Gene expression

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. Gene expression is summarized in the central dogma of molecular biology first formulated by Francis Crick in 1958, further developed in his 1970 article, and expanded by the subsequent discoveries of reverse transcription and RNA replication.
The process of gene expression is used by all known life—eukaryotes (including multicellular organisms), prokaryotes (bacteria and archaea), and utilized by viruses—to generate the macromolecular machinery for life.
In genetics, gene expression is the most fundamental level at which the genotype gives rise to the phenotype, "i.e." observable trait. The genetic information stored in DNA represents the genotype, whereas the phenotype results from the "interpretation" of that information. Such phenotypes are often expressed by the synthesis of proteins that control the organism's structure and development, or that act as enzymes catalyzing specific metabolic pathways.
All steps in the gene expression process may be modulated (regulated), including the transcription, RNA splicing, translation, and post-translational modification of a protein. Regulation of gene expression gives control over the timing, location, and amount of a given gene product (protein or ncRNA) present in a cell and can have a profound effect on the cellular structure and function. Regulation of gene expression is the basis for cellular differentiation, development, morphogenesis and the versatility and adaptability of any organism. Gene regulation may therefore serve as a substrate for evolutionary change.
Mechanism.
Transcription.
The production of a RNA copy from a DNA strand is called transcription, and is performed by RNA polymerases, which add one ribonucleotide at a time to a growing RNA strand as per the complementarity law of the nucleotide bases. This RNA is complementary to the template 3′ → 5′ DNA strand, with the exception that thymines (T) are replaced with uracils (U) in the RNA.
In prokaryotes, transcription is carried out by a single type of RNA polymerase, which needs to bind a DNA sequence called a Pribnow box with the help of the sigma factor protein (σ factor) to start transcription. In eukaryotes, transcription is performed in the nucleus by three types of RNA polymerases, each of which needs a special DNA sequence called the promoter and a set of DNA-binding proteins—transcription factors—to initiate the process (see regulation of transcription below). RNA polymerase I is responsible for transcription of ribosomal RNA (rRNA) genes. RNA polymerase II (Pol II) transcribes all protein-coding genes but also some non-coding RNAs ("e.g.", snRNAs, snoRNAs or long non-coding RNAs). RNA polymerase III transcribes 5S rRNA, transfer RNA (tRNA) genes, and some small non-coding RNAs ("e.g.", 7SK). Transcription ends when the polymerase encounters a sequence called the terminator.
mRNA processing.
While transcription of prokaryotic protein-coding genes creates messenger RNA (mRNA) that is ready for translation into protein, transcription of eukaryotic genes leaves a primary transcript of RNA (pre-RNA), which first has to undergo a series of modifications to become a mature RNA. Types and steps involved in the maturation processes vary between coding and non-coding preRNAs; "i.e." even though preRNA molecules for both mRNA and tRNA undergo splicing, the steps and machinery involved are different. The processing of non-coding RNA is described below (non-coring RNA maturation).
The processing of premRNA include 5′ "capping", which is set of enzymatic reactions that add 7-methylguanosine (m7G) to the 5′ end of pre-mRNA and thus protect the RNA from degradation by exonucleases. The m7G cap is then bound by cap binding complex heterodimer (CBC20/CBC80), which aids in mRNA export to cytoplasm and also protect the RNA from decapping.
Another modification is 3′ "cleavage and polyadenylation". They occur if polyadenylation signal sequence (5′- AAUAAA-3′) is present in pre-mRNA, which is usually between protein-coding sequence and terminator. The pre-mRNA is first cleaved and then a series of ~200 adenines (A) are added to form poly(A) tail, which protects the RNA from degradation. The poly(A) tail is bound by multiple poly(A)-binding proteins (PABPs) necessary for mRNA export and translation re-initiation. In the inverse process of deadenylation, poly(A) tails are shortened by the CCR4-Not 3′-5′ exonuclease, which often leads to full transcript decay.
A very important modification of eukaryotic pre-mRNA is "RNA splicing". The majority of eukaryotic pre-mRNAs consist of alternating segments called exons and introns. During the process of splicing, an RNA-protein catalytical complex known as spliceosome catalyzes two transesterification reactions, which remove an intron and release it in form of lariat structure, and then splice neighbouring exons together. In certain cases, some introns or exons can be either removed or retained in mature mRNA. This so-called alternative splicing creates series of different transcripts originating from a single gene. Because these transcripts can be potentially translated into different proteins, splicing extends the complexity of eukaryotic gene expression and the size of a species proteome.
Extensive RNA processing may be an evolutionary advantage made possible by the nucleus of eukaryotes. In prokaryotes, transcription and translation happen together, whilst in eukaryotes, the nuclear membrane separates the two processes, giving time for RNA processing to occur.
Non-coding RNA maturation.
In most organisms non-coding genes (ncRNA) are transcribed as precursors that undergo further processing. In the case of ribosomal RNAs (rRNA), they are often transcribed as a pre-rRNA that contains one or more rRNAs. The pre-rRNA is cleaved and modified (2′-O-methylation and pseudouridine formation) at specific sites by approximately 150 different small nucleolus-restricted RNA species, called snoRNAs. SnoRNAs associate with proteins, forming snoRNPs. While snoRNA part basepair with the target RNA and thus position the modification at a precise site, the protein part performs the catalytical reaction. In eukaryotes, in particular a snoRNP called RNase, MRP cleaves the 45S pre-rRNA into the 28S, 5.8S, and 18S rRNAs. The rRNA and RNA processing factors form large aggregates called the nucleolus.
In the case of transfer RNA (tRNA), for example, the 5′ sequence is removed by RNase P, whereas the 3′ end is removed by the tRNase Z enzyme and the non-templated 3′ CCA tail is added by a nucleotidyl transferase. In the case of micro RNA (miRNA), miRNAs are first transcribed as primary transcripts or pri-miRNA with a cap and poly-A tail and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus by the enzymes Drosha and Pasha. After being exported, it is then processed to mature miRNAs in the cytoplasm by interaction with the endonuclease Dicer, which also initiates the formation of the RNA-induced silencing complex (RISC), composed of the Argonaute protein.
Even snRNAs and snoRNAs themselves undergo series of modification before they become part of functional RNP complex. This is done either in the nucleoplasm or in the specialized compartments called Cajal bodies. Their bases are methylated or pseudouridinilated by a group of small Cajal body-specific RNAs (scaRNAs), which are structurally similar to snoRNAs.
RNA export.
In eukaryotes most mature RNA must be exported to the cytoplasm from the nucleus. While some RNAs function in the nucleus, many RNAs are transported through the nuclear pores and into the cytosol. Export of RNAs requires association with specific proteins known as exportins. Specific exportin molecules are responsible for the export of a given RNA type. mRNA transport also requires the correct association with Exon Junction Complex (EJC), which ensures that correct processing of the mRNA is completed before export. In some cases RNAs are additionally transported to a specific part of the cytoplasm, such as a synapse; they are then towed by motor proteins that bind through linker proteins to specific sequences (called "zipcodes") on the RNA.
Translation.
For some RNA (non-coding RNA) the mature RNA is the final gene product. In the case of messenger RNA (mRNA) the RNA is an information carrier coding for the synthesis of one or more proteins. mRNA carrying a single protein sequence (common in eukaryotes) is monocistronic whilst mRNA carrying multiple protein sequences (common in prokaryotes) is known as polycistronic.
Every mRNA consists of three parts: a 5′ untranslated region (5′UTR), a protein-coding region or open reading frame (ORF), and a 3′ untranslated region (3′UTR). The coding region carries information for protein synthesis encoded by the genetic code to form triplets. Each triplet of nucleotides of the coding region is called a codon and corresponds to a binding site complementary to an anticodon triplet in transfer RNA. Transfer RNAs with the same anticodon sequence always carry an identical type of amino acid. Amino acids are then chained together by the ribosome according to the order of triplets in the coding region. The ribosome helps transfer RNA to bind to messenger RNA and takes the amino acid from each transfer RNA and makes a structure-less protein out of it. Each mRNA molecule is translated into many protein molecules, on average ~2800 in mammals.
In prokaryotes translation generally occurs at the point of transcription (co-transcriptionally), often using a messenger RNA that is still in the process of being created. In eukaryotes translation can occur in a variety of regions of the cell depending on where the protein being written is supposed to be. Major locations are the cytoplasm for soluble cytoplasmic proteins and the membrane of the endoplasmic reticulum for proteins that are for export from the cell or insertion into a cell membrane. Proteins that are supposed to be expressed at the endoplasmic reticulum are recognised part-way through the translation process. This is governed by the signal recognition particle—a protein that binds to the ribosome and directs it to the endoplasmic reticulum when it finds a signal peptide on the growing (nascent) amino acid chain.
Folding.
Each protein exists as an unfolded polypeptide or random coil when translated from a sequence of mRNA into a linear chain of amino acids. This polypeptide lacks any developed three-dimensional structure (the left hand side of the neighboring figure). The polypeptide then folds into its characteristic and functional three-dimensional structure from a random coil. Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein (the right hand side of the figure) known as the native state. The resulting three-dimensional structure is determined by the amino acid sequence (Anfinsen's dogma).
The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded. Failure to fold into the intended shape usually produces inactive proteins with different properties including toxic prions. Several neurodegenerative and other diseases are believed to result from the accumulation of "misfolded" proteins. Many allergies are caused by the folding of the proteins, for the immune system does not produce antibodies for certain protein structures.
Enzymes called chaperones assist the newly formed protein to attain (fold into) the 3-dimensional structure it needs to function. Similarly, RNA chaperones help RNAs attain their functional shapes. Assisting protein folding is one of the main roles of the endoplasmic reticulum in eukaryotes.
Translocation.
Secretory proteins of eukaryotes or prokaryotes must be translocated to enter the secretory pathway. Newly synthesized proteins are directed to the eukaryotic Sec61 or prokaryotic SecYEG translocation channel by signal peptides. The efficiency of protein secretion in eukaryotes is very dependent on the signal peptide which has been used.
Protein transport.
Many proteins are destined for other parts of the cell than the cytosol and a wide range of signalling sequences or (signal peptides) are used to direct proteins to where they are supposed to be. In prokaryotes this is normally a simple process due to limited compartmentalisation of the cell. However, in eukaryotes there is a great variety of different targeting processes to ensure the protein arrives at the correct organelle.
Not all proteins remain within the cell and many are exported, for example, digestive enzymes, hormones and extracellular matrix proteins. In eukaryotes the export pathway is well developed and the main mechanism for the export of these proteins is translocation to the endoplasmic reticulum, followed by transport via the Golgi apparatus.
Regulation of gene expression.
Regulation of gene expression refers to the control of the amount and timing of appearance of the functional product of a gene. Control of expression is vital to allow a cell to produce the gene products it needs when it needs them; in turn, this gives cells the flexibility to adapt to a variable environment, external signals, damage to the cell, and other stimuli. More generally, gene regulation gives the cell control over all structure and function, and is the basis for cellular differentiation, morphogenesis and the versatility and adaptability of any organism.
Numerous terms are used to describe types of genes depending on how they are regulated; these include:
Any step of gene expression may be modulated, from the DNA-RNA transcription step to post-translational modification of a protein. The stability of the final gene product, whether it is RNA or protein, also contributes to the expression level of the gene—an unstable product results in a low expression level. In general gene expression is regulated through changes in the number and type of interactions between molecules that collectively influence transcription of DNA and translation of RNA.
Some simple examples of where gene expression is important are:
Transcriptional regulation.
Regulation of transcription can be broken down into three main routes of influence; genetic (direct interaction of a control factor with the gene), modulation interaction of a control factor with the transcription machinery and epigenetic (non-sequence changes in DNA structure that influence transcription).
Direct interaction with DNA is the simplest and the most direct method by which a protein changes transcription levels. Genes often have several protein binding sites around the coding region with the specific function of regulating transcription. There are many classes of regulatory DNA binding sites known as enhancers, insulators and silencers. The mechanisms for regulating transcription are very varied, from blocking key binding sites on the DNA for RNA polymerase to acting as an activator and promoting transcription by assisting RNA polymerase binding.
The activity of transcription factors is further modulated by intracellular signals causing protein post-translational modification including phosphorylated, acetylated, or glycosylated. These changes influence a transcription factor's ability to bind, directly or indirectly, to promoter DNA, to recruit RNA polymerase, or to favor elongation of a newly synthesized RNA molecule.
The nuclear membrane in eukaryotes allows further regulation of transcription factors by the duration of their presence in the nucleus, which is regulated by reversible changes in their structure and by binding of other proteins. Environmental stimuli or endocrine signals may cause modification of regulatory proteins eliciting cascades of intracellular signals, which result in regulation of gene expression.
More recently it has become apparent that there is a significant influence of non-DNA-sequence specific effects on transcription. These effects are referred to as epigenetic and involve the higher order structure of DNA, non-sequence specific DNA binding proteins and chemical modification of DNA. In general epigenetic effects alter the accessibility of DNA to proteins and so modulate transcription.
In eukaryotes the structure of chromatin, controlled by the histone code, regulates access to DNA with significant impacts on the expression of genes in euchromatin and heterochromatin areas.
Enhancers, transcription factors, Mediator complex and DNA loops in mammalian transcription.
Gene expression in mammals is regulated by many cis-regulatory elements, including core promoters and promoter-proximal elements that are located near the transcription start sites of genes, upstream on the DNA (towards the 5' region of the sense strand). Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include enhancers, silencers, insulators and tethering elements. Among this constellation of elements, enhancers and their associated transcription factors have a leading role in the regulation of gene expression.
Enhancers are regions of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes. Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control expression of their common target gene.
The schematic illustration at the left shows an enhancer looping around to come into close physical proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration). Several cell function specific transcription factors (there are about 1,600 transcription factors in a human cell) generally bind to specific motifs on an enhancer and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern level of transcription of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter.
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the Figure. An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration). An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.
DNA methylation and demethylation in transcriptional regulation.
DNA methylation is a widespread mechanism for epigenetic influence on gene expression and is seen in bacteria and eukaryotes and has roles in heritable transcription silencing and transcription regulation. Methylation most often occurs on a cytosine (see Figure). Methylation of cytosine primarily occurs in dinucleotide sequences where a cytosine is followed by a guanine, a CpG site. The number of CpG sites in the human genome is about 28 million. Depending on the type of cell, about 70% of the CpG sites have a methylated cytosine.
Methylation of cytosine in DNA has a major role in regulating gene expression. Methylation of CpGs in a promoter region of a gene usually represses gene transcription while methylation of CpGs in the body of a gene increases expression. TET enzymes play a central role in demethylation of methylated cytosines. Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene.
Transcriptional regulation in learning and memory.
In a rat, contextual fear conditioning (CFC) is a painful learning experience. Just one episode of CFC can result in a life-long fearful memory. After an episode of CFC, cytosine methylation is altered in the promoter regions of about 9.17% of all genes in the hippocampus neuron DNA of a rat. The hippocampus is where new memories are initially stored. After CFC about 500 genes have increased transcription (often due to demethylation of CpG sites in a promoter region) and about 1,000 genes have decreased transcription (often due to newly formed 5-methylcytosine at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming the first transient memory of this training event in the hippocampus of the rat brain.
In particular, the brain-derived neurotrophic factor gene ("BDNF") is known as a "learning gene." After CFC there was upregulation of "BDNF" gene expression, related to decreased CpG methylation of certain internal promoters of the gene, and this was correlated with learning.
Transcriptional regulation in cancer.
The majority of gene promoters contain a CpG island with numerous CpG sites. When many of a gene's promoter CpG sites are methylated the gene becomes silenced. Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, transcriptional silencing may be of more importance than mutation in causing progression to cancer. For example, in colorectal cancers about 600 to 800 genes are transcriptionally silenced by CpG island methylation (see regulation of transcription in cancer). Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs. In breast cancer, transcriptional repression of BRCA1 may occur more frequently by over-expressed microRNA-182 than by hypermethylation of the BRCA1 promoter (see Low expression of BRCA1 in breast and ovarian cancers).
Post-transcriptional regulation.
In eukaryotes, where export of RNA is required before translation is possible, nuclear export is thought to provide additional control over gene expression. All transport in and out of the nucleus is via the nuclear pore and transport is controlled by a wide range of importin and exportin proteins.
Expression of a gene coding for a protein is only possible if the messenger RNA carrying the code survives long enough to be translated. In a typical cell, an RNA molecule is only stable if specifically protected from degradation. RNA degradation has particular importance in regulation of expression in eukaryotic cells where mRNA has to travel significant distances before being translated. In eukaryotes, RNA is stabilised by certain post-transcriptional modifications, particularly the 5′ cap and poly-adenylated tail.
Intentional degradation of mRNA is used not just as a defence mechanism from foreign RNA (normally from viruses) but also as a route of mRNA "destabilisation". If an mRNA molecule has a complementary sequence to a small interfering RNA then it is targeted for destruction via the RNA interference pathway.
Three prime untranslated regions and microRNAs.
Three prime untranslated regions (3′UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that post-transcriptionally influence gene expression. Such 3′-UTRs often contain both binding sites for microRNAs (miRNAs) as well as for regulatory proteins. By binding to specific sites within the 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3′-UTR also may have silencer regions that bind repressor proteins that inhibit the expression of a mRNA.
The 3′-UTR often contains microRNA response elements (MREs). MREs are sequences to which miRNAs bind. These are prevalent motifs within 3′-UTRs. Among all regulatory motifs within the 3′-UTRs (e.g. including silencer regions), MREs make up about half of the motifs.
As of 2014, the miRBase web site, an archive of miRNA sequences and annotations, listed 28,645 entries in 233 biologic species. Of these, 1,881 miRNAs were in annotated human miRNA loci. miRNAs were predicted to have an average of about four hundred target mRNAs (affecting expression of several hundred genes). Friedman et al. estimate that >45,000 miRNA target sites within human mRNA 3′UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs.
Direct experiments show that a single miRNA can reduce the stability of hundreds of unique mRNAs. Other experiments show that a single miRNA may repress the production of hundreds of proteins, but that this repression often is relatively mild (less than 2-fold).
The effects of miRNA dysregulation of gene expression seem to be important in cancer. For instance, in gastrointestinal cancers, nine miRNAs have been identified as epigenetically altered and effective in down regulating DNA repair enzymes.
The effects of miRNA dysregulation of gene expression also seem to be important in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and autism spectrum disorders.
Translational regulation.
Direct regulation of translation is less prevalent than control of transcription or mRNA stability but is occasionally used. Inhibition of protein translation is a major target for toxins and antibiotics, so they can kill a cell by overriding its normal gene expression control. Protein synthesis inhibitors include the antibiotic neomycin and the toxin ricin.
Post-translational modifications.
Post-translational modifications (PTMs) are covalent modifications to proteins. Like RNA splicing, they help to significantly diversify the proteome. These modifications are usually catalyzed by enzymes. Additionally, processes like covalent additions to amino acid side chain residues can often be reversed by other enzymes. However, some, like the proteolytic cleavage of the protein backbone, are irreversible.
PTMs play many important roles in the cell. For example, phosphorylation is primarily involved in activating and deactivating proteins and in signaling pathways. PTMs are involved in transcriptional regulation: an important function of acetylation and methylation is histone tail modification, which alters how accessible DNA is for transcription. They can also be seen in the immune system, where glycosylation plays a key role. One type of PTM can initiate another type of PTM, as can be seen in how ubiquitination tags proteins for degradation through proteolysis. Proteolysis, other than being involved in breaking down proteins, is also important in activating and deactivating them, and in regulating biological processes such as DNA transcription and cell death.
Measurement.
Measuring gene expression is an important part of many life sciences, as the ability to quantify the level at which a particular gene is expressed within a cell, tissue or organism can provide a lot of valuable information. For example, measuring gene expression can:
Similarly, the analysis of the location of protein expression is a powerful tool, and this can be done on an organismal or cellular scale. Investigation of localization is particularly important for the study of development in multicellular organisms and as an indicator of protein function in single cells. Ideally, measurement of expression is done by detecting the final gene product (for many genes, this is the protein); however, it is often easier to detect one of the precursors, typically mRNA and to infer gene-expression levels from these measurements.
mRNA quantification.
Levels of mRNA can be quantitatively measured by northern blotting, which provides size and sequence information about the mRNA molecules. A sample of RNA is separated on an agarose gel and hybridized to a radioactively labeled RNA probe that is complementary to the target sequence. The radiolabeled RNA is then detected by an autoradiograph. Because the use of radioactive reagents makes the procedure time consuming and potentially dangerous, alternative labeling and detection methods, such as digoxigenin and biotin chemistries, have been developed. Perceived disadvantages of Northern blotting are that large quantities of RNA are required and that quantification may not be completely accurate, as it involves measuring band strength in an image of a gel. On the other hand, the additional mRNA size information from the Northern blot allows the discrimination of alternately spliced transcripts.
Another approach for measuring mRNA abundance is RT-qPCR. In this technique, reverse transcription is followed by quantitative PCR. Reverse transcription first generates a DNA template from the mRNA; this single-stranded template is called cDNA. The cDNA template is then amplified in the quantitative step, during which the fluorescence emitted by labeled hybridization probes or intercalating dyes changes as the DNA amplification process progresses. With a carefully constructed standard curve, qPCR can produce an absolute measurement of the number of copies of original mRNA, typically in units of copies per nanolitre of homogenized tissue or copies per cell. qPCR is very sensitive (detection of a single mRNA molecule is theoretically possible), but can be expensive depending on the type of reporter used; fluorescently labeled oligonucleotide probes are more expensive than non-specific intercalating fluorescent dyes.
For expression profiling, or high-throughput analysis of many genes within a sample, quantitative PCR may be performed for hundreds of genes simultaneously in the case of low-density arrays. A second approach is the hybridization microarray. A single array or "chip" may contain probes to determine transcript levels for every known gene in the genome of one or more organisms. Alternatively, "tag based" technologies like Serial analysis of gene expression (SAGE) and RNA-Seq, which can provide a relative measure of the cellular concentration of different mRNAs, can be used. An advantage of tag-based methods is the "open architecture", allowing for the exact measurement of any transcript, with a known or unknown sequence. Next-generation sequencing (NGS) such as RNA-Seq is another approach, producing vast quantities of sequence data that can be matched to a reference genome. Although NGS is comparatively time-consuming, expensive, and resource-intensive, it can identify single-nucleotide polymorphisms, splice-variants, and novel genes, and can also be used to profile expression in organisms for which little or no sequence information is available.
RNA profiles in Wikipedia.
Profiles like these are found for almost all proteins listed in Wikipedia. They are generated by organizations such as the Genomics Institute of the Novartis Research Foundation and the European Bioinformatics Institute. Additional information can be found by searching their databases (for an example of the GLUT4 transporter pictured here, see citation). These profiles indicate the level of DNA expression (and hence RNA produced) of a certain protein in a certain tissue, and are color-coded accordingly in the images located in the Protein Box on the right side of each Wikipedia page.
Protein quantification.
For genes encoding proteins, the expression level can be directly assessed by a number of methods with some clear analogies to the techniques for mRNA quantification.
The most commonly used method is to perform a Western blot against the protein of interest—this gives information on the size of the protein in addition to its identity. A sample (often cellular lysate) is separated on a polyacrylamide gel, transferred to a membrane and then probed with an antibody to the protein of interest. The antibody can either be conjugated to a fluorophore or to horseradish peroxidase for imaging and/or quantification. The gel-based nature of this assay makes quantification less accurate, but it has the advantage of being able to identify later modifications to the protein, for example proteolysis or ubiquitination, from changes in size.
mRNA-protein correlation.
Quantification of protein and mRNA permits a correlation of the two levels. The question of how well protein levels correlate with their corresponding transcript levels is highly debated and depends on multiple factors. Regulation on each step of gene expression can impact the correlation, as shown for regulation of translation or protein stability. Post-translational factors, such as protein transport in highly polar cells, can influence the measured mRNA-protein correlation as well.
Localisation.
Analysis of expression is not limited to quantification; localisation can also be determined. mRNA can be detected with a suitably labelled complementary mRNA strand and protein can be detected via labelled antibodies. The probed sample is then observed by microscopy to identify where the mRNA or protein is.
By replacing the gene with a new version fused to a green fluorescent protein (or similar) marker, expression may be directly quantified in live cells. This is done by imaging using a fluorescence microscope. It is very difficult to clone a GFP-fused protein into its native location in the genome without affecting expression levels so this method often cannot be used to measure endogenous gene expression. It is, however, widely used to measure the expression of a gene artificially introduced into the cell, for example via an expression vector. It is important to note that by fusing a target protein to a fluorescent reporter the protein's behavior, including its cellular localization and expression level, can be significantly changed.
The enzyme-linked immunosorbent assay works by using antibodies immobilised on a microtiter plate to capture proteins of interest from samples added to the well. Using a detection antibody conjugated to an enzyme or fluorophore the quantity of bound protein can be accurately measured by fluorometric or colourimetric detection. The detection process is very similar to that of a Western blot, but by avoiding the gel steps more accurate quantification can be achieved.
Expression system.
An expression system is a system specifically designed for the production of a gene product of choice. This is normally a protein although may also be RNA, such as tRNA or a ribozyme. An expression system consists of a gene, normally encoded by DNA, and the molecular machinery required to transcribe the DNA into mRNA and translate the mRNA into protein using the reagents provided. In the broadest sense this includes every living cell but the term is more normally used to refer to expression as a laboratory tool. An expression system is therefore often artificial in some manner. Expression systems are, however, a fundamentally natural process. Viruses are an excellent example where they replicate by using the host cell as an expression system for the viral proteins and genome.
Inducible expression.
Doxycycline is also used in "Tet-on" and "Tet-off" tetracycline controlled transcriptional activation to regulate transgene expression in organisms and cell cultures.
In nature.
In addition to these biological tools, certain naturally observed configurations of DNA (genes, promoters, enhancers, repressors) and the associated machinery itself are referred to as an expression system. This term is normally used in the case where a gene or set of genes is switched on under well defined conditions, for example, the simple repressor switch expression system in Lambda phage and the lac operator system in bacteria. Several natural expression systems are directly used or modified and used for artificial expression systems such as the Tet-on and Tet-off expression system.
Gene networks.
Genes have sometimes been regarded as nodes in a network, with inputs being proteins such as transcription factors, and outputs being the level of gene expression. The node itself performs a function, and the operation of these functions have been interpreted as performing a kind of information processing within cells and determines cellular behavior.
Gene networks can also be constructed without formulating an explicit causal model. This is often the case when assembling networks from large expression data sets. Covariation and correlation of expression is computed across a large sample of cases and measurements (often transcriptome or proteome data). The source of variation can be either experimental or natural (observational). There are several ways to construct gene expression networks, but one common approach is to compute a matrix of all pair-wise correlations of expression across conditions, time points, or individuals and convert the matrix (after thresholding at some cut-off value) into a graphical representation in which nodes represent genes, transcripts, or proteins and edges connecting these nodes represent the strength of association (see ).
Techniques and tools.
The following experimental techniques are used to measure gene expression and are listed in roughly chronological order, starting with the older, more established technologies. They are divided into two groups based on their degree of multiplexity.


Ranjan Ramasamy

Professor Ranjan Ramasamy is a Sri Lankan born Australian academic and scientist. He was formerly a Professor of Immunology and Biochemistry, and the Chairman of the National Science Foundation of Sri Lanka.
Educated at the Royal College, Colombo, Sri Lanka and at The Perse School, Cambridge, England, he went on to gain a BA in Natural Sciences (1971) and a PhD (1974) from University of Cambridge, Cambridge, England.
References.
2. Ranjan Ramasamy (0000-0003-0246-7053) - ORCID | Connecting Research and Researchers
3. https://www.researchgate.net/profile/Ranjan-Ramasamy


Amyris (company)

Amyris, Inc. is a synthetic biotechnology and renewable chemical company headquartered in Emeryville, California. Amyris serves the specialty and performance chemicals, flavors and fragrances, cosmetics ingredients, pharmaceuticals, and nutraceuticals markets.
History.
Amyris was founded in 2003. The company owns three brands, Biossance and Pipette, for beauty and skincare, and Purecane, a sugar substitute. The company went public on NASDAQ on September 28, 2010 (AMRS).
In November 2011, Amyris acquired Lansing, Michigan-based renewable chemicals and products company, Draths Corporation, for $7 million in stock. April 2019, the company raised $34-million in private placement of its common stock and warrants. The funding round was led by Foris Ventures and Dr. Wei-wu He, General Partner of Emerging Technology Partners, LLC, a life sciences-focused venture fund. The company has raised a total of $933.7M in funding by 17 investors over 21 rounds.
In 2020, Amyris received Bonsucro Chain of Custody Certification, ensuring that the sustainability claims along the sugarcane supply chain are traceable from farmer to end user. During the COVID 19 pandemic, the company collaborated with the Infectious Disease Research Institute (IDRI) to advance a novel ribonucleic acid (RNA) vaccine platform, including accelerating the development of a COVID-19 vaccine.
Awards and recognition.
Biossance, the skincare brand from Amyris, was recognized as Digital Innovator of the Year at the WWD Beauty Inc Awards.


Bir Bhanu

Bir Bhanu is the Marlan and Rosemary Bourns Endowed University of California Presidential Chair in Engineering, the Distinguished Professor of Electrical and Computer Engineering, and Cooperative Professor of Computer Science and Engineering, Mechanical Engineering and Bioengineering, at the Marlan and Rosemary Bourns College of Engineering at the University of California, Riverside (UCR). He is the first Founding Faculty of the Marlan and Rosemary Bourns College of Engineering at UCR and served as the Founding Chair of Electrical Engineering from 1/1991 to 6/1994 and the Founding Director of the Center for Research in Intelligent Systems (CRIS) from 4/1998 to 6/2019. He has been the director of Visualization and Intelligent Systems Laboratory (VISLab) at UCR since 1991. He was the Interim Chair of the Department of Bioengineering at UCR from 7/2014 to 6/2016. Additionally, he has been the Director of the NSF Integrative Graduate Education, Research and Training (IGERT) program in Video Bioinformatics at UC Riverside. Dr. Bhanu has been the principal investigator of various programs for NSF, DARPA, NASA, AFOSR, ONR, ARO and other agencies and industries in the areas of object/target recognition, learning and vision, image/video understanding, image/video databases with applications in security, defense, intelligence, biological and medical imaging and analysis, biometrics, autonomous navigation and industrial machine vision.
Education.
Dr. Bhanu received the S.M. and E.E. degrees in Electrical Engineering and Computer Science from the Massachusetts Institute of Technology; the Ph.D. degree in Electrical Engineering from the Image Processing Institute, University of Southern California and the M.B.A. degree from the University of California, Irvine. He also received B.S. (with Honors) in Electronics Engineering from the Indian Institute of Technology, BHU, Varanasi, and M.E. (with distinction) in Electronics Engineering from Birla Institute of Technology and Science, Pilani.
Work in Industry and Prior Affiliations.
Prior to joining UCR in 1991, Dr. Bhanu was Senior Fellow at Honeywell, Inc., Engineering Specialist at Ford Aerospace & Communications Corporation, Research Fellow at INRIA - France and Academic Associate at IBM San Jose Research Laboratory. His work in the industry dealt with computer vision, pattern recognition and machine learning with applications to target/object recognition, autonomous navigation with commercial, defense, space and intelligence applications. Dr. Bhanu has been on the faculty of the Department of Computer Science, University of Utah, where he worked on CAD-based vision and robotics, multi-sensor fusion, motion analysis, and computer vision and pattern recognition problems.
Recognition.
Dr. Bhanu is a Fellow of the Institute of Electrical and Electronics Engineers (IEEE), the American Association for the Advancement of Science (AAAS), the International Association for Pattern Recognition (IAPR), the International Society for Optical Engineering (SPIE), and the American Institute for Medical and Biological Engineering (AIMBE). Bhanu is also a member of ACM, AAAI, and BMES. Bhanu received the university, industry, and conference/journal paper awards for research excellence, outstanding contributions, team efforts, and best papers. He received an award from the President of Honeywell on patented technology on inertial navigation sensor integrated video-based navigation. He received the Dissertation Advisor/Mentoring Award of UC Riverside at the commencement held in June 2011. He received the Bourns College of Engineering Research Excellence Award in 2003 and Pioneering award in 2015. He received the UCR Faculty Research Lecturer Award, the UCR Senate's highest Award for Faculty Research in June 2019. It is the first such award for Bourns College of Engineering in 30 years. He received Distinguished Alumnus Award of BITS (Birla Institute of Technology and Science), Pilani in 2019. He has over 18 U.S. and International patents issued and several pending. He has over 550 refereed publications including over 155 journal papers. He was the General Chair for the first IEEE Workshop on Applications of Computer Vision, WACV (now renamed as IEEE Winter Conference on Applications of Computer Vision) (Palm Springs, CA, 1992, 2000, 2005 (Program Chair), 2015), Chair for the DARPA Image Understanding Workshop, IUW (Monterey, CA, 1994), General Chair for the IEEE Conference on Computer Vision and Pattern Recognition, CVPR (San Francisco, CA, 1996), General Chair for IEEE Advanced Video and Signal-based Surveillance, AVSS (Santa Fe, 2008), General Chair for ACM/IEEE International Conference on Distributed Smart Cameras ICDSC (Palm Springs in 2014), and General Chair for IEEE International Conference on Automatic Face and Gesture Recognition (Xian, China, 2018).
Authored Books.
Dr. Bhanu is the author of the following books:


Gertrude More

Dame Gertrude More (born as Helen More; 25 March 1606 - 17 August 1633) was a nun of the English Benedictine Congregation, a writer and chief founder of the abbey at Cambrai which became Stanbrook Abbey.
Life.
More was born in Low Leyton in Essex. Her father, Cresacre More, was great-grandson of Thomas More; her mother, Elizabeth Gage, was sister of Sir John Gage, 1st Baronet of Firle, Sussex, Lord Chamberlain to Queen Mary. Her mother died in 1611 and Helen's father, who had trained to be a monk, became responsible for her care and education. Dom Benet Jones, a Benedictine monk, encouraged her to join his projected religious foundation, Our Lady of Comfort, in Cambrai. She was the first of nine postulants admitted to the order on 31 December 1623. Helen More came under the prescriptive influence of the Dominican Augustine Baker and took the religious name of Gertrude. Catherine Gascoigne, one of her peers, was chosen ahead of her by the authorities in Rome as abbess in 1629 because she was older. Gascoigne was more welcoming of Baker's advice. Sister More opposed Baker's approach but eventually gave into his ways - which included writing good books.
Her writing was heavily influenced by the christian mystics such as Julian of Norwich and Teresa of Avila and other spiritual writers and she contributed to the effort to publish their work.
The row at Cumbrai continued and Baker was recalled to Douai. Before the row was settled Gertrude died at Cambrai, from smallpox, aged 27.
Posthumous.
Some papers found after her death and arranged by Father Baker, were afterwards published in two separate works: one entitled "The Holy Practices of a Divine Lover, or the Sainctly Ideot's Devotions" (Paris, 1657); the other, "Confessiones Amantis", or "Spiritual Exercises", or "Ideot's Devotions", to which was prefixed her "Apology", for herself and for her spiritual guide (Paris, 1658).


Smallpox 2002

Smallpox 2002: Silent Weapon is a fictional docudrama produced by Wall to Wall, showing how a single act of bioterrorism leads to terrifying consequences globally.
Background.
The premise of it was one man who, in 2002, creates the smallpox virus himself, infects himself, and touches ten people in New York City. This eventually leads to a pandemic across the world that is later defeated, but not before 60 million people are killed.
The film was commissioned before the September 11 attacks and is presented in the form of a fictional documentary, including false interviews and stock footage. The tagline for the movie was, "Drama, until it happens".
Reception.
Newspaper reviews of the documentary were mixed, varying from "a sick stunt" to "extraordinarily good". The docudrama proved very popular with viewers, attracting 3.4m viewers, 15% of the audience, to a 9:00pm slot on BBC2 according to overnight returns.


D-octopine dehydrogenase

Octopine dehydrogenase (N2-(D-1-carboxyethyl)-L-arginine:NAD+ oxidoreductase, OcDH, ODH) is a dehydrogenase enzyme in the opine dehydrogenase family that helps maintain redox balance under anaerobic conditions. It is found largely in aquatic invertebrates, especially mollusks, sipunculids, and coelenterates, and plays a role analogous to lactate dehydrogenase (found largely in vertebrates)
. In the presence of NADH, OcDH catalyzes the reductive condensation of an α-keto acid with an amino acid to form N-carboxyalkyl-amino acids (opines). The purpose of this reaction is to reoxidize glycolytically formed NADH to NAD+, replenishing this important reductant used in glycolysis and allowing for the continued production of ATP in the absence of oxygen.
Structure.
OcDH is a monomer with a molecular weight of 38kD made of two functionally distinct subunits. The first, Domain I, is composed of 199 amino acids and contains a Rossmann fold. Domain II is composed of 204 amino acids and is connected to the Rossmann fold of Domain I via its N-terminus.
Mechanism.
Isothermal titration calorimetry (ITR), nuclear magnetic resonance (NMR)
crystallography, and clonal studies of OcDH and its substrates have led to the identification of the enzyme reaction mechanism. First, the Rossmann fold in Domain I of OcDH binds NADH. Binding of NADH to the Rossmann fold triggers small conformational change typical in the binding of NADH to most dehydrogenases resulting in an interaction between the pyrophosphate moiety of NADH with residue Arg324 on Domain II. This interaction with Arg324 generates and stabilizes the L-arginine binding site and triggers partial domain closure (reduction in the distance between the two domains). The binding of the guanidinium headgroup of L-arginine to the active site of the OcDH:NADH complex (located between the domains) induces a rotational movement of Domain II towards Domain I (via a helix-kink-helix structure in Domain II). This conformational change forms the pyruvate binding site. Binding of pyruvate to the OcDH:NADH:L-arginine complex places the alpha-ketogroup of pyruvate in proximity with the alpha-amino group of L-arginine. The juxtaposition of these groups on the substrates results in the formation of a Schiff base which is subsequently reduced to D-octopine. The priming of the pyruvate site for hydride transfer via a Schiff base through the sequential binding of NADH and L-arginine to OcDH prevents the reduction of pyruvate to lactate.
Substrate specificity.
Octopine dehydrogenase has at least two structural characteristics that contribute to substrate specificity. Upon binding to NADH, amino acid residues lining either side of the active site within the space between the domains of OcDH act as a “molecular ruler”, physically limiting the size of the substrates that can fit into the active site. There is also a negatively charged pocket in the cleft between the two domains that acts an “electrostatic sink” that captures the positively charged side-chain of L-arginine.
Evolution.
Examination of OcDH reaction rates from different organisms in the presence of different substrates has demonstrated a trend of increasing specificity for substrates in animals of increasing complexity. Evolutionary modification in substrate specificity is seen most drastically in the amino acid substrate. OcDH from some sea anemones has been shown to be able to use non-guanidino amino acids whereas OcDH form more complex invertebrates, such as the cuttlefish, can only use L-arginine (a guanidino amino acid).


Caretaker gene

Changes in the genome that allow uncontrolled cell proliferation or cell immortality are responsible for cancer. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein grouped these cancer susceptibility genes into two classes: "caretakers" and "gatekeepers". In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa, and Martin Nowak; "landscaper" genes.
Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes.
In contrast to caretaker genes, gatekeeper genes encode gene products that act to prevent growth of potential cancer cells and prevent accumulation of mutations that directly lead to increased cellular proliferation.
The third classification of genes, the landscapers, encode products that, when mutated, contribute to the neoplastic growth of cells by fostering a stromal environment conducive to unregulated cell proliferation.
Genes in context.
Pathways to cancer via the caretakers.
The process of DNA replication inherently places cells at risk of acquiring mutations. Thus, caretaker genes are vitally important to cellular health. Rounds of cell replication allow fixation of mutated genes into the genome. Caretaker genes provide genome stability by preventing the accumulation of these mutations.
Factors that contribute to genome stabilization include proper cell-cycle checkpoints, DNA repair pathways, and other actions that ensure cell survival following DNA damage. Specific DNA maintenance operations encoded by caretaker genes include nucleotide excision repair, base excision repair, non-homologous end joining recombination pathways, mismatch repair pathways, and telomere metabolism.
Loss of function mutations in caretaker genes allow mutations in other genes to survive that can result in increased conversion of a normal cell to a neoplastic cell, a cell that; (1) divides more often than it should or (2) does not die when conditions warrant cell death. Thus, caretaker genes do not directly regulate cell proliferation. Instead, they prevent other mutations from surviving for example by slowing the cell division process to enable DNA repair to complete, or by initiating apoptosis of the cell. In genetic knock-out and rescue experiments, restoration of a caretaker gene from the mutated form to the wildtype version does not limit tumorigenesis. This is because caretaker genes only indirectly contribute to the pathway to cancer.
Inactivation of caretaker genes is environmentally equivalent to exposing the cell to mutagens incessantly. For example, a mutation in a caretaker gene coding for a DNA repair pathway that leads to the inability to properly repair DNA damage could allow uncontrolled cell growth. This is the result of mutations of other genes that accumulate unchecked as a result of faulty gene products encoded by the caretakers.
In addition to providing genomic stability, caretakers also provide chromosomal stability. Chromosomal instability resulting from dysfunctional caretaker genes is the most common form of genetic instability that leads to cancer in humans. In fact, it has been proposed that these caretaker genes are responsible for many hereditary predispositions to cancers.
In individuals predisposed to cancer via mutations in caretaker genes, a total of three subsequent somatic mutations are required to acquire the cancerous phenotype. Mutations must occur in the remaining normal caretaker allele in addition to both alleles of gatekeeper genes within that cell for the said cell to turn to neoplasia. Thus, the risk of cancer in these affected populations is much less when compared to cancer risk in families predisposed to cancer via the gatekeeper pathway.
Pathways to cancer via the gatekeepers.
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell division and death. When tissue damage occurs, for example, products of gatekeeper genes ensure that balance of cell growth over cellular death remains in check. In the presence of competent gatekeeper genes, mutations of other genes do not lead to on-going growth imbalances.
Mutations altering these genes lead to irregular growth regulation and differentiation. Each cell type has only one, or at least only very few, gatekeeper genes. If a person is predisposed to cancer, they have inherited a mutation in one of two copies of a gatekeeper gene. Mutation of the alternate allele leads to progression to neoplasia.
Historically, the term gatekeeper gene was first coined in association with the APC gene, a tumor suppressor that is consistently found to be mutated in colorectal tumors. Gatekeeper genes are in fact specific to the tissues in which they reside.
The probability that mutations occur in other genes increases when DNA repair pathway mechanisms are damaged as a result of mutations in caretaker genes. Thus, the probability that a mutation will take place in a gatekeeper gene increases when the caretaker gene has been mutated.
Apoptosis, or induced cell suicide, usually serves as a mechanism to prevent excessive cellular growth. Gatekeeper genes regulate apoptosis. However, in instances where tissue growth or regrowth is warranted, these signals must be inactivated or net tissue regeneration would be impossible. Thus, mutations in growth-controlling genes would lead to the characteristics of uncontrolled cellular proliferation, neoplasia, while in a parallel cell that had no mutations in the gatekeeper function, simple cell death would ensue.
Pathways to cancer via the landscapers.
A third group of genes in which mutations lead to a significant susceptibility to cancer is the class of landscaper genes. Products encoded by landscaper genes do not directly affect cellular growth, but when mutated, contribute to the neoplastic growth of cells by fostering stromal environments conducive to unregulated cell proliferation.
Landscaper genes encode gene products that control the microenvironment in which cells grow. Growth of cells depends both on cell-to-cell interactions and cell-to-extracellular matrix (ECM) interactions. Mechanisms of control via regulation of extracellular matrix proteins, cellular surface markers, cellular adhesion molecules, and growth factors have been proposed.
Cells communicate with each other via the ECM through both direct contact and through signaling molecules. Stromal cell abnormalities arising from gene products coded by faulty landscaper genes could induce abnormal cell growth on the epithelium, leading to cancer of that tissue.
Biochemical cascades consisting of signaling proteins occur in the ECM and play an important role to the regulation of many aspects of cell life. Landscaper genes encode products that determine the composition of the membranes in which cells live. For example, large molecular weight glycoproteins and proteoglycans have been found to in association with signaling and structural roles. There exist proteolytic molecules in the ECM that are essential for clearing unwanted molecules, such as growth factors, cell adhesion molecules, and others from the space surrounding cells. It is proposed that landscaper genes control the mechanisms by which these factors are properly cleared. Different characteristics of these membranes lead to different cellular effects, such as differing rates of cell proliferation or differentiation. If, for example, the ECM is disrupted, incoming cells, such as those of the immune system, can overload the area and release chemical signals that induce abnormal cell proliferation. These conditions lead to an environment conducive to tumor growth and the cancerous phenotype.
Gatekeepers, caretakers, and cellular aging.
Because mechanisms that control the accumulation of damage through the lifetime of a cell are essential to longevity, it is logical that caretaker and gatekeeper genes play a significant role in cellular aging. Increased activity of caretaker genes postpones aging, increasing lifespan. This is because of the regulatory function associated with caretaker genes in maintaining the stability of the genome. The actions of caretaker genes contribute to increasing lifespan of the cell.
A specific purpose of caretaker genes has been outlined in chromosomal duplication. Caretakers have been identified as crucial to encoding products that maintain the telomeres. It is believed that degradation of telomeres, the ends of chromosomes, through repeated cell cycle divisions, is a main component of cellular aging and death.
It has been suggested that gatekeeper genes confer beneficial anti-cancer affects but may provide deleterious effects that increase aging. This is because young organisms experiencing times of rapid growth necessitate significant anti-cancer mechanisms. As the organism ages, however, these formerly beneficial pathways become deleterious by inducing apoptosis in cells of renewable tissues, causing degeneration of the structure. Studies have shown an increased expression of pro-apoptotic genes in age-related pathologies. This is because the products of gatekeeper genes are directly involved in coding for cellular growth and proliferation.
However, dysfunctional caretaker genes do not always lead to a cancerous phenotype. For example, defects in nucleotide excision repair pathways are associated with premature aging phenotypes in diseases such as Xeroderma pigmentosum and Trichothiodystrophy. These patients exhibit brittle hair, nails, scaly skin, and hearing loss – characteristics associated with simple human aging. This is important because the nucleotide excision repair pathway is a mechanism thought to be encoded by a caretaker gene. Geneticists studying these premature-aging syndromes propose that caretaker genes that determine cell fate also play a significant role in aging.
Similarly, gatekeeper genes have been identified as having a role in aging disorders that exhibit mutations in such genes without an increased susceptibility to cancer. Experiments with mice that have increased gatekeeper function in the p53 gene show reduced cancer incidence (due to the protective activities of products encoded by p53) but a faster rate of aging.
Cellular senescence, also encoded by a gatekeeper gene, is arrest of the cell cycle in the G1 phase. Qualitative differences have been found between senescent cells and normal cells, including differential expression of cytokines and other factors associated with inflammation. It is believed that this may contribute, in part, to cellular aging.
In sum, although mechanisms encoded by gatekeeper and caretaker genes to protect individuals from cancer early in life, namely induction of apoptosis or senescence, later in life these functions may promote the aging phenotype.
Mutations in context.
It has been proposed that mutations in gatekeeper genes could, to an extent, offer a sort of selective advantage to the individual in which the change occurs. This is because cells with these mutations are able to replicate at a faster rate than nearby cells. This is known as "increased somatic fitness". Caretaker genes, on the other hand, confer selective disadvantage because the result is inherently decreased cellular success. However, increased somatic fitness could also arise from a mutation in a caretaker gene if mutations in tumor suppressor genes increase the net reproductive rate of the cell.
Although mutations in gatekeeper genes may lead to the same result as those of caretaker genes, namely cancer, the transcripts that gatekeeper genes encode are significantly different from those encoded by caretaker genes.
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell division and death. In cases of tissue damage, for example, gatekeeper genes would ensure that balance of cell growth over cellular death remains in check. In the presence of competent gatekeeper genes, mutations of other genes would not lead to on-going growth imbalances.
Whether or not mutations in these genes confer beneficial or deleterious effects to the animal depends partially on the environmental context in which these changes occur, a context encoded by the landscaper genes. For example, tissues of the skin and colon reside in compartments of cells that rarely mix with one another. These tissues are replenished by stem cells. Mutations that occur within these cell lineages remain confined to the compartment in which they reside, increasing the future risk of cancer. This is also protective, however, because the cancer will remain confined to that specific area, rather than invading the rest of the body, a phenomenon known as metastasis.
In areas of the body compartmentalized into small subsets of cells, mutations that lead to cancer most often begin with caretaker genes. On the other hand, cancer progression in non-compartmentalized or large cell populations may be a result of initial mutations in gatekeepers.
These delineations offer a suggestion why different types of tissue within the body progress to cancer by differing mechanisms.
Notes.
Although the classification of tumor suppressor genes into these categories is helpful to the scientific community, the potential role of many genes cannot be reliably identified as the functions of many genes are rather ill-defined. In some contexts, genes exhibit discrete caretaker function while in other situations gatekeeper characteristics are recognized. An example of one such gene is p53. Patients with Li-Fraumeni syndrome, for example, have mutations in the p53 gene that suggest caretaker function. p53 has an identified role, however, in regulating the cell cycle as well, which is an essential gatekeeper function.


Immobilized whole cell

The immobilized whole cell system is an alternative to enzyme immobilization. Unlike enzyme immobilization, where the enzyme is attached to a solid support (such as calcium alginate or activated PVA or activated PEI), in immobilized whole cell systems, the target cell is immobilized. Such methods may be implemented when the enzymes required are difficult or expensive to extract, an example being intracellular enzymes. Also, if a series of enzymes are required in the reaction; whole cell immobilization may be used for convenience. This is only done on a commercial basis when the need for the product is more justified.
Multiple enzymes may be introduced into the reaction, thus eliminating the need for immobilization of multiple enzymes. Furthermore, intracellular enzymes need not be extracted prior to the reaction; they may be used directly. However, some enzymes may be used for the metabolic needs of the cell, leading to reduced yield of the cell.


Nanjing Ange Pharmaceutical

Nanjing Ange Pharmaceutical Co., Ltd. () is a pharmaceutical company in Nanjing, in the People's Republic of China, specializing in the development of “New Drugs” (the drugs that previously have not been marketed in China, i.e., New Chemical Entities for China's FDA) as well as the research, development, production and trade of chemical APIs and pharmaceutical intermediates.
Company Profile.
Ange was founded in 2003, and is now a leading company in the Chinese pharmaceutical industry.
With almost every major university in Nanjing Ange has established cooperative relationships and laboratories, including China Pharmaceutical University, China’s first independent school of pharmacy and one of the few institutes with complete pharmaceutical fields.
Main Products.
Ange's main products are Antineoplastic medicines, which include:
It also produces relative pharmaceutical intermediates.
Recent Projects.
In the past 2 years, Ange has been working with Abbott Laboratories Ltd. and Simcere Pharmaceutical Group, etc.


Photobacterium leiognathi

Photobacterium leiognathi is a species of Gram-negative bacteria. The species is bioluminescent and a symbiont of ponyfish (family Leiognathidae).


Propynyl (psychedelic)

Propynyl (4-propynyloxy-3,5-dimethoxyphenethylamine) is a lesser-known psychedelic drug. It is closely related in structure to mescaline. Propynyl was first synthesized by Alexander Shulgin. In his book "PiHKAL", the minimum dosage is listed as 80 mg, and the duration listed as 8–12 hours. Propynyl produces a body load and few to no mental effects. Very little data exists about the pharmacological properties, metabolism, and toxicity of propynyl.


Nettle agent

Nettle agents (named after stinging nettles) or urticants are a variety of chemical warfare agents that produce corrosive skin and tissue injury upon contact, resulting in erythema, urticaria, intense itching, and a hive-like rash.
Most nettle agents, such as the best known and studied nettle agent, phosgene oxime, are often grouped with the vesicant (blister agent) chemical agents. However, because nettle agents do not cause blisters, they are not true vesicants.


Amblysomus

Amblysomus (also narrow-headed golden mole or South African golden mole) is a genus of the golden mole family, Chrysochloridae, comprising five species of the small, insect-eating, burrowing mammals endemic to Southern Africa. All five species can be found in South Africa and some are also found in Swaziland and Lesotho.
It contains the following species:
Phylogeny and morphology.
"Amblysomus" is part of the family of golden moles, Chrysochloridae. The order of golden moles and tenrecs, Afrosoricida, is part of Afrotheria, one of the four main divisions of placental mammals, along with elephant shrews, aardvarks, hyraxes, sirenians and elephants.
Golden moles are not all golden. Some have black to pale tawny-yellow fur.; the name and family name “Chrysochloridae” (meaning green-gold), refers to the coppery gold, green, purple or bronze sheen of their dense fur. They all have differences in size and color, but have a similar appearance” with compact fusiform or lozenge-shaped bodies, short and powerful forelimbs containing pick-like claws, and no external eyes, ears or tail”. Their fur consists of guard hairs that are moisture repellent. They have a woolly underfur for insulation. Their skin is thick and tough, especially on the head, containing a wedge-shaped muzzle with a leathery nosepad protecting its nostrils. upward thrust of their dorsally-flattened head and powerful down thrusts of the foreclaws help them tunnel through the soil during subsurface foraging. This creates raised visible ridges of soil. Genera Amblysomus and Neamblysomus use the head and webbed hind feet to move soil and evict it on the surface.
Similarities to fossorial mammals resulted from ecological convergence, not ancestry. The eyes are vestigial and that is why they are covered by skin. The optic nerve is degenerate because they live underground where there is little use of them. The external ear pinnae are absent as well as the external tail. The body has a streamlined shape which facilitates movement through dense substratum. On the outside, they are similar to other fossorial small mammals, but the golden moles show highly specialized characters like “a unique hyoid-dentary articulation. Some also have hypertrophied malleus bones in the middle ear that permits great sensitivity to underground vibrations and airborne sounds. They have a third bone in the forearm (i.e. ossified tendon) and a reduction of phalanges in the fore- and hindfeet. Muscle arrangements are not paralleled in the Mammalia. Most anatomical specializations shown in extant species are found in 3 fossil species (dating back to the Miocene). Chrysochlorids have been described as "spectacularly autapomorphic" due to how unusual and numerous they are.
They are blind, subterranean small mammals with small ears, tails and eyes that are all covered by skin and fur. They have unique cranial and nasal morphology. On their nose is a large leathery pad to help them burrow. They have powerful forearms and claws, but use mainly their snout to burrow. The golden mole thrusts its forearms from under its body to help it burrow deeper into the earth.
Both the male and female have a cloaca. They have tabulars in the occipital which is not found in other mammals. Their zygomatic arches form elongations of the maxillae. Their malleus is enlarged and helps in hearing under the ground. Golden moles do not have a fifth finger on their front paws. Instead, they have a huge claw on the third or second finger. Their fur has an iridescent sheen.
Their dental formula is 3,1,3,2/3,1,3,2. The first incisor is enlarged. The lateral incisors and first premolars are like canines. The molars are zalmbdodont (have v-shaped crest) like tenrecs. Zalambdodonty has arisen independently. This implies that it is due to morphological convergence, because they are not closely allied to any other family of extant mammals.
Studies show that tenrecs and golden moles should be separated from Insectivora and placed in Afrotheria which include the elephant shrews and hyraxes. They share few morphological synapomorphies. Mitochondrial/nuclear gene sequences and rare genomic changes demonstrated that chrysochlorids and tenrecs form their own clade, Afrosoricida (African shrew-like mammals). It contains no soricids (shrews) and is sometimes confused with the shrew subgenus "Afrosorex". Alternative names were "Tenrecoidea" and "Tenrecomorpha”. Divergence between golden-moles and tenrecs occurred about 50 million years ago. They are now classified as Chrysochloridea instead of a specialized members of Order Insectivora.
Natural history.
Golden moles are common throughout southern Africa. There are 7 genera and 18 species known. They resemble the Talpidae (true moles) and Notoryctidae (marsupial moles). Two subfamilies may be recognized: the Chrysochlorinae, in which the malleus bone of the middle ear is enlarged with a spherical or club-like shape and the Amblysominae, in which the malleus is not expanded and has the typical mammalian shape (i.e. Amblysomus).
All 21 species of golden moles are endemic to subSaharan Africa. They inhabit a wide altitudinal, climatic and vegetational spectrum of subterrestrial habitats. The highest diversity is found in southern Africa. Only three species occur outside the region (i.e. Calcochloris leucorhinus; Chrysochloris; and Calcochloris tytonis). The South African species fall into two ecological groups: semi-desert (Eremitalpa granti, Cryptochloris zyli and C. wintoni), karroid (Chrysochloris visagiei) or fynbos habitats (Chrysochloris asiatica) along the south-west coast; and indigenous forests, savanna woodlands and temperate grasslands in the eastern part of the subregion (Chrysospalax, Chlorotalpa, Calcochloris, Neamblysomus and Amblysomus).
Only the Hottentot golden mole ("Amblysomus hottentotus") and the Cape golden mole ("Chrysochloris asiatica") are widespread. The Stuhlmann's golden mole ("Chrysochloris stuhlmanni") and Juliana's golden mole "Neamblysomus julianae"), are known from scattered localities situated hundreds of kilometres apart, but connected by continuous favourable habitat. These may be more widespread than is indicated by the scant distribution data currently available. Other species, such as Sclater's golden mole ("Chlorotalpa sclateri"), probably have more restricted ranges than general texts indicate, since the few populations known to exist occur at localities separated by wide expanses of seemingly inhospitable habitat. Geographical continuity between these isolates seems unlikely.
Despite a high thermal conductance, the golden mole has a low basal metabolic rate. They reduce their thermoregulatory energy requirements and enter torpor, (i.e. either daily or in the cold). Body temperature in the thermal neutral zone is lower than in other small mammals. Efficient renal function effectively reduces water requirements so that they do not need to drink. Specializations allow them to survive in extreme habitats and where food is seasonally or perennially scarce.
Most golden mole species are restricted to a narrow range of habitats and environmental conditions. They have very limited mobility and dispersal abilities. They are specialized K-selected strategists, opportunistic insectivores. They eat primarily invertebrates they find. They feed on earthworms, termites and millipedes. Their diets may vary due to the abundance of prey items.
Most are solitary and subterrestrial. They construct semi-permanent tunnel systems. Their tunnels consists of an upper tier of burrows used for foraging and a lower tier with inter-connecting chambers used for resting and raising young (except the Namib ("Eremitalpa granti namibensis") who “swims" through the desert in search for termite nests.
Populations of golden moles are restricted to patches of habitat with friable soils and abundant invertebrates. Their distribution is clumped and sympatric. Different species rarely coexist to compete for resources. If two species occur in the same area they tend to occupy different microhabitats due to ecological displacement.
In courtship the male chirrups, bobs his head and stomps his foot and the female rasps and squeals. Reproductive data suggests that golden moles breed throughout the year, but peaks in the wetter months when food is more abundant. Some think they are polyoestrous. Litter sizes are usually 2. Post-natal development reaches up to 45.
The behavior of all golden moles is primarily solitary and territorial. They live in deserts and swamps. The Golden mole digs and lives in burrows. Territorial golden moles fight viciously when confined together. Studies show that small groups may hibernate together, but only in the giant golden mole. Burrows used by more than one mole. The Hottentot golden mole will fight aggressively with either sex by using their foreclaws to wrestle, and biting at the abdomen. Fighting is accompanied by high-pitched squeaks. The golden mole actively defends its burrow systems range overlap, and the dominant mole take over neighbouring burrows to increase its home range.
The IUCN Red List of Threatened Species includes 10 South African golden mole species. The De Winton's golden mole ("Cryptochloris wintoni") is critically endangered. Marley's golden mole ("Amblysomus marleyi"), Giant golden mole (Chrysospalax trevelyani), Van Zyl's golden mole ("Cryptochloris zyli"), Gunning's golden mole ("Neamblysomus gunningi"), and Juliana's golden mole ("Neamblysomus julianae") are endangered. The topotypical population of Juliana's golden mole is critically endangered. Robust golden mole ("Amblysomus robustus"), Arend's golden mole ("Carpitalpa arendsi"), Duthie's golden mole ("Chlorotalpa duthieae"), Rough-haired golden mole ("Chrysospalax villosus") are vulnerable. Grant's golden mole ("Eremitalpa granti"), Fynbos golden mole ("Amblysomus corriae"), and Highveld golden mole ("Amblysomus septentrionalis") are near threatened. Congo golden mole ("Calcochloris leucorhinus") Somali golden mole ("Calcochloris tytonis"), Visagie's golden mole ("Chrysochloris visagiei") are listed as Data Deficient.
Threatened species have restricted or fragmented distributions. Populations subjected to habitat degradation due to human activities like mining, urbanization, agriculture and the poor forest management. Husbandry projects have been conducted on the Golden mole. This included captivity for a few weeks up to nearly two years. Individuals were housed separately in containers of rich soil/sand. They were fed daily with insects and earthworms. Water was provided ad libitum because they do not drink in the wild. Some get pinky mice and frozen day-old chicks (Bronner) Room temperature is okay, but not below 15 °C or above 30 °C. This range does not disrupt their endogenous torpor rhythms. Torpor reduces the amount of food intake. DO not handle them as they sleep. They will awaken and the stress will cause them to stop eating and physiological decline others.
Research review.
The question of higher-level relationships among placental mammal centers on the order Inserctivora. Huxley argued that insectivores retain many primitive features. They are closer to their ancestor mammals than the living groups. Cladistic analysis suggests that living insectivores are “united by derived anatomical features”. Insectivores are not monophyletic, golden moles included. This clade also includes hyraxes, manatees, elephants, elephant shrews and aardvarks. They are from an African origin. Suggested from 12S ribosomal RNA transversions, African radiation came from a single common ancestor and gave rise to divergence during Cretaceous period. This is before the land connections were developed with Europe in the early Cenozoic era.
The middle ear of nine families of golden moles (family Chrysochloridae) were examined to see the ossicular apparatus. The "Amblysomus" species have ossicles typical of mammals. The "Chrysospalax", "Chrysochloris", "Cryptochloris" and "Eremitalpa" species do not. They ”have enormously hypertrophied mallei. Golden moles differ in the nature and extent of the interbullar connection, the shape of the tympanic membrane and that of the manubrium. The stapes has an unusual orientation, projecting dorsomedially from the incus. It has been proposed that hypertrophied ossicles in golden moles are adapted towards the detection of seismic vibrations. The functional morphology of the middle ear apparatus is reconsidered in this light, and it is proposed that adaptations towards low-frequency airborne hearing might have predisposed golden moles towards the evolution of seismic sensitivity through inertial bone conduction. The morphology of the middle ear apparatus sheds little light on the disputed ordinal position of the Chrysochloridae.”
Not so long ago, there was a lot of uncertainty regarding how clades of living mammals were interrelated. Many mammalian systematists believed that golden moles (Chrysochloridae) were “insectivorans” along with shrews and hedgehogs. It appears in most studies as the sister taxon to Tenrecidae-Chrysochloridae-Macroscelididae, but has also been placed as sister taxon to Chrysochloridae, Tenrecidae, or to a macroscelidid-chrysochlorid clade. Relatedly, tenrecids and chrysochlorids are generally reconstructed as sister taxa, except for those studies just noted. Different resolutions of intra-afrotherian phylogeny, particularly the intriguing possibility that tenrecids, chrysochlorids, and macroscelidids are more basal than paenungulates have important implications for understanding the afrotherian common ancestor as occupying either an ungulate- or insectivoran-grade niche. The quality of the fossil record of some afrotherian lineages, such as proboscideans, hyracoids and sirenians, is relatively good, and while that of other afrotherians is much poorer, it too is benefiting from a steady pace of discovery. ... Afrotheria (paenungulates, aardvarks, tenrecs, golden moles) comprising a single clade (Atlantogenata) at the base of Placentalia, and with all other placentals in the clade Boreoeutheria, has received relatively consistent support since 2007. Hence, there now is good phylogenetic reason to scrutinize a major division within Placentalia: afrotherians and xenarthrans (“southern” placentals) on the one hand, and boreoeutherians (“northern” placentals) on the other. For example, Leche argued that in tenrecs and golden moles, “der Zahnwechsel in eine sehr späte Lebensphase fällt” (“tooth replacement occurs in a very late period of life”) based on the observation that individuals of adult size retain deciduous teeth and/or have not yet erupted their permanent successors”.


John G. Webster

John G. Webster is an American electrical engineer and a founding pioneer in the field of biomedical engineering. In 2008, Professor Webster was awarded the University of Wisconsin, College of Engineering, Polygon Engineering Council Outstanding Instructor Award.
Books.
"Medical Instrumentation: Application and Design" is considered the classic textbook in the field.
Honors and awards.
Webster is currently professor emeritus in the College of Engineering at the University of Wisconsin–Madison. He last taught Biomedical Engineering 310: Introduction to Bioinstrumentation during spring 2015.
He first proposed the idea of electrical impedance tomography as a medical imaging technique in a publication in 1978.
In his spare time, Webster works with undergraduate biomedical engineering design teams at the University of Wisconsin-Madison, including ongoing projects with impedance cardiography and atrial fibrillation.


2-Phospho-L-lactate guanylyltransferase

2-Phospho-L-lactate guanylyltransferase (, "CofC", "MJ0887") is an enzyme with systematic name "GTP:2-phospho-L-lactate guanylyltransferase". This enzyme catalyses the following chemical reaction
This enzyme is involved in the biosynthesis of coenzyme F420.


Pandemic (Sigler novel)

Pandemic is a 2014 science fiction thriller novel by Scott Sigler and the final novel in the "Infected" trilogy. The book was released in hardback, e-book, and audiobook on January 21, 2014 through Crown Publishing and is set several years after the events in "Contagious".
Summary.
Margaret Montoya's actions at the end of "Contagious" might have saved the lives of many, however most consider her to be a monster rather than a hero. Since that time she has turned into a shut-in out of guilt, something that has torn apart her relationship with the CIA agent Clarence Otto. However now she is called forth to help fight against a new version of the alien microorganisms, one that was launched by the probe just before it was destroyed. Montoya and the others try to do their best to combat the microorganisms and help keep the general public aware, only for many to assume that this is either a coverup for something more human in origin or an outright fabrication. However, as the book progresses things grow more dire and the world is plunged into an apocalyptic environment.
Reception.
Critical reception has been positive. The "Chicago Tribune" gave "Pandemic" a mostly favorable review, writing that "The horrors get a bit tedious as the action gets more ludicrous, and the characters are about as deep as cereal boxes, but Sigler deftly revitalizes clichés — raises them from the dead, you might say." The "Washington Post" was more positive, stating "The characters are likable, even the ones who fall prey to the plague’s more monstrous side effects, and the snappy dialogue makes this a fun read."


Monoallelic gene expression

Monoallelic gene expression (MAE) is the phenomenon of the gene expression, when only one of the two gene copies (alleles) is actively expressed (transcribed), while the other is silent. Diploid organisms bear two homologous copies of each chromosome (one from each parent), a gene can be expressed from both chromosomes (biallelic expression) or from only one (monoallelic expression). MAE can be "Random monoallelic expression (RME)" or "Constitutive monoallelic expression (constitutive)". "Constitutive monoallelic expression" occurs from the same specific allele throughout the whole organism or tissue, as a result of genomic imprinting. RME is a broader class of monoallelic expression, which is defined by random allelic choice in somatic cells, so that different cells of the multi-cellular organism express different alleles.
Random monoallelic gene expression (RME).
X-chromosome inactivation (XCI), is the most striking and well-studied example of RME. XCI leads to the transcriptional silencing of one of the X chromosomes in female cells, which results in expression of the genes that located on the other, remaining active X chromosome. XCI is critical for balanced gene expression in female mammals. The allelic choice of XCI by individual cells takes place randomly in epiblasts of the preimplantation embryo, which leads to mosaic gene expression of the paternal and maternal X chromosome in female tissues. XCI is a chromosome-wide monoallelic expression, that includes expression of all genes that are located on X chromosome, in contrast to "autosomal RME (aRME)" that relates to single genes that are interspersed over the genome. aRME's can be fixed or dynamic, depending whether or not the allele-specific expression is conserved in daughter cells after mitotic cell division.
Types of aRME.
Fixed aRME are established either by silencing of one allele that previously has been biallelically expressed, or by activation of a single allele from previously silent gene. Expression activation of the silent allele is coupled with a feedback mechanism that prevents expression of the second allele. Another scenario is also possible due to limited time-window of low-probability initiation, that could lead to high frequencies of cells with single-allele expression. It is estimated that 2-10% of all genes are fixed aRME. Studies
of fixed aRME require either expansion of monoclonal cultures or lineage-traced in vivo or in vitro cells that are mitotically.
Dynamic aRME occurs as a consequence of stochastic allelic expression. Transcription happens in bursts, which results in RNA molecules being synthesized from each allele separately. So over time, both alleles have a probability to initiate transcription. Transcriptional bursts are allelically stochastic, and lead to either maternal or paternal allele being accumulated in the cell. The gene transcription burst frequency and intensity combined with RNA-degradation rate form the shape of RNA distribution at the moment of observation and thus whether the gene is bi- or monoallelic. Studies that distinguish fixed and dynamic aRME require single-cell analyses of clonally related cells.
Mechanisms of aRME.
Allelic exclusion is a process of gene expression when one allele is expressed and the other one kept silent. Two most studied cases of allelic exclusion are monoallelic expression of immunoglobulins in B and T cells and olfactory receptors in sensory neurons. Allelic exclusion is cell-type specific (as opposed to organism-wide XCI), which increases intercellular diversity, thus specificity towards certain antigens or odors.
Allele-biased expression is skewed expression level of one allele over the other, but both alleles are still expressed (in contrast to allelic exclusion). This phenomenon is often observed in cells of immune function
Methods of detection.
Methods of MAE detection are based on the difference between alleles, which can be distinguished either by the sequence of expressed mRNA or protein structure. Methods of MAE detection can be divided into single gene or whole genome MAE analysis. Whole genome MAE analysis cannot be performed based on protein structure yet, so these are completely NGS based techniques.
Single-gene analysis
Genome-wide analysis


Short-chain dehydrogenase/reductase


Chrysemys


List of Crash Bandicoot mobile games

There are various mobile games in the "Crash Bandicoot" series.
Platform.
Crash Twinsanity is a 2D platform mobile game published by I-play, developed by Vivendi Universal Games and released on November 6, 2004. The game's plot centers on Crash Bandicoot and Doctor Neo Cortex, who have reluctantly teamed up to stop the Evil Twins from stealing all of the Wumpa fruit and destroying their island home. The game features six levels; the objective of each is to play as Crash and protect Cortex from danger while collecting the energy crystals needed to activate the Reverso Engine, which will enable Crash and Cortex to enter the Tenth Dimension and defeat the Evil Twins. Levi Buchanan of IGN, giving the game a score of 7.3 out of 10, considered the game to be "infinitely more enjoyable" than its console counterpart, pointing out the colorful graphics and "well-done" character art, but noting the insensitive controls and lack of audio as negative points. Avery Score of GameSpot, giving the game a score of 7.1 out of 10, commented positively on the "tried-and-true" gameplay, "great" graphics, "decent" value and "good" character likenesses, but criticized the lack of in-game audio, "finicky" control, lack of innovation in terms of gameplay, lack of enemy characters and the fact that Cortex seemed "mindless".
Crash Bandicoot is a 2D platform mobile game published by In-Fusio and developed by Kaolink for the ExEn and released on April 25, 2005. The player controls Crash Bandicoot, who can jump, spin, slide, crawl and belly flop depending on the player's input. "Crash Bandicoot" is the longest game made for the ExEn, spanning 18 levels split into four "worlds" of differing aesthetic theme, including an Aztec city and an icy mountain. The objective of each level is to collect wumpa fruit and the two jewels hidden in each level. In addition, obstacles such as bottomless pits and TNT crates must be avoided. The WGR staff of GameSpot, giving the game a score of 9 out of 10, praised the game for its tight gameplay, "pretty" graphics and high replay value.
Crash Twinsanity 3D is a 3D platform mobile game published by Vivendi Games Mobile and Wonderphone and developed by Kuju Entertainment for an exclusive selection of 3G java-enabled handsets that accompanied the commercial launch of Vodafone live!, including the Motorola E1000, V980 and C980, the Nokia 6630, the Sony Ericsson V800, the Sharp 802 SH and 902 SH, and the Toshiba V902T. The player controls Crash Bandicoot, who must sprint along a "colorful undulating" three-dimensional road and dodge obstacles, defeat enemies and collect items en route. If Crash comes into contact with a hazard, one of three available lives will be lost. Chris James of Pocket Gamer, giving the game a score of 5 out of 10, noted the game's simple and relatively responsive controls and polished presentation, but criticized the awkward perspective, "very finicky" collision detection, lengthy character animation and long loading screens.
Crash of the Titans is a 2D platform beat 'em up mobile game published by Vivendi Games Mobile and developed by DeValley Entertainment. It is loosely based on the console game of the same name. The player controls Crash Bandicoot, who is able to "jack" enemies during fights, slamming a mask over their heads to take control of them. The game includes a fighting system including punches, flying kicks, combo attacks and a special counter-move. Vivendi Games Mobile held a competition in the United Kingdom open to customers of the O2 Store for a chance to appear in the special version of the game as a character named "Dimbo". To be eligible, contestants had to download "Crash Boom Bang!" from the O2 Active portal; alternatively, contestants could enter via email. The competition was won by Stephen Massart, whose head was superimposed onto an enemy character to create Dimbo (while in the regular version of the game the Dimbos resemble elephant mutants). Damien McFerran of Pocket Gamer, giving the game a score of 5 out of 10, commended the "generally stunning" graphics and "excellent" level design, but criticized the "unforgivably poor" combat system and "repetitive" gameplay.
Crash Bandicoot: Mutant Island is an action and platform mobile game developed by Vivendi Games Mobile and published by Glu Mobile for the BlackBerry and Java ME, released on July 30, 2009. Jon Mundy of Pocket Gamer, giving the game a score of 8 out of 10, reviewed the mobile game as a "recovery" for the series and praised the game's "excellent" level design and "tight" controls.
 is an auto-runner mobile spin-off game, soft launched on Android in select regions in Southeast Asia on April 22, 2020. The game is being published by King, and was released officially in March 25, 2021.
Racing.
Crash Nitro Kart is a racing mobile game published and developed by I-play and released on September 20, 2004. The game's plot centers on Crash Bandicoot, Doctor Neo Cortex, Coco Bandicoot and Crunch Bandicoot as they are kidnapped by the ruthless Emperor Velo XXVII and forced to race in his galactic coliseum. The game features three selectable racetracks (City, Beach and Castle) and four playable characters (Crash, Cortex, Crunch and Coco), each with unique characteristics. Power-ups scattered on the racetracks can be used to accelerate the performance of the player's kart or hinder opponents. Damon Brown of GameSpot, giving the game a score of 6.1 out of 10, commended the game for its fast gameplay, solid graphics and funny characters, but criticized the small visuals, confusing items, lack of variety, controls that are "hard on the thumb" and the fact that the game "gets boring quickly".
Crash Racing is a racing mobile game published by Vivendi Games Mobile and developed by Kaolink. The player selects from four characters to control (Crash, Cortex, Nina and Pasadena), all of whom race in karts. there are two modes of gameplay, Single Race and Tournament, with the tracks in the former mode only becoming available once the latter mode has been completed. There are nine tracks in the game split into three aesthetic themes: Pirate, Castle and Egypt. The objective of each track is to complete three laps ahead of the other three racers. Rob Hearn of Pocket Gamer, giving the game a score of 4 out of 10, said that while "Crash Racing" is "not offensive in terms of gameplay, "Crash" manages to offend nevertheless by being lazy, brief, and all but identical to "Cocoto Kart Racer"," and summed up the game as ""Cocoto", but with a shoddier kingpin."
Crash Nitro Kart 2 is a racing mobile game developed by IP4U for JME-compatible mobile phones.
Crash Bandicoot Nitro Kart 3D is a racing mobile game published by Activision (originally released by Vivendi Games Mobile) and developed by Polarbit for the iPhone / iPod Touch, N-Gage service, and Zeebo. The game was released on the App Store in Europe on June 9, 2008 and in North America on July 9, 2008.
Crash Bandicoot Nitro Kart 2 is a racing mobile game published by Activision and developed by Polarbit for the iPhone and iPod Touch. It was released on the App Store on May 27, 2010.
Party.
Crash Boom Bang! is a party mobile game published by Vivendi Games Mobile. The game is loosely based on the Nintendo DS title of the same name and features 14 minigames centered around characters of the "Crash Bandicoot" series, including Crash, Coco, Cortex and Nina. All minigames are simple in input and only require one thumb to play. The game's single-player mode allows the player to either play individual minigames or play them all in a row to accumulate the highest score. The multiplayer mode includes free-for-all games, in which the players all must lay thumbs on the handset to compete. Producer Elodie Larre described adapting a party game for the mobile phone as a "big challenge". Not wanting to make "another multiplayer game where the players just pass the phone to each other" and hoping to attract both old and new fans of the series, the development team decided to integrate the mobile phone itself into the minigames, creating such minigame gimmicks as playing with one hand behind the back, with one eye closed, playing with the chin, etc. The biggest challenge for the team was keeping the minigames inside the phone's memory, which was cited as slightly inferior to the first PlayStation console. The "WarioWare" series was described as an influence in making the game. Stuart Dredge of Pocket Gamer, giving the game a score of 6 out of 10, described the collection of minigames as "a mixed bag", but said that the multiplayer challenges were "relatively fun".
 is a Japanese party mobile game published by Vivendi Games Mobile for the DoCoMo SH904i.