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.     

Psychotherapies for depression: a network meta‐analysis covering efficacy,acceptability and long‐term outcomes of all main treatment types

The effects of psychotherapies for depression have been examined in several hundreds of randomized trials, but no recent network meta‐analysis (NMA) has integrated the results of these studies. We conducted an NMA of trials comparing cognitive behavioural, interpersonal, psychodynamic, problem‐solving, behavioural activation, life‐review and “third wave” therapies and non‐directive supportive counseling with each other and with care‐as‐usual, waiting list and pill placebo control conditions. Response (50% reduction in symptoms) was the primary outcome, but we also assessed remission, standardized mean difference, and acceptability (all‐cause dropout rate). Random‐effects pairwise and network meta‐analyses were conducted on 331 randomized trials with 34,285 patients. All therapies were more efficacious than care‐as‐usual and waiting list control conditions, and all therapies – except non‐directive supportive counseling and psychodynamic therapy – were more efficacious than pill placebo. Standardized mean differences compared with care‐as‐usual ranged from –0.81 for life‐review therapy to –0.32 for non‐directive supportive counseling. Individual psychotherapies did not differ significantly from each other, with the only exception of non‐directive supportive counseling, which was less efficacious than all other therapies. The results were similar when only studies with low risk of bias were included. Most therapies still had significant effects at 12‐month follow‐up compared to care‐as‐usual, and problem‐solving therapy was found to have a somewhat higher long‐term efficacy than some other therapies. No consistent differences in acceptability were found. Our conclusion is that the most important types of psychotherapy are efficacious and acceptable in the acute treatment of adult depression, with few significant differences between them. Patient preference and availability of each treatment type may play a larger role in the choice between types of psychotherapy, although it is possible that a more detailed characterization of patients with a diagnosis of depression may lead to a more precise matching between individual patients and individual psychotherapies.     

A re-consideration of the taxonomic status of Nebria lacustris Casey (Coleoptera,Carabidae, Nebriini) based on multiple datasets – a single species or a species complex?

This study gathered evidence from principal component analysis (PCA) of morphometric data and molecular analyses of nucleotide sequence data for four nuclear genes (28S, TpI, CAD1, and Wg) and two mitochondrial genes (COI and 16S), using parsimony, maximum likelihood, and Bayesian methods. This evidence was combined with morphological and chorological data to re-evaluate the taxonomic status of Nebria lacustris Casey sensu lato. PCA demonstrated that both body size and one conspicuous aspect of pronotal shape vary simultaneously with elevation, latitude, and longitude and served to distinguish populations from the southern Appalachian highlands, south of the French Broad, from all other populations. Molecular analyses revealed surprisingly low overall genetic diversity within Nebria lacustris sensu lato, with only 0.39% of 4605 bp varied in the concatenated dataset. Evaluation of patterns observed in morphological and genetic variation and distribution led to the following taxonomic conclusions: (1) Nebria lacustris Casey and Nebria bellorum Kavanaugh should be considered distinct species, which is a NEW STATUS for Nebria bellorum. (2) No other distinct taxonomic subunits could be distinguished with the evidence at hand, but samples from northeastern Iowa, in part of the region known as the "Driftless Zone", have unique genetic markers for two genes that hint at descent from a local population surviving at least the last glacial advance. (3) No morphometric or molecular evidence supports taxonomic distinction between lowland populations on the shores of Lake Champlain and upland populations in the adjacent Green Mountains of Vermont, despite evident size and pronotal shape differences between many of their members.     

Parachorius semsanganus sp. n. (Coleoptera, Scarabaeidae, Scarabaeinae) from Laos and its significance in the phylogeny of Oriental Deltochilini

The new species Parachorius semsanganussp. n. is described from Laos. This enigmatic Oriental deltochiline represents a "morphological link" between Parachorius and Cassolus by sharing characters of the two genera. The fact that Parachorius semsanganus cannot be unequivocally placed in either of these two genera stresses some more general problems of the current classification of Parachorius and Cassolus. Such problems can be solved only in the course of phylogenetic analysis, the need of which is briefly outlined.     

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.     

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.     

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.     

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。     

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.     

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&#x0201c;碳中和&#x0201d;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&#x0201c;三优&#x0201d;生态建设和管理原则, 即&#x0201c;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&#x0201d;。此外, 文章还对&#x0201c;后碳中和&#x0201d;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。