Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein.

The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs), which are composed of amyloid ß protein (Aß), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 µM CQ had no effect on cell viability; however, 100 µM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

Genetic signatures of lipid metabolism evolution in Cetacea since the divergence from terrestrial ancestor.

In mammalian evolutionary history, Cetacea (whales, dolphins and porpoises) achieved astonishing success by adapting to an aquatic environment. One unique characteristic of cetaceans, contributing to this adaptive success, is efficient lipid utilization. Here, we report a comparative genetic analysis of five aquatic and five terrestrial Cetartiodactyla species using 144 genes associated with lipid metabolism. Mutation ratio (dN /dS ), amino acid substitution in functional domains and metabolic pathways were evaluated using branch-site model in PAML, Pfam and KEGG, respectively. Our tests detected 20 positively selected genes in Cetacea compared to 11 in Bovidae with little overlap between the lineages. We identified lineage-specific patterns of amino acid substitutions and functional domains that were mutually exclusive between cetaceans and bovids, supporting divergent evolution of lipid metabolism since the divergence of these taxa from a common ancestor. Moreover, a pathway analysis showed that the identified genes in cetaceans were associated with lipid digestion, lipid storage and energy-producing pathways. This study emphasizes the evolutionary context of lipid metabolism modification of cetaceans and provides a foundation for future studies of elucidating the adapted biological mechanisms of cetacean lipid metabolism and a framework for incorporating ecological context into studies aimed at investigating adaptive evolution.

Strong genetic structure corresponds to small-scale geographic breaks in the Australian alpine grasshopper Kosciuscola tristis.

BACKGROUND: Mountain landscapes are topographically complex, creating discontinuous 'islands' of alpine and sub-alpine habitat with a dynamic history. Changing climatic conditions drive their expansion and contraction, leaving signatures on the genetic structure of their flora and fauna. Australia's high country covers a small, highly fragmented area. Although the area is thought to have experienced periods of relative continuity during Pleistocene glacial periods, small-scale studies suggest deep lineage divergence across low-elevation gaps. Using both DNA sequence data and microsatellite markers, we tested the hypothesis that genetic partitioning reflects observable geographic structuring across Australia's mainland high country, in the widespread alpine grasshopper Kosciuscola tristis (Sjösted). RESULTS: We found broadly congruent patterns of regional structure between the DNA sequence and microsatellite datasets, corresponding to strong divergence among isolated mountain regions. Small and isolated mountains in the south of the range were particularly distinct, with well-supported divergence corresponding to climate cycles during the late Pliocene and Pleistocene. We found mixed support, however, for divergence among other mountain regions. Interestingly, within areas of largely contiguous alpine and sub-alpine habitat around Mt Kosciuszko, microsatellite data suggested significant population structure, accompanied by a strong signature of isolation-by-distance. CONCLUSIONS: Consistent patterns of strong lineage divergence among different molecular datasets indicate genetic breaks between populations inhabiting geographically distinct mountain regions. Three primary phylogeographic groups were evident in the highly fragmented Victorian high country, while within-region structure detected with microsatellites may reflect more recent population isolation. Despite the small area of Australia's alpine and sub-alpine habitats, their low topographic relief and lack of extensive glaciation, divergence among populations was on the same scale as that detected in much more extensive Northern hemisphere mountain systems. The processes driving divergence in the Australian mountains might therefore differ from their Northern hemisphere counterparts.

Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies.

Nivolumab blocks inhibitors of T-cell activation and restores antitumor immunity but promotes T-cell activity in host tissues by blocking inhibition of the T-cell function, resulting in immune-related adverse effects. We herein report an 80-year-old man presenting with nivolumab-related myasthenia gravis with anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibodies. On day 29 after nivolumab administration, he simultaneously developed rapidly progressing right ptosis and left facial paralysis. Nivolumab administration was discontinued. He subsequently presented with bulbar paralysis, dyspnea, and muscle weakness and received intravenous immunoglobulin, methylprednisolone, and plasma exchange. The severity of nivolumab-related myasthenia gravis with anti-Kv1.4 antibodies presented with diverse clinical findings.

Magnetic resonance imaging findings of the lower limb muscles in anti-mitochondrial M2 antibody-positive myositis.

Anti-mitochondrial M2 antibody (AMA-M2)-positive myositis is an idiopathic inflammatory myopathy (IIM). Of all patients with myositis, 2.5-19.5% have AMA-M2 antibodies. However, the detailed distribution of muscles affected in AMA-positive myositis is unknown. Therefore, we examined lower muscle magnetic resonance imaging (MRI) findings of patients with AMA-positive myositis. Among the 63 patients with IIM at our institute, 5 (7.9%) were positive for AMA-M2 antibodies. However, one was also positive for anti-Jo1 antibodies; therefore, four patients were finally participated in this study. All patients had high-intensity MRI signals in the proximal muscles, including the gluteus maximus and iliopsoas muscles, and in the thigh muscles, including the vastus lateralis, vastus medialis, adductor magnus, and semimembranosus muscles. Lower leg muscles were relatively spared. Fascial edema was observed in all patients and was also present in the lower leg muscles. Subcutaneous edema was observed, particularly in the proximal portion of the lower limbs. In AMA-positive myositis, proximal muscles, including the gluteus maximus, vastus lateralis, adductor magnus, and the semimembranosus, were markedly affected, while the lower leg muscles were relatively preserved. Additionally, fascial edema was evident even in lower leg muscles. Therefore, muscle MRI can be a useful diagnostic aid for AMA-positive myositis.

Biomimetic oxidative coupling of benzylamines and 2-aminophenols: synthesis of benzoxazoles.

Aerobic oxidation: in a biomimetic approach, a mixture of redox catalysts forms couples that effect the aerobic oxidation of a mixture of benzylamine and 2-aminophenol derivatives to give the corresponding benzoxazoles. This biomimetic oxidation proceeds smoothly under mild conditions and the protocol can also be used for preparing benzimidazoles and benzothiazoles.

Biomimetic aerobic oxidation of amino alcohols to lactams.

The right path: N-protected amino alcohols undergo aerobic and biomimetic oxidation to the corresponding lactams in the presence of a ruthenium catalyst and a combination of electron-transfer mediators under air (see scheme). The reaction was used for the synthesis of five-, six-, and seven-, membered lactams and showed good tolerance to a number of N-protecting groups.

Generation and Gene Expression Profiles of Grevy's Zebra Induced Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSCs) can serve as a biological resource for functional and conservation research for various species. This realization has led to the generation of iPSCs from many species, including those identified as endangered. However, the understanding of species variation in mammalian iPSCs remains largely unknown. To gain insight into species variation in iPSCs, we generated iPSCs from a new species Grevy's zebra (Equus grevyi; gz-iPSCs), which has been listed as endangered in the IUCN (International Union for Conservation of Nature) Red List. We isolated primary fibroblast cells from an individual and successfully reprogrammed them into iPSCs. The generated gz-iPSCs continued to grow under primed-type culture condition and showed pluripotency and differentiation potential. To describe the molecular characteristics of gz-iPSCs, we performed RNA sequencing analysis. The gz-iPSC transcriptome showed robust expression of pluripotency-associated genes reported in human and mouse, suggesting evolutionary conservation among the species. This study provides insight into the iPSCs from a rare species and helps the understanding of the gene expression basis underlying mammalian pluripotent stem cells.

Effectiveness of a self-reporting yes/no survey for dementia screening-trial in Fukui, Japan.

Background: Early intervention for dementia patients is extremely important for the prevention of dementia. However, so far, it is not clear as to what kind of screening will be useful for the early detection of dementia. Objective: We aimed to investigate the relationship between the results of a short self-reporting yes/no survey selected in Kihon Checklist, developed by the Japanese Ministry of Health, Labor and Welfare to identify older adults who are at risk of requiring support/care, and other original items developed by Dementia Prevention Team, Fukui, Japan, and Mini-Mental State Examination (MMSE) scores, and determine the diagnostic efficacy of the self-reporting yes/no survey. Methods: Self-reporting yes/no surveys were conducted for 87,687 individuals aged ≥65 years, living in Fukui, Japan, and did not have Long-Term Care Insurance, Japan. According to the survey results, selected individuals were advised to visit a local hospital to be assessed with MMSE. Results: Individuals who could not make a call by looking up phone numbers and manage their own deposits and savings at the bank or automatic teller machine (ATM) had an increased risk of low MMSE score (≤23; odds ratio: 2.74 [1.89-3.97]; 95% confidence interval: 2.12 [1.46-3.07]). Conclusions: Self-reporting yes/no survey could effectively screen for dementia. Not being able to make a call by looking up phone numbers and not being able to manage their own deposits and savings at the bank or ATM are signs of dementia.

Genetic Signatures of Evolution of the Pluripotency Gene Regulating Network across Mammals.

Mammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics among species, but to date we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we carried out a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We report that mammalian genes in the pluripotency regulatory network show a remarkably high degree of evolutionary stasis, suggesting the conservation of fundamental biological process of mammalian PSCs across species. Nevertheless, despite the overall conservation of the regulatory network, we discovered rapid evolution of the downstream targets of the core regulatory elements and specific amino acid residues that have undergone positive selection. Our data indicate development of lineage-specific pluripotency regulating networks that may explain observed variations in some characteristics of mammalian PSCs. We further revealed that positively selected genes could be associated with species' unique adaptive characteristics that were not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

[A case of neuromyelitis optica spectrum disorder with persistent nausea and repeated syncope].

A 22-year-old woman was admitted to our hospital with persistent nausea and no apparent cause. There was no preceding infection. The patient lost consciousness for several seconds. Based on an electrocardiographic diagnosis of paroxysmal sinus arrest (PSA), a temporary pacemaker was implanted. She did not develop syncope, but vertigo, nystagmus, diplopia, and limb paresthesia were observed. Brain MRI revealed a high-intensity lesion in the dorsal medulla on FLAIR images. As the serum anti-aquaporin 4 (AQP4) antibody was positive, the patient was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). After she received steroid pulse therapy (methylprednisolone at 1,000 mg/day for three days) twice, her symptoms markedly improved. In this patient, PSA was considered to be a symptom of area postrema syndrome of NMOSD. Therefore, NMOSD should be considered as a possible cause of PSA.

Apolipoprotein E and clusterin inhibit the early phase of amyloid-ß aggregation in an in vitro model of cerebral amyloid angiopathy.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-ß (Aß) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aß, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aß aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aß amyloid deposition in CAA.

[A case of systemic lupus erythematosus predominantly presenting with myositis at onset].

A 42-year-old woman presented with rapid myalgia of the thigh and muscle weakness in the proximal limbs with markedly elevated serum CK. Despite positive for antibodies to anti-nuclear, anti-ds-DNA, anti-ss-DNA, anti-Sm, anti-SS-A/Ro, C-ANCA, anti-U1-RNP and anti-ribosome and slight lymphocytopenia and hypocomplementemia, there was no symptom associated with systemic lupus erythematosus (SLE). Proteinuria and hematuria were initially considered to be associated with renal damage due to myoglobinuria. Muscle MRI demonstrated high signal intensities in the rectus femoris. Muscle biopsy of the rectus femoris demonstrated a mild variation in fiber size, a few necrotic and several regenerating fibers and minimal lymphocytic infiltration in the endomysium, which suggested myopathic changes with mild necrotic and regenerating processes. Thus she was diagnosed as idiopathic myositis at first, and was treated by corticosteroid therapy. Her myalgia and CK level improved, but the proteinuria and hematuria were persistent. A renal biopsy demonstrated lupus nephritis, and SLE with myositis was confirmed. She was treated with additional tacrolimus administration, and her proteinuria and hematuria also improved. The present case suggests that patients who predominantly present with myositis accompanied by nephritis and autoantibodies should be considered as SLE with myositis.