Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.

Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

Algorithmic prediction of failure modes in healthcare.

Background: Preventing medical errors is crucial, especially during crises like the COVID-19 pandemic. Failure Modes and Effects Analysis (FMEA) is the most widely used prospective hazard analysis in healthcare. FMEA relies on brainstorming by multi-disciplinary teams to identify hazards.

Styloid Process Elongation on Cervical Spine Computed Tomography is Associated with the Enthesopathy-Related Diseases of Ankylosing Spondylitis and Diffuse Idiopathic Skeletal Hyperostosis.

Background: Enthesopathy may lead to calcification of the stylohyoid ligament and can cause elongation of the styloid process (SP).

Objectives: To evaluate whether SP elongation is associated with two common enthesitis-related diseases: ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH).

Methods: Cervical spine computed tomography (CT) examinations of patients with DISH (n=64, Resnick criteria), AS (n=24, New York criteria) and a controls (no radiological signs of DISH or AS, n=54) were retrospectively evaluated.

Notch Activation by Shootin1 Opposing Activities on 2 Ubiquitin Ligases.

The evolutionarily conserved Notch pathway plays an important role in regulation of stem cell renewal and cell fate determination in numerous organs, and as such is a key pathway in normal health and disease processes. Canonical Notch signaling is usually activated by cell contact where transmembrane ligands such as Delta-like and Jagged bind to Notch receptors. Notch activation results in the translocation of the cleaved Notch intracellular domain (NICD) into the nucleus and subsequent activation of transcription.

Proteomics insights into infantile neuronal ceroid lipofuscinosis (CLN1) point to the involvement of cilia pathology in the disease.

Mutations in the depalmitoylation enzyme, palmitoyl protein thioesterase (PPT1), result in the early onset neurodegenerative disease known as Infantile Neuronal Ceroid Lipofuscinosis. Here, we provide proteomic evidence suggesting that PPT1 deficiency could be considered as a ciliopathy. Analysis of membrane proteins from brain enriched for acylated proteins from neonate Ppt1 knock out and control mice revealed a list of 88 proteins with differential expression levels.

Shootin1 acts in concert with KIF20B to promote polarization of migrating neurons.

Shootin1 has been ascribed a role in regulating polarization of primary hippocampal neurons. To better understand the possible role of Shootin1 in the developing brain, we identified a member of the kinesin superfamily, KIF20B, as a novel Shootin1 interacting protein and a potential mediator of Shootin1 interaction with microtubules. KIF20B/Shootin1 binding was mapped to a 57 aa KIF20B sequence, which was used as a dominant-negative fragment.

Tau's role in the developing brain: implications for intellectual disability.

Microdeletions encompassing the MAPT (Tau) locus resulting in intellectual disability raised the hypothesis that Tau may regulate early functions in the developing brain. Our results indicate that neuronal migration was inhibited in mouse brains following Tau reduction. In addition, the leading edge of radially migrating neurons was aberrant in spite of normal morphology of radial glia.

Increased LIS1 expression affects human and mouse brain development.

Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.

Antagonistic effects of doublecortin and MARK2/Par-1 in the developing cerebral cortex.

Abnormal neuronal migration is manifested in brain malformations such as lissencephaly. The impairment in coordinated cell motility likely reflects a faulty mechanism of cell polarization or coupling between polarization and movement. Here we report on the relationship between the polarity kinase MARK2/Par-1 and its substrate, the well-known lissencephaly-associated gene doublecortin (DCX), during cortical radial migration.

Accurate balance of the polarity kinase MARK2/Par-1 is required for proper cortical neuronal migration.

Radial neuronal migration is key in structuring the layered cortex. Here we studied the role of MARK2/Par-1 in this process. The dual name stands for the MAP/microtubule affinity-regulating kinase 2 (MARK2) and the known polarity kinase 1 (Par-1).

The evolving doublecortin (DCX) superfamily.

Background: Doublecortin (DCX) domains serve as protein-interaction platforms. Mutations in members of this protein superfamily are linked to several genetic diseases. Mutations in the human DCX gene result in abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, and DCDC2 has been associated with dyslectic reading disabilities.

Involvement of Na(+), K(+)-ATPase and endogenous digitalis-like compounds in depressive disorders.

Background: Sodium and potassium-activated adenosine triphosphatase (Na(+), K(+)-ATPase) and endogenous digitalis-like compounds (DLC) in the brain have been implicated in the pathogenesis of mood disorders. This hypothesis was examined by the determination of Na(+), K(+)-ATPase/DLC system in parietal cortex of patients with different mood disorders and two animal models of depression.

Methods: Na(+), K(+)-ATPase concentrations in human brain synaptosomal fractions, from patients with mood disorders, schizophrenia, and normal individuals, were determined by (3)H-ouabain binding assay.

Common and divergent roles for members of the mouse DCX superfamily.

The doublecortin-like (DCX) domains serve as protein-interaction platforms. DCX tandem domains appear in the product of the X-linked doublecortin (DCX) gene, in retinitis pigmentosa-1 (RP1), as well as in other gene products. Mutations in the human DCX gene are associated with abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, while DCDC2 has been associated with dyslectic reading disabilities.

DCX's phosphorylation by not just another kinase (JNK).

The mammalian cortex is generally subdivided into six organized layers, which are formed during development in an organized fashion. This organized cortical layering is disrupted in case of mutations in the doublecortin (DCX) gene. DCX is a Microtubule Associated Protein (MAP).

DCX, a new mediator of the JNK pathway.

Mutations in the X-linked gene DCX result in lissencephaly in males, and abnormal neuronal positioning in females, suggesting a role for this gene product during neuronal migration. In spite of several known protein interactions, the involvement of DCX in a signaling pathway is still elusive. Here we demonstrate that DCX is a substrate of JNK and interacts with both c-Jun N-terminal kinase (JNK) and JNK interacting protein (JIP).

LIS1 missense mutations: variable phenotypes result from unpredictable alterations in biochemical and cellular properties.

Mutations in one allele of the human LIS1 gene cause a severe brain malformation, lissencephaly. Although most LIS1 mutations involve deletions, several point mutations with a single amino acid alteration were described. Patients carrying these mutations reveal variable phenotypic manifestations.

Sodium dodecyl sulphate-treated proteins as ligands in ELISA.

Insoluble proteins generally do not adsorb to microtitre wells and, therefore, cannot be used as antigens in enzyme-linked immunosorbent assay (ELISA). However, denaturation and solubilization with 2% sodium dodecyl sulphate (SDS) renders these proteins suitable ligands for ELISA. In quantitative ELISA using polyclonal antibodies as primary antibody, comparable results were obtained with native and SDS-denatured protein ligands.