Potential landscape and flux framework of nonequilibrium networks: robustness, dissipation, and coherence of biochemical oscillations

We established a theoretical framework for studying nonequilibrium networks with two distinct natures essential for characterizing the global probabilistic dynamics: the underlying potential landscape and the corresponding curl flux. We applied the idea to a biochemical oscillation network and found that the underlying potential landscape for the oscillation limit cycle has a distinct closed ring valley (Mexican hat-like) shape when the fluctuations are small. This global landscape structure leads to attractions of the system to the ring valley. On the ring, we found that the nonequilibrium flux is the driving force for oscillations. Therefore, both structured landscape and flux are needed to guarantee a robust oscillating network. The barrier height separating the oscillation ring and other areas derived from the landscape topography is shown to be correlated with the escaping time from the limit cycle attractor and provides a quantitative measure of the robustness for the network. The landscape becomes shallower and the closed ring valley shape structure becomes weaker (lower barrier height) with larger fluctuations. We observe that the period and the amplitude of the oscillations are more dispersed and oscillations become less coherent when the fluctuations increase. We also found that the entropy production of the whole network, characterizing the dissipation costs from the combined effects of both landscapes and fluxes, decreases when the fluctuations decrease. Therefore, less dissipation leads to more robust networks. Our approach is quite general and applicable to other networks, dynamical systems, and biological evolution. It can help in designing robust networks.     

Mesoscale networks and corresponding transitions from self-assembly of block copolymers

A series of cubic network phases was obtained from the self-assembly of a single-composition lamellae (L)-forming block copolymer (BCP) polystyrene-block-polydimethylsiloxane (PS-b-PDMS) through solution casting using a PS-selective solvent. An unusual network phase in diblock copolymers, double-primitive phase (DP) with space group of Im3¯m, can be observed. With the reduction of solvent evaporation rate for solution casting, a double-diamond phase (DD) with space group of Pn3¯m can be formed. By taking advantage of thermal annealing, order–order transitions from the DP and DD phases to a double-gyroid phase (DG) with space group of Ia3¯d can be identified. The order–order transitions from DP (hexapod network) to DD (tetrapod network), and finally to DG (trigonal planar network) are attributed to the reduction of the degree of packing frustration within the junction (node), different from the predicted Bonnet transformation from DD to DG, and finally to DP based on enthalpic consideration only. This discovery suggests a new methodology to acquire various network phases from a simple diblock system by kinetically controlling self-assembling process.

From constituted molecules to polymers, finally ordered hierarchical superstructures, self-assembled solids cover a vast area of nanostructures where the characters of building blocks direct the progress of self-assembly (1, 2). In nature, fascinating periodic network structures and morphologies from different species are appealing in nanoscience and nanotechnology due to their superior properties, especially for photonic crystal structures (3–7). For gyroid, trigonal planar network with chirality demonstrates its potential as chiropitc metamaterial (8–10). Beyond the splendid colors, networks either in macroscale or mesoscale mechanically strengthen their skeletons and protect those fragile but vital organs from impact (11, 12). Inspired by nature, biomimicking materials with mesoscale network may exceed the limitation of the intrinsic properties (13). The topology of networks could further improve their adaptability, allowing extreme deformation for energy dissipation (14). Moreover, network materials from hybridization of self-assembled block copolymers (BCPs) have been exploited to the design of mesoscale quantum metamaterials (15, 16). With the desire to acquire network textures for biomimicking nanomaterials, BCPs with immiscible constituted segments covalently joined together give the accessibility to the formation of nanonetwork morphologies via balancing enthalpic penalty from the repulsive interaction of constituted blocks and entropic penalty from the stretching of polymer chains (17–21). By taking advantage of precise synthesis procedures, it is feasible to obtain the aimed network phases from the self-assembly of BCPs such as Fddd (O⁷⁰) (22–24), gyroid (Q²¹⁴, Q²³⁰) (20, 21, 25–27), and diamond (Q²²⁴, Q²²⁷) (28–31) experimentally and theoretically. On the basis of theoretical prediction, the junction points (nodes) in the network phases could be coordinated with three, four, or six neighbors in three-dimensional space, resulting in the enhancement of packing frustration (31). Topologically, all these phases match the coordination number to neighbors (n = 3, 4, 6), showing no special case of quasicrystal. Accordingly, an order–order transition from double-diamond phase (DD, tetrapod) to double-gyroid phase (DG, trigonal planar network) has been observed (29). Yet, there is no DP phase being found in simple diblock systems except for liquid crystals (32, 33) or organic–inorganic nanocomposites from the mixtures of BCP with inorganic precursors (34, 35). Searching the rare occurrence of network phases and the corresponding phase transitions among phases will be essential to the demands for application by considering the deliberate structuring effects on aimed properties but the approaches remain challenging (8, 36–40). For instance, viewing the narrow window for network morphologies in diblock copolymer phase diagram, it demands harsh requirements for syntheses (2, 41). Recently, by taking advantage of using selective solvent for solution casting, it is feasible to acquire DG phase and even inverted DG phase from the self-assembly of lamellae (L)-forming polystyrene-block-polydimethylsiloxane (PS-b-PDMS) (42). Apart from that, a triclinic DG phase was recently discovered from the PS-b-PDMS which is commonly believed nonexisting in the conventional phase diagram (43). As a result, the phase diagram of BCPs with high interaction parameter is worthy of study for searching the metastable phases with unique network textures (44). Herein, we aim to acquire network phases from a simple diblock system by kinetically controlling the transformation mechanisms of self-assembly. As exemplified by using the PS-b-PDMS for solution casting, with the use of a PS-selective solvent (chloroform), a DP phase and a DD phase could be formed through controlled self-assembly, giving unique network phases simply from solution casting. Moreover, a DG phase can be also acquired from phase transformation. Consequently, a series of network phases with hexapod, tetrapod, and trigonal planar building units could be successfully obtained by using a single-composition L-forming PS-b-PDMS for self-assembly. The corresponding order–order transitions among these network phases examined by temperature-resolved in situ small-angle X-ray scattering (SAXS) combining with electron tomography results provide insights of network phase formation and the corresponding phase transformation mechanisms in the self-assembly of BCPs.     

Flexible and dynamic organization of bone marrow stromal compartment

The bone marrow mesenchymal compartment contains putative stem/progenitors of skeletal tissue components such as bone, cartilage, haematopoiesis-supporting stroma and adipocytes. Previously appreciated as vital to the support of haematopoiesis, these cells have also been recently recognized as having significant immunomodulatory properties with implications for allogeneic haematopoietic cell transplantation. Despite having been studied for more than three decades and currently being used in different clinical settings, their biology remains elusive. The aim of this review is to critically analyse the field of mesenchymal stem/progenitor cell biology, in respect of their relationship with other mesenchymal cell-types. Several issues concerning lineage commitment and inter-conversion potential between different mesenchymal cell-types are reviewed.     

诱导性多能干细胞及其在脑血管病研究和治疗中的应用

诱导性多能干(induced pluripotent stem,iPS)细胞由已分化的体细胞重新编程而来,在生物学特性方面与胚胎干细胞极其相似.与胚胎干细胞相比,iPS细胞不受细胞来源、免疫排斥和伦理学等方面的限制,并具有保留特定个体基因等优势,为再生医学以及组织工程等领域提供了可能的细胞资源.文章主要介绍了iPS细胞及其在脑血管病研究和治疗中的应用.     

Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control

A common strategy of metabolic engineering is to increase the endogenous supply of precursor metabolites to improve pathway productivity. The ability to further enhance heterologous production of a desired compound may be limited by the inherent capacity of the imported pathway to accommodate high precursor supply. Here, we present engineered diterpenoid biosynthesis as a case where insufficient downstream pathway capacity limits high-level levopimaradiene production in Escherichia coli. To increase levopimaradiene synthesis, we amplified the flux toward isopentenyl diphosphate and dimethylallyl diphosphate precursors and reprogrammed the rate-limiting downstream pathway by generating combinatorial mutations in geranylgeranyl diphosphate synthase and levopimaradiene synthase. The mutant library contained pathway variants that not only increased diterpenoid production but also tuned the selectivity toward levopimaradiene. The most productive pathway, combining precursor flux amplification and mutant synthases, conferred approximately 2,600-fold increase in levopimaradiene levels. A maximum titer of approximately 700 mg/L was subsequently obtained by cultivation in a bench-scale bioreactor. The present study highlights the importance of engineering proteins along with pathways as a key strategy in achieving microbial biosynthesis and overproduction of pharmaceutical and chemical products.     

白血病细胞铁变化对TPA诱导K562细胞生长分化的影响

目的：通过改变细胞培养时铁状态,观察TPA诱导K562细胞分化过程中细胞铁对K562细胞生长分化的影响,探讨铁与白血病细胞诱导分化的关系。方法：应用体外细胞培养技术,观察不同铁水平K562细胞生长抑制率;用非特异性酯酶染色观察细胞生长分化情况。结果：在TPA诱导K562细胞分化过程中TPA组和TPA＋Fe组K562细胞生长抑制率分别为8.67%、6.01%,而TPA-Fe组98.88%。对照组及TPA-Fe组K562细胞NSE染色阳性率为15.5%和13%,以弱阳性为主,氟化钠抑制率分别为16.13%和19.23%;TPA、TPA＋Fe组K562细胞NSE染色呈阳性和强阳性,阳性率分别为86%、88%,且这两组K562细胞氟化钠抑制率分别为58.72%、61.93%。结论：铁剥夺可明显抑制K562细胞生长、阻止TPA诱导K562细胞分化,故铁剥夺剂（DFO）可能作为一种辅助抗癌药用于白血病的化疗,但由于它能阻止白血病细胞的分化,故不宜用于白血病的诱导分化治疗。     

Dynamics of enzymatic digestion of elastic fibers and networks under tension

We study the enzymatic degradation of an elastic fiber under tension using an anisotropic random-walk model coupled with binding-unbinding reactions that weaken the fiber. The fiber is represented by a chain of elastic springs in series along which enzyme molecules can diffuse. Numerical simulations show that the fiber stiffness decreases exponentially with two distinct regimes. The time constant of the first regime decreases with increasing tension. Using a mean field calculation, we partition the time constant into geometrical, chemical and externally controllable factors, which is corroborated by the simulations. We incorporate the fiber model into a multiscale network model of the extracellular matrix and find that network effects do not mask the exponential decay of stiffness at the fiber level. To test these predictions, we measure the force relaxation of elastin sheets stretched to 20% uniaxial strain in the presence of elastase. The decay of force is exponential and the time constant is proportional to the inverse of enzyme concentration in agreement with model predictions. Furthermore, the fragment mass released into the bath during digestion is linearly related to enzyme concentration that is also borne out in the model. We conclude that in the complex extracellular matrix, feedback between the local rate of fiber digestion and the force the fiber carries acts to attenuate any spatial heterogeneity of digestion such that molecular processes manifest directly at the macroscale. Our findings can help better understand remodeling processes during development or in disease in which enzyme concentrations and/or mechanical forces become abnormal.     

Sex-specific effects of social networks on the prevalence, awareness, and control of hypertension among older Korean adults

Background Hypertension is a common chronic disease among older adults, and is associated with medical complications and mortality. This study aimed to examine the effects of social network characteristics on the prevalence, awareness, and control of hypertension among older adults. Methods The Korean Social Life, Health, and Aging Project (KSHAP) interviewed 814 ≥ 60-year-old residents and their spouses from a rural township between December 2011 and March 2012 (response rate: 95%). We evaluated the data from 595 participants. Multivariate logistic regression models were used to assess the effects of network characteristics on hypertension. Results We observed strong sex-specific network effects on the prevalence, awareness, and control of hypertension. Among older women, network density was associated with hypertension awareness [odds ratio (OR): 2.63, 95% confidence interval (CI): 1.03–5.37] and control (OR: 1.72; 95% CI: 0.94–3.13). Among older men, large networks were associated with a lower prevalence of hypertension (OR: 0.75; 95% CI: 0.58–0.96). Compared to older women, older men with coarse networks exhibited better hypertension awareness (OR: 0.37; 95% CI: 0.14–0.95) and control (OR: 0.42; 95% CI: 0.19–0.91). Network size interacted with density for hypertension control (P = 0.051), with controlled hypertension being associated with large and course networks. Conclusions A large network was associated with a lower risk for hypertension, and a coarse network was associated with hypertension awareness and control among older men. Older women with dense networks were most likely to exhibit hypertension awareness and control.     

Recovering time-varying networks of dependencies in social and biological studies

A plausible representation of the relational information among entities in dynamic systems such as a living cell or a social community is a stochastic network that is topologically rewiring and semantically evolving over time. Although there is a rich literature in modeling static or temporally invariant networks, little has been done toward recovering the network structure when the networks are not observable in a dynamic context. In this article, we present a machine learning method called TESLA, which builds on a temporally smoothed l₁-regularized logistic regression formalism that can be cast as a standard convex-optimization problem and solved efficiently by using generic solvers scalable to large networks. We report promising results on recovering simulated time-varying networks and on reverse engineering the latent sequence of temporally rewiring political and academic social networks from longitudinal data, and the evolving gene networks over >4,000 genes during the life cycle of Drosophila melanogaster from a microarray time course at a resolution limited only by sample frequency.     

人羊水来源c-kit+与c-kit-间充质干细胞生物学特征及体外心肌诱导分化能力的比较

目的比较人羊水来源c-kit＋与c-kit-间充质干细胞的生物学特征及体外心肌分化能力。方法通过常规产前诊断或自愿引产,以羊膜腔穿刺术获取14份孕中期羊水（15～31周）,通过流式细胞仪分选c-kit＋间充质干细胞,比较c—kit＋干细胞与c-kit-干细胞的细胞形态及生长曲线。流式细胞仪及免疫细胞化学分析对两种细胞进行表型鉴定,比较其体外向成骨、成脂及心肌样细胞诱导分化能力。RT-PCR和Westonblot检测相关基因及蛋白的表达。结果14份羊水标本中,有5份标本可以分选到c—kit＋羊水干细胞,分布在孕16-22周,分选的细胞数量占贴壁细胞的（3．30±1．24）％。羊水干细胞以成纤维状为主,可以稳定传代,体外培养可增殖到50代以上。经过c—kit分选后,细胞呈均匀一致的长纤维状,排列规律。C-kit＋及c-kit-羊水干细胞具有相似的生长曲线。两种细胞均具有间充质干细胞特征,表达间充质干细胞标记（CD29,CD44,CD73,CD90,CDl05）,不表达造血细胞系标记（CD34,CD45）,表达I类人类组织相容性抗原（HLA—ABC）,不表达II类人类组织相容性抗原（HLA—DR）。Oct-4及SSEA-4胚胎干细胞标记在c-kit＋干细胞的表达比率明显高于c．kit-干细胞。两种细胞在体外均可以向成脂细胞、成骨细胞分化。成脂细胞诱导后,可以看到细胞内脂滴聚集,油红0染色阳性。成骨细胞诱导后,可以看到钙盐沉积,VonKossa染色阳性。两种细胞分别与新生乳鼠心肌共培养,体外向心肌细胞诱导,c—kit＋羊水干细胞可以检测到GATA-4,α-actin,Cx43和cTnT基因及蛋白的表达。而c-kit-干细胞在诱导后只表达GATA-4的基因及蛋白。结论羊水来源c—kit＋及c—kit-干细胞均表达间充质干细胞表型特征,体外可以向成脂、成骨细胞分化。然而,c—kit＋干细胞的心肌样细胞分化能力明显强于c—kit-干细胞,可能与c—kit＋干细胞具有某些胚胎干细胞特征有关。     

Links between the organization of the family home environment and child obesity: a systematic review

Due to increasingly high rates of child overweight and obesity, it is important to identify risk and protective factors that may inform more effective prevention and intervention. The degree of organization in the family home environment is a studied, but not well‐specified, factor that may impact child weight. Prior research on household organization has examined an array of constructs, including family routines, limit setting, household chaos, crowding and the broad home environment. This study systematically reviews literature on organization within the family home environment and weight among children ages 2–12. Six hundred thirty‐seven studies were reviewed by four coders for eligibility, and 32 studies were included in the final synthesis. Overall, 84% of studies provided evidence for relations between at least one indicator of organization within the family home environment and child weight. Studies provided compelling evidence across several constructs, suggesting that the relevance of household organization to child weight extends beyond a single indicator. Directions for future work include (i) examining the mediating role of health behaviours, (ii) examining the moderating role of socioeconomic factors, (iii) broadening this evidence base across cultures and nationalities and (iv) integrating constructs to develop a comprehensive model of organization within the home environment.