来自用户 李翛然 的文献。
当前共找到 34 篇文献分享，本页显示第 21 - 34 篇。
21.
李翛然
(2023-03-28 21:41):
#paper A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers doi: 10.1038/s41422-022-00726-7. Cell Research
. 这篇文章是我最近精读的一篇文章，作者我都认识，做的靶点恰恰是我们正在做的。所以聊了很多。 这是很有可能针对未来一个大癌症种类的核心解决方案。 只不过现在rason 的结构还没有解析出来。 我们看看今年怎么处理一下。
Abstract:
Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS mutant. Here …
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Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-Kras; Trp53 mice. Mechanistically, RASON directly binds to KRAS and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRAS in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.
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22.
李翛然
(2023-02-26 22:56):
#paper Klippel-Feil Syndrome: Pathogenesis, Diagnosis, and Management doi: 10.1093/eurheartj/ehab424 这篇文章主要讲了先天性脊柱畸形 klippel-feil综合症一些活跃突变和关键性信号通路的研究。 与一般的假设不同，传统普遍认为先天性脊柱畸形一般都是与脊柱神经系统相关的调控基因有关。但实际上，从Kippel-feil综合症，患者同样具有其他疾病的显著特征。 带来一些新的思路
Abstract:
AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing …
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AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
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23.
李翛然
(2023-01-30 16:03):
#paper doi:https://doi.org/10.1038/s41467-022-35343-w Machine learning models to accelerate the design of polymeric long-acting injectables
2023年第一篇吸引我注意的计算生物学的论文。 这篇文章刚好提到我们最近的一个研究方向，不错不错，说明我司都踏在点子上了。 这篇文章主要是介绍了一种如何通过计算来设计长效药物结构的方法。虽然看内容，里面的计算工具和思想还是AI从业人员不难想到，通过AI学习长效药物的特征，从而预测新的药物结构释放效率。 但是揭示的结论确实和我司考虑的方向一模一样。 人类历史上很多药物都是马马虎虎上市的，有太多可以改进的地方了。 加油2023
Abstract:
Long-acting injectables are considered one of the most promising therapeutic strategies for the treatment of chronic diseases as they can afford improved therapeutic efficacy, safety, and patient compliance. The use …
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Long-acting injectables are considered one of the most promising therapeutic strategies for the treatment of chronic diseases as they can afford improved therapeutic efficacy, safety, and patient compliance. The use of polymer materials in such a drug formulation strategy can offer unparalleled diversity owing to the ability to synthesize materials with a wide range of properties. However, the interplay between multiple parameters, including the physicochemical properties of the drug and polymer, make it very difficult to intuitively predict the performance of these systems. This necessitates the development and characterization of a wide array of formulation candidates through extensive and time-consuming in vitro experimentation. Machine learning is enabling leap-step advances in a number of fields including drug discovery and materials science. The current study takes a critical step towards data-driven drug formulation development with an emphasis on long-acting injectables. Here we show that machine learning algorithms can be used to predict experimental drug release from these advanced drug delivery systems. We also demonstrate that these trained models can be used to guide the design of new long acting injectables. The implementation of the described data-driven approach has the potential to reduce the time and cost associated with drug formulation development.
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24.
李翛然
(2022-12-28 21:08):
#paper doi:10.1016/S1473-3099(22)00291-2 Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape. Lancet Infect Dis. 2022 Aug 8:S1473-3099(22)00291-2. . 这篇文章非常好的梳理了正在北美和欧洲大杀四方的rsv 病毒疫苗研发情况。 现在国门打开，未来必然是新冠+rsv+流感的轮流爆发，我司准备开一个这个管线。这篇综述写的非常好。 很有参考价值的梳理了技术路线，临床阶段，为我们的布局很有指导性意义。
Abstract:
Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a …
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Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.
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25.
李翛然
(2022-11-26 21:39):
#paper https://www.who.int/publications/m/item/plasmid-dna-vaccines-annex-2-trs-no-1028 Guidelines on the quality, safety and efficacy of plasmid DNA vaccines 最近由于工作原因，在跟踪一家国内第一个获得IND药物审批的DNA疫苗，主要团队都工作的接触，还是非常佩服的。全程听了他们的研发流程和路演，确实也经历了非常多的困难。 不过这项技术真的是走在了世界前列。 不过，我这个外行对于直接操作dna 还是或多或少有一些谨慎。 所以找来了这个WHO的指导原则仔细看了看， 结论感觉跟当年的mrna一样，都是暂未发现，但是大规模临床后如何呢？ 只能是时间给答案了。
WHO Technical Report Series,
2021.
Abstract:
Since the 1990s, a novel third approach to vaccination against a broad array of target antigens and diseases has been in development. This technology involves the direct administration of plasmid …
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Since the 1990s, a novel third approach to vaccination against a broad array of target antigens and diseases has been in development. This technology involves the direct administration of plasmid deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which an immune response is sought, leading to the in-situ production of the target immunogen(s) in the vaccine recipient. Such vaccines are referred to as “plasmid DNA vaccines” or simply “DNA vaccines” (with both terms used interchangeably throughout these Guidelines). The value and advantages of plasmid DNA products need to be assessed on a case-by-case basis; their utility will depend upon: (a) the nature of the organism being vaccinated against or the targeted disease; (b) the nature of the immunogen or activity of the gene insert; (c) the type of immune response required for effectiveness; and (d) the delivery system and route of administration. The development and application of DNA vaccines continues to progress. Since the WHO Guidelines for assuring the quality and nonclinical safety evaluation of DNA vaccines were adopted by the Expert Committee for Biological Standardization in 2005, many clinical trials of DNA vaccines have taken place and considerable experience in their manufacture and control has accrued. The current revision reflects this experience, especially in relation to data derived from nonclinical and clinical safety testing, which address many of the concerns expressed in previous versions of these Guidelines. The control of DNA vaccines should continue to be approached in a flexible manner to enable further modifications as more experience is gained in their production and use, and as other components or delivery systems are included. The intention of the current document is to provide a scientifically sound basis for the consistent manufacture and control of DNA vaccines for human use to ensure their continued safety and efficacy following licensure.
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26.
李翛然
(2022-10-31 09:48):
#paper TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis doi: https://doi.org/10.1038/s41467-020-18054-y
关于TET1 ，文献报道Tumor suppressor应该是没有问题，做为重组蛋白治疗肿瘤，我接下来要调研一下临床上哪类肿瘤病人是否有TET1缺失的现象，由此来判断肿瘤是否在TET1不缺失的情况下不好生长，确定其临床价值，还有一个要考虑的是这2篇文章介绍的TET1压抑脂肪细胞热能量代谢，维他命C作用在TET1压制somatic cell reprogramming，这2个现象是否可能导致严重的副作用，限制TET1的剂量
Abstract:
It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the …
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It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.
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27.
李翛然
(2022-09-26 21:03):
#paper doi: 10.1097/01.prs.0000436812.73412.a4 The embrace Device Significantly Decreases Scarring following Scar Revision Surgery in a Randomized Controlled Trial 这篇文章是上一篇（https://paper-hub.cn/xiangma/paper/430）的引用，主要是想看看医美的产品应用。没想到今年我们做了一些实验后，最近有个大发现，联合我们的生发蛋白及配合其中的胶原蛋白成型机制，可以甚至刺激烧伤病人的恢复后的毛囊分化。 这是个大事。下面的工作是具体的试验和基因编辑模型来看看验证一下猜测。
最近连续推荐是因为我们的药物 找到了新的联合用药和适应症方向！并且是一个前沿性靶点！我们一定要做透！
IF:3.200Q1
Plastic and reconstructive surgery,
2014-Feb.
DOI: 10.1097/01.prs.0000436812.73412.a4
PMID: 24469172
Abstract:
No abstract available.
28.
李翛然
(2022-08-30 14:08):
#paper doi:doi/full/10.1002/adfm.202010747 Thymus Extracellular Matrix-Derived Scaffolds Support Graft-Resident Thymopoiesis and Long-Term 胸腺细胞外基质衍生的支架支持移植后的胸腺造血和成年胸腺上皮细胞的长期体外培养 在这项研究中，开发了一种基于脱细胞胸腺组织细胞外基质的三维支架，命名为TS。当播种胎儿或成人胸腺组织时，TS可以以不同的效率支持淋巴前体的成熟，使其成为能够对有丝分裂刺激作出反应的常规和调节性T细胞。
一个功能性胸腺微环境的成功工程，关键取决于成年TEC的体外生长。然而，保存细胞的胸腺造血能力是在体外创建胸腺类器官的主要缺陷之一。因此，这种能力构成了一个关键的困难，需要有效地解决，以建立、研究和操纵T细胞的发展，无论是为实验研究开发一个体外平台，还是为体内替代工作开发一个器官。尽管在结构和细胞条件方面缺乏优化，可能反映在结果的稳健性相当有限，但我们的结果首次描述了允许成年TEC在体外和体内长期生存的工程条件，同时支持胸腺造血。
除了改善TS的工程之外，还需要努力确定具有长期再增殖潜力的TEC前体，能够产生所有的TEC谱系和亚群。来自小鼠TEC的单细胞转录组数据的使用揭示了TEC亚型的相当复杂性，并为确定这些细胞的发育轨迹的计算工作提供了依据。在适当的TS上长期重新填充TEC前体，将确保维持一个能够吸引血源性T细胞前体的环境，并在很长一段时间内指导他们分化和选择成熟的常规和调节性T细胞。在体外培养后，需要改进细胞检索的协议，以便对TEC进行深入的表型和定量调查。由于这些TEC前体很可能是脆弱的，因此需要部署一些条件，以保证有效、迅速和均匀地播种到ECM支架上，并允许用额外的基质细胞（包括间质细胞和内皮细胞）来补充这些基本环境，已知这有助于胸腺交叉对话。使用灌注式生物反应器和选择性条件将进一步帮助在体外创造一个自我组织的胸腺微环境，提供强大的持续T细胞输出。精确控制调节体外胸腺组织形成的化学物理条件对于可重复性和扩展性至关重要，无论是生成较小的器官用于药物筛选，还是生成较大的微环境用于器官替代策略，作为对无胸腺或胸腺发育不全者的治疗选择。
免疫治疗的核心问题：
让免疫系统恢复工作能力，目前的CarT CARNK等等 都是属于治标 如何恢复治本是全世界目前的前沿聚焦方向，也许中医真的可以发挥一些东西。
但是器官再造面临了太多挑战：
1. 类器官作为新型的药筛模型，成本虽然较PDX更低，但还是远高于细胞系。类器官成本占比较高的包括培养使用的基质胶，常用的基质胶为美国BD Biosciences公司的Matrigel，在行业内处于较为垄断的地位，价格较高。Matrigel可以产生类似于哺乳动物细胞基底膜的生物活性基质材料，帮助多种类型的细胞达到附着和分化。Matrigel的来源是小鼠肉瘤细胞系，除了成本较高的问题，同时批次间存在一定的变异性。且由于是动物来源，对于有机类的药物的检测有局限性。考虑到小鼠来源的细胞外基质对于药物筛选实验结果存在一定的干扰，因此基质的工程技术开发用于合成外源差异较小的、非动物来源的基质胶用于成本下降和性能优化将是类器官产业化需要解决的关键性问题之一。基质胶以外，培养也涉及多种细胞因子组合使用，细胞生长因子通常也价格不菲。选择效果更好的细胞因子以及尝试减少使用细胞因子的数量也可以带来成本下降的空间。
2. 目前大多类器官本身并不具备血管化的结构。因此，随着类器官体积的增长，类器官受限于氧气的缺失以及代谢废物的增加，可能导致的组织坏死。已有研究构建血管内皮细胞微环境的肿瘤类器官，将类器官肿瘤细胞和血管内皮细胞在Matrigel上共同培养，生成血管结构以期解决类器官血管化缺失的问题。
3. 血管化以外的难点还包括模拟肿瘤和免疫环境的相互作用关系。2019年Nature Protocol发表了肿瘤类器官和免疫细胞共同培养的相关protocol，可以体现和模拟出肿瘤微环境的部分特征。以上皮类器官和免疫细胞共培养模型为例，可通过在培养基中添加活化的免疫细胞、在组织消化成单细胞后和免疫细胞共同生长、添加ECM中的重组细胞因子等方法重塑类器官和免疫细胞的相互作用。
4. 相比于单个类器官，类器官系统的构建能够对药物疗效和潜在毒性做出更完整全面的评估。目前类器官仅能检测出药物对于肿瘤的抑制效果，对于其他器官组织是否存在其他副作用和安全性风险并不能做出预判。为了解决这一问题，2017年Skardal et al.构建了有心脏、肺部、肝脏组成的集成于闭合循环关注体中的类器官系统，以达到全面揭示药物对不同器官的毒性和药效的目的。
5. 重复性(reproducibility)和一致性 (consistency)也是类器官发展的重大瓶颈，这很大程度上由于过程控制的欠缺与行业标准的空白。类器官培养过程中人为因素的过多参与、自动化程度低导致因为系统偶然性造成的误差较大。同时，类器官检测手段十分匮乏，活体观察主要集中在形态学观察，断点观察集中在基于荧光的各类指标的检测，能够活体实时对类器官各项指标进行检测的光学、电化学等手段仍较为欠缺。当前，类器官很多研究者致力于制造更新的类器官，做出之前未能做出的类器官，我们可以制作海马体、垂体、腺体、脾、肾的类器官，却难以确定一个符合要求的类器官需要满足那些个体的诸如尺寸、形状、基因表达量等，群体的诸如类器官之间的方差等统计学指标。这将限制类器官的高效研究与向临床研究的转化。
6. 对于类器官培养过程中的工程控制也是亟待解决的问题。当前类器官培养大多使用Matrigel水凝胶作为培养基质，Matrigel是康宁生命科学公司生产的Engelbreth-Holm-Swarm (EHS)小鼠肉瘤细胞分泌的胶状蛋白混合物。Matrigel因其含有外源成分，难以应用在人的很多治疗场景。另一方面，虽然类器官与微流控技术已有一些结合研究的例子，但使用微流控芯片对类器官生存的流体环境进行模拟仍不成熟，如何使用微流控等技术对类器官培养时流体微环境进行控制是亟待解决的问题。同时，现有类器官的直径约在100-500μm之间，虽然具有一定程度的尺度效应，但还是难以模拟真实组织、器官的场景。倘若要制造尺度更大的类器官，类器官的血管化也是十分重要的问题。
Abstract:
The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of …
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The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of stroma cells provides surface-bound and soluble molecules that orchestrate the intrathymic maturation and selection of developing T cells. Forming an intricate 3D architecture, thymic epithelial cells (TEC) represent the most abundant and important constituent of the thymic stroma. Effective models for in and ex vivo use of adult TEC are still wanting, limiting the engineering of functional thymic organoids and the understanding of the development of a competent immune system. Here a 3D scaffold is developed based on decellularized thymic tissue capable of supporting in vitro and in vivo thymopoiesis by both fetal and adult TEC. For the first time, direct evidences of feasibility for sustained graft-resident T-cell development using adult TEC as input are provided. Moreover, the scaffold supports prolonged in vitro culture of adult TEC, with a retained expression of the master regulator Foxn1. The success of engineering a thymic scaffold that sustains adult TEC function provides unprecedented opportunities to investigate thymus development and physiology and to design and implement novel strategies for thymus replacement therapies.
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29.
李翛然
(2022-07-28 13:15):
#paper DOI: 10.1126/science.aba2374 Preventing Engrailed-1 activation in Mbrob- lasts yields wound regeneration without scarring 2021年4月份发表在Science的皮肤损伤修复靶点很有意思，号称不留伤疤，目前发现一个老药作用在这个靶点，没有其它药物进入临床，但是有其它抑制剂。那个老药Verteporfin是通过激光照射眼睛治疗眼部血管破裂的，不知道用于皮肤损伤新靶点的疗效会受制于老药靶点（假定靶点不同）。这个靶点已经成功地引起了我司注意
Abstract:
Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. lineage-positive fibroblasts (EPFs) are known to function in scarring, but lineage-negative fibroblasts (ENFs) remain …
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Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. lineage-positive fibroblasts (EPFs) are known to function in scarring, but lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).
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30.
李翛然
(2022-06-27 18:03):
#paper doi:https://doi.org/10.1038/d41573-022-00052-y Hooking FSH as a potential target for Alzheimer disease 这篇是一个比较新的关于女性老年痴呆的靶点文章，可信度很高，最近我们也在构建这个疾病的小鼠模型。这里面采用的是敲除的手段复现的FSH receptor 作用通路。我们的思路是，通过构建一个基因突变，找到合适的抑制剂。 嘿嘿，这算不算核心技术透露？
Abstract:
No abstract available.
31.
李翛然
(2022-05-31 23:45):
#paper doi:10.1038/s41586-022-04463-0 nature FSH blockade improves cognition in mice with Alzheimer’s disease FSH，2022年3月发表在Nature正刊，用于治疗老年痴呆症，调控 beta蛋白和Tau蛋白.本文是多个描述AZ疾病的论文中比较肯定的这个荷尔蒙作用。目前是一个潜在的重要靶点
Abstract:
Alzheimer's disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition. …
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Alzheimer's disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-β and Tau deposition and impair cognition in mice displaying features of Alzheimer's disease. Blocking FSH action in these mice abrogates the Alzheimer's disease-like phenotype by inhibiting the neuronal C/EBPβ-δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer's disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer's disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.
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32.
李翛然
(2022-04-28 21:30):
#paper Wohlert and Edholm (2006) J. Chem. Phys. 125: 204703
Dynamics in atomistic simulations of phospholipid membranes: Nuclear magnetic resonance relaxation rates and lateral diffusion 本论文提出了不同脂分子的面积，相转变温度，等各种参数的得出方法，并列举出了模拟当中的一些参数选择背后的原因。最近正在深耕细挖分子动力学，因为接下来要和量子计算进行合作了，需要充分理解目前的原理及参数选择，以便找到一个最适合用量子计算的场景。
Abstract:
It is shown that a long, near microsecond, atomistic simulation can shed some light upon the dynamical processes occurring in a lipid bilayer. The analysis focuses on reorientational dynamics of …
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It is shown that a long, near microsecond, atomistic simulation can shed some light upon the dynamical processes occurring in a lipid bilayer. The analysis focuses on reorientational dynamics of the chains and lateral diffusion of lipids. It is shown that the reorientational correlation functions exhibits an algebraic decay (rather than exponential) for several orders of magnitude in time. The calculated nuclear magnetic resonance relaxation rates agree with experiments for carbons at the C7 position while there are some differences for C3. Lateral diffusion can be divided into two stages. In a first stage occurring at short times, t<5 ns, the center of mass of the lipid moves due to conformational changes of the chains while the headgroup position remains relatively fixed. In this stage, the center of mass can move up to approximately 0.8 nm. The fitted short-time diffusion coefficient is D(1)=13 x 10(-7) cm(2) s(-1) On a longer time scale, the diffusion coefficient becomes D(2)=0.79 x 10(-7) cm(2) s(-1).
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33.
李翛然
(2022-03-31 00:44):
#paper doi: 10.1038/s41586-022-04654-9 Nature,2022 Design of protein binding proteins from target structure alone.
这篇文章我是一定要吐槽一下的！！！！上周5居然被Nature 接受了？！？！这个是我最我无法理解的，去年DeepMind投了预印本开始，我们就开始跟踪这个文章了。其中的所有方法我们已经复现并加以改进，但是团队的所有人都不认为应该被Nature接收。
原因是以下几点：
1，其原理非常简单易懂，就是利用现有的一些氨基酸序列，逐渐地解析靶点结构，然后拼出来新的氨基酸序列。
2，根据AlphaFlod将靶点结构拆解出来，找到相关的合适位置，然后通过检索的方式找到合适的小氨基酸序列（这一步也没有问题，AI生成模型也会这么做）
3，但是下一步就太扯了！因为最关键的步骤来了，就是如何评判找到和生成的氨基酸与靶点的对接亲和力？以及如何评价对接强度？ 也是强化学习的关键Q函数到底是啥
他居然用了DeepMind 和华盛顿大学的历史遗留工具集：RoseTTA！！！！最最关键的评分函数居然用自己团队曾经的开源工具集！（大分子准确度也就撑死20%不到）
太不可思议了！！完全没有试验验证和支持的文章居然被Nature 主刊接收了？！？！天啊，这可和ALphaFLod开创性是比不了的，人家是引入了全新的数学工具和解决问题的思路，这文章完全是蹭出来的。
只能说Google，DeepMind 以及华盛顿大学 背后的学术公关和关系网太庞大了！
不过另一方面，只能说的是，生物学过去的发展太慢了，AI行业内卷外溢之后，真的是降维打击！
Abstract:
The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a …
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The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge. Here we describe a general solution to this problem that starts with a broad exploration of the vast space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate the broad applicability of this approach through the de novo design of binding proteins to 12 diverse protein targets with different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and, following experimental optimization, bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five closely match the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvements of both. Our approach enables the targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.
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34.
李翛然
(2022-02-27 09:48):
#paper doi 10.1002 ： Image2SMILES: Transformer-Based Molecular Optical Recognition Engine (2022) https://doi.org/10.1002/cmtd.202100069 这篇文章主要讲述了如何利用transformer 模型将文献中的化学分子式识别并转换为可以进一步分析用的smiles结构。这项技术算是一个比较“有则更好，无则也能抗的过去”的模型，因为需要进行smiles识别的分子，其肯定基本上都会被关注到论文和结构价值。但是，关注到之后，相关有经验的化学专家看一眼图像就知道里面的问题，和结构细节。 那至于如何找到有价值的化学结构，其实又是NLP读取论文的事情了。所以这个技术我觉得有点鸡肋，北京的望石科技就是干这个的。
Chemistry - Methods,
2022.
DOI: 10.1002/cmtd.202100069
Abstract:
No abstract available.