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IMPORTANCE: Atopic dermatitis (AD) and plaque psoriasis are inflammatory skin diseases with unmet need for effective topical treatments with few application site reactions. OBJECTIVE: To assess the efficacy and safety of the topical phosphodiesterase 4 inhibitor PF-07038124 in patients with AD and plaque psoriasis. DESIGN, SETTING, AND PARTICIPANTS: This phase 2a, randomized, double-blind clinical trial was conducted from December 21, 2020, to August 18, 2021, at 34 sites across 4 countries. Eligible patients (aged 18-70 years) had mild to moderate AD (covering 5%-20% body surface area) or plaque psoriasis (covering 5%-15% body surface area). Data were analyzed until December 15, 2021. INTERVENTIONS: Patients were randomized (1:1) to PF-07038124, 0.01%, topical ointment or vehicle once daily for 6 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the percent change from baseline (CFB) in the Eczema Area and Severity Index (EASI) total score among patients with AD and in the Psoriasis Area and Severity Index (PASI) score among patients with plaque psoriasis at week 6. Safety measures included treatment-emergent adverse events, including application site reactions. RESULTS: Overall, 104 patients were randomized (mean [SD] age, 43.0 [15.4] years; 55 [52.9%] women; 4 [3.8%] Asian, 13 [12.5%] Black, and 87 [83.7%] White), including 70 with AD (41 women [58.6%]; mean [SD] ages, 41.4 [16.6] years in the PF-07038124 group and 36.1 [13.9] years in the vehicle group) and 34 with plaque psoriasis (20 men [58.8%]; mean [SD] ages, 51.8 [12.3] years in the PF-07038124 group and 51.2 [10.8] years in the vehicle group). Baseline characteristics were generally balanced. At week 6, the PF-07038124 groups showed significantly greater improvements compared with vehicle groups in EASI (least-squares mean CFB, −74.9% vs −35.5%; difference, −39.4% [90% CI, −58.8% to −20.1%]; P < .001) and PASI scores (CFB, −4.8 vs 0.1; difference, −4.9 [90% CI, −7.0 to −2.8]; P < .001). The number of patients with treatment-emergent adverse events was comparable between treatment groups in patients with AD (PF-07038124, 9 [25.0%]; vehicle, 9 [26.5%]) and plaque psoriasis (PF-07038124, 3 [17.6%]; vehicle, 6 [35.3%]). There were no application site reactions with PF-07038124 treatment. CONCLUSIONS AND RELEVANCE: Topical PF-07038124 was well tolerated and demonstrated superior efficacy compared with vehicle in patients with mild to moderate AD and plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04664153

In Sorbian historiography the Lutheran reformation of the early 16thcentury is seen as a starting point of Sorbian national history. It is thought that the introduction of Sorbian language into church life led to the development of Sorbian literature, a Sorbian elite and hence to a national identity. Based on research into the history of Sorbian pastoral work in Lübben, the main city of the Margraviate of Lower Lusatia, the present paper argues that the lack of pre-reformation sources about Sorbian church life and accordingly the increase of them after the reformation is primarily due to general mechanisms of source creation and preservation. In view of this, the impact of the reformation on Sorbian history needs to be evaluated with caution.

Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the GC receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here, we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation short hairpin RNA screen to identify GC-regulated “effector” genes that contribute to cell death, as well as genes that affect the sensitivity of B-ALL cells to dex. This analysis reveals a pervasive role for GCs in suppression of B-cell development genes that is linked to therapeutic response. Inhibition of phosphatidylinositol 3-kinase δ (PI3Kδ), a linchpin in the pre-B-cell receptor and interleukin 7 receptor signaling pathways critical to B-cell development (with CAL-101 [idelalisib]), interrupts a double-negative feedback loop, enhancing GC-regulated transcription to synergistically kill even highly resistant B-ALL with diverse genetic backgrounds. This work not only identifies numerous opportunities for enhanced lymphoid-specific combination chemotherapies that have the potential to overcome treatment resistance, but is also a valuable resource for understanding GC biology and the mechanistic details of GR-regulated transcription.

Oxidation of methionine disrupts the structure and function of a range of proteins, but little is understood about the chemistry that underlies these perturbations. Using quantum mechanical calculations, we found that oxidation increased the strength of the methionine-aromatic interaction motif, a driving force for protein folding and protein-protein interaction, by 0.5–1.4 kcal/mol. We found that non-hydrogen-bonded interactions between dimethyl sulfoxide (a methionine analog) and aromatic groups were enriched in both the Protein Data Bank and Cambridge Structural Database. Thermal denaturation and NMR spectroscopy experiments on model peptides demonstrated that oxidation of methionine stabilized the interaction by 0.5–0.6 kcal/mol. We confirmed the biological relevance of these findings through a combination of cell biology, electron paramagnetic resonance spectroscopy and molecular dynamics simulations on (i) calmodulin structure and dynamics, and (ii) lymphotoxin-α binding toTNFR1. Thus, the methionine-aromatic motif was a determinant of protein structural and functional sensitivity to oxidative stress.

Background:Simulation training in medical education is a valuable tool for skill acquisition. Standard audio/video-feedback systems for training surveillance and subsequent video feedback are expensive and often not available.

This paper aims to set up a collaboration typology framework based on organization structure. Considering initial stage of collaboration foundation and with a view to different features of organization structure, characteristics including ‘financial sharing’ and ‘interdependence degree’ are considered as two basic logics for the distinguishing of collaboration. Collaboration structure is further clustered into Informal Agreement, Legal Entity-Based and Contract-Based. On the basis of this cluster, a four-scale framework is constructed for the better understanding, which is confirmed to fit well with the actual cases. Thus, this work could be used as practical reference for the choosing of collaboration structure.

Previous studies have shown that public parks provide extraordinary habitats for ticks and tick-borne pathogens. Therefore, the aim of this study was to investigate the tick abundance (ticks/100m2) in urban areas and the prevalence of Anaplasma phagocytophilum. Collection of ticks was performed by the flagging method in selected Bavarian public parks in a 2-year survey. DNA from 30 ticks of each developmental stage, sampling site and month was extracted and screened by specific real-time PCR for A. phagocytophilum. Selected positive samples were further genetically differentiated by nested PCR, targeting the 16S rRNA gene. A total of 13,403 Ixodes ricinuswere collected with an average tick abundance of 15–53 ticks/100m2in 2009 and 15–35 ticks/100m2in 2010, depending on the sampling site. DNA of A. phagocytophilumwas detected in 11.6% (n=146) and 8.5% (n=50) of adult females, 13.3% (n=164) and 9.2% (n=51) of adult males as well as 5% (n=60) and 3.9% (n=29) of nymphs for 2009 (n=3685) and 2010 (n=1884), respectively. 16S rRNA gene analysis revealed 6 different genetic variants, 2 of which were 100% identical to known sequences in humans. The results give strong evidence that the occurrence of A. phagocytophilumin I. ricinusis highly variable in different habitat types due to geographical, climatic, and biological factors as well as different genetic variants of A. phagocytophilumcirculated in ticks with a noticeable habitat and host tropism.

Abstract:The article explores the role of traditional and modern actors as well as traditional methods in finding a durable solution to the separatist Casamance conflict, which has experienced an uptick in hostilities since 2009. In 2007, the government named a group of traditional actors, the Comité des Sages, as its official interlocutor with the Movement of Democratic Forces in the Casamance (MFDC), which was a armed rebel movement against the government of Senegal. However, the approach did not advance the peace process because their base was too limited, their practices of buying access to the MFDC were not sustainable, and the perception of skimming undermined their credibility. Traditional methods will have a role to play, namely, the reversing of oaths taken by combatants when they joined the MFDC, once a large-scale demobilization of forces is possible. Modern and traditional civil society actors have played a role in peacebuilding efforts in Casamance. They include micro-level village associations with localized access to nearby MFDC bases or combatants from their village, meso-level Senegalese NGOs that implement programs in different parts of the region, and macro-level national organizations and individuals based in Dakar and the Casamance with access to high-level decision-makers. Collaboration among these actors balances their strengths and weaknesses, but their interests must align for the collaboration to succeed. An MFDC call for a referendum on independence, akin to the one held in Southern Sudan in January 2011, was firmly rejected, but a more interesting parallel lies in the popular consultation process identified in Sudan’s 2004 peace agreement for the Blue Nile and South Kordofan states and suggested in the December 2004 agreement. Popular consultations allow citizens to indicate if the agreement has been implemented satisfactorily and should be the definitive solution, while the political conference discusses root causes of the conflict and proposes solutions.

Homology models of cytochrome P450 2D6 (CYP2D6) have identified serine 304 as an active-site residue and implicated a putative role for this residue in substrate enantioselectivity and the differential inhibition of enzyme activity by the diastereoisomers quinine and quinidine. The role of serine 304 in selectivity is thought to be achieved through a preferential hydrogen-bond interaction between the hydroxyl group of the residue and one of the stereoisomers of each ligand. We have tested this hypothesis by substituting serine 304 with alanine, a non-hydrogen-bonding residue, and compared the properties of the wild-type and mutant enzymes in microsomes prepared from yeast cells expressing the appropriate cDNA-derived enzyme. The Ser304Ala substitution did not alter the enantioselective oxidation of metoprolol; the O-demethylation reaction remained R-(+)-enantioselective (wild-type, RS, 1.7; mutant, RS, 1.6), whereas α-hydroxylation remained S-(-)-enantioselective (wild-type and mutant, R/S, 0.7). Similarly, the selective oxidation of the R-(+) and S-(-) enantiomers of propranolol to the major 4-hydroxy metabolite was identical with both wild-type and mutant forms of the enzyme (R/S 0.9), although the formation of minor metabolites (5-hydroxy and deisopropylpropranolol) did show some slight alteration in enantioselectivity. The differential inhibition of enzyme activity by quinine and quinidine was also identical with both forms of CYP2D6, the IC50 values for each enzyme being approx. 10 μM and 0.1 μM for quinine and quinidine, respectively. The kinetics of formation of α-hydroxymetoprolol and 4-hydroxydebrisoquine by wild-type and the Ser304Ala mutant was also very similar. However, modest changes in the regioselective oxidation of metoprolol and debrisoquine were observed with the Ser304Ala mutant. The regio- and enantioselective oxidation of an analogue of metoprolol, in which the hydroxyl group attached to the chiral carbon was replaced by a methyl moiety, was again identical with both wild-type and Ser304Ala mutant. However, the observed selectivity was the reverse of that observed with metoprolol. Collectively, these data indicate that Ser304 is unlikely to be a key ligand-binding residue, although the residue may indeed be located in the active-site cavity. The reversal of selectivity with the methyl analogue of metoprolol indicates that the hydroxyl group attached to the chiral centre of ligands, such as metoprolol, is important in defining the enzyme's selective properties, and that a hydrogen-bonding residue, other than Ser304, may be involved in this interaction. Current homology models of the active site of CYP2D6 that predict a hydrogen-bond interaction between Ser304 and specific ligands will need to be re-evaluated, and other candidate residues capable of such an interaction nominated and tested by site-directed mutagenesis studies.

Oxidation of thioethers is greatly facilitated by neighboring group participation by carboxylate, alcohol, and thioether moieties.

The idea for this workshop was born during the 1993 Conference on Organizational Computing Systems (COOCS). Researchers and developers from academia and industry who attended the conference were sharing their observations and concerns on the absence of a connection between earlier work presented at COOCS and the current presentations of workflow systems.Historically, COOCS has focused on office automation and office information systems (OIS). During the 1980s numerous OIS were presented at COOCS (e.g., [4, 6, 7, 19]). These systems acknowledge over time that the office is a distributed place composed of autonomous units and that activities, tasks, or procedures must be supported in conjunction with the accompanying office objects, such as documents in paper or electronic format.Workflow systems started appearing in the 1990s. These systems were commercially introduced as a new product category. Commercial workflow systems take advantage of the growing base of installed personal computers or workstations, Local Area Networks, and appealing graphical user interfaces. Many participants at COOCS'93 had a sense that workflow and OIS were dealing with similar issues using different labels. Both types of systems were concerned with the support of dynamic aspects of knowledge work in organizations. Both types of systems have to address issues such as• the representation of activities• the definition of roles• the capture of time and deadlines• the integration of single user tools• the coordination of work results• the structure of the organizationThis list is probably not complete. Yet the shared issues between workflow systems and office information systems are significant.To better understand the similarities and differences between workflow and OIS, to share results and experiences in developing these systems, and to foster potential collaboration between the two communities, Carson Woo and Dirk Mahling proposed this workshop at the 1994 Computer Supported Cooperative Work conference in Chapel Hill, North Carolina. Researchers and developers were invited to submit position papers concerning their view of the relation between workflow and OIS. More than twenty statements were selected. The workshop was conducted on October 22nd, 1994.The workshop consisted of a few presentations followed by breakout discussions. The presentations were targeted to bring out important issues related to the workshop, and to facilitate the focus of discussions during the breakout. The workshop begins by looking into the current organizational needs and their implication to automation (Section 2). This is to remind ourselves on why we are developing workflow and OIS systems. The problems with existing workflow systems (Section 3) and how OIS influences the development of workflow systems (Section 4) were then discussed. Next, some enabling technologies for workflow and OIS were explored (Section 5). Participants were then broken up into four groups to discuss various issues including:• A metrics to evaluate workflow technology (Section 6.1).• Differences between workflow and OIS (Section 6.2).• Issues related to the deployment of workflow in organizations (Section 6.3).• Should workflow be considered part of CSCW (Section 6.4).This report summarizes the above presentations and discussions.

Cloud point data for poly(ethylene-co-butyl acrylate) (EBA)−ethylene and poly(ethylene-co-methyl acrylate) (EMA)−ethylene mixtures are presented to 250 °C and 2600 bar as a function of butyl acrylate (BA) content from 5.2, 17.0, 25.2, 40.3, and 100 mol % BA and of molecular weight, and as a function of methyl acrylate (MA) content from 10, 18, 31, 41, and 100 mol % MA. Cloud point pressures initially decrease with increasing BA content at rate of ~17 bar/mol % BA up to ~40 mol % BA and then they remain relatively constant with further increases in BA content. The cloud point pressures increase with increasing weight-average molecular weight (Mw), at a rate of ~4 bar/10000 Mw. However, cloud point pressures for the EMA−ethylene mixtures initially decrease as the MA content increases to ~20 mol % but then increase rapidly as the MA content is further increased. In fact, it is not possible to dissolve poly(methyl acrylate) in ethylene to 240 °C and 2600 bar, although poly(butyl acrylate) readily dissolves in ethylene at pressures as low as 800 bar at 50 °C. The experimental data are modeled using the SAFT equation of state with two mixture interaction parameters. The EBA copolymers used in this study were synthesized in two different types of continuous-flow reactors at variable-feed compositions, temperatures to 225 °C, and pressures to 2000 bar. The number-average degree of polymerization decreases with increasing temperature, and it is significantly affected by transfer reactions to monomer. The chain transfer to butyl acrylate monomer plays a dominant rule among transfer reactions at 150 °C, as indicated by the decrease in EBA molecular weight with increase in BA content in the copolymer. The molecular weight polydispersity decreases slightly from 3.0 to 2.5 as the BA content in the copolymer increases to 25 mol %.

To make plan-based expert systems more accessible to end users and to support user tasks effectively, we present a system that makes the functionality of AI-planning techniques seem natural and immediately understandable. In particular, we present a task support system with a graphical interaction language for the acquisition and display of plan knowledge, where the intended users are domain experts and novices and where previous computer literacy is not required. Based on existing theories in cognitive science and on our own experimental research, we propose a cognitive model of the users' view of tasks. The model postulates the domain experts' ability to recall relevant parts of self-performed tasks in the application domain. The validity of the model is demonstrated in a paper-and-pencil experiment.

Zusammenfassung In der vorliegenden Arbeit wurdenγ-Al(OH)3 undγ-Al2O3 vergleichend auf ihre adsorptiven Eigenschaften untersucht. Es stellte sich im wesentlichen folgendes heraus: