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Cell-to-cell transmission of α-synuclein (α-syn) pathology underlies the spread of neurodegeneration in Parkinson's disease. α-Syn secretion is an important factor in the transmission of α-syn pathology. However, it is unclear how α-syn secretion is therapeutically modulated. Here, we investigated effects of monoamine oxidase (MAO)-B inhibitor selegiline on α-syn secretion. Treatment with selegiline promoted α-syn secretion in mouse primary cortical neuron cultures, and this increase was kept under glial cell-eliminated condition by Ara-C. Selegiline-induced α-syn secretion was blocked by cytosolic Ca 2+ chelator BAPTA-AM in primary neurons. Selegiline-induced α-syn secretion was retained in MAOA siRNA knockdown, whereas it was abrogated by ATG5 knockdown in SH-SY5Y cells. Selegiline increased LC3-II generation with a reduction in intracellular p62/SQSTM1 levels in primary neurons. The increase in LC3-II generation was blocked by co-treatment with BAPTA-AM in primary neurons. Additionally, fractionation experiments showed that selegiline-induced α-syn secretion occurred in non-extracellular vesicle fractions of primary neurons and SH-SY5Y cells. Collectively, these findings show that selegiline promotes neuronal autophagy involving secretion of non-exosomal α-syn via a change of cytosolic Ca 2+ levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Administration of oxygen microbubbles (OMBs) has been shown to increase oxygen and decrease carbon dioxide in systemic circulation, as well as reduce lung inflammation and promote survival in preclinical models of hypoxia caused by lung injury. However, their impact on microenvironmental oxygenation remains unexplored. Herein, we investigated the effects of intraperitoneal administration of OMBs in anesthetized rats exposed to hypoxic ventilation (FiO 2 = 0.14). Blood oxygenation and hemodynamics were evaluated over a 2 h time frame, and then organ and tissue samples were collected for hypoxic and metabolic analyses. Data showed that OMBs improved blood SaO 2 (~14%) and alleviated tissue hypoxia within the microenvironment of the kidney and intestine at 2 h of hypoxia. Metabolomic analysis revealed OMBs induced metabolic differences in the cecum, liver, kidney, heart, red blood cells and plasma. Within the spleen and lung, principal component analysis showed a metabolic phenotype more comparable to the normoxic group than the hypoxic group. In the spleen, this shift was characterized by reduced levels of fatty acids and 2-hydroxygluterate, alongside increased expression of antioxidant enzymes such as glutathione and hypoxanthine. Interestingly, there was also a shuttle effect within the metabolism of the spleen from the tricarboxylic acid cycle to the glycolysis and pentose phosphate pathways. In the lung, metabolomic analysis revealed upregulation of phosphatidylethanolamine and phosphatidylcholine synthesis, indicating a potential indirect mechanism through which OMB administration may improve lung surfactant secretion and prevent alveolar collapse. In addition, cell-protective purine salvage was increased within the lung. In summary, oxygenation with intraperitoneal OMBs improves systemic blood and local tissue oxygenation, thereby shifting metabolomic profiles of the lung and spleen toward a healthier normoxic state.

The objective of the present study was to evaluate the risk factors and outcomes associated with hyponatremia in patients with Guillain-Barré syndrome (GBS). We retrospectively studied 80 consecutive patients with GBS who visited our hospital and compared clinical, laboratory, and electrophysiological findings of patients with and without hyponatremia. Disability was evaluated using the Hughes grading system. Of the 80 patients, 18 (23%) had hyponatremia. Hyponatremia was significantly associated with older age (P = 0.003), urinary retention (P < 0.0001), Hughes grade ≥ 4 at admission and nadir (P = 0.003 and P < 0.001, respectively), acute inflammatory demyelinating polyneuropathy subtype (P = 0.017), sepsis (P = 0.001), mechanical ventilator support (P = 0.013), longer hospitalization length of stay (P < 0.0001), and inability to walk independently at 6 months (P < 0.001). Multivariate analysis performed to assess the risk factors of hyponatremia revealed that urinary retention (odds ratio [OR] 30.7, 95% confidence interval [CI] 3.6-264.4; P = 0.002) and mechanical ventilator support (OR 13.8, 95% CI 1.6-118.0; P = 0.017) were significant independent risk factors of hyponatremia. In assessing the outcomes of patients with hyponatremia, multivariate analysis showed that hyponatremia was independently associated with hospitalization length of stay ≥ 60 days and inability to walk independently at 6 month, with the former showing statistical significance but the latter not (OR 9.3, 95% CI 1.8-47.7; P = 0.007 and OR 4.9, 95% CI 0.9-26.3; P = 0.066, respectively). Therefore, we demonstrate that, along with mechanical ventilator support, urinary retention-possibly indicating autonomic dysfunction-is a risk factor of hyponatremia in GBS. Moreover, we confirm that hyponatremia is associated with poor outcome in GBS., (© 2024. The Author(s).)

Extracellular secretion is an essential mechanism for α-synuclein (α-syn) proteostasis. Although it has been reported that neuronal activity affects α-syn secretion, the underlying mechanisms remain unclear. Here, we investigated the autophagic processes that regulate the physiological release of α-syn in mouse primary cortical neurons and SH-SY5Y cells. Stimulating neuronal activity with glutamate or depolarization with high KCl enhanced α-syn secretion. This glutamate-induced α-syn secretion was blocked by a mixture of NMDA receptor antagonist AP5 and AMPA receptor antagonist NBQX, as well as by cytosolic Ca 2+ chelator BAPTA-AM. Additionally, mTOR inhibitor rapamycin increased α-syn and p62/SQSTM1 (p62) secretion, and this effect of rapamycin was reduced in primary cortical neurons deficient in the autophagy regulator beclin 1 (derived from BECN1 +/- mice). Glutamate-induced α-syn and p62 secretion was suppressed by the knockdown of ATG5, which is required for autophagosome formation. Glutamate increased LC3-II generation and decreased intracellular p62 levels, and the increase in LC3-II levels was blocked by BAPTA-AM. Moreover, glutamate promoted co-localization of α-syn with LC3-positive puncta, but not with LAMP1-positive structures in the neuronal somas. Glutamate-induced α-syn and p62 secretion were also reduced by the knockdown of RAB8A, which is required for autophagosome fusion with the plasma membrane. Collectively, these findings suggest that stimulating neuronal activity mediates autophagic α-syn secretion in a cytosolic Ca 2+ -dependent manner, and autophagosomes may participate in autophagic secretion by functioning as α-syn carriers., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A Japanese woman experienced slowness of movement in her early teens and difficulty in opening her hands during pregnancy. On admission to our hospital at 42 years of age, she showed grip myotonia with warm-up phenomenon. However, she had neither muscle weakness, muscle atrophy, cold-induced symptomatic worsening nor episodes of transient weakness of the extremities. Needle electromyography of the first dorsal interosseous and anterior tibial muscles demonstrated myotonic discharges. Whole exome sequencing of the patient revealed a heterozygous single-base substitution in the CLCN1 gene (c.1028T>G, p.F343C). The same substitution was identified in affected members of her family (mother and brother) by Sanger sequencing, but not in healthy family members (father and a different brother). We diagnosed myotonia congenita (Thomsen disease) with a novel CLCN1 mutation in this pedigree. This mutation causes a single amino acid substitution in the I-J extracellular loop region of CLCN1. Amino acid changes in the I-J loop region are rare in an autosomal-dominantly inherited form of myotonia congenita. We think that this pedigree is precious to understand the pathogenesis of myotonia congenita.

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (GJB1) mutations. We herein report a 25-year-old Japanese man with disorientation, right hemiparesis, and dysarthria. Brain magnetic resonance imaging (MRI) showed high signal intensities in the bilateral cerebral white matter on diffusion-weighted imaging. He had experienced 2 episodes of transient central nervous system symptoms (at 7 and 13 years old). A genetic analysis identified a novel GJB1 mutation, c.169C>T, p.Gln57*. MRI abnormalities shifted from the cerebral white matter to the corpus callosum and had disappeared at the five-month follow-up. Transient changes between these lesions may indicate CMTX1.

The patient is an 18-year-old female. She had a history of acute disseminated encephalomyelitis at the age of 6 and 7. She visited our hospital due to acute disturbance of consciousness, quadriplegia, and numbness of left upper and lower extremities. Brain MRI showed multiple DWI/FLAIR high-signal lesions in the bilateral cerebral hemispheres, cerebellum, and brainstem. Qualitative test indicated that serum anti-MOG antibodies was positive, and she was diagnosed with anti-MOG antibody-positive polyphasic disseminated encephalomyelitis. Intravenous mPSL pulse therapy was performed twice, but the symptoms worsened. As a second line treatment, plasma exchange was started. However, she developed transfusion related acute lung injury. Alternatively, she was treated with immunoadsorption plasmapheresis. Her symptoms were significantly improved. This case seems to be valuable because there are few reports showing effectiveness of immunoadsorption therapy on anti-MOG antibody-related diseases, especially for polyphasic disseminated encephalomyelitis.

We report a rhodium(I)-catalyzed asymmetric cyclohydroformylation reaction of 1,6-enynes with formaldehyde. The reaction of 1,6-enynes with formaldehyde in the presence of a cationic Rh(I) catalyst, such as [Rh(cod) 2 ] + OTf - , and a chiral biaryl diphosphine led to asymmetric cyclohydroformylation to produce aldehydes with higher-order structures highly enantioselectively. This transformation procedure is applicable to a variety of enynes, with wide compatibility in various atoms liking between the alkyne and alkene parts, substituents at the alkyne terminus, and substituents at the alkene part, being converted to newly formed aldehydes in 14% to 90% yields with 50% to 98% ee. The products were further transformed with various nucleophiles to alcohols, an amine, and a diene without loss of chirality at their γ-position., (© 2023 Wiley-VCH GmbH.)

Fine bubbles (FBs) are bubbles with sizes less than 100 μm and are divided into ultrafine bubbles (UFBs, < 1 μm) and microbubbles (MBs, 1-100 μm) depending on their size. Although FB aeration is known as a more efficient way than macrobubble aeration to increase the oxygen level in unoxygenated water, few reports have demonstrated whether dispersed UFBs work as oxygen carriers or not. Furthermore, oxygen supersaturation is one of the attractive characteristics of FB dispersion, but the reason is yet to be revealed. In this study, we evaluated the relationship between the FBs, especially UFB concentration, and oxygen content in several situations to reveal the two questions. The FB concentration and oxygen content were examined using particle analyzers and our developed oxygen measurement method, which can measure the oxygen content in FB dispersion, respectively. First, in the evaluations of the oxygen dispersion from UFBs with respect to the surrounding oxygen level, UFBs did become neither small nor diminish even in degassed water. Second, the changes in UFBs and oxygen content upon storage temperature and the existence of a lid during storage were evaluated, and there was no correlation between them. It means UFBs contribute little to the oxygen content in UFB dispersion. Furthermore, the oxygen content in the UFB dispersion decreased over time identically as that of the oxygen-supersaturated water with little UFBs. Third, we evaluated the relationship between FB concentration and oxygen content during FB generation by measuring them simultaneously. The results showed that dispersed MB and UFB concentrations did not account for the supersaturation of the FB dispersion. From the result, it was revealed that 100-200 nm of UFBs themselves did not work as oxygen carriers, and the oxygen supersaturation in FB dispersions was due to the supersaturated state of dissolved oxygen that was prepared during the FB generation process.

Time-resolved spectroscopic experiments, assisted with DFT calculations, were employed to study the photochemical reaction mechanism of (4-oxo-3-phenyl-4 H -thiochromen-2-yl) methoxycarbonyl-caged ethanol (TC) and (1,1-dioxido-4-oxo-3-phenyl-4 H -thiochromen-2-yl) methoxy carbonyl-caged ethanol (TS-PPG) in different solvents. TC went through an intersystem crossing to form the triplet state with π-π* character in acetonitrile (MeCN) and protic solvents. While the n-π* triplet state was generated for TS-PPG in MeCN, which further underwent Paternò-Büchi reaction to give a biradical intermediate. Then, the C-O bond was cleaved, followed by deprotonation. Besides the similar deprotection route in MeCN, another reaction pathway existed in protic solvents, where the C-O bond heterolysis took place via the singlet excited state. The unambiguous mechanism would not only guide the efficient application of TS-PPG, but also help develop more excellent PPGs based on the thiochromone framework.

Self-renewal of spermatogonial stem cells is vital to lifelong production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. Here, we show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stem cells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli cell only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation. DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Furthermore, H3K79me2 accumulates at HoxC9 and HoxC10 genes. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells., (© 2022 Lin et al.; Published by Cold Spring Harbor Laboratory Press.)

Fine bubbles (FBs) have attracted significant attention in several research fields. Although some reports have argued that FB dispersion is useful as an oxygen (gas) carrier, only a few reports have examined its properties as an oxygen carrier using experimental data. As one of the reasons for this, there are no standard methods for measuring the oxygen content in FB dispersions. Conventional oxygen measurement methods have certain drawbacks in accuracy or speed; thus, it is difficult to use oxygen content as the primary outcome. In this study, we introduce a Clark-type polarographic oxygen electrode device (OXYG1-PLUS) for oxygen measurement, allowing the dilution of FB dispersion without the influence of ambient air and the adhesion of FBs on the electrode surface due to its special shape. First, the accuracy of our dilution method was evaluated using pure water as a sample, and it was confirmed that our method could measure with an accuracy of ±0.5 mg/L from the results with conventional dissolved oxygen meters. Second, the oxygen content in FB dispersion was evaluated with our method and a chemical titration method (Winkler's method), and it was found that our method could measure the oxygen content in FB dispersions quantitively. This method satisfies the easiness (4 steps) and quickness (within 8 min) for a wide range of oxygen contents (0 to 332 mg/L, theoretical range) with low coefficient variation (< 4.7%) and requires a small sample volume (50-500 μL); thus, it is a useful method for measuring the oxygen in FB dispersions., Competing Interests: The authors have declared that no competing interests exist.

Radioactive gas of Unit 1 of the Fukushima Daiichi Nuclear Power Station was released from the exhaust stack shared by Units 1 and 2 through the venting line on March 12th, 2011. In the present study, radiochemical analysis of drain water sampled at the drain pit of the exhaust stack was conducted to study radionuclides released during venting of the Unit 1. Not only volatile 129 I, 134 Cs and 137 Cs but also 60 Co, 90 Sr, 125 Sb and Unit 1-originated stable Mo isotopes were detected. Although Unit 1-originated stable Mo isotopes were clearly detected, their amounts were quite low compared to Cs, suggesting that the formation of Cs 2 MoO 4 was suppressed under the accident condition. Approximately 90% of iodine existed as I - and 10% as IO 3 - in November 2020. Furthermore, larger amount of 129 I than 137 Cs was observed, suggesting major chemical form of 131 I was molecular iodine rather than CsI at the accident time. The 134 Cs/ 137 Cs radioactivity ratio decay-corrected to March 11th, 2011 was 0.86, supported the results that Unit 1 originated radiocesium in environment has smaller 134 Cs/ 137 Cs radioactivity ratio than Unit 2 and 3 originated radiocesium., (© 2022. The Author(s).)