from 85 consecutive PsA outpatients and 2 RA patient cohorts comprising 85 patients each were compared. The first RA cohort (RA1) consisted of age‐ and sex‐matched patients seen during the same period as the patients with PsA. The first 85 RA outpatients from September 2003 were included in the second cohort (RA2). Item weighting, factor loading, and internal consistency were assessed by factor analysis, principal component analysis, and calculation of Cronbach's alpha.The mean ± SD DAS28 scores of patients in the PsA, RA1, and RA2 cohorts were 3.2 ± 1.31, 3.21 ± 1.45, and 3.79 ± 1.44, respectively. A significant difference between the PsA and RA2 cohorts was found for DAS28 (P = 0.0063), swollen joint count (P = 0.007), and patient's global assessment (P < 0.001), but not for erythrocyte sedimentation rate. Internal consistency of the DAS28 in patients with PsA was considerably lower, item weighting showed remarkable differences, and factor analysis revealed that the DAS28 constitutes a bidimensional instrument in patients with PsA, whereas in both RA cohorts it appeared to be monodimensional.With respect to its statistical properties, the DAS28 proved to be considerably different in PsA compared with RA. Therefore its application for disease activity assessment in patients with PsA cannot be recommended without a formal validation procedure.

Objectif: Ľinteraction entre le mivacurium et les anesthésiques inhalés est bien connue, exception faite du xénon. Nous avons comparé la pharmacodynamie du mivacurium pendant ľanesthésie au xénon vs ľanesthésie exclusivement iv avec du propofol. Méthode: Ľessai randomisé et contrôlé a été mené au Aachen University Hospital. Quarante-deux patients adultes, ďétat physique ASA I ou II, de 18 à 60 ans, ont reçu au hasard une anesthésie au xénon ou au propofol. Ľinduction a été faite avec du propofol et du rémifentanil chez les patients des deux groupes (chacun n = 21). Le xénon a été administré au masque jusqu’à une minute de concentration télé-expiratoire à 60 %. Entre-temps, ľaccéléromyographe a été calibré et une stimulation en train-dequatre de ľadducteur du pouce a été amorcée. Aprés un signal stable de cinq minutes, un bolus unique de 0,6 mg·kg-1de mivacurium a été injecté. Ľanesthésie a été maintenue avec du xénon et du rémifentanil ou du propofol et du rémifentanil. Résultats: Il n’y a pas eu de différence intergroupe significative quant au délai ďinstallation du bloc (xénon 180 ± 64 vs propofol 195 ± 77 s ; P = 0,39), à sa durée (xénon 16,18 ± 4,97 vs propofol 15,68 ± 6,17 min ; P = 0,73), à ľindice de récupération (xénon 5,63 ± 2,48 vs propofol 5,73 ± 2,12 min ; P = 0,42) et à la récupération clinique (xénon 8,75 ± 2,57 vs propofol 9,28 ± 2,28 min ; P = 0,22). Conclusion: Les effets neuromusculaires bloquants du mivacurium sont similaires pendant ľanesthésie au propofol ou au xénon.

Kinases govern many cellular responses through the reversible transfer of a phosphate moiety to their substrates. However, pairing a substrate with a kinase is challenging. In proximity labeling experiments, proteins proximal to a target protein are marked by biotinylation, and mass spectrometry can be used for their identification. Here, we combine ascorbate peroxidase (APEX) proximity labeling and a phosphorylation enrichment-based workflow, Phospho-APEX (pAPEX), to rapidly identify phosphorylated and biotinylated neighbor proteins which can be considered for candidate substrates. The pAPEX strategy enriches and quantifies differences in proximity for proteins and phosphorylation sites proximal to an APEX2-tagged kinase under the kinase “ON” and kinase “OFF” conditions. As a proof of concept, we identified candidate substrates of MAPK1 in HEK293T and HCT116 cells and candidate substrates of PKA in HEK293T cells. In addition to many known substrates, C15orf39 was identified and confirmed as a novel MAPK1 substrate. In all, we adapted the proximity labeling-based platform to accommodate phosphorylation analysis for kinase substrate identification.

Fifty patients with moderate or severe bronchitis were randomly allocated into groups receiving orally either 1000 mg amoxycillin twice daily or 750 mg three times daily. Overall cure rates (both 92%) and the incidence of side-effects (4% and 8%, respectively) were similar in both groups. A twice daily regimen, therefore, seems to be as effective as conventional treatment and has the advantage of being more convenient for the patient

AbstractObjective:To describe the derivation and validation of a pulmonary tuberculosis (TB) prediction model that would enable early discontinuation of unnecessary respiratory isolation.Design:Patients placed in isolation for suspected pulmonary TB were studied retrospectively (derivation cohort) and prospectively (validation cohort). Independent predictors of pulmonary TB in the derivation cohort (January 1992-March 1994) were identified by retrospective analysis. Predictors in the model were assigned weights on the basis of the results of the multivariate analysis in order to quantitate the risk of TB in an individual patient. The prospective validation consisted of application of the model to patients placed in isolation during the period April 1994 to June 1995. The predictability of the model in the derivation and validation cohorts was evaluated using receiver operating characteristics (ROC), curve analysis, and calculation of the area under the ROC curve (AUC).Setting:A university-affiliated, urban, public hospital with a large population of prison inmates and patients with human immunodeficiency virus infection.Interventions:Prospective application of the prediction model to patients placed in isolation during the validation period.Results:Four factors were found to be independent predictors of pulmonary TB among 296 isolation episodes in the derivation cohort: positive acid-fast sputum smear (odds ratio [OR], 5.8; 95% confidence interval [CI95], 3.0-11.0; weight=3 points), localized chest radiograph findings (OR, 2.5; CI95,1.3-4.9; weight=2 points), residence in a correctional facility (OR, 2.3; CI95, 1.2-4.4; weight=2 points), and history of weight loss (OR, 1.8; CI95, 1.0-3.2; weight=1 point). Infection control practitioners applied the model prospectively to 220 isolation episodes. The mean (土SE) AUCs of the ROC curve for the derivation and validation cohorts were not significantly different (.86±.04 vs.86±.07; P=.90). There was a significant decline in the mean duration of isolation from the onset of an automatic TB isolation policy in August 1992 to the end of the study (P=.045 by analysis of variance).Conclusions:A pulmonary TB prediction model was derived and validated prospectively in a hospital with a moderately high prevalence of TB. The model quantitated the risk of TB in an individual patient and aided infection control practitioners and primary-care physicians in their decisions to discontinue isolation during the validation period. Utilization of the model was responsible, in part, for a decrease in the mean duration of isolation during the study period. Although the model may not have general applicability due to the uniqueness of the patient population studied, this study illustrates how prediction models can be developed and used effectively to deal with a clinical problem.

AbstractObjective:To describe the derivation and validation of a pulmonary tuberculosis (TB) prediction model that would enable early discontinuation of unnecessary respiratory isolation.Design:Patients placed in isolation for suspected pulmonary TB were studied retrospectively (derivation cohort) and prospectively (validation cohort). Independent predictors of pulmonary TB in the derivation cohort (January 1992-March 1994) were identified by retrospective analysis. Predictors in the model were assigned weights on the basis of the results of the multivariate analysis in order to quantitate the risk of TB in an individual patient. The prospective validation consisted of application of the model to patients placed in isolation during the period April 1994 to June 1995. The predictability of the model in the derivation and validation cohorts was evaluated using receiver operating characteristics (ROC), curve analysis, and calculation of the area under the ROC curve (AUC).Setting:A university-affiliated, urban, public hospital with a large population of prison inmates and patients with human immunodeficiency virus infection.Interventions:Prospective application of the prediction model to patients placed in isolation during the validation period.Results:Four factors were found to be independent predictors of pulmonary TB among 296 isolation episodes in the derivation cohort: positive acid-fast sputum smear (odds ratio [OR], 5.8; 95% confidence interval [CI95], 3.0-11.0; weight=3 points), localized chest radiograph findings (OR, 2.5; CI95,1.3-4.9; weight=2 points), residence in a correctional facility (OR, 2.3; CI95, 1.2-4.4; weight=2 points), and history of weight loss (OR, 1.8; CI95, 1.0-3.2; weight=1 point). Infection control practitioners applied the model prospectively to 220 isolation episodes. The mean (?SE) AUCs of the ROC curve for the derivation and validation cohorts were not significantly different (.86±.04 vs.86±.07; P=.90). There was a significant decline in the mean duration of isolation from the onset of an automatic TB isolation policy in August 1992 to the end of the study (P=.045 by analysis of variance).Conclusions:A pulmonary TB prediction model was derived and validated prospectively in a hospital with a moderately high prevalence of TB. The model quantitated the risk of TB in an individual patient and aided infection control practitioners and primary-care physicians in their decisions to discontinue isolation during the validation period. Utilization of the model was responsible, in part, for a decrease in the mean duration of isolation during the study period. Although the model may not have general applicability due to the uniqueness of the patient population studied, this study illustrates how prediction models can be developed and used effectively to deal with a clinical problem.

Statistical studies were made to test the allometric conditions in 205 uteri in the fetal and neonatal time and during childhood. They disclosed a continuosly positive allometry from the 4th fetal month to birth, followed by a postpartum decrease in the absolute size of the organ. This enantiometry persists up to a body length (bl) of 75 cm, i.e. practically until the end of the first year of life. Subsequently the allometric examination of the uterus shows no further growth up to a body length of 115 cm. Only starting from a body length of 125 cm, i.e. after the 7th year of life, there is a negative allometry of the organ.

Ohne Zusammenfassung:

The wide‐bandgap methylammonium lead bromide perovskite is promising for applications in tandem solar cells and light‐emitting diodes. Despite its utility, there is a limited understanding of its reproducibility and stability. Herein, the dependence of the properties, performance, and shelf storage of thin films and devices on minute changes to the precursor solution stoichiometry is examined in detail. Although photovoltaic cells based on these solution changes exhibit similar initial performance, shelf storage depends strongly on precursor solution stoichiometry. While all devices exhibit some degree of healing, bromide‐deficient films show a remarkable improvement, more than doubling in their photoconversion efficiency. Photoluminescence spectroscopy experiments performed under different atmospheres suggest that this increase is due, in part, to a trap‐healing mechanism that occurs upon exposure to the environment. The results highlight the importance of understanding and manipulating defects in lead halide perovskites to produce long‐lasting, stable devices. Herein, the effects of variations in precursor stoichiometry on the properties, performance, and stability of MAPbBr3photovoltaic devices are examined. It is found that while the initial device performance is similar, devices with under‐stoichiometric composition are significantly improved upon storage in air without illumination, which is associated with defect healing.

Anaplastic large‐cell lymphomas are highly associated with a chromosomal translocation t(2;5). This condition results in a chimeric protein NPM/ALK (nucleophosmin/anaplastic lymphoma kinase), in which the shuttle protein NPM is fused to the catalytic domain of the tyrosine receptor kinase ALK. Because the oncogenic potential of NPM/ALK is not well understood, we analyzed the effects of NPM/ALK and the specific contribution of ALK in a standardized cell culture system by using primary rat embryo cells (REC) as cellular targets. We demonstrate by several biological parameters that NPM/ALK is an immortalizing oncogene that provides unlimited, yet normal, growth potential to REC and, with cooperation with a c‐H‐ras oncogene, induces cellular transformation. Targeting NPM/ALK to the nucleus diminishes its oncogenicity, which indicates that the fusion protein exerts its action mainly in the cytoplasm. Expression of the mere catalytic domain of ALK is insufficient with regard to immortalization and transformation. However, reestablishing the potential of ALK to homodimerize by fusing the bacterial dimerization domain of the tetracycline repressor to ALK reenforces the immortalizing function. Collaboration of dimeric ALK with c‐H‐ras converted primary REC into aggressively growing tumor cell lines. These studies identify ALK as a new member of immortalizing oncoproteins that exerts its function within the cytoplasm.

Zusammenfassung Die Rolle von Magen-Darm-Störungen in der Rosacea-Ätiologie ist noch umstritten. Magensaugbiopsien bei 15 Rosacea-Kranken ergaben nur in 3 Fällen pathologische Befunde.