Publications by authors named "Tessarollo L"

Pathogenic variants in BRCA2 are known to significantly increase the lifetime risk of developing breast and ovarian cancers. Sequencing-based genetic testing has resulted in the identification of thousands of BRCA2 variants that are considered to be variants of uncertain significance (VUS) because the disease risk associated with them is unknown. One such variant is p.

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  • - The study explores pre-mRNA splicing, its critical role in neurodevelopment, and how mutations in spliceosome-related genes U2AF2 and PRPF19 contribute to neurodevelopmental disorders (NDDs).
  • - Researchers found multiple pathogenic variants in U2AF2 and PRPF19 across unrelated individuals, with functional analysis showing that specific U2AF2 variants disrupted normal splicing and neuritogenesis in human neurons.
  • - Additionally, investigations in Drosophila models revealed that the loss of function in U2AF2 and PRPF19 caused severe developmental defects and social issues, pointing to a genetic network wherein splicing factors like Rbfox1 play a significant role in brain development and function. *
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Background: Hypersomnolence is a common and disruptive side effect of cranial radiotherapy and is associated with fatigue and disturbances in mood and cognition in primary brain tumor (PBT) patients. The biological underpinnings of this effect are not understood. Our laboratory has previously found that the presence of a single nucleotide polymorphism (rs934945, G-E mutation) in the PERIOD2 (PER2) clock gene was associated with a decreased likelihood of fatigue in PBT patients.

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There are a number of G-protein-coupled receptors (GPCRs) that are considered "orphan receptors" because the information on their known ligands is incomplete. Yet, these receptors are important targets to characterize, as the discovery of their ligands may lead to potential new therapies. GPR75 was recently deorphanized because at least two ligands appear to bind to it, the chemokine CCL5 and the eicosanoid 20-Hydroxyeicosatetraenoic acid.

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In vitro studies suggest that mapping the spatiotemporal complexity of nuclear factor κB (NF-κB) signaling is essential to understanding its function. The lack of tools to directly monitor NF-κB proteins in vivo has hindered such efforts. Here, we introduce reporter mice with the endogenous RelA (p65) or c-Rel labeled with distinct fluorescent proteins and a double knockin with both subunits labeled.

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Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma.

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The interaction between tumor suppressor BRCA2 and DSS1 is essential for RAD51 recruitment and repair of DNA double stand breaks (DSBs) by homologous recombination (HR). We have generated mice with a leucine to proline substitution at position 2431 of BRCA2, which disrupts this interaction. Although a significant number of mutant mice die during embryogenesis, some homozygous and hemizygous mutant mice undergo normal postnatal development.

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  • Brain-derived neurotrophic factor (BDNF) is important for the growth and survival of neurons and plays a key role in the development of both the central and peripheral nervous systems in vertebrates.
  • BDNF interacts with TrkB receptors, and its therapeutic potential is being explored for neurodegenerative diseases like ALS, Huntington's, Parkinson's, and Alzheimer's.
  • The TrkB gene produces different receptor isoforms, with TrkB.T1 being the most common in adults; however, its exact role in regulating BDNF signaling remains largely unclear, prompting further investigation.
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  • - Recent research indicates that combining cognitive enhancers with exposure therapy may help improve treatment outcomes for individuals with PTSD by enhancing brain cholinergic signaling.
  • - A genetic approach was used to boost cholinergic activity in mice, leading to reduced fear responses without causing behavioral abnormalities, indicating a specific role of cholinergic signaling in fear regulation.
  • - The drug donepezil, used for dementia, showed potential in improving extinction learning in a PTSD-like model, suggesting a new application for it in enhancing psychotherapy effectiveness for PTSD.
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  • Lynch syndrome (LS) is a hereditary cancer predisposition syndrome linked to harmful genetic variants in DNA mismatch repair (MMR) genes, with a specific variant prevalent in the Canadian Inuit population.
  • A common founder variant in the PMS2 gene causes both a benign missense change and a significant splicing defect, leading to a truncated protein and increased risk of cancer in homozygous individuals.
  • Researchers developed a mouse model with a similar genetic mutation, which shows similar splicing defects and several cancer characteristics, thus providing a useful tool for studying potential treatments for this condition, particularly in the Canadian Inuit community.
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Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the promoter.

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PPM1D/Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human solid tumors. Recent reports associate gain-of-function mutations of PPM1D in immune cells with worse outcomes for several human cancers. Here we show that mice with genetic knockout of Ppm1d or with conditional knockout of Ppm1d in the hematopoietic system, in myeloid cells, or in neutrophils all display significantly reduced growth of syngeneic melanoma or lung carcinoma tumors.

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Obesity is the key driver of peripheral insulin resistance, one of the key features of type 2 diabetes (T2D). In insulin-resistant individuals, the expansion of beta-cell mass is able to delay or even prevent the onset of overt T2D. Here, we report that beta-arrestin-1 (barr1), an intracellular protein known to regulate signaling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice maintained on an obesogenic diet.

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  • * Researchers are isolating specialized antibodies called nanobodies from llamas and engineered mice, which can effectively target parts of the virus that traditional antibodies struggle with.
  • * The study identifies two groups of potent nanobodies that can neutralize various SARS-CoV-2 variants, highlighting their potential as a treatment option to address the limitations of current vaccines.
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Metabolic regulation is critical for the maintenance of pluripotency and the survival of embryonic stem cells (ESCs). The transcription factor Tfcp2l1 has emerged as a key factor for the naïve pluripotency of ESCs. Here, we report an unexpected role of Tfcp2l1 in metabolic regulation in ESCs-promoting the survival of ESCs through regulating fatty acid oxidation (FAO) under metabolic stress.

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  • The COVID-19 pandemic has led to over 2 million deaths due to the SARS-CoV-2 virus, with emerging variants like B.1.1.7, B.1.351, and B.1.526 reducing the effectiveness of existing vaccines and antibody treatments.
  • Researchers are exploring the use of small camelid-derived nanobodies as an alternative approach to respond to these evolving variants by isolating and studying anti-RBD nanobodies from llamas and engineered mice.
  • The study identifies two sets of highly neutralizing nanobodies: one targets a conserved region outside the ACE2-binding site, while the other focuses on the RBD-ACE2 interface, allowing them to effectively neutralize variants when expressed as
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Serine palmitoyltransferase complex (SPT) mediates the first and rate-limiting step in the de novo sphingolipid biosynthetic pathway. The larger subunits SPTLC1 and SPTLC2/SPTLC3 together form the catalytic core while a smaller third subunit either SSSPTA or SSSPTB has been shown to increase the catalytic efficiency and provide substrate specificity for the fatty acyl-CoA substrates. The in vivo biological significance of these smaller subunits in mammals is still unknown.

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  • * Trials with neurotrophic factor BDNF have been disappointing due to its ineffective pharmacokinetics and pharmacodynamics, despite its evaluation in clinical settings.
  • * Deleting the BDNF receptor TrkB.T1 in an ALS animal model shows delayed motoneuron death and muscle weakness, suggesting that TrkB.T1's role may limit the effectiveness of neuroprotective BDNF signaling, pointing to new potential avenues for ALS treatment.
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Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Disruption of transcription factor gene during mouse embryonic development has been shown to cause a severe loss of fetal liver HSCs; however, the underlying mechanisms and the function of in adult HSCs remain unclear. To investigate the role of in adult HSCs, we generated a novel conditional knockout mouse model and deleted in adult mouse hematopoietic system using the IFN-inducible Our results show that deletion in the adult mouse hematopoietic system has a less severe effect on HSCs, causing a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment.

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  • The anterolateral system transmits pain, itch, and temperature signals from the spinal cord to the brain, but the specific roles of these neurons are not well understood.
  • Researchers found that most spinal neurons expressing the Phox2a transcription factor target key pain-related brain areas like the parabrachial nucleus and thalamus.
  • The study reveals Phox2a's critical role in the development of these neurons and shows that its molecular identity is similar in the human fetal spinal cord, highlighting its importance across species.
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Primary culture of mouse hippocampal neurons is a very useful model for studying neuronal development, axonal and dendritic morphology, synaptic functions, and many other neuronal features. Here we describe a step-by-step process of generating primary neurons from mouse embryonic hippocampi (E17.5/E18.

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BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.

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Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors.

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NF-κB is a family of heterodimers and homodimers which are generated from subunits encoded by five genes. The predominant classical dimer RelA:p50 is presumed to operate as "NF-κB" in many contexts. However, there are several other dimer species which exist and may even be more functionally relevant in specific cell types.

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