Obtaining and Enforcing Trade Dress for Computer Graphical User Interfaces - A Practitioner\u27s Guide

A computer program that successfully incorporates an intuitive graphical user interface possesses a tremendous competitive advantage over its competitors. Interface development accordingly has become a critical aspect of software development. Without legal protection, however, this advantage is illusory as competitors are otherwise free to copy unprotected interface features. Interface creators have predominately used copyright law to protect the overall look and feel of their interfaces. However, copyright protection for interfaces increasingly appears to be the exception rather than the rule

The Genetics of Kidney Transplantation Outcomes and Autoimmune Disease

Kidney transplantation recipients face rejection despite anti-rejection drugs and matching efforts. Biopsy confirmed acute rejection (AR) and chronic allograft nephropathy (CAN) are 2 rejection phenotypes of interest. We conducted a genome-wide association study (GWAS) in European-derived kidney transplant donors and recipients. Well-functioning transplant donors (TX; N=261) were compared to AR (N=90) or CAN (N=105) participants. The same comparisons were conducted in recipients (TX N=226; AR N=71; CAN N=105). Analyses were adjusted for multiple comparisons and additionally for population substructure by including the first 2 multi-dimensional scaling dimension values as covariates in logistic regression. The most significant findings were identified in the TX vs. CAN tests (lowest unadjusted P=6.51E-08), which also displayed the largest odds ratios, and the least significant findings were identified for the TX vs. AR tests. Results need to be validated in an independent collection.Proportion of identity by state, pi-hat, was calculated between donor-recipient pairs and compared between different donor-types and also by outcome (TX, AR, CAN). No significant difference within donor-type matched pairs was observed between outcome phenotypes in European-derived samples.A set of primers was developed to sequence 112 candidate genes for AR and CAN. A custom resequencing tiling array was designed and tested. Technological development in the field called for testing the same panel on next-generation sequencing technology. We improved quality control metrics by trimming the reads and successfully called single nucleotide polymorphisms (SNPs) at a rate of 1/1000 bases sequenced.Finally, TNFAIP3, a candidate gene for autoimmune disease (AID) was sequenced in samples multiply affected with AID (N=123) and in controls (N=397). One novel intronic insertion/deletion polymorphism was significantly associated with multiple AID diagnoses (Fisher's Exact P-value=0.0090; OR (95% CI) 7.053(1.67-29.79). Coding polymorphism rs2230926 was tested for association in a panel of individuals from families with multiple AIDs. Significant association was observed with all affected individuals (P=0.0336) as well as psoriasis, Crohn's disease and rheumatoid arthritis, with marginal association for Sjogren's and Graves disease. Additionally, we conducted an association study of the entire gene locus in lupus and identified 3 independent signals of association, including coding SNP rs2230926

Linear ubiquitination in immunity

Linear ubiquitination is a post-translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types

Urine tests for Down's syndrome screening

Background Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age. Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. Objectives To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome. Search methods We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles. Selection criteria Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. Data collection and analysis We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses. Main results We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies). In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR). Authors' conclusions Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available

Mandibular Asymmetry, Generalized Joint Hypermobility, and Temporomandibular Disorders in Pre-Orthodontic Growing Individuals: A Cross-Sectional Clinical-Radiographic Study

Objective: This study aims to explore the relationship between mandibular asymmetry (MA), generalized joint hypermobility (GJH), and temporomandibular disorders (TMD) in pre-orthodontic growing individuals. Methods: This cross-sectional study included 74 pre-orthodontic individuals aged 8–16 years. Mandibular asymmetry was evaluated through posteroanterior cephalometric analysis, using menton deviation ≥ 4 mm as the threshold for asymmetry. GJH was assessed using the Beighton Score (BS ≥ 4 = GJH-positive), while TMD was diagnosed based on Axis I of the DC/TMD. Associations among the variables were tested using a chi-square test (p < 0.05; SPSS v.24). Results: The study included 74 patients (25.7% males; mean age 12.7 ± 2.16 years). The GJH-positive group (n = 41) showed a higher prevalence of TMD (85.4%) compared to the GJH-negative group (51.5%) (p = 0.002). MA was more frequent in the GJH-positive group (68.3% vs. 45.5%; p = 0.041). A significant association was also found between TMD and MA (71.2% vs. 27.3%; p < 0.001). In both groups, patients with TMD were more likely to present MA (GJH-negative p = 0.022; GJH-positive p = 0.046). Conclusions: MA emerged as a key factor associated with the presence of TMD, particularly when combined with GHJ. These findings indicate that MA alone is significantly related to the occurrence of TMD, regardless of joint hypermobility status. However, the risk appears to be amplified in individuals who also present with GJH. Effect size analysis indicated that most associations were small, with only the one between TMD and MA reaching a moderate level. This highlights the importance of evaluating statistical significance in the context of effect size to better assess clinical relevance

ICSNPathway: identify candidate causal SNPs and pathways from genome-wide association study by one analytical framework

Genome-wide association study (GWAS) is widely utilized to identify genes involved in human complex disease or some other trait. One key challenge for GWAS data interpretation is to identify causal SNPs and provide profound evidence on how they affect the trait. Currently, researches are focusing on identification of candidate causal variants from the most significant SNPs of GWAS, while there is lack of support on biological mechanisms as represented by pathways. Although pathway-based analysis (PBA) has been designed to identify disease-related pathways by analyzing the full list of SNPs from GWAS, it does not emphasize on interpreting causal SNPs. To our knowledge, so far there is no web server available to solve the challenge for GWAS data interpretation within one analytical framework. ICSNPathway is developed to identify candidate causal SNPs and their corresponding candidate causal pathways from GWAS by integrating linkage disequilibrium (LD) analysis, functional SNP annotation and PBA. ICSNPathway provides a feasible solution to bridge the gap between GWAS and disease mechanism study by generating hypothesis of SNP → gene → pathway(s). The ICSNPathway server is freely available at http://icsnpathway.psych.ac.cn/

Anesthetic management for neonate with giant cystic hygroma involved upper airway -A case report-

Significant differences exist between neonatal and adult airways. Anesthetic management of the airway may be challenging in neonate and young infant with large neck mass because these patients are at risk for sudden complete airway occlusion resulting in hypoventilation and hypoxemia. We experienced a 30-day-old baby presented with large cystic hygroma on the left side of neck. This mass was infiltrated in pharynx and large enough to disturb swallowing and breathing, and was not reduced despite of sclero-therapy. Therefore he was decided to get surgical removal. During the gaseous induction with sevoflurane, spontaneous respiration was maintained because difficulty was encountered with intubation. Intraoperatively, the endotracheal tube was dislodged unexpectedly because vigorous surgical traction. Postoperatively the baby was extubated 2 day after operation, and suffered from transient facial nerve palsy and continuous discharge from surgical wound. He was administered ICU for a long time

KM3NeT/ARCA Sensitivity to Starburst Galaxies

In this work, the expectations of the full detector KM3NeT/ARCA are presented for particular starburst galaxies signals. For the point-like search approach, we considered the most promising local starburst galaxies to be observed as point-like neutrino excesses: NGC 1068, the Small Magellanic Cloud and the Circinus Galaxy. In both cases, we provide the energy-integrated sensitivity for two ARCA building blocks in the energy range 100 GeV − 10 PeV. In the diffuse scenario, both track and shower events were considered. For the point like analysis, only νµ charge current events were taken into account. Interestingly, ARCA has the potential to constrain the selected phenomenological scenarios, providing evidence of the link between star-forming processes and hadronic emissions

A20 deletion in T cells modulates acute graft-versus-host disease in mice

The NF-kappa B regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4(+) and CD8(+) donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-gamma and systemic inflammationwas elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20(+/+) T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20(+/+) T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD

Efficacy and putative mechanisms of action of nutraceuticals in the management of erectile dysfunction: a narrative review

Erectile dysfunction (ED) is a common condition in the male population and is influenced by numerous pathophysiological factors. Recently, interest in nutraceuticals and natural remedies as complementary or alternative therapies to traditional pharmacological treatments has increased exponentially. This narrative review aims to analyze the impact of the most studied nutraceuticals in the treatment of ED, analyzing their mechanisms of action, clinical efficacy and safety. Much attention has been paid to compounds such as L-arginine, as well as several medicinal plants including ginseng, maca, Tribulus terrestris and antioxidant substances such as resveratrol and Pycnogenol. These natural products have different mechanisms of action, including modulation of endothelial function, reduction of oxidative stress and balance of sex hormones, thus addressing multiple therapeutical targets for the management of ED. However, despite promising results reported in various preclinical and clinical studies, several limitations to the use of nutraceuticals for ED persist, including variability in study designs, lack of standardized dosages of various compounds and lack of long-term safety evaluations. In fact, although nutraceuticals generally demonstrate a favorable safety profile compared to traditional drugs, they are not completely exempt from possible side effects. Furthermore, issues such as inconsistent patient adherence to treatment and potential interactions with drug therapies require further research and investigation. Therefore, high-quality, adequately sized clinical trials to better evaluate the efficacy and safety of these compounds, alone or in combination with conventional, widely adopted therapeutic regimens are warranted. In conclusion, nutraceuticals present a promising therapeutic option in the management of ED, potentially capable of improving clinical outcomes and patients’ quality of life when integrated into an all-inclusive therapeutic strategy