title: Staphylococcus aureus

text: Another notable evolutionary process within the "S. aureus" species is its co-evolution with its human hosts. Over time, this parasitic relationship has led to the bacterium's ability to be carried in the nasopharynx of humans without causing symptoms or infection. This allows it to be passed throughout the human population, increasing its fitness as a species. However, only approximately 50% of the human population are carriers of "S. aureus", with 20% as continuous carriers and 30% as intermittent. This leads scientists to believe that there are many factors that determine whether "S. aureus" is carried asymptomatically in humans, including factors that are specific to an individual person. According to a 1995 study by Hofman et al., these factors may include age, sex, diabetes, and smoking. They also determined some genetic variations in humans that lead to an increased ability for "S. aureus" to colonize, notably a polymorphism in the glucocorticoid receptor gene that results in larger corticosteroid production. In conclusion, there is evidence that any strain of this bacterium can become invasive, as this is highly dependent upon human factors.


title: Staphylococcus aureus

text: Though "S. aureus" has quick reproductive and micro-evolutionary rates, there are multiple barriers that prevent evolution with the species. One such barrier is AGR, which is a global accessory gene regulator within the bacteria. This such regulator has been linked to the virulence level of the bacteria. Loss of function mutations within this gene have been found to increase the fitness of the bacterium containing it. Thus, "S. aureus" must make a trade-off to increase their success as a species, exchanging reduced virulence for increased drug resistance. Another barrier to evolution is the Sau1 Type I restriction modification (RM) system. This system exists to protect the bacterium from foreign DNA by digesting it. Exchange of DNA between the same lineage is not blocked, since they have the same enzymes and the RM system does not recognize the new DNA as foreign, but transfer between different lineages is blocked.


title: Staphylococcus aureus

text: "S. aureus" (, Greek σταφυλόκοκκος, "grape-cluster berry", Latin "aureus", "golden") is a facultative aerobic, Gram-positive coccal (round) bacterium also known as "golden staph" and "oro staphira". "S. aureus" is nonmotile and does not form spores. In medical literature, the bacterium is often referred to as "S. aureus", "Staph aureus" or "Staph a.". "S. aureus" appears as staphylococci (grape-like clusters) when viewed through a microscope, and has large, round, golden-yellow colonies, often with hemolysis, when grown on blood agar plates. "S. aureus" reproduces asexually by binary fission. Complete separation of the daughter cells is mediated by "S. aureus" autolysin, and in its absence or targeted inhibition, the daughter cells remain attached to one another and appear as clusters.


title: Staphylococcus aureus

text: "S. aureus" is catalase-positive (meaning it can produce the enzyme catalase). Catalase converts hydrogen peroxide () to water and oxygen. Catalase-activity tests are sometimes used to distinguish staphylococci from enterococci and streptococci. Previously, "S. aureus" was differentiated from other staphylococci by the coagulase test. However, not all "S. aureus" strains are coagulase-positive and incorrect species identification can impact effective treatment and control measures.


title: Staphylococcus aureus

text: Natural genetic transformation is a reproductive process involving DNA transfer from one bacterium to another through the intervening medium, and the integration of the donor sequence into the recipient genome by homologous recombination. "S. aureus" was found to be capable of natural genetic transformation, but only at low frequency under the experimental conditions employed. Further studies suggested that the development of competence for natural genetic transformation may be substantially higher under appropriate conditions, yet to be discovered.


title: Staphylococcus aureus

text: In humans, "S. aureus" can be present in the upper respiratory tract, gut mucosa, and skin as a member of the normal microbiota. However, because "S. aureus" can cause disease under certain host and environmental conditions, it is characterized as a "pathobiont".


title: Staphylococcus aureus

text: While "S. aureus" usually acts as a commensal bacterium, asymptomatically colonizing about 30% of the human population, it can sometimes cause disease. In particular, "S. aureus" is one of the most common causes of bacteremia and infective endocarditis. Additionally, it can cause various skin and soft-tissue infections, particularly when skin or mucosal barriers have been breached.


title: Staphylococcus aureus

text: "S. aureus" infections can spread through contact with pus from an infected wound, skin-to-skin contact with an infected person, and contact with objects used by an infected person such as towels, sheets, clothing, or athletic equipment. Joint replacements put a person at particular risk of septic arthritis, staphylococcal endocarditis (infection of the heart valves), and pneumonia.


title: Staphylococcus aureus

text: "S. aureus" is a significant cause of chronic biofilm infections on medical implants, and the repressor of toxins is part of the infection pathway.


title: Staphylococcus aureus

text: "S. aureus" can lay dormant in the body for years undetected. Once symptoms begin to show, the host is contagious for another two weeks, and the overall illness lasts a few weeks. If untreated, though, the disease can be deadly. Deeply penetrating "S. aureus" infections can be severe.


title: Staphylococcus aureus

text: Skin infections are the most common form of "S. aureus" infection. This can manifest in various ways, including small benign boils, folliculitis, impetigo, cellulitis, and more severe, invasive soft-tissue infections.


title: Staphylococcus aureus

text: "S. aureus" is extremely prevalent in persons with atopic dermatitis, more commonly known as eczema. It is mostly found in fertile, active places, including the armpits, hair, and scalp. Large pimples that appear in those areas may exacerbate the infection if lacerated. This can lead to staphylococcal scalded skin syndrome, a severe form of which can be seen in newborns.


title: Staphylococcus aureus

text: The presence of "S. aureus" in persons with atopic dermatitis is not an indication to treat with oral antibiotics, as evidence has not shown this to give benefit to the patient. However, topical antibiotics combined with corticosteroids have been found to improve the condition. Colonization of "S. aureus" drives inflammation of atopic dermatitis; "S. aureus" is believed to exploit defects in the skin barrier of persons with atopic dermatitis, triggering cytokine expression and therefore exacerbating symptoms.


title: Staphylococcus aureus

text: "S. aureus" is also responsible for food poisoning and achieves this by generating toxins in the human body. Its incubation period lasts one to six hours, with the illness itself lasting from 30 minutes to 3 days.


title: Staphylococcus aureus

text: Preventive measures one can take to help prevent the spread of the disease include washing hands thoroughly with soap and water before preparing food. Stay away from any food if ill, and wear gloves if any open wounds occur on hands or wrists while preparing food. If storing food for longer than 2 hours, keep the food below 40 or above 140 °F (4.4 or 60 °C).


title: Staphylococcus aureus

text: "S. aureus" is the bacterium commonly responsible for all major bone and joint infections. This manifests in one of three forms: osteomyelitis, septic arthritis, and infection from a replacement joint surgery.


title: Staphylococcus aureus

text: "S. aureus" is a leading cause of bloodstream infections throughout much of the industrialized world. Infection is generally associated with breaks in the skin or mucosal membranes due to surgery, injury, or use of intravascular devices such as catheters, hemodialysis machines, or injected drugs. Once the bacteria have entered the bloodstream, they can infect various organs, causing infective endocarditis, septic arthritis, and osteomyelitis. This disease is particularly prevalent and severe in the very young and very old.


title: Staphylococcus aureus

text: Without antibiotic treatment, "S. aureus" bacteremia has a case fatality rate around 80%. With antibiotic treatment, case fatality rates range from 15% to 50% depending on the age and health of the patient, as well as the antibiotic resistance of the "S. aureus" strain.


title: Staphylococcus aureus

text: "S. aureus" is often found in biofilms formed on medical devices implanted in the body or on human tissue. It is commonly found with another pathogen, "Candida albicans", forming multispecies biofilms. The latter is suspected to help "S. aureus" penetrate human tissue. A higher mortality is linked with multispecies biofilms.


title: Staphylococcus aureus

text: "S. aureus" biofilm is the predominant cause of orthopedic implant-related infections, but is also found on cardiac implants, vascular grafts, various catheters, and cosmetic surgical implants. After implantation, the surface of these devices becomes coated with host proteins, which provide a rich surface for bacterial attachment and biofilm formation. Once the device becomes infected, it must by completely removed, since "S. aureus" biofilm cannot be destroyed by antibiotic treatments.


title: Staphylococcus aureus

text: Current therapy for "S. aureus" biofilm-mediated infections involves surgical removal of the infected device followed by antibiotic treatment. Conventional antibiotic treatment alone is not effective in eradicating such infections. An alternative to postsurgical antibiotic treatment is using antibiotic-loaded, dissolvable calcium sulfate beads, which are implanted with the medical device. These beads can release high doses of antibiotics at the desired site to prevent the initial infection.


title: Staphylococcus aureus

text: Novel treatments for "S. aureus" biofilm involving nano silver particles, bacteriophages, and plant-derived antibiotic agents are being studied. These agents have shown inhibitory effects against "S. aureus" embedded in biofilms. A class of enzymes have been found to have biofilm matrix-degrading ability, thus may be used as biofilm dispersal agents in combination with antibiotics.


title: Staphylococcus aureus

text: "S. aureus" can survive on dogs, cats, and horses, and can cause bumblefoot in chickens. Some believe health-care workers' dogs should be considered a significant source of antibiotic-resistant "S. aureus", especially in times of outbreak. In a 2008 study by Boost, O’Donoghue, and James, it was found that just about 90% of "S. aureus" colonized within pet dogs presented as resistant to at least one antibiotic. The nasal region has been implicated as the most important site of transfer between dogs and humans.


title: Staphylococcus aureus

text: "S. aureus" is one of the causal agents of mastitis in dairy cows. Its large polysaccharide capsule protects the organism from recognition by the cow's immune defenses.


title: Staphylococcus aureus

text: "S. aureus" produces various enzymes such as coagulase (bound and free coagulases) which facilitates the conversion of fibrinogen to fibrin to cause clots which is important in skin infections.


title: Staphylococcus aureus

text: Hyaluronidase (also known as spreading factor) breaks down hyaluronic acid and helps in spreading it. Deoxyribonuclease, which breaks down the DNA, protects "S. aureus" from neutrophil extracellular trap-mediated killing. "S. aureus" also produces lipase to digest lipids, staphylokinase to dissolve fibrin and aid in spread, and beta-lactamase for drug resistance.


title: Staphylococcus aureus

text: Depending on the strain, "S. aureus" is capable of secreting several exotoxins, which can be categorized into three groups. Many of these toxins are associated with specific diseases.


title: Staphylococcus aureus

text: A secretion system is a highly specialised multi-protein unit that is embedded in the cell envelope with the function of translocating effector proteins from inside of the cell to the extracellular space or into a target host cytosol. The exact structure and function of T7SS is yet to be fully elucidated. Currently, four proteins are known components of "S. aureus" Type VII Secretion System (T7SS); EssC is a large integral membrane ATPase - which most likely powers the secretion systems and has been hypothesised forming part of the translocation channel. The other proteins are EsaA, EssB, EssA, that are membrane proteins that function alongside EssC to mediate protein secretion. The exact mechanism of how substrates reach the cell surface is unknown, as is the interaction of the three membrane proteins with each other and EssC.


title: Staphylococcus aureus

text: EsaD is DNA endonuclease toxin secreted by "S. aureus", has been shown to inhibit growth of competitor "S. aureus" strain "in vitro". EsaD is cosecreted with chaperone EsaE, which stabilises EsaD structure and brings EsaD to EssC for secretion. Strains that produce EsaD also co-produce EsaG, a cytoplasmic anti-toxin that protects the producer strain from EsaD's toxicity.


title: Staphylococcus aureus

text: TspA is another toxin that mediates intraspecies competition. It is a bacteriostatic toxin that has a membrane depolarising activity facilitated by its c-terminal domain. Tsai is a transmembrane protein that confers immunity to the producer strain of TspA, as well as the attacked strains. There is genetic variability of the c-terminal domain of TspA therefore, it seems like the strains may produce different TspA variants to increase competitiveness.


title: Staphylococcus aureus

text: Toxins that play a role in intraspecies competition confers an advantage by promoting successful colonisation in polymicrobial communities such as the nasopharynx and lung by outcompeting lesser strains.


title: Staphylococcus aureus

text: There are also T7 effector proteins that play role a in pathogenesis, for example mutational studies of "S. aureus" have suggested that EsxB and EsxC contribute to persistent infection in a murine abscess model.


title: Staphylococcus aureus

text: EsxX is has been implicated in neutrophil lysis, therefore suggested as contributing to the evasion of host immune system. Deletion of "essX" in "S. aureus" resulted in significantly reduced resistance to neutrophils and reduced virulence in murine skin and blood infection models.


title: Staphylococcus aureus

text: Altogether, T7SS and known secreted effector proteins are a strategy of pathogenesis by improving fitness against competitor "S. aureus" species as well as increased virulence via evading the innate immune system and optimising persistent infections.


title: Staphylococcus aureus

text: The list of small RNAs involved in the control of bacterial virulence in "S. aureus" is growing. This can be facilitated by factors such as increased biofilm formation in the presence of increased levels of such small RNAs. For example, RNAIII, SprD, SprC, RsaE, SprA1, SSR42, ArtR, SprX, and Teg49.


title: Staphylococcus aureus

text: Host neutrophils cause DNA double-strand breaks in "S. aureus" through the production of reactive oxygen species. For infection of a host to be successful, "S. aureus" must survive such damages caused by the hosts’ defenses. The two protein complex RexAB encoded by "S. aureus" is employed in the recombinational repair of DNA double-strand breaks.


title: Staphylococcus aureus

text: Many mRNAs in "S. aureus" carry three prime untranslated regions (3'UTR) longer than 100 nucleotides, which may potentially have a regulatory function.


title: Staphylococcus aureus

text: Further investigation of i"caR" mRNA (mRNA coding for the repressor of the main expolysaccharidic compound of the bacteria biofilm matrix) demonstrated that the 3'UTR binding to the 5' UTR can interfere with the translation initiation complex and generate a double stranded substrate for RNase III. The interaction is between the UCCCCUG motif in the 3'UTR and the Shine-Dalagarno region at the 5'UTR. Deletion of the motif resulted in IcaR repressor accumulation and inhibition of biofilm development. The biofilm formation is the main cause of "Staphylococcus" implant infections.


title: Staphylococcus aureus

text: Biofilms are groups of microorganisms, such as bacteria, that attach to each other and grow on wet surfaces. The "S. aureus" biofilm is embedded in a glycocalyx slime layer and can consist of teichoic acids, host proteins, extracellular DNA (eDNA) and polysaccharide intercellular antigen (PIA). Not all "S. aureus" biofilms contain PIA. S. aureus biofilms are important in disease pathogenesis, as they can contribute to antibiotic resistance and immune system evasion. "S. aureus" biofilm has high resistance to antibiotic treatments and host immune response. One hypothesis for explaining this is that the biofilm matrix protects the embedded cells by acting as a barrier to prevent antibiotic penetration. However, the biofilm matrix is composed with many water channels, so this hypothesis is becoming increasingly less likely, but a biofilm matrix possibly contains antibiotic‐degrading enzymes such as β-lactamases, which can prevent antibiotic penetration. Another hypothesis is that the conditions in the biofilm matrix favor the formation of persister cells, which are highly antibiotic-resistant, dormant bacterial cells. "S. aureus" biofilms also have high resistance to host immune response. Though the exact mechanism of resistance is unknown, "S. aureus" biofilms have increased growth under the presence of cytokines produced by the host immune response. Host antibodies are less effective for "S. aureus" biofilm due to the heterogeneous antigen distribution, where an antigen may be present in some areas of the biofilm, but completely absent from other areas.


title: Staphylococcus aureus

text: Studies in biofilm development have shown to be related to changes in gene expression. There are specific genes that were found to be crucial in the different biofilm growth stages. Two of these genes include rocD and gudB, which encode for the enzyme's ornithine-oxo-acid transaminase and glutamate dehydrogenase, which are important for amino acid metabolism. Studies have shown biofilm development rely on amino acids glutamine and glutamate for proper metabolic functions.


title: Staphylococcus aureus

text: Protein A is anchored to staphylococcal peptidoglycan pentaglycine bridges (chains of five glycine residues) by the transpeptidase sortase A. Protein A, an IgG-binding protein, binds to the Fc region of an antibody. In fact, studies involving mutation of genes coding for protein A resulted in a lowered virulence of "S. aureus" as measured by survival in blood, which has led to speculation that protein A-contributed virulence requires binding of antibody Fc regions.


title: Staphylococcus aureus

text: Protein A in various recombinant forms has been used for decades to bind and purify a wide range of antibodies by immunoaffinity chromatography. Transpeptidases, such as the sortases responsible for anchoring factors like protein A to the staphylococcal peptidoglycan, are being studied in hopes of developing new antibiotics to target MRSA infections.


title: Staphylococcus aureus

text: Some strains of "S. aureus" are capable of producing staphyloxanthin — a golden-coloured carotenoid pigment. This pigment acts as a virulence factor, primarily by being a bacterial antioxidant which helps the microbe evade the reactive oxygen species which the host immune system uses to kill pathogens.


title: Staphylococcus aureus

text: Mutant strains of "S. aureus" modified to lack staphyloxanthin are less likely to survive incubation with an oxidizing chemical, such as hydrogen peroxide, than pigmented strains. Mutant colonies are quickly killed when exposed to human neutrophils, while many of the pigmented colonies survive. In mice, the pigmented strains cause lingering abscesses when inoculated into wounds, whereas wounds infected with the unpigmented strains quickly heal.


title: Staphylococcus aureus

text: These tests suggest the "Staphylococcus" strains use staphyloxanthin as a defence against the normal human immune system. Drugs designed to inhibit the production of staphyloxanthin may weaken the bacterium and renew its susceptibility to antibiotics. In fact, because of similarities in the pathways for biosynthesis of staphyloxanthin and human cholesterol, a drug developed in the context of cholesterol-lowering therapy was shown to block "S. aureus" pigmentation and disease progression in a mouse infection model.


title: Staphylococcus aureus

text: Depending upon the type of infection present, an appropriate specimen is obtained accordingly and sent to the laboratory for definitive identification by using biochemical or enzyme-based tests. A Gram stain is first performed to guide the way, which should show typical Gram-positive bacteria, cocci, in clusters. Second, the isolate is cultured on mannitol salt agar, which is a selective medium with 7.5% NaCl that allows "S. aureus" to grow, producing yellow-colored colonies as a result of mannitol fermentation and subsequent drop in the medium's pH.


title: Staphylococcus aureus

text: Furthermore, for differentiation on the species level, catalase (positive for all "Staphylococcus" species), coagulase (fibrin clot formation, positive for "S. aureus"), DNAse (zone of clearance on DNase agar), lipase (a yellow color and rancid odor smell), and phosphatase (a pink color) tests are all done. For staphylococcal food poisoning, phage typing can be performed to determine whether the staphylococci recovered from the food were the source of infection.


title: Staphylococcus aureus

text: Recent activities and food that a patient has recently eaten will be inquired about by a physician, and a physical examination is conducted to review any symptoms. With more severe symptoms, blood tests and stool culture may be in order.


title: Staphylococcus aureus

text: Diagnostic microbiology laboratories and reference laboratories are key for identifying outbreaks and new strains of "S. aureus". Recent genetic advances have enabled reliable and rapid techniques for the identification and characterization of clinical isolates of "S. aureus" in real time. These tools support infection control strategies to limit bacterial spread and ensure the appropriate use of antibiotics. Quantitative PCR is increasingly being used to identify outbreaks of infection.


title: Staphylococcus aureus

text: When observing the evolvement of "S. aureus" and its ability to adapt to each modified antibiotic, two basic methods known as "band-based" or "sequence-based" are employed. Keeping these two methods in mind, other methods such as multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), bacteriophage typing, spa locus typing, and SCCmec typing are often conducted more than others. With these methods, it can be determined where strains of MRSA originated and also where they are currently.


title: Staphylococcus aureus

text: With MLST, this technique of typing uses fragments of several housekeeping genes known as "aroE, glpF, gmk, pta, tip," and "yqiL". These sequences are then assigned a number which give to a string of several numbers that serve as the allelic profile. Although this is a common method, a limitation about this method is the maintenance of the microarray which detects newly allelic profiles, making it a costly and time-consuming experiment.


title: Staphylococcus aureus

text: With PFGE, a method which is still very much used dating back to its first success in 1980s, remains capable of helping differentiate MRSA isolates. To accomplish this, the technique uses multiple gel electrophoresis, along with a voltage gradient to display clear resolutions of molecules. The "S. aureus" fragments then transition down the gel, producing specific band patterns that are later compared with other isolates in hopes of identifying related strains. Limitations of the method include practical difficulties with uniform band patterns and PFGE sensitivity as a whole.


title: Staphylococcus aureus

text: Spa locus typing is also considered a popular technique that uses a single locus zone in a polymorphic region of "S. aureus" to distinguish any form of mutations. Although this technique is often inexpensive and less time-consuming, the chance of losing discriminatory power making it hard to differentiate between MLST clonal complexes exemplifies a crucial limitation.


title: Staphylococcus aureus

text: For susceptible strains, the treatment of choice for "S. aureus" infection is penicillin. An antibiotic derived from some "Penicillium" fungal species, penicillin inhibits the formation of peptidoglycan cross-linkages that provide the rigidity and strength in a bacterial cell wall. The four-membered β-lactam ring of penicillin is bound to enzyme DD-transpeptidase, an enzyme that when functional, cross-links chains of peptidoglycan that form bacterial cell walls. The binding of β-lactam to DD-transpeptidase inhibits the enzyme's functionality and it can no longer catalyze the formation of the cross-links. As a result, cell wall formation and degradation are imbalanced, thus resulting in cell death. In most countries, however, penicillin resistance is extremely common (>90%), and first-line therapy is most commonly a penicillinase-resistant β-lactam antibiotic (for example, oxacillin or flucloxacillin, both of which have the same mechanism of action as penicillin) or vancomycin, depending on local resistance patterns. Combination therapy with gentamicin may be used to treat serious infections, such as endocarditis, but its use is controversial because of the high risk of damage to the kidneys. The duration of treatment depends on the site of infection and on severity. Adjunctive rifampicin has been historically used in the management of "S aureus" bacteraemia, but randomised controlled trial evidence has shown this to be of no overall benefit over standard antibiotic therapy.


title: Staphylococcus aureus

text: Antibiotic resistance in "S. aureus" was uncommon when penicillin was first introduced in 1943. Indeed, the original Petri dish on which Alexander Fleming of Imperial College London observed the antibacterial activity of the "Penicillium" fungus was growing a culture of "S. aureus". By 1950, 40% of hospital "S. aureus" isolates were penicillin-resistant; by 1960, this had risen to 80%.


title: Staphylococcus aureus

text: Methicillin-resistant Staphylococcus aureus (MRSA, often pronounced or ), is one of a number of greatly feared strains of "S. aureus" which have become resistant to most β-lactam antibiotics. For this reason, vancomycin, a glycopeptide antibiotic, is commonly used to combat MRSA. Vancomycin inhibits the synthesis of peptidoglycan, but unlike β-lactam antibiotics, glycopeptide antibiotics target and bind to amino acids in the cell wall, preventing peptidoglycan cross-linkages from forming. MRSA strains are most often found associated with institutions such as hospitals, but are becoming increasingly prevalent in community-acquired infections.


title: Staphylococcus aureus

text: Minor skin infections can be treated with triple antibiotic ointment. One topical agent that is prescribed is Mupirocin, a protein synthesis inhibitor that is produced naturally by Pseudomonas fluorescens and has seen success for treatment of S. aureus nasal carriage.


title: Staphylococcus aureus

text: "S. aureus" was found to be the second leading pathogen for deaths associated with Antimicrobial resistance in 2019.


title: Staphylococcus aureus

text: Staphylococcal resistance to penicillin is mediated by penicillinase (a form of beta-lactamase) production: an enzyme that cleaves the β-lactam ring of the penicillin molecule, rendering the antibiotic ineffective. Penicillinase-resistant β-lactam antibiotics, such as methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, and flucloxacillin are able to resist degradation by staphylococcal penicillinase.


title: Staphylococcus aureus

text: Resistance to methicillin is mediated via the "mec" operon, part of the staphylococcal cassette chromosome mec (SCC"mec"). SCCmec is a family of mobile genetic elements, which is a major driving force of "S. aureus" evolution. Resistance is conferred by the "mecA" gene, which codes for an altered penicillin-binding protein (PBP2a or PBP2') that has a lower affinity for binding β-lactams (penicillins, cephalosporins, and carbapenems). This allows for resistance to all β-lactam antibiotics, and obviates their clinical use during MRSA infections. Studies have explained that this mobile genetic element has been acquired by different lineages in separate gene transfer events, indicating that there is not a common ancestor of differing MRSA strains. Interestingly, one study suggests that MRSA sacrifices virulence, for example, toxin production and invasiveness, for survival and creation of biofilms


title: Staphylococcus aureus

text: Aminoglycoside antibiotics, such as kanamycin, gentamicin, streptomycin, were once effective against staphylococcal infections until strains evolved mechanisms to inhibit the aminoglycosides' action, which occurs via protonated amine and/or hydroxyl interactions with the ribosomal RNA of the bacterial 30S ribosomal subunit. Three main mechanisms of aminoglycoside resistance mechanisms are currently and widely accepted: aminoglycoside modifying enzymes, ribosomal mutations, and active efflux of the drug out of the bacteria.


title: Staphylococcus aureus

text: Aminoglycoside-modifying enzymes inactivate the aminoglycoside by covalently attaching either a phosphate, nucleotide, or acetyl moiety to either the amine or the alcohol key functional group (or both groups) of the antibiotic. This changes the charge or sterically hinders the antibiotic, decreasing its ribosomal binding affinity. In "S. aureus", the best-characterized aminoglycoside-modifying enzyme is aminoglycoside adenylyltransferase 4' IA ("ANT(4')IA"). This enzyme has been solved by X-ray crystallography. The enzyme is able to attach an adenyl moiety to the 4' hydroxyl group of many aminoglycosides, including kamamycin and gentamicin.


title: Staphylococcus aureus

text: Glycopeptide resistance is mediated by acquisition of the "vanA" gene, which originates from the Tn1546 transposon found in a plasmid in enterococci and codes for an enzyme that produces an alternative peptidoglycan to which vancomycin will not bind.


title: Staphylococcus aureus

text: Today, "S. aureus" has become resistant to many commonly used antibiotics. In the UK, only 2% of all "S. aureus" isolates are sensitive to penicillin, with a similar picture in the rest of the world. The β-lactamase-resistant penicillins (methicillin, oxacillin, cloxacillin, and flucloxacillin) were developed to treat penicillin-resistant "S. aureus", and are still used as first-line treatment. Methicillin was the first antibiotic in this class to be used (it was introduced in 1959), but, only two years later, the first case of methicillin-resistant "Staphylococcus aureus" (MRSA) was reported in England.


title: Staphylococcus aureus

text: Despite this, MRSA generally remained an uncommon finding, even in hospital settings, until the 1990s, when the MRSA prevalence in hospitals exploded, and it is now endemic. Now, methicillin-resistant "Staphylococcus aureus" (MRSA) is not only a human pathogen causing a variety of infections, such as skin and soft tissue infection (SSTI), pneumonia, and sepsis, but it also can cause disease in animals, known as livestock-associated MRSA (LA-MRSA).


title: Staphylococcus aureus

text: MRSA infections in both the hospital and community setting are commonly treated with non-β-lactam antibiotics, such as clindamycin (a lincosamine) and co-trimoxazole (also commonly known as trimethoprim/sulfamethoxazole). Resistance to these antibiotics has also led to the use of new, broad-spectrum anti-Gram-positive antibiotics, such as linezolid, because of its availability as an oral drug. First-line treatment for serious invasive infections due to MRSA is currently glycopeptide antibiotics (vancomycin and teicoplanin). A number of problems with these antibiotics occur, such as the need for intravenous administration (no oral preparation is available), toxicity, and the need to monitor drug levels regularly by blood tests. Also, glycopeptide antibiotics do not penetrate very well into infected tissues (this is a particular concern with infections of the brain and meninges and in endocarditis). Glycopeptides must not be used to treat methicillin-sensitive "S. aureus" (MSSA), as outcomes are inferior.


title: Staphylococcus aureus

text: Because of the high level of resistance to penicillins and because of the potential for MRSA to develop resistance to vancomycin, the U.S. Centers for Disease Control and Prevention has published guidelines for the appropriate use of vancomycin. In situations where the incidence of MRSA infections is known to be high, the attending physician may choose to use a glycopeptide antibiotic until the identity of the infecting organism is known. After the infection is confirmed to be due to a methicillin-susceptible strain of "S. aureus", treatment can be changed to flucloxacillin or even penicillin, as appropriate.


title: Staphylococcus aureus

text: Vancomycin-resistant "S. aureus" (VRSA) is a strain of "S. aureus" that has become resistant to the glycopeptides. The first case of vancomycin-intermediate "S. aureus" (VISA) was reported in Japan in 1996; but the first case of "S. aureus" truly resistant to glycopeptide antibiotics was only reported in 2002. Three cases of VRSA infection had been reported in the United States as of 2005. At least in part the antimicrobial resistance in "S. aureus" can be explained by its ability to adapt. Multiple two component signal transduction pathways helps "S. aureus" to express genes that are required to survive under antimicrobial stress.


title: Staphylococcus aureus

text: Among the various mechanisms that MRSA acquires to elude antibiotic resistance (e.g., drug inactivation, target alteration, reduction of permeability) there is also the overexpression of efflux pumps. Efflux pumps are membrane-integrated proteins that are physiologically needed in the cell for the exportation of xenobiotic compounds. They are divided into six families, each of which has a different structure, function, and transport of energy. The main efflux pumps of S. Aureus are the MFS (Major Facilitator Superfamily) which includes the MdeA pump as well as the NorA pump and the MATE (Multidrug and Toxin Extrusion) to which it belongs the MepA pump. For transport, these families use an electrochemical potential and an ion concentration gradient, while the ATP-binding cassette (ABC) family acquires its energy from the hydrolysis of ATP.


title: Staphylococcus aureus

text: These pumps are overexpressed by MDR "S. aureus" (Multidrug resistant "S. aureus)" and the result is an excessive expulsion of the antibiotic outside the cell, which makes its action ineffective. Efflux pumps also contribute significantly to the development of impenetrable biofilms.


title: Staphylococcus aureus

text: By directly modulating efflux pumps' activity or decreasing their expression, it may be possible to modify the resistant phenotype and restore the effectiveness of existing antibiotics.


title: Staphylococcus aureus

text: About 33% of the U.S. population are carriers of "S. aureus" and about 2% carry MRSA. Even healthcare providers can be MRSA colonizers.


title: Staphylococcus aureus

text: The carriage of "S. aureus" is an important source of hospital-acquired infection (also called nosocomial) and community-acquired MRSA. Although "S. aureus" can be present on the skin of the host, a large proportion of its carriage is through the anterior nares of the nasal passages and can further be present in the ears. The ability of the nasal passages to harbour "S. aureus" results from a combination of a weakened or defective host immunity and the bacterium's ability to evade host innate immunity. Nasal carriage is also implicated in the occurrence of staph infections.


title: Staphylococcus aureus

text: Spread of "S. aureus" (including MRSA) generally is through human-to-human contact, although recently some veterinarians have discovered the infection can be spread through pets, with environmental contamination thought to play a relatively less important part. Emphasis on basic hand washing techniques are, therefore, effective in preventing its transmission. The use of disposable aprons and gloves by staff reduces skin-to-skin contact, so further reduces the risk of transmission.


title: Staphylococcus aureus

text: Recently, myriad cases of "S. aureus" have been reported in hospitals across America. Transmission of the pathogen is facilitated in medical settings where healthcare worker hygiene is insufficient. "S. aureus" is an incredibly hardy bacterium, as was shown in a study where it survived on polyester for just under three months; polyester is the main material used in hospital privacy curtains.


title: Staphylococcus aureus

text: The bacteria are transported on the hands of healthcare workers, who may pick them up from a seemingly healthy patient carrying a benign or commensal strain of "S. aureus", and then pass it on to the next patient being treated. Introduction of the bacteria into the bloodstream can lead to various complications, including endocarditis, meningitis, and, if it is widespread, sepsis.


title: Staphylococcus aureus

text: Ethanol has proven to be an effective topical sanitizer against MRSA. Quaternary ammonium can be used in conjunction with ethanol to increase the duration of the sanitizing action. The prevention of nosocomial infections involves routine and terminal cleaning. Nonflammable alcohol vapor in NAV-CO2 systems have an advantage, as they do not attack metals or plastics used in medical environments, and do not contribute to antibacterial resistance.


title: Staphylococcus aureus

text: An important and previously unrecognized means of community-associated MRSA colonization and transmission is during sexual contact.


title: Staphylococcus aureus

text: "S. aureus" is killed in one minute at 78 °C and in ten minutes at 64 °C but is resistant to freezing.


title: Staphylococcus aureus

text: The use of mupirocin ointment can reduce the rate of infections due to nasal carriage of "S. aureus." There is limited evidence that nasal decontamination of "S. aureus" using antibiotics or antiseptics can reduce the rates of surgical site infections.


title: Staphylococcus aureus

text: As of 2021, no approved vaccine exists against "S. aureus". Early clinical trials have been conducted for several vaccines candidates such as Nabi's StaphVax and PentaStaph, Intercell's / Merck's V710, VRi's SA75, and others.


title: Staphylococcus aureus

text: While some of these vaccines candidates have shown immune responses, others aggravated an infection by "S. aureus". To date, none of these candidates provides protection against a "S. aureus" infection. The development of Nabi's StaphVax was stopped in 2005 after phase III trials failed. Intercell's first V710 vaccine variant was terminated during phase II/III after higher mortality and morbidity were observed among patients who developed "S. aureus" infection.


title: Staphylococcus aureus

text: Nabi's enhanced "S. aureus" vaccines candidate PentaStaph was sold in 2011 to GlaxoSmithKline Biologicals S.A. The current status of PentaStaph is unclear. A WHO document indicates that PentaStaph failed in the phase III trial stage.


title: Staphylococcus aureus

text: In 2010, GlaxoSmithKline started a phase 1 blind study to evaluate its GSK2392103A vaccine. As of 2016, this vaccine is no longer under active development.


title: Staphylococcus aureus

text: Pfizer's "S. aureus" four-antigen vaccine SA4Ag was granted fast track designation by the U.S. Food and Drug Administration in February 2014. In 2015, Pfizer has commenced a phase 2b trial regarding the SA4Ag vaccine. Phase 1 results published in February 2017 showed a very robust and secure immunogenicity of SA4Ag. The vaccine underwent clinical trial until June 2019, with results published in September 2020, that did not demonstrate a significant reduction in Postoperative Bloodstream Infection after Surgery.


title: Staphylococcus aureus

text: In 2015, Novartis Vaccines and Diagnostics, a former division of Novartis and now part of GlaxoSmithKline, published promising pre-clinical results of their four-component "Staphylococcus aureus" vaccine, 4C-staph.


title: Staphylococcus aureus

text: A number of standard strains of "S. aureus" (called "type cultures") are used in research and in laboratory testing.


title: Zomato

text: Zomato () is an Indian multinational restaurant aggregator and food delivery company founded by Deepinder Goyal and Pankaj Chaddah in 2008. Zomato provides information, menus and user-reviews of restaurants as well as food delivery options from partner restaurants in select cities. , the service is available in 24 countries and in more than 10,000 cities.


title: Zomato

text: Zomato was founded as FoodieBay in 2008 by Deepinder Goyal and Pankaj Chaddah who worked for Bain & Company. The website started as a restaurant listing and recommendation portal. They renamed the company Zomato in 2010 as they were unsure if they would "just stick to food" and also to avoid a potential naming conflict with eBay.


title: Zomato

text: With the introduction of .xxx domains in 2011, Zomato also launched zomato.xxx, a site dedicated to food porn.


title: Zomato

text: In 2011, it expanded across India to Delhi NCR, Mumbai, Bangalore, Chennai, Pune, Ahmedabad and Hyderabad. In 2012, it expanded operations internationally in several countries, including the United Arab Emirates, Sri Lanka, Qatar, the United Kingdom, the Philippines, and South Africa. In 2013, expanded to in New Zealand, Turkey, Brazil and Indonesia, with website and apps available in Turkish, Portuguese, Indonesian and English languages. In April 2014, it launched in Portugal, which was followed by launches in Canada, Lebanon and Ireland in 2015.


title: Zomato

text: In January 2015, Zomato acquired Seattle-based restaurant discovery portal Urbanspoon, which led to the firm's entry into the United States and Australia. This U.S.-expansion brought Zomato into direct competition with similar models such as Yelp and Foursquare. In an effort to expand its business beyond restaurant listing, Zomato piloted an online payments facility in partnered restaurants in Dubai called Zomato Cashless in February 2015. This was discontinued a few months later.


title: Zomato

text: Zomato started its food delivery service in India in 2015, initially partnering with companies such as Delhivery and Grab to fulfill deliveries from restaurants that did not have its own delivery service. In April 2015, Zomato acquired the American online table reservation platform NexTable, which was subsequently renamed as Zomato Book. In January 2016, it launched Zomato Book's table reservation facility on its application in India. In April 2015, Zomato acquired cloud-based point of sale company MapleGraph Solutions, and in April 2016, it launched its own Android point of sale system for restaurants called Zomato Base, which was built on MaplePOS.


title: Zomato

text: In February 2017, the firm announced plans to launch Zomato Infrastructure Services, a cloud kitchen infrastructure service to help partner restaurants expand their presence without incurring any fixed costs. Later that year, it introduced a paid membership program called Zomato Gold using which subscribers could get offers and discounts on dining and food delivery at Zomato's partner restaurants.


title: Zomato

text: In February 2018, Zomato became a unicorn startup after raising 200 million from Ant Financial at a valuation of 1.1 billion. Later that year, it shut down operations of Zomato Infrastructure Services. In 2018, it acquired WOTU and rebranded it as Hyperpure to supply food ingredients such as grains, vegetables and meat to restaurants from its warehouses. In December 2018, Zomato launched its annual multi-city food and entertainment carnival called Zomaland.


title: Zomato

text: In September 2019, the firm laid off almost 10% of its workforce (540 people) tending to back-end activities like customer service, merchant and delivery partner support functions.


title: Zomato

text: In April 2020, due to a fall in food delivery and a rising demand for online grocery ordering amid the COVID-19 pandemic, the firm began delivering groceries and essentials under a service named Zomato Market in 80+ cities across India. In April 2020, Zomato introduced contactless dining at its partner restaurants. In May 2020, Zomato also began delivering alcohol in West Bengal, Jharkhand and Odisha after obtaining the permission of the governments in these states. In May 2020, Zomato further laid off 520 employees due to the COVID-19 pandemic.


title: Zomato

text: Zomato closed operations of Zomato Market in June 2020 as demand for food delivery recovered and grocery delivery business "was not scalable". In April 2021, it pulled out of alcohol delivery service citing poor unit economics and scalability.


title: Zomato

text: In July 2021, Zomato went public, opening its Initial public offering at a valuation of over 8 billion.


title: Zomato

text: Zomato reentered grocery delivery space with a pilot launch in July 2021, allowing users to place orders from neighbourhood stores under a marketplace model. It shut down the service in September 2021.


title: Zomato

text: In April 2022, Zomato launched a pilot of 10-minute food delivery in Gurgaon called Zomato Instant. In June 2022, Zomato announced the acquisition of quick-commerce company Blinkit for 568 million.


title: Zomato

text: In August 2022, Zomato discontinued its pro membership, canceling new sign-ups and renewals. In addition, Zomato launched a new service in Gurgaon and South Delhi called Intercity Legends that allows users to order dishes from famous restaurants in other cities and have them delivered to their doorstep in a few days. In November 2022, Zomato introduced Zomato Pay feature, which allowed users to make payments at partner restaurants and avail offers, and partner restaurants to promote themselves.


title: Zomato

text: Between 2010 and 2013, Zomato raised approximately from Info Edge India, giving Info Edge India a 57.9% stake in Zomato. In November 2013, it raised an additional 37 million from Sequoia Capital and Info Edge India.


title: Zomato

text: In November 2014, Zomato completed another round of funding of 60 million at a post-money valuation of ~US$660 million. This round of funding was being led jointly by Info Edge India and Vy Capital, with participation from Sequoia Capital.


title: Zomato

text: While in April 2015, Info Edge India, Vy Capital and Sequoia Capital led another round of funding for 50 million. This was followed by another 60 million funding led by Temasek, a Singapore government-owned investment company, along with Vy Capital in September.


title: Zomato

text: In October 2018, it raised $210 million from Alibaba's payment affiliate Ant Financial, which received an ownership stake of over 10% of the company as part of the round, which valued Zomato at around $2 billion. Zomato had also raised an additional $150 million from Ant Financial earlier in 2018.


title: Zomato

text: In September 2020, Zomato raised $62 million from Temasek, after previously committed capitol from Ant Financial never came through.


title: Zomato

text: In October 2020, as part of a Series J round of funding, Zomato raised $52 million from Kora, a US-based Investment firm.


title: Zomato

text: In February 2021, Zomato raised 250 million from five investors, including Tiger Global Management, at a valuation of 5.4 billion.


title: Zomato

text: On 4 June 2015, an Indian security researcher hacked the Zomato website and gained access to information about 62.5 million users. Using the vulnerability, he was able to access the personal data of users such as telephone numbers, email addresses, and Instagram private photos using their Instagram access token. Zomato fixed the issue within 48 hours of it becoming apparent. On 15 October 2015, Zomato changed business strategies from a Full-Stack market to an Enterprise market. This led Zomato to reduce its workforce by 10%, or around 300 people.


title: Zomato

text: On 18 May 2017, a security blog called HackRead claimed that over 17 million Zomato user records including emails and password hashes had been stolen due to a security breach. The company stated that no payment information or credit card details were stolen. The hacker removed the stolen user data from the dark web after Zomato agreed to start a bug bounty program.


title: Zomato

text: Started in 2014 by Ankit Kawatra, Feeding India is a nonprofit organisation which serves free meals to underprivileged people with the help of volunteers. Feeding India was acquired by Zomato in July 2019. In May 2022, Zomato claimed that Feeding India was serving over 200,000 meals every day under its Daily Feeding Program.


title: Zomato

text: In July 2019, Zomato received a customer complaint that he was assigned a non-Hindu delivery boy for his food order in Jabalpur and had asked Zomato to provide a Hindu delivery boy. The customer alleged that Zomato had refused to change the rider after which he asked to cancel the order. The customer then posted this incident on Twitter, after which Zomato responded to the message stating: "Food doesn't have a religion. It is a religion." The company's response received positive comments on Twitter, but some customers questioned the use of Jain food and halal tags on food items. According to the company, such tags are placed by individual restaurant owners, and not by Zomato.


title: Zomato

text: On 17 August 2019, more than 1,200 restaurants logged off from Zomato because of their offer of discount programmes at dine-in restaurants. In Pune alone, more than 450 restaurants stopped serving to Zomato Gold because of aggressive discounts and loss of business. Its premium subscription-based dining out service Zomato Gold had 6,500 restaurants partners and a total of 1.1 million subscribers in India as of August 2019. As part of the campaign, around 2,500 restaurants logged out from the Zomato Gold service. After Zomato made some changes, National Restaurant Association of India still refused to accept the modified version of the plan, saying that the corrective measures would not resolve the key issue of deep discounts. However, Zomato founder Goyal admitted mistake, became ready to rectify it and called for sanity and truce. He also urged restaurants to stop #Logout campaign.


title: Zomato

text: In March 2021, a video was posted on Instagram by a Bengaluru-based model Hitesha Chandranee accusing Zomato delivery person of assaulting and punching her as she refused to pay money for the food he delivered. She claimed he delivered her food very late and they both argued and had a verbal duel and then the delivery executive hit her on the nose and escaped. Hitesha then shot a video with a bleeding nose and recalled entire incident and posted it on Instagram on March 9. After the post went viral, Bengaluru police then arrested the Zomato delivery executive named Kamraj and booked him for assaulting Hitesha. Zomato temporarily suspended Kamraj and paid for Hitesha's treatment and legal charges for Kamraj. Kamraj denied the allegations and revealed that it was the girl who assaulted and abused him and her nose got hurt by her own ring amidst the scuffle. After hearing Kamraj's story and seeing inconsistencies between Hitesha's accusations and her statements, people started tweeting and campaigning in support of Kamraj. Kamraj later lodged an FIR against Hitesha in Electronic city Police Station, and she was charged with wrongful restraint, assault, intentional insult, and criminal intimidation. Hitesha left Bengaluru and did not appear before Police.


title: Zomato

text: On 19 October 2021, #Reject_Zomato trended on Twitter after a Zomato chat support executive asked a customer based in Chennai, Tamil Nadu to learn Hindi, falsely claiming that it was India's national language. The founder and CEO of the company, Deepinder Goyal, posted a public apology on Twitter but also said in a later post, "The level of tolerance and chill in our country needs to be way higher than it is nowadays", which further angered Tamil netizens.


title: Filipino language

text: Filipino (; , ) is an Austronesian language. It is the national language ( / ) of the Philippines, and one of the two official languages of the country, with English. It is a standardized variety of Tagalog based on the native dialect, spoken and written, in Metro Manila, the National Capital Region, and in other urban centers of the archipelago. The 1987 Constitution mandates that Filipino be further enriched and developed by the other languages of the Philippines. Filipino is only used as a tertiary language in the Philippine public sphere.


title: Filipino language

text: Filipino, like other Austronesian languages, commonly uses verb-subject-object order, but can also use subject-verb-object order as well. Filipino follows the trigger system of morphosyntactic alignment that is also common among Austronesian languages. It has head-initial directionality. It is an agglutinative language but can also display inflection. It is not a tonal language and can be considered a pitch-accent language and a syllable-timed language. It has nine basic parts of speech.


title: Filipino language

text: The Philippines is a multilingual state with 184 living languages originating and spoken by various ethno-linguistic groups. Many of these languages descend from a common Malayo-Polynesian language due to the Austronesian migration from Taiwan; however, there are languages brought by the indigenous people of the Philippines. The common Malayo-Polynesian language split into different languages and these languages borrowed words from other languages such as Hokkien, Sanskrit, Tamil, and Arabic. There was no single common language across every cultural group in the Philippine archipelago when the Spanish arrived in the 16th century, although chroniclers of the time noted that the kings or chiefs of small polities normally spoke five languages.


title: Filipino language

text: A Spanish exploratory mission under Ferdinand Magellan arrived in the Philippines in 1521, and Spanish colonization of the islands followed. The eventual capital established by Spain in the Philippines was Manila, situated in a Tagalog-speaking region, after the conquest of Manila from both the Muslim communities of Rajah Sulayman and Rajah Matanda and the Hindu-Buddhist Kingdom of Tondo ruled by Lakan Dula. Manila was made capital of the new colony both because of fears of raids from the Portuguese and the Dutch, and because of its strategic location. The first dictionary of Tagalog, published as the , was written by the Franciscan Pedro de San Buenaventura, and published in 1613 by the "Father of Filipino Printing" Tomás Pinpin in Pila, Laguna. A latter book of the same name was written by Czech Jesuit missionary Paul Klein (known locally as Pablo Clain) at the beginning of the 18th century. Klein spoke Tagalog and used it actively in several of his books. He wrote a dictionary, which he later passed to Francisco Jansens and José Hernández. Further compilation of his substantial work was prepared by Juan de Noceda and Pedro de Sanlúcar and published as "" in Manila in 1754 and then repeatedly re-edited, with the latest edition being published in 2013 in Manila.


title: Filipino language

text: Spanish served in an official capacity as language of the government during the Spanish colonial period. During the American colonial period, English became an additional official language of the Philippines alongside Spanish; however, the number of speakers of Spanish steadily decreased.


title: Filipino language

text: While Spanish and English were considered "official languages" during the American colonial period, there existed no "national language" initially. Article XIII, section 3 of the 1935 constitution establishing the Commonwealth of the Philippines provided that:


title: Filipino language

text: On November 13, 1936, the first National Assembly of the Philippine Commonwealth approved Commonwealth Act No. 184; creating the Institute of National Language (later the Surián ng Wikang Pambansâ or SWP) and tasking it with making a study and survey of each existing native language, hoping to choose which was to be the base for a standardized national language. Later, President Manuel L. Quezon later appointed representatives for each major regional language to form the NLI. Led by Jaime C. De Veyra, who sat as the chair of the Institute and as the representative of Samar-Leyte-Visayans, the Institute's members were composed of Santiago A. Fonacier (representing the Ilokano-speaking regions), Filemon Sotto (the Cebu-Visayans), Casimiro Perfecto (the Bikolanos), Felix S. Sales Rodriguez (the Panay-Visayans), Hadji Butu (the languages of Muslim Filipinos), and Cecilio Lopez (the Tagalogs).


title: Filipino language

text: The Institute of National Language adopted a resolution on November 9, 1937 recommending Tagalog to be basis of the national language. On December 30, President Quezon issued Executive Order No. 134, s. 1937, approving the adoption of Tagalog as the language of the Philippines, and proclaimed the national language of the Philippines so based on the Tagalog language. The order stated that it would take effect two years from its promulgation. On December 31 of the same year, Quezon proclaimed Tagalog as the basis of the "Wikang Pambansâ" (National Language) giving the following factors:


title: Filipino language

text: On June 7, 1940, the Philippine National Assembly passed Commonwealth Act No. 570 declaring that the Filipino national language would be considered an official language effective July 4, 1946 (coinciding with the country's expected date of independence from the United States). That same year, the "Balarílà ng Wikang Pambansâ" () of grammarian Lope K. Santos introduced the 20-letter Abakada alphabet which became the standard of the national language. The alphabet was officially adopted by the Institute for the Tagalog-Based National Language.


title: Filipino language

text: In 1959, the language became known as "Pilipino" in an effort to disassociate it from the Tagalog ethnic group. The changing of the name did not, however, result in universal acceptance among non-Tagalogs, especially Cebuanos who had previously not accepted the 1937 selection.


title: Filipino language

text: The 1960s saw the rise of the purist movement where new words were being coined to replace loanwords. This era of "purism" by the SWP sparked criticisms by a number of persons. Two counter-movements emerged during this period of "purism": one campaigning against Tagalog and the other campaigning for more inclusiveness in the national language. In 1963, Negros Occidental congressman Innocencio V. Ferrer took a case reaching the Supreme Court questioning the constitutionality of the choice of Tagalog as the basis of the national language (a case ruled in favor of the national language in 1970). Accusing the national language as simply being Tagalog and lacking any substantial input from other Philippine languages, Congressman Geruncio Lacuesta eventually led a "Modernizing the Language Approach Movement" (MOLAM). Lacuesta hosted a number of "anti-purist" conferences and promoted a “Manila Lingua Franca” which would be more inclusive of loanwords of both foreign and local languages. Lacuesta managed to get nine congressmen to propose a bill aiming to abolish the SWP with an "Akademia ng Wikang Filipino", to replace the "balarila" with a "Gramatica ng Wikang Filipino", to replace the 20-letter Abakada with a 32-letter alphabet, and to prohibit the creation of neologisms and the respelling of loanwords. This movement quietened down following the death of Lacuesta.


title: Filipino language

text: The national language issue was revived once more during the 1971 Constitutional Convention. While there was a sizable number of delegates in favor of retaining the Tagalog-based national language, majority of the delegates who were non-Tagalogs were even in favor of scrapping the idea of a "national language" altogether. A compromise was reached and the wording on the 1973 constitution made no mention of dropping the national language Pilipino or made any mention of Tagalog. Instead, the 1973 Constitution, in both its original form and as amended in 1976, designated English and Pilipino as official languages and provided for development and formal adoption of a common national language, termed "Filipino", to replace Pilipino. Neither the original nor the amended version specified either Tagalog or Pilipino as the basis for Filipino; Instead, tasking the National Assembly to:


title: Filipino language

text: In 1987, a new constitution designated Filipino as the national language and, along with English, as an official language. That constitution included several provisions related to the Filipino language.


title: Filipino language

text: Section 17(d) of Executive Order 117 of January 30, 1987 renamed the "Institute of National Language" as "Institute of Philippine Languages". Republic Act No. 7104, approved on August 14, 1991, created the "Komisyon sa Wikang Filipino" (Commission on the Filipino Language, or KWF), superseding the Institute of Philippine Languages. The KWF reports directly to the President and was tasked to undertake, coordinate and promote researches for the development, propagation and preservation of Filipino and other Philippine languages. On May 13, 1992, the commission issued Resolution 92-1, specifying that Filipino is the


title: Filipino language

text: However, as with the 1973 and 1987 Constitutions, 92-1 went neither so far as to categorically identify, nor so far as to dis-identify this language as Tagalog. Definite, absolute, and unambiguous interpretation of 92–1 is the prerogative of the Supreme Court in the absence of directives from the KWF, otherwise the sole legal arbiter of the Filipino language.


title: Filipino language

text: Filipino was presented and registered with the International Organization for Standardization (ISO), by Ateneo de Manila University student Martin Gomez, and was added to the ISO registry of languages on September 21, 2004, with it receiving the ISO 639-2 code "fil".


title: Filipino language

text: On August 22, 2007, it was reported that three Malolos City regional trial courts in Bulacan decided to use Filipino, instead of English, in order to promote the national language. Twelve stenographers from Branches 6, 80 and 81, as model courts, had undergone training at Marcelo H. del Pilar College of Law of Bulacan State University following a directive from the Supreme Court of the Philippines. De la Rama said it was the dream of Chief Justice Reynato Puno to implement the program in other areas such as Laguna, Cavite, Quezon, Nueva Ecija, Batangas, Rizal, and Metro Manila.


title: Filipino language

text: Since 1997, a month-long celebration of the national language occurs during August, known in Filipino as "Buwan ng Wika" (Language Month). Previously, this lasted only a week and was known as "Linggo ng Wika" (Language Week). The celebration coincides with the month of birth of President Manuel L. Quezon, regarded as the "Ama ng Wikang Pambansa" (Father of the national language).


title: Filipino language

text: In 1946, Proclamation No. 35 of March 26 provided for a week-long celebration of the national language. this celebration would last from March 27 until April 2 each year, the last day coinciding with birthday of the Filipino writer Francisco Baltazar, author of the Tagalog epic "Florante at Laura".


title: Filipino language

text: In 1954, Proclamation No. 12 of March 26 provided that the week of celebration would be from March 29 to April 4 every year. This proclamation was amended the following year by President Ramon Magsaysay by Proclamation No. 186 of September 23, moving the dates of celebration to August 13–19, every year. Now coinciding with the birthday of President Manuel L. Quezon. The reason for the move being given that the original celebration was a period "outside of the school year, thereby precluding the participation of schools in its celebration".


title: Filipino language

text: In 1988, President Corazon Aquino signed Proclamation No. 19, reaffirming the celebration every August 13 to 19. In 1997, the celebration was extended from a week to a month by Proclamation 1041 of July 15 signed by President Fidel V. Ramos.


title: Filipino language

text: While the official view (shared by the government, the Komisyon ng Wikang Filipino, and a number of educators) is that Filipino and Tagalog are considered separate languages, in practical terms, "Filipino" may be considered the official name of Tagalog, or even a synonym of it. Today's Filipino language is best described as "Tagalog-based". The language is usually called "Tagalog" within the Philippines and among Filipinos to differentiate it from other Philippine languages, but it has also come to be known as "Filipino" to differentiate it from the languages of other countries; the former implies a regional origin, the latter national. This is similar to the comparison between Castilian and Spanish, or Mandarin and Chinese.


title: Filipino language

text: Political designations aside, Tagalog and Filipino are linguistically the same; sharing, among other things, the same grammatical structure. On May 23, 2007, Ricardo Maria Nolasco, KWF chair and a linguistics expert, acknowledged in a keynote speech during the NAKEM Conference at the Mariano Marcos State University in Batac, Ilocos Norte, that Filipino was simply Tagalog in syntax and grammar, with as yet no grammatical element or lexicon coming from Ilokano, Cebuano, Hiligaynon, or any of the other Philippine languages. He said further that this is contrary to the intention of Republic Act No. 7104, which requires that the national language be developed and enriched by the lexicon of the country's other languages, something toward which the commission was working. On August 24, 2007, Nolasco elaborated further on the relationship between Tagalog and Filipino in a separate article, as follows:


title: Filipino language

text: In connection with the use of Filipino, or specifically the promotion of the national language, the related term "Tagalista" is frequently used. While the word "Tagalista" literally means "one who specializes in Tagalog language or culture" or a "Tagalog specialist", in the context of the debates on the national language and "Imperial Manila", the word "Tagalista" is used as a reference to "people who promote or would promote the primacy of Tagalog at the expense of [the] other [Philippine] indigenous tongues".


title: Filipino language

text: This is a translation of Article 1 of the Universal Declaration of Human Rights. Usually, the diacritics are not written and the syntax and grammar is based from Tagalog.


title: Night at the Museum

text: Night at the Museum is a 2006 fantasy comedy film directed by Shawn Levy and written by Robert Ben Garant and Thomas Lennon. It is based on the 1993 children's book of the same name by Croatian illustrator Milan Trenc. The film had an ensemble cast of Ben Stiller in the lead role, Carla Gugino, Dick Van Dyke, Mickey Rooney, Bill Cobbs, and Robin Williams. It tells the story of a divorced father who applies for a job as a night watchman at New York City's American Museum of Natural History and subsequently discovers that the exhibits, animated by a magical Egyptian artifact, come to life at night. 20th Century Fox released the film on December 22, 2006, and it grossed $574.5 million worldwide, becoming the 5th highest-grossing film of 2006, but received mixed reviews from critics.


title: Night at the Museum

text: Two sequels were released: "" in 2009, and "" in 2014. An animated sequel, "", was released on December 9, 2022 for the streaming service Disney+.


title: Night at the Museum

text: In Brooklyn, Larry Daley is an aspiring inventor bouncing between jobs and apartments. His ex-wife Erica is sympathetic, but considers him a bad example to their ten-year-old son Nick, and Larry worries that Nick admires Erica's fiancé Don instead. Larry is hired as the night security guard at the Museum of Natural History, replacing retiring guard Cecil Fredericks and his colleagues Gus and Reginald. Cecil gives Larry an instruction manual, warning him not to "let anything in... or out".


title: Night at the Museum

text: On his first night, Larry discovers that the museum's exhibits come to life after sunset, including: "Rexy", a playful "Tyrannosaurus" skeleton; Dexter, a mischievous stuffed capuchin monkey who destroys Larry's manual, and other taxidermied animals; rival miniature civilizations depicting the Old West, Ancient Rome, and Ancient Maya; a chewing gum-loving Easter Island Moai; wax models of Attila the Hun, American Civil War soldiers, and pyromaniacal Neanderthals, as well as Sacagawea, who is encased in glass. A mounted Teddy Roosevelt rescues Larry from feuding miniature leaders Jedediah and Octavius, and explains that ever since an ancient Egyptian artifact – the Golden Tablet of Pharaoh Ahkmenrah – arrived in 1952, the exhibits come to life each night, but turn to dust if outside the museum at sunrise. As Teddy helps restore order, Larry learns that Teddy loves Sacagawea but is too shy to speak to her.


title: Night at the Museum

text: Cecil, Reginald, and Gus check on Larry, who has decided to quit, but Nick and Don stop by to congratulate him on his new job. Larry decides to stay for his son's sake, and Cecil advises reading up on history. Larry is better able to control the exhibits, but is forced to extinguish a fire in the Neanderthals' display, while Dexter steals Larry's keys and unlocks a window, allowing a Neanderthal to escape onto the street. Frustrated, Larry again decides to quit, and is unable to save the escaped Neanderthal from disintegrating in the rising sun. Nick witnesses museum director Dr. McPhee fire Larry over the damaged Neanderthal exhibit, though Larry convinces him to reconsider. Rebecca Hutman, a museum guide and historian writing her dissertation on Sacagawea, believes Larry is mocking her when he tells her the museum's nighttime secret.


title: Night at the Museum

text: Larry brings Nick to the museum but nothing comes to life, and they discover Cecil, Gus, and Reginald stealing the deactivated tablet. Like the exhibits, the elderly guards receive enhanced vitality from the tablet, and have plotted to steal it with other valuable artifacts and frame Larry. Nick reactivates the tablet, bringing the museum back to life, but Cecil takes it and locks Nick and Larry in the Egyptian room. Larry releases Ahkmenrah's mummy from his sarcophagus, and the pharaoh helps Larry and Nick escape. They find the other exhibits fighting amongst themselves, and Larry convinces them to unite to catch the guards and recover the tablet.


title: Night at the Museum

text: Gus and Reginald are captured, while Cecil escapes in a Pony Express stagecoach, and Teddy pushes Sacagawea out of Cecil's path and is sliced in half. Larry pursues Cecil into Central Park, stopping him and regaining the tablet, and Teddy finally bonds with Sacagawea as she repairs him. Rebecca sees the exhibits returning to the museum and realizes the truth, and Larry introduces her to Sacagawea. The next day, McPhee fires Larry after news reports about the night's strange events – such as the Neanderthals leaving cave paintings in the museum's subway station, and Rexy's dinosaur tracks in Central Park – but the publicity boosts museum attendance. Larry is rehired, and celebrates that night with Nick and the exhibits.


title: Night at the Museum

text: During the end credits, Cecil, Gus and Reginald are forced to work as museum janitors as punishment for their crimes.


title: Night at the Museum

text: The building featured in the film, which was constructed on a sound stage in Burnaby, British Columbia, is based on the American Museum of Natural History in New York City, external shots of which were used in the movie.


title: Night at the Museum

text: Trainers spent several weeks training Crystal, who plays the troublemaking monkey Dexter, to slap and bite Stiller in the film.


title: Night at the Museum

text: Director Shawn Levy credited Ben Stiller for the ensemble cast: "When actors hear that Ben Stiller is in a movie they want to work with him. It['s] a high-water mark and it absolutely draws actors in and I'm convinced that's a big part of why we got this cast."


title: Night at the Museum

text: Alan Silvestri replaced John Ottman as score composer. Silvestri's score was used for the teaser trailer of "Horton Hears a Who!"


title: Night at the Museum

text: "Night at the Museum" had its premiere in New York City on December 17, 2006. It was later released on December 22, 2006 in the United States, December 26, 2006 in UK, January 12, 2007 in Brazil, on February 14, 2007 in China and on March 17, 2007 in Japan.


title: Night at the Museum

text: At the end of its box office run, "Night at the Museum" earned a gross of $250.9 million in the US and Canada and $323.6 million in other territories, for a worldwide total of $574.5 million. It was the fifth highest-grossing film of 2006 and also the highest-grossing film worldwide of the trilogy.


title: Night at the Museum

text: It was the highest-grossing film in its opening weekend, grossing $30.8 million and playing in 3,685 theaters, with a $8,258 per-theater average. For the four-day Christmas holiday weekend, it took in $42.2 million. The movie was also released in IMAX large screen format, often on site at museums of science or natural history such as the Pacific Science Center in Seattle.


title: Night at the Museum

text: In its second weekend, "Night at the Museum" expanded into 83 more theaters for a total of 3,768, and took in approximately $36.7 million, out-grossing its opening weekend. It maintained the top position in its third week, with an additional $23.7 million.


title: Night at the Museum

text: During its international opening weekend of December 22, 2006, the film grossed a figure of estimated $5 million, with the highest debut coming from South Korea ($5.04 million). The biggest market in the other territories were the UK, Japan, South Korea, and Germany, where it grossed $40.8 million, $30 million, $25.7 million, $22.9 million.


title: Night at the Museum

text: On the review aggregator Rotten Tomatoes, "Night at the Museum" has an approval rating of 43% based on 138 reviews and an average rating of 5.20/10. The site's critical consensus read, "Parents might call this either a spectacle-filled adventure or a shallow and vapid CG-fest, depending on whether they choose to embrace this on the same level as their kids." , on Metacritic, the film had a score of 48 out of 100 based on 28 critics, indicating "mixed or average reviews". CinemaScore polls conducted during the opening weekend, cinema audiences gave the film an average grade of "A−" on an A+ to F scale.


title: Night at the Museum

text: Justin Chang of "Variety" magazine wrote: "This rambunctious, "Jumanji"-style extravaganza is a gallery of special effects in search of a story; rarely has so much production value yielded so little in terms of audience engagement." James Berardinelli of Reelviews gave it 2 stars out of 4, and commented on Stiller's performance by stating "It might be fair to give Ben Stiller an 'A' for effort, but to call what he does in this movie 'acting' is a misnomer. He does a lot of running around, occasionally falling down or bumping into things." One positive review by William Arnold of the "Seattle Post-Intelligencer", gave it a B−, and stated that the film was "Out to impress and delight a family audience with the pageantry of human and natural history, and that's a surprisingly worthy ambition for a Hollywood comedy."


title: Night at the Museum

text: Museum officials at the American Museum of Natural History have credited the film for increasing the number of visitors during the holiday season by almost 20%. According to a museum official, between December 22, 2006, and January 2, 2007, there were 50,000 more visitors than during the same period the prior year.


title: Night at the Museum

text: The film was released on a 2-Disc DVD edition in the United Kingdom on April 23, 2007. It was released on 1-Disc and 2-Disc DVD editions and Blu-ray Disc format on April 24, 2007 elsewhere.


title: Night at the Museum

text: The film became the first non-Disney film to be reviewed by Ultimate Disney (now known as DVDizzy.com), due to the website dealing with other studios besides Disney.


title: Night at the Museum

text: "Night at the Museum" was followed by a sequel titled "", which was released on May 22, 2009 in North America. A third film, "", was released on December 19, 2014 in North America.


title: Night at the Museum

text: In 2016, "The Hollywood Reporter" stated that the Alibaba Pictures Group intended to remake the film. On August 6, 2019, following the purchase of 21st Century Fox and its assets by The Walt Disney Company, Disney CEO Bob Iger announced that a fully animated sequel to "Night at the Museum" is in development. The project will be released as a Disney+ exclusive film, as a co-production between Walt Disney Studios Motion Pictures and 20th Century Studios. "" was released on December 9, 2022.


title: Legal status of psilocybin mushrooms

text: The legal status of unauthorised actions with psilocybin mushrooms varies worldwide. Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances. Schedule I drugs are defined as drugs with a high potential for abuse or drugs that have no recognized medical uses. However, psilocybin mushrooms have had numerous medicinal and religious uses in dozens of cultures throughout history and have a significantly lower potential for abuse than other Schedule I drugs.


title: Legal status of psilocybin mushrooms

text: Psilocybin mushrooms are not regulated by UN treaties. From a letter, dated 13 September 2001, from Herbert Schaepe, Secretary of the UN International Narcotics Control Board, to the Dutch Ministry of Health:


title: Legal status of psilocybin mushrooms

text: As you are aware, mushrooms containing the above substances are collected and used for their hallucinogenic effects. As a matter of international law, no plants (natural material) containing psilocine and psilocybin are at present controlled under the Convention on Psychotropic Substances of 1971. Consequently, "preparations made of these plants are not under international control and, therefore, not subject of the articles of the 1971 Convention" [emphasis added]. Criminal cases are decided with reference to domestic law, which may otherwise provide for controls over mushrooms containing psilocine and psilocybin. As the Board can only speak as to the contours of the international drug conventions, I am unable to provide an opinion on the litigation in question.


title: Legal status of psilocybin mushrooms

text: Many countries, however, have some level of regulation or prohibition of psilocybin mushrooms (for example, the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act).


title: Legal status of psilocybin mushrooms

text: In many national, state, and provincial drug laws, there is a great deal of ambiguity about the legal status of psilocybin mushrooms, as well as a strong element of selective enforcement in some places, since psilocybin and psilocin are deemed illegal to possess without license as substances, but mushrooms themselves are not mentioned in these laws. The legal status of "Psilocybe" spores is even more ambiguous, as the spores contain neither psilocybin nor psilocin, and hence are not illegal to sell or possess in many jurisdictions, though many jurisdictions will prosecute under broader laws prohibiting items that are used in drug manufacture. A few jurisdictions (such as the US states of California, Georgia and Idaho) have specifically prohibited the sale and possession of psilocybin mushroom spores. Cultivation of psilocybin mushrooms is considered drug manufacture in most jurisdictions and is often severely penalized, though some countries and one US state (New Mexico) has ruled that growing psilocybin mushrooms does not qualify as "manufacturing" a controlled substance. On 3 November 2020, voters passed a ballot initiative in Oregon that made "magic mushrooms" legal for mental health treatment in supervised settings from 1 February 2021. There currently is a bill pending in the California State Legislature that would legalize the "possession, obtaining, giving away, or transportation of, specified quantities of psilocybin, psilocyn, dimethyltryptamine (DMT), ibogaine, mescaline, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA)." The bill has been approved by the California State Senate with 21 votes in favor of the same. The bill is currently in committee in the California State Assembly. On October 5, 2022, the Canadian province of Alberta announced it would be among the first to regulate and allow the use of Psilocybin, LSD, MDMA, mescaline, ketamine, and DMT for medicinal purposes in drug-assisted psychotherapy. The new regulations come into effect in January 2023. In 2022, Colorado became the second US state to legalize psilocybin mushrooms.


title: The Da Vinci Code

text: The Da Vinci Code is a 2003 mystery thriller novel by Dan Brown. It is Brown's second novel to include the character Robert Langdon: the first was his 2000 novel "Angels & Demons". "The Da Vinci Code" follows symbologist Robert Langdon and cryptologist Sophie Neveu after a murder in the Louvre Museum in Paris causes them to become involved in a battle between the Priory of Sion and Opus Dei over the possibility of Jesus Christ and Mary Magdalene having had a child together.


title: The Da Vinci Code

text: The novel explores an alternative religious history, whose central plot point is that the Merovingian kings of France were descended from the bloodline of Jesus Christ and Mary Magdalene, ideas derived from Clive Prince's "The Templar Revelation" (1997) and books by Margaret Starbird. The book also refers to "The Holy Blood and the Holy Grail" (1982) though Dan Brown has stated that it was not used as research material.


title: The Da Vinci Code

text: "The Da Vinci Code" provoked a popular interest in speculation concerning the Holy Grail legend and Mary Magdalene's role in the history of Christianity. The book has, however, been extensively denounced by many Christian denominations as an attack on the Catholic Church, and consistently criticized for its historical and scientific inaccuracies. The novel nonetheless became a massive worldwide bestseller that sold 80 million copies and has been translated into 44 languages. In November 2004, Random House published a Special Illustrated Edition with 160 illustrations. In 2006, a film adaptation was released by Columbia Pictures.


title: The Da Vinci Code

text: Louvre curator and Priory of Sion grand master Jacques Saunière is fatally shot one night at the museum by an albino Catholic monk named Silas, who is working on behalf of someone he knows only as the Teacher, who wishes to discover the location of the "keystone," an item crucial in the search for the Holy Grail.


title: The Da Vinci Code

text: After Saunière's body is discovered in the pose of the "Vitruvian Man" by Leonardo da Vinci, the police summon Harvard professor Robert Langdon, who is in town on business. Police captain Bezu Fache tells him that he was summoned to help the police decode the cryptic message Saunière left during the final minutes of his life. The message includes a Fibonacci sequence out of order and an anagram 'O, draconian devil Oh, lame saint'.


title: The Da Vinci Code

text: Langdon explains to Fache that the pentacle Saunière drew on his chest in his own blood represents an allusion to the goddess and not devil worship, as Fache believes.


title: The Da Vinci Code

text: Sophie Neveu, a police cryptographer, secretly explains to Langdon that she is Saunière's estranged granddaughter and that Fache thinks Langdon is the murderer because the last line in her grandfather's message, which was meant for Neveu, said "P.S. Find Robert Langdon," which Fache had erased prior to Langdon's arrival. However, "P.S." does not refer to "postscript", but rather to Sophie "—" the nickname given to her by her grandfather was "Princess Sophie". She understands that her grandfather intended Langdon to decipher the code, which leads to Leonardo da Vinci's "Mona Lisa", which in turn leads to his painting "Madonna of the Rocks". They find a pendant that holds the address of the Paris branch of the Depository Bank of Zurich.


title: The Da Vinci Code

text: Neveu and Langdon escape from the police and visit the bank. In the safe deposit box, they find a box containing the keystone: a cryptex, a cylindrical, hand-held vault with five concentric, rotating dials labeled with letters. When these are lined up correctly, they unlock the device. If the cryptex is forced open, an enclosed vial of vinegar breaks and dissolves the message inside the cryptex, which was written on papyrus. The box containing the cryptex contains clues to its password.


title: The Da Vinci Code

text: Langdon and Neveu take the keystone to the home of Langdon's friend, Sir Leigh Teabing, an expert on the Holy Grail, the legend of which is heavily connected to the Priory. There, Teabing explains that the Grail is not a cup, but connected to Mary Magdalene, and that she was Jesus Christ's wife and is the person to his right in "The Last Supper".


title: The Da Vinci Code

text: The trio then flee the country on Teabing's private plane, on which they conclude that the proper combination of letters spells out Neveu's given name, Sofia. Opening the cryptex, they discover a smaller cryptex inside it, along with another riddle that ultimately leads the group to the tomb of Isaac Newton in Westminster Abbey.


title: The Da Vinci Code

text: During the flight to Britain, Neveu reveals the source of her estrangement from her grandfather ten years earlier: arriving home unexpectedly from university, Neveu secretly witnessed a spring fertility rite conducted in the secret basement of her grandfather's country estate. From her hiding place, she was shocked to see her grandfather with a woman at the center of a ritual attended by men and women who were wearing masks and chanting praise to the goddess. She fled the house and broke off all contact with Saunière. Langdon explains that what she witnessed was an ancient ceremony known as "hieros gamos" or "sacred marriage."


title: The Da Vinci Code

text: By the time they arrive at Westminster Abbey, Teabing is revealed to be the Teacher for whom Silas is working. Teabing wishes to use the Holy Grail, which he believes is a series of documents establishing that Jesus Christ married Mary Magdalene and fathered children, in order to ruin the Vatican. He compels Langdon at gunpoint to solve the second cryptex's password, which Langdon realizes is "apple." Langdon secretly opens the cryptex and removes its contents before tossing the empty cryptex in the air.


title: The Da Vinci Code

text: Teabing is arrested by Fache, who by now realizes that Langdon is innocent. Bishop Aringarosa, head of religious sect Opus Dei and Silas' mentor, realizing that Silas has been used to murder innocent people, rushes to help the police find him. When the police find Silas hiding in an Opus Dei Center, Silas assumes that they are there to kill him and he rushes out, accidentally shooting Bishop Aringarosa. Bishop Aringarosa survives but is informed that Silas was found dead later from a gunshot wound.


title: The Da Vinci Code

text: The final message inside the second keystone leads Neveu and Langdon to Rosslyn Chapel, whose docent turns out to be Neveu's long-lost brother, who Neveu had been told died as a child in the car accident that killed her parents. The guardian of Rosslyn Chapel, Marie Chauvel Saint Clair, is Neveu's long-lost grandmother. It is revealed that Neveu and her brother are descendants of Mary Magdalene. The Priory of Sion hid her identity to protect her from possible threats to her life.


title: The Da Vinci Code

text: The real meaning of the last message is that the Grail is buried beneath the small pyramid directly below the "La Pyramide Inversée", the inverted glass pyramid of the Louvre. It also lies beneath the "Rose Line," an allusion to "Rosslyn." Langdon figures out this final piece to the puzzle; he follows the Rose Line (prime meridian) to "La Pyramide Inversée", where he kneels to pray before the hidden sarcophagus of Mary Magdalene, as the Templar knights did before.


title: The Da Vinci Code

text: "The Da Vinci Code" was a major success in 2003 and was outsold only by J. K. Rowling's "Harry Potter and the Order of the Phoenix".


title: The Da Vinci Code

text: The book generated criticism when it was first published for the inaccurate description of core aspects of Christianity and descriptions of European art, history, and architecture. The book has received mostly negative reviews from Catholic and other Christian communities.


title: The Da Vinci Code

text: Many critics took issue with the level of research Brown did when writing the story. "The New York Times" writer Laura Miller characterized the novel as "based on a notorious hoax", "rank nonsense", and "bogus", saying the book is heavily based on the fabrications of Pierre Plantard, who is asserted to have created the Priory of Sion in 1956.


title: The Da Vinci Code

text: The book opens with the claim by Dan Brown that "The Priory of Sion—a French secret society founded in 1099—is a real organization". This assertion is broadly disputed; the Priory of Sion is generally regarded as a hoax created in 1956 by Pierre Plantard. The author also claims that "all descriptions of artwork, architecture, documents… and secret rituals in this novel are accurate", but this claim is disputed by numerous academic scholars and experts in numerous areas.


title: The Da Vinci Code

text: Dan Brown himself addresses the idea of some of the more controversial aspects being fact on his website, stating that the "FACT" page at the beginning of the novel mentions only "documents, rituals, organization, artwork and architecture", but not any of the ancient theories discussed by fictional characters, stating that "Interpreting those ideas is left to the reader". Brown also says, "It is my belief that some of the theories discussed by these characters may have merit" and "the secret behind "The Da Vinci Code" was too well documented and significant for me to dismiss."


title: The Da Vinci Code

text: In 2003, while promoting the novel, Brown was asked in interviews what parts of the history in his novel actually happened. He replied "Absolutely all of it." In a 2003 interview with CNN's Martin Savidge he was again asked how much of the historical background was true. He replied, "99% is true… the background is all true".


title: The Da Vinci Code

text: Asked by Elizabeth Vargas in an ABC News special if the book would have been different if he had written it as non-fiction he replied, "I don't think it would have."


title: The Da Vinci Code

text: In 2005, UK TV personality Tony Robinson edited and narrated a detailed rebuttal of the main arguments of Dan Brown and those of Michael Baigent, Richard Leigh and Henry Lincoln, who authored the book "Holy Blood, Holy Grail", in the program "The Real Da Vinci Code", shown on British TV Channel 4. The program featured lengthy interviews with many of the main protagonists cited by Brown as "absolute fact" in "The Da Vinci Code".


title: The Da Vinci Code

text: Arnaud de Sède, son of Gérard de Sède, stated categorically that his father and Plantard had made up the existence of the Prieuré de Sion, the cornerstone of the Jesus bloodline theory: "frankly, it was piffle", noting that the concept of a descendant of Jesus was also an element of the 1999 Kevin Smith film "Dogma".


title: The Da Vinci Code

text: The earliest appearance of this theory is due to the 13th-century Cistercian monk and chronicler Peter of Vaux de Cernay who reported that Cathars believed that the 'evil' and 'earthly' Jesus Christ had a relationship with Mary Magdalene, described as his concubine (and that the 'good Christ' was incorporeal and existed spiritually in the body of Paul). The program "The Real Da Vinci Code" also cast doubt on the Rosslyn Chapel association with the Grail and on other related stories, such as the alleged landing of Mary Magdalene in France.


title: The Da Vinci Code

text: According to "The Da Vinci Code", the Roman Emperor Constantine I suppressed Gnosticism because it portrayed Jesus as purely human. The novel's argument is as follows: Constantine wanted Christianity to act as a unifying religion for the Roman Empire. He thought Christianity would appeal to pagans only if it featured a demigod similar to pagan heroes. According to the Gnostic Gospels, Jesus was merely a human prophet, not a demigod. Therefore, to change Jesus' image, Constantine destroyed the Gnostic Gospels and promoted the gospels of Matthew, Mark, Luke, and John, which portray Jesus as divine or semi-divine.


title: The Da Vinci Code

text: But Gnosticism did not portray Jesus as merely human. All Gnostic writings depict Christ as purely divine, his human body being a mere illusion (see Docetism). Gnostic sects saw Christ this way because they regarded matter as evil, and therefore believed that a divine spirit would never have taken on a material body.


title: The Da Vinci Code

text: The book received both positive and negative reviews from critics, and it has been the subject of negative appraisals concerning its portrayal of history. Its writing and historical accuracy were reviewed negatively by "The New Yorker", Salon.com, and "Maclean's".


title: The Da Vinci Code

text: Janet Maslin of "The New York Times" said that one word "concisely conveys the kind of extreme enthusiasm with which this riddle-filled, code-breaking, exhilaratingly brainy thriller can be recommended. That word is wow. The author is Dan Brown (a name you will want to remember). In this gleefully erudite suspense novel, Mr. Brown takes the format he has been developing through three earlier novels and fine-tunes it to blockbuster perfection."


title: The Da Vinci Code

text: David Lazarus of "The San Francisco Chronicle" said, "This story has so many twists—all satisfying, most unexpected—that it would be a sin to reveal too much of the plot in advance. Let's just say that if this novel doesn't get your pulse racing, you need to check your meds."


title: The Da Vinci Code

text: While interviewing Umberto Eco in a 2008 issue of "The Paris Review", Lila Azam Zanganeh characterized "The Da Vinci Code" as "a bizarre little offshoot" of Eco's novel, "Foucault's Pendulum". In response, Eco remarked, "Dan Brown is a character from "Foucault's Pendulum!" I invented him. He shares my characters' fascinations—the world conspiracy of Rosicrucians, Masons, and Jesuits. The role of the Knights Templar. The hermetic secret. The principle that everything is connected. I suspect Dan Brown might not even exist."


title: The Da Vinci Code

text: The book appeared at number 43 on a 2010 list of 101 best books ever written, which was derived from a survey of more than 15,000 Australian readers.


title: The Da Vinci Code

text: Salman Rushdie said during a lecture, "Do not start me on "The Da Vinci Code". A novel so bad that it gives bad novels a bad name."


title: The Da Vinci Code

text: Stephen Fry has referred to Brown's writings as "complete loose stool-water" and "arse gravy of the worst kind". In a live chat on June 14, 2006, he clarified, "I just loathe all those book[s] about the Holy Grail and Masons and Catholic conspiracies and all that botty-dribble. I mean, there's so much more that's interesting and exciting in art and in history. It plays to the worst and laziest in humanity, the desire to think the worst of the past and the desire to feel superior to it in some fatuous way."


title: The Da Vinci Code

text: Stephen King likened Dan Brown's work to "Jokes for the John", calling such literature the "intellectual equivalent of Kraft Macaroni and Cheese". "The New York Times", while reviewing the movie based on the book, called the book "Dan Brown's best-selling primer on how not to write an English sentence". "The New Yorker" reviewer Anthony Lane refers to it as "unmitigated junk" and decries "the crumbling coarseness of the style". Linguist Geoffrey Pullum and others posted several entries critical of Dan Brown's writing, at Language Log, calling Brown one of the "worst prose stylists in the history of literature" and saying Brown's "writing is not just bad; it is staggeringly, clumsily, thoughtlessly, almost ingeniously bad". Roger Ebert described it as a "potboiler written with little grace and style", although he said it did "supply an intriguing plot". In his review of the film "National Treasure", whose plot also involves ancient conspiracies and treasure hunts, he wrote: "I should read a potboiler like "The Da Vinci Code" every once in a while, just to remind myself that life is too short to read books like "The Da Vinci Code"."