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     

Elucidation of demographic,clinical and trichoscopic features for early diagnosis of self-healing acute diffuse and total alopecia

The term “acute diffuse and total alopecia” (ADTA) has been often used as a synonym for self-regressing severe alopecia areata (AA). However, ADTA is originally defined as a rapidly-progressive subtype of AA (RP-AA) with short recovery time and favorable prognosis irrespective of interventions. Indeed, a subpopulation of ADTA recovers spontaneously. We focused on this unique subset of AA, which we coined as “self-healing ADTA” (sADTA). Prompt and accurate differentiation of sADTA from other RP-AA is important to avoid unnecessary treatments, which is still challenging due to the lack of predictive diagnostic hallmarks. In this study, 18 sADTA patients were retrospectively analyzed to delineate their demographics and clinical features, including gentle hair pull test and trichoscopic findings, followed by statistical comparison with those of RP-AA. All sADTA cases were female and the average age was 38.1 ± 15.9 years. The progression of hair loss areas peaked at 3.6 ± 1.5 months, and complete hair regrowth was achieved in 7.9 ± 1.7 months. The identified factors supporting the diagnosis of sADTA included being female; the absence of scalp pain and itch; the absence of extra-scalp hair loss; club hair predominance in hair pull test; predominant short vellus hairs; and increase in vacant follicular ostia on trichoscopy. Subsequently, a scoring system for early diagnosis of sADTA was developed by counting the number of six identified factors present in a tested case. When analyzed by the developed system, all sADTA cases, including an additional four cases, had scores of 4 or above, while all RP-AA cases had scores below 3 except one case. Therefore, the system successfully differentiated sADTA from RP-AA (P < 0.01). Despite some technical limitations, the current study suggested that sADTA is a distinctive entity with unique pathophysiology and that early diagnosis before intervention is feasible based on the characteristics.     

Food Poisonings by Ingestion of Cyprinid Fish

Raw or dried gallbladders of cyprinid fish have long been ingested as a traditional medicine in the Asian countries, particularly in China, for ameliorating visual acuity, rheumatism, and general health; however, sporadic poisoning incidences have occurred after their ingestion. The poisoning causes complex symptoms in patients, including acute renal failure, liver dysfunction, paralysis, and convulsions of limbs. The causative substance for the poisoning was isolated, and its basic properties were examined. The purified toxin revealed a minimum lethal dose of 2.6 mg/20 g in mouse, when injected intraperitoneally. The main symptoms were paralysis and convulsions of the hind legs, along with other neurological signs. Liver biopsy of the euthanized mice clearly exhibited hepatocytes necrosis and infiltration of neutrophils and lymphocytes, suggesting the acute dysfunction of the liver. Blood tests disclosed the characteristics of acute renal failure and liver injury. Infrared (IR) spectrometry, fast atom bombardment (FAB) mass spectrometry, and ¹H- and ¹³C-nuclear magnetic resonance (NMR) analysis indicated, a molecular formula of C₂₇H₄₈O₈S, containing a sulfate ester group for the toxin. Thus, we concluded that the structure of carp toxin to be 5α-cyprinol sulfate (5α-cholestane-3α, 7α, 12α, 26, 27-pentol 26-sulfate). This indicated that carp toxin is a nephro- and hepato- toxin, which could be the responsible toxin for carp bile poisoning in humans.