Small Molecule Regulation of Iron Homeostasis: Design and Optimization of Novel Iron Chelators Based on a Thiosemicarbazone Scaffold.

Disrupted iron balance causes anemia and iron overload leading to hypoxia and systemic oxidative stress. Iron overload may arise from red blood cell disorders such as sickle cell disease, thalassemia major and primary hemochromatosis, or from treatment with multiple transfusions. These hematological disorders are characterized by constant red blood cell hemolysis and the release of iron.

Fat cadherin cleavage releases a transcriptionally active nuclear fragment to regulate target gene expression.

The conserved atypical cadherin fat (ft) controls cellular processes such as growth, planar cell polarity, and mitochondrial function, in organisms ranging from fruit flies to mammals. Working at the apical-junctional plasma membrane the intracellular domain of the Ft protein, FtICD, binds to and regulates components of the Hippo and PCP pathways. Unexpectedly, we show that FtICD is present in the nucleus in cultured cells as well as in embryonic and larval tissues, and identify nuclear localization and nuclear export signals in FtICD required for this localization.

Syntheses and structures of dinuclear zinc(II) acetate-bridged coordination compounds with the aromatic Schiff base chelators ,-dimethyl-2-[phen-yl(pyridin-2-yl)methyl-idene]hydrazine-1-carbothio-amide and -ethyl-2-[phen-yl(pyridin-2-yl)methyl-idene]hydrazine-1-carbo-thio-amide.

In the centrosymmetric title complexes, di-μ-acetato-bis({,-dimethyl-2-[phenyl(pyridin-2-yl)methylidene]hydrazine-1-carbothioamidato}zinc(II)), [Zn(CHNS)(CHO)] (), and di-μ-acetato-bis({-ethyl-2-[phenyl(pyridin-2-yl)methylidene]hydrazine-1-carbothioamidato}zinc(II)), [Zn(CHNS)(CHO)] (), the zinc ions are chelated by the ,,-tridentate ligands and bridged by pairs of acetate ions. The acetate ion in () is disordered over two orientations in a 0.756 (6):0.

Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.

Background: RNA sequencing (RNA-seq) is emerging as a valuable tool for identifying disease-causing RNA transcript aberrations that cannot be identified by DNA-based testing alone. Previous studies demonstrated some success in utilizing RNA-seq as a first-line test for rare inborn genetic conditions. However, DNA-based testing (increasingly, whole genome sequencing) remains the standard initial testing approach in clinical practice.

Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing.

Despite advances in genome sequencing, many individuals with rare genetic disorders remain undiagnosed. Transcriptional profiling via RNA-seq can reveal functional impacts of DNA variants and improve diagnosis. We assessed blood-derived RNA-seq in the largely undiagnosed SickKids Genome Clinic cohort (n = 134), which has been subjected to multiple analyses benchmarking the utility of genome sequencing.

Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-kB binding.

Transposable elements (TEs) provide a source of transcription factor (TF) binding sites that can rewire gene regulatory networks. NF-kB is an evolutionarily conserved TF complex primarily involved in innate immunity and inflammation. The extent to which TEs have contributed to NF-kB responses during mammalian evolution is not well established.

Extracellular Vesicle Abundance, but Not a High Aggregation-Prone Peptide Cargo, Is Associated with Dihydroartemisinin Exposure in .

Our understanding of the molecular mechanisms undergirding artemisinin (ART) resistance in is currently based on two organizing principles: reduced hemoglobin trafficking into the digestive food vacuole, resulting in lower levels of activated ART, and increased tolerance to ART-induced oxidative stress in the infected erythrocyte. We had previously proposed an extracellular vesicle (EV) export model of ART resistance in . This model predicts that EV abundance will be altered by ART exposure and that the peptide cargo of EVs from the ART-exposed condition will be enriched with aggregation-prone peptides.

Functional and molecular single-cell analyses implicate PRDM14 in the initiation of B cell leukemia in mice.

The transcription factor Prdm14 is a potent oncogene implicated in the initiation of many cancers. PRDM14 resets and maintains the pluripotent state in normal cells, but the molecular mechanisms through which PRDM14 drives oncogenesis are poorly understood. Here, we interrogated the heterogeneity of Prdm14-expressing cells in a T cell lymphoblastic leukemia/lymphoma mouse model.

iModEst: disentangling -omic impacts on gene expression variation across genes and tissues.

Many regulatory factors impact the expression of individual genes including, but not limited, to microRNA, long non-coding RNA (lncRNA), transcription factors (TFs), methylation, copy number variation (CNV), and single-nucleotide polymorphisms (SNPs). While each mechanism can influence gene expression substantially, the relative importance of each mechanism at the level of individual genes and tissues is poorly understood. Here, we present the integrative Models of Estimated gene expression (iModEst), which details the relative contribution of different regulators to the gene expression of 16,000 genes and 21 tissues within The Cancer Genome Atlas (TCGA).

Investigating Environmental Determinants of Hookworm Transmission using GPS Tracking and Metagenomics Technologies.

To identify potential sources of hookworm infections in a Ghanaian community of endemicity that could be targeted to interrupt transmission, we tracked the movements of infected and noninfected persons to their most frequented locations. Fifty-nine participants (29 hookworm positives and 30 negatives) wore GPS trackers for 10 consecutive days. Their movement data were captured in real time and overlaid on a community grid map.

LINE1 elements at distal junctions of rDNA repeats regulate nucleolar organization in human embryonic stem cells.

The nucleolus is a major subnuclear compartment where ribosomal DNA (rDNA) is transcribed and ribosomes are assembled. In addition, recent studies have shown that the nucleolus is a dynamic organizer of chromatin architecture that modulates developmental gene expression. rDNA gene units are assembled into arrays located in the p-arms of five human acrocentric chromosomes.

repeat expansion creates the unstable folate-sensitive fragile site FRA9A.

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and , is linked to multiple diseases. (GGGGCC)n expansions (Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown.

An updated reference genome sequence and annotation reveals gene losses and gains underlying naked mole-rat biology.

The naked mole-rat (NMR; ) is a eusocial subterranean rodent with a highly unusual set of physiological traits that has attracted great interest amongst the scientific community. However, the genetic basis of most of these traits has not been elucidated. To facilitate our understanding of the molecular mechanisms underlying NMR physiology and behaviour, we generated a long-read chromosomal-level genome assembly of the NMR.

expansion creates the unstable folate-sensitive fragile site FRA9A.

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and is linked to multiple diseases. (GGGGCC)n expansions ( Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown.

Inter-chromosomal contacts demarcate genome topology along a spatial gradient.

Non-homologous chromosomal contacts (NHCCs) between different chromosomes participate considerably in gene and genome regulation. Due to analytical challenges, NHCCs are currently considered as singular, stochastic events, and their extent and fundamental principles across cell types remain controversial. We develop a supervised and unsupervised learning algorithm, termed Signature, to call NHCCs in Hi-C datasets to advance our understanding of genome topology.

Age, sex, and cell type-resolved hypothalamic gene expression across the pubertal transition in mice.

Background: The hypothalamus plays a central role in regulating puberty. However, our knowledge of the postnatal gene regulatory networks that control the pubertal transition in males and females is incomplete. Here, we investigate the age-, sex- and cell-type-specific gene regulation in the hypothalamus across the pubertal transition.

Autosomal-dominant macular dystrophy linked to a chromosome 17 tandem duplication.

Hereditary macular dystrophies (HMDs) are a genetically diverse group of disorders that cause central vision loss due to photoreceptor and retinal pigment epithelium (RPE) damage. We investigated a family with a presumed novel autosomal-dominant HMD characterized by faint, hypopigmented RPE changes involving the central retina. Genome and RNA sequencing identified the disease-causing variant to be a 560 kb tandem duplication on chromosome 17 [NC_000017.

Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment.

Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs.

Mid-term outcomes using a 'kinematic retaining' total knee replacement - A multicentre prospective study at five years follow-up.

Background: Although total knee replacement (TKR) surgery has succeeded in improving pain and deformity, a proportion of patients remain incompletely satisfied with their outcome. This prospective study aims to assess the survivorship, clinical, and radiological outcomes using a novel 'kinematic retaining' (KR) implant.

Methods: 156 patients underwent TKR surgery for primary osteoarthritis using the Physica KR implant at three European Centres.

A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods.

Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to American College of Medical Genetics/Association for Molecular Pathology criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes are poorly understood. We identified 168 rare CSSVs in blood-expressed genes in 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq).

Molecular identification of Crimean-Congo haemorrhagic fever virus in Hyalomma rufipes and Amblyomma variegatum in the Upper East Region of Ghana.

Sampled ticks were screened for Crimean-Congo haemorrhagic fever virus (CCHFV) using an assay that targets the nucleoprotein gene region of the S segment, a conserved region of the CCHFV genome. Minimum infection rates of 0.34% and 0.

Biting behaviour, spatio-temporal dynamics, and the insecticide resistance status of malaria vectors in different ecological zones in Ghana.

Background: A significant decrease in malaria morbidity and mortality has been attained using long-lasting insecticide-treated nets and indoor residual spraying. Selective pressure from these control methods influences changes in vector bionomics and behavioural pattern. There is a need to understand how insecticide resistance drives behavioural changes within vector species.

Have outcomes of trauma in centenarians changed in the last 15 years?

Background: Centenarians are an often forgotten and under-reported group. Trauma in this population is a substantial cause of morbidity and mortality. 15 years ago, a small observational study examined the outcomes of trauma in centenarians in a single trauma unit, concluding that age alone should not be a determinant of treatment.