title: Sweetness

text: The development of organic chemistry in the 19th century introduced many new chemical compounds and the means to determine their molecular structures. Early organic chemists tasted many of their products, either intentionally (as a means of characterization) or accidentally (due to poor laboratory hygiene). One of the first attempts to draw systematic correlations between molecules' structures and their tastes was made by a German chemist, Georg Cohn, in 1914. He hypothesized that to evoke a certain taste, a molecule must contain some structural motif (called a "sapophore") that produces that taste. With regard to sweetness, he noted that molecules containing multiple hydroxyl groups and those containing chlorine atoms are often sweet, and that among a series of structurally similar compounds, those with smaller molecular weights were often sweeter than the larger compounds.


title: Sweetness

text: In 1919, Oertly and Myers proposed a more elaborate theory based on a then-current theory of color in synthetic dyes. They hypothesized that to be sweet, a compound must contain one each of two classes of structural motif, a "glucophore" and an "auxogluc". Based on those compounds known to be sweet at the time, they proposed a list of six candidate glucophores and nine auxoglucs.


title: Sweetness

text: From these beginnings in the early 20th century, the theory of sweetness enjoyed little further academic attention until 1963, when Robert Shallenberger and Terry Acree proposed the AH-B theory of sweetness. Simply put, they proposed that to be sweet, a compound must contain a hydrogen bond donor (AH) and a Lewis base (B) separated by about 0.3 nanometres. According to this theory, the AH-B unit of a sweetener binds with a corresponding AH-B unit on the biological sweetness receptor to produce the sensation of sweetness.


title: Sweetness

text: B-X theory proposed by Lemont Kier in 1972. While previous researchers had noted that among some groups of compounds, there seemed to be a correlation between hydrophobicity and sweetness, this theory formalized these observations by proposing that to be sweet, a compound must have a third binding site (labeled X) that could interact with a hydrophobic site on the sweetness receptor via London dispersion forces. Later researchers have statistically analyzed the distances between the presumed AH, B, and X sites in several families of sweet substances to estimate the distances between these interaction sites on the sweetness receptor.


title: Sweetness

text: The most elaborate theory of sweetness to date is the multipoint attachment theory (MPA) proposed by Jean-Marie Tinti and Claude Nofre in 1991. This theory involves a total of eight interaction sites between a sweetener and the sweetness receptor, although not all sweeteners interact with all eight sites. This model has successfully directed efforts aimed at finding highly potent sweeteners, including the most potent family of sweeteners known to date, the guanidine sweeteners. The most potent of these, lugduname, is about 225,000 times sweeter than sucrose.


title: N'Bushe Wright

text: N'Bushe Wright ( ; born September 7, 1969) is an American actress and dancer. She attended and trained as a dancer at the Alvin Ailey Dance Center and the Martha Graham School of Dance. She is known mainly for her role as Dr. Karen Jenson in the 1998 feature film "Blade".


title: N'Bushe Wright

text: Within a year of attending Stella Adler's Studio, Wright was starring in Anthony Drazan's "Zebrahead" (1992). She received positive reviews for her moving portrayal of the drug-addicted older sister of the title protagonist in Boaz Yakin's "Fresh" (1994). The following year, Wright played an idealistic member of the Black Panther Party in the Hughes Brothers' feature film "Dead Presidents" (1995). Wright played Dr. Karen Jenson in "Blade" (1998).


title: N'Bushe Wright

text: In 1992, Wright played the recurring role of Claudia, a black civil rights activist fighting for equal opportunities in education in the acclaimed but short-lived NBC television drama "I'll Fly Away". She has made guest appearances on several other television series, including "New York Undercover", "", "Chappelle's Show" and "Third Watch".


title: N'Bushe Wright

text: Wright attended the Manhattan High School for the Performing Arts. A native of Brooklyn, Wright's mother was a psychologist with the New York City Board of Education, who died in 2009 after 40+ years of marriage to Wright's father, jazz musician Stanley Wright a.k.a. Suleiman-Marim Wright, who was murdered in 2011.


title: RNA-Seq

text: RNA-Seq (named as an abbreviation of RNA sequencing) is a sequencing technique which uses next-generation sequencing (NGS) to reveal the presence and quantity of RNA in a biological sample at a given moment, analyzing the continuously changing cellular transcriptome.


title: RNA-Seq

text: Specifically, RNA-Seq facilitates the ability to look at alternative gene spliced transcripts, post-transcriptional modifications, gene fusion, mutations/SNPs and changes in gene expression over time, or differences in gene expression in different groups or treatments. In addition to mRNA transcripts, RNA-Seq can look at different populations of RNA to include total RNA, small RNA, such as miRNA, tRNA, and ribosomal profiling. RNA-Seq can also be used to determine exon/intron boundaries and verify or amend previously annotated 5' and 3' gene boundaries. Recent advances in RNA-Seq include single cell sequencing, in situ sequencing of fixed tissue, and native RNA molecule sequencing with single-molecule real-time sequencing. Other examples of emerging RNA-Seq applications due to the advancement of bioinformatics algorithms are copy number alteration, microbial contamination, transposable elements, cell type (deconvolution) and the presence of neoantigens.


title: RNA-Seq

text: Prior to RNA-Seq, gene expression studies were done with hybridization-based microarrays. Issues with microarrays include cross-hybridization artifacts, poor quantification of lowly and highly expressed genes, and needing to know the sequence "a priori". Because of these technical issues, transcriptomics transitioned to sequencing-based methods. These progressed from Sanger sequencing of Expressed sequence tag libraries, to chemical tag-based methods (e.g., serial analysis of gene expression), and finally to the current technology, next-gen sequencing of complementary DNA (cDNA), notably RNA-Seq.


title: RNA-Seq

text: The general steps to prepare a complementary DNA (cDNA) library for sequencing are described below, but often vary between platforms.


title: RNA-Seq

text: The cDNA library derived from RNA biotypes is then sequenced into a computer-readable format. There are many high-throughput sequencing technologies for cDNA sequencing including platforms developed by Illumina, Thermo Fisher, BGI/MGI, PacBio, and Oxford Nanopore Technologies. For Illumina short-read sequencing, a common technology for cDNA sequencing, adapters are ligated to the cDNA, DNA is attached to a flow cell, clusters are generated through cycles of bridge amplification and denaturing, and sequence-by-synthesis is performed in cycles of complementary strand synthesis and laser excitation of bases with reversible terminators. Sequencing platform choice and parameters are guided by experimental design and cost. Common experimental design considerations include deciding on the sequencing length, sequencing depth, use of single versus paired-end sequencing, number of replicates, multiplexing, randomization, and spike-ins.


title: RNA-Seq

text: When sequencing RNA other than mRNA, the library preparation is modified. The cellular RNA is selected based on the desired size range. For small RNA targets, such as miRNA, the RNA is isolated through size selection. This can be performed with a size exclusion gel, through size selection magnetic beads, or with a commercially developed kit. Once isolated, linkers are added to the 3' and 5' end then purified. The final step is cDNA generation through reverse transcription.


title: RNA-Seq

text: Because converting RNA into cDNA, ligation, amplification, and other sample manipulations have been shown to introduce biases and artifacts that may interfere with both the proper characterization and quantification of transcripts, single molecule direct RNA sequencing has been explored by companies including Helicos (bankrupt), Oxford Nanopore Technologies, and others. This technology sequences RNA molecules directly in a massively-parallel manner.


title: RNA-Seq

text: Massively parallel single molecule direct RNA-Seq has been explored as an alternative to traditional RNA-Seq, in which RNA-to-cDNA conversion, ligation, amplification, and other sample manipulation steps may introduce biases and artifacts. Technology platforms that perform single-molecule real-time RNA-Seq include Oxford Nanopore Technologies (ONT) Nanopore sequencing, PacBio IsoSeq, and Helicos (bankrupt). Sequencing RNA in its native form preserves modifications like methylation, allowing them to be investigated directly and simultaneously. Another benefit of single-molecule RNA-Seq is that transcripts can be covered in full length, allowing for higher confidence isoform detection and quantification compared to short-read sequencing. Traditionally, single-molecule RNA-Seq methods have higher error rates compared to short-read sequencing, but newer methods like ONT direct RNA-Seq limit errors by avoiding fragmentation and cDNA conversion. Recent uses of ONT direct RNA-Seq for differential expression in human cell populations have demonstrated that this technology can overcome many limitations of short and long cDNA sequencing.


title: RNA-Seq

text: Standard methods such as microarrays and standard bulk RNA-Seq analysis analyze the expression of RNAs from large populations of cells. In mixed cell populations, these measurements may obscure critical differences between individual cells within these populations.


title: RNA-Seq

text: Single-cell RNA sequencing (scRNA-Seq) provides the expression profiles of individual cells. Although it is not possible to obtain complete information on every RNA expressed by each cell, due to the small amount of material available, patterns of gene expression can be identified through gene clustering analyses. This can uncover the existence of rare cell types within a cell population that may never have been seen before. For example, rare specialized cells in the lung called pulmonary ionocytes that express the Cystic fibrosis transmembrane conductance regulator were identified in 2018 by two groups performing scRNA-Seq on lung airway epithelia.


title: RNA-Seq

text: Current scRNA-Seq protocols involve the following steps: isolation of single cell and RNA, reverse transcription (RT), amplification, library generation and sequencing. Single cells are either mechanically separated into microwells (e.g., BD Rhapsody, Takara ICELL8, Vycap Puncher Platform, or CellMicrosystems CellRaft) or encapsulated in droplets (e.g., 10x Genomics Chromium, Illumina Bio-Rad ddSEQ, 1CellBio InDrop, Dolomite Bio Nadia). Single cells are labeled by adding beads with barcoded oligonucleotides; both cells and beads are supplied in limited amounts such that co-occupancy with multiple cells and beads is a very rare event. Once reverse transcription is complete, the cDNAs from many cells can be mixed together for sequencing; transcripts from a particular cell are identified by each cell's unique barcode. Unique molecular identifier (UMIs) can be attached to mRNA/cDNA target sequences to help identify artifacts during library preparation.


title: RNA-Seq

text: Challenges for scRNA-Seq include preserving the initial relative abundance of mRNA in a cell and identifying rare transcripts. The reverse transcription step is critical as the efficiency of the RT reaction determines how much of the cell's RNA population will be eventually analyzed by the sequencer. The processivity of reverse transcriptases and the priming strategies used may affect full-length cDNA production and the generation of libraries biased toward the 3’ or 5' end of genes.


title: RNA-Seq

text: In the amplification step, either PCR or in vitro transcription (IVT) is currently used to amplify cDNA. One of the advantages of PCR-based methods is the ability to generate full-length cDNA. However, different PCR efficiency on particular sequences (for instance, GC content and snapback structure) may also be exponentially amplified, producing libraries with uneven coverage. On the other hand, while libraries generated by IVT can avoid PCR-induced sequence bias, specific sequences may be transcribed inefficiently, thus causing sequence drop-out or generating incomplete sequences.


title: RNA-Seq

text: RAGE-seq, Quartz-seq and C1-CAGE. These protocols differ in terms of strategies for reverse transcription, cDNA synthesis and amplification, and the possibility to accommodate sequence-specific barcodes (i.e. UMIs) or the ability to process pooled samples.


title: RNA-Seq

text: In 2017, two approaches were introduced to simultaneously measure single-cell mRNA and protein expression through oligonucleotide-labeled antibodies known as REAP-seq, and CITE-seq.


title: RNA-Seq

text: scRNA-Seq is becoming widely used across biological disciplines including Development, Neurology, Oncology, Autoimmune disease, and Infectious disease.


title: RNA-Seq

text: scRNA-Seq has provided considerable insight into the development of embryos and organisms, including the worm "Caenorhabditis elegans", and the regenerative planarian "Schmidtea mediterranea". The first vertebrate animals to be mapped in this way were Zebrafish and "Xenopus laevis". In each case multiple stages of the embryo were studied, allowing the entire process of development to be mapped on a cell-by-cell basis. Science recognized these advances as the 2018 Breakthrough of the Year.


title: RNA-Seq

text: Two methods are used to assign raw sequence reads to genomic features (i.e., assemble the transcriptome):


title: RNA-Seq

text: "A note on assembly quality:" The current consensus is that 1) assembly quality can vary depending on which metric is used, 2) assembly tools that scored well in one species do not necessarily perform well in the other species, and 3) combining different approaches might be the most reliable.


title: RNA-Seq

text: Expression is quantified to study cellular changes in response to external stimuli, differences between healthy and diseased states, and other research questions. Transcript levels are often used as a proxy for protein abundance, but these are often not equivalent due to post transcriptional events such as RNA interference and nonsense-mediated decay.


title: RNA-Seq

text: Expression is quantified by counting the number of reads that mapped to each locus in the transcriptome assembly step. Expression can be quantified for exons or genes using contigs or reference transcript annotations. These observed RNA-Seq read counts have been robustly validated against older technologies, including expression microarrays and qPCR. Tools that quantify counts are HTSeq, FeatureCounts, Rcount, maxcounts, FIXSEQ, and Cuffquant. These tools determine read counts from aligned RNA-Seq data, but alignment-free counts can also be obtained with Sailfish and Kallisto. The read counts are then converted into appropriate metrics for hypothesis testing, regressions, and other analyses. Parameters for this conversion are:


title: RNA-Seq

text: RNA spike-ins are samples of RNA at known concentrations that can be used as gold standards in experimental design and during downstream analyses for absolute quantification and detection of genome-wide effects.


title: RNA-Seq

text: The simplest but often most powerful use of RNA-Seq is finding differences in gene expression between two or more conditions ("e.g.", treated vs not treated); this process is called differential expression. The outputs are frequently referred to as differentially expressed genes (DEGs) and these genes can either be up- or down-regulated ("i.e.", higher or lower in the condition of interest). There are many tools that perform differential expression. Most are run in R, Python, or the Unix command line. Commonly used tools include DESeq, edgeR, and voom+limma, all of which are available through R/Bioconductor. These are the common considerations when performing differential expression:


title: RNA-Seq

text: Downstream analyses for a list of differentially expressed genes come in two flavors, validating observations and making biological inferences. Owing to the pitfalls of differential expression and RNA-Seq, important observations are replicated with (1) an orthogonal method in the same samples (like real-time PCR) or (2) another, sometimes pre-registered, experiment in a new cohort. The latter helps ensure generalizability and can typically be followed up with a meta-analysis of all the pooled cohorts. The most common method for obtaining higher-level biological understanding of the results is gene set enrichment analysis, although sometimes candidate gene approaches are employed. Gene set enrichment determines if the overlap between two gene sets is statistically significant, in this case the overlap between differentially expressed genes and gene sets from known pathways/databases ("e.g.", Gene Ontology, KEGG, Human Phenotype Ontology) or from complementary analyses in the same data (like co-expression networks). Common tools for gene set enrichment include web interfaces ("e.g.", ENRICHR, g:profiler, WEBGESTALT) and software packages. When evaluating enrichment results, one heuristic is to first look for enrichment of known biology as a sanity check and then expand the scope to look for novel biology.


title: RNA-Seq

text: RNA splicing is integral to eukaryotes and contributes significantly to protein regulation and diversity, occurring in >90% of human genes. There are multiple alternative splicing modes: exon skipping (most common splicing mode in humans and higher eukaryotes), mutually exclusive exons, alternative donor or acceptor sites, intron retention (most common splicing mode in plants, fungi, and protozoa), alternative transcription start site (promoter), and alternative polyadenylation. One goal of RNA-Seq is to identify alternative splicing events and test if they differ between conditions. Long-read sequencing captures the full transcript and thus minimizes many of issues in estimating isoform abundance, like ambiguous read mapping. For short-read RNA-Seq, there are multiple methods to detect alternative splicing that can be classified into three main groups:


title: RNA-Seq

text: Differential gene expression tools can also be used for differential isoform expression if isoforms are quantified ahead of time with other tools like RSEM.


title: RNA-Seq

text: Coexpression networks are data-derived representations of genes behaving in a similar way across tissues and experimental conditions. Their main purpose lies in hypothesis generation and guilt-by-association approaches for inferring functions of previously unknown genes. RNA-Seq data has been used to infer genes involved in specific pathways based on Pearson correlation, both in plants and mammals. The main advantage of RNA-Seq data in this kind of analysis over the microarray platforms is the capability to cover the entire transcriptome, therefore allowing the possibility to unravel more complete representations of the gene regulatory networks. Differential regulation of the splice isoforms of the same gene can be detected and used to predict their biological functions.


title: RNA-Seq

text: Weighted gene co-expression network analysis has been successfully used to identify co-expression modules and intramodular hub genes based on RNA seq data. Co-expression modules may correspond to cell types or pathways. Highly connected intramodular hubs can be interpreted as representatives of their respective module. An eigengene is a weighted sum of expression of all genes in a module. Eigengenes are useful biomarkers (features) for diagnosis and prognosis. Variance-Stabilizing Transformation approaches for estimating correlation coefficients based on RNA seq data have been proposed.


title: RNA-Seq

text: RNA-Seq captures DNA variation, including single nucleotide variants, small insertions/deletions. and structural variation. Variant calling in RNA-Seq is similar to DNA variant calling and often employs the same tools (including SAMtools mpileup and GATK HaplotypeCaller) with adjustments to account for splicing. One unique dimension for RNA variants is allele-specific expression (ASE): the variants from only one haplotype might be preferentially expressed due to regulatory effects including imprinting and expression quantitative trait loci, and noncoding rare variants. Limitations of RNA variant identification include that it only reflects expressed regions (in humans, <5% of the genome), could be subject to biases introduced by data processing (e.g., de novo transcriptome assemblies underestimate heterozygosity), and has lower quality when compared to direct DNA sequencing.


title: RNA-Seq

text: Having the matching genomic and transcriptomic sequences of an individual can help detect post-transcriptional edits (RNA editing). A post-transcriptional modification event is identified if the gene's transcript has an allele/variant not observed in the genomic data.


title: RNA-Seq

text: Caused by different structural modifications in the genome, fusion genes have gained attention because of their relationship with cancer. The ability of RNA-Seq to analyze a sample's whole transcriptome in an unbiased fashion makes it an attractive tool to find these kinds of common events in cancer.


title: RNA-Seq

text: The idea follows from the process of aligning the short transcriptomic reads to a reference genome. Most of the short reads will fall within one complete exon, and a smaller but still large set would be expected to map to known exon-exon junctions. The remaining unmapped short reads would then be further analyzed to determine whether they match an exon-exon junction where the exons come from different genes. This would be evidence of a possible fusion event, however, because of the length of the reads, this could prove to be very noisy. An alternative approach is to use paired-end reads, when a potentially large number of paired reads would map each end to a different exon, giving better coverage of these events (see figure). Nonetheless, the end result consists of multiple and potentially novel combinations of genes providing an ideal starting point for further validation.


title: RNA-Seq

text: Copy number alteration (CNA) analyses are commonly used in cancer studies. Gain and loss of the genes have signalling pathway implications and are a key biomarker of molecular dysfunction in oncology. Calling the CNA information from RNA-Seq data is not straightforward because of the differences in gene expression, which lead to the read depth variance of different magnitudes across genes. Due to these difficulties, most of these analyses are usually done using whole-genome sequencing / whole-exome sequencing (WGS/WES). But advanced bioinformatics tools can call CNA from  RNA-Seq.


title: RNA-Seq

text: The applications of RNA-Seq are growing day by day. Other new application of RNA-Seq includes detection of microbial contaminants, determining cell type abundance (cell type deconvolution), measuring the expression of TEs and Neoantigen prediction etc.


title: RNA-Seq

text: RNA-Seq was first developed in mid 2000s with the advent of next-generation sequencing technology. The first manuscripts that used RNA-Seq even without using the term includes those of prostate cancer cell lines (dated 2006), "Medicago truncatula" (2006), maize (2007), and "Arabidopsis thaliana" (2007), while the term "RNA-Seq" itself was first mentioned in 2008. The number of manuscripts referring to RNA-Seq in the title or abstract (Figure, blue line) is continuously increasing with 6754 manuscripts published in 2018. The intersection of RNA-Seq and medicine (Figure, gold line) has similar celerity.


title: RNA-Seq

text: RNA-Seq has the potential to identify new disease biology, profile biomarkers for clinical indications, infer druggable pathways, and make genetic diagnoses. These results could be further personalized for subgroups or even individual patients, potentially highlighting more effective prevention, diagnostics, and therapy. The feasibility of this approach is in part dictated by costs in money and time; a related limitation is the required team of specialists (bioinformaticians, physicians/clinicians, basic researchers, technicians) to fully interpret the huge amount of data generated by this analysis.


title: RNA-Seq

text: A lot of emphasis has been given to RNA-Seq data after the Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA) projects have used this approach to characterize dozens of cell lines and thousands of primary tumor samples, respectively. ENCODE aimed to identify genome-wide regulatory regions in different cohort of cell lines and transcriptomic data are paramount to understand the downstream effect of those epigenetic and genetic regulatory layers. TCGA, instead, aimed to collect and analyze thousands of patient's samples from 30 different tumor types to understand the underlying mechanisms of malignant transformation and progression. In this context RNA-Seq data provide a unique snapshot of the transcriptomic status of the disease and look at an unbiased population of transcripts that allows the identification of novel transcripts, fusion transcripts and non-coding RNAs that could be undetected with different technologies.


title: Angiogenesis

text: Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise (especially in older texts). The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.


title: Angiogenesis

text: Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. The essential role of angiogenesis in tumor growth was first proposed in 1971 by Judah Folkman, who described tumors as "hot and bloody," illustrating that, at least for many tumor types, flush perfusion and even hyperemia are characteristic.


title: Angiogenesis

text: Sprouting angiogenesis was the first identified form of angiogenesis and because of this, it is much more understood than intussusceptive angiogenesis. It occurs in several well-characterized stages. The initial signal comes from tissue areas that are devoid of vasculature. The hypoxia that is noted in these areas causes the tissues to demand the presence of nutrients and oxygen that will allow the tissue to carry out metabolic activities. Because of this, parenchymal cells will secrete vascular endothelial growth factor (VEGF-A) which is a proangiogenic growth factor. These biological signals activate receptors on endothelial cells present in pre-existing blood vessels. Second, the activated endothelial cells, also known as tip cells, begin to release enzymes called proteases that degrade the basement membrane to allow endothelial cells to escape from the original (parent) vessel walls. The endothelial cells then proliferate into the surrounding matrix and form solid sprouts connecting neighboring vessels. The cells that are proliferating are located behind the tip cells and are known as stalk cells. The proliferation of these cells allows the capillary sprout to grow in length simultaneously.


title: Angiogenesis

text: As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in tandem, using adhesion molecules called integrins. These sprouts then form loops to become a full-fledged vessel lumen as cells migrate to the site of angiogenesis. Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the vasculature. It is markedly different from splitting angiogenesis because it forms entirely new vessels as opposed to splitting existing vessels.


title: Angiogenesis

text: Intussusceptive angiogenesis, also known as "splitting angiogenesis", is the formation of a new blood vessel by splitting an existing blood vessel into two.


title: Angiogenesis

text: Intussusception was first observed in neonatal rats. In this type of vessel formation, the capillary wall extends into the lumen to split a single vessel in two. There are four phases of intussusceptive angiogenesis. First, the two opposing capillary walls establish a zone of contact. Second, the endothelial cell junctions are reorganized and the vessel bilayer is perforated to allow growth factors and cells to penetrate into the lumen. Third, a core is formed between the 2 new vessels at the zone of contact that is filled with pericytes and myofibroblasts. These cells begin laying collagen fibers into the core to provide an extracellular matrix for growth of the vessel lumen. Finally, the core is fleshed out with no alterations to the basic structure. Intussusception is important because it is a reorganization of existing cells. It allows a vast increase in the number of capillaries without a corresponding increase in the number of endothelial cells. This is especially important in embryonic development as there are not enough resources to create a rich microvasculature with new cells every time a new vessel develops.


title: Angiogenesis

text: Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to shear stress acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis. This may be due to an increase in the production of nitric oxide during exercise. Nitric oxide results in vasodilation of blood vessels.


title: Angiogenesis

text: Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several growth factors e.g. VEGF, FGF.


title: Angiogenesis

text: The fibroblast growth factor (FGF) family with its prototype members FGF-1 (acidic FGF) and FGF-2 (basic FGF) consists to date of at least 22 known members. Most are single-chain peptides of 16-18 kDa and display high affinity to heparin and heparan sulfate. In general, FGFs stimulate a variety of cellular functions by binding to cell surface FGF-receptors in the presence of heparin proteoglycans. The FGF-receptor family is composed of seven members, and all the receptor proteins are single-chain receptor tyrosine kinases that become activated through autophosphorylation induced by a mechanism of FGF-mediated receptor dimerization. Receptor activation gives rise to a signal transduction cascade that leads to gene activation and diverse biological responses, including cell differentiation, proliferation, and matrix dissolution, thus initiating a process of mitogenic activity critical for the growth of endothelial cells, fibroblasts, and smooth muscle cells.


title: Angiogenesis

text: FGF-1, unique among all 22 members of the FGF family, can bind to all seven FGF-receptor subtypes, making it the broadest-acting member of the FGF family, and a potent mitogen for the diverse cell types needed to mount an angiogenic response in damaged (hypoxic) tissues, where upregulation of FGF-receptors occurs. FGF-1 stimulates the proliferation and differentiation of all cell types necessary for building an arterial vessel, including endothelial cells and smooth muscle cells; this fact "distinguishes FGF-1 from other pro-angiogenic growth factors", such as vascular endothelial growth factor (VEGF), which primarily drives the formation of new capillaries.


title: Angiogenesis

text: Besides FGF-1, one of the most important functions of fibroblast growth factor-2 (FGF-2 or bFGF) is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures, thus promoting angiogenesis. FGF-2 is a more potent angiogenic factor than VEGF or PDGF (platelet-derived growth factor); however, it is less potent than FGF-1. As well as stimulating blood vessel growth, aFGF (FGF-1) and bFGF (FGF-2) are important players in wound healing. They stimulate the proliferation of fibroblasts and endothelial cells that give rise to angiogenesis and developing granulation tissue; both increase blood supply and fill up a wound space/cavity early in the wound-healing process.


title: Angiogenesis

text: Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Initial "in vitro" studies demonstrated bovine capillary endothelial cells will proliferate and show signs of tube structures upon stimulation by VEGF and bFGF, although the results were more pronounced with VEGF. Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. "In vitro" studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries.


title: Angiogenesis

text: VEGF causes a massive signaling cascade in endothelial cells. Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability (eNOS, producing NO), proliferation/survival (bFGF), migration (ICAMs/VCAMs/MMPs) and finally differentiation into mature blood vessels. Mechanically, VEGF is upregulated with muscle contractions as a result of increased blood flow to affected areas. The increased flow also causes a large increase in the mRNA production of VEGF receptors 1 and 2. The increase in receptor production means muscle contractions could cause upregulation of the signaling cascade relating to angiogenesis. As part of the angiogenic signaling cascade, NO is widely considered to be a major contributor to the angiogenic response because inhibition of NO significantly reduces the effects of angiogenic growth factors. However, inhibition of NO during exercise does not inhibit angiogenesis, indicating there are other factors involved in the angiogenic response.


title: Angiogenesis

text: The angiopoietins, Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse knock out studies. Ang1 and Ang2 are protein growth factors which act by binding their receptors, Tie-1 and Tie-2; while this is somewhat controversial, it seems that cell signals are transmitted mostly by Tie-2; though some papers show physiologic signaling via Tie-1 as well. These receptors are tyrosine kinases. Thus, they can initiate cell signaling when ligand binding causes a dimerization that initiates phosphorylation on key tyrosines.


title: Angiogenesis

text: Another major contributor to angiogenesis is matrix metalloproteinase (MMP). MMPs help degrade the proteins that keep the vessel walls solid. This proteolysis allows the endothelial cells to escape into the interstitial matrix as seen in sprouting angiogenesis. Inhibition of MMPs prevents the formation of new capillaries. These enzymes are highly regulated during the vessel formation process because destruction of the extracellular matrix would decrease the integrity of the microvasculature.


title: Angiogenesis

text: Delta-like ligand 4 (Dll4) is a protein with a negative regulatory effect on angiogenesis. Dll4 is a transmembrane ligand, for the notch family of receptors. There have been many studies conducted that have served to determine consequences of the Delta-like Ligand 4. One study in particular evaluated the effects of Dll4 on tumor vascularity and growth. In order for a tumor to grow and develop, it must have the proper vasculature. The VEGF pathway is vital to the development of vasculature that in turn, helps the tumors to grow. The combined blockade of VEGF and Dll4 results in the inhibition of tumor progression and angiogenesis throughout the tumor. This is due to the hindrance of signaling in endothelial cell signaling which cuts off the proliferation and sprouting of these endothelial cells. With this inhibition, the cells do not uncontrollably grow, therefore, the cancer is stopped at this point. if the blockade, however, were to be lifted, the cells would begin their proliferation once again.


title: Angiogenesis

text: Class 3 semaphorins (SEMA3s) regulate angiogenesis by modulating endothelial cell adhesion, migration, proliferation, survival and the recruitment of pericytes. Furthermore, semaphorins can interfere with VEGF-mediated angiogenesis since both SEMA3s and VEGF-A compete for neuropilin receptor binding at endothelial cells. The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis.


title: Angiogenesis

text: Angiogenesis may be a target for combating diseases such as heart disease characterized by either poor vascularisation or abnormal vasculature. Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair. Other diseases, such as age-related macular degeneration, may be created by a local expansion of blood vessels, interfering with normal physiological processes.


title: Angiogenesis

text: The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies, which angiogenic research began with, and pro-angiogenic therapies. Whereas anti-angiogenic therapies are being employed to fight cancer and malignancies, which require an abundance of oxygen and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat cardiovascular diseases, the number one cause of death in the Western world. One of the first applications of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 (FGF-1) for the treatment of coronary artery disease.


title: Angiogenesis

text: Regarding the mechanism of action, pro-angiogenic methods can be differentiated into three main categories: gene therapy, targeting genes of interest for amplification or inhibition; protein replacement therapy, which primarily manipulates angiogenic growth factors like FGF-1 or vascular endothelial growth factor, VEGF; and cell-based therapies, which involve the implantation of specific cell types.


title: Angiogenesis

text: There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, immunogenicity, inflammatory responses, and oncogenesis related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis. The most commonly occurring disorders in humans, such as heart disease, high blood pressure, diabetes and Alzheimer's disease, are most likely caused by the combined effects of variations in many genes, and, thus, injecting a single gene may not be significantly beneficial in such diseases.


title: Angiogenesis

text: By contrast, pro-angiogenic protein therapy uses well-defined, precisely structured proteins, with previously defined optimal doses of the individual protein for disease states, and with well-known biological effects. On the other hand, an obstacle of protein therapy is the mode of delivery. Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still early stages of research, with many open questions regarding best cell types and dosages to use.


title: Angiogenesis

text: Cancer cells are cells that have lost their ability to divide in a controlled fashion. A malignant tumor consists of a population of rapidly dividing and growing cancer cells that progressively accrues mutations. However, tumors need a dedicated blood supply to provide the oxygen and other essential nutrients they require in order to grow beyond a certain size (generally 1–2 mm).


title: Angiogenesis

text: Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. VEGF) and proteins. Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion. Unlike normal blood vessels, tumor blood vessels are dilated with an irregular shape. Other clinicians believe angiogenesis really serves as a waste pathway, taking away the biological end products secreted by rapidly dividing cancer cells. In either case, angiogenesis is a necessary and required step for transition from a small harmless cluster of cells, often said to be about the size of the metal ball at the end of a ball-point pen, to a large tumor. Angiogenesis is also required for the spread of a tumor, or metastasis. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. Evidence now suggests the blood vessel in a given solid tumor may, in fact, be mosaic vessels, composed of endothelial cells and tumor cells. This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of circulating tumor cells in the peripheral blood of patients with malignancies. The subsequent growth of such metastases will also require a supply of nutrients and oxygen and a waste disposal pathway.


title: Angiogenesis

text: Endothelial cells have long been considered genetically more stable than cancer cells. This genomic stability confers an advantage to targeting endothelial cells using antiangiogenic therapy, compared to chemotherapy directed at cancer cells, which rapidly mutate and acquire drug resistance to treatment. For this reason, endothelial cells are thought to be an ideal target for therapies directed against them.


title: Angiogenesis

text: The mechanism of blood vessel formation by angiogenesis is initiated by the spontaneous dividing of tumor cells due to a mutation. Angiogenic stimulators are then released by the tumor cells. These then travel to already established, nearby blood vessels and activates their endothelial cell receptors. This induces a release of proteolytic enzymes from the vasculature. These enzymes target a particular point on the blood vessel and cause a pore to form. This is the point where the new blood vessel will grow from. The reason tumour cells need a blood supply is because they cannot grow any more than 2-3 millimeters in diameter without an established blood supply which is equivalent to about 50-100 cells.


title: Angiogenesis

text: Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely "neoangiogenesis": the production of new collateral vessels to overcome the ischemic insult. A large number of preclinical studies have been performed with protein-, gene- and cell-based therapies in animal models of cardiac ischemia, as well as models of peripheral artery disease. Reproducible and credible successes in these early animal studies led to high enthusiasm that this new therapeutic approach could be rapidly translated to a clinical benefit for millions of patients in the Western world with these disorders. A decade of clinical testing both gene- and protein-based therapies designed to stimulate angiogenesis in underperfused tissues and organs, however, has led from one disappointment to another. Although all of these preclinical readouts, which offered great promise for the transition of angiogenesis therapy from animals to humans, were in one fashion or another, incorporated into early stage clinical trials, the FDA has, to date (2007), insisted that the primary endpoint for approval of an angiogenic agent must be an improvement in exercise performance of treated patients.


title: Angiogenesis

text: These failures suggested that either these are the wrong molecular targets to induce neovascularization, that they can only be effectively used if formulated and administered correctly, or that their presentation in the context of the overall cellular microenvironment may play a vital role in their utility. It may be necessary to present these proteins in a way that mimics natural signaling events, including the concentration, spatial and temporal profiles, and their simultaneous or sequential presentation with other appropriate factors.


title: Angiogenesis

text: Angiogenesis is generally associated with aerobic exercise and endurance exercise. While arteriogenesis produces network changes that allow for a large increase in the amount of total flow in a network, angiogenesis causes changes that allow for greater nutrient delivery over a long period of time. Capillaries are designed to provide maximum nutrient delivery efficiency, so an increase in the number of capillaries allows the network to deliver more nutrients in the same amount of time. A greater number of capillaries also allows for greater oxygen exchange in the network. This is vitally important to endurance training, because it allows a person to continue training for an extended period of time. However, no experimental evidence suggests that increased capillarity is required in endurance exercise to increase the maximum oxygen delivery.


title: Angiogenesis

text: Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision. Anti-angiogenic drugs targeting the VEGF pathways are now used successfully to treat this type of macular degeneration


title: Angiogenesis

text: Angiogenesis of vessels from the host body into an implanted tissue engineered constructs is essential. Successful integration is often dependent on thorough vascularisation of the construct as it provides oxygen and nutrients and prevents necrosis in the central areas of the implant. PDGF has been shown to stabilize vascularisation in collagen-glycosaminoglycan scaffolds.


title: Angiogenesis

text: Quantifying vasculature parameters such as microvascular density has various complications due to preferential staining or limited representation of tissues by histological sections. Recent research has shown complete 3D reconstruction of tumor vascular structure and quantification of vessel structures in whole tumors in animal models.


title: Napoleon (rapper)

text: Mutah Wassin Shabazz Beale (born October 7, 1977), better known as Napoleon, is an American former rapper of Tupac's rap group Outlawz. He has since converted to Islam and is now a motivational speaker.


title: Napoleon (rapper)

text: Beale grew up in Newark, New Jersey. He was raised by his Christian grandmother after his Muslim parents were murdered in their home in front of him in "an 'execution-style' slaying" when he was three.


title: Napoleon (rapper)

text: Napoleon was a member of the Outlawz (originally "Dramacydal", subsequently "tha Outlaw Immortalz"), a hip hop group founded by rapper Tupac Shakur in late 1995 after Shakur's release from prison. Collectively, they were best known for their association with Shakur, coming to prominence by appearing on his album. After Shakur's death in 1996, the group were co-billed on the posthumous album "Still I Rise", and released their first album, "Ride wit Us or Collide wit Us" in 2000. Napoleon also appeared on their next two albums, "Novakane" (2001) and "Neva Surrenda" (2002). In 2006 Napoleon released his only solo album "Loyalty Over Money".


title: Napoleon (rapper)

text: In 2001, a Muslim record producer, impressed by Napoleon's potential as a leader, motivated him to embrace Islam and forsake his former use of alcohol and drugs. Beale considers hip hop and Islam to be incompatible, because "they basically call for two different things" and that even if the song's message is positive, "if it is not according to the Sunnah (teachings) of the Prophet Muhammad, then it is unacceptable".


title: Napoleon (rapper)

text: In 2008, he and his brother owned a barbershop in Studio City, Los Angeles. In 2014, he was co-owner of a coffee shop in Riyadh.


title: Viveca Lindfors

text: Elsa Viveca Torstensdotter Lindfors (December 29, 1920 – October 25, 1995) was a Swedish stage, film, and television actress. She won an Emmy Award and a Silver Bear for Best Actress.


title: Viveca Lindfors

text: Lindfors was born in Uppsala, Sweden, the daughter of Karin Emilia Therese (née Dymling) and Axel Torsten Lindfors.


title: Viveca Lindfors

text: She trained at the Royal Dramatic Training Academy, Stockholm. Soon after, she became a theater and film star in Sweden. She moved to the United States in 1946 after being signed by Warner Bros., and began working in Hollywood. She appeared in more than 100 films, including "Night Unto Night", "No Sad Songs for Me", "Dark City", "The Halliday Brand", "King of Kings", "An Affair of the Skin", "Creepshow", "The Sure Thing", and "Stargate". She appeared with actors including Ronald Reagan, Jeffrey Hunter, Charlton Heston, Glenn Ford, Lizabeth Scott, and Errol Flynn.


title: Viveca Lindfors

text: In 1952, she appeared on Broadway alongside Edmond O'Brien in John Van Druten's "I've Got Sixpence". Two years later, she made her West End debut in J. B. Priestley's poorly received play "The White Countess".


title: Viveca Lindfors

text: Lindfors appeared frequently on television, usually as a guest star, though she played the title role in the miniseries "Frankenstein's Aunt". Most of her TV appearances were in the 1950s and 1960s, with a resurgence in the 1980s and early 1990s. In 1990, she won an Emmy Award for her guest appearance on the series "Life Goes On". She was nominated for an Emmy in 1978 for her supporting role in the TV movie "A Question of Guilt".


title: Viveca Lindfors

text: In 1962, she shared the Silver Bear for Best Actress award with Rita Gam at the Berlin Film Festival, for their performances in Tad Danielewski's "No Exit". Among her later film roles, perhaps the most memorable is the kindly and worldly wise Professor Taub in "The Sure Thing" (1985).


title: Viveca Lindfors

text: In the last years of her life, she taught acting at the School of Visual Arts in Manhattan, and had a lead role (essentially playing herself) in Henry Jaglom's "Last Summer in the Hamptons" (1995). The same year, she returned to the Strindberg Festival in Stockholm to perform in the play "In Search of Strindberg".


title: Viveca Lindfors

text: Lindfors was married four times, to Swedish cinematographer Harry Hasso, Swedish attorney and World Chess Federation president Folke Rogard, director Don Siegel, and Hungarian writer, producer, and director George Tabori. She had three children – two sons (John Tabori with Hasso, and actor Kristoffer Tabori, with Siegel) and a daughter (Lena Tabori, with Rogard).


title: Viveca Lindfors

text: Lindfors was a naturalized U.S. citizen and a liberal Democrat, who supported the presidency of Jimmy Carter.


title: Viveca Lindfors

text: Viveca Lindfors died from complications of rheumatoid arthritis at the age of 74 in Uppsala, and was buried at Uppsala Gamla cemetery.


title: Willis Carrier

text: Willis Haviland Carrier (November 26, 1876 – October 7, 1950) was an American engineer, best known for inventing modern air conditioning. Carrier invented the first electrical air conditioning unit in 1902. In 1915, he founded Carrier Corporation, a company specializing in the manufacture and distribution of heating, ventilation, and air conditioning (HVAC) systems.


title: Willis Carrier

text: Willis Haviland Carrier was born on November 26, 1876, in Angola, New York, the son of Duane Williams Carrier (1836–1908) and Elizabeth R. Haviland (1845–1888). He graduated from Angola Academy in 1894 and from the Buffalo High School in 1897.


title: Willis Carrier

text: He studied at Cornell University starting in 1897 and graduated in 1901 with a Master of Engineering degree.


title: Willis Carrier

text: In Buffalo, New York, on July 17, 1902, in response to an air quality problem experienced at the Sackett-Wilhelms Lithographing & Publishing Company of Brooklyn, New York, Willis Carrier submitted drawings for what became recognized as the world's first modern air conditioning system. It was so humid that summer that the paper grew and shrank, which resulted in poor quality images, because the color printing process involved running the same piece of paper up to four times, each with a different color ink.


title: Willis Carrier

text: The 1902 installation marked the birth of air conditioning because of the addition of humidity control, which led to the recognition by authorities in the field that A/C must perform four basic functions:


title: Willis Carrier

text: After several more years of refinement and field testing, on January 2, 1906, Carrier was granted for an "Apparatus for Treating Air," the world's first spray-type air conditioning equipment. It was designed to humidify or dehumidify air, heating water for the first function and cooling it for the second.


title: Willis Carrier

text: In 1906 Carrier discovered that "constant dew-point depression provided practically constant relative humidity," which later became known among air conditioning engineers as the "law of constant dew-point depression." On this discovery he based the design of an automatic control system, for which he filed a patent claim on May 17, 1907. was issued on February 3, 1914.


title: Willis Carrier

text: In 1908, the Carrier Air Conditioner Company of America was created as a subsidiary of the Buffalo Forge Company, with Willis Carrier as its vice president.


title: Willis Carrier

text: On December 3, 1911, Carrier presented what is perhaps the most significant document ever prepared on air conditioning –


title: Willis Carrier

text: "Rational Psychrometric Formulae" – at the annual meeting of the American Society of Mechanical Engineers. It became known as the "Magna Carta of Psychrometrics." This document tied together the concepts of relative humidity, absolute humidity, and dew-point temperature, thus making it possible to design air-conditioning systems to precisely fit the requirements at hand.


title: Willis Carrier

text: With the onset of World War I in late 1914, the Buffalo Forge Company, where Carrier had been employed for 12 years, decided to confine its activities entirely to manufacturing. The result was that seven young engineers pooled together their life savings of $32,600 to form the Carrier Engineering Corporation in New York on June 26, 1915. The seven were Carrier, J. Irvine Lyle, Edward T. Murphy, L. Logan Lewis, Ernest T. Lyle, Frank Sanna, Alfred E. Stacey, Jr., and Edmund P. Heckel. The company eventually settled on Frelinghuysen Avenue in Newark, New Jersey.


title: Willis Carrier

text: Despite the development of the centrifugal refrigeration machine and the commercial growth of air conditioning to cool buildings in the 1920s, the company ran into financial difficulties, as did many other companies, as a result of the Wall Street Crash in October 1929. In 1930, Carrier Engineering Corp. merged with Brunswick-Kroeschell Company and York Heating & Ventilating Corporation to form the Carrier Corporation, with Willis Carrier named chairman of the board.


title: Willis Carrier

text: The Great Depression slowed residential and commercial use of air conditioning. The company spread out over four cities in New Jersey and Pennsylvania until Carrier consolidated and moved his company to Syracuse, New York, in 1937. The company became one of the largest employers in central New York.


title: Willis Carrier

text: Willis Carrier's igloo-shaped pavilion in the 1939 New York World's Fair gave visitors a glimpse into the future of air conditioning, but before it became popular, World War II began. During the post-war economic boom of the 1950s, air conditioning began its tremendous growth in popularity. Today, air-conditioning and HVAC is a staple in many American homes and businesses.


title: Willis Carrier

text: In 1930, Carrier started Toyo Carrier and Samsung Applications in Japan and Korea. South Korea is now the largest producer for air conditioning in the world. The Carrier Corporation pioneered the design and manufacture of refrigeration machines to cool large spaces. By increasing industrial production in the summer months, air conditioning revolutionized American life. The introduction of residential air conditioning in the 1920s helped start the great migration to the Sunbelt. The company became a subsidiary of United Technologies Corporation in 1980, and remained so until 2020, when it was spun off again as an independent publicly traded company. The Carrier Corporation remains a world leader in commercial and residential HVAC and refrigeration. In 2018, the Carrier Corporation had sales of $18.6 billion and employed 53,000 people.


title: Willis Carrier

text: Carrier met Edith Claire Seymour at Cornell and they married on August 29, 1902. Edith Claire Seymour died in 1912. He married Jennie Tifft Martin on April 16, 1913. She died in 1939. He married Elizabeth Marsh Wise of Terre Haute, Indiana on February 7, 1941. Carrier and all three of his wives are buried in Forest Lawn Cemetery in Buffalo, New York. Carrier fathered one child, Howard Carter Willis. He also adopted another two children from Jennie Martin, Vernon Gardner Carrier (1903–1985) and Earl Gardner Carrier (1905–1983).


title: Willis Carrier

text: For his contributions to science and industry, Willis Carrier was awarded an engineering degree by Lehigh University in 1935 and an honorary Doctor of Letters degree by Alfred University in 1942; Carrier was awarded the Frank P. Brown Medal in 1942; and was inducted posthumously in the National Inventors Hall of Fame (1985) and the Buffalo Science Museum Hall of Fame (2008).


title: To be announced

text: To be announced (TBA), to be confirmed (TBC), to be determined or decided or declared (TBD), and other variations, are placeholder terms used very broadly in event planning to indicate that although something is scheduled or expected to happen, a particular aspect of that remains to be fixed or set.


title: To be announced

text: Other similar phrases sometimes used to convey the same meaning, and using the same abbreviations, include "to be ascertained", "to be arranged", "to be adjudicated", and "to be done".


title: To be announced

text: Use of the abbreviation "TBA" is formally reported in a reference work at least as early as 1955, and "TBD" is similarly reported as early as 1967.


title: To be announced

text: These various placeholder terms are often used to indicate to the public that a vacant position in a lineup of speakers, musicians, or other performers remains to be filled. The terms also frequently indicate that a creative work, such as an album or film, is forthcoming but that the date of release is not yet known. If the forthcoming project is not yet named, these placeholders may be used to indicate that the name has not yet been selected, although the project may also be designated as "untitled" pending that determination. The terms are also used in sports schedules, particularly where one team has locked in a position in a playoff schedule, but its opponent cannot yet be determined because several teams may qualify for the spot depending on their remaining wins or losses for the season, or because other teams have not yet competed in playoff games that will determine who will face the locked-in team. In government and business, the terms may be used to indicate that a vacant organizational position is expected to be filled, or conversely that a particular individual will be employed in an as-yet-uncreated position.


title: To be announced

text: In program guide listings, both paper and electronic, the term indicates that the program to be aired by a television station or channel will be announced in the near future, a last-second decision to remove a program or film where the content to be aired in its place cannot be updated on short notice by the listings provider, or that a program's airing (or delay to another time) depends on the continuation of a sports playoff series, which usually applies between the fifth and seventh matches or games of a best-of-seven series.


title: To be announced

text: The age rating system of the British Board of Film Classification (BBFC) requires the use of "tbc" (meaning "to be classified") for products that have been submitted to the BBFC and are awaiting final rating.


title: To be announced

text: "TBA" (meaning "to be announced") is also used to describe a specific type of simple mortgage investment, the forward mortgage-backed security. This is used to indicate that the investor is acquiring some portion of a pending pool of as-yet unspecified mortgages, which will be specified at a given delivery date. This usage has existed at least since the 1980s.


title: The Ninth Configuration

text: The Ninth Configuration (also known as Twinkle, Twinkle, "Killer" Kane) is a 1980 American psychological drama film written, produced, and directed by William Peter Blatty, in his directorial debut. The second installment in Blatty's "Faith Trilogy" after "The Exorcist", it is based on Blatty's 1978 novel "The Ninth Configuration", which was itself a reworking of an earlier version of his 1966 novel "Twinkle, Twinkle, "Killer" Kane!". The initial 1966 publication of the novel featured an exclamation mark at the end of the title, while all subsequent publications saw it removed.


title: The Ninth Configuration

text: The first half of the film has the predominant tone and style of a comic farce. In the second half, the film becomes darker as it delves deeper into its central issues of human suffering, sacrifice and faith. The film also frequently blurs the line between the sane and insane. The film was recognized with the Golden Globe Award for Best Screenplay and two other nominations at the 38th Golden Globe Awards.


title: The Ninth Configuration

text: Sometime in the early 1970s, "toward the end of the War in Vietnam" as stated in the opening narration, a large castle in the Pacific Northwest is used by the US government as an insane asylum for military personnel. Among the many patients there is a former astronaut, Billy Cutshaw (Scott Wilson), who aborted a moon launch and was dragged screaming from the capsule, suffering from an apparent mental breakdown.


title: The Ninth Configuration

text: Colonel Hudson Kane (Stacy Keach), a former member of a United States Marine Corps special unit, arrives at the castle to take over the treatment of the patients. He meets Colonel Fell (Ed Flanders), who helps Kane acclimate himself to the eccentricities of the patients. Kane pays special attention to Cutshaw, repeatedly asking him why he did not want to go to the moon. Cutshaw refuses to answer but instead gives him a St. Christopher medal. Later, Cutshaw talks with Lieutenant Reno about Kane. Reno, who is attempting to stage the works of William Shakespeare with a cast of dogs, suspects that Kane is crazy himself. Reno asserts that psychiatrists often go crazy and have the highest suicide rate of any profession.


title: The Ninth Configuration

text: Kane falls asleep in his office and has a nightmare. When recounting it, he explains to Fell that they are the nightmares of his brother Vincent, a former patient and murderer who is now dead.


title: The Ninth Configuration

text: Cutshaw talks with Kane again, and they debate God and the idea that there is a divine plan. Kane, who believes that the existence of a God is far more likely than humanity's having emerged from "random chance", argues that deeds of pure self-sacrifice are proof of human goodness, which can only be explained by divine purpose. Cutshaw demands that Kane recall one concrete example of pure self-sacrifice from his personal experience; Kane is unable. Kane takes Cutshaw to a church service, which Cutshaw interrupts with several outbursts, and Kane momentarily hallucinates. After returning to the castle, Cutshaw thanks Kane and asks him to send him a sign as proof of an afterlife should Kane die first. Kane promises to try.


title: The Ninth Configuration

text: When Kane meets with a new patient, the patient calls him "Killer Kane", and Kane flashes back to Vietnam, where he has killed a young boy. The soldier urges Kane to leave, and he screams. In the present, Kane collapses, unconscious. Fell explains to the staff that Kane is Vincent "Killer" Kane and suffered a breakdown in Vietnam. When Fell, who is Kane's brother Hudson, was dispatched back to America, Kane received the dispatch by accident. Kane created a new persona for himself – a healer, like his brother. Subconsciously hoping to heal people to make up for his "murders", Kane returned to the US as his brother. Realizing Kane's mental state, the Army psychiatric staff maintained the charade and sent him to Fell's hospital under the pretext of being its commanding officer. In reality, Fell has been the commanding officer all along. Kane awakens and remembers nothing of the incident.


title: The Ninth Configuration

text: Cutshaw escapes the castle and visits a bar. A biker gang recognizes Cutshaw from news reports and brutalize him. A waitress (Linda Tuero, Blatty's wife at the time) contacts the hospital, and Kane arrives to retrieve Cutshaw. Kane humbles himself to the bikers to extricate Cutshaw, but the bikers are disgusted by his behavior and assault him. The gang then attempts to rape Cutshaw, causing Kane to snap and kill most of the bikers with his bare hands.


title: The Ninth Configuration

text: Kane and Cutshaw return to the castle, and the police arrive to arrest Kane for the murders at the bar. Colonel Fell interjects and tells the policemen that Kane must stay since he was provoked. Cutshaw visits Kane, who has wrapped himself in a blanket. Dreamy and distant, Kane disjointedly mumbles to Cutshaw about God and proof of human goodness before passing out. As Cutshaw leaves, Kane's hand emerges from his blankets and drops a bloodied knife. Outside Kane's room, Cutshaw notices a spot of blood on his shoe. Rushing back in, Cutshaw discovers that Kane committed suicide to provide proof of human goodness.


title: The Ninth Configuration

text: Some time later, Cutshaw has returned to uniform, and visits the now-abandoned castle. After reading a note left by Kane, which expresses hope that his sacrifice will shock Cutshaw back to sanity, Cutshaw finds a Saint Christopher's medal has somehow appeared in his car. He turns it over to confirm whether it was the one he gave to Kane and silently rejoices at what he sees.


title: The Ninth Configuration

text: William Peter Blatty's novel "Twinkle, Twinkle, "Killer" Kane!" was first published in 1966. Blatty said: "I considered it a comic novel, but a great deal of philosophy and theology crept into it. But the farcical elements outweighed the serious elements." Blatty adapted the novel into a screenplay, and intended for it to be filmed by William Friedkin. Blatty said that the script "was what you might call bizarre material. I had hoped to direct it myself. But after seeing "The Night They Raided Minsky's" I thought the script would be safe with Friedkin. I sent it along to him. He liked it. But we couldn't find a studio that liked it." Blatty and Friedkin would later collaborate on the film version of "The Exorcist" (1973), with Blatty as screenwriter/producer and Friedkin as director, before Blatty returned to "Twinkle, Twinkle, "Killer" Kane!". In lieu of filming the novel, Blatty decided to rewrite it: "After "The Exorcist", I decided that I could develop the story a great deal. So I rewrote it and fleshed it out, Cutshaw became the astronaut in "The Exorcist" that Regan warns about going into outer space and fully developed the deeper implications and theological themes." The rewritten version of "Twinkle, Twinkle, "Killer" Kane!" was published in 1978 under the title "The Ninth Configuration".


title: The Ninth Configuration

text: However, Blatty subsequently stated he preferred the first version of the book to the second: "...the first one is infinitely funnier and wilder, and stranger and more of a one of a kind; the second one has the same plot, but the prose is more finely crafted, I think. In the first one I allowed the comedy to carry me, so I think I prefer that one...I loved the characters and it was a pleasure to write."


title: The Ninth Configuration

text: Blatty then developed "The Ninth Configuration" into a screenplay for Columbia Pictures (Blatty did not want to work with Warner Bros. as he had sued that studio over his proper share of profits from "The Exorcist"). Columbia then placed the screenplay in turnaround; Blatty took the script to Universal Pictures. Universal rejected it; according to Blatty, this was "not because of any consideration of quality, but simply because Columbia had let it go. There was nobody prepared to take a chance on their own judgement."


title: The Ninth Configuration

text: With no major film studio prepared to fund "The Ninth Configuration", Blatty decided to raise the film's $4 million budget by putting up half the money himself, and persuading the PepsiCo conglomerate to provide the remaining $2 million. As writer/director of the film, Blatty was promised complete creative control over the production by PepsiCo with only one stipulation: that the film had to be shot in Hungary (PepsiCo had blocked funds in that country, and reinvested money from the film's production into a Pepsi bottling plant there). Ironically, Warner Bros. wound up initially releasing the film in selected markets, despite Blatty's misgivings.


title: The Ninth Configuration

text: Blatty retained Jason Miller, who had played Father Karras in "The Exorcist", for "The Ninth Configuration". Ed Flanders (once considered for the role of Karras in "The Exorcist") was also cast; Michael Moriarty was set to play Captain Billy Cutshaw but dropped out of the production (he was replaced by Scott Wilson, who was originally cast in a different role). For the central role of Colonel Kane, Blatty cast Stacy Keach (another contender for the part of Father Karras in "The Exorcist"). Blatty had originally cast Nicol Williamson in the role of Kane, before deciding that the British actor was wrong for the part: "I was deluding myself. I so desperately admired [Williamson] and wanted him in my picture that I persuaded myself that he could be an American Marine corps colonel. I realised during rehearsals. He was magnificent, but there was no way he could be an American colonel. He came to Budapest and we rehearsed for two weeks. And we were coming up to the weekend before our first shoot on the following Monday, and then I remembered one of the people I'd strongly considered was Stacy Keach. And we found out that night that he was available and he was with us on Tuesday." Stacy Keach recalls the situation differently: "Ironically, I was the lucky benefactor of a Nicol tantrum in the late '70s. William Peter Blatty had cast him as Killer Kane in "The Ninth Configuration" (also known as "Twinkle, Twinkle, Killer Kane"), and the film was being shot in Budapest, Hungary. Nicol was staying at the Budapest Hilton, and was allegedly trying to make an international phone call when, presumably, something the operator did or said infuriated him, causing him to rip the phone out of the wall and toss it through the plate-glass window of his suite. Nicol was fired, and I was hired to play the role. It was a great part, and I often reflected on how Nicol would have played certain moments during the filming. I have no doubts that he would have been brilliant, as he always was. We became friends for a time, and I loved his company."


title: The Ninth Configuration

text: Tom Atkins had a minor role in the film, and in an interview in January 2009, he discussed what the film shoot was like: "I have always believed that a movie about the making of that film would have been much better than the actual movie turned out to be. It was kind of a zoo from the very beginning. William Peter Blatty wrote and directed it and financed part of it by selling a home that he had in Malibu. His idea of getting a good ensemble effort from his actors was to take people over to Budapest for two months—the part I had might have taken two weeks in the States but he had us all over there for two months. All he ended up getting was 22 really upset, angry and drunk actors who had a lot of trouble showing up for work. I thought that the script was wonderful but I don’t think that Blatty ever got what he wanted up on the screen. I think a lot of us took the job because we would be able to go to Prague and Moscow and bounce around Europe when we weren’t working. He decided that he would put up the call sheet for the next day at midnight so that you couldn’t go anywhere."


title: The Ninth Configuration

text: Blatty himself appears briefly near the start of the film as a patient pretending to be an army doctor (he is the one who stole Ed Flanders' pants), and would later cast Jason Miller, Ed Flanders, Scott Wilson, and Nicol Williamson in his next film as writer/director, "The Exorcist III" (1990).


title: The Ninth Configuration

text: United Film Distribution (UFD), affiliated with the United Artists theatre chain and best known for releasing George A. Romero's "Dawn of the Dead", picked up the film for a planned December 1979 release; however, the company dropped the picture, and Warner Bros. subsequently picked it up. After initially poor box office returns in its test markets, Warner Bros. returned the film to Blatty and allowed him to take it to another distributor. UFD re-acquired the rights and released it in other markets under the title Twinkle, Twinkle, "Killer" Kane. It was not a commercial success upon its cinematic release in 1980; however, it received generally strong reviews and a Best Picture nomination at the 38th Golden Globe Awards in January 1981. Although the film did not win, Blatty did win a Golden Globe for the film's screenplay. Blatty re-edited the film for its 1985 re-release, which was distributed by New World Pictures under the original title, "The Ninth Configuration".


title: The Ninth Configuration

text: On review aggregator Rotten Tomatoes, "The Ninth Configuration" has an approval rating of based on reviews, with an average rating of . Leonard Maltin has described the movie as "hilarious yet thought-provoking, with endlessly quotable dialogue and an amazing barroom fight scene." Blatty's screenplay was later published in 2000 with commentary by English film critic Mark Kermode (Kermode also contributed to the audio commentary and featurette on the film's DVD release in 2002). Kermode has described "The Ninth Configuration" as "a breathtaking cocktail of philosophy, eye-popping visuals, jaw-dropping pretentiousness, rib-tickling humour and heart-stopping action. From exotically hallucinogenic visions of a lunar crucifixion to the claustrophobic realism of a bar-room brawl, via such twisted vignettes as Robert Loggia karaoking to Al Jolson and Moses Gunn in Superman drag, Blatty directs like a man with no understanding of, or interest in, the supposed limits of mainstream movie-making. The result is a work of matchless madness which divides audiences as spectacularly as the waves of the Red Sea, a cult classic that continues to provoke either apostolic devotion or baffled dismissal 20 years on."


title: The Ninth Configuration

text: Several versions of "The Ninth Configuration" were released in cinemas and on video tape and DVD (one version retained the title "Twinkle, Twinkle, "Killer" Kane"). In the original theatrical release and the Blatty-endorsed DVD, it is the intention that Kane killed himself with the knife. In some versions released during the intervening years, an alternate ending was used in which it is said (via added voiceover by Stacy Keach) that Kane died of wounds inflicted by the bikers.


title: The Ninth Configuration

text: The UK company Second Sight Films and the USA company Shout! Factory remastered this film in April 2016 for DVD and Blu-ray. It featured an added memorial dedication to Blatty's late son, Peter Vincent Blatty, who died in 2006 from a rare heart disorder. The dedication mistakenly had the theme from the first two logos of Lorimar Television playing over it.


title: Metroid Fusion

text: Like previous "Metroid" games, "Fusion" is a side-scrolling game with platform jumping, shooting, and puzzle elements, but introduces mission-based progression that guides the player through certain areas. It was released the day before the GameCube game "Metroid Prime" in North America; both games can be linked using the GameCube – Game Boy Advance link cable to unlock additional content for "Prime".


title: Metroid Fusion

text: "Fusion" was acclaimed for its gameplay, controls, graphics and music, though its shorter length and greater linearity received some criticism. It received several awards, including Handheld Game of the Year at the 2002 Interactive Achievement Awards, Best Game Boy Advance Adventure Game from "IGN", and Best Action Game on Game Boy Advance from "GameSpot". It was rereleased on the Nintendo 3DS's Virtual Console in 2011 as part of the 3DS Ambassador Program, and the Wii U's Virtual Console in 2014. A sequel, "Metroid Dread", was released 19 years later in 2021 for the Nintendo Switch.


title: Metroid Fusion

text: "Metroid Fusion" is an action-adventure game in which the player controls Samus Aran. Like previous games in the series, "Fusion" is set in a large open-ended world with elevators that connect regions, which each in turn contains rooms separated by doors. Samus opens most doors by shooting at them, while some only open after she reaches a certain point. "Fusion" is more linear than other "Metroid" games due to its focus on storyline; for example, "Fusion" introduces Navigation Rooms, which tell the player where to go.


title: Metroid Fusion

text: The gameplay involves solving puzzles to uncover secrets, platform jumping, shooting enemies, and searching for power-ups that allow Samus to reach new areas. Samus can absorb X Parasites, which restore health, missiles, and bombs. Power-ups are obtained by downloading them in Data Rooms or absorbing a Core-X, which appears after defeating a boss. New features include the ability to grab ledges and climb ladders.


title: Metroid Fusion

text: The player can use the GameCube – Game Boy Advance link cable to connect to "Fusion" and unlock features in "Prime": after completing "Prime", they can unlock Samus's Fusion Suit, and after completing "Fusion", they can unlock an emulated version of the first "Metroid" game. In "" (2004), players can connect to "Fusion" using the Game Boy Advance Game Link Cable to unlock a "Fusion" picture gallery, which includes its ending images.


title: Metroid Fusion

text: Bounty hunter Samus Aran explores the surface of the planet SR388 with a survey crew from Biologic Space Laboratories (BSL). She is attacked by parasitic organisms known as X. On the way back to the BSL station, Samus loses consciousness and her ship crashes. The BSL ship she was escorting recovers her body and transfers it to the Galactic Federation for medical treatment, who discover that the X has infected Samus' central nervous system. They cure her with a vaccine made from cells taken from the infant Metroid that Samus adopted on SR388. The vaccine gives her the ability to absorb the X nuclei for nourishment, but burdens her with the Metroids' vulnerability to cold. Samus's infected Power Suit is sent to the BSL station for examination, although parts of the suit were too integrated with her body to remove during surgery.


title: Metroid Fusion

text: When Samus recovers consciousness, she discovers that an explosion has occurred on the BSL station. She is sent to investigate. The mission is overseen by her new gunship's computer, whom Samus nicknames "Adam" after her former commanding officer, Adam Malkovich. Samus learns that the X parasites can replicate their hosts' physical appearances, and that the X have infected the station with the help of the "SA-X", an X parasite mimicking Samus at full power.


title: Metroid Fusion

text: Samus avoids the SA-X and explores the space station, defeating larger creatures infected by the X to recover her abilities. She discovers a restricted lab containing Metroids, and the SA-X sets off the labs' auto-destruct sequence while also attacking the released Metroids, who also devour the SA-X. Samus escapes but the lab is destroyed. The computer berates Samus for ignoring orders, and admits that the Federation was secretly using the lab to breed Metroids. It also reveals that the SA-X has asexually reproduced, subsequently cloning itself. The computer advises Samus to leave the station.


title: Metroid Fusion

text: On her way to her ship, the computer orders Samus to leave the rest of the investigation to the Federation, which plans to capture SA-X for military purposes. Knowing that the X would only infect the arriving Federation troops and absorb their spacefaring knowledge to conquer the universe, Samus states her intention to destroy the station. Although the computer initially intends to stop Samus, she calls it "Adam", and reveals that Adam died saving her life. The computer suggests that she should alter the station's propulsion to intercept with SR388 and destroy the planet along with all X populations. Samus realizes that the computer is the consciousness of Adam, uploaded after death. En route to initiate the propulsion sequence, Samus confronts an SA-X, defeats it, and sets the BSL station on a collision course with SR388. As Samus prepares to leave, she is attacked by an Omega Metroid. The SA-X appears and attacks it, but is destroyed; Samus absorbs its nucleus and uses her newly restored Ice Beam to destroy the Omega Metroid. Her ship arrives, piloted by creatures Samus rescued from the station's Habitation Deck, and they escape before the station crashes into the planet, destroying it.


title: Metroid Fusion

text: Nintendo confirmed a "Metroid" game for the Game Boy Advance on March 23, 2001. Ken Lobb, Nintendo of America's director of game development, confirmed that it would be a new game and not a port of the 1994 Super NES game "Super Metroid". Early footage was shown at the 2001 E3 convention under the name "Metroid IV". The footage showed Samus in a dark suit, running on walls and ceilings, with simpler, more "Game Boy Color-like" graphics. At E3 2002, Nintendo demonstrated the game again, now under the title "Metroid Fusion", with updated graphics. "IGN" awarded "Metroid Fusion" Best of Show and Best Action Game.


title: Metroid Fusion

text: "Metroid Fusion" was developed by Nintendo Research & Development 1 (R&D1), the same team that created "Super Metroid". "Fusion"'s gameplay, screen layout, and controls mimic those of "Super Metroid", with enhancements. "Metroid Fusion" is the first 2D "Metroid" game with animated cutscenes; the story is revealed through text and close-ups. It was written and directed by series designer Yoshio Sakamoto, and produced by Takehiro Izushi.


title: Metroid Fusion

text: Sakamoto decided to create an original story instead of remaking a "Metroid" game because he wanted to do "something really unprecedented", and looked forward to the response. "Fusion" introduces gameplay mechanics that are new to the "Metroid" series. "Metroid Fusion" offers a more direct, almost mission-based structure that supports the player to explore areas. Objectives are also flexible in how they can be completed, acting "more as a guide for what the player should do instead of giving a completely blank map and saying 'Here you go, figure out what to do and how to do it.


title: Metroid Fusion

text: According to the lead programmer, Katsuya Yamano, Nintendo R&D1 did not consult previous "Metroid" games for programming techniques, and instead used their previous game "Wario Land 4" as a reference. The system director, Takehiko Hosokawa, states that while parts of old "Metroid" gameplay remain in "Fusion", the developers introduced new elements. Samus's suit design was revamped; the canonical explanation is that this was because an X Parasite had attacked Samus and made her lose all her abilities. Missiles were expanded with two "upgrades", much like the various beam upgrades: the Ice Missile which has a similar effect to the Ice Beam, and the Diffusion Missile which greatly increases the blast radius. Other minor abilities were added to "Fusion", such as climbing walls and ceilings. The health and missile drops are replaced by X Parasites that are similarly released after defeating enemies.


title: Metroid Fusion

text: The music was composed by Minako Hamano and Akira Fujiwara. According to Hamano, Sakamoto wanted her to create music in accordance with Adam's dialogue. Hamano aimed for "serious, ambient music rather than melody" because she did not want the exploration themes to be "annoying". She also rearranged jingles from "Super Metroid" for "Fusion". As Nintendo of America wanted the developers to look for "Hollywood-like" voice actors, Hamano added a voice of an announcer. The developers planned to feature voice acting, but the voices were only used for warning announcements due to ROM cartridge limitations.


title: Metroid Fusion

text: "Metroid Fusion" was released in North America on November 17, 2002. "Fusion" can be connected to "Metroid Prime" for the GameCube, a "Metroid" game that was released on the same day as "Fusion". In Europe, "Fusion" was released on November 22, followed by the Australian release on November 29. It was released in Japan on February 14, 2003, and in China on March 2, 2006.


title: Metroid Fusion

text: A two-disc soundtrack album, "Metroid Prime & Fusion Original Soundtracks", was published by Scitron on June 18, 2003, with the catalog number SCDC-00276/7. The second disc contains tracks from "Fusion", along with an additional track arranged by Shinji Hosoe.


title: Metroid Fusion

text: "Metroid Fusion" was released worldwide on the Nintendo 3DS Virtual Console in December 2011 as part of the "3DS Ambassadors" program, one of ten Game Boy Advance games for those who purchased their 3DS consoles before a price drop. "Metroid Fusion" was among the first three Game Boy Advance games to be released on the Wii U Virtual Console in April 2014.


title: Metroid Fusion

text: "Metroid Fusion" received "universal acclaim" according to review aggregator Metacritic. The Japanese magazine "Famitsu" gave it 34 out of 40. "X-Play" said it was a "pleasure to play", and praised its "beautiful" graphics and audio. "IGN" praised it as an "outstanding achievement on the Game Boy Advance". "GamesRadar" and "GamePro" felt that "Fusion" was too short, but "love[d] every minute of it", finding the hidden secrets and new power-ups "sublimely ingenious". "GameSpot" was disappointed that the game ended so soon, but said that "Metroid" fans would enjoy it. "Nintendo World Report" and "Eurogamer" called it the best 2D "Metroid" game and the best Game Boy Advance game so far. "Game Informer" agreed, describing it as "everything you could want from a Game Boy Advance game" from beginning to end, giving it a perfect review score. "Play" described it as a "magnified, modified, and improved" version of everything great from "Metroid" and "Super Metroid".


title: Metroid Fusion

text: "GameSpot" thought that "Metroid Fusion" offered "Super Metroid"'s best qualities packaged in a new adventure. "Nintendo Power" heralded it as a return to the classic "Metroid" action gameplay. The "perfect" controls were praised by "Electronic Gaming Monthly". "Fusion" did not feel new to "GameSpy", which complained that even the final enemy encounter draws heavy inspiration from "Super Metroid". "GameZone" found that the small screen of the Game Boy Advance was a poor environment in which to play "Metroid Fusion", but they found it an exciting game.


title: Metroid Fusion

text: "Metroid Fusion" received several accolades. It was named Handheld Game of the Year at the 2002 Interactive Achievement Awards. It was also chosen as Best Game Boy Advance Adventure Game by "IGN" and Best Action Game on Game Boy Advance by "GameSpot", which had named it the handheld's best game of November 2002 earlier in the year. It was a runner-up for "GameSpot"s annual "Best Sound", "Best Graphics", "Best Story" and overall "Game of the Year" awards among Game Boy Advance games. In 2009, "Official Nintendo Magazine" called "Fusion" "sleek, slick and perfectly formed", ranking it the 62nd-best Nintendo game.


title: Metroid Fusion

text: "Metroid Fusion" has sold over 1.6 million units worldwide. In its debut week, "Fusion" sold more than 100,000 units in North America. It finished the month of November 2002 with 199,723 copies sold in the United States alone, for total revenues of 5,590,768, making it the third best-selling Game Boy Advance game that month, and the tenth best-selling game across all platforms. It sold 940,000 copies by August 2006, with revenues of 27 million. During the period between January 2000 and August 2006, in the United States it was the twenty-first highest-selling game for the Game Boy Advance, Nintendo DS or PlayStation Portable. As of November 2004, "Fusion" had sold 180,000 units in Japan.


title: Metroid Fusion

text: A sequel, "Metroid Dread", was released in 2021 for the Nintendo Switch, developed by Nintendo and MercurySteam.


title: Immaculate Heart of Mary

text: The Immaculate Heart of Mary () is a Roman Catholic devotional name used to refer to the Catholic view of the interior life of Mary, mother of Jesus, her joys and sorrows, her virtues and hidden perfections, and, above all, her virginal love for God the Father, her maternal love for her son Jesus Christ, and her motherly and compassionate love for all mankind. Traditionally, the Immaculate Heart is depicted pierced with seven swords or wounds, in homage to the seven dolors of Mary and roses, usually red or white, wrapped around the heart.


title: Immaculate Heart of Mary

text: The Eastern Catholic Churches occasionally utilize the image, devotion, and theology associated with the Immaculate Heart of Mary. However, this is a cause of some controversy, some seeing it as a form of liturgical latinisation. The Roman Catholic view is based on scripture, particularly the Gospel of Luke.


title: Immaculate Heart of Mary

text: The veneration of the Heart of Mary is analogous to the veneration of the Sacred Heart of Jesus. There are, however, differences in this analogy as devotion to the heart of Jesus is especially directed to the "divine heart" as overflowing with love for humanity. In the devotion to Mary, however, the attraction is the love of her heart for Jesus and for God.


title: Immaculate Heart of Mary

text: The second difference is the nature of the devotion itself: in the devotion to the Sacred Heart of Jesus, the Roman Catholic venerates in a sense of love responding to love, in the devotion to the Heart of Mary, study and imitation hold as important a place as love. The aim of the devotion is to unite humankind to God through Mary's heart, and this process involves the ideas of consecration and reparation.


title: Immaculate Heart of Mary

text: In chapter 2 of the Gospel of Luke, it is twice stated that Mary kept all things in her heart, that there she might ponder over them. Luke 2:35 recounts the prophecy of Simeon that her heart would be pierced with a sword. This image (the pierced heart) is the most popular representation of the Immaculate Heart.


title: Immaculate Heart of Mary

text: The Gospel of John further invites attention to Mary's heart with its depiction of Mary at the foot of the cross at Jesus' crucifixion. Augustine of Hippo said of this that Mary was not merely passive at the foot of the cross; "she cooperated through charity in the work of our redemption". Augustine says that she was more blessed in having borne Christ in her heart than in having conceived him in the flesh.


title: Immaculate Heart of Mary

text: Devotion to the Heart of Mary began in the Middle Ages with Anselm of Canterbury, and Bernard of Clairvaux. It was practiced and developed by Mechtilde, Gertrude the Great and Bridget of Sweden. Evidence is also discernible in the pious meditations on the and the , usually attributed either to Anselm of Lucca ( 1080) or Bernard; and also in the large book (Douai, 1625) by Richard de Saint-Laurent, Penitentiary of Rouen in the 13th century.


title: Immaculate Heart of Mary

text: Bernardino of Siena ( 1444), is sometimes called "Doctor of the Heart of Mary", and from him the church has borrowed the lessons of the second nocturn for the feast of the Heart of Mary. Francis de Sales speaks of the perfections of this heart, the model of love for God, and dedicated his "Theotimus" to it.


title: Immaculate Heart of Mary

text: During this same period one finds occasional mention of devotional practices to the Heart of Mary, e.g., in the of Nicolas du Saussay ( 1488), in Pope Julius II, and in the "Pharetra" of Lanspergius. In the second half of the 16th century and the first half of the 17th, ascetic authors dwelt upon this devotion at greater length.


title: Immaculate Heart of Mary

text: It was, however, John Eudes ( 1681) who propagated the devotion, to make it public, and to have a feast celebrated in honor of the Heart of Mary, first at Autun in 1648 and afterwards in a number of French dioceses. He established several religious societies interested in upholding and promoting the devotion, of which his large book on the ("Admirable Heart"), published in 1681, resembles a summary. Jean Eudes' efforts to secure the approval of an office and feast failed at Rome, but, notwithstanding this disappointment, the devotion to the Heart of Mary progressed. Eudes began his devotional teachings with the Heart of Mary, and then extended it to the Sacred Heart of Jesus. However, it was only in 1805 that Pope Pius VII allowed a feast to honor the Immaculate Heart of Mary.


title: Immaculate Heart of Mary

text: In 1699 the priest John Peter Pinamonti ( 1703) published a short work on the Holy Heart of Mary in Italian, and in 1725, Joseph de Gallifet combined the cause of the Heart of Mary with that of the Heart of Jesus in order to obtain Rome's approbation of the two devotions and the institution of the two feasts. In 1729, his project was defeated, and in 1765, the two causes were separated, to assure the success of the principal one.


title: Immaculate Heart of Mary

text: Two factors that helped the rapid progress of the devotion were the introduction of the Miraculous Medal by Catherine Laboure in 1830 and the establishment at Notre-Dame-des-Victoires, Paris of the "Archconfraternity of the Immaculate Heart of Mary, Refuge of Sinners". More than four million Miraculous Medals were distributed throughout the world within four years and in 1838 Desgenettes, the pastor of Notre-Dame-des-Victoires, organized the Association in honor of the Holy and Immaculate Heart of Mary, which Pope Gregory XVI made a confraternity the same year. In July, 1855, the Congregation of Rites approved the Office and Mass for the Immaculate Heart.


title: Immaculate Heart of Mary

text: In 1849 Anthony Mary Claret founded the congregation of Missionary Sons of the Immaculate Heart of Mary, commonly called the Claretians.


title: Immaculate Heart of Mary

text: In its principal object this feast is identical with the feast of the "Inner Life of Mary", celebrated by the Sulpicians on 19 October. It commemorates the joys and sorrows of the Mother of God, her virtues and perfections, her love for God and her Divine Son and her compassionate love for mankind.


title: Immaculate Heart of Mary

text: As early as 1643, St. John Eudes and his followers observed 8 February as the feast of the Heart of Mary.


title: Immaculate Heart of Mary

text: In 1799 Pius VI, then in captivity in Florence, granted the Bishop of Palermo the feast of the "Most Pure Heart of Mary" for some of the churches in his diocese. In 1805 Pope Pius VII made a new concession, thanks to which the feast was soon widely observed. Such was the existing condition when a twofold movement, started in Paris, gave fresh impetus to the devotion; the two factors of this movement were, first of all, the revelation of the "Miraculous Medal" in 1830, and then the establishment at Notre-Dame-des-Victoires of the Archconfraternity of the Immaculate Heart of Mary, Refuge of Sinners, which spread rapidly.


title: Immaculate Heart of Mary

text: On 21 July 1855, the Congregation of Rites finally approved the Office and Mass of the Most Pure Heart of Mary without, however, imposing them upon the Catholic Church.