On the nonlinear relationship between the initial rates of dilution-induced microtubule disassembly and the initial free subunit concentration

We have examined the dilution-induced in vitro disassembly kinetics of bovine brain microtubules, initially at steady state, using a wider range of dilutions (2-100-fold) than previously employed. In contrast to earlier results, as well as to the simple nucleation-condensation model for microtubule formation, the initial rate of dimer loss from microtubule ends was not a linear function of the initial concentration of unpolymerized tubulin. Over a 2-20-fold dilution range, plots of the initial rate of dimer loss versus the initial unpolymerized tubulin concentration were approximately linear. However, at greater dilutions, rates of microtubule depolymerization increased nonlinearly. For example, between a 10-fold dilution and a 100-fold dilution, the initial rate of dimer loss for microtubule-associated protein-containing microtubules increased by 300%, rather than a maximum of 11% expected on the basis of a linear rate plot. The nonlinear response was observed for dimer loss from opposite microtubule ends separately and with microtubules containing and lacking associated proteins. Qualitatively similar results were obtained using a wide range of experimental protocols, from which we can reasonably exclude methodological artifact as a basis for the data. We can also reasonably exclude the dissociation of the high molecular weight microtubule-associated proteins 1 and 2 from the microtubules as an explanation for the nonlinearity of the rate plots. The nonlinearity of the rate plots indicates that kinetic constants obtained under nonsteady state conditions of extreme microtubule dilution may not describe the steady state condition accurately.     

口腔及肠道菌群与冠心病关系的研究进展

冠心病是由多种病理因素引起的复杂疾病,严重威胁人类健康,其机制尚未完全阐明。近年来,研究表明冠心病与口腔和肠道菌群密切相关。菌群失调导致的炎症反应、氧化应激反应、脂质代谢失调和氧化三甲胺累积是参与冠心病发生的主要风险因素。此外,口腔菌群与肠道菌群相关,参与冠心病的发生与发展。中医治疗疾病的优势在于辨证论治,而证型的判断缺乏客观标准。多项研究应用口腔菌群或肠道菌群分析了疾病的中医证型。本文系统地阐述了口腔菌群和肠道菌群在冠心病发病机制中的作用,阐述了不同中医证型冠心病菌群分析的研究进展,为临床开展此类研究提供参考。     

浅析肠道菌群与2型糖尿病及冠心病的关系

糖尿病和冠心病是当前危害公共健康的最普遍的问题,它们的发病率逐年升高。由糖尿病引发的心脑血管、肾、周围神经、眼、足等并发症增加了患者致残或致死的风险。冠心病的常见并发症如心肌梗塞、心源性休克和心力衰竭等,严重时也会危及患者生命。研究表明,肠道菌群紊乱可通过诱发炎症反应、胰岛素抵抗、脂质代谢异常、提高血尿酸水平等途径,增加2型糖尿病和冠心病的发病率,从而影响这些疾病的发展及预后,其诱发2型糖尿病的机制含内毒素机制、短链脂肪酸机制和胆汁酸机制等。本文从肠道菌群失调的角度综述肠道菌群与2型糖尿病及冠心病的关系。     

冠心病患者糖脂代谢与肠道菌群平衡的关系

研究冠心病(CHD)患者糖脂代谢与肠道菌群平衡的关系, 为该类患者的治疗提供参考。

选择2020年4月至2021年4月我院收治的79例CHD患者(CHD组)和82例健康体检者(对照组)为研究对象进行横断面研究。详细采集两组对象一般资料, 同时完成体格检查和生命体征检测并计算体质量指数(BMI)。采集两组对象入组第1天时空腹外周静脉血, 检测空腹血糖(FPG)和空腹胰岛素(FINS)水平并计算稳态模型胰岛素抵抗指数(HOMA-IR), 检测血清总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)等脂质代谢指标水平。收集两组研究对象新鲜晨便并采用荧光定量PCR法检测肠道双歧杆菌、乳杆菌、拟杆菌、梭菌和白假丝酵母数量。比较两组对象基本资料、糖脂代谢指标和肠道菌群分布, 分析CHD患者肠道菌群与糖脂代谢指标相关性。

CHD组患者HOMA-IR(t=2.729, P=0.007)和血清TC(t=2.915, P=0.030)、TG(t=2.567, P=0.011)水平显著高于对照组, 血清LDL-C(t=2.129, P=0.035)水平显著低于对照组。CHD组患者肠道双歧杆菌数量(t=2.247, P=0.026)和拟杆菌/梭菌比值(t=2.111, P=0.036)低于对照组。CHD患者肠道双歧杆菌数量和拟杆菌/梭菌比值与HOMA-IR(r=-0.384、-0.354, P < 0.001、=0.012)以及血清TC(r=-0.361、-0.329, P=0.005、0.027)、TG(r=-0.358、-0.341, P=0.009、0.020)和LDL-C(r=-0.326、-0.317, P=0.031、0.038)水平均呈显著负相关。

CHD患者糖脂代谢和肠道菌群分布均存在显著异常, 且HOMA-IR、血清TC、TG和LDL-C水平均与肠道双歧杆菌数量和拟杆菌/梭菌比值呈负相关, 因此对肠道菌群进行检测和合理干预有利于调节糖脂代谢。

     

Association between coronary endothelial dysfunction and local inflammation of atherosclerotic coronary arteries

We have examined a possibility whether or not severity and extent of coronary atherosclerosis may associate with degree of local inflammation in relation to endothelial dysfunction as is indicated by reduced NO formation. Blood samples were obtained from aortic root (Ao) and coronary sinus (CS) of 39 patients who underwent coronary angiography. Plasma NOx levels (nitrite + nitrate, stable NO end-products) were evaluated by HPLC-Griess system, and markers of inflammation, C-reactive protein (CRP) and serum amyloid A protein (SAA), were measured by Latex Turbidimetric Immunoassay. To evaluate the changes of these substances through coronary circulation, the percentage changes of respective markers [(CS – Ao) × 100/Ao] were calculated. The extent and severity of atherosclerosis of left coronary arteries were evaluated with Gensini Score (GS). The GS correlated with the percentage changes of NOx (r = –0.35, p < 0.05) and that of SAA (r = 0.43, p < 0.05) across coronary circulation, but not with changes in CRP. Moreover, the percentage changes of NOx correlated with that of SAA (r = –0.36, p < 0.05). These results indicated that severity and extent of coronary atherosclerosis related to degree of local inflammation which has a possible association with coronary endothelial dysfunction.     

Heart and gut chiralities are controlled independently from initial heart position in the developing zebrafish

A fundamental problem in developmental biology is how left-right (LR) asymmetry is generated, both on the whole organism level and at the level of an individual organ or structure. To investigate the relationship of organ sidedness to organ chirality, we examined 12 zebrafish mutants for initial heart tube position and later heart looping direction (chirality). Anomalous initial heart position was found in seven mutants, which also demonstrated loss of normal LR asymmetry in lateral plate mesoderm (LPM) antivin/lefty-1 and Pitx2 expression. Those with a relatively normal notochord (cyc(b16), din, and spt) displayed a predictive correlation between initial heart position and heart chirality, whereas initial heart position and heart chirality were independently randomized in those with a defective notochord (flh, boz, ntl, and mom). The predictability of heart chirality in spt, din, and b16 embryos, even in the absence of normal antivin/lefty-1 and Pitx2 expression, strongly suggests that heart chirality is controlled by a process distinct from that which controls appropriate left-sided LPM expression of antivin-Pitx2 signaling pathway molecules. In addition, there was correlation of initial heart position with gut chirality (and also between heart chirality and gut chirality) in the first class of mutants with normal notochord, but not in the second class, which appears to model human heterotaxy syndrome.     

Adaptive structures of the arteries of the heart participating in the regulation of coronary circulation

By means of a complex of anatomical, histological and histochemical methods cardiac vessels have been studied in 20 control dogs and in 84 dogs with experimentally produced circulatory disturbances peculiar for congenital heart diseases presented as an open arterial duct, coarctation of the aorta and the pulmonary trunk stenosis. The experimental animals have been observed for 6-12 months. In the animals with experimentally produced disturbances of the general and coronary hemodynamics hyperplasy in the coronary branches of the arteries appears, it is more pronounced in functionally loaded cardiac parts, as well as thickening of their walls at the expense of new formations and hyperthrophy of smooth muscle cells. In both control and experimental dogs in the coronary vessels at various branching levels certain formations are revealed; they are of compensatory-adaptive value: intimal and adventitial musculature, polypoid pulvinars, muscular-elastic constrictors, muscular cuffs and precapillary sphincters. They differ in structure, sources of their origin and in their functional value. Degree of their manifestation increases significantly after reproduction of the hemodynamic disturbances in the heart vascular system. The active role of these formations in regulation of the coronary circulation is demonstrated owing to a high content of ribonucleinic acid and glycogene in their smooth muscle cells and also an elevated succinate dehydrogenase, cytochromoxydase, acid and alcaline phosphatase activities.     

Vasculogenesis and angiogenesis: Extracellular matrix remodeling in coronary collateral arteries and the ischemic heart

Heart failure secondary to ischemic cardiomyopathy is the primary cause of cardiovascular mortality. The promise of the collateral circulation lies in its potential to alter the course of the natural history of coronary heart disease. The collateral circulation of the heart is responsible for supplying blood and oxygen to the myocardium at ischemic risk following severe stenosis and reduced vasoelasticity function of a major coronary artery. In response to flow, stress, and pressure, collateral vessels are restructured and remodeled. Vascular remodeling by its very nature implies synthesis and degradation of extracellular matrix components in the vessel wall. Under normal physiological conditions proteinases that break down the specialized matrix are tightly regulated by antiproteinases. The balance between proteinase and antiproteinase influences is discoordinated during collateral development which leads to adaptive changes in the structure, function, and regulation of extracellular matrix components in the vessel wall. The role of extracellular matrix components in coronary collateral vessel formation in a canine model of chronic coronary artery occlusion has been demonstrated. The role of matrix proteinases and antiproteinases in the collateral vessel play a significant role in the underlying mechanisms of collateral development. This review presents new and significant information regarding the role of extracellular matrix proteinases and antiproteinases in vascular remodeling, function, and collateral development. Such information will have a significant impact on the understanding of the basic biology of the vascular extracellular matrix turnover, remodeling, and function as well as on elucidating potential avenues for pharmacological approaches designed to increase collateral formation and optimize myocardial blood flow in the treatment of ischemic heart disease. J. Cell. Biochem. 65:388–394. © 1997 Wiley-Liss, Inc.     

On the relationship between trophic position, body mass and temperature: reformulating the energy limitation hypothesis

Understanding the factors that constrain and drive changes in food chain length represents an open challenge in ecology. Although several explanatory hypotheses have been proposed, no synthesis has yet been achieved. The role of body size has been well-studied in recent years because the hierarchy of trophic connections – in which large animals consume small ones – suggests a positive relationship between trophic position and body size. Empirical evidence, however, supports the existence of both positive and negative associations, and some studies have even reported no significant relationship between trophic position and body size. These results suggest that the relationship may be non-monotonic and driven by several interacting mechanisms. Here, we analyze the effects of energetic limitations and structural constraints on species' trophic positions. We show that the trophic position of small-bodied animals can be limited by their ability to consume large prey, whereas energetic limitations strongly constrain trophic positions for large-bodied animals, with the intensity of this constraint depending on the amount of energy available to top predators. These differences in limiting mechanisms can account for the observed variability in the association between the trophic position of top predators and size. Furthermore, our derivation makes use of the Metabolic theory of ecology and predicts a negative relationship between temperature and the maximum achievable food chain length, providing a mechanistic foundation for the observed reductions in food chain length with temperature.     

On the relation between initial value and slope

Suppose measurements of a particular feature are collected at baseline and at a number of subsequent time points and that for each individual there is a roughly linear trend in time. This paper takes three approaches to testing whether there is a relation between the initial value and the slope. It also considers whether the initial value for an individual is a useful predictor of the slope for that individual. The problems are formulated in terms of regression models with random coefficients. The solutions are illustrated using data from an observational study of clinical correlates of disability and progression in Huntington's disease.     

Evolutionary relationship between initial enzymes of tetrapyrrole biosynthesis

Glutamate-1-semialdehyde 2,1-aminomutase (GSAM) is the second enzyme in the C(5) pathway of tetrapyrrole biosynthesis found in most bacteria, in archaea and in plants. It catalyzes the transamination of glutamate-1-semialdehyde to 5-aminolevulinic acid (ALA) in a pyridoxal 5'-phosphate (PLP)-dependent manner. We present the crystal structure of GSAM from the thermophilic cyanobacterium Thermosynechococcus elongatus (GSAM(Tel)) in its PLP-bound form at 2.85A resolution. GSAM(Tel) is a symmetric homodimer, whereas GSAM from Synechococcus (GSAM(Syn)) has been described as asymmetric. The symmetry of GSAM(Tel) thus challenges the previously proposed negative cooperativity between monomers of this enzyme. Furthermore, GSAM(Tel) reveals an extensive flexible region at the interface of the proposed complex of GSAM with glutamyl-tRNA reductase (GluTR), the preceding enzyme in tetrapyrrole biosynthesis. Compared to GSAM(Syn), the monomers of GSAM(Tel) are rotated away from each other along the dimerization interface by 10 degrees . The associated flexibility of GSAM may be essential for complex formation with GluTR to occur. Unexpectedly, we find that GSAM is structurally related to 5-aminolevulinate synthase (ALAS), the ALA-producing enzyme in the Shemin pathway of alpha-proteobacteria and non-plant eukaryotes. This structural relationship applies also to the corresponding subfamilies of PLP-dependent enzymes. We thus propose that the CoA-subfamily (including ALAS) and the aminotransferase subfamily II (including GSAM) are evolutionarily closely related and that ALAS may thus have evolved from GSAM.     

Landscape of the relationship between type 2 diabetes and coronary heart disease through an integrated gene network analysis

Type 2 diabetes (T2D) and coronary artery disease (CAD) are closely related chronic diseases with high prevalence and morbidity. However, a comprehensive comparison of the two diseases is lacking. Recent genome-wide association studies (GWAS) have identified a handful of single nucleotide polymorphisms (SNPs) that are significantly associated with the risk of T2D and CAD. These most significant findings may help interpret the pathogenesis of T2D and CAD. However, tremendous results from these GWAS are ignored. Here we revisited the raw datasets of these GWAS and performed an integrated gene network analysis to unveil the relationship between T2D and CAD by combining multiple datasets including protein–protein interaction (PPI) database, publication libraries, and pathway datasets. Our results showed that majority of genes were involved in the first module (1122 genes in T2D and 895 in CAD). Four pathways were found to be common in both T2D and CAD, including regulation of actin cytoskeleton, calcium signaling pathway, MAPK signaling pathway and focal adhesion (all P < 0.00001). MAX which was involved in small cell lung cancer pathway was a hub gene unique to T2D (OR = 1.2, P = 0.006) but not in CAD. In contrast, three hub genes including PLEKHG5 (T2D: OR = 1, P = 1; CAD: OR = 1.12, P = 0.006), TIAM1 (T2D: OR = 1, P = 1; CAD: OR = 1.48, P = 0.004) and AKAP13 (T2D: OR = 1, P = 1; CAD: OR = 1.38, P = 0.001) were hub genes unique to CAD. Moreover, for some hub genes (such as SMAD3) that were susceptible to both T2D and CAD, their associated polymorphisms were unique to each of the two diseases. Our findings might provide a landscape of the relationship between T2D and CAD.     

Blood flow patterns in the proximal human coronary arteries: relationship to atherosclerotic plaque occurrence

Atherosclerotic plaques in human coronary arteries are focal manifestations of systemic disease, and biomechanical factors have been hypothesized to contribute to plaque genesis and localization. We developed a computational fluid dynamics (CFD) model of the ascending aorta and proximal sections of the right and left coronary arteries of a normal human subject using computed tomography (CT) and magnetic resonance imaging (MRI) and determined the pulsatile flow field. Results demonstrate that flow patterns in the ascending aorta contribute to a pro-atherosclerotic flow environment, specifically through localization of low and oscillatory wall shear stress in the neighborhood of coronary orifices. Furthermore, these patterns differ in their spatial distribution between right and left coronary arteries. Entrance effects of aortic flow diminish within two vessel diameters. We examined relationships between spatial distributions of wall shear stress and reports of plaque occurrence in the literature. Results indicate low wall shear stress is co-located with increased incidence of lesions, and higher wall shear stresses are associated with lesion-resistant areas. This investigation does not consider plaque progression or advanced lesions, inasmuch as the CFD model was developed from a normal individual and the clinical data used for comparisons were obtained from autopsy specimens of subjects who died from non-cardiovascular causes. The data reported are consistent with the hypothesis that low wall shear stress is associated with the localization of atherosclerotic lesions, and the results demonstrate the importance of aortic flow on flow patterns in the proximal segments of the coronary arteries.     

On the relationship between handedness and longevity

Abstract

During the past five years, there have been numerous studies of the relationship between handedness and longevity. In this report, I review previous contributions and use methods of survival analysis on a set of 4,448 males to determine the strength of the relationship between handedness and longevity. The results indicate that left‐handers have small, yet significant, declines in survival probabilities between the ages of 65 and 85.