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Background: Malaria is a significant parasitic infection, and human infection is mediated by mosquito (Anopheles) biting and subsequent transmission of protozoa (Plasmodium) to the blood. Carbonic anhydrases (CAs) are known to be highly expressed in the midgut and ectoperitrophic space of Anopheles gambiae. Transmembrane CAs (tmCAs) in Plasmodium may be potential vaccine candidates for the control and prevention of malaria. Methods: In this study, two groups of transmembrane CAs, including α-CAs and one group of η-CAs were analysed by immunoinformatics and computational biology methods, such as predictions on transmembrane localization of CAs from Plasmodium spp., affinity and stability of different HLA classes, antigenicity of tmCA peptides, epitope and proteasomal cleavage of Plasmodium tmCAs, accessibility of Plasmodium tmCAs MHC-ligands, allergenicity of Plasmodium tmCAs, disulfide-bond of Plasmodium tmCAs, B cell epitopes of Plasmodium tmCAs, and Cell type-specific expression of Plasmodium CAs. Results: Two groups of α-CAs and one group of η-CAs in Plasmodium spp. were identified to contain tmCA sequences, having high affinity towards MHCs, high stability, and strong antigenicity. All putative tmCAs were predicted to contain sequences for proteasomal cleavage in antigen presenting cells (APCs). Conclusions: The predicted results revealed that tmCAs from Plasmodium spp. can be potential targets for vaccination against malaria. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant ( p < 5 × 10) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic ( p = 0.012) and systolic ( p = 0.035) BP levels, as well as peripheral vascular resistance ( p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease. [ABSTRACT FROM AUTHOR]

Killer cell immunoglobulin-like receptors (KIRs) influence the outcome of haematopoetic stem cell transplantation by modulating the cytotoxic ability of natural killer (NK) cells and a subset of T cells. KIRs are also highly polymorphic and could therefore be good population genetic markers, much like their human leukocyte antigen (HLA) ligands. This study represents the first report on distribution of 16 KIR genes in 162 unrelated healthy Saudi individuals. All the 16 KIR genes were observed in the studied population and the four framework genes ( KIR2DL4, 3DL2, 3DL3 and 3DP1) were present in all individuals. Forty- one distinct KIR profiles were expressed in our population, 11 of which had not been previously described in other populations including the Middle Eastern population. AA1, the most common genotypic profile was observed at a frequency of 26.5%. The group A haplotype was more frequent (53%) in the Saudi population compared to the group B haplotype (47%). The pattern of the inhibitory KIR/HLA ligands were also analyzed and 52.3% of the Saudi population was found to express two pairs of the inhibitory KIR/HLA-C. The KIR gene frequencies suggests that the Saudi population shares common general features with the Middle Eastern and other populations, but still has its own unique frequencies of several KIR loci. [ABSTRACT FROM AUTHOR]

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4–4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity. [ABSTRACT FROM AUTHOR]

Background: Extensive allelic matching in the human leukocyte antigen (HLA) genes is regarded as a prerequisite for good clinical success of allogeneic haematopoietic stem cell transplantation (HSCT). Also other genetic factors can be assumed to play a role in preventing and controlling the complications associated with allogeneic HSCT, in particular graft-versus-host disease (GvHD). Interleukin-10 (IL-10) and its receptor (IL-10R), key regulators of the immune response, are among these candidates. We studied the association of IL-10 and IL-10Rβ gene polymorphisms with the occurrence of GvHD in 309 HLA-identical sibling donor and recipient pairs. Results: The difference in genotypic IL-10 production between patient and donor in combination with patient IL-10Rβ A/A genotype predisposed strongly to acute GvHD (OR = 7.15, p = 0.000023). On the other hand, a combination of same genotypic IL-10 production with patient IL-10Rβ A/A genotype protected from chronic GvHD (OR = 0.407, p = 0.0097). Conclusion: Our results suggest that IL-10 and IL-10Rβ genes have a synergistic effect on the risk of GvHD. [ABSTRACT FROM AUTHOR]

Background: Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world.Methods: A retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic.Results: A total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004).Conclusion: The diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population. [ABSTRACT FROM AUTHOR]

Background: Early patient contacts are considered important in medical education. Aims: We studied the influence of a real patient trigger on study motivation and learning in problem-based study groups of first-year medical and dentistry students. Methods: 156 eligible students were allocated into 17 groups. Six randomly selected groups received both the real patient and paper trigger, and 11 groups received only the paper trigger. The immediate and later effects of the trigger were assessed with qualitative and quantitative questionnaires and exam scores. The tutors answered questionnaires concerning learning outcomes. Results: The students reported that the real patient trigger significantly improved their study motivation, understanding of the learning objectives and confidence in future patient encounters. The real patient trigger was considered significantly more interesting than the paper case. No statistically significant difference was observed in the exam scores. The tutors observed that groups with poor previous performance gained better results in study sessions. Conclusions: Real patient triggers motivate students to learn basic medical sciences. Ways to present real patients to students should be considered in medical curricula from early on. [ABSTRACT FROM AUTHOR]

The avidin protein family members are well known for their high affinity towards D-biotin and high structural stability. These properties make avidins valuable tools for a wide range of biotechnology applications. We have identified a new member of the avidin family in the zebrafish (Danio rerio) genome, hereafter called zebavidin. The protein is highly expressed in the gonads of both male and female zebrafish and in the gills of male fish, but our data suggest that zebavidin is not crucial for the developing embryo. Biophysical and structural characterisation of zebavidin revealed distinct properties not found in any previously characterised avidins. Gel filtration chromatography and native mass spectrometry suggest that the protein forms dimers in the absence of biotin at low ionic strength, but assembles into tetramers upon binding biotin. Ligand binding was analysed using radioactive and fluorescently labelled biotin and isothermal titration calorimetry. Moreover, the crystal structure of zebavidin in complex with biotin was solved at 2.4 Å resolution and unveiled unique ligand binding and subunit interface architectures; the atomic-level details support our physicochemical observations. [ABSTRACT FROM AUTHOR]