bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single Cell T Cell Receptor Repertoire Profiling for Dogs
Authors: Skidmore Zachary L. , Rindt Hans , Chu Shirley , Fisk Bryan , Fronick Catrina , Fulton Robert , Zhou Mingyi , Bivens Nathan J. , Reinero Carol N. , Griffith Malachi , Bryan Jeffrey N. , Griffith Obi L. 
Published: July 2021

AbstractBackgroundSpontaneous cancers in companion dogs are increasingly recognized as robust models of human disease. This recognition has led to translational clinical trials in companion dogs with osteosarcoma, lymphoma, melanoma, squamous cell carcinoma, and soft tissue sarcoma. The ability to precisely track tumor-specific immune responses in such clinical trials would benefit from reagents to perform species-specific single cell T cell receptor sequencing (scTCRseq). This technology defines clones of T cells reacting to immune interventions and can help identify the specific epitope of response. Single cell gene expression data give insights into the activity and polarization of the T cell. To date, scTCRseq has not been demonstrated for canine samples.MethodsSamples from two responding dogs in a trial of an autologous deglycosylated melanoma vaccine were selected to demonstrate applicability of scTCRseq in a cancer immunotherapy setting. A single-cell suspension of cryopreserved peripheral blood mononuclear cells (PBMC) was prepared for 10X single cell sequencing. Full length 10X cDNA was amplified using a custom-designed nested PCR of the alpha/beta V(D)J region. A library made from this enriched product (scTCRseq) and a 10X gene expression (GEX) library (scRNAseq) were sequenced on the NovaSeq 6000.Results1,850-2,172 estimated V(D)J-expressing cells yielded 87-103.7 million reads with 73.8%-75.8% mapped to a V(D)J gene (beta/alpha chains ratio 1.5:1). 43 TRAJ, 29 TRAV, 12 TRBJ, and 22 TRBV gene segments were observed representing 72.9%, 51.8%, 100%, and 62.9% of all known V and J gene segments respectively. A large diversity of clonotypes was captured with 966-1,253 TRA/TRB clonotypes identified. Both dogs also exhibited a small number of highly abundant T cell clonotypes suggesting the presence of an anti-tumor T cell population. GEX enriched libraries successfully defined large clusters of CD8+ and CD4+ T cells that overlapped with V(D)J-expressing cells.DiscussionThe developed reagents successfully generated scTCRseq data, for the first time, which allowed the T cell repertoire to be surveyed in dogs responding to anti-tumor immunotherapy. These reagents will allow longitudinal tracking of anti-tumor T cell dynamics in canine cancer immunotherapy trials.
Epitope order Matters in multi-epitope-based peptide (MEBP) vaccine design: Anin silicostudy
Authors: Salaikumaran Muthu Raj , Kasamuthu Prasanna Sudharson , Burra V L S Prasad 
Published: July 2021

AbstractWith different countries facing multiple waves, with some SARS-CoV-2 variants more deadly and virulent, the COVID-19 pandemic is becoming more dangerous by the day and the world is facing an even more dreadful extended pandemic with exponential positive cases and increasing death rates. There is an urgent need for more efficient and faster methods of vaccine development against SARS-CoV-2. Compared to experimental protocols, the opportunities to innovate are very high in immunoinformatics/in silicoapproaches especially with the recent adoption of structural bioinformatics in peptide vaccine design. In recent times, multi-epitope-based peptide vaccine candidates (MEBPVCs) have shown extraordinarily high humoral and cellular responses to immunization. Most of the publications claim that respective reported MEBPVC(s) assembled using a set ofin silicopredicted epitopes, to be the computationally validated potent vaccine candidate(s) ready for experimental validation. However, in this article, for a given set of predicted epitopes, it is shown that the published MEBPVC is one among the many possible variants and there is high likelihood of finding more potent MEBPVCs than the published candidate. To test the same, a methodology is developed where novel MEBP variants are derived by changing the epitope order of the published MEBPVC. Further, to overcome the limitations of current qualitative methods of assessment of MEBPVC, to enable quantitative comparison, ranking, and the discovery of more potent MEBPVCs, novel predictors, Percent Epitope Accessibility (PEA), Receptor specific MEBP vaccine potency(RMVP), MEBP vaccine potency(MVP) are introduced. The MEBP variants indeed showed varied MVP scores indicating varied immunogenicity. When the MEBP variants were ranked in descending order of their MVP scores, the published MEBPVC had the least MVP score. Further, the MEBP variants with IDs, SPVC_387 and SPVC_206, had the highest MVP scores indicating these variants to be more potent MEBPVCs than the published MEBPVC and hence should be prioritized for experimental testing and validation. Through this method, more vaccine candidates will be available for experimental validation and testing. This study also opens the opportunity to develop new software tools for designing more potent MEBPVCs in less time. The computationally validated top-ranked MEBPVCs must be experimentally tested, validated, and verified. The differences and deviations between experimental results and computational predictions provide an opportunity for improving and developing more efficient algorithms and reliable scoring schemes and software.
Comparative computational modeling of the bat and human immune response to viral infection with the Comparative Biology Immune Agent Based Model
Authors: Cockrell Chase , An Gary 
Published: July 2021

AbstractGiven the impact of pandemics due to viruses of bat origin there is increasing interest in comparative investigation into the differences between bat and human immune responses. The practice of comparative biology can be enhanced by computational methods used for dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. We present an agent-based model that encompasses and bridges the differences between bat and human responses to viral infection: the Comparative Biology Immune Agent-based Model, or CBIABM. The CBIABM examines differences in innate immune mechanisms between bats and humans, specifically regarding inflammasome activity and Type 1 Interferon dynamics, in terms of tolerance to viral infection. Simulation experiments with the CBIABM demonstrate the efficacy of bat-related features in conferring viral tolerance and also suggest a crucial role for endothelial inflammasome activity as a mechanism for bat systemic viral tolerance and affecting the severity of disease in human viral infections. We hope that this initial study will inspire additional comparative modeling projects to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and aid in the preparation for future viral pandemics of zoonotic origin.
Benchmarking supervised signature-scoring methods for single-cell RNA sequencing data in cancer
Authors: Noureen Nighat , Ye Zhenqing , Chen Yidong , Wang Xiaojing , Zheng Siyuan 
Published: July 2021

AbstractQuantifying the activity of gene expression signatures is common in analyses of single-cell RNA sequencing data. Methods originally developed for bulk samples are often used for this purpose without accounting for contextual differences between bulk and single-cell data. More broadly, these methods have not been benchmarked. Here we benchmark four such supervised methods, including single sample gene set enrichment analysis (ssGSEA), AUCell, Single Cell Signature Explorer (SCSE), and a new method we developed, Jointly Assessing Signature Mean and Inferring Enrichment (JASMINE). Using cancer as an example, we show cancer cells consistently express more genes than normal cells. This imbalance leads to bias in performance by bulk-sample-based ssGSEA in gold standard tests and down sampling experiments. In contrast, single-cell-based methods are less susceptible. Our results suggest caution should be exercised when using bulk-sample-based methods in single-cell data analyses, and cellular contexts should be taken into consideration when designing benchmarking strategies.
Metabolic and transcriptomic profiles of glioblastoma invasion revealed by comparisons between patients and corresponding orthotopic xenografts in mice
Authors: Cudalbu Cristina , Bady Pierre , Lai Marta , Xin Lijing , Gusyatiner Olga , Hamou Marie-France , Lepore Mario , Brouland Jean Philippe , Daniel Roy T. , Hottinger Andreas F. , Hegi Monika E. 
Published: July 2021

AbstractThe invasive behavior of glioblastoma, the most aggressive primary brain tumor, is considered highly relevant for tumor recurrence. However, the invasion zone is difficult to visualize by Magnetic Resonance Imaging (MRI) and is protected by the blood brain barrier, posing a particular challenge for treatment. We report biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes observed in patient derived orthotopic xenografts (PDOX) in the mouse and the corresponding patients’ tumors. The evolution of metabolic changes, followedin vivolongitudinally by1H-Magnetic Resonance Spectroscopy (MRS) at ultra-high field, reflected growth and the invasive properties of the human glioblastoma transplanted into the brains of mice (PDOX). Comparison of MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel MRS analyses sampled across different areas of the patients’ tumors. Pathway analyses of the transcriptome associated with the metabolite profiles of the PDOX, identified molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Specific analysis of expression signatures from the invaded mouse brain, revealed extent of invasion dependent induction of immune response, recapitulating respective signatures observed in glioblastoma. Integrating metabolic profiles and gene expression of highly invasive PDOX provided insights into progression and invasion associated mechanisms of extracellular matrix remodeling that is essential for cell-cell communication and regulation of cellular processes. Structural changes and biochemical properties of the extracellular matrix are of importance for the biological behavior of tumors and may be druggable. Ultra-high field MRS reveals to be suitable forin vivomonitoring of progression in the non-enhancing infiltration zone of glioblastoma.
Promoting long-term forest landscape resilience in the Lake Tahoe basin
Authors: Abelson Eric S. , Reynolds Keith M. , White Angela M. , Long Jonathan W. , Maxwell Charles , Manley Patricia N. 
Published: July 2021

ABSTRACTRapid environmental changes expected in the 21stcentury challenge the resilience of wildlands around the world. The western portion of the Lake Tahoe basin (LTW) in California is an important ecological and cultural hotspot that is at risk of degradation from current and future environmental pressures. Historical uses, fire suppression, and a changing climate have created forest landscape conditions at risk of drought stress, destructive fire, and loss of habitat diversity. We prospectively modeled forest landscape conditions for a period of 100 years to evaluate the efficacy of five unique management scenarios in achieving desired landscape conditions across the 23,600 hectares of LTW. Management scenarios ranged from no management other than fire suppression to applying treatments consistent with historical fire frequencies and extent (i.e., regular and broadscale biomass reduction). We developed a decision support tool to evaluate environmental and social outcomes within a single framework to provide a transparent set of costs and benefits; results illuminated underlying mechanisms of forest resilience and provided actionable guidance to decision makers. Sixteen attributes were assessed in the model after assigning weights to each, derived through a survey of stakeholder priorities, so that the contribution of each attribute to evaluations of scenario performance was influenced by the combined priorities of stakeholders. We found that removing forest biomass across the landscape, particularly when accomplished using extensive fire-based removal techniques, led to highly favorable conditions for environmental quality and promoting overall landscape resilience. Environmental conditions resulting from extensive fire-based biomass removal also had nominal variation over time, in contrast with strategies that had less extensive and/or used physical removal techniques, namely thinning. Our analysis provided a transparent approach to data assessment, considering the priorities of stakeholders, to provide insights into the complexities of maintaining optimal conditions and managing landscapes to promote ecosystem resilience in a changing world.
The Lifespan and Levels of Oxidative Stress between Feral and Managed Honey Bee Colonies
Authors: Ward Kilea , Li-Byarlay Hongmei 
Published: July 2021

AbstractMolecular damage caused by oxidative stress may lead to organismal aging and resulted in acute mortality in organisms. Oxidative stress resistance and longevity are closely linked. Honey bees are the most important managed pollinator in agriculture but the long-term survival of honey bees is seriously threatened. Feral honey bee colonies displayed persistence to Varroa mites. However, it is unknown whether feral honey bees are stress-resistant or survive longer than managed bee populations. More work is needed to determine the impact of oxidative stress on honey bee health and survival. We used the paired colony design to determine the lifespan and levels of oxidative stress on worker bees from either a feral or a managed colony. Each pair of colonies shared similar foraging resources. Results exhibit longer survival time and lifespans of foragers in feral colonies than the managed colonies. The levels of oxidative stress from the lipid damage of feral colonies are higher than the managed colonies, indicating a tolerant mechanism not a repair mechanism to survive. Our study provided new insights into colony difference of physiology and oxidative stress resistance between feral honey bees and commercial stocks.
Aspirin Protective Effect Against Cyclophosphamide Hematological Toxicity In Experimental Animals
Authors: Hashim Imad , Al-Attar Zaid , Hamdan Saba Jasim 
Published: July 2021

ABSTRACTBone marrow toxicity is the most important factor limiting the use of cytotoxic drugs like alkylating agents in cancer treatment. Recently PG synthase enzyme inhibitors have been reported to potentiate the cytotoxic effects of these agents on cancer cells but little is known if they can affect the toxicity of these agents on bone marrow or other tissues. Cyclophosphamide is one of the most commonly used alkylating agent.In the present work, the effect of these PG synthase enzyme inhibitors, aspirin on cyclophosphamide myelotoxicity was determined employing the peripheral blood count to reflect bone marrow injury. The effect on body weight changes caused by cyclophosphamide was also determined.Cyclophosphamide in doses of 25, 50 and 75 mg/kg i. v. produced as a dose dependent reduction in total WBC count, granulocyte, non granulocyte, and Hb% which was maximum on second day after injection and still present on 5th day post injection. It also produced a dose dependent reduction in body weight on day 5 after injection.Aspirin in doges of 75, 150 and 300 mg/kg i. m. protected against the reduction in WBC counts ‘measured for 5 days after injection of cyclophosphamide (50 mg/kg). This protection was not dose dependent, though it was more optimum with 300 mg/kg and disappeared largely when a dose of 450 mg/kg was used. Aspirin did not prevent the changes in Hb% but retard the reduction in body weight caused by cyclophosphamide.It is concluded that aspirin can help to reduce injury and enhance recovery from bone marrow toxicity caused by cytotoxic agents such as the alkylating drugs cyclophosphamide for which no specific antidote is available. Aspirin produces this effect possibly by eliminating the harmful inhibitory effect of excess PGs or leukotrienes, released by bone marrow injury on growth factors of haemopoietic progenitor cells.The magnitude of this protection on WBC counts does not seem to differ between either PG synthase enzyme inhibitors or steroids when used alone or in combination although a synergistic effect in protecting erythropoiesis is observed.
Host cellular RNA helicases regulate SARS-CoV-2 infection
Authors: Ariumi Yasuo 
Published: July 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has largest RNA genome of approximately 30kb among RNA viruses. The DDX DEAD-box RNA helicase is a multifunctional protein involved in all aspects of RNA metabolism. Therefore, host RNA helicases may regulate and maintain such large viral RNA genome. In this study, I investigated the potential role of several host cellular RNA helicases in SARS-CoV-2 infection. Notably, DDX21 knockdown markedly accumulated intracellular viral RNA and viral production, as well as viral infectivity of SARS-CoV-2, indicating that DDX21 strongly restricts the SARS-CoV-2 infection. As well, MOV10 RNA helicase also suppressed the SARS-CoV-2 infection. In contrast, DDX1, DDX5, and DDX6 RNA helicases were required for SARS-CoV-2 replication. Indeed, SARS-CoV-2 infection dispersed the P-body formation of DDX6 and MOV10 RNA helicases as well as XRN1 exonuclease, while the viral infection did not induce stress granule formation. Accordingly, the SARS-CoV-2 nucleocapsid (N) protein interacted with DDX6, DDX21, and MOV10 and disrupted the P-body formation, suggesting that SARS-CoV-2 N hijacks DDX6 to utilize own viral replication and overcomes their anti-viral effect of DDX21 and MOV10 through as interaction with host cellular RNA helicase. Altogether, host cellular RNA helicases seem to regulate the SARS-CoV-2 infection.ImportanceSARS-CoV-2 has large RNA genome of approximately 30kb. To regulate and maintain such large viral RNA genome, host RNA helicases may involve in SARS-CoV-2 replication. In this study, I have demonstrated that DDX21 and MOV10 RNA helicases limit viral infection and replication. In contrast, DDX1, DDX5 and DDX6 are required for the SARS-CoV-2 infection. Interestingly, the SARS-CoV-2 infection disrupted P-body formation and attenuated or suppressed stress granule formation. Thus, SARS-CoV-2 seems to hijack host cellular RNA helicases to play a proviral role by facilitating viral infection and replication and, by suppressing host innate immune system.
Highly-Neutralizing COVID-19-Convalescent-Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters
Authors: Takamatsu Yuki , Imai Masaki , Maeda Kenji , Nakajima Noriko , Higashi-Kuwata Nobuyo , Iwatsuki-Horimoto Kiyoko , Ito Mutsumi , Kiso Maki , Maemura Tadashi , Takeda Yuichiro , Omata Kazumi , Suzuki Tadaki , Kawaoka Yoshihiro , Mitsuya Hiroaki 
Published: July 2021

ABSTRACTDespite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma (hn-plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn-plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas (mn-plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn-plasmas also reduced viral titers in lungs than those from the two mn-plasmas. The severity of lung lesions seen in hamsters receiving hn-plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19.ImportanceConvalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.
Locating and Quantifying Carbon Steel Corrosion Rates Linked to Fungal B20 Biodiesel Degradation
Authors: Floyd James G. , Stamps Blake W. , Goodson Wendy J. , Stevenson Bradley S. 
Published: July 2021

ABSTRACTFungi that degrade B20 biodiesel in storage tanks have also been linked to microbiologically influenced corrosion (MIC). A member of the filamentous fungal genus Byssochlamys, and a yeast from the genus Wickerhamomyces were isolated from heavily contaminated B20 storage tanks from multiple Air Force bases. Although these taxa were linked to microbiologically influenced corrosion in situ, precise measurement of their corrosion rates and pitting severity on carbon steel was not available. In the experiments described here, we directly link fungal growth on B20 biodiesel to higher corrosion rates and pitting corrosion of carbon steel under controlled conditions. When these fungi were growing solely on B20 biodiesel for carbon and energy, consumption of FAME and n-alkanes was observed. The corrosion rates for both fungi were highest at the interface between the B20 biodiesel and the aqueous medium, where they acidified the medium and produced deeper pits than abiotic controls. Byssochlamys produced the most corrosion of carbon steel and produced the greatest pitting damage. This study characterizes and quantifies the corrosion of carbon steel by fungi that are common in fouled B20 biodiesel through their metabolism of the fuel, providing valuable insight for assessing MIC associated with storage and dispensing B20 biodiesel.IMPORTANCEBiodiesel is widely used across the United States and worldwide, blended with ultralow sulfur diesel in various concentrations. In this study we were able to demonstrate that the filamentous fungi Byssochlamys AF004 and the yeast Wickerhamomyces SE3 were able to degrade fatty acid methyl esters and alkanes in biodiesel causing increases in acidity. Both fungi also accelerated the corrosion of carbon steel, especially at the interface of the fuel and water, where their biofilms were located. This research provides controlled, quantified measurements and the localization of microbiologically influenced corrosion caused by common fungal contaminants in biodiesel fuels.