The GWAS Central resource provides a toolkit for integrative access and visualization of a uniquely extensive collection of genome-wide association study data, while ensuring safe open access to prevent research participant identification. GWAS Central is the world's most comprehensive openly accessible repository of summary-level GWAS association information, providing over 70 million P-values for over 3800 studies investigating over 1400 unique phenotypes. The database content comprises direct submissions received from GWAS authors and consortia, in addition to actively gathered data sets from various public sources. GWAS data are discoverable from the perspective of genetic markers, genes, genome regions or phenotypes, via graphical visualizations and detailed downloadable data reports. Tested genetic markers and relevant genomic features can be visually interrogated across up to sixteen multiple association data sets in a single view using the integrated genome browser. The semantic standardization of phenotype descriptions with Medical Subject Headings and the Human Phenotype Ontology allows the precise identification of genetic variants associated with diseases, phenotypes and traits of interest. Harmonization of the phenotype descriptions used across several GWAS-related resources has extended the phenotype search capabilities to enable cross-database study discovery using a range of ontologies. GWAS Central is updated regularly and available at https://www.gwascentral.org.

Organic dirt on touch surfaces can be biological contaminants (microbes) or nutrients for those but is often invisible by the human eye causing challenges for evaluating the need for cleaning. Using hyperspectral scanning algorithm, touch surface cleanliness monitoring by optical imaging was studied in a real-life hospital environment. As the highlight, a human eye invisible stain from a dirty chair armrest was revealed manually with algorithms including threshold levels for intensity and clustering analysis with two excitation lights (green and red) and one bandpass filter (wavelength λ = 500 nm). The same result was confirmed by automatic k-means clustering analysis from the entire dirty data of visible light (red, green and blue) and filters 420 to 720 nm with 20 nm increments. Overall, the collected touch surface samples (N = 156) indicated the need for cleaning in some locations by the high culturable bacteria and adenosine triphosphate counts despite the lack of visible dirt. Examples of such locations were toilet door lock knobs and busy registration desk armchairs. Thus, the studied optical imaging system utilizing the safe visible light area shows a promising method for touch surface cleanliness evaluation in real-life environments.

There is increasing interest in the use of adipose-derived mesenchymal stromal cells (ASCs) for wound repair. As the fate of administered cells is still poorly defined, we aimed to establish the location, survival, and effect of ASCs when administered either systemically or locally during wound repair under physiological conditions. To determine the behavior of ASCs, a rat model with wounds on the dorsal aspect of the hind paws was used and two treatment modes were assessed: ASCs administered systemically into the tail vein or locally around the wound. ASCs were transduced to express both firefly luciferase (Fluc) and green fluorescent protein to enable tracking by bioluminescence imaging and immunohistological analysis. Systemically administered ASCs were detected in the lungs 3 hours after injection with a decrease in luminescent signal at 48 hours and signal disappearance from 72 hours. No ASCs were detected in the wound. Locally administered ASCs remained strongly detectable for 7 days at the injection site and became distributed within the wound bed as early as 24 hours post injection with a significant increase observed at 72 hours. Systemically administered ASCs were filtered out in the lungs, whereas ASCs administered locally remained and survived not only at the injection site but were also detected within the wound bed. Both treatments led to enhanced wound closure. It appears that systemically administered ASCs have the potential to enhance wound repair distally from their site of entrapment in the lungs whereas locally administered ASCs enhanced wound repair as they became redistributed within the wound bed.

Registration of clinical trials has been initiated in order to assess adherence of the reported results to the original trial protocol. This study aimed to investigate the publication rates, timely dissemination of results, and the prevalence of consistency in hypothesis, sample size, and primary endpoint of Dutch investigator-initiated randomized controlled clinical trials (RCTs).

Action execution is prone to errors and, while engaged in interaction, our brain is tuned to detect deviations from what one expects from other's action. Prior research has shown that Event-Related-Potentials (ERPs) are specifically modulated by the observation of action mistakes interfering with goal achievement. However, in complex and modular actions, embedded motor errors do not necessarily produce an immediate effect on the global goal. Here we dissociate embedded motor goals from global action goals by asking subjects to observe familiar but untrained knotting actions. During knotting an embedded motor error (i.e. the rope is inserted top-down instead of bottom-up during the formation of a loop) while not producing any immediate mistake, may strongly affect the final result. We found that embedded errors elicit in the observer specific early fronto-central negativity (120-180 ms). In a second experiment, we online administered exicitatory transcranial magnetic stimulation (TMS) over central (C3) or occipital (Oz) scalp locations, at the timing of the ERP components observed in the first experiment. C3 stimulation produced a significant improvement in embedded error discrimination performance. These results show that sensorimotor areas are instrumental in the early detection of embedded motor errors. We conclude that others' embedded errors provide fundamental cues which, inserted within a complex hierarchical action plan, might be used by the observer to anticipate whether an action will eventually fail.

Background and purpose - Hip arthroplasty is one of the most performed surgeries in Sweden, and the rate of adverse events (AEs) is fairly high. All patients in publicly financed healthcare in Sweden are insured by the Mutual Insurance Company of Swedish County Councils (Löf). We assessed the proportion of patients that sustained a major preventable AE and filed an AE claim to Löf.Patients and methods - We performed retrospective record review using the Global Trigger Tool to identify AEs in a Swedish multi-center cohort consisting of 1,998 patients with a total or hemi hip arthroplasty. We compared the major preventable AEs with all patient-reported claims to Löf from the same cohort and calculated the proportion of filed claims.Results - We found 1,066 major preventable AEs in 744 patients. Löf received 62 claims for these AEs, resulting in a claim proportion of 8%. 58 of the 62 claims were accepted by Löf and received compensation. The claim proportion was 13% for the elective patients and 0.3% for the acute patients. The most common AE for filing a claim was periprosthetic joint infection; of the 150 infections found 37 were claimed.Interpretation - The proportion of filed claims for major preventable AEs is very low, even for obvious and serious AEs such as periprosthetic joint infection.

Components of bacteria and viruses activate Toll-Like Receptors in host cells, triggering the formation of the Myddosome and a signalling network that culminates in the production and release of the inflammatory mediators required to combat pathogenic infection. The Myddosome initiates signalling by recruiting and activating five E3 ligases that generate hybrid ubiquitin chains and attach them to components of the Myddosome. These ubiquitin chains act as a scaffold for the recruitment and activation of ubiquitin-binding proteins, which include the "master" protein kinases TAK1 and IKKβ that drive inflammatory mediator production, as well as other proteins like ABIN1 and A20 that restrict activation of the network to prevent the overproduction of these substances that can lead to autoimmunity and organ damage. Here we review recent developments in our understanding of this network, focusing on the unexpected discovery that the E3 ligase HOIL-1 initiates the formation of hybrid ubiquitin chains by forming an ester bond between the first ubiquitin and the protein components of the Myddosome.

Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of hematopoietic stem cells (HSCs) for collection and subsequent autologous hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM). This international, multicenter, noninterventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF + plerixafor (G-CSF + P) versus G-CSF-; G-CSF + P versus G-CSF + chemotherapy (G-CSF + C); and G-CSF + P + C versus G-CSF + C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF + P versus G-CSF cohorts, 129 versus 129 in the G-CSF + P versus G-CSF + C cohorts, and 117 versus 117 in the G-CSF + P + C versus G-CSF + C cohorts were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded prespecified boundaries; noninferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF + P remains an option for the mobilization of HSCs in poor mobilizers with MM with no substantial differences in PFS, OS, and CIR in comparison with other regimens.

Transurethral resection of the prostate (TURP) is a minimally invasive endoscopic procedure that requires experience and skill of the surgeon. To permit surgical training under realistic conditions we report a novel phantom of the human prostate that can be resected with TURP. The phantom mirrors the anatomy and haptic properties of the gland and permits quantitative evaluation of important surgical performance indicators. Mixtures of soft materials are engineered to mimic the physical properties of the human tissue, including the mechanical strength, the electrical and thermal conductivity, and the appearance under an endoscope. Electrocautery resection of the phantom closely resembles the procedure on human tissue. Ultrasound contrast agent was applied to the central zone, which was not detectable by the surgeon during the surgery but showed high contrast when imaged after the surgery, to serve as a label for the quantitative evaluation of the surgery. Quantitative criteria for performance assessment are established and evaluated by automated image analysis. We present the workflow of a surgical simulation on a prostate phantom followed by quantitative evaluation of the surgical performance. Surgery on the phantom is useful for medical training, and enables the development and testing of endoscopic and minimally invasive surgical instruments.

There is no effective treatment to face Alzheimer's disease complexity. Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression. In this context, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234) has been tested achieving promising results. ASS234 has demonstrated to cross the blood-brain barrier in vivo, and a good in silico safety profile being less toxic than donepezil. Besides, ASS234 reversibly inhibits human acetyl- and butyryl-cholinesterase, and irreversibly inhibits human monoamine oxidase A and B. Moreover, this multitarget molecule has antioxidant and neuroprotective properties, and inhibits Αβ1-42 and Αβ1-40 self-aggregation. Inquiring about the mechanism of action, several signaling pathways related to Alzheimer's disease had been explored showing that ASS234 induces the wingless-type MMTV integration site (Wnt) family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes. Finally, in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus, ameliorating scopolamine-induced learning deficits. Here we gather the information regarding ASS234 evaluated so far, showing its ability to face different targets, necessary to counteract a neurodegenerative disease as complex as the Alzheimer's disease.

No abstract available

Ilexonin A is a compound isolated from the root of Ilex pubescens, a traditional Chinese medicine. Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia. However, the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear. Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats. Ilexonin A (20, 40 or 80 mg/kg) was administered immediately after ischemia/reperfusion. The astrocyte marker glial fibrillary acidic protein, microglia marker Iba-1, neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay. Expression levels of tumor necrosis factor-α and interleukin 1β were determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue. Astrocytes were activated immediately in progressively increasing numbers from 1, 3, to 7 days post-ischemia/reperfusion. The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A. Microglial cells remained quiescent after ischemia/reperfusion, but became activated after treatment with ilexonin A. Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-α and interleukin 1β in the hippocampus post-ischemia/reperfusion. The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion, probably through regulating astrocytes and microglia activation, promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors. This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital, China.

Cavernous nerve injury is the main cause of erectile dysfunction following radical prostatectomy. The recovery of erectile function following radical prostatectomy remains challenging. Our previous studies found that injecting adipose-derived stem cells (ADSCs) into the cavernosa could repair the damaged cavernous nerves, but the erectile function of the treated rats could not be restored to a normal level. We evaluated the efficacy of ADSCs infected with a lentiviral vector encoding rat brain-derived neurotrophic factor (lenti-rBDNF) in a rat model of cavernous nerve injury. The rats were equally and randomly divided into four groups. In the control group, bilateral cavernous nerves were isolated but not injured. In the bilateral cavernous nerve injury group, bilateral cavernous nerves were isolated and injured with a hemostat clamp for 2 minutes. In the ADSCGFP and ADSCrBDNF groups, after injury with a hemostat clamp for 2 minutes, rats were injected with ADSCs infected with lenti-GFP (1 × 106 in 20 μL) and lenti-rBDNF (1 × 106 in 20 μL), respectively. Erectile function was assessed 4 weeks after injury by measuring intracavernosal pressures. Then, penile tissues were collected for histological detection and western blot assay. Results demonstrated that compared with the bilateral cavernous nerve injury group, erectile function was significantly recovered in the ADSCGFP and ADSCrBDNF groups, and to a greater degree in the ADSCrBDNF group. Neuronal nitric oxide synthase content in the dorsal nerves and the ratio of smooth muscle/collagen were significantly higher in the ADSCrBDNF and ADSCGFP groups than in the bilateral cavernous nerve injury group. Neuronal nitric oxide synthase expression was obviously higher in the ADSCrBDNF group than in the ADSCGFP group. These findings confirm that intracavernous injection with ADSCs infected with lenti-rBDNF can effectively improve erectile dysfunction caused by cavernous nerve injury. This study was approved by the Medical Animal Care and Welfare Committee of Wuhan University, China (approval No. 2017-1638) on June 20, 2017.

Despite widespread age-of-sale restrictions on tobacco, adolescents continue to obtain cigarettes and experiment with smoking. This mixed-methods study aimed to understand how European adolescents access cigarettes and how the policy context may influence this process, using a realist evaluation approach. This is the first study to assess access to cigarettes across various European contexts.

Dual contrast micro computed tomography (CT) shows potential for detecting articular cartilage degeneration. However, the performance of conventional CT systems is limited by beam hardening, low image resolution (full-body CT), and long acquisition times (conventional microCT). Therefore, to reveal the full potential of the dual contrast technique for imaging cartilage composition we employ the technique using synchrotron microCT. We hypothesize that the above-mentioned limitations are overcome with synchrotron microCT utilizing monochromatic X-ray beam and fast image acquisition. Human osteochondral samples (n = 41, four cadavers) were immersed in a contrast agent solution containing two agents (cationic CA4+ and non-ionic gadoteridol) and imaged with synchrotron microCT at an early diffusion time point (2 h) and at diffusion equilibrium (72 h) using two monochromatic X-ray energies (32 and 34 keV). The dual contrast technique enabled simultaneous determination of CA4+ (i.e., proteoglycan content) and gadoteridol (i.e., water content) partitions within cartilage. Cartilage proteoglycan content and biomechanical properties correlated significantly (0.327 < r < 0.736, p < 0.05) with CA4+ partition in superficial and middle zones at both diffusion time points. Normalization of the CA4+ partition with gadoteridol partition within the cartilage significantly (p < 0.05) improved the detection sensitivity for human osteoarthritic cartilage proteoglycan content, biomechanical properties, and overall condition (Mankin, Osteoarthritis Research Society International, and International Cartilage Repair Society grading systems). The dual energy technique combined with the dual contrast agent enables assessment of human articular cartilage proteoglycan content and biomechanical properties based on CA4+ partition determined using synchrotron microCT. Additionally, the dual contrast technique is not limited by the beam hardening artifact of conventional CT systems. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:563-573, 2020.

To enable free-breathing whole-heart 3D T2 mapping with high isotropic resolution in a clinically feasible and predictable scan time. This 3D motion-corrected undersampled signal matched (MUST) T2 map is achieved by combining an undersampled motion-compensated T2 -prepared Cartesian acquisition with a high-order patch-based reconstruction.

In cereal grain, sucrose is converted into storage carbohydrates: mainly starch, fructan, and mixed-linkage (1,3;1,4)-β-glucan (MLG). Previously, endosperm-specific overexpression of the HvCslF6 gene in hull-less barley was shown to result in high MLG and low starch content in mature grains. Morphological changes included inwardly elongated aleurone cells, irregular cell shapes of peripheral endosperm, and smaller starch granules of starchy endosperm. Here we explored the physiological basis for these defects by investigating how changes in carbohydrate composition of developing grain impact mature grain morphology. Augmented MLG coincided with increased levels of soluble carbohydrates in the cavity and endosperm at the storage phase. Transcript levels of genes relating to cell wall, starch, sucrose, and fructan metabolism were perturbed in all tissues. The cell walls of endosperm transfer cells (ETCs) in transgenic grain were thinner and showed reduced mannan labelling relative to the wild type. At the early storage phase, ruptures of the non-uniformly developed ETCs and disorganization of adjacent endosperm cells were observed. Soluble sugars accumulated in the developing grain cavity, suggesting a disturbance of carbohydrate flow from the cavity towards the endosperm, resulting in a shrunken mature grain phenotype. Our findings demonstrate the importance of regulating carbohydrate partitioning in maintenance of grain cellularization and filling processes.

Chitinase 3-like protein 1 (CHI3L1) is most likely a malignant tumor metastasis-associated gene. However, the functions of CHI3L1 in colon cancer cell proliferation and its cetuximab sensitivity are still unclear. We aimed to investigate the mechanism of CHI3L1 in promoting colon cancer cell proliferation and its sensitivity to cetuximab.

Reproduction in vertebrates is controlled by the brain-pituitary-gonad axis, where the two gonadotropins follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) play vital parts by activating their cognate receptors in the gonads. The main purpose of this work was to study intra- and interspecies ligand promiscuity of teleost gonadotropin receptors, since teleost receptor specificity is unclear, in contrast to mammalian receptors. Receptor activation was investigated by transfecting COS-7 cells with either Fsh receptor (mdFshr, tiFshr) or Lh receptor (mdLhr, tiLhr), and tested for activation by recombinant homologous and heterologous ligands (mdFshβα, mdLhβα, tiFshβα, tiLhβα) from two representative fish orders, Japanese medaka (Oryzias latipes, Beloniformes) and Nile tilapia (Oreochromis niloticus, Cichliformes). Results showed that each gonadotropin preferentially activates its own cognate receptor. Cross-reactivity was detected to some extent as mdFshβα was able to activate the mdLhr, and mdLhβα the mdFshr. Medaka pituitary extract (MPE) stimulated CRE-LUC activity in COS-7 cells expressing mdlhr, but could not stimulate cells expressing mdfshr. Recombinant tiLhβα, tiFshβα and tilapia pituitary extract (TPE) could activate the mdLhr, suggesting cross-species reactivity for mdLhr. Cross-species reactivity was also detected for mdFshr due to activation by tiFshβα, tiLhβα, and TPE, as well as for tiFshr and tiLhr due to stimulation by mdFshβα, mdLhβα, and MPE. Tissue distribution analysis of gene expression revealed that medaka receptors, fshr and lhr, are highly expressed in both ovary and testis. High expression levels were found for lhr also in brain, while fshr was expressed at low levels. Both fshr and lhr mRNA levels increased significantly during testis development. Amino acid sequence alignment and three-dimensional modelling of ligands and receptors highlighted conserved beta sheet domains of both Fsh and Lh between Japanese medaka and Nile tilapia. It also showed a higher structural homology and similarity of transmembrane regions of Lhr between both species, in contrast to Fshr, possibly related to the substitution of the conserved cysteine residue in the transmembrane domain 6 in medaka Fshr with glycine. Taken together, this is the first characterization of medaka Fshr and Lhr using homologous ligands, enabling to better understand teleost hormone-receptor interactions and specificities. The data suggest partial ligand promiscuity and cross-species reactivity between gonadotropins and their receptors in medaka and tilapia.

CO2 inhalation can provoke panic attacks in humans, and the likelihood is increased in patients with panic disorder. Identifying brain sites involved could provide important mechanistic insight into the illness. In mice, the amygdala has been suggested to promote CO2 responses; however, recent studies in humans with amygdala damage indicate the amygdala is not required for CO2-induced fear and panic and might actually oppose these responses. To clarify the role of the amygdala, we produced lesions in mice paralleling the human lesions, and characterized behavioral responses to CO2. Compared to sham controls, we found that amygdala-lesioned mice froze less to 10% CO2, and unlike shams they also began to jump frenetically. At 20% CO2, controls also exhibited jumping, suggesting it is a normal response to more extreme CO2 concentrations. The effect of amygdala lesions was specific to CO2 as amygdala-lesioned mice did not jump in response to a predator odor or to an auditory conditioned stimulus. In amygdala-lesioned mice, jumping evoked by 10% CO2 was eliminated by co-lesioning the dorsal periaqueductal gray, a structure implicated in panic and escape-related behaviors. Together, these observations suggest a dual role for the amygdala in the CO2 response: promoting CO2-induced freezing, and opposing CO2-induced jumping, which may help explain the exaggerated CO2 responses in humans with amygdala lesions.