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PDF file, 157K, Ex vivo serum rescue assay.

PDF file, 304K, Effect of copper on virus therapy for glioma cells.

Purpose: Copper in serum supports angiogenesis and inhibits replication of wild-type HSV-1. Copper chelation is currently being investigated as an antiangiogenic and antineoplastic agent in patients diagnosed with cancer. Herpes simplex virus–derived oncolytic viruses (oHSV) are being evaluated for safety and efficacy in patients, but several host barriers limit their efficacy. Here, we tested whether copper inhibits oHSV infection and replication and whether copper chelation would augment therapeutic efficacy of oHSV.Experimental Design: Subcutaneous and intracranial tumor-bearing mice were treated with oHSV ± ATN-224 to evaluate tumor burden and survival. Virus replication and cell killing was measured in the presence or absence of the copper chelating agent ATN-224 and in the presence or absence of copper in vitro. Microvessel density and changes in perfusion were evaluated by immunohistochemistry and dynamic contrast enhanced MRI (DCE-MRI). Serum stability of oHSV was measured in mice fed with ATN-224. Tumor-bearing mice were injected intravenously with oHSV; tumor burden and amount of virus in tumor tissue were evaluated.Results: Combination of systemic ATN-224 and oHSV significantly reduced tumor growth and prolonged animal survival. Immunohistochemistry and DCE-MRI imaging confirmed that ATN-224 reduced oHSV-induced blood vessel density and vascular leakage. Copper at physiologically relevant concentrations inhibited oHSV replication and glioma cell killing, and this effect was rescued by ATN-224. ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery.Conclusion: This study shows that combining ATN-224 with oHSV significantly increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy. Clin Cancer Res; 18(18); 4931–41. ©2012 AACR.

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PDF file, 65K, ATN-224 by itself does not affect glioma cell viability or oHSV efficacy in the absence of copper.

PDF file, 46K, Quantification of color coded Ktrans and ve parametric images following DCE-MRI.

Supplementary Methods, Table 1, Figures 1-8 from Loss of Metallothionein Predisposes Mice to Diethylnitrosamine-Induced Hepatocarcinogenesis by Activating NF-κB Target Genes

Budynek archiwum państwowego to miejsce służące przede wszystkim długoterminowej ochronie materiałów archiwalnych. Musi także spełniać wymagania stawiane przyjaznej instytucji publicznej, związane z obsługą i zaspokajaniem różnorodnych potrzeb użytkowników w zakresie działalności prowadzonej przez archiwa. Pełnione przez archiwa funkcje determinują, już na etapie opracowywania koncepcji, a następnie dokumentacji projektowej, kwestie konstrukcji, wyposażenia oraz zastosowanych instalacji i technologii. Szczególne znaczenie w przypadku archiwum państwowego mają pomieszczenia magazynowe, służące przechowywaniu materiałów archiwalnych. W wypadku nowej siedziby Archiwum Narodowego w Krakowie, dla ośmiokondygnacyjnego segmentu magazynowego opracowano koncepcję z pasywną regulacją klimatu. Jest on wyodrębnioną strukturą, w której nie ma stałych stanowisk pracy, a pasywną stabilizację mikroklimatu zapewniono w znacznym stopniu przez przemyślane rozwiązania budowlane: dobrą izolację termiczną, wysoką szczelność przegród zewnętrznych oraz wykonanie powierzchni architektonicznych z porowatych materiałów o dobrej zdolność do wymiany pary wodnej. Temperatura we wnętrzu magazynu podąża za rocznym cyklem zmian temperatury na zewnątrz, a wilgotność względna utrzymuje się samoistnie na optymalnym poziomie około 50% przez znaczną część roku. W porze ciepłej powietrze jest osuszane. Suche warunki i niska w porze zimnej temperatura ograniczają szybkość degradacji materiałów archiwalnych. New building of the National Archives in Krakow. Functional and operational assumptions and the concept of archival holdings storage with passive climate control A state archive building is a place that serves primarily the long-term preservation of archival materials. It must also meet the requirements of a friendly public institution, which include serving and satisfying various user needs in the field of archival activity. The archives’ functions determine the construction, equipment, installation and technology considerations at the very conceptual stage and later in the design documentation. In case of a state archive, storage facilities used for the storage of archival materials are of particular importance. In case of the new building of the National Archives in Kraków, a concept involving passive climate control has been developed for the eight-storey storage segment. The storage segment is a separate structure, with no permanent workstations. The largely passive stabilization of the microclimate was ensured by well-thought-out construction solutions: good thermal insulation, high-performance external partitions and installation of architectural surfaces made of porous materials with good water vapor exchange capacity. Temperature inside the storage facility follows the annual cycle of external emperaturę changes, and relative humidity remains spontaneously at the optimum level of approximately 50% throughout much of the year. During the warm season, the air is dehumidified. Dry conditions and low temperatures in the cold season reduce the rate of degradation of archival materials.

Panel paintings—complex multi-layer structures consisting of wood support and a paint layer composed of a preparatory layer of gesso, paints, and varnishes—are among the category of cultural objects most vulnerable to relative humidity fluctuations and frequently found in museum collections. The current environmental specifications in museums have been derived using the criterion of crack initiation in an undamaged, usually new gesso layer laid on wood. In reality, historical paintings exhibit complex crack patterns called craquelures. The present paper analyses the structural response of a paint layer with a virtual network of rectangular cracks under environmental loadings using a three-dimensional model of a panel painting. Two modes of loading are considered—one induced by one-dimensional moisture response of wood support, termed the tangential loading, and the other isotropic induced by drying shrinkage of the gesso layer. The superposition of the two modes is also analysed. The modelling showed that minimum distances between cracks parallel to the wood grain depended on the gesso stiffness under the tangential loading. Despite a nonzero Poisson’s ratio, gesso cracks perpendicular to the wood grain could not be generated by the moisture response of the wood support. The isotropic drying shrinkage of gesso produced cracks that were almost evenly spaced in both directions. The modelling results were cross-checked with crack patterns obtained on a mock-up of a panel painting exposed to several extreme environmental variations in an environmental chamber.

[EN] Understanding how the evolving molecular composition of an oil paint layer on its transition to an aged solid film affects its dimensional change and mechanical properties is fundamental to the assessment of material durability and more broadly risk of degradation of oil paintings. Tensile properties-modulus of elasticity and strain at break-as well as cumulative shrinkage were determined for a selection of oil paints from Mecklenburg¿s Paint Reference Collection now after approximately 30 years of drying. The oil paints were found to get stiffer and more brittle with diminishing plastic deformation and increasingly elastic behaviour. For some paints, the increases in stiffness and decreases in the strain at break were dramatic during the late stage of drying. The observations modify the current physical model of paintings in which the mismatch in the response of glue-based ground layer and unrestrained wood or canvas support to variations in relative humidity (RH) has been identified as the worst-case condition for the fracturing of the entire pictorial layer. This study demonstrated that some paints were more brittle than the glue-based ground layer and as a consequence more vulnerable to cracking. The shrinkage of paints due to molecular relocation and/or evaporation of organic medium as they dry and age was measured. This shrinkage can exceed their strain at break and lead to fracturing of the oil paint layer if it is restrained by a dimensionally stable substrate. Consequently, after long-term drying, the cumulative shrinkage can cause oil paints to crack even in absence of fluctuations in RH or temperature. An example of cracking developed in an oil paint layer on the top of an undamaged ground layer in a historic panel painting was made evident by the X-ray microtomography., This work was funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 814624 and the statutory research fund of the Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences. Lukasz Bratasz's work was financed by the Polish National Agency for Academic Exchange, project Polish Returns [Grant PPN/PPO/2018/1/00004/U/00001].

[EN] Understanding canvas paintings as physical systems is fundamental to develop evidence-based environmental specifications for museums. A number of tests were carried out to determine mechanical properties of canvas, canvas sized with animal glue and animal glue-based ground layer (gesso) as a function of relative humidity (RH). The mechanical properties of the canvas samples tested exhibited an anisotropy dependent on the measurement direction, being the stiffness corresponding to the weft direction greater than the warp and diagonal ones. Sizing the canvas with a layer of animal glue significantly increased its modulus of elasticity while the anisotropy of mechanical properties was kept in the composite material. The application of an animal glue-based ground layer on sized canvas increased the elasticity modulus of the system by another order of magnitude (similar to 2 GPa) whereas the anisotropy of the material disappeared. The measurements were carried out in a wide range of RH from 30 to 90%. An increase in RH caused a decrease in the material stiffness. Cracking of the gesso layer, which is often responsible for the formation of cracks in paintings, was observed at strains of the order of a few thousandths. Swelling of glue sizing dominated the moisture-induced swelling of the composite material in the less stiff warp direction, completely overriding the shrinkage of the untreated canvas. In contrast, the swelling of the composite material in the stiffer weft direction was much smaller than for pure glue alone, being clearly affected by the textile., This work was funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 814624 and the statutory research fund of the Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences. Lukasz Bratasz's work was financed by the Polish National Agency for Academic Exchange, project Polish Returns [Grant PPN/PPO/2018/1/00004/U/00001]

[EN] Mechanical damage in oil paintings on canvas show up as cracks and loss of original paint. Several parameters can contribute to this type of degradation. These paintings have a complex layered structure, typically composed of minimum four or more hygroscopic materials, each of which has different (non-linear) material properties and geometrical complexities. The mechanical degradation of canvas paintings occurs because each of these materials have diverse responses under fluctuating environmental conditions, especially temperature and relative humidity (RH). By examining the geometrical complexities and the non-linear material properties, this paper presents an investigation of three degradation phenomena under desiccation: (1) bulging formation around the corners, (2) crack formation in glue and ground layers, and (3) plastic deformation in the ground and oil paint layers. This on-going investigation provides further insights into the global and local stress distribution in typically constructed oil canvas paintings. This includes finite element method (FEM) and extended-FEM (XFEM) computer models at various scales, under desiccation from the initial RH of 90%, and 50¿10%. The models consist of four to five different materials, namely lead white oil paint, red iron oxide oil paint, rabbit skin glue, linen canvas, and a spruce stretcher. The models were constructed using several combinations of materials to conduct parametric studies on the effects of glue shrinkage in paintings due to desiccation, and changing the mechanical properties of the ground layers. The relevant geometrical and mechanical properties with respect to the stress relaxation conditions are discussed in detail. The simulation results of the full-scale models show that the shrinkage of glue lowers the level of induced tension stresses in the paint layers in the central area of the painting due to the inward bowing of the stretcher. The inward deformation of the stretcher can be 4.5 times as large in a painting with a glue layer as in one without. This indicates the difficulty in forming cracks near the center of paintings purely by desiccation; however, in close-up cross-section model, cracks of 20 ¿m in length could still be observed in the ground exposed to an extreme RH change of 90% to 10%. The analysis of cross-section models with the full geometrical complexity for the corners showed that multiple cracks are likely to form in ground and paint layers in the corners when desiccated by 40%; RH 50¿10%. Furthermore, in extreme cases with stiffer ground/paint such as zinc white, cracks can form from smaller drop in RH; RH 50% to 35%. Such cracks are form in the ground layers, and therefore, are not initially visible as they are positioned below the uncracked paint layer. This result can be the possible explanation for cracks in the ground, which are initially invisible with the naked eye, but can be revealed with X-radiographs. The results support the hypothesis that fluctuations in relative humidity can cause hidden cracks in the lower layers, which can eventually propagate further into the upper-lying paint layers of paintings. The cracks typically form when the desiccation reaches a 40% drop, but in cases of brittle materials the drop causing cracks can be lower. The actual RH drop causing cracks depends on the specific material composition., This research was funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 814624. Lukasz Bratasz's work was financed by also the Polish National Agency for Academic Exchange, project Polish Returns [grant PPN/PPO/2018/1/00004/U/00001].

BackgroundAromatase Inhibitors (AIs) block physiological estrogen production in peripheral tissues and are used clinically to reduce disease recurrences and improve overall survival rates in hormone receptor-positive breast cancer patients. However, half of patients taking these drugs develop aromatase inhibitor induced arthralgia (AIIA), which is characterized by severe pain and inflammation in various joints and the surrounding musculoskeletal tissue. While the pathophysiology is not currently understood, it has been proposed to be associated with systemic estrogen deficiency resulting from AI treatment. Since AIIA leads to suspension of therapy in 20-30% of patients, reducing AIIA incidence may provide sustained AI treatment and enhance long-term survival.ObjectiveIn order to establish a better understanding of disease pathology and to create a platform that can be used to explore future interventional strategies, our objective in this study was to design a novel animal model of AIIA.MethodsFemale BALB/C-Tg(NFκB-RE-luc)-Xen mice, which have a firefly luciferase cDNA reporter transgene under the regulation of NFκB binding sites, were oophorectomized and treated with AI (letrozole) by daily subcutaneous injections for 5 weeks. Control groups included oophorectomized mice receiving vehicle injections and non-oophorectomized mice treated with AI. Knee joints and surrounding muscle tissue were imaged on the BioSpec 94/30 micro-MRI. The primary weight-bearing joint (hind limb) was examined histopathologically and NFκB activity was measured by bioluminescent imaging. Serum was collected for cytokine analysis. Additionally, healthy human PBMCs were treated with letrozole, estrogen, or both, and RNA sequencing was performed at 36 hrs.ResultsBioluminescent imaging showed significantly enhanced NFκB activation with AI treatment in the hind limbs compared to controls receiving vehicle treatment. Moreover, analysis of knee joints and legs by MRI showed enhanced signal detection in the joint space and surrounding tissue following daily AI injections. Surprisingly, the enhanced MRI detection and NFκB activation was observed with AI treatment independent of the oophorectomy procedure. This indicates that the induction of musculoskeletal-directed inflammation by AI is not mediated by changes in physiological estrogen levels, which is contrary to proposed mechanisms of disease pathogenesis. Similarly, histopathological analysis showed tenosynovitis and musculoskeletal infiltrates in all mice receiving AI with or without oophorectomy. IHC analysis of the infiltrates demonstrated a predominantly macrophage-mediated inflammatory response with scattered CD4+ T cells. Additionally, serum cytokine levels of IL-2, IL-4, IL-6, and CXCL1 were significantly elevated in mice with AI treatment. RNA sequencing of human PBMCs after in vitro AI stimulation did not demonstrate an AI-specific gene expression pattern associated with immune system activation directly, suggesting that the pathogenesis of AIIA may be mediated through cells in other tissues in vivo.ConclusionsCollectively, these data establish a novel mouse model of AIIA and identify an estrogen-independent stimulation of disease pathology via AI-mediated induction. This suggests that the pathogenesis of AIIA may not be mediated by estrogen deficiency, as previously hypothesized, and indicates that AI-induced inflammation may not be regulated directly through a pathogenic mechanism initially derived from circulating mononuclear cells. Future studies aim to characterize this inflammatory mechanism in vivo with a focus on other cells, including macrophages, synovial cells and chondrocytes, to provide insight into putative therapeutic strategies directed at mitigating disease pathology.

Moisture adsorption and related dimensional change were examined in several samples of historic and contemporary parchment. The tensile behaviour was determined for contemporary parchment and two selected historic materials. The moisture-related data for most parchments are close to the contemporary material while aging and past treatments may lower adsorption of moisture and, in consequence, the dimensional change induced by changes in the moisture content. Contemporary parchment exhibited larger water vapour adsorption and moisture-related response compared to most historic materials and, therefore, can be regarded as the worst-case material in terms of the climate-induced risks to parchment. Tensile parameters of parchment varied significantly with increasing relative humidity (RH). Elasticity modulus declined from on average 1200 to 400 MPa and strain at failure doubled when RH increased from 30 to 85%. Parchment’s critical strain at which permanent deformation occurred decreased dramatically with increasing RH reaching zero at 80%. Irreversible curling produced by variations in RH to which flat parchment specimens were subjected were measured by scanning the specimen surface with the use of a laser triangulation sensor. The degree of curling was expressed quantitatively as standard deviation of local curvatures in the parchment sheet. The study opens a perspective of using the relationship between degree of curling and magnitude of RH variations to derive categories of risk to parchment from indoor climate variations, under the condition that quantitative loss of aesthetical/display value of parchment objects resulting from increased curling is agreed. Historical parchment documents generally demonstrating considerable curling engendered by uncontrolled storage conditions in the past are not vulnerable to further distortion when subjected to variations in RH even of considerable magnitude.

Aortic aneurism open repair surgery can cause spinal cord (SC) injury with 5–15% of patients developing paraparesis or paraplegia. Using a mouse model of transient aortic cross-clamping (ACC), we have previously found that the expression of proinflammatory microRNA miR-155 increases in motoneurons (MNs) and endothelial cells (ECs) of ischemic SCs, and that global miR-155 deletion decreases the percentage of paraplegia by 37.4% at 48-h post-ACC. Here, we investigated the cell-specific contribution of miR-155 in choline acetyltransferase-positive (ChAT+) neurons (that include all MNs of the SC) and ECs to SC injury after ACC. Mice lacking miR-155 in ChAT+ neurons (MN-miR-155-KO mice) developed 24.6% less paraplegia than control mice at 48-h post-ACC. In contrast, mice lacking miR-155 in ECs (ECs-miR-155-KO mice) experienced the same percentage of paraplegia as control mice, despite presenting smaller central cord edema. Unexpectedly, mice overexpressing miR-155 in ChAT+ neurons were less likely than control mice to develop early paraplegia during the first day post-ACC, however they reached the same percentage of paraplegia at 48-h. In addition, all mice overexpressing miR-155 in ECs (ECs-miR-155-KI mice) were paraplegic at 48-h post-ACC. Altogether, our results suggest that miR-155 activity in ChAT+ neurons protects the SC against ischemic injury during the first day post-ACC before becoming deleterious during the second day, which indicates that early and late paraplegias arise from different molecular malfunctions. These results point to the need to develop specific protective therapeutics aimed at inhibiting both the early and late deleterious events after open repair surgery of aortic aneurisms.

We describe the advantages of diffuse illumination in laser holography for ophthalmology. The presence of a diffusing element introduces an angular diversity of the optical radiation and reduces its spatial coherence, which spreads out the energy distribution of the illumination beam in the focal plane of the eyepiece. The field of view of digitally computed retinal images can easily be increased as the eyepiece can be moved closer to the cornea to obtain a Maxwellian view of the retina without compromising ocular safety. Compliance with American and European safety standards for ophthalmic devices is more easily obtained by preventing the presence of a laser hot spot observed in front of the cornea in the absence of a scattering element. Diffuse laser illumination does not introduce any adverse effects on digitally computed laser Doppler images., Comment: 9 pages

Introduction: Spontaneously hypertensive stroke-prone rats (SHRSP) are used to model clinically relevant aspects of human cerebral small vessel disease (CSVD). To decipher and understand the underlying disease dynamics, assessment of the temporal progression of CSVD histopathological and neuroimaging correlates is essential.Materials and Methods: Eighty age-matched male SHRSP and control Wistar Kyoto rats (WKY) were randomly divided into four groups that were aged until 7, 16, 24 and 32 weeks. Sensorimotor testing was performed weekly. Brain MRI was acquired at each study time point followed by histological analyses of the brain.Results: Compared to WKY controls, the SHRSP showed significantly higher prevalence of small subcortical hyperintensities on T2w imaging that progressed in size and frequency with aging. Volumetric analysis revealed smaller intracranial and white matter volumes on brain MRI in SHRSP compared to age-matched WKY. Diffusion tensor imaging (DTI) showed significantly higher mean diffusivity in the corpus callosum and external capsule in WKY compared to SHRSP. The SHRSP displayed signs of motor restlessness compared to WKY represented by hyperactivity in sensorimotor testing at the beginning of the experiment which decreased with age. Distinct pathological hallmarks of CSVD, such as enlarged perivascular spaces, microbleeds/red blood cell extravasation, hemosiderin deposits, and lipohyalinosis/vascular wall thickening progressively accumulated with age in SHRSP.Conclusions: Four stages of CSVD severity in SHRSP are described at the study time points. In addition, we find that quantitative analyses of brain MRI enable identification of in vivo markers of CSVD that can serve as endpoints for interventional testing in therapeutic studies.

Aortic aneurism open repair surgery can cause spinal cord (SC) injury with 5-15% of patients developing paraparesis or paraplegia. Using a mouse model of transient aortic cross-clamping (ACC), we have previously found that the expression of proinflammatory microRNA

Panel paintings—complex multi-layer structures consisting of wood support and a paint layer composed of a preparatory layer of gesso, paints, and varnishes—are among the category of cultural objects most vulnerable to relative humidity fluctuations and frequently found in museum collections. The current environmental specifications in museums have been derived using the criterion of crack initiation in an undamaged, usually new gesso layer laid on wood. In reality, historical paintings exhibit complex crack patterns called craquelures. The present paper analyses the structural response of a paint layer with a virtual network of rectangular cracks under environmental loadings using a three-dimensional model of a panel painting. Two modes of loading are considered—one induced by one-dimensional moisture response of wood support, termed the tangential loading, and the other isotropic induced by drying shrinkage of the gesso layer. The superposition of the two modes is also analysed. The modelling showed that minimum distances between cracks parallel to the wood grain depended on the gesso stiffness under the tangential loading. Despite a nonzero Poisson’s ratio, gesso cracks perpendicular to the wood grain could not be generated by the moisture response of the wood support. The isotropic drying shrinkage of gesso produced cracks that were almost evenly spaced in both directions. The modelling results were cross-checked with crack patterns obtained on a mock-up of a panel painting exposed to several extreme environmental variations in an environmental chamber.

Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI+DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreER(T2):mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI.

Introduction: Spontaneously Hypertensive Rats- Stroke Prone (SHRSP) are a relevant model for human cerebral small vessel disease (cSVD). However, data are still lacking regarding the neuroimaging correlates of cSVD lesions in SHRSP and their temporal evolution in relationship to histological findings. Methods: 40 SHRSP and 40 Wistar Kyoto control (WKY) male rats were divided into 4 groups (10 WKY and 10 SHRSP) per group. Systolic blood pressure (SBP) was measured using tail-cuff device, weekly. Select animals of each group had brain MRI at 9.4T machine at 7, 16, 24, and 32 weeks of age. Volumetric analysis was completed using manual segmentation of the total brain, ventricles and bilateral hippocampi. Following MRI, brain histology was completed at the same time points. Results: At 6 weeks, SBP was similar (WKY 123.8±0.1 vs SHRSP 130.7±3.2, P=0.09). SHRSP developed hypertension between 9-11 weeks of age and maintained it throughout the experiment (SBP at 31 weeks: WKY 138.1±6 vs SHRSP 169.1±6.7, p=0.0006). At 7 weeks, brain MRI was normal in SHRSP and WKY. Histology was largely unremarkable except for few areas of red blood cell extravasation in couple of SHRSP. At 16 weeks, MRI was normal in WKY and it showed small subcortical hyperintensity on T2 sequences in one SHRSP while histology showed microbleeds (MBs) in 85% of SHRSP. At 24 weeks, brain MRI consistently identified subcortical hyperintensities in SHRSP and H&E showed MBs in all SHRSP in addition to hemosiderin deposition and arteriosclerosis. LFB staining showed areas of demyelination in the corpus callosum. At 32 weeks, SHRSP had hydrocephalus and H&E showed widespread hemosiderin deposition. Volumetric analysis showed larger ventricles in SHRSP (SHRSP 42.3±18.1 ml vs WKY 28.4±7.2 ml, p=0.013) and ventricle size significantly increased with age in SHRSP. Hippocampal and brain volumes were similar in both groups (hippocampal volume: WKY 84.5±8.1 ml vs SHRSP 81.6±2.6 ml, p=0.39; brain volume WKY 2103.4±100.4 ml vs SHRSP 2169.6 ±164.2 ml, p=0.2). Conclusions: SHRSP develop cSVD histological changes early in life and brain MRI showed consistent abnormalities at a later time point. These results have implications in defining cSVD phenotypes in SHRSP in future mechanistic studies.

The relationship between adiposity and metabolic health is well established. However, very little is known about the fat depot, known as paracardial fat (pCF), located superior to and surrounding the heart. Here, we show that pCF remodels with aging and a high-fat diet and that the size and function of this depot are controlled by alcohol dehydrogenase 1 (ADH1), an enzyme that oxidizes retinol into retinaldehyde. Elderly individuals and individuals with obesity have low ADH1 expression in pCF, and in mice, genetic ablation of Adh1 is sufficient to drive pCF accumulation, dysfunction, and global impairments in metabolic flexibility. Metabolomics analysis revealed that pCF controlled the levels of circulating metabolites affecting fatty acid biosynthesis. Also, surgical removal of the pCF depot was sufficient to rescue the impairments in cardiometabolic flexibility and fitness observed in Adh1-deficient mice. Furthermore, treatment with retinaldehyde prevented pCF remodeling in these animals. Mechanistically, we found that the ADH1/retinaldehyde pathway works by driving PGC-1α nuclear translocation and promoting mitochondrial fusion and biogenesis in the pCF depot. Together, these data demonstrate that pCF is a critical regulator of cardiometabolic fitness and that retinaldehyde and its generating enzyme ADH1 act as critical regulators of adipocyte remodeling in the pCF depot.

Objective Since enhanced cardiac magnetic resonance imaging (cMRI) signals have been associated with lupus disease activity in humans prior to renal failure and novel, cardiac-focused therapeutic strategies could be investigated with an associated animal model, autoimmune myocarditis was characterized in murine lupus nephritis (NZM2410). Methods Weekly blood urea nitrogen (BUN) levels and weights were recorded. Cardiac function was assessed by echocardiogram. Myocardial edema was measured with quantitative T2 cMRI mapping. Endpoint serum and cardiac tissue were collected for histopathological analysis and cytokine measurements. Results Despite showing no signs of significant renal disease, mice displayed evidence of myocarditis and fibrosis histologically at 30–35 weeks. Moreover, T2 cMRI mapping displayed robust signals and analysis of sagittal heart sections showed significant myocardium thickening. Cytokine expression levels of IL-2, IL-10, TNF-α, CXCL1, and IL-6 were significantly enhanced in serum. Echocardiograms demonstrated significantly increased ventricular diameters and reduced ejection fractions, while immunohistochemical staining identified CD4+ and CD8+ T cells, and IL-17 in cardiac infiltrates. Human lupus cardiac tissue showed similar histopathology with enhanced infiltrates by H&E, fibrosis, and CD4+ detection. Conclusions Histopathology, functional abnormalities, and enhanced cMRI signals indicative of myocarditis are detected in NZM2410 mice without glomerulonephritis, which supports the primary pathological role of autoimmune-mediated, cardiac-targeted inflammation in lupus.

Metastatic spread of cancer is an unfortunate consequence of disease progression, aggressive cancer subtypes, and/or late diagnosis. Brain metastases are particularly devastating, difficult to treat, and confer a poor prognosis. While the precise incidence of brain metastases in the United States remains hard to estimate, it is likely to increase as extracranial therapies continue to become more efficacious in treating cancer. Thus, it is necessary to identify and develop novel therapeutic approaches to treat metastasis at this site. To this end, intracranial injection of cancer cells has become a well-established method in which to model brain metastasis. Previously, the inability to directly measure tumor growth has been a technical hindrance to this model; however, increasing availability and quality of small animal imaging modalities, such as magnetic resonance imaging (MRI), are vastly improving the ability to monitor tumor growth over time and infer changes within the brain during the experimental period. Herein, intracranial injection of murine mammary tumor cells into immunocompetent mice followed by MRI is demonstrated. The presented injection approach utilizes isoflurane anesthesia and a stereotactic setup with a digitally controlled, automated drill and needle injection to enhance precision, and reduce technical error. MRI is measured over time using a 9.4 Tesla instrument in The Ohio State University James Comprehensive Cancer Center Small Animal Imaging Shared Resource. Tumor volume measurements are demonstrated at each time point through use of ImageJ. Overall, this intracranial injection approach allows for precise injection, day-to-day monitoring, and accurate tumor volume measurements, which combined greatly enhance the utility of this model system to test novel hypotheses on the drivers of brain metastases.

Objectives Gout is the most prevalent inflammatory arthritis. To study the effects of regular physical activity and exercise intensity on inflammation and clinical outcome, we examined inflammatory pathogenesis in an acute model of murine gout and analyzed human gout patient clinical data as a function of physical activity. Methods NF-κB-luciferase reporter mice were organized into four groups and exercised at 0 m/min (non-exercise), 8 m/min (low-intensity), 11 m/min (moderate-intensity), and 15 m/min (high-intensity) for two weeks. Mice subsequently received intra-articular monosodium urate (MSU) crystal injections (0.5mg) and the inflammatory response was analyzed 15 hours later. Ankle swelling, NF-κB activity, histopathology, and tissue infiltration by macrophages and neutrophils were measured. Toll-like receptor (TLR)2 was quantified on peripheral monocytes/neutrophils by flow cytometry and both cytokines and chemokines were measured in serum or synovial aspirates. Clinical data and questionnaires accessing overall physical activity levels were collected from gout patients. Results Injection of MSU crystals produced a robust inflammatory response with increased ankle swelling, NF-κB activity, and synovial infiltration by macrophages and neutrophils. These effects were partially mitigated by low and moderate-intensity exercise. Furthermore, IL-1β was decreased at the site of MSU crystal injection, TLR2 expression on peripheral neutrophils was downregulated, and expression of CXCL1 in serum was suppressed with low and moderate-intensity exercise. Conversely, the high-intensity exercise group closely resembled the non-exercised control group by nearly all metrics of inflammation measured in this study. Physically active gout patients had significantly less flares/yr, decreased C-reactive protein (CRP) levels, and lower pain scores relative to physically inactive patients. Conclusions Regular, moderate physical activity can produce a quantifiable anti-inflammatory effect capable of partially mitigating the pathologic response induced by intra-articular MSU crystals by downregulating TLR2 expression on circulating neutrophils and suppressing systemic CXCL1. Low and moderate-intensity exercise produces this anti-inflammatory effect to varying degrees, while high-intensity exercise provides no significant difference in inflammation compared to non-exercising controls. Consistent with the animal model, gout patients with higher levels of physical activity have more favorable prognostic data. Collectively, these data suggest the need for further research and may be the foundation to a future paradigm-shift in conventional exercise recommendations provided by Rheumatologists to gout patients.

Additional file 1. Preparing and determining mechanical and moisture related properties of gessoes.

ObjectivesGout is the most prevalent inflammatory arthritis. To study the effects of regular physical activity and exercise intensity on inflammation and clinical outcome, we examined inflammatory pathogenesis in an acute model of murine gout and analyzed human gout patient clinical data as a function of physical activity.MethodsNF-κB-luciferase reporter mice were organized into four groups and exercised at 0 m/min (non-exercise), 8 m/min (low-intensity), 11 m/min (moderate-intensity), and 15 m/min (high-intensity) for two weeks. Mice subsequently received intra-articular monosodium urate (MSU) crystal injections (0.5mg) and the inflammatory response was analyzed 15 hours later. Ankle swelling, NF-κB activity, histopathology, and tissue infiltration by macrophages and neutrophils were measured. Toll-like receptor (TLR)2 was quantified on peripheral monocytes/neutrophils by flow cytometry and both cytokines and chemokines were measured in serum or synovial aspirates. Clinical data and questionnaires accessing overall physical activity levels were collected from gout patients.ResultsInjection of MSU crystals produced a robust inflammatory response with increased ankle swelling, NF-κB activity, and synovial infiltration by macrophages and neutrophils. These effects were partially mitigated by low and moderate-intensity exercise. Furthermore, IL-1β was decreased at the site of MSU crystal injection, TLR2 expression on peripheral neutrophils was downregulated, and expression of CXCL1 in serum was suppressed with low and moderate-intensity exercise. Conversely, the high-intensity exercise group closely resembled the non-exercised control group by nearly all metrics of inflammation measured in this study. Physically active gout patients had significantly less flares/yr, decreased C-reactive protein (CRP) levels, and lower pain scores relative to physically inactive patients.ConclusionsRegular, moderate physical activity can produce a quantifiable anti-inflammatory effect capable of partially mitigating the pathologic response induced by intra-articular MSU crystals by downregulating TLR2 expression on circulating neutrophils and suppressing systemic CXCL1. Low and moderate-intensity exercise produces this anti-inflammatory effect to varying degrees, while high-intensity exercise provides no significant difference in inflammation compared to non-exercising controls. Consistent with the animal model, gout patients with higher levels of physical activity have more favorable prognostic data. Collectively, these data suggest the need for further research and may be the foundation to a future paradigm-shift in conventional exercise recommendations provided by Rheumatologists to gout patients.

The Peabody Museum of Natural History at Yale University has a long tradition of promoting and maintaining high standards of care for their collection of more than 13 million objects. Recently, an analysis of the current environmental conditions in the three primary museum buildings— Peabody Museum of Natural History, Kline Geology Laboratory, and the Class of 1954 Environmental Science Center—showed that the stability of environmental conditions and efficiency in air-handling systems are poorly constrained. An analysis of energy use in climate control showed that the Class of 1954 Environmental Science Center, the most modern building of the complex, is the least energy-efficient of the three and one of the least energy-efficient museum buildings at Yale University. The Yale Peabody Museum, in collaboration with the Yale Institute for the Preservation of Cultural Heritage, evaluated the current climate control strategy with an eye toward achieving a more practical and responsible approach, which considers the historic character of the buildings, high cost of climate control, and sensitivity to energy sustainability. This is a key mission of the University, as outlined in the Yale Sustainability Plan 2025. The main element in the transformation to a new strategy of climate management is the assessment of climate-related risks to collections. Our assessment indicates that degradation of chemically unstable polymers is the process that dominates loss of value of those collections due to climate- related risks. It is estimated that chemical degradation processes have approximately two orders of magnitude larger impact on collection value than the degradation of pyrite and pyrite-containing materials and even more than pest damage. Other climate-related processes are relatively negligible in effect. These findings allow us to change the strategy of climate control, giving priority to maintaining low temperature in rooms housing collections made of organic materials and relaxing the range of allowable relative humidity parameters. The new strategy includes a shift from climate control to climate management, including: dual set-point (deadband) controllers to reduce energy consumption and lower CO2 emissions, nightly shutdowns of the air-handling system serving dry collections in a modern building, broader thermal criteria, and a reduction of the amount of fresh air introduced to the buildings. These will be implemented sequentially. Progress and outcomes will be the focus of a subsequent article.

Spinal cord paralysis is relatively common after surgical repair of thoraco-abdominal aortic aneurysm (TAAA) and its etiology is unknown. The present study was designed to examine the histopathology of the disease and investigate whether miR-155 ablation would reduce spinal cord ischemic damage and delayed hindlimb paralysis induced by aortic cross-clamping (ACC) in our mouse model. The loss of locomotor function in ACC-paralyzed mice correlated with the presence of extensive gray matter damage and central cord edema, with minimal white matter histopathology. qRTPCR and Western blotting showed that the spinal cords of wild-type ACC mice that escaped paralysis showed lower miR-155 expression and higher levels of transcripts encoding Mfsd2a, which is implicated in the maintenance of blood-brain barrier integrity. In situ based testing demonstrated that increased miR-155 detection in neurons was highly correlated with the gray matter damage and the loss of one of its targets, Mfsd2a, could serve as a good biomarker of the endothelial cell damage. In vitro, we demonstrated that miR-155 targeted Mfsd2a in endothelial cells and motoneurons and increased endothelial cell permeability. Finally, miR-155 ablation slowed the progression of central cord edema, and reduced the incidence of paralysis by 40%. In sum, the surgical pathology findings clearly indicated that the epicenter of the ischemic-induced paralysis was the gray matter and that endothelial cell damage correlated to Mfsd2a loss is a good biomarker of the disease. MiR-155 targeting therefore offers new therapeutic opportunity for edema caused by traumatic spinal cord injury and diagnostic pathologists, by using immunohistochemistry, can clarify if this mechanism also is important in other ischemic diseases of the CNS, including stroke.

This paper analyzes the process of crack saturation, which is fundamental to understanding why panel paintings have survived remarkably well in the uncontrolled environments of historic houses or p...

HERIe is a web-based decision-supporting software tool to facilitate the management of collection environments by precise assessment of climate-induced risk of physical damage to vulnerable objects...

In older adults, the loss of muscle strength (dynapenia) and the loss of muscle mass (sarcopenia) are important contributors to the loss of physical function. We sought to investigate dynapenia, sarcopenia, and the loss of motor unit function in aging mice. C57BL/6J mice were analyzed with cross-sectional (males: 3 vs. 27 months; males and females: 8 vs. 12 vs. 20 months) and longitudinal studies (males: 10–25 months) using in vivo electrophysiological measures of motor unit connectivity (triceps surae compound muscle action potential and motor unit number estimation), in vivo measures of plantar flexion torque, magnetic resonance imaging of hind limb muscle volume, and grip strength. Compound muscle action potential amplitude, motor unit number estimation, and plantar flexion torque were decreased at 20 months. In contrast, grip strength was reduced at 24 months. Motor unit number estimates correlated with muscle torque and hind limb muscle volume. Our results demonstrate that the loss of motor unit connectivity is an early finding in aging male and female mice and that muscle size and contractility are both associated with motor unit number.

Nanoparticles have been widely explored for combined therapeutic and diagnostic applications. For example, lipid-based nanoparticles have been used to encapsulate multiple types of agents and achieve multi-functions. Herein, we enabled a co-delivery of mRNA molecules and superparamagnetic iron oxide nanoparticles (SPIONs) by using an amino-ester lipid-like nanomaterial. An orthogonal experimental design was used to identify the optimal formulation. The optimal formulation, MPA-Ab-8 LLNs, not only showed high encapsulation of both mRNA and SPIONs, but also increased the r(2) relaxivity of SPIONs by more than 1.5-fold in vitro. MPA-Ab-8 LLNs effectively delivered mRNA and SPIONs into cells, and consequently induced high protein expression as well as strong MRI contrast. Consistent herewith, we observed both mRNA-mediated protein expression and an evident negative contrast enhancement of MRI signal in mice. In conclusion, amino-ester nanomaterials demonstrate great potential as delivery vehicles for theranostic applications.

Moisture adsorption and diffusion were examined in 17 samples of historical and modern papers and cardboards, differing in the time of production and the pulping process. The moisture adsorption data for paper materials made of rags, gelatin-sized were close to each other whereas wood-pulp papers showed higher intra-group variability due to varying contents of lignin and rosin sizing. The average adsorption curve for all specimens was close to that of pure cellulose. In-plane diffusivities along the paper sheets in a stack, primary direction of uptake and release moisture by library objects, were determined as a function of relative humidity and paper compression. Typically, the in-plane diffusivities fell within the range of 6 × 10−6–1.7 × 10−5 m2/s and were significantly affected by the paper fraction in the specimens which were combination of paper sheets and thin air layers or pockets between the sheets. The external mass transfer coefficient at the surface of the paper objects perpendicular to the paper sheets exceeded 2 × 10−3 m/s and significantly depended on the intensity of air motion in typical environments. Effective use of the adsorption and diffusion information obtained was demonstrated in modelling buffering capacities of books.

People who suffer a traumatic spinal cord injury (SCI) are at increased risk for developing dermatological complications. These conditions increase cost of care, incidence of rehospitalization, and the risk for developing other infections. The consequences of dermatological complications after SCI are likely exacerbated further by post-injury deficits in neural-immune signaling. Indeed, a functional immune system is essential for optimal host defense and tissue repair. Here, we tested the hypothesis that SCI at high spinal levels, which causes systemic immune suppression, would suppress cutaneous inflammation below the level of injury. C57BL/6 mice received an SCI (T3 spinal level) or sham injury; then one day later complete Freund's adjuvant (CFA) was injected subcutaneously below the injury level. Inflammation was quantified by injecting mice with V-Sense, a perfluorocarbon (PFC) tracer that selectively labels macrophages, followed by in vivo imaging. The total radiant efficiency, which is proportional to the number of macrophages, was measured over a 4-day period at the site of CFA injection. Fluorescent in vivo imaging revealed that throughout the analysis period, the macrophage reaction in SCI mice was reduced ∼50% compared with sham-injured mice. Radiant efficiency data were confirmed using magnetic resonance imaging (MRI), and together the data indicate that SCI significantly impairs subcutaneous inflammation. Future studies should determine whether enhancing local inflammation or boosting systemic immune function can improve the rate or efficiency of cutaneous wound healing in individuals with SCI. Doing so also could limit wound infections or secondary complications of impaired healing after SCI.

Multi-functional nanomaterials possess unique properties, facilitating both therapeutic and diagnostic applications among others. Herein, we developed dual-functional lipid-like nanoparticles for simultaneous delivery of mRNA and magnetic resonance imaging (MRI) contrast agents in order to express functional proteins and provide real-time visualization. TT3-Gd18 LLNs were identified as a lead formulation, which was able to encapsulate 91% of mRNA and 74% of Gd. This formulation showed a comparable or a slightly higher delivery efficiency of mRNA compared to the initial TT3 LLNs. Moreover, a strong MRI signal was observed in the cell pellets treated with TT3-Gd18 LLNs. More importantly, TT3-Gd18 LLNs demonstrated an efficient delivery of mRNA and Gd contrast agents in vivo.

The particle concentrations outside and inside two historical churches were monitored for at least ten months. The highest levels of outdoor concentrations were recorded in winter. This was caused by high levels of particle emissions from the burning of predominantly solid fuel for domestic heating in premises around the two churches monitored. These high levels of particle concentrations declined over the warmer periods of the year with the lowest concentrations occurring in the summer months. Owing to the marked winter–summer pattern for outdoor concentrations, the particles of outdoor origin accounted for 80%–90% of the overall indoor particle concentrations in the period of predominantly cold weather conditions (December to March) and for 50%–60% in the warm period (June to September). Reducing air exchange between the external space and the church interiors by keeping windows and doors closed had a limited effect on the reduction of average particle concentrations indoors (by less than 10%). A controlled air exchange system, which would increase the ventilation of a church when the particle concentration outdoors is lower than indoors and reduce ventilation when the outdoor air is polluted, would produce a further reduction of 10% in the indoor average particle concentration. The general conclusion is that the protection of the interiors of historical churches against soiling is primarily achieved by the improved particle filtering capacity of building envelopes and the gradual reduction of the overall outdoor particle concentration. Use of air cleaning systems with particle filtration may be a viable long-term option.

The drying shrinkage accumulation from exposure of freshly prepared gesso layers to relative humidity (RH) cycles was determined to elucidate the mechanism of craquelure pattern formation on panel paintings. The progresive drying shrinkage of the gesso is observed only under the cycles going to high RH levels which bring about transitions from brittle to ductile state of the material. The first incidence of fracture on the gesso layers occurred after a limited number of cycles ranging between a few and 100 for a range of layer thickness between 0.5 and 1 mm. The craquelure patterns stabilised also after a limited number of cycles (30 for the 1-mm thick layer). Upon increase in the gesso layer thickness, the strength of the layer is reduced and the spacing of shrinkage fractures increases. The study demonstrated that craquelure patterns, mimicking historical ones, can be realistically produced in laboratory conditions. Such studies would provide useful information for preparing specimens simulating histori...

The microclimatic monitoring of the historic church of Mogila Abbey (Krakow, Poland) was carried out to study the impact of the environmental parameters on the organic and hygroscopic artworks. Specific indexes were proposed to objectively assess the quality of time series of temperature (T), relative humidity (RH), and carbon dioxide (CO2) before applying the exploratory data analysis. The series were used to define the historic environmental conditions as stated in the European Standard EN 15757:2010 and with the use of the climate evaluation chart (CEC). It was found that the percentage of time in which T and RH values are within the allowable limits of the ASHRAE (2011) Class B is more than 85 %. This means that, for about 15 % of the time, there is a high risk of mechanical damage to highly vulnerable objects mainly due to the RH variability. The environment at the chancel resulted moister than that at the cornice, and the fungal growth is possible. In addition, the time-weighted preservation index (TWPI) is computed to evaluate the life expectancy of the objects, taking into account the environmental conditions of the site under study. The method of analogues, developed to predict the evolution of a system given observations of the past and without the knowledge of any equation among variables, was proposed and applied to the time series of temperature, relative humidity, and carbon dioxide with a 1-h sampling time to avoid the influence of the autocorrelation.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.

Particle sources and deposition inside two historical churches, differing in size and construction were examined. The particle concentrations indoors and outdoors were monitored for at least 10 months. The air exchange rate (AER) was determined by fitting an exponential decay curve to the recorded concentration of indoor-generated CO 2 . The two-parameter mass balance equation, taking into account the particle sources and sinks in the indoor environment of churches, was used to determine the particle deposition velocities and penetration factors. Large indoor and outdoor particle concentration variability helped to separate the effects of penetration and deposition losses. For example, liturgical services regularly generated high indoor particle concentrations, owing to the burning of incense. During the particle concentration decay after the services, losses due to deposition could be reliably determined, whereas the events of high outdoor aerosol concentrations with no emission of particles indoors allowed the penetration factors to be precisely determined. The minimal AER values of 0.1 and 0.3 h −1 were observed in the closed brick and wooden church, respectively. Typically, area-averaged deposition velocities for particles of diameters 0.3–1 μm or above 1 μm were 1.5·10 −5 and 2.1·10 −5 m/s, respectively, and were very consistent between the two churches studied in spite of the differences in their design, size, construction materials and pattern of use. Penetration factors ranged from 0.7 to 0.86.

BACKGROUND: Clinical multi-electrode mapping of atrial fibrillation (AF) drivers suffers from variable contact, signal processing, and structural complexity within the 3D human atrial wall, raising questions on the validity of such drivers. OBJECTIVES: To improve AF driver identification by integrating clinical multi-electrode mapping with driver fingerprints defined by high-resolution ex-vivo 3D functional and structural imaging. METHODS: Sustained AF was mapped in coronary-perfused explanted human hearts (n=11) with transmural near-infrared optical mapping (NIOM, ~0.3mm(2) resolution). Simultaneously, custom FIRMap catheters (~9×9mm(2) resolution) mapped endocardial and epicardial surfaces, which were analyzed by Focal Impulse and Rotor Mapping (FIRM) activation and Rotational Activity Profile (RAP). Functional maps were integrated with contrast-enhanced MRI (CE-MRI, ~0.1mm(3) resolution) analysis of 3D fibrosis architecture. RESULTS: During sustained AF, NIOM identified 1-2 intramural, spatially stable reentrant AF drivers per heart. Driver targeted ablation affecting 2.2±1.1% of the atrial surface terminated and prevented AF. Driver regions had significantly higher phase singularity density, and dominant frequency versus neighboring non-driver regions. FIRM had 80% sensitivity to NIOM-defined driver locations (16/20), and matched 14/20 driver visualizations: 10/14 reentries seen with RAP, and 4/6 breakthrough/focal patterns. FIRM detected 1.1±0.9 false-positive RAP per recording, but these regions had lower intramural CE-MRI fibrosis than driver regions (14.9±7.9% vs 23.2±10.5%, p

Aims The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial–epicardial (Endo–Epi) mapping coupled with high-resolution 3D structural imaging. Methods and results Coronary-perfused human right atria from explanted diseased hearts ( n = 8, 43–72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo–Epi views (330 µm2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7–6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30–100 µM) perfusion. Dual-sided sub-Endo–sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or ‘breakthrough’ patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 × 6.0 ± 2.3 mm2, 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF. Conclusions Integrated 3D structural–functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles.

X-ray fluorescence (XRF) analysis has become a standard method in archaeological science due to its non-invasive and non-destructive nature. This technique has extensively been used for the study of numismatic collections since the data derived from it can be correlated with manufacturing processes, provenance of raw materials, and geographical distribution of ancient mints. A group of 71 silver coins of the first Piasts: Boleslaus the Brave (996–1025) and Mieszko II Lambert (1025–1034) belonging to the collections of the National Museum in Krakow have been characterized using micro-XRF spectrometry. This is the most numerous collection of their coins representing nearly 30% of all known coins from these rulers. The research has focused on evaluating the use of this technique as a screening tool for elemental surface characterization of the alloys. Surveyed coins are mainly constituted by Ag, Cu and Pb along with trace levels of Fe, Ni, Zn, Au, Hg, Bi, and Br. Quantitative analyses have revealed Ag contents in the 81.6–97.5% range for all the evaluated coins. This study had the goal of providing information about the elemental composition of these objects, which will serve to enhance the existing knowledge about geographical and chronological diversification of Polish numismatic collections.