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Humans perceive and construct the world as an arrangement of simple parametric models. In particular, we can often describe man-made environments using volumetric primitives such as cuboids or cylinders. Inferring these primitives is important for attaining high-level, abstract scene descriptions. Previous approaches for primitive-based abstraction estimate shape parameters directly and are only able to reproduce simple objects. In contrast, we propose a robust estimator for primitive fitting, which meaningfully abstracts complex real-world environments using cuboids. A RANSAC estimator guided by a neural network fits these primitives to a depth map. We condition the network on previously detected parts of the scene, parsing it one-by-one. To obtain cuboids from single RGB images, we additionally optimise a depth estimation CNN end-to-end. Naively minimising point-to-primitive distances leads to large or spurious cuboids occluding parts of the scene. We thus propose an improved occlusion-aware distance metric correctly handling opaque scenes. Furthermore, we present a neural network based cuboid solver which provides more parsimonious scene abstractions while also reducing inference time. The proposed algorithm does not require labour-intensive labels, such as cuboid annotations, for training. Results on the NYU Depth v2 dataset demonstrate that the proposed algorithm successfully abstracts cluttered real-world 3D scene layouts.

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12Cinhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12Cinhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12CC12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

The article reviews a revival of Rimsky-Korsakov's "The Night Before Christmas," directed by Christof Loy and starring performers such as Enkelejda Shkoza, Georgy Vasiliev, and Andrei Popov, performed at the Oper Frankfurt in Frankfurt, Germany.

AbstractThis paper presents a comprehensive technical overview of the Linac Coherent Light Source II (LCLS-II) photoinjector laser system, its first and foremost component. The LCLS-II photoinjector laser system serves as an upgrade to the original LCLS at SLAC National Accelerator Laboratory. This advanced laser system generates high-quality laser beams for the LCLS-II, contributing to the instrument’s unprecedented brightness, precision and flexibility. Our discussion extends to the various subsystems that comprise the photoinjector, including the photocathode laser, laser heater and beam transport systems. Lastly, we draw attention to the ongoing research and development infrastructure underway to enhance the functionality and efficiency of the LCLS-II, and similar X-ray free-electron laser facilities around the world, thereby contributing to the future of laser technology and its applications.

This subanalysis of the CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial aimed to address the association between atrial fibrillation (AF) recurrence, AF burden, and hard clinical outcomes in heart failure (HF) patients with AF.

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

Plastid biogenesis and the coordination of plastid and nuclear genome expression through anterograde and retrograde signaling are essential for plant development. GENOMES UNCOUPLED1 (GUN1) plays a central role in retrograde signaling during early plant development. The putative function of GUN1 has been extensively studied, but its molecular function remains controversial. Here, we evaluate published transcriptome data and generate our own data from gun1mutants grown under signaling-relevant conditions to show that editing and splicing are not relevant for GUN1-dependent retrograde signaling. Our study of the plastid (post)transcriptome of gun1seedlings with white and pale cotyledons demonstrates that GUN1 deficiency significantly alters the entire plastid transcriptome. By combining this result with a pentatricopeptide repeat code-based prediction and experimental validation by RNA immunoprecipitation experiments, we identified several putative targets of GUN1, including tRNAs and RNAs derived from ycf1.2, rpoC1, and rpoC2 and the ndhH–ndhA–ndhI–ndhG–ndhE–psaC–ndhDgene cluster. The absence of plastid rRNAs and the significant reduction of almost all plastid transcripts in white gun1mutants account for the cotyledon phenotype. Our study provides evidence for RNA binding and maturation as the long-sought molecular function of GUN1 and resolves long-standing controversies. We anticipate that our findings will serve as a basis for subsequent studies on mechanisms of plastid gene expression and will help to elucidate the function of GUN1 in retrograde signaling.

A prognostic index for nonfatal recurrences of ventricular tachycardia (VT) was developed using a retrospective analysis of a group of 206 patients with sustained monomorphic VT or ventricular fibrillation (VF) after healing of actue myocardial infarction. 74 patients (36%) (64 with VT and 10 with VF) had recurrences of sustained monomorphic VT during 3.4 [+ or -] 9 years of follow-up. Three clinical variables were selected and weighted by stepwise logistic discriminant analysis of the study group. They were coded as follows: interval of myocardial infarction to arrhythmia (6 months = 3), drug therapy with or without sotalol (with = 1, without =2), and VT or VF as the presenting arrhythmia (VT = 1, VF = 2). The prognostic index was: 3.41 - (0.56 X interval) - ( (1.94 X therapy) + (0.86 X arrhythmia). This index was validated prospectively in a test group of 158 consecutive patients with VT or VF after healing of acute myocardial infarction. Patients were allocated into different classes with decreasing prognostic index values associated with increasing risk for recurrences of VT. In the test group, 27 of 158 917%) patients (22 with VT and 5 with VF) had recurrences of VT (follow-up of 2 [+ or -] 2 years). Two risk classes of patients were identified: high risk for recurrences of VT (61%) corresponding to patients with a negative index; and low risk (4%) consisting of those with a positive index. Thus, using 0 as the cutoff point, the sensitivity, specificity, and positive and negative predictive values were 81, 89, 62 and 96%, respectively. This prognostic index may be used in selecting treatment for patients with severe ventricular arrhythmias after healing of acute myocardial infarction.

Supplemental Digital Content is available in the text.Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non–vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non–vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Supplemental Digital Content is available in the text.

Biosynthetic gene clusters (BGCs) bridging genotype and phenotype continuously evolve through gene mutations and recombinations to generate chemical diversity. Phenazine BGCs are widespread in bacteria, and the biosynthetic mechanisms of the formation of the phenazine structural core have been illuminated in the last decade. However, little is known about the complex phenazine core-modification machinery. Here, we report the diversity-oriented modifications of the phenazine core through two distinct BGCs in the entomopathogenic bacterium Xenorhabdus szentirmaii, which lives in symbiosis with nematodes. A previously unidentified aldehyde intermediate, which can be modified by multiple enzymatic and non-enzymatic reactions, is a common intermediate bridging the pathways encoded by these BGCs. Evaluation of the antibiotic activity of the resulting phenazine derivatives suggests a highly effective strategy to convert Gram-positive specific phenazines into broad-spectrum antibiotics, which might help the bacteria–nematode complex to maintain its special environmental niche.

The article presents an interview with director of the Oper Frankfurt theater in Frankfurt am Main, Germany Bernd Loebe on the selection of the theater as "theater of the year" by the opera periodical "Opernwelt", the fundamental attributes of a good opera house, and Loebe's alleged reputation as a specialist in singers.

The formation of the intermetallic compounds at the interface between cold-sprayed coatings and steel as well as interaction between coatings and aluminum melt was investigated. Coatings of AA7075 (AlZn5.5MgCu) and AA4145 (AlSi10Cu4) were deposited on the sheets of the deep drawing steel DC04. The coated samples were then immersed in the aluminum melt AlSi9Mn at the temperature of T= 610 °C for different durations in the range 30 s < t< 10 min. The reaction layer growth was examined metallographically and by means of scanning electron microscope with energy-dispersive spectroscopy. Furthermore, the intermetallic phases were identified by X-ray diffraction analysis and characterized by microhardness measurements. For both coatings, β-AlFeSi phases were shown to be the major constituent in the reaction zone. The growth kinetics of the intermetallic phases appeared to be similar for AA4145 and AA7075 coatings, while their morphology was completely different.

Ixodes persulcatus, a hard-bodied tick species primarily found in Asia and Eastern Europe, is a vector of pathogens to human and livestock hosts. Little research has been done on the microbiome of this species, especially using individual non-pooled samples and comparing different geographical locations. Here, we use 16S rRNA amplicon sequencing to determine the individual microbial composition of 85 Borrelia-positive I. persulcatusfrom the Japanese islands of Hokkaido and Honshu. The resulting data (164 unique OTUs) were further analyzed to compare the makeup and diversity of the microbiome by sex and location, as well as to determine the presence of human pathogens. We found that, while location had little influence, the diversity of I. persulcatusmicrobiome was predominantly dependent on sex. Males were seen to have higher microbiome diversity than females, likely due to the high presence of endosymbiotic CandidatusLariskella arthropodarum within the female microbial communities. Furthermore, high read counts for five genera containing potentially human pathogenic species were detected among both male and female microbiomes: Ehrlichia, Borrelia, Rickettsia, CandidatusNeoehrlichia and Burkholderiaand co-infections between different pathogens were frequent. We conclude that the microbiome of I. persulcatusdepends mainly on sex and not geographical location and that the major difference between sexes is due to the high abundance of Ca.L. arthropodarum in females. We also stress the importance of this tick species as a vector of potential human pathogens frequently found in co-infections.

Nowadays the development of smartphones entails is very fast the effect that not only the development of hardware is needed but of the batteries responsible for supplying sensors. The increased resource requirements drain mobile devices’ batteries faster and faster. People usually can be seen searching for opportunities of recharging their mobile devices at airports, coaches, trains, stations. In our present research, we seek the answer to what is the cause for rapid drainage of batteries, how it is possible to avoid it, and furthermore how recharging affects the lifespan of batteries, thus of devices too.

Supplemental Digital Content is available in the text.Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

The article discusses the history of opera in the Russia, Denmark, and Finland within the context of the 150th anniversary of the births of composers Jean Sibelius, Alexander Glasunow, and Carl Nielsen. The exploration of socioeconomic themes in the opera "Kullervo" composed by Sibelius is analyzed.

‘Second Generation’ ductile iron with a silicon content of up to 4.3 wt- exhibits a fully ferritic matrix, which is solution strengthened by silicon. Outstanding advantages of these ductile iron grades result in their strongly increasing demand. However, due to a presumed formation of a silicon long range order, the maximum strength is limited to 600 MPa at 4.3 wt- silicon. At higher silicon content, the mechanical properties dramatically decrease. In order to increase the maximum achievable strength, the potential of additional solution strengthening elements is subject of present research. Initially, the effects of cobalt and nickel on matrix, graphite shape and nodule count are investigated. Cobalt and nickel are identified as promising candidates for further solid solution hardening.

‘Second Generation’ ductile iron with a silicon content of up to 4.3 wt- exhibits a fully ferritic matrix, which is solution strengthened by silicon. Outstanding advantages of these ductile iron grades result in their strongly increasing demand. However, due to a presumed formation of a silicon long range order, the maximum strength is limited to 600 MPa at 4.3 wt- silicon. At higher silicon content, the mechanical properties dramatically decrease. In order to increase the maximum achievable strength, the potential of additional solution strengthening elements is subject of present research. Initially, the effects of cobalt and nickel on matrix, graphite shape and nodule count are investigated. Cobalt and nickel are identified as promising candidates for further solid solution hardening.

The article presents a review of performances of the opera "Alcina" composed by Georg Frideric Händel including a February 21, 2015 performance in Copenhagen, Denmark directed by Francisco Negrin and starring Nicole Heaston, Itziar Lesaka, and Ruxandre Donose and a January 28,2015 performance in Brussels, Belgium directed by Pierre Audi and starring Sandrine Piau, Maité Beaumont, and Angélique Noldus.

The article presents a review of productions of the operas "Kullervo," composed by Aulis Sallinen, which premiered in Savonlinna, Finland, on July 4, 2014, and was directed by Kari Heiskanen, conducted by Hannu Linntu, and starred Tommi Hakala, Ville Rusanen, and Tuija Knihtilä, among others, and "Der Silbersee," composed by Kurt Weill, which premiered on July 24, 2014, in Kokkola, Finland, and was directed by Anu Komsi and Juho Kuosmanen, conducted by Sakari Oramo, and starred Lasse Penttinen, Annami Hylkilä, and Leea Klemola, among others.

An increasing number of patients with heart failure receive implantable cardioverter-defibrillators (ICDs) or cardiac resynchronisation defibrillators (CRT-Ds) with telemonitoring function. Early detection of worsening heart failure, or upstream factors predisposing to worsening heart failure, by implant-based telemonitoring might enable pre-emptive intervention and improve outcomes, but the evidence is weak. We investigated this possibility in IN-TIME, a clinical trial.

ObjectiveIncreasing utilization rates of implantable cardioverter-defi brillators (ICDs) tend to overburden follow-up resources at the implanting electrophysiological centres (ECs). Remote monitoring technology allows physicians from diff erent institutions to simultaneously review ICD data of shared patients. We studied if an integrated follow-up care involving ECs and general cardiologists (GCs) may reduce the frequency of in-offi ce follow-ups at ECs by using remote monitoring data to identify routine checks that may be conducted at GCs.Methods and resultsThe analysis included 109 patients (aged 63 ± 11 years, 84.4% male) followed for a cumulative study duration of 155 patient-years. The patients underwent 436 in-offi ce controls after hospital discharge: 143 (33%) at two ECs and 293 (67%) at two GCs (each cooperating with one EC). The mean duration of in-offi ce follow-up sessions was 13.7 min (EC) and 10.3 min (GC). The average distance between patients’ homes and follow-up sites was 31.6 km (EC) vs. 16.2 km (GC). Investigators considered a follow-up to be of ‘high or medium’ importance in 78% (EC) vs. 45% (GC) of all in-offi ce follow-ups. At one EC, the integrated follow-up care concept appeared highly successful, with 97% of follow-ups transferred to the corresponding GC and, on average, 103.8 km shorter patient trips per follow-up.ConclusionsIntegrated follow-up care guided by remote monitoring allows to direct the more signifi cant follow-ups towards ECs and routine follow-ups towards GCs. This concept may contribute to the needed adaptations of the health-care system to the rising numbers of patients with implanted devices.

ABSTRACTMembers of the Glomeromycotaform the arbuscular mycorrhiza (AM) symbiosis. They supply plants with inorganic nutrients, including nitrogen, from the soil. To gain insight into transporters potentially facilitating nitrogen transport processes, ammonium transporters (AMTs) of Geosiphon pyriformis, a glomeromycotan fungus forming a symbiosis with cyanobacteria, were studied. Three AMT genes were identified, and all three were expressed in the symbiotic stage. The localization and functional characterization of the proteins in a heterologous yeast system revealed distinct characteristics for each of them. AMT1 of G. pyriformis(GpAMT1) and GpAMT2 were both plasma membrane localized, but only GpAMT1 transported ammonium. Neither protein transported the ammonium analogue methylammonium. Unexpectedly, GpAMT3 was localized in the vacuolar membrane, and it has as-yet-unknown transport characteristics. An unusual cysteine residue in the AMT signature of GpAMT2 and GpAMT3 was identified, and the corresponding residue was demonstrated to play an important role in ammonium transport. Surprisingly, each of the three AMTs of G. pyriformishad very distinct features. The localization of an AMT in the yeast vacuolar membrane is novel, as is the described amino acid residue that clearly influences ammonium transport. The AMT characteristics might reflect adaptations to the lifestyle of glomeromycotan fungi.

We report on a calibration procedure that enhances the precision of an interferometer based frequency stabilization by several orders of magnitude. For this purpose, the frequency deviations of the stabilization are measured precisely by means of a frequency comb. This allows us to implement several calibration steps that compensate different systematic errors. The resulting frequency deviation is shown to be less than 5.7 MHz (rms 1.6 MHz) in the whole wavelength interval 750–795 nm. Wide tuning of a stabilized laser at this exceptional precision is demonstrated.

Structure elucidation of natural products including the absolute configuration is a complex task that involves different analytical methods like mass spectrometry, NMR spectroscopy, and chemical derivation, which are usually performed after the isolation of the compound of interest. Here, a combination of stable isotope labeling of Photorhabdusand Xenorhabdusstrains and their transaminase mutants followed by detailed MS analysis enabled the structure elucidation of novel cyclopeptides named GameXPeptides including their absolute configuration in crude extracts without their actual isolation.

Diagnosis and treatment of coronary heart disease are performed in the catheter laboratory using an angiographic X-ray C-arm system. The morphology of the coronary tree and potentially ischemic lesions are determined in 2D projection views. The hemodynamic impact of the lesion would be valuable information for treatment decision. Using other modalities for functional imaging is disrupting the clinical workflow since the patient has to be transferred from the catheter laboratory to another scanner, and back to the catheter laboratory for performing the treatment. In this work a novel technology is used for simultaneous 3D imaging of first pass perfusion and the morphology of the coronary tree from a single rotational angiogram. A selective, single shot of contrast agent of less than 20ml directly into the coronaries is sufficient for a proper contrast resolution. Due to the long acquisition time cardiac motion has to be considered. A novel reconstruction technique for estimation and compensation of cardiac motion from the acquired projection data is used. The overlay of the 3D structure of the coronary tree and the perfusion image shows the correlation of myocardial areas and the associated coronary sections supporting that region. In a case example scar lesions caused by a former myocardial infarct are investigated. A first pass perfusion defect is found which is validated by a late enhancement magnetic resonance image. No ischemic defects are found. The non vital regions are still supported by the coronary vasculature.

Objective Atrial fibrillation (AF) is the most common complication following coronary artery bypass grafting or valve surgery. The autonomic nervous system is an important determinant in the development of AF. We have assessed the role of injection of fibrin sealant (FS) as a method to modify conduction in the fad pads, to mimic temporary denervation and to reduce the incidence of postoperative AF in patients undergoing coronary artery bypass grafting or valve surgery.Patients and Methods Twenty eligible patients who underwent coronary bypass grafting or aortic valve surgery in our Institution were included in this pilot – study. Detection of AF after surgical intervention was based on patient symptomatology and on daily electrocardiograms obtained on all patients. Telemetry was used in all patients for the entire hospitalization period.Results 20% of the studied population (n = 4) developed postoperative AF. At the time of discharge one patient (5%) had persistent AF. Postoperative mortality was 5% (n = 1) and not cardiac related. None of the patients required permanent pacemaker implantation.Conclusions This first human study of FS injected into the anterior fad pads following low to moderate risk open heart surgery shows, that this procedure is safe and feasible. Moreover, CM -1 injection appears to reduce the need for postoperative intervention and/or treatment of AF by diminishing its incidence.

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Beta-catenin is the key transcriptional activator of the Wnt pathway important for development and tissue homeostasis of multicellular organisms. Its deregulation contributes to many human cancers. The beta-catenin transcriptional activator complex continues to be defined, but already contains several proteins with chromatin remodeling activity. Here we show that two members of histone acetyltransferase complexes without enzymatic activity, hADA2a and hADA3, are required for full activity of beta-catenin. hADA2a and hADA3 physically interact with beta-catenin, and the interaction is mediated through Armadillo repeats 6 through 12 and the C-terminal transactivation domain of beta-catenin. Both hADA2a and hADA3 reside with beta-catenin at the enhancer for the Wnt target gene c-Myc. RNA interference-mediated reduction of hADA2a and hADA3 results in reduced beta-catenin acetylation, reduced activity in reporter gene assays and reduced activation of endogenous beta-catenin target genes. Overall, loss of hADA2a and hADA3 negatively impacts beta-catenin-mediated proliferation. Our studies identify hADA2a and hADA3 as crucial cofactors of beta-catenin that are likely involved in the assembly of transactivation-competent beta-catenin complexes at Wnt target genes.

The article focuses on the risk and challenges faced by the Frankfurt Ensemble Modern, which has been promoting contemporary music for 40 years. Topics include the impact of the COVID-19 pandemic on their planned performances and tours, the financial strain on freelance musicians, and efforts to address issues like retirement planning and financial stability for future generations.

The article reviews a performance of Claudio Monteverdi's "l'Orfeo" at Copenhagen's alternative opera house, on March 7, 2020, including the challenges faced by the arts during the COVID-19 pandemic and the artistic significance of historical music ensembles such as Concerto Copenhagen.

We describe a versatile strategy for generating gene replacement mutants in the phytopathogenic fungusUstilago maydis. The system includes the choice of 32 different insertion cassettes for genetic engineering purposes, such as gene disruption and more sophisticated insertions of reporter genes, heterologous promoters or combinations of the two. PCR-amplified flanking sequences needed for homologous recombination are ligated to the respective insertion cassettes viaSfi I sites. As proof of principle we generated two replacement mutants in which the endogenous promoter of the pheromone genemfa1drives expression of the Green Fluorescent Protein gene (gfp). Simultaneously, expression of themfa1ORF is controlled either by the carbon source-regulatedcrg1promoter or the nitrogen source-regulatednar1promoter. In both casesgfpexpression was pheromone-inducible and pheromone expression was only detected when the heterologous promoters were active.

Recent scientific discoveries have thrust mutants of the tumor suppressor protein p53 into the forefront of the war on cancer, and hold out eventual hope for a small molecule drug that will be useful in treating human cancers with mutant p53 protein.

In the phytopathogenic fungus Ustilago maydis, pheromone-mediated cell fusion is a prerequisite for the generation of the infectious dikaryon. The pheromone signal elevates transcription of the pheromone genes and elicits formation of conjugation hyphae. Cyclic AMP and mitogen-activated protein kinase (MAPK) signaling are involved in this process. The MAPK cascade is presumed to be composed of Ubc4 (MAPK kinase kinase), Fuz7 (MAPK kinase), and Ubc3/Kpp2 (MAPK). We isolated the kpp4 gene and found it to be allelic to ubc4. Epistasis analyses with constitutively active alleles of kpp4 and fuz7 substantiate that Kpp4, Fuz7, and Kpp2/Ubc3 are components of the same module. Moreover, we demonstrate that Fuz7 activates Kpp2 and shows interactions in vitro. Signaling via this cascade regulates expression of pheromone-responsive genes, presumably through acting on the transcription factor Prf1. Interestingly, the same cascade is needed for conjugation tube formation, and this process does not involve Prf1. In addition, fuz7 as well as kpp4 deletion strains are nonpathogenic, while kpp2 deletion mutants are only attenuated in pathogenesis. Here we show that strains expressing the unphosphorylatable allele kpp2(T182A/Y184F) are severely affected in tumor induction and display defects in early infection-related differentiation.

ABSTRACTIn the phytopathogenic fungus Ustilago maydis, pheromone-mediated cell fusion is a prerequisite for the generation of the infectious dikaryon. The pheromone signal elevates transcription of the pheromone genes and elicits formation of conjugation hyphae. Cyclic AMP and mitogen-activated protein kinase (MAPK) signaling are involved in this process. The MAPK cascade is presumed to be composed of Ubc4 (MAPK kinase kinase), Fuz7 (MAPK kinase), and Ubc3/Kpp2 (MAPK). We isolated the kpp4gene and found it to be allelic to ubc4. Epistasis analyses with constitutively active alleles of kpp4and fuz7substantiate that Kpp4, Fuz7, and Kpp2/Ubc3 are components of the same module. Moreover, we demonstrate that Fuz7 activates Kpp2 and shows interactions in vitro. Signaling via this cascade regulates expression of pheromone-responsive genes, presumably through acting on the transcription factor Prf1. Interestingly, the same cascade is needed for conjugation tube formation, and this process does not involve Prf1. In addition, fuz7as well as kpp4deletion strains are nonpathogenic, while kpp2deletion mutants are only attenuated in pathogenesis. Here we show that strains expressing the unphosphorylatable allele kpp2T182A/Y184Fare severely affected in tumor induction and display defects in early infection-related differentiation.