Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence

The telomere-capping complex shelterin protects functional telomeres and prevents the initiation of unwanted DNA-damage-response pathways. At the end of cellular replicative lifespan, uncapped telomeres lose this protective mechanism and DNA-damage signalling pathways are triggered that activate p53 and thereby induce replicative senescence. Here, we identify a signalling pathway involving p53, Siah1 (a p53-inducible E3 ubiquitin ligase) and TRF2 (telomere repeat binding factor 2; a component of the shelterin complex). Endogenous Siah1 and TRF2 were upregulated and downregulated, respectively, during replicative senescence with activated p53. Experimental manipulation of p53 expression demonstrated that p53 induces Siah1 and represses TRF2 protein levels. The p53-dependent ubiquitylation and proteasomal degradation of TRF2 are attributed to the E3 ligase activity of Siah1. Knockdown of Siah1 stabilized TRF2 and delayed the onset of cellular replicative senescence, suggesting a role for Siah1 and TRF2 in p53-regulated senescence. This study reveals that p53, a downstream effector of telomere-initiated damage signalling, also functions upstream of the shelterin complex.     

The Recognition of Mental Illness,Schizophrenia Identification,and Help-Seeking from Friends in Late Adolescence

Objective

The recognition of mental illness without anticipating stigma might encourage adolescents’ help-seeking behavior. We aimed to identify the relationship between mental illness identification and adolescents’ intention to seek help if faced with mental illness.

Method

We examined the relationships between help-seeking intentions and recognition of mental illness (RMI) without correctly identifying the disease name, as well as correct labelling of schizophrenia (LSC) using a vignette about a person with schizophrenia in a cross-sectional survey of 9,484 Japanese high-school students aged 15–18 years.

Results

When compared with adolescents who were unable to recognize the mental illness (UMI) in the vignette, those in the RMI group reported they were significantly more likely to seek help from friends (odds ratio [OR] = 1.29; 95% confidence interval [CI] = 1.17–1.41; P < 0.001) and expressed an increased likelihood to seek help from professionals (all P < .05). Those in the LSC group reported they were significantly less likely to exhibit help-seeking behavior (OR = 0.77, 95% CI = 0.65–0.92, P = 0.003) and expressed an increased likelihood of help-seeking from health professionals than the UMI group (all P < .05).

Conclusion

The ability to recognize mental illness without identifying the disease may increase help-seeking from friends, while the ability to identify the disease as schizophrenia might decrease late adolescents’ help-seeking. To promote help-seeking behavior among adolescents, improving their ability to recognize mental illness generally is recommended.     

Molecular characterization of proteins in protein-body membrane that disappear most rapidly during transformation of protein bodies into vacuoles

During the post-germination growth of seeds, protein bodies fuse with one another and are converted to a central vacuole. To investigate this transition, protein-body membranes from dry seeds of pumpkin (Cucurbita sp.) were prepared and their protein components characterized. Five major proteins (designated MP23, MP27, MP28, MP32 and MP73) were detected in the protein-body membranes. A cDNA clone encoding both MP27 and MP32 has been isolated. The deduced precursor polypeptide was composed of a hydrophobic signal sequence, MP27 and MP32, in that order. A putative site of cleavage between MP27 and MP32 was located on the COOH-terminal side of asparagine 278, an indication that the post-translational cleavage may occur by the action of a vacuolar processing enzyme that converts proprotein precursors of seed proteins into the mature forms. Immunoelectron microscopic analysis showed that MP27 and MP32 were associated with protein-body membrane of dry pumpkin seeds. Among the five membrane proteins, MP27 and MP32 disappeared most rapidly during seedling growth. The degradation of MP27 and MP32 starts just after seed germination and proceeds in parallel with the transformation of the protein bodies into a vacuole.     

Research plan to study allelopathy under microgravity]

Living organisms interact each others and form ecological system on the earth. Such interactions between organisms and species have been long known, and studied at a global scale. Allelopathy is a phenomenon observed in many plants that emit specific chemicals acting on other organisms, including animals and microorganisms, in either inhibitory or excitatory ways. We propose to study whether phenomena of allelopathy are modified under altered gravity or not. If biosynthesis, emission and sensing mechanism of allelopathic substances would be affected by gravity, many organisms and ecological system might show different behaviors based on the inter-organisms and species interactions under microgravity. In the macroscopic scale, transport of the substances between organisms is largely affected by convection induced by gravity. Furthermore, the fate of allelopathic substances in confined environment differs from that seen on the earth, because of lacking sink compartment for removal and producing exotic bio-active substances by man-made system. We design basic ground experiment to evaluate gravitational effects on allelopathy applying pseudo-microgravity. Our study contributes to the synthesis of ecological system and its control on spacecrafts and extraterrestrial bodies. It also makes possible to sustain qualitative human life even on the ground under confined artificial environment that dominates in many scenes.     

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry

IntroductionThe objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice.MethodsThis prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis.ResultsPatients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37).ConclusionsThe adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0583-8) contains supplementary material, which is available to authorized users.     

Z-Spectrum Analysis Provides Proton Environment Data (ZAPPED): A New Two-Pool Technique for Human Gray and White Matter

A new technique – Z-spectrum Analysis Provides Proton Environment Data (ZAPPED) – was used to map cross-relaxing free and restricted protons in nine healthy subjects plus two brain tumor patients at 3T. First, MT data were acquired over a wide symmetric range of frequency offsets, and then a trio of quantitative biomarkers, i.e., the apparent spin-spin relaxation times (T_2,f, T_2,r) in both free and restricted proton pools as well as the restricted pool fraction F_r, were mapped by fitting the measured Z-spectra to a simple two-Lorentzian compartment model on a voxel-by-voxel basis. The mean restricted exchangeable proton fraction, F_r, was found to be 0.17 in gray matter (GM) and 0.28 in white matter (WM) in healthy subjects. Corresponding mean values for apparent spin-spin relaxation times were 785 µs (T_2,f) and 17.7 µs (T_2,r) in GM, 672 µs (T_2,f) and 23.4 µs (T_2,r) in WM. The percentages of F_f and F_r in GM are similar for all ages, whereas F_r shows a tendency to decrease with age in WM among healthy subjects. The patient ZAPPED images show higher contrast between tumor and normal tissues than traditional T₂-weighted and T₁-weighted images. The ZAPPED method provides a simple phenomenological approach to estimating fractions and apparent T₂ values of free and restricted MT-active protons, and it may offer clinical useful information.     

Inflammatory and healing environment in synovial fluid after anterior cruciate ligament reconstruction: Granulocytes and endogenous opioids as new targets of postoperative pain

BackgroundBiological processes after anterior cruciate ligament reconstruction (ACLR) is crucial for recovery. However, alterations in the of synovial fluid cell population during the acute phase following ACLR and the relationship between these cells and postoperative pain is unclear. The goal of this study was to reveal alterations in synovial fluid cell population during the acute phase following ACLR and relationship between postoperative pain and proportion of synovial fluid cells.MethodsSynovial fluids were obtained from all patients (n = 50) before surgery and from patients who showed hydrarthrosis at days 4 (n = 25), and 21 (n = 42) post-surgery. The cell population was analyzed by flow cytometry. IL1β, IL8, and met-enkephalin in synovial fluid were quantitated by enzyme-linked immunosorbent assay. Patients answered numerical rating scale (NRS) questionnaire at 4 days and approximately 4 weeks postoperatively.ResultsThe granulocyte population was significantly higher at 4 days after surgery than at any other time points. The population of macrophages was 3.2 times and 7.7 times as high as at surgery on days 4 and 21, respectively. T cell population was significantly higher 21 days after surgery compared to 4 days after surgery. All NRS 4 weeks after surgery showed a significant negative correlation with the granulocyte population in synovial fluid 4 days after surgery. Granulocyte population in synovial fluid significantly correlated with the levels of IL1β and IL8. Postoperative pain at rest tended to decrease with an increase in met-enkephalin concentration 4 days after ACLR.ConclusionsSynovial fluid after ACLR had an inflammatory environment at early time points and a healing environment in the subsequent phase about concerning to the cellular composition. A proportion of synovial fluid cells and endogenous opioids affected postoperative pain.     

Neolignan Licarin A presents effect against Leishmania (Leishmania) major associated with immunomodulation in vitro

Leishmaniasis’ treatment is based mostly on pentavalent antimonials or amphotericin B long-term administration, expensive drugs associated with severe side effects. Considering these aforementioned, the search for alternative effective and safe leishmaniasis treatments is a necessity. This work evaluated a neolignan, licarin A anti-leishmanial activity chemically synthesized by our study group. It was observed that licarin A effectively inhibited Leishmania (Leishmania) major promastigotes (IC₅₀ of 9.59 ± 0.94 μg/mL) growth, by inducing in these parasites genomic DNA fragmentation in a typical death pattern by apoptosis. Additionally, the neolignan proved to be even more active against intracellular amastigotes of the parasite (EC₅₀ of 4.71 ± 0.29 μg/mL), and significantly more effective than meglumine antimoniate (EC₅₀ of 216.2 ± 76.7 μg/mL) used as reference drug. The antiamastigote activity is associated with an immunomodulatory activity, since treatment with licarin A of the infected macrophages induced a decrease in the interleukin (IL)-6 and IL-10 production. This study demonstrates for the first time the antileishmanial activity of licarin A and suggests that the compound may be a promising in the development of a new leishmanicidal agent.