Low-Temperature Orientation Dependence of Step Stiffness on {111} Surfaces

For hexagonal nets, descriptive of {111} fcc surfaces, we derive from combinatoric arguments a simple, low-temperature formula for the orientation dependence of the surface step line tension and stiffness, as well as the leading correction, based on the Ising model with nearest-neighbor (NN) interactions. Our formula agrees well with experimental data for both Ag and Cu{111} surfaces, indicating that NN-interactions alone can account for the data in these cases (in contrast to results for Cu{001}). Experimentally significant corollaries of the low-temperature derivation show that the step line tension cannot be extracted from the stiffness and that with plausible assumptions the low-temperature stiffness should have 6-fold symmetry, in contrast to the 3-fold symmetry of the crystal shape. We examine Zia's exact implicit solution in detail, using numerical methods for general orientations and deriving many analytic results including explicit solutions in the two high-symmetry directions. From these exact results we rederive our simple result and explore subtle behavior near close-packed directions. To account for the 3-fold symmetry in a lattice gas model, we invoke a novel orientation-dependent trio interaction and examine its consequences.Comment: 11 pages, 8 figure

Recovery of Evoked Potentials, Metabolic Activity and Behavior in a Mouse Model of Somatosensory Cortex Lesion: Role of the Neural Cell Adhesion Molecule (NCAM)

Understanding the processes that underlie functional recovery after cortical injury is a major challenge for neurobiology and clinical neurology. The aim of the present study was to establish a mouse model of functional recovery that would facilitate the investigation of the molecular and cellular events involved in cortical dynamics. We show that a focal injury of ∼0.5 mm of diameter and 1 mm depth made in the barrel cortex of adult mice induced a transitory deficit that could be characterized using somatosensory evoked potential (SEP), metabolic mapping and a behavioral test. SEP recordings of short latency responses using an epicranial multi-array system showed a decreased cortical activity in the peri-lesion regions 2 weeks after the injury and a partial recovery to normal pattern 6 weeks after the lesion. Delayed SEP signals over the motor cortex were not altered by the injury. Metabolic mapping with [14C]deoxyglucose uptake in the surround of the injury reproduced the time course of deficit and recovery. Finally, a deficit in vibrissae related performance in a gap-crossing test 1 week after injury was followed by a functional recovery in the following 2 weeks. We show in addition that the recovery process is deficient and significantly delayed in NCAM knockout mice lacking all isoforms of NCAM (neural cell adhesion molecule)and PSA-NCAM. These results support the hypothesis that impairment and recovery of functions after focal cortical lesion involves remodeling of intact circuits surrounding the lesion and that the NCAM molecule participate in this process. The model opens new possibilities for investigating the role of candidate molecules in functional recovery using genetically modified mic

Patient and public involvement in cancer research: A scoping review.

Patient and public involvement (PPI) in research emphasizes the importance of doing research with, rather than for people with lived health/illness experience(s). The purpose of this scoping review is to investigate the breadth and depth of scientific literature on PPI in cancer research and to identify how is PPI applied and reported in cancer research. We searched MEDLINE, Embase, CINAHL, and PsycInfo up to March 2022. All titles/abstracts and full-text results were screened by two reviewers. Data were analyzed and are presented in both narrative and tabular format. We screened 22,009 titles/abstract, reviewed 375 full-text articles, of which 101 studies were included in this review. 66 papers applied PPI; 35 used co-design methodologies. PPI in cancer research in published research has increased steadily since 2015 and often includes those with a past diagnosis of cancer or relatives/informal caregivers. The most common applied methods were workshops or interviews. PPI was generally used at the level of consultation/advisor and occurred mainly in early stages of research. Costs related to PPI were mentioned in 25 papers and four papers described training provided for PPI. Results of our review demonstrate the nature and extent of PPI expansion in cancer research. Researchers and research organizations entering the fray of PPI should consider planning and reporting elements such as the stage, level, and role type of PPI, as well as methods and strategies put in place to assure diversity. Furthermore, a thorough evaluation of whether all these elements meet the stated PPI purpose will help to grasp its impact on research outcomes. Two patients participated in the stakeholder consultation as part of the scoping review methodology, contributed to the discussion on refining the results, and critically reviewed the manuscript. Both are co-authors of this manuscript

The effect of viscosity and diffusion on the HO₂ uptake by sucrose and secondary organic aerosol particles

We report the first measurements of HO2 uptake coefficients, γ, for secondary organic aerosol (SOA) particles and for the well-studied model compound sucrose which we doped with copper(II). Above 65% relative humidity (RH), γ for copper(II)-doped sucrose aerosol particles equalled the surface mass accommodation coefficient α=0.22±0.06, but it decreased to γ=0.012±0.007 upon decreasing the RH to 17 %. The trend of γ with RH can be explained by an increase in aerosol viscosity and the contribution of a surface reaction, as demonstrated using the kinetic multilayer model of aerosol surface and bulk chemistry (KM-SUB). At high RH the total uptake was driven by reaction in the near-surface bulk and limited by mass accommodation, whilst at low RH it was limited by surface reaction. SOA from two different pre-cursors, α-pinene and 1,3,5-trimethylbenzene (TMB), was investigated, yielding low uptake coefficients of γ<0.001 and γ=0.004±0.002, respectively. It is postulated that the larger values measured for TMB-derived SOA compared to α-pinene-derived SOA are either due to differing viscosity, a different liquid water content of the aerosol particles, or an HO2 + RO2 reaction occurring within the aerosol particles

Synthesis and characterisation of peroxypinic acids as proxies for highly oxygenated molecules (HOMs) in secondary organic aerosol

Peroxy acids were recently found to be involved in new particle formation in the atmosphere and could also substantially contribute towards particle toxicity. However, a lack of suitable analytical methods for the detection and characterisation of peroxy acids in the particle phase is currently hindering the quantitative investigation of their contribution to these important atmospheric processes. Further development of appropriate techniques and relevant standards is therefore urgently needed. In this study, we synthesised three peroxypinic acids, developed a liquid chromatography separation method and characterised them with tandem mass spectrometry. The observed fragmentation patterns clearly distinguish the different peroxypinic acids from both the acid and each other, showing several neutral losses previously already observed for other peroxy acids. Both monoperoxypinic acids were found to be present in secondary organic aerosol generated from ozonolysis of α-pinene in laboratory experiments. The yield of monoperoxypinic acid formation was not influenced by humidity. Monoperoxypinic acid quickly degrades on the filter, with about 60% lost within the first 5h. This fast degradation shows that time delays in traditional off-line analysis will likely lead to severe underestimates of peroxy compound concentrations in ambient particles.Sarah S. Steimer acknowledges funding support from the Swiss National Science Foundation (project no. 162258). Funding by the European Research Council (ERC starting grant 279405) and the European Union’s Horizon 2020 research and innovation programme through the EUROCHAMP-2020 Infrastructure Activity under grant agreement no. 730997 is acknowledged

Recovery of evoked potentials, metabolic activity and behavior in a mouse model of somatosensory cortex lesion: role of the neural cell adhesion molecule (NCAM)

Understanding the processes that underlie functional recovery after cortical injury is a major challenge for neurobiology and clinical neurology. The aim of the present study was to establish a mouse model of functional recovery that would facilitate the investigation of the molecular and cellular events involved in cortical dynamics. We show that a focal injury of approximately 0.5 mm of diameter and 1 mm depth made in the barrel cortex of adult mice induced a transitory deficit that could be characterized using somatosensory evoked potential (SEP), metabolic mapping and a behavioral test. SEP recordings of short latency responses using an epicranial multi-array system showed a decreased cortical activity in the peri-lesion regions 2 weeks after the injury and a partial recovery to normal pattern 6 weeks after the lesion. Delayed SEP signals over the motor cortex were not altered by the injury. Metabolic mapping with [14C]deoxyglucose uptake in the surround of the injury reproduced the time course of deficit and recovery. Finally, a deficit in vibrissae related performance in a gap-crossing test 1 week after injury was followed by a functional recovery in the following 2 weeks. We show in addition that the recovery process is deficient and significantly delayed in NCAM knockout mice lacking all isoforms of NCAM (neural cell adhesion molecule)and PSA-NCAM. These results support the hypothesis that impairment and recovery of functions after focal cortical lesion involves remodeling of intact circuits surrounding the lesion and that the NCAM molecule participate in this process. The model opens new possibilities for investigating the role of candidate molecules in functional recovery using genetically modified mice

Simultaneous determination of natural and synthetic steroid estrogens and their conjugates in aqueous matrices by liquid chromatography / mass spectrometry

An analytical method for the simultaneous determination of nine free and conjugated steroid estrogens was developed with application to environmental aqueous matrices. Solid phase extraction (SPE) was employed for isolation and concentration, with detection by liquid chromatography/mass spectrometry (LC/MS) using electrospray ionisation (ESI) in the negative mode. Method recoveries for various aqueous matrices (wastewater, lake and drinking water) were determined, recoveries proving to be sample dependent. When spiked at 50 ng/l concentrations in sewage influent, recoveries ranged from 62-89 % with relative standard deviations (RSD) < 8.1 %. In comparison, drinking water spiked at the same concentrations had recoveries between 82-100 % with an RSD < 5%. Ion suppression is a known phenomenon when using ESI; hence its impact on method recovery was elucidated for raw sewage. Both ion suppression from matrix interferences and the extraction procedure has bearing on the overall method recovery. Analysis of municipal raw sewage identified several of the analytes of interest at ng/l concentrations, estriol (E3) being the most abundant. Only one conjugate, estrone 3-sulphate (E1-3S) was observe

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring

BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types