The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target.

Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic.

Characterizing pathways of seafood access in small island developing states.

Ensuring healthy and sustainable food systems in increasing social, economic, and ecological change is a key global priority to protect human and environmental health. Seafood is an essential component of these food systems and a critical source of nutrients, especially in coastal communities. However, despite rapid transformations in aquatic food systems, and our urgent need to understand them, there is a dearth of data connecting harvested food production to actualized food consumption. Many analyses suggest institutional, legal, or technological innovations to improve food systems, but few have analyzed the pathways through which people already gain access to nutritious food. Here, using a random forest model and cluster analysis of a nationally representative data set from Kiribati, we operationalize access theory to trace the flows of consumptive benefit in a fisheries-based food system. We demonstrate that the market access mechanism is the key mechanism mediating seafood access in Kiribati, but importantly, the highest seafood consumption households showed lower market access, pointing to the importance of non-market acquisition (e.g., home production and gifting). We reveal six distinct household strategies that employ different sets of access mechanisms to ensure high levels of local seafood consumption in different contexts. We demonstrate the impacts of these strategies on the composition of household seafoods consumed, stressing the need to support these existing successful strategies. Finally, we point to key policy and management insights (e.g., improved infrastructure, shifts in species management) that may be more effective in reinforcing these existing pathways than commonly proposed food system interventions.

Biallelic FANCA variants detected in sisters with isolated premature ovarian insufficiency.

Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, Fanconi anemia complementation group A (FANCA), is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous FANCA variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic FANCA variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel FANCA variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in FANCA, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes.

Health Within Reach-a Patient-Centered Intervention to Increase Hepatitis B Screening Among Asian Americans: a Randomized Clinical Trial.

BACKGROUND: There are few studies to date of interventions to increase viral hepatitis screening among Asian Americans, who have high rates of chronic hepatitis B (HBV) infection. OBJECTIVE: To develop, implement, and test the efficacy of a mobile application (Hepatitis App) delivered in four languages to increase HBV screening among Asian Americans. DESIGN: Cluster-randomized clinical trial. PARTICIPANTS: Four hundred fifty-two Asian American patients ≥ 18 years of age, who had no prior HBV testing, and received primary care within two healthcare systems in San Francisco, CA. INTERVENTIONS: The intervention group received the Hepatitis App, delivering interactive video education on viral hepatitis in English, Cantonese, Mandarin, or Vietnamese and a provider printout (Provider Alert) and Provider Panel Notification. The comparison group received a mobile application delivering nutrition and physical activity education and Provider Panel Notification. MAIN MEASURES: Primary outcomes were patient-provider discussion about HBV and documentation of a HBV screening test within 3 months post-intervention. Secondary outcome was documentation of an order for a HBV screening test. KEY RESULTS: Participants had a mean age of 57 years and were 64% female, 80% foreign-born, and 44% with limited English fluency. At post-visit, over 80% of intervention participants reported they liked using the Hepatitis App. At 3-month follow-up, the intervention group was more likely than the comparison group (all P < 0.001) to have discussed HBV with their provider (70% vs.16%), have a HBV test ordered (44% vs.10%), and receive a HBV test (38% vs.8%). In multivariable analyses, the intervention odds ratio for HBV test ordering was 7.6 (95% CI: 3.9, 14.8) and test receipt was 7.5 (95% CI: 3.6, 15.5). CONCLUSIONS: A multi-lingual educational intervention using a mobile application in primary care clinics was well received by Asian American patients, enhanced patient-provider communication about HBV, and increased HBV screening. Technology can improve healthcare quality among Asian Americans. TRIAL REGISTRATION: ClinicalTrials.gov NCT02139722 ( https://clinicaltrials.gov/ct2/show/NCT02139722 ).

Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer.

Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.

Procedural Guide for System-Level Impact Evaluation of Industrial Artificial Intelligence-Driven Technologies: Application to Risk-Based Investment Analysis for Condition Monitoring Systems in Manufacturing.

Industrial artificial intelligence (IAI) and other analysis tools with obfuscated internal processes are growing in capability and ubiquity within industrial settings. Decision-makers share their concern regarding the objective evaluation of such tools and their impacts at the system level, facility level, and beyond. One application where this style of tool is making a significant impact is in Condition Monitoring Systems (CMSs). This paper addresses the need to evaluate CMSs, a collection of software and devices that alert users to changing conditions within assets or systems of a facility. The presented evaluation procedure uses CMSs as a case study for a broader philosophy evaluating the impacts of IAI tools. CMSs can provide value to a system by forewarning faults, defects, or other unwanted events. However, evaluating CMS value through scenarios that did not occur is rarely easy or intuitive. Further complicating this evaluation are the ongoing investment costs and risks posed by the CMS from imperfect monitoring. To overcome this, an industrial facility needs to regularly and objectively review CMS impacts to justify investments and maintain competitive advantage. This paper's procedure assesses the suitability of a CMS for a system in terms of risk and investment analysis. This risk-based approach uses the changes in the likelihood of good and bad events to quantify CMS value without making any one-time point-wise estimates. Fictional case studies presented in this paper illustrate the procedure and demonstrate its usefulness and validity.

Evaluation of energy dissipation rate as a predictor of mechanical blood damage.

A long-standing goal in the field of biofluid mechanics has been to reliably predict hemolysis across the wide range of flows that can occur in prosthetic cardiovascular devices. A scalar representation of the complex three-dimensional fluid stresses that are exerted on cells is an attractive alternative for the simplicity that it lends to the computations. The appropriateness of the commonly used von-Mises-like scalar stress as a universal hemolysis scaling parameter was previously evaluated, finding that erythrocyte membrane tensions calculated for laminar shear and extensional flows and for three cases of turbulent flow were widely divergent for the same value of scalar stress. The same techniques are applied in this study to laminar and turbulent flows that each have the same energy dissipation rate. Results showed that agreement of membrane tension between laminar shear and turbulent shear inside an eddy was improved relative to the common scalar stress cases, but disagreement between laminar shear and laminar extension remained the same and disagreement between laminar shear and other turbulent flows increased. It is therefore concluded that energy dissipation rate alone is also likely not sufficient to universally scale blood damage across the range of different flows that can be encountered clinically.

Colorectal cancer beliefs, knowledge, and screening among Filipino, Hmong, and Korean Americans.

BACKGROUND: To the authors' knowledge, there are few studies to date regarding colorectal cancer (CRC) beliefs, knowledge, and screening among multiple Asian American populations, who are reported to have lower CRC screening rates compared with white individuals. The current study was performed to assess knowledge and beliefs regarding the causes of CRC, its prevention, and factors associated with CRC screening among 3 Asian American groups. METHODS: The authors conducted an in-language survey with Filipino (Honolulu, Hawaii), Hmong (Sacramento, California), and Korean (Los Angeles, California) Americans aged 50 to 75 years who were sampled through social networks. Bivariate and multivariable analyses were conducted to assess factors associated with CRC screening. RESULTS: The sample of 981 participants was 78.3% female and 73.8% reported limited proficiency in English. Few of the participants were aware that age (17.7%) or family history (36.3%) were risk factors for CRC; 6.2% believed fate caused CRC. Only 46.4% of participants knew that screening prevented CRC (74.3% of Filipino, 10.6% of Hmong, and 55.8% of Korean participants; P<.001). Approximately two-thirds of participants reported ever having undergone CRC screening (76.0% of Filipino, 72.0% of Hmong, and 51.4% of Korean participants; P<.001) and 48.6% were up to date for screening (62.2% of Filipino, 43.8% of Hmong, and 41.4% of Korean participants; P<.001). Factors found to be significantly associated with ever screening were being Korean (compared with Filipino), having a family history of CRC, having health insurance or a regular source of health care, and knowing that a fatty diet caused CRC. Believing that fate caused CRC and that praying prevented it were found to be negatively associated with ever screening. Factors associated with being up to date for CRC screening included being born in the United States, having a family history of CRC, and having access to health care. CONCLUSIONS: Knowledge regarding the causes of CRC and its prevention among Filipino, Hmong, and Korean individuals is low. However, health care access, not knowledge or beliefs, was found to be a key determinant of CRC screening. Cancer 2018;124:1552-9. © 2018 American Cancer Society.

Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified EFEMP2 as a novel PITX2 interacting protein.

PURPOSE: Mutations in the homeobox transcription factor paired-like homeodomain transcription factor 2 (PITX2) cause Axenfeld-Reiger syndrome (ARS), which is associated with anterior segment dysgenesis (ASD) and glaucoma. To understand ARS pathogenesis, it is essential to know the normal functions of PITX2 and the proteins with which PITX2 interacts in the eye. Therefore, we used a unique cDNA library that we created from human trabecular meshwork (TM) primary cells to discover PITX2-interacting proteins (PIPs). METHODS: A human TM cDNA library was created from primary cells in the ProQuest Two-Hybrid prey vector: pEXP-AD502. Human PITX2A and PITX2C isoforms were used independently as "bait" to identify novel PIPs. A total of 1.25×106 clones were screened by yeast two-hybrid (Y2H) analyses. PIPs obtained from each Y2H experiment were confirmed by yeast retransformation and mammalian co-immunoprecipitation assays. RESULTS: EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) was identified by both PITX2A and PITX2C isoforms as a novel PIP from Y2H analyses. EFEMP2 is 443 amino acids long with six epidermal growth factor (EGF)-like modules and one fibulin-like module. The PITX2-interaction domain in EFEMP2 lies between the second EGF-like module and the COOH-terminal fibulin-like module. Co-immunoprecipitation assays in COS-7 cells confirmed the interaction between PITX2 and EFEMP2. CONCLUSIONS: We discovered EFEMP2 as a novel PITX2-interacting protein. Further, our cDNA library made from human TM primary cells is a unique and effective resource to identify novel interacting proteins for glaucoma and ASD candidates. This resource could be used both for discovery and validation of interactomes identified from in silico analysis.

Accounting for uncertainty in model-based prevalence estimation: paratuberculosis control in dairy herds.

BACKGROUND: A common approach to the application of epidemiological models is to determine a single (point estimate) parameterisation using the information available in the literature. However, in many cases there is considerable uncertainty about parameter values, reflecting both the incomplete nature of current knowledge and natural variation, for example between farms. Furthermore model outcomes may be highly sensitive to different parameter values. Paratuberculosis is an infection for which many of the key parameter values are poorly understood and highly variable, and for such infections there is a need to develop and apply statistical techniques which make maximal use of available data. RESULTS: A technique based on Latin hypercube sampling combined with a novel reweighting method was developed which enables parameter uncertainty and variability to be incorporated into a model-based framework for estimation of prevalence. The method was evaluated by applying it to a simulation of paratuberculosis in dairy herds which combines a continuous time stochastic algorithm with model features such as within herd variability in disease development and shedding, which have not been previously explored in paratuberculosis models. Generated sample parameter combinations were assigned a weight, determined by quantifying the model's resultant ability to reproduce prevalence data. Once these weights are generated the model can be used to evaluate other scenarios such as control options. To illustrate the utility of this approach these reweighted model outputs were used to compare standard test and cull control strategies both individually and in combination with simple husbandry practices that aim to reduce infection rates. CONCLUSIONS: The technique developed has been shown to be applicable to a complex model incorporating realistic control options. For models where parameters are not well known or subject to significant variability, the reweighting scheme allowed estimated distributions of parameter values to be combined with additional sources of information, such as that available from prevalence distributions, resulting in outputs which implicitly handle variation and uncertainty. This methodology allows for more robust predictions from modelling approaches by allowing for parameter uncertainty and combining different sources of information, and is thus expected to be useful in application to a large number of disease systems.

Correlation between social media utilization by academic neurosurgery departments and higher online patient ratings.

OBJECTIVE: Patients increasingly utilize online physician review websites (PRWs) and social media to inform healthcare-related decisions. This provides neurosurgeons with opportunities for increased patient engagement. And despite the growing use of social media among neurosurgeons, the relationship between social media utilization and online reviews remains unknown. The goal of this study was to characterize the relationship between social media utilization and PRW ratings across academic neurosurgery departments. METHODS: Social media accounts (Twitter, Facebook, YouTube, Instagram) of academic neurosurgery departments were identified. Online reviews for individual faculty were obtained from Healthgrades, Vitals, WebMD, and Google. Reviews were aggregated to identify the total number of reviews per department, to generate a composite departmental rating, and to calculate a summed departmental score. US News & World Report (USNWR) and Doximity rankings were recorded for each department. Social media utilization by individual neurosurgeons and associated ratings were investigated within the departments with the highest social media utilization. RESULTS: Seventy-eight percent of academic neurosurgery departments utilized social media. The most prevalent platform was YouTube (49.1%), followed by Twitter (46.5%), Facebook (38.6%), and Instagram (16.7%). Higher patient ratings on PRWs were associated with the utilization of YouTube (p = 0.048) or Twitter (p = 0.02). The number of social media platforms utilized demonstrated a significant, positive correlation with patient ratings (p = 0.006) and summed patient ratings (p = 0.048). Although USNWR (p = 0.02) and Doximity (p = 0.0008) rankings correlated with patient ratings, only the number of social media platforms utilized remained a significant predictor of patient ratings on multivariate analysis (p = 0.0001). Thirty-one percent of academic neurosurgeons from departments with high social media utilization were active on social media. The most prevalent social media platform among individual neurosurgeons was Twitter (27.4%), followed by Instagram (8.4%), Facebook (4.9%), and YouTube (2.2%). Higher summed patient scores were associated with individual neurosurgeon utilization of YouTube (p = 0.04), Facebook (p < 0.0001), and Instagram (p = 0.01). Increased social media utilization among neurosurgeons was correlated with a greater number of patient reviews (p = 0.006) and higher summed patient scores (p = 0.003). On multivariate analysis, only Facebook use remained a significant predictor of the number of patient reviews received (p = 0.002) and summed patient satisfaction scores (p < 0.001). CONCLUSIONS: An increased social media presence is associated with higher ratings on PRWs. As neurosurgeons continue to expand their online presence, they should be aware of the possible impact of social media on online patient reviews.

Study Protocol: Interactive Dynamics of Coral Reef Fisheries and the Nutrition Transition in Kiribati.

The Kiribati 2019 Integrated Household Income and Expenditure Survey (Integrated HIES) embeds novel ecological and human health research into an ongoing social and economic survey infrastructure implemented by the Pacific Community in partnership with national governments. This study seeks to describe the health status of a large, nationally representative sample of a geographically and socially diverse I-Kiribati population through multiple clinical measurements and detailed socio-economic surveys, while also conducting supporting food systems research on ecological, social, and institutional drivers of change. The specific hypotheses within this research relate to access to seafood and the potential nutritional and health benefits of these foods. We conducted this research in 21 of the 23 inhabited islands of Kiribati, excluding the two inhabited islands-Kanton Islands in the Phoenix Islands group with a population of 41 persons (2020 census) and Banaba Island in the Gilbert Islands group with a population of 333 persons (2020 census)-and focusing exclusively on the remaining islands in the Gilbert and Line Islands groups. Within this sample, we focused our intensive human health and ecological research in 10 of the 21 selected islands to examine the relationship between ecological conditions, resource governance, food system dynamics, and dietary patterns. Ultimately, this research has created a baseline for future Integrated HIES assessments to simultaneously monitor change in ecological, social, economic, and human health conditions and how they co-vary over time.

Changes in mechanical load and extensor muscle activity in the cervico-thoracic spine induced by sitting posture modification.

The influence of whole body sitting posture on cervico-thoracic posture, mechanical load and extensor muscle activity was examined in 23 asymptomatic adults. Cervical and upper thoracic extensor muscle activity measured in guided slouched and lumbo-pelvic neutral postures was normalised to that measured in a self-selected habitual posture. Head and neck posture and gravitational load moment measurements were obtained in each posture. Sagittal head translation, upper cervical extension and load moment were significantly greater in the slouched posture (p < 0.001). Contrasting patterns of cervical and thoracic extensor activity were observed in the slouched and neutral postures, with cervical extensor activity 40% higher in the slouched posture (p < 0.0001). Thoracic extensor activity was significantly higher in the lumbo-pelvic neutral posture than the habitual posture (p = 0.002). The significant changes in extensor muscle activity with postural modification appear to be induced by the associated change in mechanical load moment of the head. STATEMENT OF RELEVANCE: More neutral sitting postures reduce the demand on the cervical extensor muscles and modify the relative contribution of cervical and thoracic extensors to the control of head and neck posture. Postures that promote these patterns of muscular activity may reduce cervical spine loading and the development of posture-related neck pain.

Long live A(me)rica! An examination of the interplay between nationalistic-symbolic immortality striving and belief in life after death.

Terror management theory (TMT) proposes that the awareness of our eventual death is at odds with our evolved desire to live and that humans attempt to resolve this psychological conflict by investing in cultural worldviews that grant symbolic or literal immortality. The present studies examine the interplay between symbolic and literal immortality striving. Three studies show that, following a death reminder, only individuals who did not have a route to literal immortality (belief in an afterlife) increased how long they believe their culture (Canada in Studies 1 and 2, the United States in Study 3), will last by thousands of years. Study 4 demonstrated that this moderation effect cannot be explained by general religiosity; Study 5 conceptually replicated this finding using a different measure of perceived cultural longevity. Finally, Study 6 demonstrates that for those who were highly invested in their nation but did not believe in an afterlife, perceived cultural longevity was associated with decreased death anxiety. These results are consistent with the notion that people possess a primary path to immortality that follows directly from their worldview. The need for increased specificity in study design in TMT and the threat and defense literature more broadly is discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Pediatric Workplace Learning Opportunities for Medical Students: Is Scribing a Win-Win?

This study examined if preclerkship medical students would find it educational to scribe in a pediatric setting. Scribing promoted students' learning about pediatric clinical encounters enhanced their competency with electronic health record use, and moderately reduced attending physician documentation burden.

A Typology of Food Environments in the Pacific Region and Their Relationship to Diet Quality in Solomon Islands.

Extensive literature describes the importance of food environments (FEs) as a driver of food choices and nutrition outcomes; yet existing FE frameworks do not adequately capture the diversity of FEs relevant to the Pacific Region. This limits identification of opportunities in food systems to reduce the multiple burden of malnutrition. We present a conceptual typology of FEs including six primary FEs relevant in the Pacific; wild; cultivated; kin and community; informal retail; formal retail; and food aid and services. We then apply this typology to food acquisition data from Solomon Islands 2012/13 Household Income and Expenditure Survey and analyse the relationship between FEs and diet quality. The cultivated FE accounts for 60% of the quantity of food acquired nationally, followed by wild (15%), kin and community (9%), and formal and informal retail FEs (8% each), with wide variation between urban and rural households, provinces and wealth groups. Reliance on different FEs is a significant predictor of diet quality and affirms the importance of subsistence fisheries and agriculture, and community and kinship networks. Integration of a FE typology such as the one presented here in commonly conducted household expenditure surveys offers significant opportunity to advance our understanding of food system leverage points to improve nutrition and health.

Samarium isotope compositions of uranium ore concentrates: A novel nuclear forensic signature.

Uranium ore is mined and milled to produce uranium ore concentrate (UOC), a regulated product of the nuclear fuel cycle. Diversion of UOC from the fuel cycle into possible weapons production is a key concern in global nonproliferation efforts. As such, the ability to trace the origin of seized nuclear materials is imperative to law enforcement efforts. Although isotopic signatures of UOCs have proven fruitful to pinpoint sample provenance, new isotopic signatures are needed because most existing isotopic signatures are not indicative of the original ore body from which the U is derived. In this work, we developed a new method to separate samarium (Sm) from a U-rich sample matrix and report the first Sm isotope compositions of 32 UOCs derived from a variety of worldwide uranium mines. Relative to terrestrial standards, approximately half the UOCs have resolved and anticorrelated 149Sm-150Sm isotope compositions, consistent with the capture of thermal neutrons by 149Sm in the ore body. The UOCs with anomalous Sm isotope compositions tend to derive from older (~>1.5Ga) and higher-grade ore bodies, although other factors, such as the presence of neutron moderators like water, also play a role. Nonetheless, the Sm isotope compositions of UOCs directly reflects the neutron fluence over the history of the original ore body and can be used to discern different geologic conditions associated with that ore body. As such, this work demonstrates the potential use of Sm isotopes as a novel nuclear forensics signature for origin assessment of UOCs.

IgE and IgG4 epitopes revealed on the major fish allergen Lat c 1.

BACKGROUND: The IgE- and IgG4-binding patterns of the major fish allergen parvalbumins are not clearly understood. IgE antibody-binding to parvalbumin from Asian seabass, Lat c 1.01, is implicated in up to 90 % of allergic reactions, although the region of IgE or IgG4 epitopes are unknown. In the present study, we characterized the specific IgE- and IgG4-binding regions of Lat c 1.01 using serum from pediatric and adult patients with clinically-confirmed fish allergy. METHODS: A comparative investigation of patient IgE- and IgG4-binding to recombinant Lat c 1.01 was performed by immunoblotting and indirect ELISA using serum from 15 children and eight adults with clinically confirmed IgE-mediated reactions to fish. The IgE- and IgG4-binding regions of Lat c 1.01 were determined by inhibition ELISA using seven overlapping peptides spanning the entire 102 amino acid sequence. Elucidated IgE-binding regions were modelled and compared to known antibody-binding regions of parvalbumins from five other fish species. RESULTS: Ninety five percent (22/23) patients demonstrated IgE-binding to rLat c 1.01, while fewer patients (10/15 children and 7/8 adults) demonstrated robust IgG4 binding when determined by immunoblots. IgE-binding for both cohorts was significantly higher compared to IgG4-binding by ELISA. All patients in this study presented individual IgE and IgG4 epitope-recognition profiles. In addition to these patient-specific antibody binding sites, general IgE epitopes were also identified at the C- and N-terminal regions of this major fish allergen. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings demonstrate two specific IgE epitopes on parvalbumin from Asian seabass, while IgG4 binding is much lower and patient specific. This study highlights the importance of advancement in epitope analysis regardless of the age group for diagnostics and immunotherapies for fish allergy.

Hit to lead studies on (hetero)arylpyrimidines--agonists of the canonical Wnt-beta-catenin cellular messaging system.

A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone.