Discrimination among American Indian and Alaska Native people: implications for public health communication.

Introduction: American Indian and Alaska Native People (AI/AN) have experienced discrimination stemming from sustained attempts to erase AI/AN People and their culture or livelihood. Research identifying the types of discrimination experienced by AI/AN People is needed to help individuals recognize discrimination in daily life. We examine experiences of discrimination among an urban AI/AN population using a mixed methods approach.

HMGB2-induced calreticulin translocation required for immunogenic cell death and ferroptosis of cancer cells are controlled by the nuclear exporter XPO1.

Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) protein from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the cell nucleus into the extracellular milieu.

Protein Disulfide Isomerase Endoplasmic Reticulum Protein 57 (ERp57) is Protective Against ALS-Associated Mutant TDP-43 in Neuronal Cells.

Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease affecting motor neurons. Pathological forms of Tar-DNA binding protein-43 (TDP-43), involving its mislocalisation to the cytoplasm and the formation of misfolded inclusions, are present in almost all ALS cases (97%), and ~ 50% cases of the related condition, frontotemporal dementia (FTD), highlighting its importance in neurodegeneration. Previous studies have shown that endoplasmic reticulum protein 57 (ERp57), a member of the protein disulphide isomerase (PDI) family of redox chaperones, is protective against ALS-linked mutant superoxide dismutase (SOD1) in neuronal cells and transgenic SOD1 mouse models.

Short tandem repeat expansions in are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry.

In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether CGG repeat expansions were also present in ALS patients of European ancestry.

C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.

Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR.

Expression and processing of mature human frataxin after gene therapy in mice.

Friedreich's ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results in FXN protein deficiency and mitochondrial dysfunction. While gene therapy approaches are promising, consistent induction of therapeutic FXN protein expression that is sub-toxic has proven challenging, and numerous therapeutic approaches are being tested in animal models. FXN (hFXN in humans, mFXN in mice) is proteolytically modified in mitochondria to produce mature FXN.

Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1.

Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the nucleus into the extracellular milieu.

Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma.

Unlabelled: Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis.

Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling.

Cyclin F can alter the turnover of TDP-43.

Previously, we demonstrated that the SCF complex directly mediates the poly-ubiquitylation of TDP-43, raising the question of whether cyclin F can be used to enhance the turnover of TDP-43. A hurdle to the use of cyclin F, however, is that the overexpression of cyclin F can lead to the initiation of cell death pathways. Accordingly, the aim of this study was to identify and evaluate a less toxic variant of cyclin F.

Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2.

Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort.

Background: Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. Treatments in clinical trials include frataxin restoration by gene therapy, protein replacement, and epigenetic therapies, all of which necessitate sensitive assays for assessing frataxin levels.

ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.

Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear.

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy.

Deficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich's ataxia (FRDA). It results primarily through epigenetic silencing of the FXN gene by GAA triplet repeats on intron 1 of both alleles. GAA repeat lengths are most commonly between 600 and 1200 but can reach 1700.

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

Aim: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood.

Chimeric kinase ALK induces expression of NAMPT and selectively depends on this metabolic enzyme to sustain its own oncogenic function.

As we show in this study, NAMPT, the key rate-limiting enzyme in the salvage pathway, one of the three known pathways involved in NAD synthesis, is selectively over-expressed in anaplastic T-cell lymphoma carrying oncogenic kinase NPM1::ALK (ALK + ALCL). NPM1::ALK induces expression of the NAMPT-encoding gene with STAT3 acting as transcriptional activator of the gene. Inhibition of NAMPT affects ALK + ALCL cells expression of numerous genes, many from the cell-signaling, metabolic, and apoptotic pathways.

Cisplatin Dependent Secretion of Immunomodulatory High Mobility Group Box 1 (HMGB1) Protein from Lung Cancer Cells.

High mobility group box 1 (HMGB1) is secreted from activated immune cells, necrotic cells, and certain cancers. Previous studies have reported that different patterns of post-translational modification, particularly acetylation and oxidation, mediate HMGB1 release and confer distinct extracellular HMGB1 signaling activity. Here we report that cisplatin but not carboplatin induces secretion of HMGB1 from human A549 non-small cell lung cancer (NSCLC) cells.

The androgen receptor.

The Androgen Receptor (AR) is a ligand (androgen) activated transcription factor and a member of the nuclear receptor (NR) superfamily. It is required for male sex hormone function. AR-FL (full-length) has the domain structure of NRs, an N-terminal domain (NTD) required for transactivation, a DNA-binding domain (DBD), a nuclear localization signal (NLS) and a ligand-binding domain (LBD).

Characterising the Genetic Landscape of Amyotrophic Lateral Sclerosis: A Catalogue and Assessment of Over 1,000 Published Genetic Variants.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with genetic and phenotypic heterogeneity. Pathogenic genetic variants remain the only validated cause of disease, the majority of which were discovered in familial ALS patients. While causal gene variants are a lesser contributor to sporadic ALS, an increasing number of risk alleles (low penetrance genetic variants associated with a small increase in disease risk) and variants of uncertain significance have been reported.

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy.

Deficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich's ataxia (FRDA). It results primarily by epigenetic silencing the FXN gene due to up to 1400 GAA triplet repeats in intron 1 of both alleles of the gene; a subset of approximately 3% of FRDA patients have a mutation on one allele. FRDA patients die most commonly in their 30s from heart disease.