The dependence of crystal structure assembly on molecular changes is studied for a series of monosubstituted acetanilide compounds. A library of 81 crystal structures is obtained from the Cambridge ...Structural Database, structural similarities are determined, and energetic preferences are assessed. Two dominant amide–amide hydrogen bond geometries and a molecular stack are frequently observed especially in the para-acetanilide subgroup. In all cases, the amide functional group has a greater effect on the chain geometry and resultant crystal packing than the phenyl substituent. The study concludes with a short review of the polymorphism of paracetamol and suggests an alternative concept for overcoming the compaction issues currently encountered in the manufacture of the oral dosage form.
Background
Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte ...differentiation and function as well as skin barrier formation.
Objective
Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis.
Methods
3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL‐4 and IL‐13. Psoriasis‐like conditions were induced by incubation with IL‐17A, IL‐22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real‐time PCR were used for gene expression analysis.
Results
Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD‐like and STAT3 phosphorylation of psoriasis‐like culture conditions in 3D skin models compared to sham‐controls. Filaggrin expression was fully maintained in the AD‐like models, but only partially in psoriasis‐like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD‐like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis‐like conditions.
Conclusion
JAK1/3 inhibition counteracted cytokine‐induced AD‐ and psoriasis‐like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD‐like models compared to the psoriasis‐like 3D skin models.
The determination of nucleus–nucleus potentials is important not only to describe the properties of the colliding system, but also to extract nuclear-structure information and for modelling nuclear ...reactions for astrophysics. We present the first determination of double-folding potentials based on chiral effective field theory at leading, next-to-leading, and next-to-next-to-leading order. To this end, we construct new soft local chiral effective field theory interactions. We benchmark this approach in the 16O–16O system, and present results for cross sections computed for elastic scattering up to 700 MeV in energy, as well as for the astrophysical S-factor of the fusion reaction.
Molecular effects of various ablative and non-ablative laser treatments on human skin cells—especially primary effects on epidermal keratinocytes and dermal fibroblasts—are not yet fully understood. ...We present the first study addressing molecular effects of fractional non-sequential ultrapulsed CO
2
laser treatment using a 3D skin model that allows standardized investigations of time-dependent molecular changes ex vivo. While histological examination was performed to assess morphological changes, we utilized gene expression profiling using microarray and qRT-PCR analyses to identify molecular effects of laser treatment. Irradiated models exhibited dose-dependent morphological changes resulting in an almost complete recovery of the epidermis 5 days after irradiation. On day 5 after laser injury with a laser fluence of 100 mJ/cm
2
, gene array analysis identified an upregulation of genes associated with tissue remodeling and wound healing (e.g., COL12A1 and FGF7), genes that are involved in the immune response (e.g., CXCL12 and CCL8) as well as members of the heat shock protein family (e.g., HSPB3). On the other hand, we detected a downregulation of matrix metalloproteinases (e.g., MMP3), differentiation markers (e.g., LOR and S100A7), and the pro-inflammatory cytokine IL1α.
Overall, our findings substantiate the understanding of time-dependent molecular changes after CO
2
laser treatment. The utilized 3D skin model system proved to be a reliable, accurate, and reproducible tool to explore the effects of various laser settings both on skin morphology and gene expression during wound healing.
Hendra virus (HeV) continues to cause fatal infection in horses and threaten infection in close-contact humans in eastern Australia. Species of Pteropus bats (flying-foxes) are the natural reservoir ...of the virus. We caught and sampled flying-foxes from a multispecies roost in southeast Queensland, Australia on eight occasions between June 2013 and June 2014. The effects of sample date, species, sex, age class, body condition score (BCS), pregnancy and lactation on HeV antibody prevalence, log-transformed median fluorescent intensity (lnMFI) values and HeV RNA status were assessed using unbalanced generalised linear models. A total of 1968 flying-foxes were sampled, comprising 1012 Pteropus alecto, 742 P. poliocephalus and 214 P. scapulatus. Sample date, species and age class were each statistically associated with HeV RNA status, antibody status and lnMFI values; BCS was statistically associated with HeV RNA status and antibody status. The findings support immunologically naïve sub-adult P. alecto playing an important role in maintaining HeV infection at a population level. The biological significance of the association between BCS and HeV RNA status, and BCS and HeV antibody status, is less clear and warrants further investigation. Contrary to previous studies, we found no direct association between HeV infection and pregnancy or lactation. The findings in P. poliocephalus suggest that HeV exposure in this species may not result in systemic infection and virus excretion, or alternatively, may reflect assay cross-reactivity with another (unidentified) henipavirus.
Silicon Photomultipliers (SiPMs) are attractive candidates for light detectors for next generation liquid xenon double-beta decay experiments, like nEXO (next Enriched Xenon Observatory). In this ...paper we discuss the requirements that the SiPMs must satisfy in order to be suitable for nEXO and similar experiments, describe the two test setups operated by the nEXO collaboration, and present the results of characterization of SiPMs from several vendors. In particular, we find that the photon detection efficiency at the peak of xenon scintillation light emission (175-178 nm) approaches the nEXO requirements for tested FBK and Hamamatsu devices. Additionally, the nEXO collaboration performed radio-assay of several grams of bare FBK devices using neutron activation analysis, indicating levels of 40 K, 232 Th, and 238 U of the order of <; 0.15, (6.9 · 10 - 4 - 1.3 · 10 - 2 ), and <; 0.11 mBq/kg, respectively.
The CLIC Tracker Detector (CLICTD) is a monolithic pixel sensor. It is fabricated in a 180 nm CMOS imaging process, modified with an additional deep low-dose n-type implant to obtain full lateral ...depletion. The sensor features a small collection diode, which is essential for achieving a low input capacitance. The CLICTD sensor was designed as a technology demonstrator in the context of the tracking detector studies for the Compact Linear Collider (CLIC). Its design characteristics are of broad interest beyond CLIC, for HL-LHC tracking detector upgrades. It is produced in two different pixel flavours: one with a continuous deep n-type implant, and one with a segmented n-type implant to ensure fast charge collection. The pixel matrix consists of 16 × 128 detection channels measuring 300μm×30μm. Each detection channel is segmented into eight sub-pixels to reduce the amount of digital circuity while maintaining a small collection electrode pitch. This paper presents the characterisation results of the CLICTD sensor in a particle beam. The different pixel flavours are compared in detail by using the simultaneous time-over-threshold and time-of-arrival measurement functionalities. Most notably, a spatial resolution down to (4.6±0.2)μm is measured. A time resolution down to (5.8±0.1)ns is observed, after applying an offline time-walk correction using the pixel-charge information. The hit detection efficiency is found to be well above 99.7% for thresholds of the order of several hundred electrons.
To evaluate whether five-year changes in self-reported physical activity level were associated with changes in waist circumference, weight, serum lipids and blood pressure.
In the Inter99 study ...(1999-2006) in Copenhagen, Denmark, 4039 men and women (30-60 years) answered questions on lifestyle and provided blood samples and anthropometric measures at baseline and after five years. Multiple regression analyses were performed with five-year value of each cardiovascular biomarker as outcome and change in physical activity level as explanatory variable.
Approximately 50% of the study population were men (n=2023). Change in physical activity level was inversely associated with change in weight (p<0.0001), waist (p<0.0001), diastolic blood pressure (p=0.04), total cholesterol (p=0.006), LDL (p=0.007), triglycerides (p=0.02) and with a composite risk score "the Copenhagen risk score" (p<0.0001), and positively associated with HDL in men (p=0.01).
Five-year changes in physical activity level were significantly associated with relevant changes in weight, waist circumference, diastolic BP and serum lipids in a population-based cohort of adult men and women. Change in physical activity level induced a significant change in HDL concentration in men only. Women's use of hormone replacement therapy may partly explain this gender difference.
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