scholarly journals Modulation of RNA-dependent interactions in stress granules prevents persistent TDP-43 accumulation in ALS/FTD

2018 ◽  
Author(s):  
Mark Y. Fang ◽  
Sebastian Markmiller ◽  
William E. Dowdle ◽  
Anthony Q. Vu ◽  
Paul J. Bushway ◽  
...  
Keyword(s):  
Open Source Software ◽  
Genetic Variants ◽  
Data Representation ◽  
Lookup Table ◽  
Memory Allocation ◽  
Computer Memory ◽  
List Type ◽  
Dependent Manner ◽  
Chromosome Position ◽  
The Individual

ABSTRACTHuman genetic variants are usually represented by four values with variable length: chromosome, position, reference and alternate alleles. Thereis no guarantee that these components are represented in a consistent way across different data sources, and processing variant-based data can be inefficient because four different comparison operations are needed for each variant, three of which are string comparisons. Working with strings, in contrast to numbers, poses extra challenges on computer memory allocation and data-representation. Existing variant identifiers do not typicallyrepresent every possible variant we may be interested in, nor they are directly reversible. To overcome these limitations, VariantKey, a novel reversible numerical encoding schema for human genetic variants, is presented here alongside a multi-language open-source software implementation (http://github.com/genomicspls/variantkey). VariantKey represents variants as single 64 bit numeric entities, while preserving the ability to be searched and sorted by chromosome and position. The individual components of short variants can be directly read back from the VariantKey, while long variants are supported with a fast lookup table.Highlights~100 compounds identified by high-content screen inhibit SGs in HEK293, NPCs and iPS-MNs.ALS-associated RBPs are recruited to SGs in an RNA-dependent mannerMolecules with planar moieties prevent recruitment of ALS-associated RBPs to SGsCompounds inhibit TDP-43 accumulation in SGs and in TARDBP mutant iPS-MNs.

scholarly journals VariantKey: A Reversible Numerical Representation of Human Genetic Variants

2018 ◽  
Author(s):  
Nicola Asuni ◽  
Steven Wilder
Keyword(s):  
Open Source Software ◽  
Genetic Variants ◽  
Data Representation ◽  
Lookup Table ◽  
Memory Allocation ◽  
Computer Memory ◽  
Numerical Representation ◽  
Chromosome Position ◽  
The Individual ◽  
Genomic Regions

AbstractHuman genetic variants are usually represented by four values with variable length: chromosome, position, reference and alternate alleles. There is no guarantee that these components are represented in a consistent way across different data sources, and processing variant-based data can be inefficient because four different comparison operations are needed for each variant, three of which are string comparisons. Existing variant identifiers do not typically represent every possible variant we may be interested in, nor they are directly reversible. Similarly, genomic regions are typically represented inconsistently by three or four values. Working with strings, in contrast to numbers, poses extra challenges on computer memory allocation and data-representation. To overcome these limitations, a novel reversible numerical encoding schema for human genetic variants (VariantKey) and genomics regions (RegionKey), is presented here alongside a multi-language open-source software implementation (https://github.com/Genomicsplc/variantkey). VariantKey and RegionKey represents variants and regions as single 64 bit numeric entities, while preserving the ability to be searched and sorted by chromosome and position. The individual components of short variants can be directly read back from the VariantKey, while long variants are supported with a fast lookup table.

scholarly journals In VitroAnalyses of the Effects of Heparin and Parabens on Candida albicans Biofilms and Planktonic Cells

2011 ◽  
Vol 56 (1) ◽  
pp. 148-153 ◽  
Author(s):  
Marisa H. Miceli ◽  
Stella M. Bernardo ◽  
T. S. Neil Ku ◽  
Carla Walraven ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
High Dose ◽  
Dependent Manner ◽  
Planktonic Cells ◽  
Content Type ◽  
Heparin Sodium ◽  
The Individual

ABSTRACTInfections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin onCandida albicansbiofilms and planktonic cells have not been previously studied. Therefore, we sought to determine thein vitroeffect of a heparin sodium preparation (HP) on biofilms and planktonic cells ofC. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformedC. albicansbiofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P< 0.0001). Pure-H, MP, and PP each inhibitedC. albicansbiofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H havein vitroantifungal activity againstC. albicansmature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention ofC. albicansbiofilms is warranted.

scholarly journals Antiviral Activity of the PropylamylatinTM Formula against the Novel Coronavirus SARS-CoV-2 In Vitro Using Direct Injection and Gas Assays in Virus Suspensions

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 415
Author(s):  
Ashley N. Brown ◽  
Gary Strobel ◽  
Kaley C. Hanrahan ◽  
Joe Sears
Keyword(s):  
Propionic Acid ◽  
Infectious Virus ◽  
Direct Injection ◽  
Plaque Assay ◽  
Antiviral Effect ◽  
Dependent Manner ◽  
Global Public Health ◽  
Novel Coronavirus ◽  
The Individual

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of novel coronavirus disease 2019 (COVID-19), has become a severe threat to global public health. There are currently no antiviral therapies approved for the treatment or prevention of mild to moderate COVID-19 as remdesivir is only approved for severe COVID-19 cases. Here, we evaluated the antiviral potential of a Propylamylatin formula, which is a mixture of propionic acid and isoamyl hexanoates. The Propylamylatin formula was investigated in gaseous and liquid phases against 1 mL viral suspensions containing 105 PFU of SARS-CoV-2. Viral suspensions were sampled at various times post-exposure and infectious virus was quantified by plaque assay on Vero E6 cells. Propylamylatin formula vapors were effective at inactivating infectious SARS-CoV-2 to undetectable levels at room temperature and body temperature, but the decline in virus was substantially faster at the higher temperature (15 min versus 24 h). The direct injection of liquid Propylamylatin formula into viral suspensions also completely inactivated SARS-CoV-2 and the rapidity of inactivation occurred in an exposure dependent manner. The overall volume that resulted in 90% viral inactivation over the course of the direct injection experiment (EC90) was 4.28 µls. Further investigation revealed that the majority of the antiviral effect was attributed to the propionic acid which yielded an overall EC90 value of 11.50 µls whereas the isoamyl hexanoates provided at most a 10-fold reduction in infectious virus. The combination of propionic acid and isoamyl hexanoates was much more potent than the individual components alone, suggesting synergy between these components. These findings illustrate the therapeutic promise of the Propylamylatin formula as a potential treatment strategy for COVID-19 and future studies are warranted.

184 Two types of anti-TIGIT antibodies with distinct binding epitope and functional activities

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A198-A198
Author(s):  
Tingting Zhong ◽  
Xinghua Pang ◽  
Zhaoliang Huang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Mixed Culture ◽  
Cell Activity ◽  
Cross Reactivity ◽  
Binding Activity ◽  
Jurkat Cells ◽  
List Type ◽  
Dependent Manner ◽  
Vitro Assay

BackgroundTIGIT is an inhibitory receptor mainly expressed on natural killer (NK) cells, CD8+ T cells, CD4+ T cells and Treg cells. TIGIT competes with CD226 for binding with CD155. In cancers, CD155 has been reported to up-regulate on tumor cells, and TIGIT was found to increase on TILs.1 Activation of TIGIT/CD155 pathway would mediate immunosuppression in tumor; while blockade of TIGIT promotes anti-tumor immune response.MethodsAK126 and AK113 are two humanized anti-human TIGIT monoclonal antibodies developed by Akesobio. Binding activity of AK126 and AK113 to human TIGIT, and competitive binding activity with CD155 and CD112, were performed by using ELISA, Fortebio, and FACS assays. Cross-reactivity with cynomolgus monkey TIGIT and epitope binning were also tested by ELISA assay. In-vitro assay to investigate the activity to promote IL-2 secretion was performed in mixed-culture of Jurkat-TIGIT cells and THP-1 cells.ResultsAK126 and AK113 could specifically bind to human TIGIT with comparative affinity and effectively blocked the binding of human CD155 and CD112 to human TIGIT. X-ray crystal structure of TIGIT and PVR revealed the C’-C’’ loop and FG loop regions of TIGIT are the main PVR interaction regions.2 The only amino acid residue differences in these regions between human and monkey TIGIT are 70C and 73D. AK126 binds to both human and monkey TIGIT, AK113 binds only to monkey TIGIT. This suggests that these residues are required for AK113 binding to human TIGIT, but not required for AK126. Interestingly, results from cell-based assays indicated that AK126 and AK113 showed significantly different activity to induce IL-2 secretion in mixed-culture of Jurkat-TIGIT cells and THP-1 cells (figure 1A and B), in which AK126 had a comparable capacity of activity to 22G2, a leading TIGIT mAb developed by another company, to induce IL-2 secretion, while, AK113 showed a significantly higher capacity than 22G2 and AK126.Abstract 184 Figure 1Anti-TIGIT Antibodies Rescues IL-2 Production in Vitro T-Cell Activity Assay in a dose dependent manner. Jurkat-TIGIT cells (Jurkat cells engineered to over-express human TIGIT) were co-cultured with THP-1 cells, and stimulated with plate-bound anti-CD3 mAb in the presence of TIGIT ligand CD155 (A) or CD112 (B) with anti-TIGIT antibodies. After incubated for 48h at 37° C and 5.0% CO2, IL-2 levels were assessed in culture supernatants by ELISA. Data shown as mean with SEM for n = 2.ConclusionsWe discovered two distinct types of TIGIT antibodies with differences in both epitope binding and functional activity. The mechanism of action and clinical significance of these antibodies require further investigation.ReferencesSolomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 2018;67:1659–1667.Stengel KF, Harden-Bowles K, Yu X, et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci USA 2012;109:5399–5404.

734 A novel NQO1 specific anti-tumor agent, SBSC-S3001, selectively regresses the growth of tumors with high NQO1 expression

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A778-A778
Author(s):  
Minhyuk Yun ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Changhoon In ◽  
Gyu-Young Moon ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
High Expression ◽  
List Type ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Quinone Oxidoreductase ◽  
Key Enzymes

BackgroundNAD(P)H-quinone oxidoreductase 1 (NQO1) is a cytosolic two-electron oxidoreductase overexpressed in many types of cancers, including breast cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, uterine cervical cancer, melanoma, and lung cancer.1Up-regulation of NQO1 protects cells from oxidative stress and various cytotoxic quinones and is associated with late clinical stage, poor prognosis and lymph node metastasis.2 3 NQO1 increases stability of HIF-1α protein, which has been implicated in survival, proliferation, and malignance of cancer.1 Therefore, accumulating evidences suggest NQO1 as a promising therapeutic target for cancer. Accordingly, we have characterized the effect of a novel synthetic NQO1 substrate SBSC-S3001, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1.MethodsIn vitro cytotoxicity was determined by sulforhodamine B (SRB) assay in cancer cells with high NQO1 expression and CRISPR-mediated NQO1 knockout cells. The effect of SBSC-S3001 on the energy metabolism pathway was evaluated by western blot analysis of metabolism associated proteins from NQO1-overexpressed cancer cells treated with the compound for 24 hours. In vivo anti-tumor activity was evaluated in MC38 syngeneic and DLD-1 orthotopic mice models.ResultsSBSC-S3001 exhibited selective cytotoxicity in cancer cells with high expression of NQO1 in a dose-dependent manner. The cytotoxicity was observed in both normoxia and hypoxia conditions, correlating with the energy metabolism, mitochondrial biogenesis, and cancer proliferative pathways. Also, stronger cytotoxicity was observed in NQO1-overexpressed cancer cells treated with SBSC-S3001 compared to beta-lapachone and analogue treatment.4 When evaluated in vivo, SBSC-S3001 effectively inhibited the growth of syngeneic and orthotopic tumors when administered as a monotherapy. SBSC-S3001 treatment associated with reduction in key enzymes of the glycolytic pathway (LDHa and GAPDH) and HIF-1α and increase in levels of mitochondrial oxidative phosphorylation (OXPHOS) complex.ConclusionsTreatment of SBSC-S3001, a novel, NQO1-specific substrate reduces HIF-1α and key enzymes associated with glycolysis and suppresses the growth of tumors overexpressing NQO1. Further characterization of SBSC-S3001 as a novel metabolic anti-cancer agent for cancers with NQO1 overexpression is warranted.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2031.ReferencesOh ET, Kim JW, Kim JMet. al., NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 2016; 14:13593.Ma, Y. et al. NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 2014;14: 414Yang, Y. et al. Clinical implications of high NQO1 expression in breast cancers. J. Exp. Clin. Cancer Res 2014;33:144.Yang Y, Zhou X, Xu M, et al., β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 2017;7:2681.

Optimal computer memory allocation for the Poisson flows

2008 ◽  
Vol 69 (9) ◽  
pp. 1510-1516 ◽  
Author(s):  
V. V. Mazalov ◽  
M. Tamaki ◽  
S. V. Vinnichenko
Keyword(s):  
Memory Allocation ◽  
Computer Memory

scholarly journals Knowledge sharing in open source software communities: motivations and management

2015 ◽  
Vol 19 (4) ◽  
pp. 791-813 ◽  
Author(s):  
Zilia Iskoujina ◽  
Joanne Roberts
Keyword(s):  
Knowledge Sharing ◽  
Open Source ◽  
Open Source Software ◽  
Online Communities ◽  
Descriptive Analysis ◽  
Online Questionnaire ◽  
Content Type ◽  
The Individual ◽  
The Impact

Purpose – This paper aims to add to the understanding of knowledge sharing in online communities through an investigation of the relationship between individual participant’s motivations and management in open source software (OSS) communities. Drawing on a review of literature concerning knowledge sharing in organisations, the factors that motivate participants to share their knowledge in OSS communities, and the management of such communities, it is hypothesised that the quality of management influences the extent to which the motivations of members actually result in knowledge sharing. Design/methodology/approach – To test the hypothesis, quantitative data were collected through an online questionnaire survey of OSS web developers with the aim of gathering respondents’ opinions concerning knowledge sharing, motivations to share knowledge and satisfaction with the management of OSS projects. Factor analysis, descriptive analysis, correlation analysis and regression analysis were used to explore the survey data. Findings – The analysis of the data reveals that the individual participant’s satisfaction with the management of an OSS project is an important factor influencing the extent of their personal contribution to a community. Originality/value – Little attention has been devoted to understanding the impact of management in OSS communities. Focused on OSS developers specialising in web development, the findings of this paper offer an important original contribution to understanding the connections between individual members’ satisfaction with management and their motivations to contribute to an OSS project. The findings reveal that motivations to share knowledge in online communities are influenced by the quality of management. Consequently, the findings suggest that appropriate management can enhance knowledge sharing in OSS projects and online communities, and organisations more generally.

Monoclonal antibodies reveal the alteration of the rhodocetin structure upon α2β1 integrin binding

2011 ◽  
Vol 440 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Thilo Bracht ◽  
Flávia Figueiredo de Rezende ◽  
Jörg Stetefeld ◽  
Lydia M. Sorokin ◽  
Johannes A. Eble
Keyword(s):  
Monoclonal Antibodies ◽  
Dependent Manner ◽  
Hydrophilic Surfaces ◽  
Sequence Homologies ◽  
Molecular Masses ◽  
The Individual ◽  
Β Chain ◽  
Α2β1 Integrin ◽  
Characteristic Domain ◽  
Integrin Α2

The α2β1 antagonist rhodocetin from Calloselasma rhodostoma is a heterotetrameric CLRP (C-type lectin-related protein) consisting of four distinct chains, α, β, γ and δ. Via their characteristic domain-swapping loops, the individual chains form two subunits, αβ and γδ. To distinguish the four chains which share similar molecular masses and high sequence homologies, we generated 11 mAbs (monoclonal antibodies) with different epitope specificities. Four groups of distinct mAbs were generated: the first targeted the rhodocetin β chain, the second group bound to the αβ subunit mostly in a conformation-dependent manner, the third group recognized the γδ subunit only when separated from the αβ subunit, whereas a fourth group interacted with the γδ subunit both in the heterotetrameric molecule and complexed with the integrin α2 A-domain. Using the specific mAbs, we have shown that the rhodocetin heterotetramer dissociates into the αβ and γδ subunit upon binding to the integrin α2 A-domain at both the molecular and cellular levels. After dissociation, the γδ subunit firmly interacts with the α2β1 integrin, thereby blocking it, whereas the rhodocetin αβ subunit is released from the complex. The small molecular interface between the αβ and γδ subunits within rhodocetin is mostly mediated by charged residues, which causes the two dissociated subunits to have hydrophilic surfaces.

scholarly journals Will You Come Back to Contribute? Investigating the Inactivity of OSS Core Developers in GitHub

2021 ◽  
Author(s):  
Fabio Calefato ◽  
Marco Aurelio Gerosa ◽  
Giuseppe Iaffaldano ◽  
Filippo Lanubile ◽  
Igor Fabio Steinmacher
Keyword(s):  
Open Source ◽  
Open Source Software ◽  
State Transition ◽  
Active State ◽  
State Model ◽  
Novel Method ◽  
To Come ◽  
One Year ◽  
The Individual ◽  
To Receive

Abstract Several Open-Source Software (OSS) projects depend on the continuity of their development communities to remain sustainable. Understanding how developers become inactive or why they take breaks can help communities prevent abandonment and incentivize developers to come back. In this paper, we propose a novel method to identify developers’ inactive periods by analyzing the individual rhythm of contributions to the projects. Using this method, we quantitatively analyze the inactivity of core developers in 18 OSS organizations hosted on GitHub. We also survey core developers to receive their feedback about the identified breaks and transitions. Our results show that our method was effective for identifying developers’ breaks. About 94% of the surveyed core developers agreed with our state model of inactivity; 71% and 79% of them acknowledged their breaks and state transition, respectively. We also show that all core developers take breaks (at least once) and about a half of them (~ 45%) have completely disengaged from a project for at least one year. We also analyzed the probability of transitions to/from inactivity and found that developers who pause their activity have a ~ 35 to ~ 55% chance to return to an active state; yet, if the break lasts for a year or longer, then the probability of resuming activities drops to ~ 21–26%, with a ~ 54% chance of complete disengagement. These results may support the creation of policies and mechanisms to make OSS community managers aware of breaks and potential project abandonment.

scholarly journals Pooling size sorted malaise trap fractions to maximise taxon recovery with metabarcoding

2020 ◽  
Author(s):  
Vasco Elbrecht ◽  
Sarah J. Bourlat ◽  
Thomas Hörren ◽  
Angie Lindner ◽  
Adriana Mordente ◽  
...  
Keyword(s):  
Size Fraction ◽  
Sequencing Depth ◽  
List Type ◽  
Malaise Trap ◽  
Size Fractions ◽  
Size Classes ◽  
Size Sorting ◽  
The Individual ◽  
Size Heterogeneity ◽  
Wet Sieving

AbstractSmall and rare specimens can remain undetected when metabarcoding bulk samples with a high size heterogeneity of specimens. This is especially critical for malaise trap samples, where most of the biodiversity is often contributed by small specimens. How to size sort and in which proportions to pool these samples has not been widely explored. We set out to find a size sorting strategy that maximizes taxonomic recovery but remains highly scalable and time efficient.Three 3 malaise trap samples where size sorted into 4 size classes using dry sieving. Each fraction was homogenized and lysed. The corresponding lysates were pooled to simulate samples never sorted, pooled in equal proportions and in 4 different proportions favoring the small size fractions. DNA from the pooled fractions as well as the individual size classes were extracted and metabarcoded using the FwhF2 and Fol-degen-rev primer set. Additionally wet sieving strategies were explored.The small size fractions harbored the highest diversity, and were best represented when pooling in favor of small specimens. Not size sorting a sample leads to a 45-77% decrease in taxon recovery compared to size sorted samples. A size separation into only 2 fractions (below 4 mm and above) can already double taxon recovery compared to not sorting. However, increasing the sequencing depth 3-4 fold can also increase taxon recovery to comparable levels, but remains biased toward biomass rich taxa in the sample.We demonstrate that size fractionizing bulk malaise samples can increase taxon recovery. The most practical approach is wet sieving into two size fractions, and proportional pooling of the lysates in favor of the small size fraction (80-90% volume). However, in large projects with time constraints, increasing sequencing depth can also be an alternative solution.

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