Conditional knockout mice to study alternative splicing in vivo

Analysis of genomes has revealed that the total number of human genes is comparable to those of simpler organisms, and thus, the number of genes does not correlate with the complexity and functional diversity of different organisms. Multiple mechanisms, including alternative splicing, are believed to contribute to the molecular complexity in higher eukaryotes. Given the fact that more than half of human genes undergo alternative splicing, however, little is known about the biological relevance of most alternative splicing events and their regulatory mechanisms. Recent work has highlighted the power of reverse genetic approaches in addressing regulated splicing in animal models. Here, we focus on the conditional knockout approach adapted for splicing research with the intention to provide a general guide to the generation of mouse models to study regulated splicing in development and disease.     

BAFF inhibition: a new class of drugs for the treatment of autoimmunity

BAFF (BLyS) and APRIL are TNF-like cytokines that support survival and differentiation of B cells. Recent studies have discovered a role for BAFF in augmenting both innate and adaptive immune responses as well as in collaborating with other inflammatory cytokines to promote the activation and differentiation of effector immune cells. BAFF is an important pathogenic factor in lupus mouse models and BAFF inhibition successfully delays disease onset in these mice, although the responsiveness to BAFF inhibition varies among different strains. These results have led to the development of inhibitors targeting BAFF and APRIL in humans. An anti-BAFF antibody has shown significant but modest efficacy in two Phase III clinical trials for moderately active SLE and other inhibitors are being developed or at early stages of clinical testing.     

A stochastic model for the membrane potential of a stimulated neuron

We present a simple model describing the transition between the prefiring, firing and postfiring phases of a single neuron in a large neural net. Using typical values for the physiological parameters that enter the model, we find average interspike times that are close to those reported in experimental measurements.     

Search for substrate-based inhibitors fitting the S2' space of malarial aspartic protease plasmepsin II.

Plasmepsin (Plm) has been identified as an important target for the development of new antimalarial drugs, since its inhibition leads to the starvation of Plasmodium falciparum. A series of substrate-based dipeptide-type Plm II inhibitors containing the hydroxymethylcarbonyl isostere as a transition-state mimic were synthesized. The general design principle was provision of a conformationally restrained hydroxyl group (corresponding to the set residue at the P2' position in native substrates) and a bulky unit to fit the S2' pocket.     

NaCl胁迫对PSII光能利用和耗散的影响

用荧光动力学的方法研究了不同浓度的ＮａＣｌ 处理对ＰＳＩＩ光能利用和耗散的影响。结果表明,在较低的光强下,与对照、１００ｍ ｍｏｌ／Ｌ 和２００ｍ ｍｏｌ／Ｌ ＮａＣｌ 处理相比,经３００ｍ ｍｏｌ／Ｌ 和４００ｍ ｍｏｌ／Ｌ ＮａＣｌ 处理的小麦,其荧光光化学淬灭效率较低,荧光非光化学淬灭效率较高,Ｆｏ 淬灭系数较大,ＱＢ － 非还原性ＰＳＩＩ反应中心含量较大; 而在较高光强下, 其荧光非光化学淬灭效率和Ｆｏ 淬灭系数则相对较低。     

Inverted pendular running: a novel gait predicted by computer optimization is found between walk and run in birds

Idealized models of walking and running demonstrate that, energetically, walking should be favoured up to, and even somewhat over, those speeds and step lengths that can be achieved while keeping the stance leg under compression. Around these speeds, and especially with relatively long step lengths, computer optimization predicts a third, ‘hybrid’, gait: (inverted) pendular running (Srinivasan & Ruina 2006 Nature 439, 72–75 (doi:10.1038/nature04113)). This gait involves both walking-like vaulting mechanics and running-like ballistic paths. Trajectories of horizontal versus vertical centre of mass velocities—‘hodographs’—over the step cycle are distinctive for each gait: anticlockwise for walk; clockwise for run; figure-of-eight for the hybrid gait. Both pheasants and guineafowl demonstrate each gait at close to the predicted speed/step length combinations, although fully aerial ballistic phases are never achieved during the hybrid or ‘Grounded Inverted Pendular Running’ gait.     

Irradiated cationic mesoporphyrin induces larger damage to isolated rat liver mitochondria than the anionic form

The action of irradiated cationic Fe(III)TMPyP and anionic Fe(III)TPPS4 forms of mesoporphyrins on mitochondrial functions was investigated using experimental conditions that caused minimal effects on mitochondria in the dark. Treatment of mitochondria with 1 microM Fe(III)TMPyP for 2 min decreased the respiratory control by 3% in the dark and 28% after irradiation. Fe(III)TPPS4 (1 microM) had no significant effect on respiratory control under any of the above conditions. Both porphyrins increased the mitochondrial production of reactive oxygen species in the presence of Ca2+; however, the effect of Fe(III)TMPyP was significantly stronger. In both cases, this overproduction was associated with membrane lipid peroxidation. It was also observed that the association constant of Fe(III)TMPyP with mitochondria was 11 times higher than that of Fe(III)TPPS4. In conclusion, the damage to isolated mitochondria induced by Fe(III)TMPyP under illumination was larger than by Fe(III)TPPS4, probably because its cationic charge favors association with the mitochondrial membrane. This is supported by the decrease in the association constant of Fe(III)TMPyP with mitochondria in higher salt medium.     

不同手术方式治疗慢性鼻-鼻窦炎对上颌窦黏膜纤毛传输功能的影响

目的:比较不同手术方式治疗慢性鼻-鼻窦炎的疗效及其对上颌窦黏膜纤毛传输功能的影响,为临床制定治疗慢性鼻-鼻窦炎的优选术式提供参考依据。方法:选取2013年9月-2014年12月于本院耳鼻咽喉科就诊的160例确诊为慢性鼻-鼻窦炎的患者作为研究对象,将其随机分为4组,分别为治疗组1~4,每组各60例。治疗组1接受上颌窦自然开口扩大术,治疗组2接受上颌窦开窗术,治疗组3接受经泪前隐窝上颌窦开放术,治疗组4接受上颌窦口球囊扩张术。观察和比较4组患者的术后鼻腔黏膜的覆盖、水肿、囊泡形成、骨质暴露、瘢痕形成等情况,上颌窦窦腔内分泌物性状、蓄积情况以及术后3个月和6个月时行上颌窦腔糖精实验及窦口周黏膜活检情况。结果:四组手术后均取得较好临床疗效,而组4的临床总有效率显著高于其他三组(均P0.05)。术后3、6个月,组4Lund-Kennedy评分和MMT时间均明显低于其他三组(均P0.05);在上颌窦黏膜活检方面:术后炎性细胞数量及状细胞和黏膜下腺体细胞形态及黏膜下结构水肿改善程度亦在中组四最为显著(P0.05)。结论:上颌窦窦球囊扩张术治疗慢性鼻-鼻窦炎疗效较高,可有效改善状细胞和黏膜下腺体细胞形态及鼻窦黏膜水肿、窦口通畅引流等作用,且安全性高。     

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

Radiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001).