IFNL4
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IFNL4
Interferon lambda 4 (gene symbol: ''IFNL4'') is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection. ''IFNL4'' is similar to three neighboring genes ''(IFNL1, IFNL2'' and ''IFNL3'') in that proteins encoded by these genes bind to a shared co-receptor complex. Formation of this complex leads to activation of the JAK-STAT signalling pathway and upregulation of numerous interferon-stimulated genes. Genetics variants within or near this gene have been linked to clearance of hepatitis C virus (HCV) infection and other phenotypes. Discovery The first three interferon lambda genes were discovered in 2003 by two independent research groups that used different nomenclatures in their reports. In 2013, Prokunina-Olsson et al. reported the presence of a fourth gene in this region, which they discovered after treating human hepatocyt ...
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Interferon Type III
The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3 (also known as IL29, IL28A and IL28B respectively), and IFN-λ4. They were discovered in 2003. Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium. Genomic location Genes encoding this group of interferons are all located on the long arm of chromosome 19 in human, specifically in region between 19q13.12 and 19q13.13. The ''IFNL1'' gene, encoding IL-29, is located downstream of ''IFNL2'', encoding IL-28A. ''IFNL3'', encoding IL28B, is located downstream of IFNL4. In mice, the genes encoding for type III interferons are located on chromosome 7 and the family consists only of IFN-λ2 and IFN-λ3. Structure Interferons All interferon groups belong to class II cytokine family which have a conserved structure that comprises six α-hel ...
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Evolutionary Pressure
Evolutionary pressure, selective pressure or selection pressure is exerted by factors that reduce or increase reproductive success in a portion of a population, driving natural selection. It is a quantitative description of the amount of change occurring in processes investigated by evolutionary biology, but the formal concept is often extended to other areas of research. In population genetics, selective pressure is usually expressed as a selection coefficient. Amino acids selective pressure It has been shown that putting an amino acid bio-synthesizing gene like ''HIS4'' gene under amino acid selective pressure in yeast causes enhancement of expression of adjacent genes which is due to the transcriptional co-regulation of two adjacent genes in Eukaryota. Antibiotic resistance Drug resistance in bacteria is an example of an outcome of natural selection. When a drug is used on a species of bacteria, those that cannot resist die and do not produce offspring, while those that ...
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Ombitasvir
Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection by AbbVie. In the United States, it is approved by the Food and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1, and with paritaprevir and ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ... in the product Technivie for the treatment of HCV genotype 4. Ombitasvir is an NS5A inhibitor that acts by inhibiting the HCV protein NS5A. See also * Discovery and development of NS5A inhibitors References Further reading * * Carbamates NS5A inhibitors Pyrrolidines {{Antiinfective-drug-stub ...
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Ledipasvir
Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination tablet for genotype 1 hepatitis C. The ledipasvir/sofosbuvir combination is a direct-acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotypes 1a or 1b without PEG-interferon or ribavirin. Ledipasvir is an inhibitor of NS5A, a hepatitis C virus protein. Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of the nucleotide analog inhibitor sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1. The sofosbuvir/ledipasvir coformulation is being tested with and without rib ...
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Daclatasvir
Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and Interferon#Drug formulations, interferon, vary depending on the virus type and whether the person has cirrhosis. It is taken by mouth. Common side effects when used with sofusbivir and daclatasvir include headache, fatigue (medicine), feeling tired, and nausea. With daclatasvir, sofosbuvir, and ribavirin the most common side effects are headache, feeling tired, nausea, and hemolytic anemia, red blood cell breakdown. It should not be used with St. John's wort, rifampin, or carbamazepine. It works by inhibiting the HCV protein NS5A. Daclatasvir was approved for use in the European Union in 2014, and the United States and India in 2015. It is on the WHO Model List of Essential Medicines, World Health Organization's List of Essential Medicines. The brand Dakli ...
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Tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is from the Greek ''tyrós'', meaning ''cheese'', as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA. The one-letter symbol Y was assigned to tyrosine for being alphabetically nearest of those letters available. Note that T was assigned to the structurally simpler threonine, U was avoided for its similarity with V for valine, W was assigned to tryptophan, while X was reserved for undetermined or atypical amino acids. The mnemonic t''Y''rosine was ...
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Histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic acid group (which is in the deprotonated –COO− form under biological conditions), and an imidazole side chain (which is partially protonated), classifying it as a positively charged amino acid at physiological pH. Initially thought essential amino acid, essential only for infants, it has now been shown in longer-term studies to be essential for adults also. It is Genetic code, encoded by the Genetic code, codons CAU and CAC. Histidine was first isolated by Albrecht Kossel and Sven Gustaf Hedin in 1896. The name stems from its discovery in tissue, from ''histós'' "tissue". It is also a Precursor (chemistry), precursor to histamine, a vital inflammatory agent in immune responses. The acyl radical (chemistry), radical is histidyl. Pro ...
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NS5A
Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without ''trans''-membrane helices. Structure NS5A is derived from a large polyprotein that is translated from the HCV genome, and undergoes post-translation processing by nonstructural protein 3 (NS3) viral protease. Despite no inherent enzymatic activity being attributed to NS5A, its function is mediated through interaction with other nonstructural (NS) viral and cellular proteins. NS5A has two phosphorylated forms: p56 and p58, which differ in the electrophoretic mobility. p56 is basally phosphorylated by host cellular protein kinase at the center and near the C terminus, whereas p58 is a form of hyper-phosphorylated NS5A at the center of the serine-rich region. Protein mass spectrometry identified several phosphorylated serine residues in this region including serine 225, 229, 232, and 235 re ...
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Odds Ratio
An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of event A taking place in the presence of B, and the odds of A in the absence of B. Due to symmetry, odds ratio reciprocally calculates the ratio of the odds of B occurring in the presence of A, and the odds of B in the absence of A. Two events are independent if and only if the OR equals 1, i.e., the odds of one event are the same in either the presence or absence of the other event. If the OR is greater than 1, then A and B are associated (correlated) in the sense that, compared to the absence of B, the presence of B raises the odds of A, and symmetrically the presence of A raises the odds of B. Conversely, if the OR is less than 1, then A and B are negatively correlated, and the presence of one event reduces the odds of the other event occurring. Note that the odds ratio is symmetric in the two events, and no causa ...
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Food And Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, caffeine products, dietary supplements, Prescription drug, prescription and Over-the-counter drug, over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), cosmetics, Animal feed, animal foods & feed and Veterinary medicine, veterinary products. The FDA's primary focus is enforcement of the Federal Food, Drug, and Cosmetic Act (FD&C). However, the agency also enforces other laws, notably Section 361 of the Public Health Service Act as well as associated regulations. Much of this regulatory-enforcement work is ...
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Interferon Type I
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα (''IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17'' and ''IFNA21''), IFNω (''IFNW1''), IFNɛ (''IFNE''), IFNк (''IFNK'') and IFNβ (''IFNB1''), plus 11 IFN pseudogenes. Interferons bind to interferon receptors. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor ( IFNAR) that consists of IFNAR1 and IFNAR2 chains. Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species. Sources and functions IFN-α and IFN-β are secreted by many cell types including lymphocytes ( NK cells, B-cells and T-cells), macropha ...
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PEGylation
PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated. PEGylation affects the resulting derivatives or aggregates interactions, which typically slows down their coalescence and degradation as well as elimination in vivo. PEGylation is routinely achieved by the incubation of a reactive derivative of PEG with the target molecule. The covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system (reducing immunogenicity and antigenicity), and increase its hydrodynamic size (size in solution), which prolongs its circulatory time by reducing renal clearance. PEGylation can also provide water solubility to hydrophobic drugs and proteins. Having proven its pharmacological advantages and acceptability, ...
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