Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix

The lateral habenula (LHb) attracts a growing interest as a regulator of monoaminergic activity which were frequently reported to be defective in depression. Here we found that chronic social defeat stress (CSDS) increased production of pro-inflammatory cytokines in LHb associated with mobilization of monocytes and remodeling of extracellular matrix by increased matrix metalloproteinase (MMP) activity. RNA-seq analysis identified proprotein convertase Pcsk5 as an upstream regulator of MMP activation, with upregulation in LHb neurons of mice with susceptibility to CSDS. PCSK5 facilitated motility of microglia in vitro by converting inactive pro-MMP14 and pro-MMP2 to their active forms, highlighting its role in mobilization of microglia and monocytes in neuroinflammation. Suppression of Pcsk5 expression via small interfering RNA (siRNA) ameliorated depressive-like behaviors and pathological mobilization of monocytes in mice with susceptibility to CSDS. PCSK5-MMPs signaling pathway could be a target for development of the antidepressants targeting the inflammatory response in specific brain regions implicated in depression.Subject terms: Cellular neuroscience, Gene expression analysis     

Methodological extensions of meta-analysis with excess relative risk estimates: application to risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy

Although radiotherapy is recognized as an established risk factor for second malignant neoplasms (SMNs), the dose response of SMNs following radiotherapy has not been well characterized. In our previous meta-analysis of the risks of SMNs occurring among children who have received radiotherapy, the small number of eligible studies precluded a detailed evaluation. Therefore, to increase the number of eligible studies, we developed a method of calculating excess relative risk (ERR) per Gy estimates from studies for which the relative risk estimates for several dose categories were available. Comparing the calculated ERR with that described in several original papers validated the proposed method. This enabled us to increase the number of studies, which we used to conduct a meta-analysis. The overall ERR per Gy estimate of radiotherapy over 26 relevant studies was 0.60 (95%CI: 0.30–1.20), which is smaller than the corresponding estimate for atomic bomb survivors exposed to radiation as young children (1.7; 95% CI: 1.1–2.5). A significant decrease in ERR per Gy with increase in age at exposure (0.85 times per annual increase) was observed in the meta-regression. Heterogeneity was suggested by Cochran''s Q statistic (P < 0.001), which may be partly accounted for by age at exposure.     

Effectiveness and fabrication of mouthguards

Abstract –  Although mouthguards have been suggested as a means for preventing dental traumatic injuries, there are still some controversies over some aspects such as effectiveness in preventing concussions, material selections, method for fabrication, design, side effects and so on. The purpose of this literature review was to clarify differences in opinions with supporting evidence on these issues and find the best guidelines for promoting usage and providing mouthguards with better protective capability and fewer side effects such as difficulty in breathing and speaking.     

Perinatal changes in bombesin-stimulated muscle contraction in rabbit stomach and colon

Bombesin and its mammalian homologue, gastrin-releasing peptide, stimulate smooth muscle contraction and may promote the growth of gastrointestinal tissues. Isometric contraction of strips from circular muscle of the gastric fundus and longitudinal muscle of the distal colon were used to compare changes in the response to bombesin in newborn and weanling rabbits. There was an age-related qualitative change in gastric muscle from biphasic contractions including phasic and tonic components in the newborn to phasic contractions alone in the weanling. The colon contractions were tonic at both ages. In both tissues there was an age-related fivefold increase in stress in response to maximally effective concentrations of bethanechol (P less than 0.05). In contrast, in the stomach age-related decreases in the response to maximally effective concentrations of bombesin were observed, from 2930 +/- 179 mN/cm2 (98% of the maximal response to bethanechol) in the newborn to 565 +/- 81 mN/cm2 (4% of the maximal response to bethanechol) in the weanling (P less than 0.005). In the colon, a twofold increase in response to bombesin was observed, from 446 +/- 59 mN/cm2 (82% of the response to bethanechol) in the newborn to 862 +/- 11 mN/cm2 (29% of the response to bethanechol) in the weanling (P less than 0.05). No age-related changes were observed in the potency of bombesin in either tissue. Neither atropine nor tetrodotoxin altered the contractions in either tissue, suggesting that bombesin interacted directly with myocytes. There was three times as much bombesinlike immunoreactivity in the stomach compared with the colon, but no age-related changes in either tissue. In summary, by the age of weanling the stomach lost the tonic component of contraction and 80% of the efficacy of bombesin-stimulated phasic contraction that had been present in the newborn. The loss of efficacy, absolute in the stomach and relative to bethanechol in the colon, suggest that bombesin may be most important in stimulating motility in the neonatal period.