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Found 35740 matches. Displaying 71-80
Gomez-Arteaga A, Shah GL, Baser RE, Scordo M, Ruiz JD, Bryant A, Dahi PB, Ghosh A, Lahoud OB, Landau HJ, Landgren O, Shaffer BC, Smith EL, Koehne G, Perales MA, Giralt SA, Chung DJ
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Prognostic Factors for Postrelapse Survival after ex Vivo CD34(+)-Selected (T Cell-Depleted) Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graftversus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before a11oHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early ( <6 months; 28%), early (6 to 24 months; 50%), or late (>24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD, a11oHCT, On multivariate analysis adjusted for age and sex, very early relapse (hazard ratio [HR], 4.37; 95% confidence interval [CI], 1.42 to 13.5), relapse with EMD (HR, 5.20; 95% CI, 2.10 to 12.9), and DLI for relapse prevention (HR, .11; 95% CI, 2.10 to 12.9) were significant predictors for postrelapse survival. Despite their shared inherent high-risk status, patients with MM have significantly disparate post-HCT relapse courses, with some demonstrating long-term survival despite relapse. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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.
Armstrong J, Hickey G, Diekhans M, Fiddes IT, Novak AM, Deran A, Fang Q, Xie D, Feng SH, Stiller J, Genereux D, Johnson J, Marinescu VD, Alfoldi J, Harris RS, Lindblad-Toh K, Haussler D, Karlsson E, Jarvis ED, Zhang GJ, Paten B
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Progressive Cactus is a multiple-genome aligner for the thousand-genome era

NATURE 2020 NOV 12; 587(7833):246-251
New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies(1-3). For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database(4) increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies(5) are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus(6), a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far. The Progressive Cactus program can create reference-free alignments of hundreds of large vertebrate genomes efficiently, and is used for the alignment of more than 600 amniote genomes.
Peiretti F, Montanari R, Capelli D, Bonardo B, Colson C, Amri EZ, Grimaldi M, Balaguer P, Ito K, Roeder RG, Pochetti G, Brunel JM
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A Novel N-Substituted Valine Derivative with Unique Peroxisome Proliferator-Activated Receptor gamma Binding Properties and Biological Activities

JOURNAL OF MEDICINAL CHEMISTRY 2020 NOV 12; 63(21):13124-13139
A proprietary library of novel N-aryl-substituted amino acid derivatives bearing a hydroxamate head group allowed the identification of compound 3a that possesses weak proadipogenic and peroxisome proliferator-activated receptor gamma (PPAR gamma) activating properties. The systematic optimization of 3a, in order to improve its PPAR gamma agonist activity, led to the synthesis of compound 7j (N-aryl-substituted valine derivative) that possesses dual PPAR gamma/PPAR alpha agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPAR gamma agonists with, however, a unique high-affinity binding mode. Furthermore, 7j is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPAR gamma serine 273. Although less proadipogenic than rosiglitazone, 7j significantly increases adipocyte insulin-stimulated glucose uptake and efficiently promotes white-to-brown adipocyte conversion. In addition, 7j prevents oleic acid-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound 7j suggest that it would be a promising candidate for the development of compounds to reduce insulin resistance, obesity, and nonalcoholic fatty liver disease.
Pisupati A, Mickolajczyk KJ, Hancock WO, Jegla T
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What is the correct stoichiometry of Kv2.1:Kv6.4 heteromers?

Horioka M, Ceraudo E, Lorenzen E, Sakmar TP, Huber T
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Purinergic Receptors Crosstalk with CCR5 to Amplify Ca2+ Signaling

Many G protein-coupled receptors (GPCRs) signal through more than one subtype of heterotrimeric G proteins. For example, the C-C chemokine receptor type 5 (CCR5), which serves as a co-receptor to facilitate cellular entry of human immunodeficiency virus 1 (HIV-1), normally signals through the heterotrimeric G protein, Gi. However, CCR5 also exhibits G protein signaling bias and certain chemokine analogs can cause a switch to Gq pathways to induce Ca2+ signaling. We want to understand how much of the Ca2+ signaling from Gi-coupled receptors is due to G protein promiscuity and how much is due to transactivation and crosstalk with other receptors. We propose a possible mechanism underlying the apparent switching between different G protein signaling pathways. We show that chemokine-mediated Ca2+ flux in HEK293T cells expressing CCR5 can be primed and enhanced by ATP pretreatment. In addition, agonist-dependent lysosomal exocytosis results in the release of ATP to the extracellular milieu, which amplifies cellular signaling networks. ATP is quickly degraded via ADP and AMP to adenosine. ATP, ADP and adenosine activate different cell surface purinergic receptors. Endogenous Gq-coupled purinergic P2Y receptors amplify Ca2+ signaling and allow for Gi- and Gq-coupled receptor signaling pathways to converge. Associated secretory release of GPCR ligands, such as chemokines, opioids, and monoamines, should also lead to concomitant release of ATP with a synergistic effect on Ca2+ signaling. Our results suggest that crosstalk between ATP-activated purinergic receptors and other Gi-coupled GPCRs is an important cooperative mechanism to amplify the intracellular Ca2+ signaling response.
Viant C, Weymar GHJ, Escolano A, Chen S, Hartweger H, Cipolla M, Gazumyan A, Nussenzweig MC
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Antibody Affinity Shapes the Choice between Memory and Germinal Center B Cell Fates

CELL 2020 NOV 25; 183(5):1298-1311.e11
Immunological memory is required for protection against repeated infections and is the basis of all effective vaccines. Antibodies produced by memory B cells play an essential role in many of these responses. We have combined lineage tracing with antibody cloning from single B cells to examine the role of affinity in B cell selection into germinal centers (GCs) and the memory B cell compartment in mice immunized with an HIV-1 antigen. We find that contemporaneously developing memory and GC B cells differ in their affinity for antigen throughout the immune response. Whereas GC cells and their precursors are enriched in antigen binding, memory B cells are not. Thus, the polyclonal memory B cell compartment is composed of B cells that were activated during the immune response but whose antigen binding affinity failed to support further clonal expansion in the GC.
Gareau DS, Browning J, Da Rosa JC, Suarez-Farinas M, Lish S, Zong AM, Firester B, Vrattos C, Renert-Yuval Y, Gamboa M, Vallone MG, Barragan-Estudillo ZF, Tamez-Pena AL, Montoya J, Jesus-Silva MA, Carrera C, Malvehy J, Puig S, Marghoob A, Carucci JA, Krueger JG
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Deep learning-level melanoma detection by interpretable machine learning and imaging biomarker cues

JOURNAL OF BIOMEDICAL OPTICS 2020 NOV; 25(11):? Article 112906
Significance: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics. Aim: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration. Approach: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves. Results: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs. Conclusions: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License.
Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Zha SSN, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Lim SA, Zhou XX, Hobman TC, Kortemme T, Wells JA
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Engineered ACE2 receptor traps potently neutralize SARS-CoV-2

An essential mechanism for severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begins with the viral spike protein binding to the human receptor protein angiotensinconverting enzyme II (ACE2). Here, we describe a stepwise engineering approach to generate a set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARSCoV-2 infection of cells. These optimized receptor traps tightly bind the receptor binding domain (RBD) of the viral spike protein and prevent entry into host cells. We first computationally designed the ACE2-RBD interface using a two-stage flexible protein backbone design process that improved affinity for the RBD by up to 12-fold. These designed receptor variants were affinity matured an additional 14-fold by random mutagenesis and selection using yeast surface display. The highest-affinity variant contained seven amino acid changes and bound to the RBD 170-fold more tightly than wild-type ACE2. With the addition of the natural ACE2 collectrin domain and fusion to a human immunoglobulin crystallizable fragment (Fc) domain for increased stabilization and avidity, the most optimal ACE2 receptor traps neutralized SARS-CoV-2-pseudotyped lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50s) in the 10- to 100-ng/mL range. Engineered ACE2 receptor traps offer a promising route to fighting infections by SARS-CoV-2 and other ACE2-using coronaviruses, with the key advantage that viral resistance would also likely impair viral entry. Moreover, such traps can be predesigned for viruses with known entry receptors for faster therapeutic response without the need for neutralizing antibodies isolated from convalescent patients.
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.