Genetics of immunoglobulin a deficiency

Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasian populations. It is defined as a serum IgA level below 0.07 g/L with normal IgM and IgG levels in an individual older than four years of age. Approximately one-third of these patients present with recurrent respiratory and gastrointestinal tract infections, allergic disorders and autoimmune manifestations. High familial clustering and prevalence variation by ethnicity both suggest the existence of a strong genetic component of the disease. Traditionally, IgAD has been reported as permanent, and sub-normal IgA levels remain static and persist after 20 years of observation. However, a few cases of reversion have been observed. We thus investigated the frequency of reversal in children and more than one-fifth (>20%) of Swedish children who were diagnosed before 10 years of age, reversed their IgAD status. Our observation suggests that the diagnosis of IgAD should not be made before the early teens using a cutoff level of 0.07 g/L of IgA in serum. After suggesting improved diagnostic guidelines, we investigated the role of genetics in IgAD in a Swedish Twin cohort. Surprisingly, the prevalence of IgAD was found to be markedly increased in a twin cohort as compared with the normal Swedish adult population. Although the MHC is the main genetic factor associated with IgAD development, the MHC haplotypes were not the primary factor causing the differences observed. Nonetheless, risk-conveying MHC haplotypes including HLA-A*01, HLA-B*08 and HLA-DRB1*01 were found to be associated with significantly lower serum IgA concentration in the twin cohort. On the contrary, individuals who carried the protective HLA alleles B*07, DRB1*15 and DQB1*06 were found to have significantly higher mean IgA concentration. We then performed a comprehensive analysis within the MHC region in order to identify the potential susceptibility genes/loci within the MHC region. In our large-scale case-control study, we identified an independent MHC haplotype (HLA-DPB1*1301) in the class II region associated with IgAD. In addition, MHC recombination analysis suggested a region around 110 Kbp which may contain a portion of the ancestral block. However, verification using complete sequencing did not identify any differences. Nonetheless, identification of 4310 new variants from ancestral 8.1 haplotypes will provide valuable information for the investigation of other MHC associated diseases. We also identified novel genes/variants within the MHC class III region including AGER (rs1800625), RNF5 (rs3130349), BTNL2 (rs1980493) and HCG23 (rs3117097) that are associated with IgAD risk. Subsequently, we investigated the association of non-MHC genes using different MHC risk haplotypes as category factors. In total, 14 different genes/loci were identified as potentially associated with IgAD in individuals carrying different MHC risk alleles, including one from HLA-B*0801-DRB1*0301-DQB1*0201 (ancestral haplotype), three from the HLA-DRB1*0701-DQB1*0202 cohort, two from HLA-DRB1*01-DQB1*0501 and seven from patients who do not carry any susceptibility MHC allele. These findings suggest that the development of IgAD may be variable depending on the presence of potentially different genes within selected MHC susceptibility haplotypes that interact with the respective disease-causing non-MHC genes. Understanding the interaction between MHC and non-MHC genes and proteins may facilitate identification of the IgAD etiology. In summary, this thesis not only helped to identify the genetic basis of IgAD, but also improved the current diagnostic definition of the disease. Further work, including protein-protein interaction investigations, gene knock-in/out and expression analyses are required to validate the functional role of the novel associations described in this thesis. As IgAD has been shown to be markedly overrepresented among patients with autoimmune diseases, further potential studies will aim to identify the link between IgAD and autoimmunity which may ultimately result in improved patient care

Studies of Wilms’ Tumor (WT1) Gene Expression in Adult Acute Leukemias in Singapore

Biomarkers provide certain values for diagnosis, monitor treatment efficacy, or for the development of novel therapeutic approach for particular diseases. Thus, the identification of specific of biomarkers for specific medical problems, including malignant diseases may be valuable in medical practice. In the study, we have used the Wilms’ tumor gene (WT1) as a biomarker to evaluate its expression in local adult patients with newly diagnosed acute leukemia, including both acute myeloid and lymphoid leukemias (AML and ALL)

Gold nanoparticles conjugated with anti-CD133 monoclonal antibody and 5-fluorouracil chemotherapeutic agent as nanocarriers for cancer cell targeting

The enhanced permeability and retention effect allows for passive targeting of solid tumours by nanoparticles carrying anticancer drugs. However, active targeting by incorporation of various ligands onto nanoparticles can provide for a more selective and enhanced chemotherapeutic effect and complement the deficiencies of the passive targeting approach. Here we report on the design of the carboxyl-terminated PEGylated gold nanoparticles (AuNPs), their functionalization with anti-CD133 monoclonal antibody (mAb) via a crosslinking reaction, and subsequent 5-fluorouracil (5-FU) drug loading. The synthesized products in the form of stable colloids were characterised using a range of physicochemical techniques, including X-ray diffraction (XRD), UV-Vis spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Conjugation of anti-CD133 mAb onto PEGylated AuNPs was confirmed with the use of UV-Vis, BCA protein assay and fluorescence microscopy. HCT116 colorectal cancer cells abundantly expressed CD133: 92.4 ± 1.3%, as measured by flow cytometry. Whereas PEGylated AuNPs not conjugated with anti-CD133 mAb accumulated mainly at the cellular membrane, nanoparticles conjugated with anti-CD133 mAb were contained within the nuclear region of the cells. Anti-CD133 mAb conjugation facilitated the specific intracellular uptake due to specific antigen–antibody binding interaction. In vitro cytotoxicity studies on HCT116 cells showed that PEGylated AuNPs and PEGylated AuNPs-CD133 did not elicit any toxicity at any of the tested concentrations. Meanwhile, 5-FU-PEGylated AuNPs-CD133 significantly reduced the cell viability relative to the treatment with 5-FU-PEGylated AuNPs without anti-CD133 mAb conjugates (p < 0.0001). This study shows that the conjugation of nanocarriers with the anti-CD133 antibody improves the specific targeting of 5-FU against colorectal cancer cells. These results demonstrate that simultaneous functionalisation of PEGylated AuNPs with antibodies and chemotherapeutic drugs is a viable strategy to combat cancer through targeted drug delivery

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Progress and prospects for event tourism research

This paper examines event tourism as a field of study and area of professional practice updating the previous review article published in 2008. In this substantially extended review, a deeper analysis of the field’s evolution and development is presented, charting the growth of the literature, focusing both chronologically and thematically. A framework for understanding and creating knowledge about events and tourism is presented, forming the basis which signposts established research themes and concepts and outlines future directions for research. In addition, the review article focuses on constraining and propelling forces, ontological advances, contributions from key journals, and emerging themes and issues. It also presents a roadmap for research activity in event tourism

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Muon reconstruction and identification efficiency in ATLAS using the full Run 2 pp collision data set at \sqrt{s}=13 TeV

This article documents the muon reconstruction and identification efficiency obtained by the ATLAS experiment for 139 \hbox {fb}^{-1} of pp collision data at \sqrt{s}=13 TeV collected between 2015 and 2018 during Run 2 of the LHC. The increased instantaneous luminosity delivered by the LHC over this period required a reoptimisation of the criteria for the identification of prompt muons. Improved and newly developed algorithms were deployed to preserve high muon identification efficiency with a low misidentification rate and good momentum resolution. The availability of large samples of Z\rightarrow \mu \mu and J/\psi \rightarrow \mu \mu decays, and the minimisation of systematic uncertainties, allows the efficiencies of criteria for muon identification, primary vertex association, and isolation to be measured with an accuracy at the per-mille level in the bulk of the phase space, and up to the percent level in complex kinematic configurations. Excellent performance is achieved over a range of transverse momenta from 3 GeV to several hundred GeV, and across the full muon detector acceptance of |\eta |<2.7