Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all “single mutant active” with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of “single mutant active” ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) “double mutant active” ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities (“singe mutant active” versus “double mutant active”) rather than the loosely-defined “generational” (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.     

Mantel test in population genetics

The comparison of genetic divergence or genetic distances, estimated by pairwise F_ST and related statistics, with geographical distances by Mantel test is one of the most popular approaches to evaluate spatial processes driving population structure. There have been, however, recent criticisms and discussions on the statistical performance of the Mantel test. Simultaneously, alternative frameworks for data analyses are being proposed. Here, we review the Mantel test and its variations, including Mantel correlograms and partial correlations and regressions. For illustrative purposes, we studied spatial genetic divergence among 25 populations of Dipteryx alata (“Baru”), a tree species endemic to the Cerrado, the Brazilian savannas, based on 8 microsatellite loci. We also applied alternative methods to analyze spatial patterns in this dataset, especially a multivariate generalization of Spatial Eigenfunction Analysis based on redundancy analysis. The different approaches resulted in similar estimates of the magnitude of spatial structure in the genetic data. Furthermore, the results were expected based on previous knowledge of the ecological and evolutionary processes underlying genetic variation in this species. Our review shows that a careful application and interpretation of Mantel tests, especially Mantel correlograms, can overcome some potential statistical problems and provide a simple and useful tool for multivariate analysis of spatial patterns of genetic divergence.     

Qualitative difference between “bulb” membranes and other vacuolar membranes

“Bulb” is a mobile and complex structure appearing in vacuolar membrane of plant cell. We recently reported new fluorescent marker lines for bulbs and bulb-less mutants. We tried multicolor visualization of vacuolar membrane to show distinct segregation of bulb-positive protein (γTIP or AtVAM3) and bulb-negative protein (AtRab75). Unexpectedly, GFP-AtRab75 resulted to localize in bulb under the condition of co-expression with TagRFP-AtVAM3. The signal intensities of GFP-AtRab75 and TagRFP-AtVAM3 were quantified and compared. The result indicates that TagRFP-AtVAM3 is concentrated in bulb than GFP-AtRab75.     

Molecular Disruption of the Power Stroke in the ATP-binding Cassette Transport Protein MsbA

ATP-binding cassette transporters affect drug pharmacokinetics and are associated with inherited human diseases and impaired chemotherapeutic treatment of cancers and microbial infections. Current alternating access models for ATP-binding cassette exporter activity suggest that ATP binding at the two cytosolic nucleotide-binding domains provides a power stroke for the conformational switch of the two membrane domains from the inward-facing conformation to the outward-facing conformation. In outward-facing crystal structures of the bacterial homodimeric ATP-binding cassette transporters MsbA from Gram-negative bacteria and Sav1866 from Staphylococcus aureus, two transmembrane helices (3 and 4) in the membrane domains have their cytoplasmic extensions in close proximity, forming a tetrahelix bundle interface. In biochemical experiments on MsbA from Escherichia coli, we show for the first time that a robust network of inter-monomer interactions in the tetrahelix bundle is crucial for the transmission of nucleotide-dependent conformational changes to the extracellular side of the membrane domains. Our observations are the first to suggest that modulation of tetrahelix bundle interactions in ATP-binding cassette exporters might offer a potent strategy to alter their transport activity.     

碳中和的生态学透视

在简述碳中和概念的基础上, 重点对碳中和的实现途径及生态系统碳汇的重要性进行了评述, 认为碳减排和碳增汇是实现“碳中和”的两个决定因素; 碳减排的核心是节能、调结构、增效和发展清洁能源, 碳增汇的核心是生态保护、建设和管理。由于植被自然生长和生态建设等因素, 中国陆地生态系统发挥了, 并将在未来继续发挥着重要的碳汇作用。为增强生态系统的固碳能力, 作者提出“三优”生态建设和管理原则, 即“最优的生态系统布局、最优的物种配置、最优的生态系统管理”。此外, 文章还对“后碳中和”时代可能出现的问题和挑战进行了展望, 认为碳中和后, 由于气候变化, 特别是大气CO₂浓度增速减缓甚至下降等因素, 可能导致全球性的植被生产力下降, 对此可能带来的新的环境问题需要提前谋划和应对。     

Oxidative Stress in the Heart of Rats Infected with Trypanosoma evansi

This study was conducted to investigate the occurrence of oxidative stress in the heart tissue of rats infected with Trypanosoma evansi. Rats were divided into 2 groups (A and B) with 12 animals each, and further subdivided into 4 subgroups (A1 and A2, 6 animals/each; and B1 and B2, 6 animals/each). Animals in the groups B1 and B2 were subcutaneously inoculated with T. evansi. Thiobarbituric acid reactive substances (TBARS), superoxide dismutase activity (SOD), glutathione S-transferase activity (GST), reduced glutathione activity (GSH), and non-protein thiols (NPSH) in the heart tissue were evaluated. At day 5 and 15 post-infection (PI), an increase in the TBARS levels and a decrease in the SOD activity (P<0.05) were observed. GSH and GST activities were decreased in infected animals at day 15 PI (P<0.05). Considering the proper functioning of the heart, it is possible that the changes in the activity of these enzymes involved in the oxidative stress may be related, at least in part, in the pathophysiology of rats infected with T. evansi.     

Rasnitsynala sigambrorum gen. et sp. n., a small odonatopterid ("Eomeganisoptera", "Erasipteridae") from the early Late Carboniferous of Hagen-Vorhalle (Germany)

Besides Erasipteroides valentini (Brauckmann in Brauckmann, Koch & Kemper, 1985), Zessinella siope Brauckmann, 1988, and Namurotypus sippeli Brauckmann & Zessin, 1989, Rasnitsynala sigambrorum gen. et sp. n. is the fourth species of the Odonatoptera from the early Late Carboniferous (Early Pennsylvanian: Namurian B, Marsdenian) deposits of the important Hagen-Vorhalle Konservat-Lagerstätte in Germany. With its wing-span of about 55 mm it is unusually small even for the “Eomeganisoptera”. Its venation resembles other small “Eomeganisoptera”, in particular Zessinella siope. This is why it is here assigned to the probably paraphyletic “Erasipteridae” Carpenter, 1939.     

“地衣”词考

本文考证了中国先秦时期到清末古籍中对“地衣”的解释;其中有共生学意义的“地衣”一词,是在清代李善兰的《植物学》一书中被提出的。     

细胞核和有性生殖是如何起源的?

真核生物的起源是一个根本性的、令人生畏的进化谜题, 目前设想的关于“核”起源的流行情景还远谈不上清晰。关于真核生物的起源可谓众说纷纭, 有共营模型、自演化模型、病毒性真核生物起源模型和外膜假说, 等等。迄今为止, 真核演化的动因则鲜有涉及。笔者发现, 从原核生物到真核生物, 基因组的DNA总量大约增加了3.5个数量级, 而这与现代真核生物的DNA压缩比(packing ratio)惊人地一致! 这样, 仅仅用偶然的吞噬、共生或寄生来解释真核生物的起源, 无论如何是难以让人信服的(其实, 正是内共生理论将人们引入了歧途), 而关键是需要解释基因组为何急剧增大。这可能与DNA的复制错误或多倍化现象不无关系, 当然并非完全排除不同种类个体之间的侧向的基因流动或整合的可能贡献。不难理解, DNA压缩机制的成型应该就是迈向真核生物的关键一步, 自然还伴随了细胞内部的结构分化、更为精巧而复杂的细胞分裂机制的发展, 等等。因此, 本文提出细胞核起源的新学说——压缩与结构化假说。此外, 从分子遗传学的角度来说, “性”一点都不神秘, 就是将两个个体的基因组拼在一起而已, 藉此种族多样的遗传信息分散到了个体之中; 而从生态的角度来看, “性”的原始动机就是与休眠事件的偶联。     

Erratum to: Immune maintenance in glaucoma: boosting the body’s own neuroprotective potential

Glaucoma, a slow progressive neurodegenerative disorder associated with death of retinal ganglion cells and degeneration of their connected optic nerve fibers, has been classically linked to high intraocular pressure. Regardless of the primary risk factor, degeneration may continue, resulting in further loss of neurons and subsequent glaucomatous damage. During the past decade, scientists and clinicians began to accept that, in addition or as an alternative to fighting off the primary risk factor(s), there is a need to protect the tissue from the ongoing spread of damage—an approach collectively termed “neuroprotection.” We found that the immune system, the body’s own defense mechanism, plays a key role in the ability of the optic nerve and the retina to withstand glaucomatous conditions. This defense involves recruitment of both innate and adaptive immune cells that together create a protective niche and thereby halt disease progression. The spontaneous immune response might not be sufficient, and therefore, we suggest boosting it by immunization (with the appropriate antigen, at specific timing and predetermined optimal dosing) which may be developed into a suitable therapeutic vaccination to treat glaucoma. This view of immune system involvement in glaucoma will raise new challenges in glaucoma research, changing the way in which clinicians perceive the disease and the approach to therapy.     

Immune maintenance in glaucoma: boosting the body’s own neuroprotective potential

Glaucoma, a slow progressive neurodegenerative disorder associated with death of retinal ganglion cells and degeneration of their connected optic nerve fibers, has been classically linked to high intraocular pressure. Regardless of the primary risk factor, degeneration may continue, resulting in further loss of neurons and subsequent glaucomatous damage. During the past decade, scientists and clinicians began to accept that, in addition or as an alternative to fighting off the primary risk factor(s), there is a need to protect the tissue from the ongoing spread of damage—an approach collectively termed “neuroprotection.” We found that the immune system, the body’s own defense mechanism, plays a key role in the ability of the optic nerve and the retina to withstand glaucomatous conditions. This defense involves recruitment of both innate and adaptive immune cells that together create a protective niche and thereby halt disease progression. The spontaneous immune response might not be sufficient, and therefore, we suggest boosting it by immunization (with the appropriate antigen, at specific timing and predetermined optimal dosing) which may be developed into a suitable therapeutic vaccination to treat glaucoma. This view of immune system involvement in glaucoma will raise new challenges in glaucoma research, changing the way in which clinicians perceive the disease and the approach to therapy.     

“教学、实践、科研、临床”四位一体的医学遗传学教学体系建设探索与实践

医学遗传学课程介于基础医学和临床医学之间,是一门应用性很强的学科,在现代医学教育体系中有着重要的地位。教学团队在多年的医学遗传学教学实践中,在建设省级精品课程的过程中,构建了“教学、实践、科研、临床”四位一体的医学遗传学教学体系,主要内容包括“课堂教学、社会实践、科学研究、临床应用”四者之间相互渗透、相互补充、相互促进,以课堂教学为基础,用社会实践补充教学,科学研究提升教学,临床应用促进教学。“四位一体”教学体系为基础课程与临床课程的有机整合探索了一条切实可行的路子。实施几年来,课程建设收到了良好效果,学科团队科研水平、社会声誉、医疗服务能力也有明显提高。