BACKGROUND & AIMS: The kinetic properties of wild-type rat brain IIa sodium channels in excised macropatches were studied using step depolarizations and ramp depolarizations to imitate the slow settling-time of voltage in two-electrode voltage clamp. Ramp depolarizations longer than 1 ms produce an increasing suppression of peak sodium current (I[Na]). Two rates of inactivation can be seen in macroscopic sodium current records from excised patches following both step and ramp depolarizations. During slow ramp depolarizations, reduction in peak I[Na] is associated with selective loss of the fastest rate of test-pulse inactivation. This change can be interpreted as resulting from inactivation of a separate sub-population of 'fast mode' channels. The slow rate of test-pulse inactivation is relatively unaffected by changing ramp durations. These results are sufficient to explain the typically slow inactivation kinetics seen in two-electrode voltage clamp recordings of sodium channels in Xenopus oocytes. Thus, the kinetics of sodium channels expressed in Xenopus oocytes are not readily characterizable by two-electrode clamp because of the large membrane capacitance and resulting slow clamp settling time which artifactually selects for slow mode channels.

背景与目标： 使用逐步去极化和斜坡去极化来模拟两电极电压钳位中电压的缓慢建立时间，研究了切除的大斑块中野生型大鼠脑IIa钠通道的动力学特性。长于1 ms的斜坡去极化会增加对峰值钠电流 (I[Na]) 的抑制。在阶跃和斜坡去极化之后，从切除的斑块的宏观钠电流记录中可以看到两种失活速率。在缓慢的斜坡去极化过程中，峰值I[Na] 的降低与最快的测试脉冲失活速率的选择性损失有关。此更改可以解释为由于 “快速模式” 通道的单独子种群的失活而导致。测试脉冲失活的缓慢速度相对不受斜坡持续时间变化的影响。这些结果足以解释非洲爪蟾卵母细胞中钠通道的两电极电压钳制记录中看到的典型的缓慢失活动力学。因此，非洲爪蟾卵母细胞中表达的钠通道的动力学不容易通过两电极钳来表征，因为膜电容大，并且会导致人为选择慢模式通道而产生的慢钳建立时间。

BACKGROUND & AIMS: :A novel mechatronic body weight support (BWS) system has been developed to provide precise body weight unloading for patients with neurological or other impairments during treadmill training. The system is composed of a passive elastic spring element to take over the main unloading force and an active closed-loop controlled electric drive to generate the exact desired force. Both force generating units, the passive spring and the active electric drive, act on the patient via a polyester rope connected to a harness worn by the patient. The length of the rope can be adjusted with an electric winch to adapt the system to different patient sizes. The system is fully computer controlled. At unloading loads of up to 60 kg and walking speeds of up to 3.2 km/h, the mean unloading error and the maximum unloading error of the presented BWS system was less than 1 and 3 kg, respectively. The performance was compared with those of two purely passive BWS systems currently being used by most other rehabilitation groups. This comprised counterweight systems and static BWS systems with fixed rope lengths. Counterweight systems reached mean and maximum unloading errors of up to 5.34 and 16.22 kg, respectively. The values for the static BWS were 11.02 kg and 27.67 kg, respectively. The novel mechatronic BWS system presented in this study adjusts desired unloading changes of up to 20 kg within less than 100 ms. Thus, not only constant BWS, but also gait cycle dependent or time variant oscillations of the desired force can be realized with high accuracy. Precise and constant unloading force is believed to be an important prerequisite for BWS gait therapy, where it is important to generate physiologically correct segmental dynamics and ground reaction forces. Thus, the novel BWS system presented in this paper is an important contribution to maximize the therapeutic outcome of human gait rehabilitation.

背景与目标： : 已开发出一种新颖的机电一体化体重支持 (BWS) 系统，可为跑步机训练期间患有神经系统或其他障碍的患者提供精确的体重卸载。该系统由被动弹性弹簧元件组成，用于接管主卸载力，以及主动闭环控制的电驱动器，以产生精确的期望力。两个力产生单元，即被动弹簧和主动电驱动器，通过连接到患者佩戴的安全带的聚酯绳作用于患者。绳索的长度可以用电动绞盘调节，以使系统适应不同的患者尺寸。该系统完全由计算机控制。在高达60千克的卸载载荷和高达3.2千米/h的步行速度下，所提出的BWS系统的平均卸载误差和最大卸载误差分别小于1和3千克。将性能与大多数其他康复小组目前使用的两种纯被动BWS系统的性能进行了比较。这包括配重系统和具有固定绳索长度的静态BWS系统。配重系统的平均和最大卸载误差分别达到5.34和16.22千克。静态BWS的值分别为11.02千克和27.67千克。本研究中提出的新型机电BWS系统在不到100毫秒的时间内调节高达20千克的所需卸载变化。因此，不仅可以实现恒定的BWS，而且可以实现步态周期相关或所需力的时变振荡。精确且恒定的卸荷力被认为是BWS步态疗法的重要先决条件，在该疗法中，重要的是产生生理上正确的节段动力学和地面反作用力。因此，本文提出的新型BWS系统是最大程度地提高人类步态康复治疗效果的重要贡献。

BACKGROUND & AIMS: :The purpose of this study was to examine the acute effects of a caffeine-containing supplement on upper- and lower-body strength and muscular endurance as well as anaerobic capabilities. Thirty-seven resistance-trained men (mean +/- SD, age: 21 +/- 2 years) volunteered to participate in this study. On the first laboratory visit, the subjects performed 2 Wingate Anaerobic Tests (WAnTs) to determine peak power (PP) and mean power (MP), as well as tests for 1 repetition maximum (1RM), dynamic constant external resistance strength, and muscular endurance (TOTV; total volume of weight lifted during an endurance test with 80% of the 1RM) on the bilateral leg extension (LE) and free-weight bench press (BP) exercises. Following a minimum of 48 hours of rest, the subjects returned to the laboratory for the second testing session and were randomly assigned to 1 of 2 groups: a supplement group (SUPP; n = 17), which ingested a caffeine-containing supplement, or a placebo group (PLAC; n = 20), which ingested a cellulose placebo. One hour after ingesting either the caffeine-containing supplement or the placebo, the subjects performed 2 WAnTs and were tested for 1RM strength and muscular endurance on the LE and BP exercises. The results indicated that there was a significant (p < 0.05) increase in BP 1RM for the SUPP group, but not for the PLAC group. The caffeine-containing supplement had no effect, however, on LE 1RM, LE TOTV, BP TOTV, PP, and MP. Thus, the caffeine-containing supplement may be an effective supplement for increasing upper-body strength and, therefore, could be useful for competitive and recreational athletes who perform resistance training.

背景与目标： : 这项研究的目的是检查含咖啡因补充剂对上半身和下半身力量，肌肉耐力以及无氧能力的急性影响。37名接受过抵抗训练的男性 (平均/- SD，年龄: 21/- 2岁) 自愿参加了这项研究。在第一次实验室访问时，受试者进行了2次Wingate厌氧测试 (想要) 以确定峰值功率 (PP) 和平均功率 (MP)，以及1次重复最大值 (1RM)，动态恒定外阻力强度和肌肉耐力 (TOTV; 在双侧腿部伸展 (LE) 和自由重量卧推 (BP) 练习的耐力测试中，重量的总体积为1RM的80%。休息至少48小时后，受试者返回实验室进行第二次测试，并被随机分配到2组中的1组: 补充剂组 (SUPP; n = 17)，摄入含咖啡因补充剂，或安慰剂组 (PLAC; n = 20)，摄入纤维素安慰剂。摄入含咖啡因补充剂或安慰剂一小时后，受试者进行了2次想要，并在LE和BP锻炼中测试了1RM力量和肌肉耐力。结果表明，SUPP组的BP 1RM显着增加 (p <0.05)，而PLAC组则没有。但是，含咖啡因的补充剂对LE 1RM，LE TOTV，BP TOTV，PP和MP没有影响。因此，含咖啡因的补充剂可能是增加上身力量的有效补充剂，因此对于进行阻力训练的竞技和休闲运动员可能有用。

BACKGROUND & AIMS: :Varicocele is considered a predominantly unilateral left-sided disease. However, since male fertility is preserved with only one healthy testis, infertility perforce represents bilateral testicular dysfunction. It was hypothesized that: (i) right varicocele cannot be diagnosed by palpation and therefore has not been treated in the past by the traditional treatment, and (ii) right varicocele causes impaired oxygen supply in the right testicular microcirculation, leading to germ cell degeneration. This study performed venographies of both right and left internal spermatic veins during the treatment of 840 infertile men with varicocele and analysed the results using tools of fluid mechanics. Histopathology of the right testis revealed stagnation of blood flow and degenerative changes attributed to lack of adequate oxygenation in all testicular cell types. Right varicocele was found in the vast majority of the patients. We found that due to the destruction of one-way valves, pathologic hydrostatic pressure is produced in the testicular venous microcirculatory system about five times higher than normal, exceeding arteriolar pressure. The pressure gradient between the arterioles and venules in the testicular tissue is therefore reversed, leading to persistent hypoxia. Right varicocele, although undetected, is prevalent in infertile men with varicocele, hence only bilateral occlusion of the internal spermatic veins, including the associated bypasses, eliminating the pathologic hydrostatic pressure will lead to resumption of arterial blood flow in the testicular microcirculation.

背景与目标： : 精索静脉曲张被认为是一种主要的单侧左侧疾病。但是，由于只有一个健康的睾丸可以保留男性的生育能力，因此不育表现为双侧睾丸功能障碍。假设 :( i) 无法通过触诊来诊断右精索静脉曲张，因此过去没有通过传统疗法进行治疗，并且 (ii) 右精索静脉曲张会导致右睾丸微循环中的氧气供应受损，导致生殖细胞变性。这项研究在治疗840名患有精索静脉曲张的不育男性期间对左右精索内静脉进行了静脉造影，并使用流体力学工具分析了结果。右睾丸的组织病理学显示，由于所有睾丸细胞类型缺乏足够的氧合，导致血流停滞和退行性变化。在绝大多数患者中发现了右精索静脉曲张。我们发现，由于单向阀的破坏，睾丸静脉微循环系统中产生的病理性静水压力约为正常水平的五倍，超过了小动脉压力。因此，睾丸组织中小动脉和小静脉之间的压力梯度相反，导致持续的缺氧。右精索静脉曲张虽然未被发现，但在患有精索静脉曲张的不育男性中很普遍，因此只有双侧精索内静脉 (包括相关的旁路) 闭塞，消除病理性静水压将导致睾丸微循环中动脉血流的恢复。

BACKGROUND & AIMS: PURPOSE:To identify genes preferentially expressed in the stem-cell-rich limbal epithelium of the rat cornea. METHODS:The limbal and central corneal epithelial cells of 6-week-old rats were isolated by microdissection. Serial analysis of gene expression (SAGE) libraries were constructed and analyzed, and in situ hybridization, reverse transcription-polymerase chain reaction (RT-PCR) and cDNA cloning were conducted by conventional procedures. RESULTS:The rat limbal and central corneal epithelial SAGE libraries consisted of 41,894 and 40,691 tags, respectively. After annotation, this was reduced to 759 transcripts specific for the limbal library and 844 transcripts specific for the central corneal library; 2292 transcripts overlapped. Transcripts encoding proteins with metabolic functions comprised the major functional category in both libraries. In situ hybridization and/or RT-PCR results of 12 of the most abundant, highly enriched transcripts in the limbal epithelium were in general agreement with the SAGE data and showed that these proteins are also expressed in the conjunctival epithelium. Interesting limbal-enriched transcripts encode WDNM1-like protein (similar to WDNM1/Expi, a putative secreted proteinase and inhibitor of metastasis), mesothelin (a cancer marker), marapsin (a trypsin-like serine protease that may control cell growth and migration), K4 and K15 (both cytokeratins), and membrane-spanning four-domain subfamily A member 8B. WDNM1-like protein was cloned and confirmed as a member of the four-disulfide core family. CONCLUSIONS:The SAGE results extend the database of genes expressed in the rodent cornea and suggest an association between several genes preferentially expressed in the limbal epithelium with cellular proliferation and migration.

背景与目标：

BACKGROUND & AIMS: :Consonant identification was measured for a stationary and amplitude-modulated noise masker in four listeners with flat cochlear hearing loss, and four age-matched normal-hearing listeners. The masker modulation rate was systematically varied between 2 and 128 Hz. Masking release (MR), that is better identification performance in fluctuating, than in stationary noise, was highest in a masker fluctuating at 8-16 Hz in all normal-hearing listeners. In comparison, MR was only observed in two out of the four impaired listeners. In these listeners, MR was poorer than normal, and peaked at lower rates, that is 2 or 8 Hz. MR corresponded to increased reception of information for voicing, place, and manner between 2 and 64 Hz in all normal-hearing listeners. In impaired listeners, increased reception of information was mainly observed for manner, and mainly reduced for place, but these differences were not significant. For all phonetic features, MR was observed at lower masker fluctuation rates (< or =32 Hz) than in normal-hearing listeners. This study therefore shows that cochlear damage affects MR, both quantitatively and qualitatively.

背景与目标： : 在四个患有扁平耳蜗听力损失的听众和四个年龄匹配的正常听力听众中，测量了固定和幅度调制的噪声masker的辅音识别。掩蔽器调制速率在2和128Hz之间系统地变化。在所有正常听力的听众中，掩蔽释放 (MR) 在波动中比在固定噪声中更好的识别性能，在8-16Hz波动的掩蔽器中最高。相比之下，仅在四个受损听众中的两个中观察到MR。在这些听众中，MR比正常人差，并且以较低的速率 (即2或8Hz) 达到峰值。MR对应于所有正常听力的听众在2到64Hz之间的发声，位置和方式的信息接收增加。在受损的听众中，主要观察到方式的信息接收增加，而地点的信息接收则主要减少，但这些差异并不显着。对于所有语音特征，与正常听力的听众相比，以较低的掩蔽率 (<或 = 32Hz) 观察到MR。因此，这项研究表明，耳蜗损伤在定量和定性上都会影响MR。

BACKGROUND & AIMS: The involvement of antigen-specific T cells in the pathogenesis of collagen diseases is still controversial. The final stages of collagen diseases are usually characterized by the dominance of inflammation. Therefore, antigen non-specific factors, such as inflammatory cytokines, probably play an important role in this process. On the other hand, the methods available to analyze the antigen-specific aspects of the immune response are still limited. Here we review our novel system of T cell clonality analysis based on the idea that activated antigen-specific T cells should form accumulating clones among the lymphocyte population. Using this method, dynamic changes of clonal accumulation of T cells could be evaluated during antigenic stimulation in vivo and in vitro. The significance of antigen-specific T cell clones in collagen diseases is discussed using data obtained from patients with rheumatoid arthritis and systemic lupus erythematosus.

背景与目标： 抗原特异性T细胞参与胶原疾病的发病机理仍存在争议。胶原蛋白疾病的最后阶段通常以炎症为主。因此，抗原非特异性因子 (如炎性细胞因子) 可能在这一过程中起重要作用。另一方面，用于分析免疫应答的抗原特异性方面的方法仍然有限。在这里，我们基于激活的抗原特异性T细胞应在淋巴细胞群体中形成累积克隆的想法，回顾了我们的新型T细胞克隆分析系统。使用该方法，可以在体内和体外评估抗原刺激过程中T细胞克隆积累的动态变化。使用类风湿关节炎和系统性红斑狼疮患者获得的数据讨论了抗原特异性T细胞克隆在胶原疾病中的意义。

BACKGROUND & AIMS: OBJECTIVE:To review the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in the treatment of Raynaud's phenomenon (RP). DATA SOURCES:Biomedical literature was accessed through July 2006 via PubMed, the Iowa Drug Information System (IDIS), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus. PubMed database terms included Raynaud's disease, angiotensin-converting enzyme inhibitors, and angiotensin II type 1 receptor blockers [pharmacological action]; IDIS terms included hypotensive agents-ace inhib 24080200, raynaud's syndrome 443.0, and hypotensive agents-angioten II 24080400; and CINAHL Plus terms included Raynaud's disease, angiotensin-converting enzyme inhibitors, losartan, and irbesartan. STUDY SELECTION AND DATA EXTRACTION:All clinical trials published in English that reported both subjective and objective outcomes of efficacy were reviewed. DATA SYNTHESIS:Several small, short-term studies have evaluated captopril, enalapril, and losartan in the treatment of RP. The studies of ACE inhibitors have found conflicting results in their ability to improve digit blood flow and reduce both frequency and severity of RP attacks. Two studies have focused on the use of losartan for RP treatment, with both finding a statistically significant reduction in attacks and one showing improvement in symptoms of RP in comparison with the commonly utilized calcium-channel blocker, nifedipine. Most of the studies were short term (< or =12 wk) and included a limited number of patients (<60). CONCLUSIONS:ACE inhibitors and ARBs may provide some minor benefits in the relief of RP, although no definite evidence exists to suggest that they are superior to traditionally used treatments such as calcium-channel blockers. Larger, randomized controlled trials of longer duration are needed to compare the effectiveness of ACE inhibitors and ARBs with conventional treatment.

背景与目标：

BACKGROUND & AIMS: :In 4 experiments, the authors investigated the reversal of spatial congruency effects when participants concurrently practiced incompatible mapping rules (J. G. Marble & R. W. Proctor, 2000). The authors observed an effect of an explicit spatially incompatible mapping rule on the way numerical information was associated with spatial responses. The authors also observed an effect of an incompatible numerical mapping rule (if smaller than 5, press right; if larger than 5, press left) on the Simon effect. This effect was observed only when both tasks used the same effectors. The results point to a shared spatial representation for explicit spatial information (locations) and implicit spatial information (numbers).

背景与目标： : 在4个实验中，作者研究了参与者同时实践不兼容映射规则时空间一致性效应的逆转 (J. G. Marble & R. W. Proctor，2000)。作者观察到明确的空间不兼容映射规则对数字信息与空间响应相关联的方式的影响。作者还观察到不兼容的数值映射规则 (如果小于5，则按右; 如果大于5，则按左) 对Simon效果的影响。仅当两个任务使用相同的效应器时才观察到这种效果。结果指向显式空间信息 (位置) 和隐式空间信息 (数字) 的共享空间表示。

BACKGROUND & AIMS: OBJECTIVE:The purpose of our study was to evaluate the effects of 0.3-second high-resolution CT (HRCT) of the lung using partial reconstruction on cardiac motion artifacts and image noise. SUBJECTS AND METHODS:Thirty-seven pairs of 0.3-second (partial reconstruction) and 0.75-second (full reconstruction) HRCT images were obtained for the lower lung zone during full-inspiration breath-holding. Imaging parameters other than temporal resolution were identical for each patient. Two radiologists visually graded motion artifacts of the cardiac border, bronchi, pulmonary vessels, and fissure in the left lung on a 4-point scale (with 4 indicating no artifacts). The maximum width of motion along the left cardiac border and the area percentage of motion artifacts in the left lung were calculated. Image noise in the air and lung was also determined. Cardiac motion artifacts and image noises were compared between the two sets of CT images. RESULTS:Visual grades for the cardiac border (4 +/- 0), bronchi (3.8 +/- 0.7), pulmonary vessels (3.6 +/- 0.8), and fissure (3.9 +/- 0.5) were higher for 0.3-second images than for 0.75-second images (1.7 +/- 0.7, 2.0 +/- 1.0, 1.6 +/- 0.7, and 2.4 +/- 0.9, respectively) (p < 0.001). The maximum width of motion along the left cardiac border (0.1 +/- 0.5 mm) and the area percentage of motion artifacts in the left lung (6.7% +/- 18.4%) were smaller for 0.3-second images than for 0.75-second images (4.5 +/- 1.7 mm and 36.2% +/- 20.9%, respectively) (p < 0.001). Image noises in the air (38.0 +/- 9.2) and the lung (86.0 +/- 23.1) were greater for 0.3-second images than for 0.75-second images (35.6 +/- 9.6 and 76.0 +/- 20.3, respectively) (p < 0.01). CONCLUSION:Compared with 0.75-second HRCT using full reconstruction, 0.3-second HRCT using partial reconstruction substantially reduces cardiac motion artifacts in the lung at the expense of increasing image noise.

背景与目标：

BACKGROUND & AIMS: :Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.

背景与目标： : 我们的目标是使用非侵入性高分辨率 (117x70 microm) 磁共振 (microMRI) 和视觉系统诱发电位 (VEP) 技术，跟踪畸形疾病的过程，然后在转基因小鼠中进行部分恢复。我们使用了JOE (用于J37 golli过表达) 转基因小鼠，该小鼠经过工程改造以过表达golli J37，Golli-mbp基因复合物的产物，特别是在少突胶质细胞中。从21天到75天大，在11.7 T扫描仪上使用非侵入性体内vep和3D T2-weighted显微mri跟踪了JOE transgenics及其未受影响的兄弟姐妹，我们认为这是同类研究中的首次纵向研究。microMRI数据表明，在髓鞘形成峰值期间 (21-42天)，明显的整体髓鞘减少，与对照组相比，JOE小鼠在以后的年龄 (>60天) 得到了部分纠正。这些显微mri数据与 [Campagnoni在 (1995) “髓鞘形成的分子生物学” 处具有很好的相关性。In: Ransom B，Kettenmann H (eds) 神经胶质-一篇论文。牛津大学出版社，伦敦，pp 555-570] 髓磷脂染色，[Campagnoni AT，macklin WB (1988) 髓鞘蛋白基因表达的细胞和分子方面。Mol Neurobiol 2:41-89] 在髓鞘形成的高峰期短暂的意图震颤，在以后的年龄减弱，并且 [Lees MB，Brostoff SW (1984) 蛋白在髓鞘中: morell (ed) 髓鞘。纽约和伦敦的Plenum出版社，pp 197-224] VEPs，所有这些都表明乔小鼠中枢神经系统髓鞘发育和持续的低髓鞘作用显着延迟。总体而言，这些非侵入性技术能够在空间上解决正常发育和发育延迟的小鼠大脑中髓鞘形成的增加。

BACKGROUND & AIMS: :A mechanistic understanding of adipose tissue differentiation is critical for the treatment and prevention of obesity and type 2 diabetes. Conventional in vitro models of adipogenesis are preadipocytes or freshly isolated adipocytes grown in two-dimensional (2D) cultures. Optimal results using in vitro tissue culture models can be expected only when adipocyte models closely resemble adipose tissue in vivo. Thus the design of an in vitro three-dimensional (3D) model which faithfully mimics the in vivo environment is needed to effectively study adipogenesis. Pluripotent embryonic stem (ES) cells are a self-renewing cell type that can readily be differentiated into adipocytes. In this study, a 3D culture system was developed to mimic the geometry of adipose tissue in vivo. Murine ES cells were seeded into electrospun polycaprolactone scaffolds and differentiated into adipocytes in situ by hormone induction as demonstrated using a battery of gene and protein expression markers along with the accumulation of neutral lipid droplets. Insulin-responsive Akt phosphorylation, and beta-adrenergic stimulation of cyclic AMP synthesis were demonstrated in ES cell-derived adipocytes. Morphologically, ES cell-derived adipocytes resembled native fat cells by scanning electron and phase contrast microscopy. This tissue engineered ES cell-matrix model has potential uses in drug screening and other therapeutic developments.

背景与目标： : 对脂肪组织分化的机械理解对于治疗和预防肥胖和2型糖尿病至关重要。常规的脂肪生成体外模型是在二维 (2D) 培养物中生长的前脂肪细胞或新鲜分离的脂肪细胞。仅当脂肪细胞模型与体内脂肪组织非常相似时，才能预期使用体外组织培养模型的最佳结果。因此，需要设计忠实地模仿体内环境的体外三维 (3D) 模型来有效地研究脂肪形成。多能胚胎干 (ES) 细胞是一种自我更新的细胞类型，可以很容易地分化为脂肪细胞。在这项研究中，开发了3D培养系统来模拟体内脂肪组织的几何形状。将鼠ES细胞接种到电纺聚己内酯支架中，并通过激素诱导原位分化为脂肪细胞，如使用一系列基因和蛋白质表达标记以及中性脂质滴的积累所证明的那样。在ES细胞衍生的脂肪细胞中证实了胰岛素反应性Akt磷酸化和 β-肾上腺素能刺激环状AMP合成。通过扫描电子和相差显微镜，从形态上讲，ES细胞衍生的脂肪细胞类似于天然脂肪细胞。这种组织工程的ES细胞基质模型在药物筛选和其他治疗开发中具有潜在用途。

BACKGROUND & AIMS: :Rhodopseudomonas palustris is a purple, facultatively phototrophic bacterium that uses hydrogen gas as an electron donor for carbon dioxide fixation during photoautotrophic growth or for ammonia synthesis during nitrogen fixation. It also uses hydrogen as an electron supplement to enable the complete assimilation of oxidized carbon compounds, such as malate, into cell material during photoheterotrophic growth. The R. palustris genome predicts a membrane-bound nickel-iron uptake hydrogenase and several regulatory proteins to control hydrogenase synthesis. There is also a novel sensor kinase gene (RPA0981) directly adjacent to the hydrogenase gene cluster. Here we show that the R. palustris regulatory sensor hydrogenase HupUV acts in conjunction with the sensor kinase-response regulator protein pair HoxJ-HoxA to activate hydrogenase expression in response to hydrogen gas. Transcriptome analysis indicated that the HupUV-HoxJA regulatory system also controls the expression of genes encoding a predicted dicarboxylic acid transport system, a putative formate transporter, and a glutamine synthetase. RPA0981 had a small effect in repressing hydrogenase synthesis. We also determined that the two-component system RegS-RegR repressed expression of the uptake hydrogenase, probably in response to changes in intracellular redox status. Transcriptome analysis indicated that about 30 genes were differentially expressed in R. palustris cells that utilized hydrogen when growing photoheterotrophically on malate under nitrogen-fixing conditions compared to a mutant strain that lacked uptake hydrogenase. From this it appears that the recycling of reductant in the form of hydrogen does not have extensive nonspecific effects on gene expression in R. palustris.

背景与目标： : 红假单胞菌 (Rhodopseudomonas palustris) 是一种紫色的兼性光养细菌，在光自养生长过程中使用氢气作为电子供体进行二氧化碳固定或在固氮过程中进行氨合成。它还使用氢作为电子补充剂，以使氧化的碳化合物 (例如苹果酸盐) 在光异养生长过程中完全同化为细胞材料。R. palustris基因组预测了膜结合的镍铁吸收氢化酶和几种控制氢化酶合成的调节蛋白。还有一个新的传感器激酶基因 (RPA0981) 直接与氢化酶基因簇相邻。在这里，我们显示了R. palustris调节传感器氢化酶HupUV与传感器激酶响应调节蛋白对HoxJ-HoxA共同作用，以响应氢气激活氢化酶表达。转录组分析表明，HupUV-HoxJA调节系统还控制编码预测的二羧酸转运系统，推定的甲酸转运蛋白和谷氨酰胺合成酶的基因的表达。RPA0981在抑制氢化酶合成方面的作用很小。我们还确定，两组分系统RegS-RegR抑制了摄取氢化酶的表达，可能是对细胞内氧化还原状态变化的响应。转录组分析表明，与缺乏摄取氢化酶的突变菌株相比，在固氮条件下在苹果酸上光异养生长时利用氢的R. palustris细胞中约30个基因差异表达。由此看来，以氢形式回收还原剂对R. palustris的基因表达没有广泛的非特异性影响。

BACKGROUND & AIMS: :Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin increased dopamine receptors in the rat prefrontal cortex [Q. Wang, W.L. Ting, H. Yang, P.T. Wong, High doses of simvastatin upregulate dopamine D(1) and D(2) receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase, Br. J. Pharmacol. 144 (2005) 933-939] and restored its downregulation in a model of Parkinson's disease (PD) [Q. Wang, P.H. Wang, C. McLachlan, P.T. Wong, Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats, Brain Res. 1045 (2005) 229-233]. Here we explore the effects of simvastatin treatment on tissue dopamine content and reuptake. Sprague-Dawley rats were given simvastatin (1 and 10 mg kg(-1)day(-1), p.o.) for 4 weeks. Brain tissue from prefrontal cortex and striatum were taken out for dopamine content and its reuptake. Using high-performance liquid chromatographic-mass spectrometer (HPLC-MS), simvastatin (10 mg kg(-1)day(-1)) was found to increase dopamine content by 110% in the striatum but decreased by 76% in the prefrontal cortex compared with the saline treated group. Dopamine (DA) reuptake was unchanged in both brain regions. These results suggest that chronic treatment with high dose of simvastatin may affect DA tissue level in prefrontal cortex and striatum without changing on DA reuptake. This may have important clinical implications in psychiatric and striatal dopaminergic disorders.

背景与目标： : 他汀类药物越来越多地用于治疗各种疾病，超出了其降低胆固醇的原始适应症。我们先前报道辛伐他汀增加了大鼠前额叶皮层的多巴胺受体 [Q. Wang，W.L. Ting，H. Yang，P.T. Wong，高剂量辛伐他汀上调了大鼠前额叶皮层的多巴胺D(1) 和D(2) 受体表达: 可能参与内皮型一氧化氮合酶，br.J. Pharmacol. 144 (2005) 933-939] 并在帕金森氏病 (PD) 模型中恢复了其下调 [Q. Wang，P.H. Wang，C. McLachlan，P.T. Wong，辛伐他汀可逆转6-羟基多巴胺诱导的帕金森病大鼠前额叶皮层多巴胺D1和D2受体表达的下调，脑Res. 1045 (2005) 229-233]。在这里，我们探讨辛伐他汀治疗对组织多巴胺含量和再摄取的影响。Sprague-Dawley大鼠给予辛伐他汀 (1和10 mg kg(-1) 天 (-1)，p.o.) 4周。取出前额叶皮层和纹状体的脑组织以获取多巴胺含量及其再摄取。使用高效液相色谱-质谱仪 (hplc-ms)，发现辛伐他汀 (10 mg kg(-1) 天 (-1)) 在纹状体中110% 增加多巴胺含量，但在前额叶皮层中减少76% 与生理盐水治疗组相比。两个大脑区域的多巴胺 (DA) 再摄取均未改变。这些结果表明，高剂量辛伐他汀的慢性治疗可能会影响前额叶皮层和纹状体的DA组织水平，而不会改变DA的再摄取。这可能对精神病和纹状体多巴胺能疾病具有重要的临床意义。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： : 热休克蛋白90 (HSP90) 是各种蛋白质的结构折叠和构象完整性维持所必需的，包括与细胞信号传导相关的几种。利用HSP90抑制剂17-allylamino-17-demethoxygeldanamycin (17-AAG) 的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向多发性骨髓瘤 (MM) 患者，我们首先通过免疫荧光和流式细胞仪分析研究了HSP90在骨髓瘤细胞系 (U266) 和原发性骨髓瘤细胞中的表达。在证明骨髓瘤细胞中HSP90表达后，通过免疫过氧化物酶染色分析了32 MM患者的档案样本。所有患者的骨髓瘤细胞在所有样品中均显示出HSP90的强细胞质表达，并且55% 还显示出同时的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266和原代MM细胞可显着增加细胞凋亡。对与17-aag孵育的MM细胞中抗凋亡BCL2家族蛋白和akt的分析表明，BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但17AAG和硼替佐米的组合治疗显示出对U266细胞系的协同凋亡作用。这些数据表明，靶向抑制HSP90可能被证明是开发MM患者未来治疗选择的有效且创新的策略。