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Abstract The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease.

BackgroundTransforming growth factor (TGF)-ß1 is a pleiotropic cytokine that can promote tumor growth and suppress antitumor immune responses. Latent TGF-ß1 associates with glycoprotein-A repetition predominant (GARP) on the surface of regulatory T cells prior to its activation and release. Livmoniplimab is a monoclonal antibody (mAb) that binds the GARP:TGF-ß1 complex to inhibit activation and release of TGF-ß1. It is in clinical development in combination with budigalimab, an anti-programmed cell death protein 1 Fc-modified mAb. The first-in-human, phase 1, dose-escalation results are presented herein (ClinicalTrials.gov: NCT03821935).MethodsThe dose-escalation phase enrolled adult patients with advanced solid tumors. Patients received escalating doses of livmoniplimab ranging from 3mg to 1500mg, once every 2 weeks (Q2W), as monotherapy or in combination with a 500mg fixed dose of budigalimab Q4W. The primary objective of the dose escalation was to determine the recommended phase 2 dose. Secondary objectives were to assess safety and pharmacokinetics (PK), and exploratory objectives included evaluating preliminary efficacy.ResultsFifty-seven patients enrolled in the dose escalation: 23 in monotherapy cohorts and 34 in combination therapy cohorts. Dose-limiting toxicities were limited, no maximum tolerated dose was reached, and the maximum administered dose of 1500mg was selected for dose expansion. The most common adverse events reported in monotherapy-treated patients were fatigue, anemia, and nausea, and those in combination therapy-treated patients were pruritus, fatigue, nausea, and anemia. Livmoniplimab exhibited dose-proportional PK, and peripheral blood biomarker data demonstrated saturation of the GARP:TGF-ß1 complex on platelets at livmoniplimab doses within the linear PK range. No objective tumor responses were observed in the monotherapy dose escalation. However, the objective response rate was 15% in the combination dose escalation, with a median response duration of 8.4 months.ConclusionLivmoniplimab was well-tolerated as monotherapy and in combination with budigalimab in the dose-escalation phase. Encouraging preliminary efficacy was demonstrated in the combination dose escalation in heavily pretreated patients, supporting further development of this novel drug combination in patients with advanced solid tumors.

Abstract Hydrogen can have an impact on the service life of safety critical components, such as coolant pipes in nuclear reactors, where it may interact with other factors including irradiation. Hence, it is important to characterise such behaviour which in turn requires the capability to charge representative material specimens with hydrogen and to quantity the levels of hydrogen present. Hydrogen concentrations resulting from cathodic charging of 316LN stainless steel over short time periods (

Abstract Cancer immunotherapy has significantly advanced the treatment paradigm in oncology, with approvals of immuno‐oncology agents for over 16 indications, many of them first line. Checkpoint inhibitors (CPIs) are recognized as an essential backbone for a successful anticancer therapy regimen. This review focuses on the US Food and Drug Administration (FDA) regulatory approvals of major CPIs and the evolution of translational advances since their first approval close to a decade ago. In addition, critical preclinical and clinical pharmacology considerations, an overview of the pharmacokinetic and dose/regimen aspects, and a discussion of the future of CPI translational and clinical pharmacology as combination therapy becomes a mainstay of industrial immunotherapy development and in clinical practice are also discussed.

Ulcerative colitis and gastric ulcer are ulcers of gastrointestinal track, especially associated with elevated oxidative stress and inflammation. Dimethyl fumarate (DMF) is used for the treatment of multiple sclerosis and psoriasis and is considered useful in a variety of conditions associated with inflammation. We have investigated the effect of oral DMF (1, 10, 25, 50, 100, 200 mg/kg) in ethanol-induced gastric ulcers in rats. The effect of oral (15, 30, and 60 mg/kg) and intracecal (15 mg/kg) DMF was also investigated in dextran sulfate sodium (DSS)-induced colitis in mice. Treatment of DMF by oral route prevented the development of ethanol-induced gastric ulcers by decreasing oxidative stress in a dose-related manner. Oral and intracecal administration of DMF attenuated body weight loss, increase in disease activity score, colon length shortening, colon weight loss, inflammation and fibrosis, and decreased myeloperoxidase activity. Oral and intracecal DMF prevented a decrease in hemoglobin and suppressed oxidative stress, and also decreased MCP-1, IL-1ß, and IL-6 levels in the inflamed colon. Unlike oral DMF, intracecal DMF treatment did not reduce spleen weight. The effect of intracecal DMF was similar to the highest tested dose of oral DMF (60 mg/kg). These results demonstrated that intracecal DMF suppresses inflammation and oxidative stress in ethanol and DSS-induced colitis without alteration of spleen weight. This suggests that the localized DMF administration could be beneficial approach of treating gastrointestinal ulcers.

Hitachi is advancing their designs for a conceptual reactor called the resource-renewable boiling water reactor (RBWR), a concept reactor similar to the advanced boiling water reactor with a harder neutron spectrum. This design aims to minimise construction costs and waste production as well as to utilise separated plutonium and minor actinide fuel. However, the axial heterogeneity of the design poses calculation difficulties. The aim of this work is to use a known method, reactivity-equivalent physical transformation (RPT), for calculating fuel with double heterogeneity and apply it to a BWR-type fuel pin. This could reduce the calculation time needed for optimisation of the design of the RBWR. The objective of the study is to use SCALE 6.2 to produce an equivalent axial pin model by comparison with the burnup and neutron spectra of a radial model of the fuel. This model can then be used for 2D burnup calculations, and in future work will be used for the generation of two-group and multigroup cross-sections for further deterministic calculations as part of a two-step approach for analysis of the RBWR. The RPT method has been extensively tested on spherical fuel, and SCALE is a standard industry code. The initial radial model is a hexagonal assembly with 20% enriched UO2 fuel in a zircaloy cladding, surrounded by light water moderator. The derived axial model has a water density distribution taken from Hitachi’s RBWR designs. Criticality over 70 GWd/tU burnup is estimated using the model. The application of the RPT to the BWR pin was shown to be possible, but to have limitations with the introduction of additional radial complexity. For a single pin, excellent agreement between the radial and axial models could be found across a range of water densities, but in the case of an assembly level calculation distinct equivalence models were required for each water density. In addition, the produced RPT model is validated using SCALE’s 3D Monte Carlo module, KENO.

Traditionally, there has been a gap between reactor operation and the consideration of nuclear waste in the final disposal. Fuel is produced, and fuel must be disposed. In the view of the reactor operator, fuel has to be cleaned in the reprocessing, and new solid fuel has to be produced in the view of the chemist. iMAGINE is designed to overcome this separation through a breakthrough development applying an optimized, integrative approach from cradle to grave of nuclear energy production as a first step to come as close as possible to the vision of zero waste nuclear power. It is described here for the first time in three steps: reactor, fuel cycle, and waste, providing the rationality behind each of the choices made to come to the overall solution to open the discussion and thinking process on what could be achieved by a very innovative approach to integrated nuclear energy production. The opportunities regarding the handling of the remaining waste are discussed with a view on the expectation of the final disposal community, the study “Nuclear waste from small modular reactors”, and the IAEA report “waste from innovative types of reactors and fuel cycles—a preliminary study”. The aim of this work is not to find answers to each of the raised points, but to identify potential approaches and promising ways to go, as well as to stimulate a discussion among experts. In the best case, this could lead to a change of track for nuclear power to become even more sustainable and an important, trusted technology to help solve the net-zero challenge.

Abstract Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host’s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14–15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual’s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4–5, 2019.

We report the complete genome sequencing of novel Pseudomonas stutzeri strain MP4687 isolated from cattle rumen. Various strains of P. stutzeri have been reported from different environmental samples including oil-contaminated sites, crop roots, air, and human clinical samples, but not from rumen samples, which is being reported here for the first time. The genome of P. stutzeri MP4687 has a single replicon, 4.75 Mb chromosome and a G + C content of 63.45%. The genome encodes for 4,790 protein coding genes including 164 CAZymes and 345 carbohydrate processing genes. The isolate MP4687 harbors LCB hydrolyzing potential through endoglucanase (4.5 U/mL), xylanase (3.1 U/mL), β-glucosidase (3.3 U/mL) and β-xylosidase (1.9 U/mL) activities. The pangenome analysis further revealed that MP4687 has a very high number of unique genes (>2100) compared to other P. stutzeri genomes, which might have an important role in rumen functioning.

Abstract Anti-cancer immunotherapy is encountering its own checkpoint. Responses are dramatic and long lasting but occur in a subset of tumors and are largely dependent upon the pre-existing immune contexture of individual cancers. Available data suggest that three landscapes best define the cancer microenvironment: immune-active, immune-deserted and immune-excluded. This trichotomy is observable across most solid tumors (although the frequency of each landscape varies depending on tumor tissue of origin) and is associated with cancer prognosis and response to checkpoint inhibitor therapy (CIT). Various gene signatures (e.g. Immunological Constant of Rejection - ICR and Tumor Inflammation Signature - TIS) that delineate these landscapes have been described by different groups. In an effort to explain the mechanisms of cancer immune responsiveness or resistance to CIT, several models have been proposed that are loosely associated with the three landscapes. Here, we propose a strategy to integrate compelling data from various paradigms into a “Theory of Everything”. Founded upon this unified theory, we also propose the creation of a task force led by the Society for Immunotherapy of Cancer (SITC) aimed at systematically addressing salient questions relevant to cancer immune responsiveness and immune evasion. This multidisciplinary effort will encompass aspects of genetics, tumor cell biology, and immunology that are pertinent to the understanding of this multifaceted problem.

MicroRNAs are a newly discovered class of non-protein small RNAs with 22–24 nucleotides. They play multiple roles in biological processes including development, cell proliferation, apoptosis, stress responses and many other cell functions. In this research, several approaches were combined to make a computational prediction of potential miRNAs and their targets in Helianthus annuus (H. annuus). The already available information of the plant miRNAs present in miRBase v21 was used against expressed sequence tags (ESTs). A total of three miRNAs were detected from which one potential novel miRNA was identified following a range of strict filtering criteria. The target prediction was carried out for these three miRNAs having various targets. These targets were functionally annotated and GO terms were assigned. To study the conserved nature of the miRNAs, predicted phylogenetic analysis was carried out. These findings will significantly provide the broader picture for understanding the functions in H. annuus.

The effects of methyl jasmonate (MeJA), an elicitor of plant defense mechanisms, on the biosynthesis of diosgenin, a steroidal saponin, were investigated in six fenugreek (Trigonella foenum-graecum) varieties (Gujarat Methi-2, Kasuri-1, Kasuri-2, Pusa Early Branching, Rajasthan Methi and Maharashtra Methi-5). Treatment with 0.01% MeJA increased diosgenin levels, in 12 days old seedlings, from 0.5%–0.9% to 1.1%–1.8%. In addition, MeJA upregulated the expression of two pivotal genes of the mevalonate pathway, the metabolic route leading to diosgenin: 3-hydroxy-3-methylglutaryl-CoA reductase (HMG) and sterol-3-β-glucosyl transferase (STRL). In particular, MeJA increased the expression of HMG and STRL genes by 3.2- and 22.2-fold, respectively, in the Gujarat Methi-2 variety, and by 25.4- and 28.4-fold, respectively, in the Kasuri-2 variety. Therefore, MeJA may be considered a promising elicitor for diosgenin production by fenugreek plants.

Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.

Assembling novel genomes from scratch is a never ending process unless and until the homo sapiens cover all the living organisms! On top of that, this denovo approach is employed by RNASeq and Metagenomics analysis. Functional identification of the scaffolds or transcripts from such drafted assemblies is a substantial step routinely employes a well-known BlastX program which facilitates a user to search DNA query against NCBI-Protein (NR:~120Gb) database. In spite of having multicore-processing option, blastX is an elongated process for the bulk of lengthy Queryinputs. Tremendous efforts are constantly being applied to solve this problem by increasing computational power, GPU-Based computing, Cloud computing and Hadoop based approach which ultimately requires gigantic cost in terms of money and processing. To address this issue, here we have come up with SHIVGAMI, which automates the entire process using perl and shell scripts, which divide, distribute and process the input FASTA sequences as per the CPU-cores availability amongst the computational units individually. Linux operating system, NR database and blastX program installations are prerequisites for each system. The beauty of this stand-alone automation program SHIVGAMI is it requires the LAN connection exactly twice: During ‘query distribution’ and at the time of ‘proces completion’. In initial phase, it divides the fasta sequences according to the individual computer's core-capability. Then it will evenly distribute all the data along with small automation scripts which will run the blastX process to the respective computational unit and send back the results file to the master computer. The master computer finally combines and compiles the files into a single result. This simple automation converts a computer lab into a GRID without investment of any software, hardware and man-power. In short, SHIVGAMI is a time and cost savior tool for all users starting from commercial firm to a common man, utilises the "Little Drops of Water make a Mighty Ocean" concept without any requirement of parallel processing. The automation and compilation of SHIVGAMI is under process and will be freely available shortly to the users.

MicroRNAs are a newly discovered class of non-protein small RNAs with 22-24 nucleotides and evolutionary conserved post-transcriptional regulatory RNAs, which shows an enormous role in several biological and metabolic process. Plant derived miRNA entered into the body fluid and regulated the expression of host mRNA. Salvia miltiorrhiza is an important medicinal plant known for its potent cardiovascular and anticancer activity and hence, it was selected to identify the cross kingdom regulatory mechanism between medicinal plant and human. In this study, total 8 highly stable putative novel miRNA were predicted from the publically available ESTs of Salvia miltiorrhiza, out of which 2 miRNA were found to be regulating 32 target genes in human. Functional annotation, gene ontology and network analysis were carried out based on their significance and find out the association with the prominent disease like cancer and cardiac diseases. The network analysis showed the some important network protein like SOCS2, CD274, STAT3, TRAF3 and CXCL2 with their associated pathways. The predicted miRNA have a significant potential role in cytokine, Apoptosis and EGFR receptor signaling pathways and its biological regulation. It may be further validated using in-vivo experiment for broader picture into their miRNA epigenetic mechanism and action.

Next Generation Sequencing (NGS) exhibited rapid developments through its high speed sequence annotation and assembly tasks which has changed the perspectives of genome era. NGS brings the great power to make several new biological observations and discoveries from genomes and helped in the growth of allied areas including Metagenomics, De novo sequencing, Amplicon Analysis, Transcriptomics and Small RNA profiling. Carica papaya small RNA sequencing helps in the understanding the role of known miRNA and identification of novel miRNA. Functional genomics often begins with studying the gene expression patterns and identification of potential targets that relies on the assumption of small RNA and the mRNA (target) sequence complementarity. The identification of Known miRNA sequences are searched through against the current miRBase version and sequences with less than 2 mismatches with known miRNAs in miRBase was considered and 1724 known miRNA depicted. Computational algorithms predict miRNA targets on the basis of the presumed mode of miRNA–mRNA interactions and also depend on the conservation of their binding sites. The mirDeep prediction software is used to predict new miRNAs where 11 novel miRNA are estimated. In addition, the functional studies of small RNAs can rely on conventional genetic strategies. Intriguingly, the advent of fast and cost effective NGS platforms in the recent past has enabled the proliferation of new ideas regarding the application of characteristic gene structures to different species.

Malaria is a malignant disease which is growing all over the world and its causative agent. Plasmodium species easily develops resistant to commonly used antimalarial drugs easily. These empower different strains of Plasmodium e.g. Plasmodium falciparum and Plasmodium vivax to infect humans with malaria. To get the deeper molecular insights, next generation sequencing data were used for further analysis as it has shifted the paradigm of genomics to address biological questions with high confidence and in timely manner. The short reads for above mentioned parasites were retrieved from SRA (Sequence read archive) and de novo assembly was performed. Several novel genes along with known genes were predicted from assembled contigs, Functional annotation followed by gene ontology and pathway analysis. Comparison between species gave structural and functional diversity of the specific genes responsible for disease condition which further can be studied for disease biology.