On the intrinsic constraint of bacterial growth rate: M. tuberculosis’s view of the protein translation capacity

In nature, the maximal growth rates vary widely among different bacteria species. Fast-growing bacteria species such as Escherichia coli can have a shortest generation time of 20?min. Slow-growing bacteria species are perhaps best known for Mycobacterium tuberculosis, a human pathogen with a generation time being no less than 16?h. Despite of the significant progress made on understanding the pathogenesis of M. tuberculosis, we know little on the origin of its intriguingly slow growth. From a global view, the intrinsic constraint of the maximal growth rate of bacteria remains to be a fundamental question in microbiology. In this review, we analyze and discuss this issue from the angle of protein translation capacity, which is the major demand for cell growth. Based on quantitative analysis, we propose four parameters: rRNA chain elongation rate, abundance of RNA polymerase engaged in rRNA synthesis, polypeptide chain elongation rate, and active ribosome fraction, which potentially limit the maximal growth rate of bacteria. We further discuss the relation of these parameters with the growth rate for M. tuberculosis as well as other bacterial species. We highlight future comprehensive investigation of these parameters for different bacteria species to understand how bacteria set their own specific growth rates.     

Nonlinear conduction via solitons in a topological mechanical insulator

Networks of rigid bars connected by joints, termed linkages, provide a minimal framework to design robotic arms and mechanical metamaterials built of folding components. Here, we investigate a chain-like linkage that, according to linear elasticity, behaves like a topological mechanical insulator whose zero-energy modes are localized at the edge. Simple experiments we performed using prototypes of the chain vividly illustrate how the soft motion, initially localized at the edge, can in fact propagate unobstructed all of the way to the opposite end. Using real prototypes, simulations, and analytical models, we demonstrate that the chain is a mechanical conductor, whose carriers are nonlinear solitary waves, not captured within linear elasticity. Indeed, the linkage prototype can be regarded as the simplest example of a topological metamaterial whose protected mechanical excitations are solitons, moving domain walls between distinct topological mechanical phases. More practically, we have built a topologically protected mechanism that can perform basic tasks such as transporting a mechanical state from one location to another. Our work paves the way toward adopting the principle of topological robustness in the design of robots assembled from activated linkages as well as in the fabrication of complex molecular nanostructures.Mechanical structures composed of folding components, such as bars or plates rotating around pivots or hinges, are ubiquitous in engineering, materials science, and biology (1). For example, complex origami-like structures can be created by folding a paper sheet along suitably chosen creases around which two nearby faces can freely rotate (2–4). Similarly, linkages can be viewed as 1D versions of origami where rigid bars (links) are joined at their ends by joints (vertices) that permit full rotation of the bars (Fig. 1 A–C). Some of the joints can be pinned to the plane while the remaining ones rotate relative to each other under the constraints imposed by the network structure of the linkage (5). Familiar examples include the windshield wiper, robotic arms, biological linkages in the jaw and knee, and toys like the Jacob’s ladder (6) and the Hoberman sphere. Moreover, linkages and origami can be used in the design of microscopic and structural metamaterials whose peculiar properties are controlled by the geometry of the unit cell (7, 8).Open in a separate windowFig. 1.The chain of rotors in the flipper phase. (A) The translation symmetric system with θ=θ¯ constant. We show a linkage made from plastic and metal screws. (B) A computer sketch of the elastic chain (11): The masses are blue, rigid rotors are black, and springs are dashed red lines. The green arrows depict the amplitude of displacement of each mass of the edge-localized zero mode of the system. (C) A configuration of the linkage showing a soliton as a domain wall between right-leaning and left-leaning states. (D) A computer-simulated static configuration. The arrows beneath show the x projections of each rotor.Many of these examples are instances of what mechanical engineers call mechanisms: structures where the degrees of freedom are nearly balanced by carefully chosen constraints so that the allowed free motions encode a desired mechanical function. However, as the number of components increases, more can go wrong: lack of precision machining or undesired perturbations. Robustness in this sense is a concern relevant to the design of complex mechanical structures from the microscopic to the architectural scale, typically addressed at the cost of higher manufacturing tolerances or active feedback.Here, we take an alternative approach inspired by recent developments in the design of fault tolerant quantum devices (9). Consider, as an example, the quantized Hall conductivity of a 2D electron gas that is topologically protected in the sense that it cannot change when the Hamiltonian is smoothly varied (10). In this article, we present a topologically protected classical mechanism that can transport a mechanical state across a chain-like linkage without being affected by changes in material parameters or smooth deformations of the underlying structure, very much like its quantum counterparts.Kane and Lubensky (11) recently took an important step toward establishing a dictionary between the quantum and classical problems. Their starting point, which seems at first disconnected from the linkages we study here, was to analyze the phonons in elastic systems composed of stretchable springs. In particular they derived a mathematical mapping between electronic states in topological insulators and superconductors (10) and the mechanical zero modes in certain elastic lattices (12). The simplest is the 1D elastic chain, shown in Fig. 1B, inspired by the Su–Schrieffer–Heeger (SSH) model for polyacetylene (13), a linear polymer chain with topologically protected electronic states at its free boundaries. In the mechanical chain, the electronic modes map onto zero-energy vibrational modes with a nontrivial topological index, whose eigenvectors represented as green arrows in Fig. 1B are localized at one of the edges (11). An intriguing question then arises: Could these zero-energy edge modes propagate through the system in the form of finite deformations?We address this question by building and analyzing a linkage of rigid bars as an extreme limit of the 1D lattice of springs. This linkage allows no stretching deformations, yet it still displays the distinctive zero-energy mode localized at the edges (Fig. 1 and Movie S1). By nudging the rotors along the direction of the zero-energy mode (Fig. 1B and Movie S2), we provide a vivid demonstration of how the initially localized edge mode can indeed propagate and be moved around the chain at an arbitrarily small energy cost. We then show analytically and numerically that the mechanism underlying the mechanical conduction is in fact an evolution of the edge mode into a nonlinear topological soliton, which is the only mode of propagation in the chain of linkages that costs zero potential energy. The soliton or domain wall interpolates between two distinct topological mechanical phases of the chain and derives its robustness from the presence of a band gap within linear elasticity and the boundary conditions imposed at the edges of the chain. Although the topological protection ensures the existence of a domain wall, the dynamical nature of the soliton falls into two distinct classes that can ultimately be traced to the geometry of the unit cell. The prototypes we built therefore provide simple examples of structures that we dub topological metamaterials whose excitations are topologically protected zero-energy solitons (9).     

A cellular solution to an information-processing problem

Signaling receptors on the cell surface are mobile and have evolved to efficiently sense and process mechanical or chemical information. We pose the problem of identifying the optimal strategy for placing a collection of distributed and mobile sensors to faithfully estimate a signal that varies in space and time. The optimal strategy has to balance two opposing objectives: the need to locally assemble sensors to reduce estimation noise and the need to spread them to reduce spatial error. This results in a phase transition in the space of strategies as a function of sensor density and efficiency. We show that these optimal strategies have been arrived at multiple times in diverse cell biology contexts, including the stationary lattice architecture of receptors on the bacterial cell surface and the active clustering of cell-surface signaling receptors in metazoan cells.The molecular characteristics of signaling receptors and their spatiotemporal organization have evolved to optimize different facets of information processing at the cell surface. A canonical information-processing problem involves designing strategies for a collection of distributed, noisy, mobile sensors to faithfully estimate a signal or function that varies in space and time (1). This problem appears naturally in many contexts, biological and nonbiological: (i) chemoattractant protein sensors on the bacteria cell surface (2, 3); (ii) galectin-glycoprotein assemblies designed for effective immune response on the surface of metazoan cells (4, 5); (iii) ligand-activated signaling protein receptors on the surface of eukaryotic cells (6–10); (iv) coclustering of integrin receptors to faithfully read and discriminate the rigidity and chemistry of a substrate (11); (v) clustering of e-cadherin receptors for effective adherence at cell–cell junctions (12); and even (vi) radio frequency (RF) sensor networks monitoring the environment or mobile targets (13). In the signal-processing community, this problem is known as data fusion or more generally information fusion (14, 15); however typical applications do not consider mobile sensors.In this paper we show how biology has, on multiple occasions, arrived at a solution to this optimization problem. The optimal solution needs to balance two opposing objectives, the need to locally assemble sensors to reduce estimation noise and the need to spread them out for broader spatial coverage. We show that in the space of strategies, this leads to a phase transition as a function of sensor density, sensor characteristics, and function properties. At very low sensor density, the optimal design corresponds to freely diffusing sensors. For sensor density above a threshold, there are two different optimal solutions as a function of a dimensionless parameter constructed from the sensor advection velocity and the correlation length and time of the incident signal. One optimal solution is that the sensors are static and located on a regular lattice grid. This is the strategy used in bacteria, such as Escherichia coli, to organize their chemoattractant receptors in a regular lattice array (3, 16), and in metazoan cells, where galectin-glycoproteins are organized in a lattice on the cell surface to effect an optimal immune response (4, 5). To realize this strategy, the cell needs to provide a rigid cortical scaffold that holds the receptors in place. Another optimal solution is to make the receptors mobile in such a way that a fraction of them form multiparticle nanoclusters, which then break up and reform randomly, the rest being uniformly distributed. Recent studies on the steady-state distribution of several cell-surface proteins reveal a stereotypical distribution of a fixed fraction of monomers and dynamic nanoclusters (6–9), and our information theoretic perspective could provide a general explanation for this. To realize this dynamic strategy, the cell surface needed to be relieved of the constraints imposed by the rigid scaffold and to be more regulatable. This strategy change needed the innovation of motor proteins and dynamic actin filaments, a regulated actomyosin machinery fueled by ATP, and a coupling of components of the cell surface to this cortical dynamic actin (17).     

经颅直流电刺激对基于偏定向相干因效脑网络特征的影响

利用脑网络研究经颅直流电刺激(tDCS)对脑功能机制和脑皮层状态的影响具有重要意义。本研究基于偏定向相干因果分析方法,构建被试在不同tDCS刺激实验范式下进行运动想象的因效性脑网络。以因效性脑网络的功能脑区通道信息流入、流出率为局部特征,平均聚类系数、全局效率为全局特征,分析研究tDCS对运动想象脑网络特征的影响。16名健康被试均为右利手。结果显示,被试执行左手运动想象下,伪刺激和阳极刺激C4后的C4通道信息流出率、流入率、平均聚类系数和全局效率分别为0.142±0.014、0.193±0.013、0.585±0.046、0.347±0.031和0.223±0.025、0.258±0.023、0.817±0.021、0.491±0.091,均存在显著性差异(P<0.05);tDCS阴极刺激C4后的C4通道信息流出率、平均聚类系数和全局效率分别为0.109±0.009、0.356±0.037和0.252±0.024,与伪刺激相比差异显著(P<0.05),C4通道信息流入率为0.184±0.008,与伪刺激相比无显著差异(P>0.05)。研究表明,阳极tDCS有效激活该脑区皮层的活跃性,使脑区信息交流更加频繁,增加脑网络的聚集程度,提高脑网络的连通性;阴极tDCS刺激则会抑制脑区皮层的活跃性,降低了脑区信息的流出,减少脑网络的聚集程度,降低脑网络的连通性。     

新型长效脂质声学造影剂增强兔肝脏VX2肿瘤的实验研究

目的　验证长效造影剂“脂氟显”在新西兰白兔 VX2 肝癌中的造影增强效果。方法　 12只患有 VX2 肝癌的新西兰白兔经耳缘静脉团注脂氟显 0 .0 2 ml/ kg;使用二次谐波显像模式观察记录造影过程 ;用定性视觉评分和定量视频密度分析造影效果。结果　肿瘤视觉增强效果从 10 s开始 ,持续时间长约 4 0～ 6 0 min。视觉评分在造影后 10、 2 0和 4 0 min与造影前比较有显著性差异 ,6 0 min则无明显差异。造影前后总体视觉效果有非常显著差异 (P<0 .0 1)。视频密度分析 ,造影后 10到 6 0 min的 VX2肿瘤灰阶值非常显著地小于正常肝组织 (P<0 .0 1)。结论　脂氟显能持续增强兔肝脏 VX2 肿瘤超声影像长达 4 0～ 6 0 min,优于多种同类声学造影剂。     

Inactivation of a Defined Active Site in the Mouse 20S Proteasome Complex Enhances Major Histocompatibility Complex Class I Antigen Presentation of a Murine Cytomegalovirus Protein

Proteasomes generate peptides bound by major histocompatibility complex (MHC) class I molecules. Avoiding proteasome inhibitors, which in most cases do not distinguish between individual active sites within the cell, we used a molecular genetic approach that allowed for the first time the in vivo analysis of defined proteasomal active sites with regard to their significance for antigen processing. Functional elimination of the δ/low molecular weight protein (LMP) 2 sites by substitution with a mutated inactive LMP2 T1A subunit results in reduced cell surface expression of the MHC class I H-2L^d and H-2D^d molecules. Surface levels of H-2L^d and H-2D^d molecules were restored by external loading with peptides. However, as a result of the active site mutation, MHC class I presentation of a 9-mer peptide derived from a protein of murine cytomegalovirus was enhanced about three- to fivefold. Our experiments provide evidence that the δ/LMP2 active site elimination limits the processing and presentation of several peptides, but may be, nonetheless, beneficial for the generation and presentation of others.     

循环微小RNA对活动性结核病诊断效能的荟萃分析

目的用荟萃(meta)分析评价循环微小RNA对活动性结核病的诊断效能。方法检索PubMed、Web of Science、Embase、中国知网、万方、维普及中国生物医学文献数据库(CBM)等数据库收集文献,检索时限均为从建库至2019年4月。并根据文献中的原始资料评价循环miRNA检测活动性结核病的准确性,采用Stata 15.0软件进行meta分析。结果共纳入21篇文献,累计1142例患者和1231例对照者。meta分析结果显示合并敏感性为0.85(95%CI:0.78~0.89)、特异性为0.85(95%CI:0.81~0.88)、阳性似然比为5.49(95%CI:4.21~7.15)、阴性似然比为0.18(95%CI:0.13~0.26)、合并诊断比值比为30.06(95%CI:16.88~53.52),SROC曲线下面积(AUC)为0.91(95%CI:0.88~0.93)。亚组分析显示,miRNA-155用于诊断活动性结核病的AUC为0.90(95%CI:0.87~0.92)。结论循环miRNA是诊断活动性结核病的重要生物标志物,有较高敏感性和特异性。