Macrophage inflammatory protein-1α: A link between innate immunity and familial mediterranean fever?

The aim of this study is to investigate the relationship between chemokines and the inflammation in Familial Mediterranean Fever (FMF). Forty-nine patients with FMF (41 in remission and 8 in acute attack period) and 20 healthy controls were included in the study. Serum levels of macrophage inflammatory protein-1alpha (MIP-1alpha) were assessed in the patients and the controls, along with other parameters of disease activity, i.e., fibrinogen, C-reactive protein and erythrocyte sedimentation rate. Serum MIP-1alpha levels of the patients with FMF in acute attack period were significantly higher than the patients in remission and healthy controls (p=0.02 and p=0.038, respectively). MIP-1alpha levels were weakly correlated with CRP (r=0.32, p=0.032) levels. MIP-1alpha may have a role in the pathogenesis of FMF attacks. MIP-1alpha and other chemokines may constitute a link between the innate immune system and FMF.     

Long-term effects of 900 MHz radiofrequency radiation emitted from mobile phone on testicular tissue and epididymal semen quality

The purpose of this study is to bridge this gap by investigating effects of long term 900?MHz mobile phone exposure on reproductive organs of male rats. The study was carried out on 14 adult Wistar Albino rats by dividing them randomly into two groups (n: 7) as sham group and exposure group. Rats were exposed to 900?MHz radiofrequency (RF) radiation emitted from a GSM signal generator. Point, 1?g and 10?g specific absorption rate (SAR) levels of testis and prostate were found as 0.0623?W/kg, 0.0445?W/kg and 0.0373?W/kg, respectively. The rats in the exposure group were subject to RF radiation 3?h per day (7?d a week) for one year. For the sham group, the same procedure was applied, except the generator was turned off. At the end of the study, epididymal sperm concentration, progressive sperm motility, abnormal sperm rate, all-genital organs weights and testis histopathology were evaluated. Any differences were not observed in sperm motility and concentration (p?>?0.05). However, the morphologically normal spermatozoa rates were found higher in the exposure group (p?p?p?相似文献   

Modulation of the Chromatin Phosphoproteome by the Haspin Protein Kinase

Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr³ of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date, histone H3 is the only confirmed Haspin substrate. We used a combination of biochemical, pharmacological, and mass spectrometric approaches to study the consequences of Haspin inhibition in mitotic cells. We quantified 3964 phosphorylation sites on chromatin-associated proteins and identified a Haspin protein-protein interaction network. We determined the Haspin consensus motif and the co-crystal structure of the kinase with the histone H3 tail. The structure revealed a unique bent substrate binding mode positioning the histone H3 residues Arg² and Lys⁴ adjacent to the Haspin phosphorylated threonine into acidic binding pockets. This unique conformation of the kinase-substrate complex explains the reported modulation of Haspin activity by methylation of Lys⁴ of the histone H3. In addition, the identification of the structural basis of substrate recognition and the amino acid sequence preferences of Haspin aided the identification of novel candidate Haspin substrates. In particular, we validated the phosphorylation of Ser¹³⁷ of the histone variant macroH2A as a target of Haspin kinase activity. MacroH2A Ser¹³⁷ resides in a basic stretch of about 40 amino acids that is required to stabilize extranucleosomal DNA, suggesting that phosphorylation of Ser¹³⁷ might regulate the interactions of macroH2A and DNA. Overall, our data suggest that Haspin activity affects the phosphorylation state of proteins involved in gene expression regulation and splicing.Eukaryotic protein kinases (ePK)¹ constitute a large family of enzymes that coordinate virtually any cellular processes by the phosphorylation of their target proteins at specific sites (1, 2). Active kinases often modulate the activity of other enzymes, including other kinases, thus amplifying and extending an initial signal that affect sometimes thousands of proteins (3). This creates a highly complex network of feedback and forward loops where multiple kinases can mutually influence each other''s activity. Kinases adopt three molecular strategies to select and specifically phosphorylate their substrates in the crowded environment of a cell (2). First, tight control of cellular kinase localization assures that only proteins present in the close proximity of the kinase can be phosphorylated; second, the kinase specific activity can be regulated via post-translational modifications or the recruitment of cofactor molecules; and third, the recognition of specific consensus motifs on substrates ensures that phosphorylation only occurs at the intended site or sites (2).The Haspin kinase is a member of the ePK family that structurally diverges from most ePKs (1, 4). The Haspin kinase domain displays structural features that have never been observed in other ePK family members (5, 6). Specifically, the possibility of activation loop phosphorylation, a frequent regulatory mechanisms to control kinase activity, is absent in Haspin (5). Haspin is characterized by an active conformation that is stabilized by a hydrophobic lock of the helix αC inducing a stable S conformation of the structurally unique activation segment. These specific structural features also create a structurally diverse substrate binding site comprising a highly electronegative cleft for the histone H3 basic tails (5). Interestingly, the recognition of H3 has been shown to be modulated by methylation at H3 residue Lys⁴, thus coupling Haspin activity with epigenetic mechanisms of chromatin regulation (5). Histone H3 that is phosphorylated at Thr³ is so far the only well-characterized Haspin substrate (7). H3Thr³ phosphorylation (H3Thr^3ph) is required for the localization of Aurora B at the centromere (8–10). Inactivation of Haspin catalytic activity by ATP mimetic inhibitors induces Aurora B centromeric delocalization, leading to a loss of phosphorylation in chromatin associated Aurora B substrates (11, 12). To date, apart from this well-characterized centromeric function of Haspin activity, the broader cellular functions of the kinase and the phosphorylation events that control these remain essentially unknown.In this study, we used an integrated biochemical, proteomic, pharmacologic, and structural biology approach to study the Haspin kinase, its substrates and the cellular consequences of its activity. Specifically, we determined a new mode of kinase substrate binding and identified a Haspin kinase substrate recognition motif. We identified 3964 phosphorylation sites in chromatin-associated proteins, quantified their response to Haspin inhibition, and verified the mitotic phosphorylation of MacroH2A Ser¹³⁷ (13) as directly dependent by Haspin activity. Altogether, our data suggest that Haspin regulates the phosphorylation of proteins involved in mechanisms that control gene expression, including the modifications of histones, and provide evidence for novel molecular effects of Haspin activity on mitotic chromatin.     

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

Radiation induced genomic instability is a well-studied phenomenon, the underlying mechanisms of which are poorly understood. Persistent oxidative stress, mitochondrial dysfunction, elevated cytokine levels and epigenetic changes are among the mechanisms invoked in the perpetuation of the phenotype. To determine whether epigenetic aberrations affect genomic instability we measured DNA methylation, mRNA and microRNA (miR) levels in well characterized chromosomally stable and unstable clonally expanded single cell survivors of irradiation. While no changes in DNA methylation were observed for the gene promoters evaluated, increased LINE-1 methylation was observed for two unstable clones (LS12 and CS9) and decreased Alu element methylation was observed for the other two unstable clones (115 and Fe5.0–8). These relationships also manifested for mRNA and miR expression. mRNA identified for the LS12 and CS9 clones were most similar to each other (261 mRNA), while the 115 and Fe5.0–8 clones were more similar to each other, and surprisingly also similar to the two stable clones, 114 and 118 (286 mRNA among these four clones). Pathway analysis showed enrichment for pathways involved in mitochondrial function and cellular redox, themes routinely invoked in genomic instability. The commonalities between the two subgroups of clones were also observed for miR. The number of miR for which anti-correlated mRNA were identified suggests that these miR exert functional effects in each clone. The results demonstrate significant genetic and epigenetic changes in unstable cells, but similar changes are almost as equally common in chromosomally stable cells. Possible conclusions might be that the chromosomally stable clones have some other form of instability, or that some of the observed changes represent a sort of radiation signature and that other changes are related to genomic instability. Irrespective, these findings again suggest that a spectrum of changes both drive genomic instability and permit unstable cells to persist and proliferate.     

Is there any role of thrombin activatable fibrinolysis inhibitor in the development of a hypercoagulable state in gastric cancer

ABSTRACT: BACKGROUND: The purpose of this study was to investigate plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI) and TAFI's relationship with coagulation markers (prothrombin fragment 1 + 2) in gastric cancer patients. METHODS: Thirty-three patients with gastric adenocarcinoma and 29 healthy control subjects were prospectively enrolled in the study. Patients who had a history of secondary malignancy, thrombosis related disease, oral contraceptive use, diabetes mellitus, chronic renal failure or similar chronic metabolic disease were excluded from the study. A fasting blood sample was drawn from patients to determine the plasma levels of TAFI and Prothrombin Fragment 1 + 2 (F 1 + 2). In addition, data on patient age, sex, body mass index (BMI) and stage of disease were recorded. The same parameters, except stage of disease, were also recorded for the control group. Subsequently, we assessed the difference in the levels of TAFI and F 1 + 2 between the patient and control groups. Moreover, we investigated the relation of TAFI and F 1 + 2 levels with age, sex, BMI and stage of disease in the gastric cancer group. RESULTS: There were no statistical differences in any demographic variables (age, gender and BMI) between the groups (Table 1). The mean plasma TAFI levels of the gastric cancer group (69.4 [PLUS-MINUS SIGN] 33.1) and control group (73.3 [PLUS-MINUS SIGN] 27.5) were statistically similar (P = 0.62). The mean plasma F 1 + 2 level in the gastric cancer group was significantly higher than for those in the control group (549.7 [PLUS-MINUS SIGN] 325.3 vs 151.9 [PLUS-MINUS SIGN] 67.1, respectively; P < 0.001). In the gastric cancer group, none of the demographic variables (age, gender and BMI) were correlated with either TAFI or F 1 + 2 levels. Also, no significant associations were found between the stage of the cancer and either TAFI or F 1 + 2 levels. CONCLUSION: In our study, TAFI levels of gastric cancer patients were similar to healthy subjects. The results of our study suggest that TAFI does not play a role in pathogenesis of the hypercoagulable state in gastric cancer patients.     

Regulatory NK cells suppress antigen-specific T cell responses

The immune system has a variety of regulatory/suppressive processes, which are decisive for the development of a healthy or an allergic immune response to allergens. NK1 and NK2 subsets have been demonstrated to display counterregulatory and provocative roles in immune responses, similar to Th1 and Th2 cells. T regulatory cells suppressing both Th1 and Th2 responses have been the focus of intensive research during the last decade. In this study, we aimed to investigate regulatory NK cells in humans, by characterization of NK cell subsets according to their IL-10 secretion property. Freshly purified IL-10-secreting NK cells expressed up to 40-fold increase in IL-10, but not in the FoxP3 and TGF-beta mRNAs. PHA and IL-2 stimulation as well as vitamin D3/dexamethasone and anti-CD2/CD16 mAbs are demonstrated to induce IL-10 expression in NK cells. The effect of IL-10+ NK cells on Ag-specific T cell proliferation has been examined in bee venom major allergen, phospholipase A2- and purified protein derivative of Mycobecterium bovis-induced T cell proliferation. IL-10+ NK cells significantly suppressed both allergen/Ag-induced T cell proliferation and secretion of IL-13 and IFN-gamma, particularly due to secreted IL-10 as demonstrated by blocking of the IL-10 receptor. These results demonstrate that a distinct small fraction of NK cells display regulatory functions in humans.     

Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis

Mammalian target of rapamycin, mTOR, is a major sensor of nutrient and energy availability in the cell and regulates a variety of cellular processes, including growth, proliferation, and metabolism. Loss of the tuberous sclerosis complex genes (TSC1 or TSC2) leads to constitutive activation of mTOR and downstream signaling elements, resulting in the development of tumors, neurological disorders, and at the cellular level, severe insulin/IGF-1 resistance. Here, we show that loss of TSC1 or TSC2 in cell lines and mouse or human tumors causes endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR). The resulting ER stress plays a significant role in the mTOR-mediated negative-feedback inhibition of insulin action and increases the vulnerability to apoptosis. These results demonstrate ER stress as a critical component of the pathologies associated with dysregulated mTOR activity and offer the possibility to exploit this mechanism for new therapeutic opportunities.     

干旱区胡杨叶片含水量和叶绿素含量特征

在阿拉干样区内,距河道不同距离选取40棵胡杨树(Populus euphratica)采样,使用相关分析方法探讨胡杨叶片相对含水量(fuel moisture content,FMC)、等效水厚度(equiv-alent water thickness,EWT)、叶绿素含量随距河道距离的空间差异,以及随地面温度的变化特征,并讨论了FMC、EWT和叶绿素含量之间的相关性。结果表明:FMC、EWT、叶绿素含量与河道距离有极显著的相关关系(P<0.01)。距河道越远,3项指标均随距河道距离的增加极显著的减少,其中EWT与距河道距离的相关性最大(-0.577)。温度变化对FMC和EWT均有极显著的影响(P<0.01),但对叶绿素含量影响不大(P>0.05)。因FMC、EWT的物理含义不同,它们的平均值在胡杨树个体尺度/水平上极显著相关,但在单片叶子尺度上FMC和EWT之间无显著相关(P>0.05),而胡杨树个体平均和单片叶子的EWT与叶绿素含量均极显著相关(P<0.01)。由于EWT与距河道距离和叶绿素含量的相关性极显著,而且对温度变化不敏感,因此,具有很好的开发应用潜力,建议将EWT作为干旱区河岸生态系统植被含水量遥感监测的一个指标。     

Quantifying the hydrodynamic stress for bioprocesses

Hydrodynamic stress is an influential physical parameter for various bioprocesses, affecting the performance and viability of the living organisms. However, different approaches are in use in various computational and experimental studies to calculate this parameter (including its normal and shear subcomponents) from velocity fields without a consensus on which one is the most representative of its effect on living cells. In this letter, we investigate these different methods with clear definitions and provide our suggested approach which relies on the principal stress values providing a maximal distinction between the shear and normal components. Furthermore, a numerical comparison is presented using the computational fluid dynamics simulation of a stirred and sparged bioreactor. It is demonstrated that for this specific bioreactor, some of these methods exhibit quite similar patterns throughout the bioreactor—therefore can be considered equivalent—whereas some of them differ significantly.     

The effect of glutamine on radiation-induced organ damage

Radiation enteritis is a significant clinical problem in patients receiving ionizing radiation directed to the abdomen or pelvis. Although radiation is aimed to be directed against the malignant tissue, adjacent healthy tissues are also affected. The small intestine is the most sensitive organ to radiation. The present study was undertaken to investigate the possible protective effect of glutamine against radiation-induced intestinal, hepatic and pancreatic toxicity. Rats received 1 g/kg/day glutamine for seven days before irradiation and continued for three days after irradiation until sacrifice. Then intestinal, pancreatic and hepatic myeloperoxidase (MPO) activities, malondialdehyde (MDA) levels and caspase-3 activities of the sacrificed rats were measured. Irradiation significantly increased the intestinal and pancreatic MPO and caspase-3 activities and MDA levels in comparison to sham group. Glutamine treatment significantly decreased this elevation. Histopathological examination revealed that the intestinal mucosal structure was preserved and pancreatic inflammation decreased in the glutamine treated group. In irradiation group, NF-kappaB over expression was detected. There was no significant difference in histopathological and biochemical examinations of the liver between the groups. In conclusion, glutamine has beneficial effects on intestinal and pancreatic damage in abdominal irradiation through the inflammatory process and apoptosis.