Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation and initial results of a multi-lingual, international questionnaire to assess self-reported quantity and quality of perception in three distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, 8 other, ages 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± SD), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell, but also affects taste and chemesthesis. The multimodal impact of COVID-19 and lack of perceived nasal obstruction suggest that SARS-CoV-2 infection may disrupt sensory-neural mechanisms.

In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<OR<10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable.

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A ؊/؊ ) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A ؊/؊ expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at Ϸ8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase ␤-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in ob͞ob mice and obese patients who are at risk for nonalcoholic steatohepatitis. S-adenosylmethionine (AdoMet) is an essential metabolite in all cells. AdoMet serves as the methyl donor for many biological methylation reactions, provides the propylamino group for the synthesis of polyamines, and, in the liver, is an intermediary metabolite in the synthesis of glutathione (1-4). Methionine adenosyltransferase (MAT) catalyzes the only known AdoMet biosynthetic reaction from methionine and ATP (5, 6). In mammals, there are three MAT isoforms (MAT I, MAT II, and MAT III) encoded by two distinct genes (MAT1A and MAT2A; refs. 7-11). MAT I and MAT III are a tetramer and a dimer, respectively, of a catalytic ␣ 1 -subunit encoded by the gene MAT1A (4, 6). A second gene, MAT2A, encodes for a catalytic ␣ 2 -subunit that forms MAT II (4, 6). The three enzymes catalyze the same reaction, but their cellular distribution, kinetics, and regulation are different. Although MAT II is the only isoform expressed in extrahepatic tissues (refs. 12 and 13; with the exception of the pancreas, which expresses both MAT1A and MAT2A; ref. 14), both MAT III and I, and to a lesser extent MAT II, are expressed in the liver (13). MAT II expression also predominates in fetal liver and is progressively replaced by MAT III and I during liver development (13). In adult liver, increased expression of MAT2A is associated with rapid growth or de-differentiation of the liver, as during liver regeneration induced by partial hepatectomy (15, 16) and in hepatocarcinogenesis (17)(18)(19).MAT1A silencing in extrahepatic tissues and during liver neoplastic transformation correlates with methylation of the gene promoter and its association with nonacetylated histones (20). Seemingly, these epigenetic modificatio...

Olfactory dysfunction is among the earliest features of Alzheimer’s disease (AD). Although neuropathological abnormalities have been detected in the olfactory bulb (OB), little is known about its dynamic biology. Here, OB- proteome analysis showed a stage-dependent synaptic proteostasis impairment during AD evolution. In addition to progressive modulation of tau and amyloid precursor protein (APP) interactomes, network-driven proteomics revealed an early disruption of upstream and downstream p38 MAPK pathway and a subsequent impairment of Phosphoinositide-dependent protein kinase 1 (PDK1)/Protein kinase C (PKC) signaling axis in the OB from AD subjects. Moreover, a mitochondrial imbalance was evidenced by a depletion of Prohibitin-2 (Phb2) levels and a specific decrease in the phosphorylated isoforms of Phb1 in intermediate and advanced AD stages. Interestingly, olfactory Phb subunits were also deregulated across different types of dementia. Phb2 showed a specific up-regulation in mixed dementia, while Phb1 isoforms were down-regulated in frontotemporal lobar degeneration (FTLD). However, no differences were observed in the olfactory expression of Phb subunits in progressive supranuclear palsy (PSP). To sum up, our data reflect, in part, the missing links in the biochemical understanding of olfactory dysfunction in AD, unveiling Phb complex as a differential driver of neurodegeneration at olfactory level.

Myeloid-derived suppressor cells (MDSCs) exhibit potent immunosuppressive activities in cancer. MDSCs infiltrate tumors and strongly inhibit cancer-specific cytotoxic T cells. Their mechanism of differentiation and identification of MDSC-specific therapeutic targets are major areas of interest. We have devised a highly efficient and rapid method to produce very large numbers of melanoma-infiltrating MDSCs ex vivo without inducing tumors in mice. These MDSCs were used to study their differentiation, immunosuppressive activities and were compared to non-neoplastic counterparts and conventional dendritic cells using unbiased systems biology approaches. Differentially activated/deactivated pathways caused by cell type differences and by the melanoma tumor environment were identified. MDSCs increased the expression of trafficking receptors to sites of inflammation, endocytosis, changed lipid metabolism, and up-regulated detoxification pathways such as the expression of P450 reductase. These studies uncovered more than 60 potential novel therapeutic targets. As a proof of principle, we demonstrate that P450 reductase is the target of pro-drugs such as Paclitaxel, which depletes MDSCs following chemotherapy in animal models of melanoma and in human patients. Conversely, P450 reductase protects MDSCs against the cytotoxic actions of other chemotherapy drugs such as Irinotecan, which is ineffective for the treatment of melanoma.

Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2 mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time-and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates. Keywords Globular glial tauopathy • Tau • Astrogliopathy • Oligodendrogliopathy • Phosphoproteome • Seeding and spreading alien hand, myoclonus, and dystonic movements...

Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. (Hepatology 2018;67:1420-1440).

Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1–treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.