3'-UTR Sequence of Exosomal NANOGP8 DNA as an Extracellular Vesicle-Localization Signal.

Extracellular vesicles (EVs) are garnering attention as a safe and efficient biomolecule delivery system. EVs intrinsically play a crucial role in intercellular communication and pathophysiology by transporting functionally active DNA molecules. The internalized DNA pleiotropically affects the recipient cells. Considering these salient features, an intentional incorporation of specific DNA gene cassettes into EVs and their subsequent delivery to the target cells has potential applications in genetic engineering. Moreover, efficient ways to insert the DNA into EVs during their biogenesis is valuable. Our current research is a step in the development of this technology. As such, cancer cells are known to secrete exosomes containing increased amounts of double-stranded DNA than normal cells. The clonal analysis in our previously published data revealed that exosomes released from various cancer cells contained a significantly larger population of NANOGP8 DNA with a 22-base pair insertion in the 3'-untranslated region (UTR) compared to those secreted by normal cells. This finding led us to hypothesize that the 22-base pair insertion may act as a signal to facilitate the incorporation of NANOGP8 DNA into the exosomes. To test this hypothesis, we compared the EV localization of an Enhanced Green Fluorescent Protein (EGFP) gene fused with the NANOGP8 3'-UTR, with and without the 22-base pair insertion. The quantitative PCR analysis showed a significantly higher EGFP DNA accumulation in exosomes released from cells transfected with the gene cassette containing the 3'-UTR with the 22-base pair insertion. The discovery of a DNA localization signal in exosomal DNA's 3'-UTR could pave the way for the development of an EV-based DNA delivery system. This technology will open new possibilities in genetic engineering and innovative therapies using nucleic acid medicine.

Regulatory Mechanisms of Prg4 and Gdf5 Expression in Articular Cartilage and Functions in Osteoarthritis.

Owing to the rapid aging of society, the numbers of patients with joint disease continue to increase. Accordingly, a large number of patients require appropriate treatment for osteoarthritis (OA), the most frequent bone and joint disease. Thought to be caused by the degeneration and destruction of articular cartilage following persistent and excessive mechanical stimulation of the joints, OA can significantly impair patient quality of life with symptoms such as knee pain, lower limb muscle weakness, or difficulty walking. Because articular cartilage has a low self-repair ability and an extremely low proliferative capacity, healing of damaged articular cartilage has not been achieved to date. The current pharmaceutical treatment of OA is limited to the slight alleviation of symptoms (e.g., local injection of hyaluronic acid or non-steroidal anti-inflammatory drugs); hence, the development of effective drugs and regenerative therapies for OA is highly desirable. This review article summarizes findings indicating that proteoglycan 4 (Prg4)/lubricin, which is specifically expressed in the superficial zone of articular cartilage and synovium, functions in a protective manner against OA, and covers the transcriptional regulation of Prg4 in articular chondrocytes. We also focused on growth differentiation factor 5 (Gdf5), which is specifically expressed on the surface layer of articular cartilage, particularly in the developmental stage, describing its regulatory mechanisms and functions in joint formation and OA pathogenesis. Because several genetic studies in humans and mice indicate the involvement of these genes in the maintenance of articular cartilage homeostasis and the presentation of OA, molecular targeting of Prg4 and Gdf5 is expected to provide new insights into the aetiology, pathogenesis, and potential treatment of OA.

Does trapeziectomy with ligament reconstruction and tendon interposition arthroplasty correct the metacarpophalangeal joint hyperextension associated with trapeziometacarpal osteoarthritis?

INTRODUCTION: Trapeziometacarpal osteoarthritis sometimes results in hyperextension of the thumb metacarpophalangeal (MCP) joint, which could negatively impact outcomes following trapeziectomy with ligament reconstruction and tendon interposition (LRTI) arthroplasty. Although algorithms on performing trapeziectomy with LRTI for the management of this deformity are available, they lack clear evidence. Here, we investigate the function of the thumb MCP joint after trapeziectomy with LTRI and whether this procedure alone corrects preoperative MCP hyperextension, and also analyze clinical factors correlated with MCP hyperextension post-surgery. MATERIALS AND METHODS: Twenty-eight patients who underwent trapeziectomy with LRTI and followed up for at ≥ 1 year (mean, 27.2 months) were retrospectively analyzed. No patient had concomitant surgery to the thumb MCP joint at the time of trapeziectomy with LRTI. Patients were divided into the < 30° (n = 19) and > 30° (n = 9) hyperextension groups as per their preoperative passive range of motion (ROM) of the MCP joint. Changes in ROM of the MCP joint post-surgery, clinical factors correlated with postoperative MCP hyperextension, and correlations between clinical outcomes and postoperative MCP extension were analyzed. RESULTS: In the < 30° MCP hyperextension group, active and passive extensions of the MCP joint did not significantly change after surgery, and no worsening of postoperative MCP hyperextension was observed. In the > 30° hyperextension group, passive extension of the MCP joint significantly decreased (mean, 49.6°-29.8°). Preoperative MCP hyperextension improved in seven patients, was unchanged in 1, and worsened in 1. Postoperative passive MCP extension was negatively correlated with active/passive radial abduction, MCP flexion, trapezial space height, subjective outcomes, and hand strength post-surgery. CONCLUSIONS: Trapeziectomy with LRTI alone could prevent postoperative thumb MCP hyperextension deformity for patients with thumb MCP extension < 30° and improve preoperative thumb MCP hyperextension. However, for patients with loss of radial abduction and MCP flexion due to the contracture, indirect correction of the MCP hyperextension was improbable.

HMGB2 expression is associated with transition from a quiescent to an activated state of adult neural stem cells.

BACKGROUND: Although quiescent neural stem cells (NSCs) in the adult hippocampus proliferate in response to neurogenic stimuli and subsequently give rise to new neurons continuously throughout life, misregulation of NSCs in pathological conditions, including aging, leads to the impairment of learning and memory. High mobility group B family 1 (HMGB1) and HMGB2, HMG family proteins that function as transcriptional activators through the modulation of chromatin structure, have been assumed to play some role in the regulation of adult NSCs; however, their precise functions and even expression patterns in the adult hippocampus remain elusive. RESULTS: Here we show that expression of HMGB2 but not HMGB1 is restricted to the subset of NSCs and their progenitors. Furthermore, running, a well-known positive neurogenic stimulus, increased the proliferation of HMGB2-expressing cells, whereas aging was accompanied by a marked decrease in these cells. Intriguingly, HMGB2-expressing quiescent NSCs, which were shifted toward the proliferative state, were decreased as aging progressed. CONCLUSIONS: HMGB2 expression is strongly associated with transition from the quiescent to the proliferative state of NSCs, supporting the possibility that HMGB2 is involved in the regulation of adult neurogenesis and can be used as a novel marker to identify NSCs primed for activation in the adult hippocampus. Developmental Dynamics 247:229-238, 2018. © 2017 Wiley Periodicals, Inc.

DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus.

UNLABELLED: Development of the hippocampal dentate gyrus (DG) in the mammalian brain is achieved through multiple processes during late embryonic and postnatal stages, with each developmental step being strictly governed by extracellular cues and intracellular mechanisms. Here, we show that the maintenance DNA methyltransferase 1 (Dnmt1) is critical for development of the DG in the mouse. Deletion of Dnmt1 in neural stem cells (NSCs) at the beginning of DG development led to a smaller size of the granule cell layer in the DG. NSCs lacking Dnmt1 failed to establish proper radial processes or to migrate into the subgranular zone, resulting in aberrant neuronal production in the molecular layer of the DG and a reduction of integrated neurons in the granule cell layer. Interestingly, prenatal deletion of Dnmt1 in NSCs affected not only the developmental progression of the DG but also the properties of NSCs maintained into adulthood: Dnmt1-deficient NSCs displayed impaired neurogenic ability and proliferation. We also found that Dnmt1 deficiency in NSCs decreased the expression of Reelin signaling components in the developing DG and increased that of the cell cycle inhibitors p21 and p57 in the adult DG. Together, these findings led us to propose that Dnmt1 functions as a key regulator to ensure the proper development of the DG, as well as the proper status of NSCs maintained into adulthood, by modulating extracellular signaling and intracellular mechanisms. SIGNIFICANCE STATEMENT: Here, we provide evidence that Dnmt1 is required for the proper development of the hippocampal dentate gyrus (DG). Deletion of Dnmt1 in neural stem cells (NSCs) at an early stage of DG development impaired the ability of NSCs to establish secondary radial glial scaffolds and to migrate into the subgranular zone of the DG, leading to aberrant neuronal production in the molecular layer, increased cell death, and decreased granule neuron production. Prenatal deletion of Dnmt1 in NSCs also induced defects in the proliferation and neurogenic ability of adult NSCs. Furthermore, we found that Dnmt1 regulates the expression of key extracellular signaling components during developmental stages while modulating intracellular mechanisms for proliferation and neuronal production of NSCs in the adult.

Exploring the association between number of teeth, food intake, and cognitive function: A 9-year longitudinal study.

OBJECTIVES: This study aimed to investigate the association between the number of teeth, food intake, and cognitive function in Japanese community-dwelling older adults. METHODS: This 9-year longitudinal study included a total of 293 analyzable participants who participated in baseline and follow-up surveys. Dental status (number of teeth and periodontal pocket depth), dietary assessment using the brief-type self-administered diet history questionnaire, cognitive function, and the following confounding factors were evaluated: educational level, financial satisfaction, living situation, smoking and drinking habits, history of chronic diseases, apolipoprotein E-ε4 carrier, body mass index, handgrip strength, instrumental activities of daily living, and depressive symptomatology. The Japanese version of the Montreal Cognitive Assessment was used to evaluate cognitive function. A multinomial logistic regression analysis for the intake level of each food categorized into three groups (low, moderate, high), and a generalized estimating equation (GEE) for cognitive function over nine years were performed. RESULTS: After controlling for confounding factors, the number of teeth was shown to be associated with the intake of green-yellow vegetables and meat. Furthermore, the GEE indicated that the lowest quartile of intake of green-yellow vegetables significantly associated with lower cognitive function (unstandardized regression coefficient [B] = -0.96, 95 % confidence interval [CI]: -1.72 to -0.20), and the lowest quartile of intake of meat significantly associated with lower cognitive function (B = -1.42, 95 % CI: -2.27 to -0.58). CONCLUSIONS: The intake of green and yellow vegetables and meat, which is influenced by the number of teeth, was associated with cognitive function in Japanese community-dwelling older adults. CLINICAL SIGNIFICANCE: There are few studies that have examined the association between oral health, food intake, and cognitive function. This 9-year longitudinal study suggests that it is important to maintain natural teeth to enable the functional means to consume green-yellow vegetables and meat, and thereby help maintain cognitive function.

Preoperative prognostic factors associated with poor early recovery after trapeziectomy with ligament reconstruction and tendon interposition arthroplasty for thumb carpometacarpal osteoarthritis.

BACKGROUND: Trapeziectomy with ligament reconstruction and tendon interposition (LRTI) is performed for treating thumb carpometacarpal osteoarthritis. However, patients occasionally experience delayed postoperative recovery. Although several prognostic factors associated with long-term outcomes have been identified, the factors associated with delayed recovery after trapeziectomy with LRTI have not been identified. HYPOTHESIS: When we define major disability in the early postoperative period at 3 months after LRTI surgery as delayed recovery, some preoperative factors can influence with delayed recovery. Moreover, delayed recovery can influence the long-term therapeutic outcome. PATIENTS AND METHODS: Thirty thumbs that underwent trapeziectomy with LRTI (mean follow-up period, 29.3 months) were retrospectively analyzed. Major disability was defined by both DASH and Hand20 scores≥35 after surgery, and patients were divided into groups 1 (major disability; n=9) and 2 (no major disability; n=21) according to the scores at 3 months after surgery. Preoperative data, including age, sex, preoperative symptom duration, dominant hand surgery, concurrent surgery with LRTI, previous orthopedic surgery, employment, stage of osteoarthritis, thickness of the trapezium, metacarpophalangeal hyperextension deformity, DASH score, Hand20 score, visual analogue scale (VAS) scores for pain, grip strength, pinch strength, and range of motion of the thumb were compared between groups to identify the factors indicating a poor prognosis at 3 months after surgery. We also compared the clinical outcomes at the 12-month and final follow-up. RESULTS: Dominant hand surgery, previous orthopedic surgery, and preoperative poor DASH score were significantly more frequent in group 1, while the other factors did not show significant intergroup differences. Moreover, group 1 showed significantly poorer DASH score, grip and pinch strength, and active flexion of the thumb metacarpal joint at both the 12-month and final follow-up. This group also showed significantly poorer Hand20 and VAS scores at the final follow-up. DISCUSSION: Dominant hand surgery, previous orthopedic surgery, and preoperative poor DASH score were associated with poor recovery at 3 months after trapeziectomy with LRTI. Moreover, major disability at 3 months after surgery influenced poor clinical outcomes at the 12-month and final follow-ups. These data could be useful for counseling patients regarding the expected recovery duration and outcomes after LRTI surgery. LEVEL OF EVIDENCE: IV; retrospective therapeutic study.

Erratum: Hematopoietic stem cell gene therapy ameliorates CNS involvement in murine model of GM1-gangliosidosis.

[This corrects the article DOI: 10.1016/j.omtm.2022.04.012.].

Hematopoietic stem cell gene therapy ameliorates CNS involvement in murine model of GM1-gangliosidosis.

GM1-gangliosidosis is a progressive neurodegenerative glycosphingolipidosis resulting from a GLB1 gene mutation causing a deficiency of the lysosomal enzyme ß-galactosidase, which leads to the abnormal accumulation of GM1 ganglioside in the central nervous system. In the most severe early infantile phenotype, excessive ganglioside accumulation results in a rapid decline in neurological and psychomotor functions, and death occurs within 2 years of age. Currently, there is no effective therapy for GM1-gangliosidosis. In this study, we evaluated the therapeutic efficacy of ex vivo gene therapy targeting hematopoietic stem cells using a lentiviral vector to increase enzyme activity, reduce substrate accumulation, and improve astrocytosis and motor function. Transplanting GLB1-transduced hematopoietic stem cells in mice increased ß-galactosidase enzyme activity in the central nervous system and visceral organs. Specifically, this gene therapy significantly decreased GM1 ganglioside levels in the brain, especially in the cerebrum. More important, this gene therapy rectified astrocytosis in the cerebrum and improved motor function deficits. Furthermore, the elevation of serum ß-galactosidase activity in secondary-transplanted mice suggested the ability of transduced hematopoietic stem cells to repopulate long term. These data indicate that ex vivo gene therapy with lentiviral vectors is a promising approach for the treatment of brain deficits in GM1 gangliosidosis.

Five-Year Impacts of Antithrombotic Therapy Based on 10-Year Clinical Outcomes of Cypher™ Stent Implantation.

INTRODUCTION: Few researchers have investigated the optimal long-term antithrombotic therapy regimen, especially after first-generation drug-eluting stent (DES) use. This study aimed to evaluate the impact of mid-term antithrombotic therapy on long-term outcomes in patients treated with the first sirolimus-eluting coronary stent (Cypher™). METHODS: Between 2004 and 2009, 1021 patients underwent Cypher™ implantation at our institute; among them, 567 patients had available data on antithrombotic therapy at year 5. We assessed patients' antithrombotic therapy at year 5 post Cypher™ implantation and examined their association with adverse events from year 5 to year 10 post Cypher™ implantation. RESULTS: Patients with dual-antiplatelet therapy (DAPT) at year 5 had significantly lower risk of stent thrombosis (ST) than those with single-antiplatelet therapy (SAPT) (hazard ratio [HR] 0.24, p = 0.034). The HR of major bleeding in DAPT, compared to SAPT, was high, but the difference was not significant (HR 1.72, p = 0.26). Risk of major bleeding was significantly higher in patients on oral anticoagulants (OAC) than in those in other groups (OAC/SAPT; HR 5.31, p = 0.0048, OAC/DAPT; HR 3.08, p = 0.022), without significant reduction in the risk of cardiovascular events. CONCLUSIONS: The incidence of ST after Cypher™ implantation in patients with DAPT at year 5 was significantly lower than that in SAPT. However, the risk of bleeding was higher with DAPT than with SAPT. Moreover, the risk of major bleeding was significantly higher in patients on anticoagulant therapy than in other patients. New options for the use of antithrombotic drugs after percutaneous coronary intervention warrant further studies on the optimal antithrombotic therapy for first-generation DES.

COVID-19-associated pulmonary aspergillosis in hemodialysis patients.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a fatal complication in the general population. However, there are few reports on CAPA in patients undergoing hemodialysis (HD). Methods: This retrospective observational cohort study was conducted at a single center between December 2020 and June 2021. We enrolled 21 HD patients with COVID-19 undergoing treatment and divided them into two groups, CAPA and non-CAPA (COVID-19 with and without pulmonary aspergillosis), and evaluated their characteristics, clinical outcomes and comorbidities. Results: The log-rank test revealed that the 90-day survival rate after the initiation of treatment for COVID-19 was significantly lower in the CAPA (n = 6) than in the non-CAPA group (n = 15) (P = 0.0002), and the 90-day mortality rates were 66.6% and 0% in the CAPA and non-CAPA groups, respectively. In the CAPA group, four patients died due to respiratory failure (on Days 6 and 20), gastrointestinal bleeding (Day 8) and sepsis (Day 33); the reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remained positive when they died. The remaining two patients survived and the negative conversion of RT-PCR for SARS-CoV-2 was confirmed on Days 10 and 15. The negative conversion of serum (1, 3)-ß-d-glucan (BDG) was confirmed on Day 15 in one patient; the BDG remained positive on Day 64 in the other. Conclusions: CAPA is a fatal complication in HD patients and the general population. Therefore, clinicians should consider the possibility of testing for CAPA in patients undergoing HD. Mycological workups may be helpful for the early detection of CAPA.

Smoc1 and Smoc2 regulate bone formation as downstream molecules of Runx2.

Runx2 is an essential transcription factor for bone formation. Although osteocalcin, osteopontin, and bone sialoprotein are well-known Runx2-regulated bone-specific genes, the skeletal phenotypes of knockout (KO) mice for these genes are marginal compared with those of Runx2 KO mice. These inconsistencies suggest that unknown Runx2-regulated genes play important roles in bone formation. To address this, we attempted to identify the Runx2 targets by performing RNA-sequencing and found Smoc1 and Smoc2 upregulation by Runx2. Smoc1 or Smoc2 knockdown inhibited osteoblastogenesis. Smoc1 KO mice displayed no fibula formation, while Smoc2 KO mice had mild craniofacial phenotypes. Surprisingly, Smoc1 and Smoc2 double KO (DKO) mice manifested no skull, shortened tibiae, and no fibulae. Endochondral bone formation was also impaired at the late stage in the DKO mice. Collectively, these results suggest that Smoc1 and Smoc2 function as novel targets for Runx2, and play important roles in intramembranous and endochondral bone formation.

Chronological changes in surgical outcomes after trapeziectomy with ligament reconstruction and tendon interposition arthroplasty for thumb carpometacarpal osteoarthritis.

BACKGROUND: Despite satisfactory mid-term and long-term outcomes of trapeziectomy with ligament reconstruction and tendon interposition (LRTI) procedures for thumb carpometacarpal osteoarthritis, there is limited literature describing detailed chronological changes in early-phase postoperative outcomes. We investigated chronological changes of subjective, objective, and radiological outcomes within 1 year post-trapeziectomy with LRTI using a longitudinal evaluation and analyzed clinical factors associated with patient-reported subjective outcomes. HYPOTHESIS: Some parameters influence patient-reported subjective outcomes during the early postoperative period. PATIENTS AND METHODS: Nineteen patients (mean age, 67.3 years) who underwent trapeziectomy with LRTI were evaluated preoperatively and at 3, 6, and 12 months postoperatively to investigate objective (grip strength, pinch strength, range of motion [ROM] of the interphalangeal [IP] joint, metacarpophalangeal [MP] joint, and carpometacarpal [CMC] joint, Kapandji score), subjective (Disabilities of the Arm, Shoulder, and Hand [DASH] score, Hand20 questionnaire score, and visual analog scale [VAS] for pain), and radiological outcomes (trapezial space height and its ratio). Factors affecting DASH and Hand20 scores were analyzed. RESULTS: Grip strength and pinch strength were decreased at 3-month follow-up. It required 6 months to recover preoperative strength and 12 months for significant improvement. VAS for pain, DASH, and Hand20 scores were significantly improved at 3-month follow-up, continuing to improve until 12 months. The trapezial space height and its ratio decreased approximately 50% at 3-month follow-up, with no further changes at 6 or 12 months. Both DASH and Hand20 scores were strongly correlated with VAS for pain during activity within 6 months post-surgery and moderately correlated with ROM of the thumb at 3 months post-surgery; however, they were not correlated with grip and pinch strength as well as the trapezial space height ratio within 12 months post-surgery. DISCUSSION: Trapeziectomy with LRTI for thumb carpometacarpal osteoarthritis provided early subjective improvements in outcomes as early as 3 months post-procedure. However, more than 6 months are required to determine objective improvements in outcomes. To obtain early patient-reported satisfactory outcomes, we should focus not on improving hand and finger strength, but on treating postoperative surgical site pain and preventing thumb stiffness. LEVEL OF EVIDENCE: IV, retrospective therapeutic study.

Photoactivatable oncolytic adenovirus for optogenetic cancer therapy.

Virotherapy using oncolytic adenovirus is an effective anticancer strategy. However, the tumor selectivity of oncolytic adenoviruses is not enough high. To develop oncolytic adenovirus with a low risk of off-tumor toxicity, we constructed a photoactivatable oncolytic adenovirus (paOAd). In response to blue light irradiation, the expression of adenoviral E1 genes, which are necessary for adenoviral replication, is induced and replication of this adenovirus occurs. In vitro, efficient lysis of various human cancer cell lines was observed by paOAd infection followed by blue light irradiation. Importantly, there was no off-tumor toxicity unless the cells were irradiated by blue light. In vivo, tumor growth in a subcutaneous tumor model and a mouse model of liver cancer was significantly inhibited by paOAd infection followed by blue light irradiation. In addition, paOAd also showed a therapeutic effect on cancer stem cells. These results suggest that paOAd is useful as a safe and therapeutically effective cancer therapy.

Chronic brain blood-flow imaging device for a behavioral experiment using mice.

A chronic brain blood-flow imaging device was developed for cerebrovascular disease treatment. This device comprises a small complementary metal-oxide semiconductor image sensor and a chronic fiber-optic plate window on a mouse head. A long-term cerebral blood-flow imaging technique was established in a freely moving mouse. Brain surface images were visible for one month using the chronic FOP window. This device obtained brain surface images and blood-flow velocity. The blood-flow changes were measured in behavioral experiments using this device. The chronic brain blood-flow imaging device may contribute to determining the cause of cerebrovascular disease and the development of cerebrovascular disease treatment.

Highly sensitive lens-free fluorescence imaging device enabled by a complementary combination of interference and absorption filters.

We report a lens-free fluorescence imaging device using a composite filter composed of an interference filter and an absorption filter, each applied to one side of a fiber optic plate (FOP). The transmission of angled excitation light through the interference filter is absorbed by the absorption filter. The auto-fluorescence of the absorption filter is reduced by the reflection from the interference filter of normally incident excitation light. As a result, high-performance rejection of excitation light is achieved in a lens-free device. The FOP provides a flat, hard imaging device surface that does not degrade the spatial resolution. We demonstrate excitation rejection of approximately 108:1 at a wavelength of 450 nm in a fabricated lens-free device. The resolution of fluorescence imaging is approximately 12 µm. Time-lapse imaging of cells containing green fluorescent protein was performed in a 5-µm thin-film chamber. The small dimensions of the device allow observation of cell culturing in a CO2 incubator. We also demonstrate that the proposed lens-free filter is compatible with super-resolution bright-field imaging techniques. These features open a way to develop a high-performance, dual-mode, lens-free imaging device that is expected to be a powerful tool for many applications, such as imaging of labeled cells and point-of-care assay.

Prenatal deletion of DNA methyltransferase 1 in neural stem cells impairs neurogenesis and causes anxiety-like behavior in adulthood.

Despite recent advances in our understanding of epigenetic regulation of central nervous system development, little is known regarding the effects of epigenetic dysregulation on neurogenesis and brain function in adulthood. In the present study, we show that prenatal deletion of DNA methyltransferase 1 (Dnmt1) in neural stem cells results in impaired neurogenesis as well as increases in inflammatory features (e.g., elevated glial fibrillary acidic protein [GFAP] expression in astrocytes and increased numbers of microglia) in the adult mouse brain. Moreover, these mice exhibited anxiety-like behavior during an open-field test. These findings suggest that Dnmt1 plays a critical role in regulating neurogenesis and behavior in the developing brain and into adulthood.

An Adult Case of Anti-Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-associated Multiphasic Acute Disseminated Encephalomyelitis at 33-year Intervals.

Acute disseminated encephalomyelitis (ADEM) followed by optic neuritis (ON) has been reported as a distinct phenotype associated with anti-myelin oligodendrocyte protein (MOG) antibody. We herein report the case of a 37-year-old woman who was diagnosed with ADEM at 4 years old of age and who subsequently developed ON followed by recurrent ADEM 33 years after the initial onset. A serum analysis showed anti-MOG antibody positivity. This phenotype has only previously been reported in pediatric cases. Neurologists thus need to be aware that the phenotype may occur in adult patients, in whom it may be assumed to be atypical multiple sclerosis.

Expression of DNMT1 in neural stem/precursor cells is critical for survival of newly generated neurons in the adult hippocampus.

Adult neurogenesis persists throughout life in the dentate gyrus (DG) of the hippocampus, and its importance has been highlighted in hippocampus-dependent learning and memory. Adult neurogenesis consists of multiple processes: maintenance and neuronal differentiation of neural stem/precursor cells (NS/PCs), followed by survival and maturation of newborn neurons and their integration into existing neuronal circuitry. However, the mechanisms that govern these processes remain largely unclear. Here we show that DNA methyltransferase 1 (DNMT1), an enzyme responsible for the maintenance of DNA methylation, is highly expressed in proliferative cells in the adult DG and plays an important role in the survival of newly generated neurons. Deletion of Dnmt1 in adult NS/PCs (aNS/PCs) did not affect the proliferation and differentiation of aNS/PCs per se. However, it resulted in a decrease of newly generated mature neurons, probably due to gradual cell death after aNS/PCs differentiated into neurons in the hippocampus. Interestingly, loss of DNMT1 in post-mitotic neurons did not influence their survival. Taken together, these findings suggest that the presence of DNMT1 in aNS/PCs is crucial for the survival of newly generated neurons, but is dispensable once they accomplish neuronal differentiation in the adult hippocampus.