Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress

It is unclear how stress granule (SG) formation and cellular apoptosis are coordinately regulated. MCPIP1 (monocyte chemotactic protein-induced protein 1), also known as Zc3h12a, is a critical regulator of the inflammatory response and immune homeostasis. However, the role of MCPIP1 in stress response remains unknown. Here, we report that overexpression of MCPIP1 inhibited the assembly of SGs in response to various stresses. Conversely, MCPIP1-deficient splenocytes developed more SGs even without stress. On the other hand, overexpression of MCPIP1 sensitized RAW 264.7 cells to apoptosis under stress, whereas MCPIP1-deficient cells were resistant to stress-induced apoptosis. Mutagenesis study showed that the ability of MCPIP1 to repress SG formation is dependent on its deubiquitinating activity. Consistently, MCPIP1 negatively regulated stress-induced phosphorylation of eIF2α and thus released stress-induced inhibition of protein translation. However, MCPIP1 also inhibited 15-deoxy-Δ(12,14)-prostaglandin J(2)-induced SG formation, which was reported to be independent of eIF2α phosphorylation. Taken together, these results suggest that MCPIP1 coordinates SG formation and apoptosis during cellular stress and may play a critical role in immune homeostasis and resolution of macrophage inflammation.     

Effects of Aluminum on Immune Functions of Cultured Splenic T and B Lymphocytes in Rats

The effects of Aluminum (Al) exposure on immune functions of cultured splenic T and B lymphocytes of rats were studied. The lymphocytes were isolated from spleen of healthy male Wistar rats weighing 110-120 g. The cultured cells in RPMI-1640 medium were exposed to 0 (control group), 0.035 (low-dose group), 0.07 (medial-dose group), and 0.14 (high-dose group) mg/mL Al(3+) as aluminum trichloride (AlCl(3)) in an incubator under 5% CO(2) at 37°C for 24 h. The T and B lymphocyte proliferation was measured with a tetrazolium dye colorimetric assay. The levels of interleukin (IL)-2, IL-6, and tumor necrosis factor (TNF)-α were determined by iodine [(125)I] IL-2, IL-6, and TNF-α radioimmunoassay kits, respectively. The proportions of CD3(+), CD4(+), and CD8(+) T lymphocytes were measured with a flow cytometer. The results showed that the T and B lymphocyte proliferation, the levels of IL-2, IL-6, TNF-α, the proportions of CD3(+) and CD4(+) T lymphocytes, and the ratio of CD4(+)/CD8(+) T lymphocytes were lowered by Al treatments, while the proportion of CD8(+) T lymphocytes was increased. These findings indicate that Al exposure can inhibit the immune functions of splenic T and B lymphocytes of rats in vitro.     

基于同步辐射显微CT研究冻融循环对黑土团聚体结构特征的影响

在我国东北地区,土壤不同程度的受到季节性冻融的影响。冻融作用会改变土壤微观结构,团聚体作为土壤结构的基本单元,其结构特征的改变反映了冻融作用对土壤微观结构的影响。同步辐射显微CT可以无损获取高分辨率、强对比度的内部结构图像,是研究土壤团聚体三维微结构的有效手段。采集了室内冻融循环试验下不同冻融循环次数的土壤团聚体样品,应用同步辐射显微CT扫描获取了3.25μm分辨率的团聚体内部结构图像,然后应用CT图像处理方法和Image J软件观察并定量分析了团聚体微结构特征。结果表明:随着冻融循环次数的增加,土壤孔隙度不断增大,瘦长型孔隙度占比与100μm的非毛管孔隙度不断增大;当冻融循环次数达到7次以上,团聚体孔隙连通度随冻融循环次数的增加而变大。冻融循环对黑土团聚体孔隙度、孔隙形状、孔隙分级、连通性等结构特征影响显著。该研究为春季解冻期土壤侵蚀机理的研究及水土流失的防治提供理论依据。     

Synthesis,Biological Evaluation,and Docking Study of Ring-Opening Amide Analogs of Matrine as Antitumor Agents

In this article, we designed and synthesized two series of matrine analogs with ring-opening in the lactam portion of the molecule. Our in vitro cytotoxicity study showed that analog N-(3-bromophenyl)-4-[(1R,3aS,10aR,10bS)-decahydro-1H,4H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl]butanamide ( B11 ) with a meta-bromide on the phenyl ring displayed the best antiproliferative activity. Moreover, B11 induced cell cycle arrest in G1 phase and cell apoptosis in a dose-dependent manner in A549 cells. Molecular modeling revealed that B11 achieved a higher docking score compared to its precursor tert-butyl (1R,3aS,10aR,10bS)-1-[4-(3-bromoanilino)-4-oxobutyl]octahydro-1H,4H-pyrido[3,2,1-ij][1,6]naphthyridine-2(3H)-carboxylate ( A11 , an analog of B11 with a Boc group) and parent compound matrine, possibly because B11 formed a hydrogen bond with SER91 and a halogen bond with GLN320 on the binding site of annexin A2. Overall, we discovered the potential anticancer lead compound B11 , which can be used for further study both in vitro and in vivo.     

Water-protein interplay reveals the specificity of α-lytic protease

Wild type and mutant α-lytic protease, differing by only one amino acid, have distinct specificities. Previous studies have shown that motion patterns of the binding pocket play an important role. However, it is still unclear how these differences are generated from a single amino acid mutation. Based on comparative molecular dynamics simulations using explicit and implicit solvent models, we studied the dynamic properties of both protein and water. The explicit solvent simulations showed specificity related differences in the energy landscapes and the power spectra between the two enzymes, whereas implicit solvent simulations did not. Moreover, the explicit solvent simulations demonstrated obvious distinctions in dynamic behaviors of water, such as their residence behaviors and hydrogen bonding. These results suggest that the interplay between water and enzyme is essential in determining the substrate specificity, and the detail knowledge of such interplay can greatly improve our understanding of bio-molecules.     

Effect of Neoadjuvant Chemotherapy in Patients with Resectable Colorectal Liver Metastases

Background

Whether patients with resectable colorectal liver metastases (CRLM) receive survival benefit from neoadjuvant chemotherapy remains controversial.

Methods

We retrospectively analyzed 466 patients with resectable CRLM between 2000 and 2010. Patient characteristics and survival data were recorded.

Results

The patients were divided into one group with neoadjuvant chemotherapy (group NC, n = 121) and another without (group WN, n = 345). There was no difference in 5-year survival (52% vs. 48%) between the two groups. No significant differences were identified between the two groups in terms of 30-day mortality (1.7% vs. 1.2%) or morbidity (33.9% vs. 25.8%). A primary tumor at stage T4, ≥4 liver metastases, the largest liver metastasis ≥5 cm in diameter, and a serum CEA level ≥5 ng/ml were independent prognostic factors. By assigning one point to each, the patients were divided into a low-risk group (0–2) and a high-risk (3–4). The patients in the low-risk group received no survival benefit from neoadjuvant chemotherapy, whereas those in the high-risk group received survival benefit (5-year survival, 39% vs. 33%, P = 0.028).

Conclusions

Preoperative neoadjuvant chemotherapy did not increase mortality or complications. Not all resectable patients, only those with >2 independent risk factors, received survival benefit from neoadjuvant chemotherapy.     

Characterization of the agent of "high plains disease": mass spectrometry determines the sequence of the disease-specific protein

The "32-kDa" protein specifically associated with high plains disease was characterized by time-of-flight mass spectrometry, after the agent had been isolated in pure culture by "vascular puncture inoculation," a novel mechanical means of transmission. Two isolates from different geographic locations each consisted of a mixture of subpopulations that were highly homologous to an amino acid sequence derived from a nucleotide sequence (U60141) deposited in GenBank trade mark by the Nebraska group as "the probable N-protein of high plains virus." However, the U60141 sequence was found to be incomplete; de novo sequencing of peptides produced by proteolytic digestions of the 32-kDa band from an SDS-PAGE separation showed that an additional 18 amino acid residues were present at the N terminus. BLAST (basic local alignment search tool) examination of the sequence showed no significant homology with any protein in the databases, indicating that the infectious agent of high plains disease is likely a member of a hitherto unclassified virus group.