Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.A myotrophic lateral sclerosis (ALS) is a fatal idiopathic adultonset neurodegenerative disease characterized by a loss of motor neurons in the brain, brain stem, and spinal cord, with consequent atrophy of associated muscles (1, 2). Incidence rates are 1 to 3 cases per 100,000 individuals per year. Pathogenic mechanisms underlying the disease are not fully understood. Approximately 5 to 10% of all ALS cases are familial (3), with the remaining cases being termed sporadic, contributing to the clinical heterogeneity within the patient population. Nevertheless, typical hallmarks of ALS include neuronal atrophy, mitochondrial dysfunction, excitotoxicity, oxidative stress, and ubiquitinated cellular inclusions (4, 5). A growing number of genes with diverse functions have been implicated in the disease etiology. Mutations in a number of RNA binding proteins have been linked to ALS, including TAR DNA binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) (6). Mutations in these genes result in reduced levels in the nucleus and their accumulation in cytoplasmic ubiquitin-positive inclusions (7). Both TDP-43 and FUS possess prion-like domains and relocate to cytoplasmic stress granules under stress conditions, suggesting potential pathology commonalities (8). Genetic alterations in these and other RNA binding proteins link RNA metabolism to the pathobiology of ALS.Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10). RBM45 possesses three RNA recognition motifs (RRMs) as well as a C-terminal nuclear localization sequence (10). By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbia...

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Background:We have previously shown that the initiation of antiretroviral therapy (ART) is associated with a decrease in skeletal muscle density (greater fat accumulation), suggesting that gains in lean body mass seen in many ART studies may reflect gains in low quality, fatty muscle. Here, we explore whether skeletal muscle density and area are associated with markers of inflammation and immune activation.Methods: ART-naïve people with HIV were randomized to raltegravir or ritonavir-boosted atazanavir or darunavir, each with tenofovir disoproxil fumarate/emtricitabine. Abdominal computed tomography scans from baseline and week 96 were reanalyzed for psoas density and area and correlations explored with inflammation [interleukin-6 (IL-6) and high-sensitivity C-reactive protein] and immune activation [soluble CD14 (sCD14), soluble CD163 (sCD163), and %CD38 + HLADR + on CD4 + or CD8 + T cells].Results: Two hundred twenty-two participants had available inflammation/immune activation markers and paired computed tomog-raphy scans. At baseline, lower psoas density (greater fat) correlated with higher IL-6 (r = 20.26, P , 0.001) and sCD163 (r 20.15, P = 0.03) and lower lean psoas area correlated with higher IL-6, highsensitivity C-reactive protein, sCD14, sCD163, and %CD38 + HLADR + on CD4 + T cells (r = 20.30-0.13; all P # 0.05). From baseline to week 96, greater percent decrease in total psoas density (more fat) correlated with greater increase in IL-6 (r = 20.14; P = 0.04); greater % decrease in lean psoas area correlated greater increases in IL-6, sCD14, sCD163, and %CD38 + HLADR + on CD8 + T cells (r = 20.15 to 20.18; all P , 0.04).Conclusions: Greater fat infiltration within the psoas muscle (lower density) and greater loss in lean psoas muscle area were associated with higher inflammation and immune activation, which may portend important effects on muscle function and cardiometabolic risk.

We report two immigrants from Cuba seen in a US travel clinic with a confirmed diagnosis of cutaneous leishmaniasis in whom we also suspected malaria co-infection. Both individuals likely acquired leishmaniasis in the Darien Gap region of Panama during their migratory path to the United States. As part of their clinical workup to rule out malaria, a rapid malaria antigen testing for P. falciparum was obtained and reported positive in both patients, However, both a qualitative reverse transcription-polymerase chain reaction (RT-PCR) for Plasmodium falciparum in blood and repeated thick-and-thin smear direct microscopy were negative in both, deeming the rapid malaria test as a false-positive. Thus, confirmation of malaria in travelers requires thick-and-thin film microscopy. Clinicians should be aware of the growing recognition of the possibility of false-positive malaria rapid diagnostic tests in those with some forms of leishmaniasis