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Found 35618 matches. Displaying 1-10
Al-Hashimi A, Venugopalan V, Sereesongsaeng N, Tedelind S, Pinzaru AM, Hein Z, Springer S, Weber E, Fuhrer D, Scott CJ, Burden RE, Brix K
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Significance of nuclear cathepsin V in normal thyroid epithelial and carcinoma cells

Altered expression and/or localization of cysteine cathepsins is believed to involve in thyroid diseases including cancer. Here, we examined the localization of cathepsins B and V in human thyroid tissue sections of different pathological conditions by immunolabeling and morphometry. Cathepsin B was mostly found within endo-lysosomes as expected. In contrast, cathepsin V was detected within nuclei, predominantly in cells of cold nodules, follicular and papillary thyroid carcinoma tissue, while it was less often detected in this unusual localization in hot nodules and goiter tissue. To understand the significance of nuclear cathepsin V in thyroid cells, this study aimed to establish a cellular model of stable nuclear cathepsin V expression. As representative of a specific form lacking the signal peptide and part of the propeptide, N-terminally truncated cathepsin V fused to eGFP recapitulated the nuclear localization of endogenous cathepsin V throughout the cell cycle in Nthy-ori 3-1 cells. Interestingly, the N-terminally truncated cathepsin V-eGFP was more abundant in the nuclei during S phase. These findings suggested a possible contribution of nuclear cathepsin V forms to cell cycle progression. Indeed, we found that N-terminally truncated cathepsin V-eGFP expressing cells were more proliferative than those expressing full-length cathepsin V-eGFP or wild type controls. We conclude that a specific molecular form of cathepsin V localizes to the nucleus of thyroid epithelial and carcinoma cells, where it might involve in deregulated pathways leading to hyperproliferation. These findings highlight the necessity to better understand cathepsin trafficking in health and disease. In particular, cell type specificity of mislocalization of cysteine cathepsins, which otherwise act in a functionally redundant manner, seems to be important to understand their non-canonical roles in cell cycle progression.
Altenberg L, Cohen JE
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Nonconcavity of the spectral radius in Levinger's theorem

Let A is an element of R-n x n be a nonnegative irreducible square matrix and let r (A) be its spectral radius and Perron-Frobenius eigenvalue. Levinger asserted and several have proven that r(t) := r((1-t)A + tA(T) ) increases over t is an element of [0, 1/2] and decreases over t is an element of [1/2, 1]. It has further been stated that r(t) is concave over t is an element of (0, 1). Here we show that the latter claim is false in general through a number of counterexamples, but prove it is true for A is an element of R-2 x 2, weighted shift matrices (but not cyclic weighted shift matrices), tridiagonal Toeplitz matrices, and the 3-parameter Toeplitz matrices from Fiedler, but not Toeplitz matrices in general. A general characterization of the range of t, or the class of matrices, for which the spectral radius is concave in Levinger's homotopy remains an open problem. (C) 2020 Elsevier Inc. All rights reserved.
Salamango DJ, McCann JL, Demir O, Becker JT, Wang JY, Lingappa JR, Temiz NA, Brown WL, Amaro RE, Harris RS
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Functional and Structural Insights into a Vif/PPP2R5 Complex Elucidated Using Patient HIV-1 Isolates and Computational Modeling

JOURNAL OF VIROLOGY 2020 NOV; 94(21):? Article e00631-20
Human immunodeficiency virus type 1 (HIV-1) Vif recruits a cellular ubiquitin ligase complex to degrade antiviral APOBEC3 enzymes (APOBEC3C-H) and PP2A phosphatase regulators (PPP2R5A to PPP2R5E). While APOBEC3 antagonism is the canonical function of HIV-1 Vif, this viral accessory protein is also known to trigger G(2)/M cell cycle arrest. Vif initiates G(2)/M arrest by degrading multiple PPP2R5 family members, an activity prevalent among diverse HIV-1 and simian immunodeficiency virus (SIV) isolates. Here, computational protein-protein docking was used to delineate a Vif/CBF-beta/PPP2R5 complex in which Vif is predicted to bind the same PPP2R5 surface as physiologic phosphatase targets. This model was tested using targeted mutagenesis of amino acid residues within or adjacent to the putative interface to show loss or retention, respectively, of Vif-induced PPP2R5 degradation activity. Additionally, expression of a peptide that mimics cellular targets of PPP2R5s robustly inhibited Vif-mediated degradation of PPP2R5A but not APOBEC3G. Moreover, live-cell imaging studies examining Vif-mediated degradation of PPP2R5A and APOBEC3G within the same cell revealed that PPP2R5A degradation kinetics are comparable to those of APOBEC3G with a half-life of roughly 6 h postinfection, demonstrating that Vif can concurrently mediate the degradation of distinct cellular substrates. Finally, experiments with a panel of patient-derived Vif isolates indicated that PPP2R5A degradation activity is common in patient-derived isolates. Taken together, these results support a model in which PPP2R5 degradation and global changes in the cellular phosphoproteome are likely to be advantageous for viral pathogenesis. IMPORTANCE A critical function of HIV-1 Vif is to counteract the family of APOBEC3 innate immune proteins. It is also widely accepted that Vif induces G(2)/M cell cycle arrest in several different cell types. Recently, it has been shown that Vif degrades multiple PPP2R5 phosphoregulators to induce the G(2)/M arrest phenotype. Here, computational approaches are used to test a structural model of the Vif/PPP2R5 complex. In addition, imaging studies are used to show that Vif degrades these PPP2R5 substrates in roughly the same time frame as APOBEC3 degradation and that this activity is prevalent in patient-derived Vif isolates. These studies are important by further defining PPP2R5 proteins as a bona fide substrate of HIV-1 Vif.
Windisch KA, Kreek MJ
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Review of addiction risk potential associated with adolescent opioid use

Adolescence is a critical period of development with robust behavioral, morphological, hormonal, and neurochemical changes including changes in brain regions implicated in the reinforcing effects of drugs such as opioids. Here we examine the preclinical and, where appropriate complementary clinical literature, for the behavioral and neurological changes induced by adolescent opioid exposure/use and their long-term consequences during adulthood. Adolescent opioid exposure results in a widened biphasic shift in reinforcement with increased impact of positive rewarding aspects during initial use and profound negative reinforcement during adulthood. Females may have enhanced vulnerability due to fast onset of antinociceptive tolerance and reduced severity of somatic withdrawal symptoms during adolescence. Overall, adolescent opioid exposure, be it legally prescribed protracted intake or illicit consumption, results in significant and prolonged consequences of increased opioid reward concomitant with reduced analgesic efficacy and exacerbated somatic withdrawal severity during opioid use/exposure in adulthood. These findings are highly relevant to physicians, parents, law makers, and the general public as adolescent opioid exposure/misuse results in heightened risk for substance use disorders.
Hallal PC, Hartwig FP, Horta BL, Silveira MF, Struchiner CJ, Vidaletti LP, Neumann NA, Pellanda LC, Dellagostin OA, Burattini MN, Victora GD, Menezes AMB, Barros FC, Barros AJD, Victora CG
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SARS-CoV-2 antibody prevalence in Brazil: results from two successive nationwide serological household surveys

LANCET GLOBAL HEALTH 2020 NOV; 8(11):E1390-E1398
Background Population-based data on COVID-19 are essential for guiding policies. There are few such studies, particularly from low or middle-income countries. Brazil is currently a hotspot for COVID-19 globally. We aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody prevalence by city and according to sex, age, ethnicity group, and socioeconomic status, and compare seroprevalence estimates with official statistics on deaths and cases. Methods In this repeated cross-sectional study, we did two seroprevalence surveys in 133 sentinel cities in all Brazilian states. We randomly selected households and randomly selected one individual from all household members. We excluded children younger than 1 year. Presence of antibodies against SARS-CoV-2 was assessed using a lateral flow point-of-care test, the WONDFO SARS-CoV-2 Antibody Test (Wondfo Biotech, Guangzhou, China), using two drops of blood from finger prick samples. This lateral-flow assay detects IgG and IgM isotypes that are specific to the SARS-CoV-2 receptor binding domain of the spike protein. Participants also answered short questionnaires on sociodemographic information (sex, age, education, ethnicity, household size, and household assets) and compliance with physical distancing measures. Findings We included 25 025 participants in the first survey (May 14-21) and 31165 in the second (June 4-7). For the 83 (62%) cities with sample sizes of more than 200 participants in both surveys, the pooled seroprevalence increased from 1.9% (95% CI 1.7-2.1) to 3.1% (2.8-3.4). City-level prevalence ranged from 0% to 25.4% in both surveys. 11(69%) of 16 cities with prevalence above 2.0% in the first survey were located in a stretch along a 2000 km of the Amazon river in the northern region. In the second survey, we found 34 cities with prevalence above 2.0%, which included the same 11 Amazon cities plus 14 from the northeast region, where prevalence was increasing rapidly. Prevalence levels were lower in the south and centre-west, and intermediate in the southeast, where the highest level was found in Rio de Janeiro (7.5% [4.2-12.2]). In the second survey, prevalence was similar in men and women, but an increased prevalence was observed in participants aged 20-59 years and those living in crowded conditions (4.4% [3.5-5.6] for those living with households with six or more people). Prevalence among Indigenous people was 6.4% (4.1-9.4) compared with 1.4% (1.2-1.7) among White people. Prevalence in the poorest socioeconomic quintile was 3.7% (3- 2-4.3) compared with 1.7% (1.4-2-2) in the wealthiest quintile. Interpretation Antibody prevalence was highly heterogeneous by country region, with rapid initial escalation in Brazil's north and northeast. Prevalence is strongly associated with Indigenous ancestry and low socioeconomic status. These population subgroups are unlikely to be protected if the policy response to the pandemic by the national government continues to downplay scientific evidence. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.
Pfaender S, Mar KB, Michailidis E, Kratzel A, Boys IN, V'kovski P, Fan WC, Kelly JN, Hirt D, Ebert N, Stalder H, Kleine-Weber H, Hoffmann M, Hoffmann HH, Saeed M, Dijkman R, Steinmann E, Wight-Carter M, McDougal MB, Hanners NW, Pohlmann S, Gallagher T, Todt D, Zimmer G, Rice CM, Schoggins JW, Thiel V
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LY6E impairs coronavirus fusion and confers immune control of viral disease

NATURE MICROBIOLOGY 2020 NOV; 5(11):1330-1339
Zoonotic coronaviruses (CoVs) are substantial threats to global health, as exemplified by the emergence of two severe acute respiratory syndrome CoVs (SARS-CoV and SARS-CoV-2) and Middle East respiratory syndrome CoV (MERS-CoV) within two decades(1-3). Host immune responses to CoVs are complex and regulated in part through antiviral interferons. However, interferon-stimulated gene products that inhibit CoVs are not well characterized(4). Here, we show that lymphocyte antigen 6 complex, locus E (LY6E) potently restricts infection by multiple CoVs, including SARS-CoV, SARS-CoV-2 and MERS-CoV. Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in immune cells were highly susceptible to a murine CoV-mouse hepatitis virus. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic immune cells, higher splenic viral burden and reduction in global antiviral gene pathways. Accordingly, we found that constitutive Ly6e directly protects primary B cells from murine CoV infection. Our results show that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo-knowledge that could help inform strategies to combat infection by emerging CoVs. Here, the authors identify lymphocyte antigen 6E (LY6E) as a coronavirus (CoV) restriction factor that prevents infection of B cells and dendritic cells. LY6E inhibits both human and mouse CoV entry into cells by interfering with viral spike protein-mediated membrane fusion. It facilitates an antiviral immune response that prevents liver disease and reduces death in the mouse model of MHV-A59 CoV infection.
Conti BA, Smogorzewska A
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Mechanisms of direct replication restart at stressed replisomes

DNA REPAIR 2020 NOV; 95(?):? Article 102947
Partanen T, Chen J, Lehtonen J, Kuismin O, Rusanen H, Vapalahti O, Vaheri A, Anttila VJ, Bode M, Hautala N, Vuorinen T, Glumoff V, Kraatari M, Astrom P, Saarela J, Kauma H, Lorenzo L, Casanova JL, Zhang SY, Seppanen M, Hautala T
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Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%,p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-lambda and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
Okada S, Asano T, Moriya K, Boisson-Dupuis S, Kobayashi M, Casanova JL, Puel A
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HumanSTAT1Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

Heterozygous gain-of-function (GOF) mutations inSTAT1in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection byCandidafungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus.STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients withSTAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.
Lafont E, Marciano BE, Mahlaoui N, Neven B, Bustamante J, Rodriguez-Nava V, Rawat A, Unzaga MJ, Fischer A, Blanche S, Lortholary O, Holland SM, Lebeaux D
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Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review

Purpose Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). Methods This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Results Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis ofNocardiainfection was 20 (2-257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Conclusions Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.