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Suppose there are two proteins inhibiting a particular gene. Its not necessary that both will inhibit the gene at the same time instance right? So if one protein has already inhibited that gene before the other protein, what is left for the other protein to inhibit this gene? It has already been inhibited right? What more does the other protein inhibit?
Can genes be turned on and off in cells?
Each cell expresses, or turns on, only a fraction of its genes at any given time. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood.
Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is passed to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine when and how much protein product is made by a gene.
Pathogens are organisms which cause disease. We’re all adapted to prevent these from getting into our bodies in the first place. If a pathogen does manage to sneak it’s way in, our immune system kicks into action, activating various types of white blood cells to manufacture antibodies and kill the pathogen.
Barriers to prevent entry of pathogens
Our bodies have several defensive barriers to prevent us becoming infected by pathogens. For example:
Our body cavities (e.g. eyes, nose, mouth, genitals) are lined with a mucus membrane which contain an enzyme called lysozyme. Lysozyme kills bacteria by damaging their cell walls, causing them to burst open.
Our skin acts as a physical barrier to stop pathogens from getting inside of us. If our skin is cut or wounded, our blood quickly clots to minimise the entry of pathogens.
The trachea (windpipe) contains goblet cells which secrete mucus. Pathogens that we inhale become trapped in the mucus, which is swept towards the stomach by the action of ciliated epithelial cells.
Our stomach contains gastric juices which are highly acidic - these will denature proteins and kill any pathogens that have been ingested in our food and drinks.
The insides of our intestines and the surface of our skin are covered in harmless bacteria which will compete with any pathogenic organisms and reduce their ability to grow.
Barriers against the entry of pathogens into the body.
Non-Specific Immune Response
The non-specific immune response is our immediate response to infection and is carried out in exactly the same way regardless of the pathogen (i.e. it is not specific to a particular pathogen). The non-specific immune response involves inflammation, the production of interferons and phagocytosis.
Inflammation - the proteins which are found on the surface of a pathogen (antigens) are detected by our immune system. Immune cells release molecules to stimulate vasodilation (the widening of blood vessels) and to make the blood vessels more permeable. This means that more immune cells can arrive at the site of infection by moving out of the bloodstream and into the infected tissue. The increased blood flow is why an inflamed part of your body looks red and swollen.
Production of interferons - if the pathogen which has infected you is a virus, your body cells that have been invaded by the virus will start to manufacture anti-viral proteins called interferons. They slow down viral replication in three different ways:
Stimulate inflammation to bring more immune cells to the site of infection
Inhibit the translation of viral proteins to reduce viral replication
Activate T killer cells to destroy infected cells
Phagocytes are a type of white blood cell which can destroy pathogens - types of phagocyte include macrophages, monocytes and neutrophils. They first detect the presence of the pathogen when receptors on its cell surface bind to antigens on the pathogen. The phagocyte then wraps its cytoplasm around the pathogen and engulfs it. The pathogen is contained within a type of vesicle called a phagosome. Another type of vesicle, called a lysosome, which contains digestive enzymes (lysozymes) will fuse with the phagosome to form a phagolysosome. Lysozymes digest the pathogen and destroy it. The digested pathogen will be removed from the phagocyte by exocytosis but they will keep some antigen molecules to present on the surface of their cells - this serves to alert other cells of the immune system to the presence of a foreign antigen. The phagocyte is now referred to as an antigen-presenting cell (APC).
Battle of the Pleiades against plant immunity
Mythological nymphs reincarnate as a group of corn smut proteins to launch a battle on maize immunity. One of these proteins appears to stand out among its sister Pleiades, much like its namesake character in Greek mythology. The research carried out at GMI—Gregor Mendel Institute of Molecular Plant Biology of the Austrian Academy of Sciences—is published in the journal PLOS Pathogens.
Pathogenic organisms exist under various forms and use diverse strategies to survive and multiply at the expense of their hosts. Some of these pathogens are termed "biotrophic," as they are parasites that maintain their hosts alive. These biotrophic pathogens deregulate physiological processes in their hosts by suppressing their immune defenses and favoring disease development. In plant biotrophic pathogens, such hostile actions are inflicted by secreted molecules including proteins, termed "effectors." One biotrophic pathogen infecting maize plants is Ustilago maydis, or corn smut. Up until present, the arsenal used by the U. maydis effector proteins to wage war against the maize immune response remained largely unstudied. Now, researchers around University of Bonn professor and previous GMI group leader Armin Djamei unveil the function of the Pleiades, a heterogeneous group of effector proteins in corn smut, and tell a tale worthy of Greek mythologies.
The Pleiades: Between mythology, stars and maize immunity
Whether the star cluster in the Taurus constellation was named after the seven daughters of Atlas and Pleione, or whether the opposite is true, is still subject to debate. However, what brings the name "Pleiades" on a group of effector proteins in corn smut? In fact, the genes encoding the Pleiades are arranged as a co-regulated cluster in the U. maydis genome, hence the analogy with the star cluster. Furthermore, the genetic cluster in question is particularly dynamic. This phenomenon is partly due to the high prevalence of transposon sequences, or "jumping genes." As a result, the high sequence diversity in the Pleiades' genetic cluster produces effector proteins that lack conserved domains. Therefore, a sequence-based prediction of the Pleiades' functions is simply not possible. In this sense, the forces at play in the battle against maize immunity were still awaiting close examination.
Different tactics leading to the same goalThe pleiades gene cluster in the Ustilago maydis (corn smut) genome encodes a family of proteins, the Pleiades, that target maize immunity. The two Pleiades Taygeta1 (Tay1) and Merope1 (Mer1) inhibit Reactive Oxygen Species (ROS) production, albeit in different cell compartments. Additionally, Mer1 acts in the nucleus to modify the activity of RFI2 homologues (Red and Far-Red Insensitive 2), a family of enzymes involved in early immune responses and that govern flowering time in plants. Credit: ©Djamei/GMI
Promoting flowering to better fight immunity
In fact, Djamei and his team demonstrate that two of the Pleiades, Taygeta1 and Merope1, inhibit ROS production in different plant cell compartments. Taygeta1 does so in the cell cytoplasm, whereas Merope1 acts in the nucleus. These two "sisters" appear to be taking the lead, mechanistically speaking, in the battle against plant immunity by investing new roles. However, the researchers uncover an even more developed arsenal in the hands of Merope1: this Pleiade appears to affect a family of enzymes that also control flowering time. "An effector that dampens immunity while simultaneously promoting flowering would be a great advantage for smuts, which usually sporulate only in the host floral tissues," explains Djamei.
In Greek Mythology, Merope is the only Pleiade to fade away upon marrying a mortal, while her sisters conserve their eternal glow. Could it be possible that this "Lost Pleiade," as she is often portrayed in 19th century works of art, found her vocation in fighting plant immunity?
CH 105 - Chemistry and Society
DNA is the carrier of genetic information in organisms. What does that mean? Large molecules in organism can have many functions: they can provide structure, act as catalyst for chemical reactions, serve to sense changes in their environment (leading to immune responses to foreign invaders and to neural responses to stimuli such as light, heat, sound, touch, etc) and provide motility. DNA really does none of these things. Rather you can view it as an information storage system. The information must be decode to allow the construction of other large molecules. The other molecules are usually proteins, another class of large polymers in the body. Chromosomes are located in the nucleus of a cell.
Chromosomes are located in the nucleus of a cell. DNA must be duplicated in a process called replication before a cell divides. The replication of DNA allows each daughter cell to contain a full complement of chromosomes.
The actual information in the DNA of chromosomes is decoded in a process called transcription through the formation of another nucleic acid, ribonucleic acid or RNA. The RNA, made by the enzyme RNA polymerase, is complementary to one strand of the DNA. RNA differs from DNA in that RNA contains a ribose, not deoxyribose, sugar in its backbone. In addition, RNA lacks the base T. It is replaced, instead, with the base U, which is complementary to A (as T is complementary to A in DNA). The RNA formed acts as a messenger, which passes from the nucleus into the cytoplasm of the cell. In fact, this type of RNA is often called messenger RNA, mRNA. Since the information in a nucleic acid (DNA) is converted into information in the form of another nucleic acid (RNA), this process is called transcription (since the language is still the same, such as when you transcribe a written speech in English into written English).
The information from the DNA, now in the form of a linear RNA sequence, is decoded in a process called translation, to form a protein, another biological polymer. The monomer in a protein is called an amino acid, a completely different kind of molecule than a nucleotide. There are twenty different naturally occurring amino acids that differ in one of the 4 groups connected to the central carbon. In an amino acid, the central (alpha) carbon has an amine group (RNH2), a carboxylic acid group (RCO2H), and H, and an R group attached to it. Since the information in a nucleic acid (RNA) is converted into information in the form of a different molecule, a protein, this process is called translation (since the language of nucleic acids is changed to that of proteins, such as when you translate English into Chinese).
In contrast to the complementarity of DNA and RNA (1 base in RNA complementary to 1 base in DNA), there is not a 1:1 correspondence between a base (part of the monomeric unit of RNA) in RNA to the monomer in a protein. After much work it was discovered that a contiguous linear sequence of 3 nucleotides in RNA is decoded by the molecular machinery of the cytoplasm with the result that 1 amino acid is added to the growing protein. Hence a triplet of nucleotides in DNA and RNA have the information for 1 amino acid in a protein. That there was not a 1:1 correspondence between nucleotides in nucleic acids and amino acids in proteins was evident long ago since there are only 4 different DNA monomers (with A, T, G, and C) and 4 different RNA monomers (with A, U, G, and C) but there are 20 different amino acid monomers that compose proteins.
Now, it turns out that not all the information in the DNA sequence of a organism encodes for a protein. In fact only about 2% of the 3 billion base pairs seem to be transcribed into RNA which can be translated into protein. The function of the rest of the DNA is at present uncertain. How does the molecular machinery of the cell know which part of the DNA encodes for proteins. It turns out that there are unique DNA sequences at the beginning and end of the part of the DNA sequence that codes for a protein. Proceed down the DNA of a chromosome and suddenly you come to those signals, which are recognized by the cells machinery. A complementary RNA is made from that section, and the complementary RNA is then decoded into a single protein. Continue further down the DNA sequence and another such coding sequence is found, which can be transcribed into a mRNA, which then can be translated into another unique protein. In all there are about 30,000 such sections of DNA in all the chromosomes that encode the information for 30,000 unique proteins. These unique coding sections of DNA that ultimately are transcribed into unique mRNA which are translated into unique proteins are called genes. For our purposes, we conclude that one gene has the information for one protein. Each of the protein differ from each other in both length, and the specific sequence of amino acids in the protein. The DNA is indeed the blueprint of the cell. What determines the actual characteristics of the cells are the actual proteins that are made by the cell.
Not only must DNA be transcribed into DNA, but the genetic information in the DNA must be replicated before a given cell divides, so that the daughter cells both contain the same genetic information. In replication, the dsDNA separate, and an enzyme, DNA polymerase, makes complimentary copies of each strand. The two resulting dsDNA strands separate to different daughter cells during division. The process where by DNA is replicated when cells divide, and is transcribed into RNA which is translated into protein is called the Central Dogma of Biology. (disregard tRNA, rRNA, and snRNA in the preceding web link)
As mentioned above, each amino acid is specified by a particular combination of three nucleotides in RNA. The three bases are called a codon. The Genetic Code consists of a chart which shows what triplet RNA sequence or codon in mRNA codes for which of the 20 amino acids. One of the codon codes for no amino acids and serves to stop the synthesis of the protein from the mRNA sequence. The genetic code is shown below:
Determining the protein sequence from a DNA sequence.
For a given gene, only one strand of the DNA serves as the template for transcription. An example is shown below. The bottom (blue) strand in this example is the template strand, which is also called the minus (-) strand, or the sense strand. It is this strand that serves as a template for the mRNA synthesis. The enzyme RNA polymerase synthesizes an mRNA in the 5' to 3' direction complementary to this template strand. The opposite DNA strand (red) is called the c oding strand, the nontemplate strand, the plus (+) strand, or the antisense strand.
The easiest way to find the corresponding mRNA sequence (shown in green below) is to read the c oding, nontemplate , plus (+) , or antisense strand directly in the 5' to 3' direction substituting U for T. Find the triplet in the coding strand, change any T's to U's, and read from the Genetic Code the corresponding amino acid that would be incorporated into the growing protein. (The strands below are separated into triplets for ease of visualization.) An example is show below.
END BASIS REVIEW CENTRAL DOGMA OF BIOLOGY
In contrast to the linear polymers of DNA and RNA, proteins (linear polymers of amino acids) fold in 3D space to form structures of unique shapes. Each unique protein sequence (of a given length and sequence of amino acids) folds to a unique 3D shape. Hence there are about 30,000 proteins of different shapes in humans. Not only do proteins have unique shapes, but they also have unique nooks and crannies and pockets which allow them to bind other molecules. Binding of other molecules to proteins or DNA initiates or terminates the function of the protein or nucleic, much like an on/off switch. The example below show different protein structures, some of which have small molecules or large molecules (like DNA) bound to them. Some common motifs are found within the 3D structure of the protein. The include alpha helices and beta sheets. These are held together by H-bonds between the slightly positive H on the N in the protein backbone and a slightly negative O further away on the protein backbone. In the Chime models below, use the mouse controls to rotate the molecule. (Also shift L-mouse click will change the size of the molecule). Click on the command in the right hand frame to change the rendering of the proteins. The cartoon view allows a simple way to interpret the overall structure of the main chain.
If the DNA sequence in a coding region becomes changed, the resulting mRNA will also be changed, which will lead to changes in the protein sequence. These changes might have no effect and be silent, if the change in the protein does not affect the folding of the protein or its binding to another important molecule. However, if the changes affects either the folding or the binding region, the protein may not be able to perform its usual function. Mutations which substitute nonpolar amino acids for polar/charged ones (or the reverse) have the greatest chance of causing significant changes in structure and/or activity.
If the function was to put on break on cell division, the result might lead the cell to become a cancerous. Likewise, if the normal protein had a role in causing the cell to die after its intended life span, the cell with the mutant protein might not die and more likely become a tumor. The opposite scenarios could happen leading the cell to a premature death.
- Point mutations: From bad luck and nucleotide analogs
- Point mutations: From chemical mutagens
- Large mutations: Deletions, insertions, duplications, and inversions
Check out the model of sickle cell hemoglobin below, which shows how a single base pair change in the DNA can change one amino acid in a protein with lethal consequences.
Genes and Disease
Activation and Repression of Gene Transcription:
- How might gene expression be repressed in the absence of mercury
- How might gene expression be activated in the presence of mercury
One of the central questions of modern biology is what controls gene expression. As we have previously described, genes must be "turned on" at the right time, in the right cell. To a first approximation, all the cells in an organism contains the same DNA (with the exception of germ cells and immune cells). Cell type is determined by what genes are expressed at a given time. Likewise, cell can change ( differentiate ) into different types of cells by altering the expression of genes. The central dogma of biology describes how genes are first transcribed to RNA, and then the mRNA is translated into a corresponding protein sequence. Proteins can then be post-translationally modified, localized to certain locales within the cells, and ultimately degraded. If functional proteins are considered the end-product of gene expression, the control of gene expression could theoretically occur at any of these steps in the process.
Mostly, however, gene expression is controlled at the level of transcription. This makes great biological sense, since it would be less energetically wasteful to induce or inhibit the ultimate expression of a functional protein at a step early in the process. How can gene expression be regulated at the transcriptional level? Many examples have been documented. The main control is typically exerted at the level of RNA polymerase binding just upstream (5') of a a site for transcriptional initiation. Other factors, called transcription factors (which are usually proteins), bind to the same region and promote the binding of RNA polymerase at its binding site, called the promoter. Proteins can also bind to sites on DNA (operator in prokaryotes) and inhibit the assembly of the transcription complex and hence transcription. Regulation of gene transcription then becomes a matter of binding the appropriate transcription factors and RNA polymerase to the appropriate region at the start site for gene transcription. Regulation of gene expression by proteins can be either positive or negative. Regulation in prokaryotes is usually negative while it is positive in eukaryotes.
Most eukaryotic genes have about 5 regulatory sites for binding transcription factors and RNA polymerase. Examples of these transcription factors are show in the figure below.
STRUCTURAL FEATURES OF SPECIFIC DNA BINDING SITES
Since RNA polymerase must interact at the promoter site of all genes, you might expect that all genes would have a similar nucleotide sequence in the promoter region. This is found to be true for both prokaryotic (such as bacteria) and eukaryotic genes. You would expect, however, that all transcription factors would not have identical DNA binding sequences. The sequences of DNA just upstream of the start site of the gene that binds protein (RNA polymerase, transcription factors, etc) are called promoters. The table below shows the common DNA sequence motif called the Pribnow or TATA box found at around -10 base pairs upstream from the start site, and another at -35. Proteins bind to these sites and facilitate binding of RNA polymerase, leading to gene transcripton.
Prokaryotic Promoter Sequences
In addition, in eukaryotes promoters, sequences further upstream called response elements bind specific proteins (such as CREB or cyclic AMP response element binding protein) to further control gene transcription.
Eukaryotic Response Elements (RE)s
Proteins can interact specifically with DNA through electrostatic, H-bond, and hydrophobic interactions. AT and GC base pairs have available H bond donors and acceptors which are exposed in the major and minor grove of the ds DNA helix, allowing specific protein-DNA interactions.
Jmol : Simple DNA Tutorial (see last selection buttons to see H bond donors and acceptors in the major grove.
STRUCTURAL FEATURES OF DNA-BINDING PROTEINS
- helix-turn-helix : found in prokaryotic DNA binding proteins. The figures shows two such proteins, the cro repressor form bacteriophage 434 and the lambda repressor from the bacteriophage lambda. (Bacteriophages are viruses that infect bacteia.) Notice how specificity is achieved, in part, by the formation of specific H-bonds between the protein and the major grove of the operator DNA.
- Lambda Repressor/DNA Complex
- H Bond interactions between l repressor and DNA
- zinc finger : (eukaryotes) These proteins have a common sequence motif of
X3- Cys -X2-4- Cys -X12- His -X3-4- His -X4- in which X is any amino acid. Zn 2+ is tetrahedrally coordinated with the Cys and His side chains, which are on one of two antiparallel beta strands, and an alpha helix, respectively. The zinc finger, stabilized by the zinc, binds to the major groove of DNA.
- steroid hormone receptors : (eukaryotes) In contrast to most hormones, which bind to cell surface receptors, steroid hormones (derivatives of cholesterol) pass through the cell membrane and bind to cytoplasmic receptors through a hormone binding domain. This changes the shape of the receptor which then binds to a specific site on the DNA (hormone response element) though a DNA binding domain. In a structure analogous to the zinc finger, Zn 2+ is tetrahedrally coordinated to 4 Cys, in a globular-like structure which binds as a dimer to two identical, but reversed sequences of DNA (palindrome) within the major grove. (An example of a palindrome: Able was I ere I saw Elba.)
- leucine zippers : (eukaryotes) These proteins contain stretches of 35 amino acids in which Leu is found repeatly at intervals of 7 amino acids. These regions of the protein form amphiphilic helices, with Leu on one face. Two of these proteins can form a dimer, stabilized by the binding of these amphiphilic helices to one another, forming a coiled-coil, much as in the muscle protein myosin. Hence the leucine zipper represents the protein binding domain of the protein. The DNA binding domain is found in the first 30 N-terminal amino acids, which are basic and form an alpha helix when the protein binds to DNA. The leucine zipper then functions to bring two DNA binding proteins together, allowing the N-terminal bases helices to interact with the major grove of DNA in a base-specific fashion.
PHOSPHORYLATION AND CONTROL OF GENE EXPRESSION
A common way to control gene expression is by controlling the phosphorylation of transcription factors by ATP. This modification might activate or inhibit the transcription factor in turning on gene expression. The added phosphate groups might be necessary for direct binding interactions leading to gene transcription or they might lead to a conformational change in the transcription factor, which could activate or inhibit gene transcription. A recent example of this later case is the control of the activity of the transcription factor p53. p53 has many activities in the cell, a primary one as a suppressor of tumor cell growth. If a cell is subjected to stress that results in genetic damage (an evident which could lead a cell to transform into a tumor cell), this protein becomes an active transcription factor, leading to the expression of many genes, including those involved in programmed cell death and cell cycle regulation. Both of these effects could clearly inhibit cell proliferation. Hence p53 is a tumor suppressor gene. p53 is usually bound to the protein HDM2 which down regulates its activity by leading to its degradation. Stress signals lead to the activation of protein kinases in the cell (such as p38, JNK, and cdc2), causing phosphorylation of serine and threnine amino acids in p53 (Ser 33 and 315 and Thr 81). This leads to the binding of the proteni Pin 1, which changes the shape of p53 and leads to its activation as a transcription factor.
DCas9-p300 CRISPR Gene Activator
The dCas9-p300 CRISPR Gene Activator system is based on a fusion of dCas9 to the catalytic histone acetyltransferase (HAT) core domain of the human E1A-associated protein p300. This approach has been independently validated by the Gersbach lab (Duke University) to activate genes at both proximal and distal locations relative the transcriptional start site (TSS). The dCas9-p300 histone acetylation approach represents a distinct mechanism of action relative to dCas9-VP64 or other similar gene activation motifs. While activation domains, such as VP64, help recruit transcription complexes to the promoter region, they are at the mercy of the epigenetic state of the gene and dependent on the availability of additional transcriptional proteins. Conversely, the p300 histone acetyltransferase protein opens a transcriptional highway by releasing the DNA from its heterochromatin state and allowing for continued and robust gene expression by the endogenous cellular machinery.
Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.5427713.
Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
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A form of gene expression maintenance in which the heritable state of gene activity neither requires the continuous presence of the initiating signal nor involves changes in the DNA sequence.
(HOX genes). A family of genes that encode transcription factors which are essential for patterning along the anterior–posterior body axis.
The consequences of mutations that lead to the transformation of the identity of one body segment into the identity of another.
(Su(var)3-9, Enhancer of Zeste, Trithorax). A motif ∼ 130 amino acids in length that provides histone methyltransferase activity. It is found in many chromatin-associated proteins, including some Trithorax group and Polycomb group proteins.
A family of histone acetyltransferases that is defined by the founding members Moz, Ybf2 (Sas3), Sas2 and Tip60.
An intracellular signal transduction pathway involving RAS. RAS activates many signalling cascades involved in multiple developmental events controlling cell proliferation, migration and survival.
(Switch/sucrose nonfermentable). A chromatin-remodelling complex family that was first identified genetically in yeast as a group of genes required for mating type switching and growth on alternative sugar sources to sucrose. This complex is required for the transcriptional activation of ∼ 7% of the genome.
A conserved protein module, which was first identified in the Drosophila melanogaster protein Brahma and has subsequently been found in many chromatin-associated proteins. This domain can recognize acetyl-Lys motifs.
A conserved histone-binding domain that takes its name from the proteins in which it was initially identified: Swi3, ADA2, N-CoR and TFIIB.
(NURF). A chromatin-remodelling complex identified in Drosophila melanogaster and belonging to the imitation switch subfamily.
A motif of ∼ 60 amino acids that is found in many chromatin-associated proteins and forms a binding pocket for methylated histone residues.
Bivalent chromatin domains
Domains that are characterized by the juxtaposition of active and inactive epigenetic histone marks.
(PHD finger). A PHD-linked zinc-finger that chelates double zinc ions. This protein motif is found in many chromatin regulators and binds histones in a methylation-dependent or -independent manner.
This term describes the fact that post-translational modifications on one histone tail can influence those on another, even when they are located on different histones, resulting in a specific gene expression output.
(Cyclin-dependent kinase inhibitor). Members of the CIP and KIP family of CDKIs (p21, p27 and p57) inhibit CDK2- and CDK1-containing complexes, and members of the INK4 family (p15, p16, p18 and p19) inhibit cyclin D-containing complexes. Expression of CDKIs generally causes growth arrest and, when CDKIs are acting as tumour suppressors, may cause cell cycle arrest and apoptosis.
(Skp–cullin–F box and anaphase-promoting complex (also known as the cyclosome)). Multiprotein E3 ubiquitin ligase complexes that are involved in the recognition and ubiquitylation of specific cell cycle target proteins for proteasomal degradation.
Enzymes that target specific proteins for degradation by the proteasome by causing the attachment of ubiquitin to Lys residues on their substrates.
A change undergone by animal cells, caused by escape from control mechanisms (for example, upon infection by a cancer-causing virus). Transformed cells have increased growth potential, alterations in cell surface, karyotypic abnormalities and the ability to invade and metastasize.
(Ataxia-telangiectasia- and RAD3-related). A caffeine-sensitive, DNA-activated protein kinase that is involved in DNA damage checkpoints.
Radioresistant DNA synthesis
(RDS). When mutant cells fail to repress the firing of DNA replication origins in the presence of ionizing radiation-induced DNA damage.
This pathway is a highly conserved intercellular signalling mechanism that is essential not only for cell proliferation but also for numerous cell fate-specification events.
Extracellular signal-regulated kinase
(ERK). A protein involved in a mitogen-activated protein kinase signal transduction pathway that functions in cellular proliferation, differentiation and survival. Its inappropriate activation is a common occurrence in the human cancers.
The rapid phosphorylation of histone H3 that occurs concomitantly with the induction of immediate early genes, which is mediated through alternative mitogen-activated protein kinase cascades.
A signalling pathway involving widely conserved secreted signalling molecules of the Wingless family, which regulate many processes during animal development.
(Janus kinase–signal transducer and activator of transcription). A rapid signal transduction pathway used by a range of cytokines and growth factors. Binding of a cytokine or growth factor to its receptor activates cytoplasmic JAK, which then phosphorylates STAT and triggers its translocation into the nucleus, where it induces the transcription of specific genes.
(NPCs). A stem cell type found in adult neural tissue that can give rise to neuron and supporting cells (glia). During development, NPCs produce the enormous diversity of neurons and glia in the developing central nervous system, and they have been also shown to engage in the replacement of dying neurons.
(LT-HSCs). Haematopoietic stem cells that have long-term regeneration capacities and can restore the haematopoietic system of an irradiated mouse over months.
(ST-HSCs). Haematopoietic stem cells that, under normal circumstances, cannot renew themselves over a long term. They are also referred to as progenitor or precursor cells, as they are relatively immature cells that are precursors to a fully differentiated cell of the same tissue type.
Genes and gene products interact on several levels. At the genomic level, transcription factors can activate or inhibit the transcription of genes to give mRNAs. Since these transcription factors are themselves products of genes, the ultimate effect is that genes regulate each other's expression as part of gene regulatory networks. Similarly, proteins can participate in diverse post-translational interactions that lead to modified protein functions or to formation of protein complexes that have new roles the totality of these processes is called a protein-protein interaction network. The biochemical reactions in cellular metabolism can likewise be integrated into a metabolic network whose fluxes are regulated by enzymes catalyzing the reactions. In many cases these different levels of interaction are integrated - for example, when the presence of an external signal triggers a cascade of interactions that involves both biochemical reactions and transcriptional regulation.
A system of elements that interact or regulate each other can be represented by a mathematical object called a graph (Bollobás, 1979). Here the word `graph' does not mean a `diagram of a functional relationship' but `a collection of nodes and edges', in other words, a network. At the simplest level, the system's elements are reduced to graph nodes (also called vertices) and their interactions are reduced to edges connecting pairs of nodes (Fig. 1). Edges can be either directed, specifying a source (starting point) and a target (endpoint), or non-directed. Directed edges are suitable for representing the flow of material from a substrate to a product in a reaction or the flow of information from a transcription factor to the gene whose transcription it regulates. Non-directed edges are used to represent mutual interactions, such as protein-protein binding. Graphs can be augmented by assigning various attributes to the nodes and edges multi-partite graphs allow representation of different classes of node, and edges can be characterized by signs (positive for activation, negative for inhibition), confidence levels, strengths, or reaction speeds. Here I aim to show how graph representation and analysis can be used to gain biological insights through an understanding of the structure of cellular interaction networks. For information on other important related topics, such as computational methods of network inference and mathematical modeling of the dynamics of cellular networks, several excellent review articles are available elsewhere (Friedman, 2004 Longabaugh et al., 2005 Ma'ayan et al., 2004 Papin et al., 2005 Tyson et al., 2003).
In summary, although Id proteins were initially identified as controllers of terminal myogenic differentiation, they play important roles in development including neural stem cell differentiation, osteoblast differentiation, and lymphocyte maturation. In the cardiovascular system, Id proteins play major roles in cardiogenesis. The major function of Id proteins in cancer appears to be to promote proliferation and inhibition of differentiation. 32, 98 Although BMPs are critical regulators on Id protein expression, additional growth factors and cytokines regulate Id gene expression in a highly cell- and tissue-specific context to impact on vascular cell proliferation, differentiation, and function. Research in atherosclerosis has revealed that Id protein expression is important in the multistep process of disease development. Furthermore, targeting Id proteins have proved to be an effective therapeutic strategy in PAH where they impact on PASMC proliferation and EC survival. However, the role of the individual Id proteins in the complex process of vascular disease remains to be fully elucidated. Determining the regulation and function of Id proteins during vascular development and disease will contribute to our understanding of cardiovascular disease, particularly PAH, and will be essential to develop approaches with tissue selectivity for targeted therapies.
Regulator Molecules of the Cell Cycle
The cell cycle is controlled by regulator molecules that either promote the process or stop it from progressing.
Differentiate among the molecules that regulate the cell cycle
- Two groups of proteins, cyclins and cyclin-dependent kinases (Cdks), are responsible for promoting the cell cycle.
- Cyclins regulate the cell cycle only when they are bound to Cdks to be fully active, the Cdk/cyclin complex must be phosphorylated, which allows it to phosphorylate other proteins that advance the cell cycle.
- Negative regulator molecules (Rb, p53, and p21) act primarily at the G1 checkpoint and prevent the cell from moving forward to division until damaged DNA is repaired.
- p53 halts the cell cycle and recruits enzymes to repair damaged DNA if DNA cannot be repaired, p53 triggers apoptosis to prevent duplication.
- Production of p21 is triggered by p53 p21 halts the cycle by binding to and inhibiting the activity of the Cdk/cyclin complex.
- Dephosphorylated Rb binds to E2F, which halts the cell cycle when the cell grows, Rb is phosphorylated and releases E2F, which advances the cell cycle.
- cyclin: any of a group of proteins that regulates the cell cycle by forming a complex with kinases
- cyclin-dependent kinase: (CDK) a member of a family of protein kinases first discovered for its role in regulating the cell cycle through phosphorylation
- retinoblastoma protein: (Rb) a group of tumor-suppressor proteins that regulates the cell cycle by monitoring cell size
Regulator Molecules of the Cell Cycle
In addition to the internally controlled checkpoints, there are two groups of intracellular molecules that regulate the cell cycle. These regulatory molecules either promote progress of the cell to the next phase (positive regulation) or halt the cycle (negative regulation). Regulator molecules may act individually or they can influence the activity or production of other regulatory proteins. Therefore, the failure of a single regulator may have almost no effect on the cell cycle, especially if more than one mechanism controls the same event. Conversely, the effect of a deficient or non-functioning regulator can be wide-ranging and possibly fatal to the cell if multiple processes are affected.
Positive Regulation of the Cell Cycle
Two groups of proteins, called cyclins and cyclin-dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints. The levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable pattern. Increases in the concentration of cyclin proteins are triggered by both external and internal signals. After the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded.
Cyclin Concentrations at Checkpoints: The concentrations of cyclin proteins change throughout the cell cycle. There is a direct correlation between cyclin accumulation and the three major cell cycle checkpoints. Also, note the sharp decline of cyclin levels following each checkpoint (the transition between phases of the cell cycle) as cyclin is degraded by cytoplasmic enzymes.
Cyclins regulate the cell cycle only when they are tightly bound to Cdks. To be fully active, the Cdk/cyclin complex must also be phosphorylated in specific locations. Like all kinases, Cdks are enzymes (kinases) that phosphorylate other proteins. Phosphorylation activates the protein by changing its shape. The proteins phosphorylated by Cdks are involved in advancing the cell to the next phase.. The levels of Cdk proteins are relatively stable throughout the cell cycle however, the concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form. The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.
Activation of Cdks: Cyclin-dependent kinases (Cdks) are protein kinases that, when fully activated, can phosphorylate and activate other proteins that advance the cell cycle past a checkpoint. To become fully activated, a Cdk must bind to a cyclin protein and then be phosphorylated by another kinase.
Although the cyclins are the main regulatory molecules that determine the forward momentum of the cell cycle, there are several other mechanisms that fine tune the progress of the cycle with negative, rather than positive, effects. These mechanisms essentially block the progression of the cell cycle until problematic conditions are resolved. Molecules that prevent the full activation of Cdks are called Cdk inhibitors. Many of these inhibitor molecules directly or indirectly monitor a particular cell cycle event. The block placed on Cdks by inhibitor molecules will not be removed until the specific event being monitored is completed.
Negative Regulation of the Cell Cycle
The second group of cell cycle regulatory molecules are negative regulators. Negative regulators halt the cell cycle. Remember that in positive regulation, active molecules cause the cycle to progress.
The best understood negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21. Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells. Much of what is known about cell cycle regulation comes from research conducted with cells that have lost regulatory control. All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably (became cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein.
Rb, p53, and p21 act primarily at the G1 checkpoint. p53 is a multi-functional protein that has a major impact on the cell’s commitment to division it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G1. If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis (cell suicide) to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by binding to and inhibiting the activity of the Cdk/cyclin complexes. As a cell is exposed to more stress, higher levels of p53 and p21 accumulate, making it less likely that the cell will move into the S phase.
Rb exerts its regulatory influence on other positive regulator proteins. Rb monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly to E2F. Transcription factors “turn on” specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to E2F, production of proteins necessary for the G1/S transition is blocked. As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb releases E2F, which can now turn on the gene that produces the transition protein and this particular block is removed. For the cell to move past each of the checkpoints, all positive regulators must be “turned on” and all negative regulators must be “turned off.”
Function of the Rb Regulator Molecule: Rb halts the cell cycle by binding E2F. Rb releases its hold on E2F in response to cell growth to advance the cell cycle.

domain: biology


The tank, one of 381 that briefly broke through the German lines, is the first to be recovered in nearly complete condition since the First World War ended 80 years ago next Wednesday.
"It is a historic find and extraordinary in its way," said Philippe Gorczynski. "But perhaps not so extraordinary. We knew the tanks were there. It was just a question of patience and hard work to find one."
Mr Gorczynski hopes to excavate the tank completely on 20 November - the 81st anniversary of the Cambrai battle, with help from friends in the Royal Tank Regiment. Ultimately, he hopes it will form part of a permanent memorial to the men who died in the battle.
The discovery, under six feet of soil in a field near the village of Flecquiers, ends a six-year search by Mr Gorczynski, a local hotel owner, and expert on the use of tanks in the Great War. Using German aerial photographs from 1918, British military dispatches and old, eyewitness accounts, he identified the rough locations of half a dozen tanks abandoned during the battle.
He believes the tank he has found is nicknamed Demon 2, which was commanded by 2nd Lieutenant G H Vose, who survived a German shelling that killed several crew members.Reuse content


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Alexandra Swanson of Pittsfield High School and Benjamin Vengalil of Taconic High School were both recognized with the Massachusetts Association of School Superintendents' Certificate of Academic Excellence.
The Hoosac Valley High senior was presented on Monday with the Superintendent's Academic Excellence Award, and attended the School Committee meeting to receive directly from Superintendent Aaron Dean's hands.
Booth, daughter of Eric and Laurie Booth of Clarksburg, holds the highest grade-point average in her class and has taken 13 Advanced Placement courses, two dual enrollment courses through Massachusetts College of Liberal Arts, and a course through Berkshire Community College.
Typically the award is given out in December, however, the multi-talented Vanessa Harrington was unable to attend because she was performing in a dance competition in Disney World in the state of Florida.
Francisco Alicandri, a senior and the student representative on the School Committee, was presented with the Superintendent's Certificate for Academic Excellence on Tuesday. His sister, Vincienza, had earned the same honor last year.

domain: news


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Set design from Warhorse
Costumes from The Lion King
Chicago worn by Ruthie Henshaw
And The Audience worn by Helen Mirren
The most impressive display was from a Curious Incident of the Dog at Night Time
Not quite sure I've done it justice but hopefully you get the idea.
There was a whole section of headwear mainly of pantomime dames
So there we have it. I should add that I was allowed to take photos in the free Curtain Up exhibition and was indeed encouraged to snap away. I was, however, incredibly disappointed by the Bottecelli exhibition though I suppose it didn't really help that I'm not a huge fan of the original art work at the best of times. But I do get frustrated by galleries not allowing you to take photos.
As you may know I live in central Brixton but luckily where I live is surrounded by a huge communal garden. I have bird feeders which seem to attract more and more birds which is fantastic. Yesterday I decided I would take a few snaps of some of the visitors. Sadly everyone was photo shy except the cheeky starlings.
Despite there being three feeders they still like to have a fight over dinner. Some people just have no table manners!
Hopefully in the next couple of weeks I can get some decent shots of the seventeen or so House Sparrows who have made their home in the garden, or the Blue Tit, Robin, Wren, Dunnock, Green Finch or Lesser Spotted Woodpecker I've seen. The city - there is more wildlife than you think!
This weekend I was super excited as a new exhibition called 'Clangers, Bagpuss & Co' had opened at the V&A Museum of Childhood over in Bethnal Green. Except when we arrived we realised that we were actually a week early! Doh! Our plans for the day were scuppered and we had to think on our feet. OH suggested walking along the canal which was close by and I requested that we pop over to Broadway Market which was on the way. Here is what we saw:

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Scott McCoy, Business Manager
Penguin Plunge Fundraising Champions
IBEW LOCAL #457 — $6700 raised for SPECIAL OLYMPICS CT. (Crystal Lake, Middletown)
Great day…Thanks to all who donated and came out to support this worthy cause…And to the group of Apprentices that were led into the icy bath by Penguin Captain Mark Acosta.
Our Local has a long relationship with SOCT and it was great to see the participation and fundraising at an all-time high.
Special thanks to Tall Paul Smith, Mark Acosta and the East Hampton District for the intense fundraising efforts.
Now, the bar has been set, next year we’ll have to outdo ourselves.

domain: geography


Annual Heirloom Seed Sale
Wylie House’s annual sale of heirloom variety flower, vegetable, and herb seeds.
Wylie House invites the public to our annual seed sale in the museum’s Morton C. Bradley, Jr. Education Center (the barn next door to the museum). The museum grows, harvests, cleans, and packages seeds from its heirloom gardens. They are grown without chemical pesticides or fertilizer.
Seeds are $2.50 - $3.00 ea.
2020 Seed List: https://libraries.indiana.edu/2020-seed-list?_ga=2.206093776.21311574.1579623763-476819746.1579623763
Wylie House garden staff and volunteers will be available to answer all your questions. Seeds remain on sale throughout the year but select varieties are limited and often sell out on the day of the sale.


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All the crises in the world, like coronavirus, then the war in Ukraine, made inflation increase in a lot of countries, if not in all. In the USA it increases at almost 8,6% and in Eurozone stands at 8.1%.
All kinds of businesses are affected, not only in this area but in the whole world, from small businesses to big companies. The small business owners are asking themselves about how to price their products in an era where almost everything is getting more expensive: transport, raw materials, energy, and logistic costs. It’s hard to bear the new higher costs, but it’s harder to tell the people about raising prices.
So you have more expensive costs on the one side, and your customers, who should be always satisfied on the other side? Is it possible to make them satisfied in crazy times like this? The answer is yes. Just a reminder, it’s not so easy to do inflation pricing, because you have to pay attention to how much your consumers are ready to pay for products like yours, and also here is your competitor.
You should look at them so you can make better inflation pricing on your products or services.
Let’s see how tricky pricing looks like and keeping your customers satisfied:
So, imagine you sell furniture, and you have both: cheaper and more expensive. You have broadened the audience, people with low and high revenue. The second one is the people willing to pay higher prices even in a crisis. Also, you see that your competitors have already raised the price of products like these. Don’t think twice, but raise the price only of the more expensive products, and there you go. Both you and your customers are happy.
If you increase the price of cheaper products, which are actually for audiences with low revenue, you can just watch them blur out.
Inflation pricing includes more expensive products or services but is expanded. This means that you have to add new features to the product or add something to the order, so your customer won’t notice, or won’t mind the raising price.
Imagine you have a jewelry business. The golden rings before the crisis were 100$ and now their price should be increased to 150$. To make inflation pricing unnoticed you can give the people a small gift with the ring in order to keep them satisfied and happy.
Or if you sell techniques expand your guarantee, if it was 1 year make it 2 years now (the opportunity of returning the product back).
These are just two examples of the ocean, and you can choose which one is more relatable for your business.
Also, instead of increasing the price of the already existing products, you can create new products instead, so the pricing won’t be that irritating.
With lower costs, I mean reducing packaging, designing, and distribution costs. Maybe this is difficult to be done, but imagine how much you’ll save in the long term.
By the way, you’ll lose more if you raise the price, because that may mean losing customers.
As a business owner, you want loyal customers, but also your customers want you to be loyal to them. Why don’t you try to message them directly and tell them personally that your products or services will be more expensive when they come next time? This is an awesome approach because you don’t want them to come into your store and don’t have enough money on their card to pay for what they want.
Or you can tell them personally when they come to your store. Make them feel special by saying that even if the prices are higher they can shop now with the old ones, just because they were not informed.
It’s again about loyalty. You’ve spent so much time building trust and connection with your customers. And it may happen when you say “increasing price” on your Social Media pages, people get angry. It would be very nice of you if you put the effort into making a short explanation of why you raise the price of your products or services.
Also, when telling the story about inflation pricing, tell the people what will you invest in. Tell them that you expand your product’s offer or services and that the benefits they get will be bigger in the future. People love to be a part of companies’ stories so make them a part of yours.
Tell them that they won’t lose anything but instead they will get more from you.
For e.g. if you have a cosmetics salon, and your service is making gel nails, tell your customers that now you will use more high-quality gel than the one you use now.
If you are a pet-shop owner, tell to your customers (dog parents) that you will bring new, healthier food for their pets.
Increasing pricing is a must, except if you want to fail, but that’s not the choice. All you can do is using all the tools you have as discounts, expanding offers, and more products. Use your marketing as a tool so you can tell people in an easier way that your prices are higher now.
All of your staff should know about the new prices because they have to be ready to promote it in new customers’ calls. Have in mind, that people as loyal customers love to be a part of a community so keep them informed. Appreciate them, and they’ll appreciate you back, and love your Brand more.
I know that everything seems overwhelmed, but the UIXlabs team is here to help again. We can do the inflation pricing instead of you. All you can do is send us your email, so you can explain more about your business and products/services.
Let’s talk about your pricing problems, and let’s make inflation pricing fair pricing.

domain: economics


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Map North Florida
Former U.S. rep says North Florida is America’s next economic powerhouse. North Florida legislators must unite with key players for region’s growth. Florida Futures Academy North Campus is ranked #13,394-17,857 in the National Rankings. Schools are ranked on their performance on state-required tests, graduation and how well they prepare students After a decade pause, earmarks – or “member-directed appropriations requests” – are back in the federal budgetary process and 16 of Florida’s 27 Congressional reps are
The Lone Star and Sunshine states have gone decisively for the GOP in recent presidential elections, and Republicans will control the redistricting process in both. The 2020 census is shifting states’ clout in presidential politics. And while the changes won’t upend the parties’ basic strategies for securing the votes needed to win the White House, they do hint
After the U.S. Census reported that Idaho was the second-fastest growing state in the nation in population (as well as speedily in some other ways), some Idahoans may be surprised Sharks are the ocean’s world travellers, and now scientists have found they use the Earth’s magnetic fields to navigate.
Map North Florida : U.S. Census data released Monday will shift political power in Congress, reapportioning two House seats to Texas and one each to Florida, North Carolina, Oregon, Colorado, and Montana — and stripping This additional seat will bring the total of North Carolina’s congressional districts to 14. Currently, North Carolina’s representation in the House is held by eight Republicans and five Democrats. As MIAMI — Miami-based Norwegian Cruise Line is threatening to skip Florida ports because of the governor’s order banning businesses from requiring that customers be vaccinated against COVID-19. The


Amr Kandil, head of the Preventive Medicine Department at the Ministry of Health and Population, denied the existance of any reported mysterious virus or epidemic disease in Shubra al-Kheima area. The analysis results of the withdrawn samples gave a negative result, he added in a meeting with the parliament's Health Affairs Committee.
The meeting discussed the briefing requests presented earlier by MPs Nidal al-Said and Thuraya al-Sheikh, on rumors about the existence of a mysterious virus in the Shubra al-Kheima area.
There are no cases of infection outside the two families that caught the virus earlier, said Kandil.
He added that all the hospitals have been reviewed in the vicinity of injuries that have emerged, and it was confirmed that there are no similar cases or an increase in the number of patients with similar symptoms of the disease. He reiterrated that more than 2,000 people were examined and samples withdrawn in dozens of houses adjacent to the families' homes in Shubra al-Kheima, including samples of water and food. All the results were negative.
The infection may be the result of toxicity, Kandil pointed out.
Hospitals in the area of the reported infections have been examined for similar disease cases, with similar symptoms, said Kandil.
He pointed out that more than 2,000 samples had been taken from dozens of people in houses adjacent to the infected two families' homes in Shubra al-Kheima. The results were all negative, Kandil stressed.
Edited translation from Al-Masry Al-Youm


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- This event has passed.
LEASIDE LIBRARY – December 2017
December 1, 2017 @ 8:30 am - December 31, 2017 @ 11:00 pm
165 McRae Drive, 416-396-3835.
ADULT & TEEN PROGRAMMING:
Adult Colouring Party Experience the latest trend in relaxation! Colouring sheets, crayons, markers and relaxing music supplied. Tuesdays: 7-8:15pm. Dec. 5, 12, 19. For all teens/adults.
Face Paintings Exhibit in the Community Room by Parastoo Mahmoudi. Dec 1-Dec 30.
Enjoy solving/completing jigsaw puzzles or playing games. Tuesdays: 6:30- 8:15pm. Dec. 5, 12, 19 Drop in.
Leaside Writer’s Group
Are you looking for a creative place to meet with other like-minded individuals? Join us. Saturdays: 10-11:45am. Dec. 9, 23 Drop in. Everyone welcome.
Leaside Needleworx Group
(Knitting and Crocheting at the Library)Bring your own projects or start something new. Recurring Fridays: 10-11:45am. Dec. 1, 08, 15, 22, 29 Everyone welcome.
Law at the Library Series: Seniors’ Issues Talks: Decisional Capacity. Decisional capacity as it relates to powers of attorney, guardianship, late-life “predatory” marriages and potential financial abuse can be very confusing and an issue of great concern. Kimberly A. Whaley, CS, TEP, LLM; Amanda Bettencourt, JD and Alex Sawbuck, JD, legal experts in these areas will present and address your concerns. Wednesday, Dec. 6, 7-8:15pm. Drop in.
LEGO Express Club Open to All Ages. Come to the Library during opening hours and play on your own time. Ongoing throughout December.
Christmas Movie Matinée
Join us for a screening of “Mickey’s Christmas Carol” plus other holiday favourites. Tuesday: 4:00 p.m. – 5:00 p.m. Dec. 19 Drop in. Everyone welcome.
Ready for Reading Christmas Family Time (Ages 19 mos – 5 years) Christmas stories, songs, and rhymes for children with their parents or caregivers. Wednesday: 10-10:30am. Dec. 20. Drop in.
Library Closed: Monday/Tuesday December 25/26.
Send us your free listing for January by December 10th –

domain: library


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This is a fine art print reproduction of my original mixed media watercolor and pencil drawing. Originally painted on a 5 x 7 sheet of Winsor & Newton watercolor paper, this piece was professionally printed on archival heirloom-quality thick smooth paper stock using fade-proof professional inks.
This print comes carefully packaged in a clear cello-sleeve shipped in a flat bend-proof cardboard mailer via USPS First Class (to save you money)
Inspired by my time growing up in Maine, my mixed media fine art paintings are influenced by nature's moody colors and textures. I am interested the unique shapes of individual animals that I enhance by depicting their silhouettes. My mixed media style consists of a restrained use of watercolor, pencil line art, and sparse compositions. My special pieces are perfect for framing in groups for a wall in your home or in a child's room.
Thanks for looking!
Woodland art, mother deer and fawn, deer art, fawn art, nursery art print, woodland nursery print

domain: design


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Lady Threatens To Leak Akuapem Poloo Sextapez
A middle-aged lady on social media has revealed that she has access to Akuapem Poloo’s Atopa video. Is she releasing it? Find out from the video below.
In the video sighted by OccupyGh.com, the middle-aged lady who looks like a media presenter revealed what she saw Akuapem Poloo and another man in the viral video do.
The lady in the video also claimed that she knows the man involved in the video with Akuapem Poloo. She also revealed that she knows the person who released the video first and who the video was sent to.
She claimed to have cried profusely for Akuapem Poloo after she gained access to her Atopa video.
The reasons why this lady in the video wants to release Akuapem Poloo’s Atopa video is still unclear.
It is also unclear what she stands to gain from releasing the video, although she sounded a bit advisory in the backlash.
Check out the video below
Ow Akuapem Poloo low key the thing bash me ??? pic.twitter.com/Qo8RMzBwb8— DON'T BE LAZY ??? (@Dont_Be__Lazy) September 14, 2020


Organizing for Power (O4P), which has trained more than 35,000 people in 1,400+ organizations coming from over 110 countries since 2019 – recently concluded a week-long intensive training for Public Services International (PSI), a global union federation representing 30 million public services workers in 700 unions across 154 countries.
Over four days of intensive sessions, O4P gave a special version of its Core Fundamentals training, instructing PSI staff on organizing methods including leader identification, semantics, structured organizing conversations, charting, and structure tests – and how to best incorporate these methods into the particular nature of their work as a global union federation. The training was prepared by O4P lead trainer Jane McAlevey and program coordinator Ethan Earle – in close coordination with PSI’s newly elected General Secretary Daniel Bertossa – and was led by McAlevey and other senior O4P trainers, alongside brand-new trainers from PSI’s staff.
All 45 members of PSI staff from the Americas, Europe, Africa, and the Middle East were present (the timing making it impossible for Asia-based staff). This means that everybody – from the General Secretary, to regional and thematic program officers, to administrative staff and secretaries – came together, not just to teach new skills but to help PSI build a shared language and culture, an organizing ethos to pervade all of their varied work supporting public service unions across the globe.
As responsible for a PSI sub region, the training is directly connected to my work. I feel enlightened.Najwa Hanna, sub regional secretary for Arab Countries, PSI


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Introduction to Vermont Slot Machine Casino Gambling 2018
Vermont slot machine casino gambling does not exist. There are no casinos or racetracks within the state of Vermont. However, casino gambling is available relatively nearby, right across each of its borders, including:
- To the west: New Hampshire;
- To the south: Massachusetts;
- To the north: Province of Quebec, Canada; and
- To the west: New York.
This post continues the weekly blog series “Slot Machine Casino Gambling, State-By-State“, a year-long online resource project dedicated to guiding slot machine gambling enthusiasts to success.
Keep Reading … or Listen Instead!
Relevant Legal Statutes on Gambling in Vermont*
The minimum legal age for casino gambling in Vermont is not available. It is 18 for the lottery and bingo.
The laws against gambling in Vermont are comprehensive and strict, even going so far as to restrict simple social gambling. The only gambling legally allowed is the state lottery.
*The purpose of this section is to inform the public of state gambling laws and how the laws apply to various forms of gambling. This information is not intended to provide legal advice.
Slot Machine Private Ownership in Vermont
It is legal to privately own a slot machine in the state of Vermont if it was manufactured prior to 1954.
Gaming Control Board in Vermont
No state gaming commission exists except for the Vermont Lottery Commission regulating the state’s lottery.
List of Casinos in Vermont
There are no casinos or racetracks in Vermont.
Summary of Vermont Slot Machine Casino Gambling 2018
Vermont slot machine casino gambling does not exist, as this state currently has no casinos or racetracks. The nearest available gaming opportunities exist across Vermont’s borders in Massachusetts, New Hampshire, New York as well as at a tribal casino in Montreal, Canada. Vermont has had a state lottery since 1978.
Professor Slots Video on Vermont Slot Machine Casino Gambling 2018
Other State-By-State Articles from Professor Slots
- Series: Online Resource: State-By-State Slots Gambling Summaries – Now in its second year, this series is an online resource dedicated to slot machine casino gambling enthusiasts. It provides 56 weekly, detailed gambling summarizes covering each U.S. state, territory, and the federal district to capture dynamic changes occurring of late in the U.S. gaming/gambling industry specific to slots play.
- Previous: Utah Slot Machine Casino Gambling 2018 – Utah slot machine casino gambling does not exist. Utah is one of only two states, the other being Hawaii, where gambling is considered strictly illegal. The nearest slot machines are located in West Wendover in Nevada, 123 miles directly west of Salt Lake City, Utah. However, bingo is allowed if offered free of charge.
- Next: Virginia Slot Machine Casino Gambling 2018 – Virginia slot machine casino gambling does not exist, although slot-like historical race wagering machines will become available later in 2018 at Colonial Downs in eastern Virginia. Horse racing and pari-mutuel wagering are allowed at licensed facilities, with one horseracing track, simulcast, and OTB currently open.

domain: entertainment


In recent years the manufacturers increasingly bet less by manual changes in its sports products. The automatic gearboxes used in high-performance cars are faster and more effective than any human, it must be added that the driver does not have to release the hands on the steering wheel at any time when wheel at the limit.
On the other hand we have reliability, since the manual boxes have limitations of reliability with very powerful engines. More robust manual transmissions could be used to increase its durability, but the feel of change would be far worse and also raise their weight. All this combination makes that, with few exceptions like the return of the Porsche 911 GT3 to manual change, increasingly harder to see a manual gearbox in a high performance car.
In recent years we have been aware of this change in the industry, seeing as the manufacturers they resorted especially to the changes of double clutch. In BMW you can now buy versions with 6-speed manual transmission or with dual-clutch 7-speed change. A recent statements of Peter Quintus to our colleagues from The Drive leave us open-mouthed: “La DCT had two advantages: it was light and its rate of change was increased, now much of that advantage of switching time has disappeared to Automation improve and become more intelligent“.
It is at least curious that a senior BMW make these statements when currently products of your company using this type of change. Quintus also declared that the DCT left between six and seven years of life. He praised developments receiving boxes automatic torque converter stating, inter alia, that “we are now seeing with nine and even ten speeds, automatic transmissions so there is much technology in automatic“.
The performance figures, both power and torque, in the cars of high-performance, complexity that adds in the hybrid systems and the comfort of an automatic gearbox March makes a manual almost impossible to see in a new supercar. The oddest thing is that, according to BMW, exactly the same reasons “will kill” the double clutch in the torque converter.