Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation

Nutlins, the newly developed small molecule antagonists of MDM2, activate p53 and induce apoptosis in cancer cells, offering a novel strategy of chemotherapy. Recent studies have further suggested synergistic effects of nutlins with other chemotherapeutic drugs. However, it is unclear whether nutlins increase or decrease the side effects of these drugs in normal non-malignant cells or tissues. Cisplatin is a widely used chemotherapy drug, which has a major side effect of kidney injury. Here we show that Nutlin-3 protected kidney cells against cisplatin-induced apoptosis. The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment. Moreover, the protective effects were shown in MDM2-, MDM4-, or p53-deficient cells. On the other hand, Nutlin-3 suppressed mitochondrial events of apoptosis during cisplatin incubation, including Bax activation and cytochrome c release. Nutlin-3 attenuated cisplatin-induced oligomerization of Bax and Bak but not their interactions with Bcl-XL. In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca2+, Bim peptide, and recombinant tBid. Importantly, it blocked both Bax and Bak oligomerization under these conditions. Together, the results have uncovered a new pharmacological function of nutlins, i.e. suppression of Bax and Bak, two critical mediators of apoptosis.     

Study of gene function based on spatial co-expression in a high-resolution mouse brain atlas

Background  

The Allen Brain Atlas (ABA) project systematically profiles three-dimensional high-resolution gene expression in postnatal mouse brains for thousands of genes. By unveiling gene behaviors at both the cellular and molecular levels, ABA is becoming a unique and comprehensive neuroscience data source for decoding enigmatic biological processes in the brain. Given the unprecedented volume and complexity of the in situ hybridization image data, data mining in this area is extremely challenging. Currently, the ABA database mainly serves as an online reference for visual inspection of individual genes; the underlying rich information of this large data set is yet to be explored by novel computational tools. In this proof-of-concept study, we studied the hypothesis that genes sharing similar three-dimensional expression profiles in the mouse brain are likely to share similar biological functions.     

Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5

Normal Cdk5 activity, conferred mainly by association with its primary activator p35, is critical for normal function of the cell and must be tightly regulated. During neurotoxicity, p35 is cleaved to form p25, which becomes a potent and mislocalized hyperactivator of Cdk5, resulting in a deregulation of Cdk5 activity. p25 levels have been found to be elevated in Alzheimer's disease (AD) brain and overexpression of p25 in a transgenic mouse results in the formation of phosphorylated tau, neurofibrillary tangles and cognitive deficits that are pathological hallmarks of AD. p25/Cdk5 also hyperphosphorylates neurofilament proteins that constitute pathological hallmarks found in Parkinson's disease and amyotrophic lateral sclerosis. The selective targeting of p25/Cdk5 activity without affecting p35/Cdk5 activity has been unsuccessful. In this review we detail our recent studies of selective p25/Cdk5 inhibition without affecting p35/Cdk5 or mitotic Cdk activities. We found that a further truncation of p25 to yield a Cdk5 inhibitory peptide (CIP) can specifically inhibit p25/Cdk5 activity in transfected HEK cells and primary cortical neurons. CIP was able to reduce tau hyperphosphorylation and neuronal death induced caused by p25/Cdk5 and further studies with CIP may develop a specific Cdk5 inhibition strategy in the treatment of neurodegeneration.     

Drought-resistant physiological characteristics of four shrub species in arid valley of Minjiang River, China

The formation of 161 km-long arid valley (170 km²) of Mingjiang River is attributed to the effect of foehn. The arid valley presents harsh conditions for the growth of vegetation, which include higher annual evaporation and transpiration rate (1400–2000 mm), lower annual precipitation rate (400–700 mm), steep slope, and infertile soils. Although the vegetation is dominated by xerophilous bushes and grasses, it plays a significant role in soil and water conservation in watershed and provides important references in the arid valley as it is very difficult to grow trees. Drought-resistant physiological characteristics of four native species, i.e., Sophora davidiana, Bauhinia faberi var. microphylla, Convolvulus tragacanthoides, and Artemisia gmelinii, have been measured. It was found that the content of chlorophyll, free proline and soluble sugars showed an increase, whereas evaporation ratio, WSD, RWC and cytolemma osmosis showed a decrease under drought stress. Integrated assessment of the four species indicated that the integrated drought resistance index was the highest in July (0.507), followed by September, August and June, whereas it was the lowest in May (0.442). The result provided a basis for vegetation restoration, especially it improved survival of planted species in May and June when plant species exhibit the weakest drought resistance.     

Waist-to-height ratio is an accurate and easier index for evaluating obesity in children and adolescents

Objectives: The present study aims to evaluate the accuracy of the index of waist‐to‐height ratio (WHTR), and proposed the optimal thresholds of WHTR in the definition of childhood overweight and obesity in a bi‐ethnic Chinese school‐aged population. Research Methods and Procedures: Overweight and obese were identified by BMI for age and gender in a random sample including 2055 Han and 2132 Uygur ethnic school‐aged children (8 to 18 years old). WHTR was calculated by waist circumference divided by height on the basis of standard anthropometric measurements. Receiver operating characteristic (ROC) curve analyses were performed to assess the accuracy of WHTR as a diagnostic test for childhood overweight and obesity, compared with waist circumference. The optimal thresholds of WHTR for defining overweight and obesity were recommended respectively by gender. The correlation between WHTR and age was analyzed and compared with BMI. Results: A‐values (area under curve) of WHTR for diagnosing overweight and obesity were both over 0.90 in both genders and better than those of waist circumference. A threshold of 0.445 was identified for overweight in both genders, with the sensitivity and specificity >0.80. The thresholds for defining obesity was 0.485 in boys and 0.475 in girls, both having the sensitivity and specificity >0.90. WHTR showed less association with age than BMI. Conclusions: WHTR is a simple, easy, accurate, and non‐age‐dependent index with high applicability to screening overweight and obesity in children and adolescents. The use of WHTR in the general childhood population has been justified by this study.     

A mutation in MRH2 kinesin enhances the root hair tip growth defect caused by constitutively activated ROP2 small GTPase in Arabidopsis

Root hair tip growth provides a unique model system for the study of plant cell polarity. Transgenic plants expressing constitutively active (CA) forms of ROP (Rho-of-plants) GTPases have been shown to cause the disruption of root hair polarity likely as a result of the alteration of actin filaments (AF) and microtubules (MT) organization. Towards understanding the mechanism by which ROP controls the cytoskeletal organization during root hair tip growth, we have screened for CA-rop2 suppressors or enhancers using CA1-1, a transgenic line that expresses CA-rop2 and shows only mild disruption of tip growth. Here, we report the characterization of a CA-rop2 enhancer (cae1-1 CA1-1) that exhibits bulbous root hairs. The cae1-1 mutation on its own caused a waving and branching root hair phenotype. CAE1 encodes the root hair growth-related, ARM domain-containing kinesin-like protein MRH2 (and thus cae1-1 was renamed to mrh2-3). Cortical MT displayed fragmentation and random orientation in mrh2 root hairs. Consistently, the MT-stabilizing drug taxol could partially rescue the wavy root hair phenotype of mrh2-3, and the MT-depolymerizing drug Oryzalin slightly enhanced the root hair tip growth defect in CA1-1. Interestingly, the addition of the actin-depolymerizing drug Latrunculin B further enhanced the Oryzalin effect. This indicates that the cross-talk of MT and AF organization is important for the mrh2-3 CA1-1 phenotype. Although we did not observe an apparent effect of the MRH2 mutation in AF organization, we found that mrh2-3 root hair growth was more sensitive to Latrunculin B. Moreover, an ARM domain-containing MRH2 fragment could bind to the polymerized actin in vitro. Therefore, our genetic analyses, together with cell biological and pharmacological evidence, suggest that the plant-specific kinesin-related protein MRH2 is an important component that controls MT organization and is likely involved in the ROP2 GTPase-controlled coordination of AF and MT during polarized growth of root hairs.     

Mosaic genome architecture of the Anopheles gambiae species complex

Background

Attempts over the last three decades to reconstruct the phylogenetic history of the Anopheles gambiae species complex have been important for developing better strategies to control malaria transmission.

Methodology

We used fingerprint genotyping data from 414 field-collected female mosquitoes at 42 microsatellite loci to infer the evolutionary relationships of four species in the A. gambiae complex, the two major malaria vectors A. gambiae sensu stricto (A. gambiae s.s.) and A. arabiensis, as well as two minor vectors, A. merus and A. melas.

Principal Findings

We identify six taxonomic units, including a clear separation of West and East Africa A. gambiae s.s. S molecular forms. We show that the phylogenetic relationships vary widely between different genomic regions, thus demonstrating the mosaic nature of the genome of these species. The two major malaria vectors are closely related and closer to A. merus than to A. melas at the genome-wide level, which is also true if only autosomes are considered. However, within the Xag inversion region of the X chromosome, the M and two S molecular forms are most similar to A. merus. Near the X centromere, outside the Xag region, the two S forms are highly dissimilar to the other taxa. Furthermore, our data suggest that the centromeric region of chromosome 3 is a strong discriminator between the major and minor malaria vectors.

Conclusions

Although further studies are needed to elucidate the basis of the phylogenetic variation among the different regions of the genome, the preponderance of sympatric admixtures among taxa strongly favor introgression of different genomic regions between species, rather than lineage sorting of ancestral polymorphism, as a possible mechanism.     

Identification of the gene imds-60 in mouse epididymis

Sperm maturation, including the acquisition of motility and the full ability to fertilize oocyte, occurs during its transit through the dynamic environment of the epididymis. However, the roles of many genes involved in the process of sperm maturation still remain to be found. Based on an expressed sequence tag named imds-60, which was first found in uterus but is highly expressed in epididymis, the full-length cDNA sequence of imds-60 with a complete open reading frame was obtained in mouse epididymis by GenBank searching, polymerase chain reaction-based procedures, and 5＇- and 3＇-rapid amplification of cDNA ends. This protein was predicted to have an N-terminal signal peptide and a C-terminal DNase I-like domain with nine transmembrane motifs in the middle part of the protein. Northern blot analysis showed that the mRNA of imds-60 was highly expressed in epididymis but at a rather lower level in uterus, seminal vesicle gland, and stomach. Further study revealed that the mRNA of imds-60 is only expressed in corpus and cauda regions of epididymis, not in caput. It is regulated partially by androgen and peaked in male mice aged from 3 weeks to adult. The imds-60 protein might play an important role in cell communication during sperm maturation.     

甘草腺毛的形态发生和组织化学研究

利用扫描电镜及薄切片技术对甘草的腺毛形态发生和发育过程进行了观察,并对腺毛发育过程中黄酮类成分积累进行了组织化学定位研究。结果表明：甘草腺毛为多细胞构成的盾状腺毛,有长柄和短柄2种类型;前者主要分布在花萼片上,而后者主要分布于叶片上。组化鉴定结果显示：腺毛中存在着黄酮类成分、其他亲脂类和非纤维素多糖类成分;在腺毛的发育过程中,黄酮类物质是随腺毛的发育成熟,在头部盘状结构的分泌细胞及角质层下腔中积累。研究结果对进一步探讨甘草叶中黄酮类成分的合成及其作用提供科学依据。