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Life Science Alliance Aug 2024Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the...
Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of (SOD1)- and in particular (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.
Topics: Humans; Amyotrophic Lateral Sclerosis; RNA-Binding Protein FUS; Glycolates; Mitochondria; Protein Deglycase DJ-1; Lactic Acid; Superoxide Dismutase-1; Membrane Potential, Mitochondrial; Motor Neurons; Lysosomes
PubMed: 38760174
DOI: 10.26508/lsa.202302535 -
BMJ Open May 2024DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in...
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.
INTRODUCTION
DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.
METHODS AND ANALYSIS
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.
ETHICS AND DISSEMINATION
The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.
TRIAL REGISTRATION NUMBER
NCT05667766.
Topics: Humans; Child; Drug-Related Side Effects and Adverse Reactions; Pharmacogenetics; Prospective Studies; Randomized Controlled Trials as Topic; Neoplasms; Multicenter Studies as Topic; Precision Medicine; Hematopoietic Stem Cell Transplantation
PubMed: 38760050
DOI: 10.1136/bmjopen-2024-085115 -
BMJ Open May 2024Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality. Often little is known... (Observational Study)
Observational Study
INTRODUCTION
Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality. Often little is known about expected growth and phenotypes in these children. Parents have responded by setting up social media groups to generate data themselves. Given the significant clinical evidence gaps, this research will attempt to identify growth patterns, developmental profiles and phenotypes, providing data on long-term medical and educational outcomes. This will guide clinicians when to investigate, monitor or treat symptoms and when to search for additional or alternative diagnoses.
METHODS AND ANALYSIS
This is an observational, multicentre cohort study recruiting between March 2023 and February 2026. Children aged 6 months up to 16 years with a pathogenic or likely pathogenic variant in a specified gene will be eligible. Children will be identified through the National Health Service and via self-recruitment. Parents or carers will complete a questionnaire at baseline and again 1 year after recruitment. The named clinician (in most cases a clinical geneticist) will complete a clinical proforma which will provide data from their most recent clinical assessment. Qualitative interviews will be undertaken with a subset of parents partway through the study. Growth and developmental milestone curves will be generated through the DECIPHER website (https://deciphergenomics.org) where 5 or more children have the same genetic syndrome (at least 10 groups expected).
ETHICS AND DISSEMINATION
The results will be presented at national and international conferences concerning the care of children with genetic syndromes. Results will also be submitted for peer review and publication.
Topics: Humans; Rare Diseases; Child; Child, Preschool; United Kingdom; Infant; Adolescent; Research Design; Female; Male; Observational Studies as Topic; Neurodevelopmental Disorders; Cohort Studies; Multicenter Studies as Topic; Genetic Diseases, Inborn; Quality Improvement; Parents
PubMed: 38760043
DOI: 10.1136/bmjopen-2024-085237 -
Cell Reports Methods May 2024Organoids, self-organizing three-dimensional (3D) structures derived from stem cells, offer unique advantages for studying organ development, modeling diseases, and... (Review)
Review
Organoids, self-organizing three-dimensional (3D) structures derived from stem cells, offer unique advantages for studying organ development, modeling diseases, and screening potential therapeutics. However, their translational potential and ability to mimic complex in vivo functions are often hindered by the lack of an integrated vascular network. To address this critical limitation, bioengineering strategies are rapidly advancing to enable efficient vascularization of organoids. These methods encompass co-culturing organoids with various vascular cell types, co-culturing lineage-specific organoids with vascular organoids, co-differentiating stem cells into organ-specific and vascular lineages, using organoid-on-a-chip technology to integrate perfusable vasculature within organoids, and using 3D bioprinting to also create perfusable organoids. This review explores the field of organoid vascularization, examining the biological principles that inform bioengineering approaches. Additionally, this review envisions how the converging disciplines of stem cell biology, biomaterials, and advanced fabrication technologies will propel the creation of increasingly sophisticated organoid models, ultimately accelerating biomedical discoveries and innovations.
PubMed: 38759654
DOI: 10.1016/j.crmeth.2024.100779 -
Stem Cell Reports May 2024Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate... (Review)
Review
Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.
PubMed: 38759644
DOI: 10.1016/j.stemcr.2024.04.008 -
Poultry Science Apr 2024Individual differences in free-range chicken systems are important factors influencing how birds use the range (or not), even if individuals are reared in the same...
Individual differences in free-range chicken systems are important factors influencing how birds use the range (or not), even if individuals are reared in the same environmental conditions. Here, we investigated how various aspects of the birds' behavioral and cognitive tendencies, including their optimism/pessimism, cognitive flexibility, sociability, and exploration levels, are associated with range use and how they may change over time (before and after range access). To achieve this, 100 White Leghorn laying hen chicks underwent three distinct behavioral/cognitive tests-the cognitive bias test, the detour test, and the multivariate test-prior to gaining access to the range, between 9 and 39 days of age. After range access was allowed (from day 71), birds' range use was evaluated over 7 nonconsecutive days (from 74-91 days of age). Subsequently, a subset of birds, classified as high rangers (n = 15) and low rangers (n = 15) based on their range use, underwent retesting on the same three previous tests between 94 and 108 days of age. Our results unveiled a negative correlation trend between birds' evaluation of the ambiguous cue and their subsequent range use (rho = -0.19, p = 0.07). Furthermore, low rangers were faster to learn the detour task (χ2 = 7.34, df = 1, p = 0.006), coupled with increased sociability during the multivariate test (rho = -0.23, p = 0.02), contrasting with their high-ranging counterparts, who displayed more exploratory behaviors (F[1,27] = 3.64, p = 0.06). These behavioral patterns fluctuated over time (before and after range access); however, conclusively attributing these changes to birds' aging and development or the access to the range remains challenging. Overall, our results corroborate that behavioral and cognitive individual differences may be linked to range use and offer novel perspectives on the early behavioral and cognitive traits that may be linked to range use. These findings may serve as a foundation for adapting environments to meet individual needs and improve animal welfare in the future.
PubMed: 38759569
DOI: 10.1016/j.psj.2024.103813 -
Performance and economic efficiency of laying hens in response to adding zeolite to feed and litter.Poultry Science Apr 2024This study investigated the effect of different levels of zeolite in laying hen (Silver Montazah) diet and litter on productive performance, egg quality criteria, and...
This study investigated the effect of different levels of zeolite in laying hen (Silver Montazah) diet and litter on productive performance, egg quality criteria, and economics during the second stage of production (40-56 wk of age). An experiment with a 3 × 4 factorial design was performed to study the effects of four levels of zeolite (0, 10, 15, and 20 g/kg feed) in the diet and three levels of zeolite (0, 1.5, and 2 kg/m) in the litter. Adding zeolite to diet and litter significantly improved final BW and BW change, egg number, egg weight, egg mass, laying rate, feed consumption (FC), and feed conversion ratio (FCR), as well as egg quality criteria when compared to the unsupplemented group. Additionally, adding zeolite at a level of 2 kg /m litter and 20 g/kg diet achieved the greatest enhancement in productive performance features. Therefore, it can be suggested that the greatest results were obtained in laying farms when zeolite was added as a litter addition and as a supplement to feed.
PubMed: 38759566
DOI: 10.1016/j.psj.2024.103799 -
Neoplasia (New York, N.Y.) May 2024Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of...
Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.
PubMed: 38759377
DOI: 10.1016/j.neo.2024.101003 -
Parasite (Paris, France) 2024In the last few years, the number of studies on feline hepatozoonosis has increased, but our knowledge on the actual species of Hepatozoon and/or different genotypes...
In the last few years, the number of studies on feline hepatozoonosis has increased, but our knowledge on the actual species of Hepatozoon and/or different genotypes affecting felines is still incipient. At least three species, namely Hepatozoon felis, H. canis, and H. silvestris, have been isolated from domestic cats in various countries. Additionally, there are indications that other species and genotypes may affect felines in given geographic areas. This study was carried out to investigate the occurrence of Hepatozoon spp. in cats from Niterói, a municipality within the metropolitan area of Rio de Janeiro, Brazil. Individual blood samples were collected from 28 cats enrolled in a spaying/castration program. DNA was extracted from all samples and subjected to sequencing specific for Hepatozoon spp. DNA of H. felis was found in 21/28 cats (75%), and four genetic polymorphisms never described thus far were detected. This is the first report of H. felis in cats living in the State of Rio de Janeiro, and the present data confirm that H. felis is a species complex encompassing different genotypes circulating within cat populations. Further studies are warranted to investigate whether different genotypes have different biology or pathogenicity for felids.
Topics: Animals; Cats; Brazil; Cat Diseases; Coccidiosis; Eucoccidiida; Male; DNA, Protozoan; Female; Genotype; Polymorphism, Genetic; Phylogeny
PubMed: 38759154
DOI: 10.1051/parasite/2024026 -
Parasite (Paris, France) 2024Eimeria tenella is an obligate intracellular parasite which causes great harm to the poultry breeding industry. Protein phosphorylation plays a vital role in host...
Quantitative phosphoproteomic analysis of chicken DF-1 cells infected with Eimeria tenella, using tandem mass tag (TMT) and parallel reaction monitoring (PRM) mass spectrometry.
Eimeria tenella is an obligate intracellular parasite which causes great harm to the poultry breeding industry. Protein phosphorylation plays a vital role in host cell-E. tenella interactions. However, no comprehensive phosphoproteomic analyses of host cells at various phases of E. tenella infection have been published. In this study, quantitative phosphoproteomic analysis of chicken embryo DF-1 fibroblasts that were uninfected (UI) or infected with E. tenella for 6 h (PI6, the early invasion phase) or 36 h (PI36, the trophozoite development phase) was conducted. A total of 10,122 phosphopeptides matched to 3,398 host cell phosphoproteins were identified and 13,437 phosphorylation sites were identified. Of these, 491, 1,253, and 275 differentially expressed phosphorylated proteins were identified in the PI6/UI, PI36/UI, and PI36/PI6 comparisons, respectively. KEGG pathway enrichment analysis showed that E. tenella modulated host cell processes through phosphorylation, including focal adhesion, regulation of the actin cytoskeleton, and FoxO signaling to support its early invasion phase, and modulating adherens junctions and the ErbB signaling pathway to favor its trophozoite development. These results enrich the data on the interaction between E. tenella and host cells and facilitate a better understanding of the molecular mechanisms underlying host-parasite relationships.
Topics: Animals; Eimeria tenella; Chickens; Proteomics; Phosphoproteins; Tandem Mass Spectrometry; Phosphorylation; Fibroblasts; Cell Line; Poultry Diseases; Host-Parasite Interactions; Coccidiosis; Chick Embryo; Signal Transduction
PubMed: 38759153
DOI: 10.1051/parasite/2024027