deamidation is one of those subjects where the details matter more than the headlines. This page pulls together the background, the mechanisms, and the practical points readers ask about most.
Updated 2025-12-24. Numbers and descriptions here follow the published literature rather than marketing material.
关于降解产物的免疫原性风险，文献中仍有讨论空间。体外聚集水平与临床免疫反应之间的定量关系尚未确立。多数公开研究只报告理化指标，缺少长期随访的对应数据。这一问题在生物类似物比对中尤其受到关注。
市售注射用制剂通常要求在二至八摄氏度冷藏保存，并避免光照与冻结。部分多剂量笔在首次使用后允许在不超过三十摄氏度的环境中存放有限周数，具体期限由辅料与防腐剂体系决定。反复冻融会促进肽链聚集并改变可见颗粒计数，因此应予避免。冻干粉末在干燥、避光、低温条件下更为稳定。溶液配制后宜使用低吸附容器，以减少肽类在塑料或玻璃表面的损失。
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。
Semaglutide 是一种经结构修饰的胰高血糖素样肽-1 类似物，其主链与内源性 GLP-1(7-36) 约有百分之九十四的序列一致性。第 8 位丙氨酸被 α-氨基异丁酸取代，使二肽基肽酶-4 无法识别原有切割位点。第 34 位赖氨酸换为精氨酸，进一步降低酶解速率。第 26 位赖氨酸经间隔基连接一条含十八个碳的二酸脂肪链，该侧链赋予分子与血浆白蛋白结合的能力。
| Property | Value | Notes |
|---|---|---|
| 保存温度 | 2 至 8 摄氏度 | 避免冻结，部分制剂允许短期室温 |
| 粉末外观 | 白色至类白色固体 | 吸湿后易结块 |
| 纯度检测方法 | 反相高效液相色谱 | 紫外检测，常用 214 纳米 |
| 分子量确认方法 | 液相色谱串联质谱 | 偏差通常以 ppm 表示 |
| 常见降解产物 | 氧化与脱酰胺变体 | 源自甲硫氨酸与天冬酰胺残基 |
Clinical studies of semaglutide generally measure glycated hemoglobin, fasting plasma glucose, body weight, and composite cardiovascular endpoints. The SUSTAIN program enrolled adults with type 2 diabetes, while the STEP program focused on obesity without diabetes. Administration follows a stepwise escalation schedule designed to limit gastrointestinal effects during the first weeks. Reported outcomes include mean percentage weight change, the proportion of participants reaching defined weight-loss thresholds, and rates of nausea, vomiting, and diarrhea. Long-term data on durability after treatment stops are still limited and remain a topic of ongoing research.
Semaglutide is a synthetic peptide analog of human glucagon-like peptide-1, developed by Novo Nordisk and first approved in 2017 for type 2 diabetes. It belongs to the incretin mimetic class, a group of agents that reproduce the glucose-dependent actions of endogenous GLP-1. The molecule was engineered to resist degradation by dipeptidyl peptidase-4 and to bind serum albumin, extending its half-life from minutes to roughly one week. Approval for chronic weight management followed in 2021, based on large cardiovascular and obesity outcome trials.
GLP-1 receptors are expressed on pancreatic beta cells, in the gut, and in several brain regions. Receptor activation raises cyclic AMP, enhances glucose-dependent insulin secretion, and suppresses glucagon release when blood glucose is high. Effects on gastric emptying and on hypothalamic appetite circuits reduce energy intake. Because insulin release remains glucose-dependent, the risk of hypoglycemia is low when the drug is used alone. The precise contribution of each pathway to body weight change in humans remains an area of active investigation.
Reverse-phase high-performance liquid chromatography is the standard method for purity assessment, separating the peptide from truncated or oxidized variants. Mass spectrometry confirms molecular mass and detects modifications, while ultraviolet absorbance near 280 nanometers supports concentration measurement through tryptophan and tyrosine residues. Circular dichroism can indicate secondary structure, though the peptide is largely helical in solution, and ion-exchange chromatography resolves charge variants. Purity values above 95 percent are typical for research-grade material. Stability studies track degradation over time under defined conditions.
Lyophilized semaglutide is typically stored at temperatures between minus 20 and minus 80 degrees Celsius for long-term preservation. Short-term storage at 2 to 8 degrees Celsius is common for working aliquots. Repeated freeze-thaw cycles can degrade the peptide and are usually avoided. The molecule is hygroscopic in its solid form, so containers should remain sealed with desiccant. Solutions are less stable than powders and are generally prepared fresh. Light exposure is limited because aromatic residues can undergo photo-oxidation.
The compound binds the GLP-1 receptor on pancreatic beta cells and other tissues, activating a G-protein signaling cascade that raises intracellular cyclic AMP. This action increases glucose-dependent insulin secretion when blood glucose is elevated, while binding also slows gastric emptying and reduces glucagon release. In the central nervous system, receptor activation in the hypothalamus and brainstem contributes to reduced appetite. The fatty acid chain binds albumin, which protects the peptide from renal filtration and enzymatic degradation. This albumin binding is central to its extended circulation time.
Native GLP-1 is degraded rapidly by dipeptidyl peptidase-4. Semaglutide resists this cleavage because alanine at position 8 is replaced by alpha-aminoisobutyric acid. A second substitution at position 34 introduces arginine, which further stabilizes the peptide. The most distinctive modification is a spacer and C18 fatty diacid attached at lysine 26, enabling strong albumin affinity. These three changes together produce a half-life measured in days rather than minutes, and the same structural logic underlies other long-acting analogs in this class.
Semaglutide is a synthetic peptide analog of glucagon-like peptide-1, a hormone released from intestinal L-cells after food intake. It contains 31 amino acids and differs from native GLP-1 through modifications that slow enzymatic breakdown. The peptide was developed to extend the short circulating half-life of endogenous GLP-1, which is measured in minutes. Researchers introduced the compound in the early 2010s. Two backbone changes and a fatty acid side chain define its structure, distinguishing it from earlier GLP-1 receptor agonists.
Stability studies examine how temperature, pH, and moisture influence degradation rates over time. In aqueous solution, hydrolysis and deamidation accelerate as pH moves away from mildly acidic conditions. Light exposure and residual metal ions can also trigger oxidation of susceptible residues. Accelerated aging at elevated temperature is used to estimate shelf life, though extrapolation to room temperature carries uncertainty because individual degradation pathways do not always scale predictably.
Lyophilized semaglutide powder is typically held at minus twenty degrees Celsius for long-term storage. At that temperature, solid-state degradation reactions proceed slowly and the peptide remains intact for extended periods. Repeated freeze-thaw cycles are best avoided because they promote aggregation and can shift the proportion of monomeric peptide present. Working aliquots are often prepared so that each portion is thawed only once, and desiccant is placed inside the vial to limit moisture uptake.
=== Pharmacodynamics === SR-17018 acts as a biased partial agonist of the μ-opioid receptor (MOR), with strong selectivity for activation of G protein signaling over β-arrestin2 recruitment. Its affinities (Ki) for the human opioid receptors have been reported to be 11 nM for the MOR, 68 nM for the κ-opioid receptor (KOR), and >10,000 nM for the δ-opioid receptor (DOR). In terms of MOR activation, the drug had activational potencies and efficacies (EC50Tooltip half-maximal effective concentration and EmaxTooltip maximal efficacy) of 97–193 nM (72–75%) for GTPγS binding, 76 nM (105%) for cAMPTooltip cyclic adenosine monophosphate accumulation, and >10,000 nM (10%) for β-arrestin2 recruitment. Both GTPγS binding and cAMP accumulation are measures of G protein signaling. The drug showed a calculated bias factor for GTPγS binding over β-arrestin2 recruitment of 80 to 100 relative to DAMGO. SR-17018 also showed strong bias for G protein activation over β-arrestin2 recruitment using mouse proteins, albeit with reduced efficacy for GTPγS binding (Emax = 37%). β-Arrestin2 activation may contribute to opioid tolerance, though it is not the only mechanism of tolerance to these drugs. SR-17018 shows a strikingly different MOR phosphorylation profile from other MOR biased, partial, and full agonists. Additional studies have characterized the interactions of SR-17018 with the MOR, including activational potencies and efficacies at downstream signaling pathways, as well.
Tafasitamab, sold under the brand name Monjuvi, is an anti-cancer medication used in combination with lenalidomide for the treatment of adults with diffuse large B-cell lymphoma; or, when used in combination with lenalidomide and rituximab, for the treatment of follicular lymphoma. Tafasitamab is a humanized Fc-modified cytolytic CD19 antibody. Tafasitamab may cause serious side effects including infusion related reactions, bone marrow suppression, infections, and harm to an unborn baby. The most common side effects of tafasitamab are low blood cell counts, fatigue, diarrhea, cough, fever, limb swelling, upper respiratory infection, and decreased appetite. Tafasitamab was approved for medical use in the United States in July 2020, and in the European Union in August 2021. The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.
An example of a molecule that does not have a mirror plane or an inversion and yet would be considered achiral is 1,1-difluoro-2,2-dichlorocyclohexane (or 1,1-difluoro-3,3-dichlorocyclohexane). This may exist in many conformers (conformational isomers), but none of them has a mirror plane. In order to have a mirror plane, the cyclohexane ring would have to be flat, widening the bond angles and giving the conformation a very high energy. This compound would not be considered chiral because the chiral conformers interconvert easily. An achiral molecule having chiral conformations could theoretically form a mixture of right-handed and left-handed crystals, as often happens with racemic mixtures of chiral molecules (see Chiral resolution#Spontaneous resolution and related specialized techniques), or as when achiral liquid silicon dioxide is cooled to the point of becoming chiral quartz.
The crew landed on the reciprocal runway with no further incident. No casualties. On September 21, 2001, RA-86074 (c/n 041) operating as Aeroflot Flight 521 belly-landed at Dubai after a flight from Moscow, the flight crew having switched off the ground proximity warning due to heavy workload on the approach and then neglected to extend the landing gear; no casualties; aircraft written off. On July 28, 2002, Pulkovo Aviation Enterprise Flight 9560 RA-86060 (c/n 027) crashed shortly after departure from Moscow on a repositioning flight to Saint Peterburg. The trim toggle button on the control column caused a spontaneous retrimming of the tailplane, rapid transition to nose-heavy trim and a dive. The four flightdeck crew, two ground support staff and ten cabin crew aboard the aircraft died, making the crash the deadliest aviation accident involving the Il-86. The two injured survivors were cabin crew members. Following the Moscow crash in July 2002, the MAK Interstate Aviation Committee withdrew the Il-86's certificate of airworthiness, temporarily grounding the type. The certificate was rapidly restored in stages by early 2003. The accident prompted the Egyptian civil aviation authorities to attempt to ban Il-86 operations to Egypt. Amid continuing negotiations, by 2007 the intention had lapsed, with intensive Il-86 operations to and from Egypt continuing.
Sources: en.wikipedia.org
Fluorinated surfactants or fluorosurfactants are a subgroup of PFAS characterized by a hydrophobic fluorinated "tail" and a hydrophilic "head" that behave as surfactants. These are more effective at reducing the surface tension of water than comparable hydrocarbon surfactants. Fluorosurfactants tend to concentrate at the phase interfaces. Fluorocarbons are both lipophobic and hydrophobic, repelling both oil and water. Their lipophobicity results from the relative lack of London dispersion forces compared to hydrocarbons, a consequence of fluorine's large electronegativity and small bond length, which reduce the polarizability of the surfactants' fluorinated molecular surface. Fluorosurfactants are more stable than hydrocarbon surfactants due to the stability of the carbon–fluorine bond. Perfluorinated surfactants persist in the environment for the same reason. Fluorosurfactants such as PFOS, PFOA, and perfluorononanoic acid (PFNA) have caught the attention of regulatory agencies because of their persistence, toxicity, and widespread occurrence in the blood of general populations.
=== Models === It was suggested that the problem with building and maintaining larger, more complex, and more accurately replicated molecules can be circumvented if several information carriers, each of them storing a small piece of information, are connected such that they only control their own concentration. Studies of the mathematical model describing replicating molecules revealed that to observe a cooperative behaviour among self-replicating molecules, they have to be connected by a positive feedback loop of catalytic actions. This kind of closed network consisting of self-replicating entities connected by a catalytic positive-feedback loop was named an elementary hypercycle. Such a concept, apart from an increased information capacity, has another advantage. Linking self-replication with mutual catalysis can produce nonlinear growth of the system. This, first, makes the system resistant to so-called parasitic branches. Parasitic branches are species coupled to a cycle that do not provide any advantage to the reproduction of a cycle, which, in turn, makes them useless and decreases the selective value of the system. Secondly, it reinforces the self-organization of molecules into the hypercycle, allowing the system to evolve without losing information, which solves the error threshold problem.
Repligen Corporation is an American life sciences company that develops and manufactures products used in biological drug manufacturing. The company is headquartered in Waltham, Massachusetts, and is listed on the Nasdaq under the symbol RGEN.
Apart from several bog bodies, Denmark has also yielded several other mummies, such as the three Borum Eshøj mummies, the Skrydstrup Woman and the Egtved Girl, who were all found inside burial mounds, or tumuli. In 1875, the Borum Eshøj grave mound was uncovered, which had been built around three coffins, which belonged to a middle aged man and woman as well as a man in his early twenties. Through examination, the woman was discovered to be around 50–60 years old. She was found with several artifacts made of bronze, consisting of buttons, a belt plate, and rings, showing she was of higher class. All of the hair had been removed from the skull later when farmers had dug through the casket. Her original hairstyle is unknown. The two men wore kilts, and the younger man wore a sheath which contained a bronze dagger. All three mummies were dated to 1351–1345 BC. The Skrydstrup Woman was unearthed from a tumulus in Southern Jutland, in 1935. Carbon-14 dating showed that she had died around 1300 BC; examination also revealed that she was around 18–19 years old at the time of death, and that she had been buried in the summertime. Her hair had been drawn up in an elaborate hairstyle, which was then covered by a horse hair hairnet made by the sprang technique. She was wearing a blouse and a necklace as well as two golden earrings, showing she was of higher class. The Egtved Girl, dated to 1370 BC, was also found inside a sealed coffin within a tumulus, in 1921. She was wearing a bodice and a skirt, including a belt and bronze bracelets.
Donohue syndrome is an autosomal recessive genetic disorder. The mutations responsible for the disorder are found on the short arm chromosome 19 (19p13.2) within the coding sequence of the INSR gene (insulin receptor) causing the production of inactive receptor molecules. There are several mutations that can be responsible for the disease, as any mutation that severely impairs the functionality of the insulin receptor will have similar effects. The INSR gene spans over one hundred and twenty thousand base pairs, which contain twenty-two exons coding for a protein that consists of 1382 amino acids. Some of the introns may or may not be spliced out depending on the kind of cell. Known mutations to the gene which can cause Donohue syndrome include a nonsense mutation that resulted in early termination of the protein, an addition or deletion mutation that resulted in a frame shift, a single missense mutation and in the milder form mentioned above, a single codon change that altered isoleucine to methionine in the receptor protein. Some mutations to the gene instead result in insulin resistant diabetes without Donohue syndrome. Because mutations in the gene are extremely rare, most cases result from consanguineous matings, for example, between cousins. However, the exact mutation need not be the same. Disease can be caused by inheritance of two different mutant alleles, one from each parent, in which case the patient is a compound heterozygote. A heterozygous individual (i.e.
Sources: en.wikipedia.org
The Arabia hit a tree snag and sank in the Missouri River on September 5, 1856. All 130 passengers survived, but an estimated 220 tons of cargo went down with it. Shortly thereafter, the river changed course, and the Arabia was buried underground. The cargo, destined for 16 towns on the frontier, was buried under a cornfield in Wyandotte County, Kansas, for 132 years until it was discovered in 1988 by River Salvage Inc., a group of self-proclaimed treasure hunters who began excavations. David, Greg, and Bob Hawley owned a refrigeration repair business. They partnered with Jerry Mackey, owner of Hi-Boy restaurants in Independence, Missouri, and David Lutrell from the construction industry, along with other family and friends, to form River Salvage Inc. With the permission of the land owner, they dug between November 1988 and February 1989. Although their original goal was to sell their discoveries, the historical importance of the finding quickly became apparent, and they started to plan a museum. Today, it is still owned and operated by the Hawley family, who are present there most days, often greeting visitors and answering questions.
Agribusinesses and service providers: Increased reliance on big data may increase the power differential between agribusinesses/information service providers and farmers. If smallholders lack access to and/or control of their data, they may lose bargaining power vis-à-vis large value chain actors (like supermarkets) and data collectors.
The Laminin Protein Laminin at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Overview of all the structural information available in the PDB for UniProt: P19137 (Laminin subunit alpha-1) at the PDBe-KB. Overview of all the structural information available in the PDB for UniProt: P24043 (Laminin subunit alpha-2) at the PDBe-KB. Overview of all the structural information available in the PDB for UniProt: O15230 (Laminin subunit alpha-5) at the PDBe-KB. "How I learned to love laminin". YouTube. Imperial College London. April 13, 2011. (lecture by Professor Erhard Hoheneseter)
=== Environmental issues === On January 23, 2019, Pritzker committed Illinois to the United States Climate Alliance, which aimed to reduce the state's greenhouse gas emissions by over 26% by 2025. In 2017, it was revealed that both Pritzker and his 2018 gubernatorial primary opponent Christopher G. Kennedy held stock in ExxonMobil, Chevron Corporation, Occidental Petroleum, and ConocoPhillips. In 2024, Pritzker signed the SAFE CCS Act, making Illinois the second state after California to halt approval of carbon dioxide pipelines.
The 1906 general election also represented a shift to the left by the Liberal Party. In the 1905/06 election campaign, nearly seven out of ten Liberal candidates mentioned social reform, which (as noted by one study) "usually included Poor Law reform and old age pensions." According to Rosemary Rees, almost half of the Liberal MPs elected in 1906 were supportive of New liberalism (ideology), while five-sixths of the Liberal party were described as left wing. Important junior offices were also held in the cabinet by what Duncan Tanner has termed "genuine New Liberals, Centrist reformers, and Fabian collectivists," and much legislation was pushed through by the Liberals in government. This included the regulation of working hours, National Insurance and welfare. One study has questioned the extent to which the Liberal Party experienced a leftward shift, estimating that only between 50 and 60 Liberal MPs out of the 400 in the parliamentary party after 1906 were Social Radicals, with a core of 20 to 30. In a 1905 speech in Edinburgh, the Liberal politician Augustine Birrell made a reference to the leftward shift of his party, arguing (as noted by one study) "that Liberals at all levels were coming to accept" state intervention "on a large and national scale for the benefit the unsuccessful and for those who started life at grievous disadvantage." Additionally, as one observer has noted:
Sources: en.wikipedia.org
冻融过程中冰晶形成与局部浓度升高会促使肽链发生界面吸附和聚集。聚集不仅降低有效含量，还会改变可见异物与不溶性微粒的计数结果。将溶液分装为单次使用的小体积等份可减少循环次数。
该方法依据疏水性差异分离主峰与相关杂质，对缺失序列、氧化产物和脱酰胺变体具有较好分辨能力。流动相中加入离子对试剂可改善峰形。紫外检测在肽键吸收区工作，灵敏度足以支持常规放行检验。
加速条件可以放大多数化学降解，但聚集与界面诱导的变化对容器、摇动和温度历史更敏感。某些固态转变在短时高温下不一定出现。因此实时稳定性数据仍不可替代，加速结果一般只作为趋势参考。
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。