Aib substitution comes up often in conversation and rarely with the context attached. Here we lay out the basics in order, then work through the practical considerations.
Updated 2026-04-07. Numbers and descriptions here follow the published literature rather than marketing material.
The company that developed the compound filed it as a long-acting analogue, and it gained first approval in 2017 for type 2 diabetes. Later authorisations from several regulators extended the indication to chronic weight management, and the World Health Organization added the glucagon-like peptide-1 receptor agonist drug class to its model list of essential medicines in 2023. Production uses solid-phase peptide synthesis followed by side-chain conjugation and chromatographic purification. Supply constraints and cost differences across regions are well documented. Literature on long-term outcomes continues to grow, with many trials reporting surrogate endpoints rather than hard clinical endpoints.
Semaglutide is a synthetic peptide of thirty-one amino acids that shares roughly ninety-four percent sequence identity with human glucagon-like peptide-1. Two substitutions resist enzymatic cleavage by dipeptidyl peptidase-4, and a fatty diacid side chain attached through a linker promotes binding to serum albumin. That albumin binding slows renal clearance and extends the circulating half-life from minutes to approximately one week. The structural changes are well established in the published literature. Whether the same modifications affect receptor signalling bias in ways that matter clinically remains an open question.
该分子作为 GLP-1 受体的选择性激动剂发挥作用，受体属于 B 类 G 蛋白偶联受体家族，激活后经 Gs 通路提升细胞内环腺苷酸水平。在胰腺 β 细胞，信号促进葡萄糖依赖性的胰岛素释放，血糖偏低时该作用明显减弱。在胰岛 α 细胞，胰高血糖素分泌受到抑制。中枢神经系统与胃肠道同样存在受体表达，相应信号参与食欲调节以及胃排空速率的降低。
皮下注射后吸收相对缓慢，绝对生物利用度约为百分之八十九，血药浓度峰值通常出现在给药后一到三天。与白蛋白结合使清除减慢，终末半衰期约为一百六十五小时，接近一周。连续给药约四到五周后达到稳态暴露水平。表观分布容积约为每千克零点二五升，血浆蛋白结合率超过百分之九十九。代谢以蛋白水解切割和脂肪二酸侧链的 β-氧化为主，相关产物主要经尿液与粪便排出。
序列层面的改动同时解决了两个问题，即酶解稳定性与肾脏清除速度。天然 GLP-1 在循环中的半衰期仅约两分钟，主要被二肽基肽酶-4 迅速灭活。酰化侧链与白蛋白的可逆结合形成循环储库，使分子缓慢释放并持续激活受体。这种设计思路后来被广泛用于同类长效肽的开发，属于该类药物化学改造的典型范式。
| Property | Value | Notes |
|---|---|---|
| Molecular class | 31-amino-acid peptide | Modified glucagon-like peptide-1 analogue |
| Molecular mass | approximately 4114 Da | Calculated for the free peptide backbone |
| Appearance | white to off-white powder | Typical of purified lyophilised peptide batches |
| Solubility class | freely soluble in water | Aqueous solubility improves at slightly alkaline pH |
| Typical storage | -20 degrees Celsius, dry, dark | Protect from repeated freeze-thaw cycles |
Large randomised trials in adults with type 2 diabetes and in adults with obesity have reported reductions in body weight and improvements in several cardiovascular risk markers. One outcome trial found a lower incidence of major adverse cardiovascular events in participants with diabetes and established cardiovascular disease. Gastrointestinal effects such as nausea and vomiting are the most frequently reported adverse events and often diminish over time. Changes in lean body mass during weight loss are an area of ongoing investigation. Effects in adolescents and in pregnancy are less well characterised, and current labelling advises against use during pregnancy.
Semaglutide is a synthetic peptide analogue of glucagon-like peptide-1, a gut hormone released after nutrient intake. The molecule contains 31 amino acid residues and differs from the native sequence at several positions. A non-natural residue at position eight resists the enzyme that normally truncates the hormone, while a lysine-linked fatty diacid side chain promotes binding to serum albumin. These two modifications extend the circulating half-life from minutes to roughly one week. The peptide is produced by solid-phase synthesis followed by selective acylation, and its identity and purity are confirmed by spectrometric and chromatographic techniques.
The primary target is the GLP-1 receptor, a class B G protein-coupled receptor expressed on pancreatic beta cells, in the gut, and in several brain regions. Receptor activation raises intracellular cyclic AMP, which potentiates glucose-dependent insulin secretion and lowers glucagon release when blood glucose is elevated. Signalling in the hypothalamus and brainstem is associated with reduced appetite and slower gastric emptying. Because the insulinotropic effect depends on prevailing glucose levels, the hypoglycaemic risk of the peptide alone is described as low in most study settings. The relative contribution of peripheral and central actions remains an active research question.
Activation of the GLP-1 receptor couples to Gs signalling and raises intracellular cyclic AMP in pancreatic beta cells. The resulting insulin release depends on prevailing glucose concentrations, so the effect is greater when glucose is elevated. Receptor engagement also suppresses glucagon secretion and slows gastric emptying, which flattens post-meal glucose excursions. In the central nervous system, signalling in hypothalamic and brainstem regions is associated with reduced appetite and lower energy intake. Studies continue to examine effects on cardiac, renal and hepatic endpoints; whether those benefits are independent of weight change remains an open question.
Clinical development of this compound followed earlier short-acting GLP-1 analogues that required frequent injection. Once-weekly subcutaneous formulations entered use after 2017, and an oral formulation using a permeation enhancer later became available. The oral version pairs the peptide with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, a carrier that improves uptake across the gastric epithelium. Interest has expanded from glycaemic control into weight management and metabolic liver disease. Regulatory status and approved indications differ between countries, and the product remains subject to ongoing safety monitoring.
Semaglutide is a synthetic peptide that acts as an agonist at the glucagon-like peptide-1 receptor. It is a structural analogue of human GLP-1(7-37), modified to resist enzymatic degradation by dipeptidyl peptidase-4. The peptide backbone contains alpha-aminoisobutyric acid at position 8, a substitution that stabilises the helix and slows cleavage. A fatty diacid side chain attached through a linker at lysine 34 promotes binding to serum albumin, which extends the circulating half-life. These two modifications together allow less frequent administration than native GLP-1 requires.
Semaglutide is a synthetic peptide analog of glucagon-like peptide-1, a hormone released from intestinal L cells after food intake. The molecule is a 31-amino-acid backbone modified at three positions to resist cleavage by dipeptidyl peptidase-4, the enzyme that degrades native GLP-1 within minutes. A lysine residue at position 26 carries a linker and a C18 fatty diacid, which promotes binding to serum albumin and slows renal clearance. These changes extend the circulating half-life from roughly two minutes to about one week in humans.
The sequence incorporates alpha-aminoisobutyric acid at position 8, replacing the alanine found in the natural hormone. This substitution blocks the primary DPP-4 recognition site and contributes most of the enzymatic stability. Albumin binding further protects the peptide and reduces the frequency of administration required to maintain active plasma levels. Because the fatty acid chain increases lipophilicity, the compound is formulated as a solution rather than a simple aqueous buffer. Researchers describe the design as an incremental optimization of earlier GLP-1 analogs rather than a wholly new scaffold.
== Puberty onset == Puberty is preceded by adrenarche, marking an increase of adrenal androgen production between ages 6–10. Adrenarche is sometimes accompanied by the early appearance of axillary and pubic hair. The first androgenic hair resulting from adrenarche can be also transient and disappear before the onset of true puberty. The onset of puberty is associated with high GnRH pulsing, which precedes the rise in sex hormones, LH and FSH. Exogenous GnRH pulses cause the onset of puberty. Brain tumors which increase GnRH output may also lead to premature puberty. The cause of the GnRH rise is unknown. Leptin might be the cause of the GnRH rise. Leptin has receptors in the hypothalamus which synthesizes GnRH. Individuals who are deficient in leptin fail to initiate puberty. The levels of leptin increase with the onset of puberty, and then decline to adult levels when puberty is completed. The rise in GnRH might also be caused by genetics. A study discovered that a mutation in genes encoding both neurokinin B as well as the neurokinin B receptor can alter the timing of puberty. The researchers hypothesized that neurokinin B might play a role in regulating the secretion of kisspeptin, a compound responsible for triggering direct release of GnRH as well as indirect release of LH and FSH.
Initially directed only against Russia, in the 1930s, the Kokuryūkai expanded its activities around the world, and stationed agents in such diverse places as Ethiopia, Turkey, Morocco, throughout Southeast Asia and South America, as well as Europe and the United States.
Surface charge practically always appears on the particle surface when it is placed into a fluid. Most fluids contain ions, positive (cations) and negative (anions). These ions interact with the object surface. This interaction might lead to the adsorption of some of them onto the surface. If the number of adsorbed cations exceeds the number of adsorbed anions, the surface would have a net positive electric charge. Dissociation of the surface chemical group is another possible mechanism leading to surface charge.
==== Hypopharyngeal or base of tongue obstruction ==== Base-of-tongue advancement by means of advancing the genial tubercle of the mandible, tongue suspension, or hyoid suspension (aka hyoid myotomy and suspension or hyoid advancement) may help with the lower pharynx. Other surgery options may attempt to shrink or stiffen excess tissue in the mouth or throat, procedures done at either a doctor's office or a hospital. Small shots or other treatments, sometimes in a series, are used for shrinkage, while the insertion of a small piece of stiff plastic is used in the case of surgery whose goal is to stiffen tissues.
Pediatric (also paediatric or pædiatric) dentists promote the dental health of children as well as serve as educational resources for parents. It is recommended by the American Academy of Pediatric Dentistry (AAPD) and the American Academy of Pediatrics (AAP) that a dental visit occurs after the presence of the first tooth or by a child's first birthday. The AAPD has said that it is important to establish a comprehensive and accessible ongoing relationship between the dentist and patient – referring to this as the patient's "dental home". This is because early oral examination aids in the detection of the early stages of tooth decay. Early detection is essential to maintain oral health, modify aberrant habits, and treat as needed and as simply as possible. Additionally, parents are given a program of preventive home care (brushing, flossing and fluorides), a caries risk assessment, information on finger, thumb, and pacifier habits, and may include advice on preventing injuries to the mouth and teeth of children, diet counseling, and information on growth and development.
Sources: en.wikipedia.org
After details of past social media posts made by two Reform UK candidates, Lee Bunker and Angela Begbie-Carter, are reported in the media, the party releases a statement in which it says candidates are free to express views that "are not shared by all their party colleagues" as they are not "political zombies". Secret government files seen by BBC News show work has been underway with consultants since January to limit "severe implications" to essential IT services by lining up alternative providers after Atos, the UK subsidiary of which has contracts for NHS records and disability benefit claims, is more than £3bn in debt and undergoing restructuring. Sinn Féin launches its 2024 election manifesto, which includes plans for the transfer of fiscal powers from Westminster to Stormont and the creation of an all-Ireland national health service. Businessman Zia Yusuf donates an undisclosed amount of money, but reported to be several thousand pounds, to Reform UK, saying the UK has "lost control of our borders". The Workers Party of Britain launches its election manifesto, with promises to improve "poverty pay" and provide more social housing. BBC News reports that Laura Saunders, the Conservative candidate for Bristol North West, has become the second Conservative candidate to face an investigation by the Gambling Commission over betting on the date of the general election. It is subsequently reported that her husband, Tony Lee, the Conservative Party's campaigns director, is also being investigated by the Commission.
As noted by Carl Johnson in Ambio, "Exposures of a large population in the Denver area to plutonium and other radionuclides in the exhaust plumes from the plant date back to 1953." Weapons production at the Rocky Flats plant was halted after a combined FBI and EPA raid in 1989 and years of protests. The plant has since been shut down, with its buildings demolished and completely removed from the site. In the U.S., some plutonium extracted from dismantled nuclear weapons is melted to form glass logs of plutonium oxide that weigh two tonnes. The glass is made of borosilicates mixed with cadmium and gadolinium. These logs are planned to be encased in stainless steel and stored as much as 4 km (2 mi) underground in bore holes that will be backfilled with concrete. The U.S. planned to store plutonium in this way at the Yucca Mountain nuclear waste repository, which is about 100 miles (160 km) north-east of Las Vegas, Nevada. On March 5, 2009, Energy Secretary Steven Chu told a Senate hearing "the Yucca Mountain site no longer was viewed as an option for storing reactor waste". Starting in 1999, military-generated nuclear waste is being entombed at the Waste Isolation Pilot Plant in New Mexico. In a Presidential Memorandum dated January 29, 2010, President Obama established the Blue Ribbon Commission on America's Nuclear Future. In their final report the Commission put forth recommendations for developing a comprehensive strategy to pursue, including:
The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13). G protein-coupled receptors are an important drug target and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research.
=== Leadership under Gilbert F. Amelio === On May 27, 1991, Charles E. Sporck was replaced by Gil Amelio as CEO and president. Amelio was then president of Rockwell International's semiconductor division and had a Ph.D. in physics from Georgia Institute of Technology. Amelio had also been formerly employed at Fairchild. Amelio was faced with a company plagued with over-capacity and shrinking market share. Amelio found that, just prior to his taking helm, despite having spent US$1 billion over the last five years on research and development, National Semiconductor had a disappointing record in new products. The Business section of The New York Times January 11, 1991, reflected the over-capacity generated by Sporck that had to be inherited by Amelio. Amelio disposed of the non-core products and assets in which National Semiconductor had no market motivation or expertise and turned the company towards its core expertise—analog semiconductors. National Semiconductor under Amelio emphasized on reduction of cost of sales, improving capacity utilization, scrap reduction and cycle-time reduction. Redundant facilities were sold and consolidated. With the progress of restructuring, National Semiconductor increased revenues each year. In 1994, National Semiconductor under Amelio posted record net revenues of US$2.29 billion. It was also a time when US semiconductor companies had regained market leadership.
=== Acute === Acute poisoning is exposure to a poison on one occasion or during a short period of time. Symptoms develop in close relation to the exposure. Absorption of a poison is necessary for systemic poisoning. Furthermore, many common household medications are not labeled with skull and crossbones, although they can cause severe illness or even death. Poisoning can be caused by excessive consumption of generally safe substances, as in the case of water intoxication. Agents that act on the nervous system can paralyze in seconds or less, and include both biologically derived neurotoxins and so-called nerve gases, which may be synthesized for warfare or industry. Inhaled or ingested cyanide, used as a method of execution in gas chambers, or as a suicide method, almost instantly starves the body of energy by inhibiting the enzymes in mitochondria that make ATP. Intravenous injection of an unnaturally high concentration of potassium chloride, such as in the execution of prisoners in parts of the United States, quickly stops the heart by eliminating the cell potential necessary for muscle contraction. Most biocides, including pesticides, are created to act as acute poisons to target organisms, although acute or less observable chronic poisoning can also occur in non-target organisms (secondary poisoning), including the humans who apply the biocides and other beneficial organisms. For example, the herbicide 2,4-D imitates the action of a plant hormone, which makes its lethal toxicity specific to plants. Indeed, 2,4-D is not a poison, but classified as "harmful" (EU).
Sources: en.wikipedia.org
=== Performing arts and cinema === Moscow is the heart of Russian performing arts, including ballet and cinema: 68 museums, 103 theaters, 132 cinemas, and 24 concert halls. Among Moscow's theaters and ballet studios are the Bolshoi Theatre, the Malyi Theatre, the Vakhtangov Theatre, and the Moscow Art Theatre. The Moscow International Performance Arts Center, opened in 2003—also called the Moscow International House of Music—is known for classical music performances. This center contains Russia's largest organ, which is installed in Svetlanov Hall. In addition, Moscow contains two large circuses: the Moscow State Circus and the Moscow Circus on Tsvetnoy Boulevard (also called Nikulin's Circus, after Yuri Nikulin). The Mosfilm studio was at the heart of many classic films, as it has been responsible for both artistic and mainstream productions. However, despite the ongoing participation and reputation of internationally known Russian filmmakers, previously prolific domestic studios have become less active. The Salut cinema screens rare and historical films, and films from the Museum of Cinema are regularly shown. International film festivals are held in Moscow, including the Moscow International Film Festival, Stalker (focusing on human rights), Artdocfest (focusing on documentaries), and the Moscow Jewish Film Festival.
== Animal models == Knockout mice of GPX4 die at embryonic day 8 and conditional inducible deletion in adult mice (neurons) results in degeneration and death in less than a month. Targeted disruption of the mitochondrial GPX4 isoform (mGPX4) caused infertility in male mice and disruption of the nuclear GPX4 isoform (nGPX4) reduced the structural stability of sperm chromatin, yet both knockout mouse models (for mGPX4 and nGPX4) were fully viable. Surprisingly, knockout of GPX4 heterozygously in mice (GPX4+/−) increases their median life span. Knockout studies with GPX1, GPX2, or GPX3 deficient mice showed that cytosolic GPX4 is so far the only glutathione peroxidase that is indispensable for embryonic development and cell survival. As mechanisms to dispose of both hydrogen peroxide and lipid hydroperoxides are essential to life, this indicates that in contrast to the multiple metabolic pathways that can be utilized to dispose of hydrogen peroxide, pathways for the disposal of lipid hydroperoxides are limited. While mammals have only one copy of the GPX4 gene, fish have two copies, GPX4a and GPX4b. The GPX4's appear to play a greater role in the fish GPX system than in mammals. For example, in fish GPX4 activity contributes to a greater extent to total GPX activity, GPX4a is the most highly expressed selenoprotein mRNA (in contrast to mammals where it is GPX1 mRNA) and GPX4a appears to be highly inducible to changes within the cellular environment, such as changes in methylmercury and selenium status.
Autotransporter proteins are outer membrane or secreted proteins found in a broad variety of Gram-negative bacteria. These proteins contain three structural motifs: a signal sequence, a passenger domain located at the N-terminal, and a translocator or autotransporter domain located at the C-terminal, forming a beta barrel structure. These structures promote the protein self-transport. Autotransporter proteins are usually related to virulence functions. This fact, their interaction with host cells and the broad occurrence of autotransporter encoding genes, bring up the possibility to represent therapeutic targets for the design of vaccines against Gram-negative pathogens. Two of the families in which the MEROPS database classifies asparagine peptide lyases are autotransporter proteins, families N4 and N6. Family N4 includes secreted virulence factors, or autotransporters, from enterobacteria. Their only proteolytic activity is releasing the virulence factor from the precursor, enabling it to be secreted. The active site residues in family N4 asparagine peptide lyases are N1100, Y1227, E1249 and R1282. Family N6 includes autoprocessing endopeptidases involved in type III protein secretion system, in which autoproteolysis is essential for mediating the secretion of proteins. Type III secretion system secretes proteins directly into host cells by an injectisome, a hollow tubular structure that penetrates into the host cell. Secreted proteins can pass through the injectisome into the host cell cytoplasm.
Between 1517 and 1917, most of the Middle East consisted of the Ottoman Empire. In the Ottoman capital of Constantinople, about one-fifth of the population consisted of slaves. The city was a major centre of the slave trade in the 15th and later centuries. Eastern European slaves were provided for slavery in the Ottoman Empire via the Crimean slave trade by Tatar raids on Slavic villages but also by conquest and the suppression of rebellions, in the aftermath of which entire populations were sometimes enslaved and sold across the Empire, reducing the risk of future rebellion. The Ottomans also purchased slaves from traders who brought slaves into the Empire from Europe and Africa. It has been estimated that some 200,000 slaves – mainly Circassians – were imported into the Ottoman Empire between 1800 and 1909. In 1908, women slaves were still sold in the Ottoman Empire. German orientalist, Gustaf Dalman, reported seeing slaves in Muslim houses in Aleppo, belonging to Ottoman Syria, in 1899, and that boys could be bought as slaves in Damascus and Cairo in as late as 1909.
Sources: en.wikipedia.org
It is a glucagon-like peptide-1 receptor agonist, often grouped with the incretin mimetics. Its backbone is modified from the human hormone to resist enzymatic degradation and to bind albumin. These two features distinguish it from the native peptide.
No. It shares high sequence identity but carries non-natural modifications that alter its stability and clearance. The naturally occurring hormone is broken down within minutes, while the synthetic analogue circulates far longer.
Attachment to serum albumin reduces renal filtration of the peptide and shields it from enzymatic breakdown. The consequence is a much longer interval between administrations than unmodified peptides allow. The precise contribution of binding affinity to overall duration is still being quantified.
差别集中在三处：第 8 位残基被非天然氨基酸取代，第 34 位换成精氨酸，第 26 位增加一条脂肪酸侧链。前两处改动降低酶解速率，侧链则通过白蛋白结合延长循环时间。综合结果是半衰期从约两分钟延长到约一周。