Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors

Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Representative compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. The design, synthesis, and preliminary biological evaluation of these pyrazole compounds are reported.     

Three-dimensional structure of the HSV1 nucleocapsid

The three-dimensional structures of full and empty capsids of HSV1 were determined by computer analysis of low dose cryo-electron images of ice embedded capsids. The full capsid structure is organized into outer, intermediate, and inner structural layers. The empty capsid structure has only one layer which is indistinguishable from the outer layer of the full capsids. This layer is arranged according to T = 16 icosahedral symmetry. The intermediate layer of full capsids appears to lie on a T = 4 icosahedral lattice. The genomic DNA is located inside the T = 4 shell and is the component of the innermost layer of the full capsids. The outer and intermediate layers interact in such a way that the channels along their icosahedral two-fold axis coincide and form a direct pathway between the DNA and the environment outside the capsid.     

两种光敏化合物对斜纹夜蛾超氧物歧化酶影响的比较研究(英文)

室内测试了斜纹夜蛾Ｓｐｏｄｏｐｔｅｒａ ｌｉｔｕｒａ Ｆ． ４龄幼虫超氧物歧化酶的活性,并就α－三噻吩（α－ｔｅｒｔｈｉｅｎｙｌ）和化合物５,即１－苯基－４－（３,４－亚甲基二氧）苯基－丁二炔等两种光敏化合物对其产生的影响进行了比较研究。结果表明,近紫外光照（３００－４００ｎｍ）基本不影响对照幼虫超氧物歧化酶活体（ｉｎｖｉｖｏ）活力,但对其离休（ｉｎ ｖｉｔｒｏ）活力有抑制作用。经光敏化合物处理后,在紫外光照下,超氧物歧化酶活体活力基本不受化合物５的影响,但能被α－三噻吩抑制。离体情况下,两种化合物均促进其活力,α－三噻吩尤甚。表明无论在离体还是活体情况下,幼虫对α－三噻吩均比化合物５具有更高的光敏性。对两种光敏化合物可能的作用机理进行了探讨。     

Structures of single‐layer β‐sheet proteins evolved from β‐hairpin repeats

Free‐standing single‐layer β‐sheets are extremely rare in naturally occurring proteins, even though β‐sheet motifs are ubiquitous. Here we report the crystal structures of three homologous, single‐layer, anti‐parallel β‐sheet proteins, comprised of three or four twisted β‐hairpin repeats. The structures reveal that, in addition to the hydrogen bond network characteristic of β‐sheets, additional hydrophobic interactions mediated by small clusters of residues adjacent to the turns likely play a significant role in the structural stability and compensate for the lack of a compact hydrophobic core. These structures enabled identification of a family of secreted proteins that are broadly distributed in bacteria from the human gut microbiome and are putatively involved in the metabolism of complex carbohydrates. A conserved surface patch, rich in solvent‐exposed tyrosine residues, was identified on the concave surface of the β‐sheet. These new modular single‐layer β‐sheet proteins may serve as a new model system for studying folding and design of β‐rich proteins.     

Clinical Impact of Speed Variability to Identify Ultramarathon Runners at Risk for Acute Kidney Injury

BackgroundUltramarathon is a high endurance exercise associated with a wide range of exercise-related problems, such as acute kidney injury (AKI). Early recognition of individuals at risk of AKI during ultramarathon event is critical for implementing preventative strategies.ObjectivesTo investigate the impact of speed variability to identify the exercise-related acute kidney injury anticipatively in ultramarathon event.MethodsThis is a prospective, observational study using data from a 100 km ultramarathon in Taipei, Taiwan. The distance of entire ultramarathon race was divided into 10 splits. The mean and variability of speed, which was determined by the coefficient of variation (CV) in each 10 km-split (25 laps of 400 m oval track) were calculated for enrolled runners. Baseline characteristics and biochemical data were collected completely 1 week before, immediately post-race, and one day after race. The main outcome was the development of AKI, defined as Stage II or III according to the Acute Kidney Injury Network (AKIN) criteria. Multivariate analysis was performed to determine the independent association between variables and AKI development.Results26 ultramarathon runners were analyzed in the study. The overall incidence of AKI (in all Stages) was 84.6% (22 in 26 runners). Among these 22 runners, 18 runners were determined as Stage I, 4 runners (15.4%) were determined as Stage II, and none was in Stage III. The covariates of BMI (25.22 ± 2.02 vs. 22.55 ± 1.96, p = 0.02), uric acid (6.88 ± 1.47 vs. 5.62 ± 0.86, p = 0.024), and CV of speed in specific 10-km splits (from secondary 10 km-split (10^th – 20^th km-split) to 60^th – 70^th km-split) were significantly different between runners with or without AKI (Stage II) in univariate analysis and showed discrimination ability in ROC curve. In the following multivariate analysis, only CV of speed in 40^th – 50^th km-split continued to show a significant association to the development of AKI (Stage II) (p = 0.032).ConclusionsThe development of exercise-related AKI was not infrequent in the ultramarathon runners. Because not all runners can routinely receive laboratory studies after race, variability of running speed (CV of speed) may offer a timely and efficient tool to identify AKI early during the competition, and used as a surrogate screening tool, at-risk runners can be identified and enrolled into prevention trials, such as adequate fluid management and avoidance of further NSAID use.     

Single and combined effects of carbamazepine and vinpocetine on depolarization-induced changes in Na+, Ca2+ and glutamate release in hippocampal isolated nerve endings

The single and combined effects of carbamazepine and vinpocetine on the release of the excitatory amino acid neurotransmitter glutamate, on the rise in internal Na+ (Na(i), as determined with SBFI), and on the rise in internal Ca2+ (Ca(i), as determined with fura-2) induced by an increased permeability of presynaptic Na+ channels, with veratridine, or by an increased permeability of presynaptic Ca2+ channels with high K+, were investigated in isolated hippocampal nerve endings. The present study shows that carbamazepine and vinpocetine, both inhibit dose dependently the release of preloaded [3H]Glu induced by veratridine. However, carbamazepine is two orders of magnitude less potent than vinpocetine. The calculated IC(50)'s for carbamazepine and vinpocetine to inhibit veratridine-induced [3H]Glu release are 200 and 2 microM, respectively. Consistently 150 microM carbamazepine and 1.5 microM vinpocetine reduce the veratridine-induced rise in Na(i) in a similar extent. The single effects of carbamazepine and of vinpocetine on the presynaptic Na+ channel mediated responses, namely the rise in Na(i) and the release of Glu induced by veratridine, are additive. Responses that depend on the entrance of external Ca2+ via presynaptic Ca2+ channels, such as the release of [3H]Glu and the rise in Ca(i) induced by high K+, are insensitive to 300 microM carbamazepine and slightly reduced by 5 microM vinpocetine. It is concluded that the additive effects of carbamazepine, which is one of the most common antiepileptic drugs, and vinpocetine that besides its known neuroprotective action and antiepileptic potential is a memory enhancer, may perhaps be advantageous in the treatment of epileptic patients.     

Temperature-dependent development and population growth of Tetraneura nigriabdominalis (Homoptera: Pemphigidae) on three host plants

The root aphid Tetraneura nigriabdominalis (Sasaki) (Homoptera: Pemphigidae) is a pest of many Gramineae species; however, little is known about its biology and relationships with host plants. The objectives of this study were to quantify the effects of temperature on development, longevity, fecundity, and population growth of T. nigriabdominalis and to assess the effects of host plant on development of T. nigriabdominalis. The effects of temperature on performance of this root aphid were determined at 10, 15, 20, 25, 30, and 35 +/- 1 degrees C on rice roots, Oryza sativa L. Nymphal stages from birth to adult decreased from 46.3 d at 10 degrees C to 8.5 d at 30 degrees C. Aphid survival and development were lowest at 35 degrees C, and no aphid produced progeny at this temperature. Average adult longevity decreased from 23.3 d at 15 degrees C to 8.2 d at temperatures up to 35 degrees C. Average number of nymphs produced per female was highest at 25 degrees C; averaging near 30 nymphs per female, but it dropped to near zero at both 10 and 35 degrees C. The highest intrinsic rate of increase (r(m)) was 0.241 at 30 degrees C. Net reproductive rate (R(0)) ranged from 29.8 at 25 degrees C to 0.2 at 10 degrees C. The generation time (GT) decreased with increasing temperatures from 60.3 d at 10 degrees C to 13.8 d at 30 degrees C. In addition, root aphids reared at 30 degrees C on three host plants [O. sativa, Zea mays L. and Sorghum bicolor (L.) Moench] revealed that the developmental time of the nymphal stages averaged 6.9 d when reared on O. sativa and 10.7 d when reared on Z. mays. Comparison of the nitrogen content of the three host plants indicated that the root nitrogen content was highest in O. sativa. The effect of nitrogen content on aphid performance, however, is still not clear. Other factors, such as plant secondary chemistry, may play a role in affecting aphid performance.