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EMBO Reports Mar 2024The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID)...
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.
Topics: Humans; Mice; Animals; Intellectual Disability; Repressor Proteins; Mental Retardation, X-Linked; Epilepsy; Transcription Factors; Obesity; Face; Hypogonadism; Growth Disorders; Fingers
PubMed: 38429579
DOI: 10.1038/s44319-024-00082-0 -
Haematologica Feb 2024Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding...
Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and about 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF. We demonstrate that UBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that UBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem celllike programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.
PubMed: 38426285
DOI: 10.3324/haematol.2023.284683 -
Neurobiology of Aging May 2024Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose...
Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.
Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.
Topics: Humans; Frontotemporal Dementia; Magnetic Resonance Imaging; Positron-Emission Tomography; Pick Disease of the Brain; Frontal Lobe; Brain; Neuropsychological Tests
PubMed: 38422798
DOI: 10.1016/j.neurobiolaging.2024.01.015 -
PLoS Pathogens Feb 2024Trypanosomatid parasites undergo developmental regulation to adapt to the different environments encountered during their life cycle. In Trypanosoma brucei, a genome...
Trypanosomatid parasites undergo developmental regulation to adapt to the different environments encountered during their life cycle. In Trypanosoma brucei, a genome wide selectional screen previously identified a regulator of the protein family ESAG9, which is highly expressed in stumpy forms, a morphologically distinct bloodstream stage adapted for tsetse transmission. This regulator, TbREG9.1, has an orthologue in Trypanosoma congolense, despite the absence of a stumpy morphotype in that parasite species, which is an important cause of livestock trypanosomosis. RNAi mediated gene silencing of TcREG9.1 in Trypanosoma congolense caused a loss of attachment of the parasites to a surface substrate in vitro, a key feature of the biology of these parasites that is distinct from T. brucei. This detachment was phenocopied by treatment of the parasites with a phosphodiesterase inhibitor, which also promotes detachment in the insect trypanosomatid Crithidia fasciculata. RNAseq analysis revealed that TcREG9.1 silencing caused the upregulation of mRNAs for several classes of surface molecules, including transferrin receptor-like molecules, immunoreactive proteins in experimental bovine infections, and molecules related to those associated with stumpy development in T. brucei. Depletion of TcREG9.1 in vivo also generated an enhanced level of parasites in the blood circulation consistent with reduced parasite attachment to the microvasculature. The morphological progression to insect forms of the parasite was also perturbed. We propose a model whereby TcREG9.1 acts as a regulator of attachment and development, with detached parasites being adapted for transmission.
Topics: Animals; Cattle; Trypanosoma congolense; Trypanosoma brucei brucei; RNA Interference; Gene Silencing
PubMed: 38408115
DOI: 10.1371/journal.ppat.1011889 -
BioRxiv : the Preprint Server For... Feb 2024Androgen deprivation therapy (ADT) is an effective but not curative treatment for advanced and recurrent prostate cancer (PC). We investigated the mechanisms controlling...
Androgen deprivation therapy (ADT) is an effective but not curative treatment for advanced and recurrent prostate cancer (PC). We investigated the mechanisms controlling the response to androgen-deprivation by surgical castration in genetically-engineered mouse models (GEMM) of PC, using high frequency ultrasound imaging to rigorously measure tumor volume. Castration initially causes almost all tumors to shrink in volume, but many tumors subsequently recur within 5-10 weeks. Blockade of tumor necrosis factor (TNF) signaling a few days in advance of castration surgery, using a TNFR2 ligand trap, prevents regression in a PTEN-deficient GEMM. Following tumor regression, a basal stem cell-like population within the tumor increases along with TNF protein levels. Tumor cell lines in culture recapitulate these in vivo observations, suggesting that basal stem cells are the source of TNF. When TNF signaling blockade is administered immediately prior to castration, tumors regress but recurrence is prevented, implying that a late wave of TNF secretion within the tumor, which coincides with the expression of NFkB regulated genes, drives recurrence. The inhibition of signaling downstream of one NFkB-regulated protein, chemokine C-C motif ligand 2 (CCL2), prevents post-castration tumor recurrence, phenocopying post-castration (late) TNF signaling blockade. CCL2 was originally identified as a macrophage chemoattractant and indeed at late times after castration gene sets related to chemotaxis and migration are up-regulated. Importantly, enhanced CCL2 signaling during the tumor recurrence phase coincides with an increase in pro-tumorigenic macrophages and a decrease in CD8 T cells, suggesting that recurrence is driven at least in part by tumor immunosuppression. In summary, we demonstrate that a therapy-induced switch in TNF signaling, a consequence of the increased stem cell-like character of the residual tumor cells surviving ADT, induces an immunosuppressive tumor microenvironment and concomitant tumor recurrence.
PubMed: 38405929
DOI: 10.1101/2023.12.01.569685 -
BioRxiv : the Preprint Server For... Feb 2024During cell movement, cortical actin balances mechanical and osmotic forces to maintain cell function while providing the scaffold for cell shape. Migrating CD4 T cells...
During cell movement, cortical actin balances mechanical and osmotic forces to maintain cell function while providing the scaffold for cell shape. Migrating CD4 T cells have a polarized structure with a leading edge containing dynamic branched and linear F-actin structures that bridge intracellular components to surface adhesion molecules. These actin structures are complemented with a microtubular network beaded with membrane bound organelles in the trailing uropod. Disruption of actin structures leads to dysregulated migration and changes in morphology of affected cells. In HIV-1 infection, CD4 T cells have dysregulated movement. However, the precise mechanisms by which HIV-1 affects CD4 T cell movement are unknown. Here, we show that HIV-1 infection of primary CD4 T cells causes at least four progressive morphological differences as a result of virally induced cortical cytoskeleton disruption, shown by ultrastructural and time lapse imaging. Infection with a ΔNef virus partially abrogated the dysfunctional phenotype in infected cells and partially restored a wild-type shape. The pathological morphologies after HIV-1 infection phenocopy leukocytes which contain genetic determinants of specific T cell Inborn Errors of Immunity (IEI) or Primary Immunodeficiencies (PID) that affect the actin cytoskeleton. To identify potential actin regulatory pathways that may be linked to the morphological deformities, uninfected CD4 T cell morphology was characterized following addition of small molecule chemical inhibitors. The ARP2/3 inhibitor CK-666 recapitulated three of the four abnormal morphologies we observed in HIV-1 infected cells. Restoring ARP2/3 function and cortical actin integrity in people living with HIV-1 infection is a new avenue of investigation to eradicate HIV-1 infected cells from the body.
PubMed: 38405733
DOI: 10.1101/2023.07.27.550856 -
Journal of Ayub Medical College,... 2023Hyperkalaemia is a potentially fatal clinical problem frequently seen in the emergency department (ED). It causes a spectrum of electrocardiogram (ECG) changes such as...
Hyperkalaemia is a potentially fatal clinical problem frequently seen in the emergency department (ED). It causes a spectrum of electrocardiogram (ECG) changes such as peaked T-waves, prolonged PR interval, widened QRS complexes, intraventricular/fascicular/bundle branch blocks, etc. Brugada Phenocopy (BrP) is a rare ECG finding seen in severe hyperkalaemia associated with the prevalence of malignant cardiac arrhythmias and all-cause mortality. Unlike Brugada Syndrome (BrS) it is a transient phenomenon and completely resolves with the normalization of hyperkalaemia. Here we report a Brugada Phenocopy (BrP) case observed in a middle-aged male with severe hyperkalaemia.
Topics: Middle Aged; Humans; Male; Hyperkalemia; Brugada Syndrome; Phenotype; Electrocardiography; Emergency Service, Hospital
PubMed: 38404099
DOI: 10.55519/JAMC-03-11542 -
Angiogenesis May 2024Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current...
Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current anti-angiogenic treatments still have major drawbacks like limited efficacy in diseases that also rely on inflammation. Therefore, new anti-angiogenic approaches are sorely needed, and simultaneous inhibition of angiogenesis and inflammation is desirable. Here, we show that 2-desaza-annomontine (C81), a derivative of the plant alkaloid annomontine previously shown to inhibit endothelial inflammation, impedes angiogenesis by inhibiting CDC2-like kinases (CLKs) and WNT/β-catenin signaling. C81 reduced choroidal neovascularization in a laser-induced murine in vivo model, inhibited sprouting from vascular endothelial growth factor A (VEGF-A)-activated murine aortic rings ex vivo, and reduced angiogenesis-related activities of endothelial cells in multiple functional assays. This was largely phenocopied by CLK inhibitors and knockdowns, but not by inhibitors of the other known targets of C81. Mechanistically, CLK inhibition reduced VEGF receptor 2 (VEGFR2) mRNA and protein expression as well as downstream signaling. This was partly caused by a reduction of WNT/β-catenin pathway activity, as activating the pathway induced, while β-catenin knockdown impeded VEGFR2 expression. Surprisingly, alternative splicing of VEGFR2 was not detected. In summary, C81 and other CLK inhibitors could be promising compounds in the treatment of diseases that depend on angiogenesis and inflammation due to their impairment of both processes.
Topics: Animals; Humans; Mice; Angiogenesis; Angiogenesis Inhibitors; beta Catenin; Carbolines; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Inflammation; Neovascularization, Pathologic; Pyrimidines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Wnt Signaling Pathway
PubMed: 38403816
DOI: 10.1007/s10456-024-09906-y -
Nature Communications Feb 2024Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming...
Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b cells - monocytes, macrophages, and neutrophils - were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity.
Topics: Humans; Amidohydrolases; Enzyme Inhibitors; Hyperalgesia; Lipids; Monocytes; Pain; PPAR alpha; Animals; Mice
PubMed: 38402219
DOI: 10.1038/s41467-024-46139-5 -
Nature Communications Feb 2024Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1...
Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.
Topics: Child; Humans; Paired Box Transcription Factors; Rhabdomyosarcoma, Alveolar; Cell Line, Tumor; Rhabdomyosarcoma; Forkhead Box Protein O1; Oncogene Proteins, Fusion; Gene Expression Regulation, Neoplastic; PAX3 Transcription Factor; Jumonji Domain-Containing Histone Demethylases; Histone Demethylases
PubMed: 38402212
DOI: 10.1038/s41467-024-45902-y