A Molecular Link between the Circadian Clock, DNA Damage Responses, and Oncogene Activation

Circadian clocks enhance the efficiency and survival of living things by organizing their behavior and body functions. There has been a long history of research seeking a link between circadian clock and tumorigenesis. Studies of animal models and human tumor samples have revealed that the dysregulation of circadian clocks is an important endogenous factor causing mammalian cancer development. The core circadian clock regulators have been implicated in the control of both the cell cycle and DNA damage responses (DDR). Conversely, several intracellular signaling cascades that play important roles in regulation of the cell cycle and the DDR also contribute to circadian clock regulation. This review describes selected regulatory aspects of circadian clocks, providing evidence of a molecular link of the circadian clocks with cellular DDR

Light-Dependent Regulation of Circadian Clocks in Vertebrates

Circadian clocks are intrinsic time-tracking systems that endow organisms with a survival advantage. The core of the circadian clock mechanism is a cell-autonomous and self-sustained oscillator called a cellular clock, which operates via a transcription-/translation-based negative feedback loop. Under natural conditions, circadian clocks are entrained to a 24-hour day by environmental time cues, most commonly light. In mammals, circadian clocks are regulated by cellular clocks located in the central nervous system, such as the suprachiasmatic nucleus (SCN), and in other peripheral tissues. Importantly, mammals have no photoreceptors in the peripheral tissues; therefore the effect of light on peripheral clocks is indirect. By striking contrast, zebrafish peripheral cellular clocks are directly light responsive. This characteristic of the zebrafish cellular clock has contributed to the identification of molecules and signaling pathways that are involved in the light-dependent regulation of the cellular clock. Here, selected light-dependent regulatory mechanisms of circadian clocks in mammals and zebrafish are described

Talonavicular joint abnormalities and walking ability of patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is often associated with deformities of the feet, and foot pain often arises in the talonavicular joint of patients with RA. The object of this study was to assess the relationship between magnetic resonance imaging (MRI) findings of the talonavicular joint and walking ability. The subjects were 35 RA patients (10 feet in 5 males and 56 feet in 30 females) aged 34-87 years (mean: 70 years +/- 12.1), with a disease duration from 1-54 years (mean: 14 years +/- 12.1). MRI findings were classified as follows: Grade 1, almost normal; Grade 2, early articular destruction; Grade 3, moderate articular destruction; Grade 4, severe articular destruction; and Grade 5, bony ankylosis dislocation. Walking ability was classified into one of 9 categories ranging from normal gait to bedridden status according to the system of Fujibayashi. As the grade of MRI images became higher the walking ability decreased, and these parameters showed a correlation by Spearman's rank correlation coefficient analysis (P = 0.003). Thus, in the present cohort group of patients with RA, the deterioration of walking ability increased with the severity of destruction of the talonavicular joint.</p

Evaluation of the Luciferase Assay-Based In Vitro Elicitation Test for Serum IgE

ABSTRACTBackgroundAn in vitro elicitation test employing human high-affinity IgE receptor-expressing rat mast cell lines appears to be a useful method for measuring mast cell activation using a patient's IgE and an allergen; however, such cell lines are sensitive to human complements in the serum. We have recently developed a new luciferase-reporting mast cell line (RS-ATL8) to detect IgE crosslinking-induced luciferase expression (EXiLE) with relatively low quantities of serum IgE.MethodsA total of 30 patients suspected of having egg white (EW) allergy were subjected to an oral food challenge (OFC) test; then, the performances of EW-specific serum IgE (CAP-FEIA), EW-induced degranulation, and EXiLE responses in RS-ATL8 cells were compared using receiver-operating characteristic (ROC) curve analysis. The patients' sera were diluted to 1:100, which causes no cytotoxicity when sensitizing the RS-ATL8 cells for the degranulation and EXiLE tests.ResultsThe area under the ROC curves was highest in the EXiLE test (0.977), followed by CAP-FEIA (0.926) and degranulation (0.810). At an optimal cutoff range (1.648-1.876) calculated from the ROC curve of the EXiLE test, sensitivity and specificity were 0.944 and 0.917, respectively. A 95% positive predictive value was given at a cutoff level of 2.054 (fold increase in luciferase expression) by logistic regression analysis. Conclusions: In contrast to in vivo tests, the EXiLE test appears to be a useful tool in diagnosing patients suspected of having IgE-dependent EW allergy without the risk of severe systemic reactions

Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7.

c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family and controls various physiological processes including apoptosis. A specific upstream activator of JNKs is the mitogen-activated protein kinase kinase 7 (MKK7). It has been reported that MKK7-JNK signaling plays an important regulatory role in neural development, however, post-developmental functions in the nervous system have not been elucidated. In this study, we generated neuron-specific Mkk7 knockout mice (MKK7 cKO), which impaired constitutive activation of JNK in the nervous system. MKK7 cKO mice displayed impaired circadian behavioral rhythms and decreased locomotor activity. MKK7 cKO mice at 8 months showed motor dysfunctions such as weakness of hind-limb and gait abnormality in an age-dependent manner. Axonal degeneration in the spinal cord and muscle atrophy were also observed, along with accumulation of the axonal transport proteins JNK-interacting protein 1 and amyloid beta precursor protein in the brains and spinal cords of MKK7 cKO mice. Thus, the MKK7-JNK signaling pathway plays important roles in regulating circadian rhythms and neuronal maintenance in the adult nervous system

Retrospective Comparison of Non-Skin-Sparing Mastectomy and Skin-Sparing Mastectomy with Immediate Breast Reconstruction

Background. We compared Skin-sparing mastectomy (SSM) with immediate breast reconstruction and Non-skin-sparing mastectomy (NSSM), various types of incision in SSM. Method. Records of 202 consecutive breast cancer patients were reviewed retrospectively. Also in the SSM, three types of skin incision were used. Type A was a periareolar incision with a lateral extension, type B was a periareolar incision and axillary incision, and type C included straight incisions, a small elliptical incision (base line of nipple) within areolar complex and axillary incision. Results. Seventy-three SSMs and 129 NSSMs were performed. The mean follow-up was 30.0 (SSM) and 41.1 (NSSM) months. Respective values for the two groups were: mean age 47.0 and 57; seven-year cumulative local disease-free survival 92.1% and 95.2%; post operative skin necrosis 4.1% and 3.1%. In the SSM, average areolar diameter in type A & B was 35.4 mm, 43.0 mm in type C and postoperative nipple-areolar plasty was performed 61% in type A & B, 17% in type C, respectively. Conclusion. SSM for early breast cancer is associated with low morbidity and oncological safety that are as good as those of NSSM. Also in SSM, Type C is far superior as regards cost and cosmetic outcomes

Ground-state electric quadrupole moment of 31Al

Ground-state electric quadrupole moment of 31Al (I =5/2+, T_1/2 = 644(25) ms) has been measured by means of the beta-NMR spectroscopy using a spin-polarized 31Al beam produced in the projectile fragmentation reaction. The obtained Q moment, |Q_exp(31Al)| = 112(32)emb, are in agreement with conventional shell model calculations within the sd valence space. Previous result on the magnetic moment also supports the validity of the sd model in this isotope, and thus it is concluded that 31Al is located outside of the island of inversion.Comment: 5 page

VLA Observations of H2O Masers in the Class 0 Protostar S106 FIR: Evidence for a 10 AU-Scale Accelerating Jet-like Flow

We conducted VLA observations at 0".06 resolution of the 22 GHz water masers toward the Class 0 source S106 FIR (d=600 pc; 15" west of S106-IRS4) on two epochs separated by ~3 months. Two compact clusters of the maser spots were found in the center of the submillimeter core of S106 FIR. The separation of the clusters was ~80 mas (48 AU) along P. A. = 70 degrees and the size of each cluster was ~20 mas x 10 mas. The western cluster, which had three maser components, was 7.0 km/s redshifted with respect to the ambient cloud velocity. Each component was composed of a few spatially localized maser spots and was aligned on a line connecting the clusters. We found relative proper motions of the components with ~30 mas/yr (18 AU/yr) along the line. In addition, a series of single-dish observations show that the maser components drifted with a radial acceleration of ~1 km/s/yr. These facts indicate that the masers could be excited by a 10 AU-scale jet-like accelerating flow ejected from an assumed protostar located between the two clusters. The outflow size traced by the masers was 50 AU x 5 AU after correction for an inclination angle of 10 degrees which was derived from the relative proper motions and radial velocities of the maser components. The three-dimensional outflow velocity ranged from 40 to 70 km/s assuming symmetric motions for the blue and red components. Since no distinct CO molecular outflows have been detected so far, we suggest that S106 FIR is an extremely young protostar observed just after the onset of outflowing activity.Comment: 24 pages, 6 figures, No. 5 color. Accepted, Astrophysical Journa

Air-sea interactive forcing on phytoplankton productivity and community structure changes in the East China Sea during the Holocene

Phytoplankton productivity and community structure in the East China Sea (ECS) play an important role in marine ecology and carbon cycle, but both have been changing rapidly in response to recent oceanic and atmospheric circulation changes. However, the lack of long-term records of phytoplankton productivity and community structure variability in the region hinders our understanding of natural forcing mechanisms. Here, we use the phytoplankton biomarker (brassicasterol, dinosterol and alkenones) contents as well as the ratios between these biomarkers in three sediment cores from the ECS shelf to reconstruct the spatiotemporal variations of productivity and community of diatoms, dinoflagellates and coccolithophores during the Holocene, respectively. During 9–7 ka, the ECS shelf was characterized by low phytoplankton productivity with low coccolithophore contribution, caused by the oligotrophic condition mainly owing to the restricted Kuroshio Current (KC) intrusion under low sea-level conditions, thus the lack of nutrient input. Phytoplankton productivity generally increased during 7–4.6 ka, in response to the initial intrusion of the Yellow Sea Warm Current (YSWC, a branch of the KC), bringing nutrient from the subsurface KC to the upper layer of the ECS for phytoplankton growth. Phytoplankton productivity continuously increased during 4.6–1 ka, due to an enhanced circulation system (YSWC and Yellow Sea Coastal Current (YSCC)) driven by strong East Asia Winter Monsoon (EAWM). Significantly, high alkenone contents and coccolithophore contribution in the eastern core F11A was associated with its location closer to the warm and saline YSWC, which was suitable for coccolithophore growth. Beyond diagenetic processes which could partly account for higher biomarker contents near core tops, elevated phytoplankton productivity during the last 1 ka might be induced by more nutrient supply from the intensified circulation system driven by enhanced KC and anthropogenic activities. The latter also resulted in high dinoflagellate proportions in all three cores. These temporal and spatial changes of phytoplankton productivity and community structure in the ECS during the Holocene corresponded to different mechanisms by the air-sea interaction, providing insights into distinguishing natural forcing and anthropogenic influences on marine ecology