AMPK在妊娠期糖尿病发病机制中的作用

腺苷酸活化蛋白激酶是一种重要的蛋白激酶,主要作用是协调代谢和能量平衡.腺苷酸活化蛋白激酶被激活后,在增加骨骼肌对葡萄糖摄取、增强胰岛素敏感性、增加脂肪酸氧化以及调节基因转录等方面发挥重要作用.已经证实脂联素有调节糖脂代谢的作用,但其作用机制尚不十分清楚,很可能是通过腺苷酸活化蛋白激酶介导,对脂联素信号转导通路的研究将成为进一步理解脂联素作用的关键所在.而脂联素又是妊娠期糖尿病的预测因子,所以腺苷酸活化蛋白激酶逐渐成为对妊娠期糖尿病研究中的焦点.     

Catastrophic failure of modular Zirconia—Ceramic femoral head components after total hip arthroplasty

Catastrophic failure of two zirconia—ceramic modular femoral heads occurred, despite the theoretical improved toughness of zirconia—ceramic relative to alumina—ceramic. This experience led the authors to return to cobalt—chromium as the metal of choice for articulation against polyethylene in total hip arthroplasty.     

藏汉民族线粒体基因组全序列的比较研究

目的 以藏汉民族线粒体基因组全序列为基础,进行Haplogroup构建和系统发生分析,在全序列水平上比较核苷酸的变异,阐释可能的变异机制和蕴含的生物学意义.方法 采用Applied Biosystems 3730DNA自动测序仪分别对40名藏族和50名汉族的标本进行线粒体DNA序列测定,应用phredPhrap 16.0软件进行全序列拼接,并以rCRS(revised Cambridge Reference Sequence)为标准与测定序列进行比对分析;根据MTTO-MAP的标准,通过Network方法进行Haplogroup构建和系统发生的分析,并结合其它方法对产生的数据进行深入解读.结果 数据分析结果显示:在系统发生上,藏汉民族90个线粒体DNA序列归类到13个Haplogroups,除M9以外,其它各Haplogroup出现频率之间比较差异无统计学意义;通过两个民族的线粒体DNA全序列比对,发现21个分布频率有统计学意义的变异位点,其中的5个为新变异位点;另外,对D-Loop区的5个突变位点进行了单倍型构建,90个标本可分为2种Supertype,发现在藏汉民族之间Supertypel和Supertype 2的分布频率均有统计学意义.结论 藏汉民族在种族起源和系统发生上具有较近的母系遗传关系;在全序列有统计学意义的位点究竟是适应性或者中性选择,抑或是一种病理性突变尚需深入的探讨.     

Evaluation of Job Strain of Family Physicians in COVID-19 Pandemic Period- An Example from Turkey

Journal of Community Health - The purpose of this study was to evaluate family physicians’ job strain during the Covid-19 pandemic and determine the effective factors. The study was carried...     

An information theory model of hydrophobic interactions

A molecular model of poorly understood hydrophobic effects is heuristically developed using the methods of information theory. Because primitive hydrophobic effects can be tied to the probability of observing a molecular-sized cavity in the solvent, the probability distribution of the number of solvent centers in a cavity volume is modeled on the basis of the two moments available from the density and radial distribution of oxygen atoms in liquid water. The modeled distribution then yields the probability that no solvent centers are found in the cavity volume. This model is shown to account quantitatively for the central hydrophobic phenomena of cavity formation and association of inert gas solutes. The connection of information theory to statistical thermodynamics provides a basis for clarification of hydrophobic effects. The simplicity and flexibility of the approach suggest that it should permit applications to conformational equilibria of nonpolar solutes and hydrophobic residues in biopolymers.     

Serum concentrations of thyrotropin, thyroid hormones and thyroid hormone-binding proteins during acute and recovery stages of idiopathic respiratory distress syndrome.

A total number of 27 premature infants with idiopathic respiratory distress syndrome (IRDS) and 52 healthy controls with comparable gestational age and body weights were studied during the first month of life. In infants with IRDS a reduced thyrotropin (TSH) response to birth was suggested, as serum TSH was lower in IRDS patients than in controls during the first two days of life. Low serum concentrations of thyroid hormones were found in the acute stage of IRDS reaching minimal values by day 3--5. After that period an increase in thyroid hormone levels occurred. The serum T2 increased to the level of healthy prematures by day 6--10, whereas the serum T4 increased to normal levels by day 21--30. Serum concentrations of thyroxine-binding globulin (TBG) were significantly lower in IRDS patients than in healthy controls; a gradual increase to normal levels occurred during recovery. Serum prealbumin (TBPA) levels in IRDS infants increased rapidly after birth and exceeded levels of healthy infants. Serum albumin values were not significantly different in the two groups of infants. The serum T4/TBG ratios were low during recovery from IRDS.     

Phosphate release coupled to rotary motion of F1-ATPase

F₁-ATPase, the catalytic domain of ATP synthase, synthesizes most of the ATP in living organisms. Running in reverse powered by ATP hydrolysis, this hexameric ring-shaped molecular motor formed by three αβ-dimers creates torque on its central γ-subunit. This reverse operation enables detailed explorations of the mechanochemical coupling mechanisms in experiment and simulation. Here, we use molecular dynamics simulations to construct a first atomistic conformation of the intermediate state following the 40° substep of rotary motion, and to study the timing and molecular mechanism of inorganic phosphate (P_i) release coupled to the rotation. In response to torque-driven rotation of the γ-subunit in the hydrolysis direction, the nucleotide-free αβ_E interface forming the “empty” E site loosens and singly charged P_i readily escapes to the P loop. By contrast, the interface stays closed with doubly charged P_i. The γ-rotation tightens the ATP-bound αβ_TP interface, as required for hydrolysis. The calculated rate for the outward release of doubly charged P_i from the αβ_E interface 120° after ATP hydrolysis closely matches the ∼1-ms functional timescale. Conversely, P_i release from the ADP-bound αβ_DP interface postulated in earlier models would occur through a kinetically infeasible inward-directed pathway. Our simulations help reconcile conflicting interpretations of single-molecule experiments and crystallographic studies by clarifying the timing of P_i exit, its pathway and kinetics, associated changes in P_i protonation, and changes of the F₁-ATPase structure in the 40° substep. Important elements of the molecular mechanism of P_i release emerging from our simulations appear to be conserved in myosin despite the different functional motions.F₁-ATPase (F₁), the catalytic domain of F_oF₁-ATP synthase, is a rotary molecular motor that reversibly interconverts ATP hydrolysis free energy and mechanical work associated with the rotation of the central stalk (1). The minimal functional F₁ consists of a hexameric ring formed by three αβ-subunit dimers, with the rod-like γ-subunit located at its center (2). The rotation of the γ-subunit is tightly coupled to the reactions in the three catalytic sites located at the αβ interfaces and hosted mainly by the β-subunits. As a result, F₁ is a unique reversible motor that rotates γ by converting ATP hydrolysis energy at high efficiency (3–5) and, conversely, synthesizes ATP from ADP and inorganic phosphate (P_i) by forced rotation of γ in the reverse direction (6, 7). The three nucleotide-binding sites are in different phases of catalysis, reflecting the asymmetric structure of the γ-subunit. Correspondingly, the αβ-subunits hosting the catalytic interfaces are in different conformational states, empty (E), ATP-bound (TP), and ADP+P_i-bound (DP), as seen in crystal structures (2). They communicate through the γ-subunit or directly within the α₃β₃ ring (8, 9) and cooperatively drive the rotation of the γ-subunit.Single-molecule experiments have shown that the γ-subunit rotates in 120° steps (4). Distinct substeps of 80° and 40° (10) are driven by ATP binding plus ADP release, and ATP hydrolysis plus P_i release, respectively (10–13). We thus expect two metastable conformations of F₁, one before the 80° substep (binding dwell) and the other before the 40° substep (catalytic dwell) (14, 15) (Fig. 1A). Most crystal structures correspond to the catalytic dwell state (1, 14–19), with the F₁ conformation of the binding dwell state still elusive (16).Open in a separate windowFig. 1.Mechanochemical coupling scheme and P_i release of F₁-ATPase. (A) Mechanochemical coupling scheme deduced from recent single-molecule experiments (13). ATP hydrolysis reaction steps in one of the three catalytic sites (yellow circles) as a function of the γ-rotation (red arrow). T, D−P, D+P, and P stand for ATP bound, hydrolyzing ATP, ADP+P_i bound, and P_i bound, respectively. At an angle of 0°, ATP is bound. States differing by integer multiples of 120° are functionally equivalent. The timing and pathway of P_i release (purple) has been controversial. (B) Crystal structure (PDB ID code 2jdi) of F₁-ATPase that represents the ∼80° catalytic dwell state, with α-, β-, γ-subunits colored in blue, orange, and red, respectively. (C) Tightly bound P_i in the E site modeled on the basis of yeast structures (SI Text). The blue and orange ribbon backbones correspond to the α_E- and β_E-subunit, respectively. The five residues that participate in P_i binding are shown with thick bonds. VMD was used to prepare structural figures (64).The transition from the catalytic dwell to the binding dwell involves P_i release, but the release site and the exact timing in the full cycle remain controversial. In most kinetic models of F₁ (1), but not all (20), P_i is assumed to exit first, followed by ADP release. This order appears to be consistent with kinetic (21) and structural studies (22) showing all three sites occupied by nucleotide (22); by contrast, the single-molecule experiments of Watanabe et al. (13) and structural studies of yeast F₁ (23) suggest that ADP is released before P_i. With γ-rotation stalled in the catalytic dwell state by magnetic tweezers, the hydrolysis reaction was found to be reversible without excess P_i in solution (13), suggesting that P_i is released at 320°, i.e., from the E site (13, 24) (where ATP binding defines 0°; Fig. 1A).Here, we reconcile these conflicting interpretations by determining the kinetics of P_i release from the E site and the DP site with atomistic molecular dynamics simulations. These simulations also allow us to explore the coupling between the 40° substep and P_i release, and to examine the underlying molecular mechanisms. F₁ has been studied by molecular simulations at various levels of resolution, including quantum chemical calculations of ATP hydrolysis (25–27), all-atom simulations of conformational changes in the β-subunit (28, 29), of ATP release (30), of fluctuations in the complex (31, 32), and of γ-rotation (33, 34), as well as coarse-grained simulations of γ-rotation (35–37). As in experiment and in earlier simulations (33), we apply external torque to modulate the rates of the functional processes, including P_i release.We first characterize the molecular motions of F₁ during the 40° substep in atomically detailed simulations. By rotating the γ-subunit with the help of a newly developed flexible rotor method, we show how the γ-angle and the protonation state of P_i (i.e., HPO₄²⁻ or H₂PO₄⁻) affect the conformation of αβ-dimers and the stability of P_i binding in the E site. We then estimate rates of P_i release from the E site and from the DP site with the help of metadynamics simulations (38). From the simulations and by relating the calculated rates to experiment, we determine the timing, pathway, and charge state dependence of P_i release. Finally, we show that key elements of P_i release appear to be conserved in myosin, despite the different functional motions.     

松质骨中两种纵波的传播特性分析

基于松质骨的层状模型，利用Schoenberg理论分析了松质骨中两种纵波(快纵波和慢纵波)的传播特性；并在理论和实验上详细分析了骨小梁方向与传播方向间的夹角对松质骨中快纵波和慢纵波传播特性的影响。分析结果表明，当超声波平行于骨小梁入射时，松质骨中两种纵波都传播，入射角度在60度附近时，松质骨中两种纵波的相速度曲线有一个转折点，入射角度在60度以上，角度越大时，骨髓和骨小梁耦合得越紧，因此阻止了慢纵波的传播，而只有快纵波传播。