Characterization of taxonomically restricted genes in a phylum-restricted cell type

Computational and functional genomic analyses in Hydra magnipapillata suggest that taxonomically-restricted genes are involved in the evolution of morphological novelties such as the cnidarian nematocyt

The time consuming nature of phenylketonuria: A cross-sectional study investigating time burden and costs of phenylketonuria in the Netherlands

Abstract Background Phenylketonuria (PKU) is a rare inborn error of metabolism that affects the ability of patients to metabolise phenylalanine (Phe). Lifelong management of blood Phe levels is required in order to avoid the complications associated with PKU. This constitutes a severely protein restricted diet, and regular monitoring of Phe levels. Management of PKU may be costly and time-consuming for adult patients or caregivers of PKU-affected children. A cross-sectional study was performed with patients or their caregivers in the Netherlands to gain insight into the personal time burden and cost of living with PKU. Methods A systematic literature review was performed to identify all aspects of PKU management that may pose a financial or time burden on patients or caregivers. Findings were confirmed through interviews with PKU experts and feedback from patients and caregivers, and consolidated into a questionnaire that aimed to evaluate the impact of each of these factors. Early and continuously treated adult patients and caregivers from seven metabolic centres were recruited to complete the questionnaire online. Results 22 adult patients and 24 caregivers participated in the study. Managing a Phe-restricted diet represented an extra time burden of 1 h and 24 min for caregivers and 30 min for adult patients per day. Caregivers reported a significantly higher time burden than adult patients. The median total out-of-pocket cost (OOPC) for patients was €604 annually, with 99% of expenditure on low-protein food products. Greater disease severity was significantly associated with increased OOPC and time burden for both adult patients and caregivers. Conclusions Management of PKU is associated with a considerable time burden for both caregivers of children with PKU and adult patients. Caregivers of PKU-affected children reported a significantly higher time burden than adult patients. The OOPC of caregivers and patients was mainly driven by the expenditure on low protein food

Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab

Background Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesized that common germline variants within these pathways may also play similar roles. Methods We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy +cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. Results We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab - in patients with KRAS wild type CRCs, 36.4% of patients with one allele encoding proline responded, as compared to 71.2% of patients homozygous for alleles encoding serine (OR 0.23, 95% CI 0.09-0.56, P=0.0014) and this association was predictive for cetuximab (Pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. Conclusions Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity

Empirical approaches for investigating the origins of structure in speech

© John Benjamins Publishing Company. In language evolution research, the use of computational and experimental methods to investigate the emergence of structure in language is exploding. In this review, we look exclusively at work exploring the emergence of structure in speech, on both a categorical level (what drives the emergence of an inventory of individual speech sounds), and a combinatorial level (how these individual speech sounds emerge and are reused as part of larger structures). We show that computational and experimental methods for investigating population-level processes can be effectively used to explore and measure the effects of learning, communication and transmission on the emergence of structure in speech. We also look at work on child language acquisition as a tool for generating and validating hypotheses for the emergence of speech categories. Further, we review the effects of noise, iconicity and production effects

Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer

We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumor-specific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken

Galactokinase deficiency:lessons from the GalNet registry

PURPOSE Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. METHODS Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020. RESULTS Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17-5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial. CONCLUSION The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed

Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

The appearance of multi-drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross-reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging-particularly in the most dangerous malaria parasite, Plasmodium falciparum. Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials

A Delphi Survey Study to Formulate Statements on the Treatability of Inherited Metabolic Disorders to Decide on Eligibility for Newborn Screening

The Wilson and Jungner (W&amp;J) and Andermann criteria are meant to help select diseases eligible for population-based screening. With the introduction of next-generation sequencing (NGS) methods for newborn screening (NBS), more inherited metabolic diseases (IMDs) can technically be included, and a revision of the criteria was attempted. This study aimed to formulate statements and investigate whether those statements could elaborate on the criterion of treatability for IMDs to decide on eligibility for NBS. An online Delphi study was started among a panel of Dutch IMD experts (EPs). EPs evaluated, amended, and approved statements on treatability that were subsequently applied to 10 IMDs. After two rounds of Delphi, consensus was reached on 10 statements. Application of these statements selected 5 out of 10 IMDs proposed for this study as eligible for NBS, including 3 IMDs in the current Dutch NBS. The statement: ‘The expected benefit/burden ratio of early treatment is positive and results in a significant health outcome’ contributed most to decision-making. Our Delphi study resulted in 10 statements that can help to decide on eligibility for inclusion in NBS based on treatability, also showing that other criteria could be handled in a comparable way. Validation of the statements is required before these can be applied as guidance to authorities.</p