Search

Abstract Titin, a giant sarcomeric protein, regulates diastolic left ventricular (LV) passive stiffness as a molecular spring and could be a therapeutic target for diastolic dysfunction. Sacubitril/valsartan (Sac/Val), an angiotensin receptor neprilysin inhibitor, has been shown to benefit patients with heart failure with preserved ejection fraction. The effect of Sac/Val is thought to be due to the enhancement of the cGMP/PKG pathway via natriuretic peptide. In this study, the effects of Sac/Val on LV diastolic dysfunction are demonstrated in a mouse diabetic cardiomyopathy model focusing on titin phosphorylation. Sac/Val-treated diabetic mice showed a greater increase in myocardial levels of cGMP-PKG than Val-treated and control mice. Conductance catheter analysis showed a significant reduction in LV stiffness in diabetic mice, but not in non-diabetic mice. Notably, diastolic LV stiffness was significantly reduced in Sac/Val-treated diabetic hearts compared with Val-treated or vehicle-treated diabetic mice. The phosphorylation level of titin (N2B), which determines passive stiffness and modulates active contraction, was higher in Sac/Val-treated hearts compared with Val-treated hearts in diabetic mice. Given that alteration of titin phosphorylation through PKG contributes to myocardial stiffness, the beneficial effects of Sac/Val in heart failure might be partly attributed to the induction of titin phosphorylation.

Abstract All-solid-state lithium–sulfur batteries exhibit high energy densities, operate safely, and suppress polysulfide shuttling. However, their electrochemical performance is restricted by the insulating nature of sulfur and Li2S, and by severe cathode-related volumetric changes during cycling. Here, we prepare a Li2S-based cathode composite with high mixed-conductivity and stability, by infiltrating a Li2S–LiI active material solution into a mesoporous carbon replica with ~10-nm-sized pores, followed by mixing with a liquid-phase-synthesized Li6PS5Br solid electrolyte and vapour-grown carbon fibres. Benefiting from a mechanically reinforced, three-dimensional ion/electron-conducting structure, the cathode exhibits high discharge capacity (1009 mAh g−1, 20 cycles, 298 K, 0.05 C) and high reversible capacity (650 mAh g−1, 100 cycles, 298 K, 0.1 C). These findings underscore the feasibility of developing high-performance all-solid-state lithium-sulfur batteries by designing three-dimensional mixed-conducting mechanically robust cathodes.

Abstract We aimed to identify gut microbial features in Parkinson’s disease (PD) across countries by meta-analyzing our fecal shotgun sequencing dataset of 94 PD patients and 73 controls in Japan with five previously reported datasets from USA, Germany, China1, China2, and Taiwan. GC-MS and LC-MS/MS assays were established to quantify fecal short-chain fatty acids (SCFAs) and fecal polyamines, respectively. α-Diversity was increased in PD across six datasets. Taxonomic analysis showed that species Akkermansia muciniphila was increased in PD, while species Roseburia intestinalis and Faecalibacterium prausnitzii were decreased in PD. Pathway analysis showed that genes in the biosyntheses of riboflavin and biotin were markedly decreased in PD after adjusting for confounding factors. Five out of six categories in carbohydrate-active enzymes (CAZymes) were decreased in PD. Metabolomic analysis of our fecal samples revealed that fecal SCFAs and polyamines were significantly decreased in PD. Genes in the riboflavin and biotin biosyntheses were positively correlated with the fecal concentrations of SCFAs and polyamines. Bacteria that accounted for the decreased riboflavin biosynthesis in Japan, the USA, and Germany were different from those in China1, China2, and Taiwan. Similarly, different bacteria accounted for decreased biotin biosynthesis in the two country groups. We postulate that decreased SCFAs and polyamines reduce the intestinal mucus layer, which subsequently facilitates the formation of abnormal α-synuclein fibrils in the intestinal neural plexus in PD, and also cause neuroinflammation in PD.

Abstract Information on the cathode/organic–electrolyte interface structure provides clues regarding the rate and reversibility of lithium intercalation reactions in lithium‐ion batteries. Herein, structural changes within the LiCoO2 electrode, throughout the interphase region, and in the LiPF6/propylene carbonate electrolyte are observed concurrently by in situ neutron reflectometry. The formation of an electrical double layer (EDL) during the early stages of charging and discharging is investigated and compared with that at an intercalation‐inactive Nb:SrTiO3 electrode. At the intercalation‐inactive interface between Nb:SrTiO3 and the electrolyte, a voltage‐dependent ionic distribution corresponding to the EDL forms on the electrolyte side without the formation of a cathode/electrolyte interphase (CEI) layer. In contrast, at the intercalation‐active LiCoO2/electrolyte interface, a CEI layer forms immediately after cell construction, and the ionic distribution in the electrolyte formed outside the CEI layer scarcely changes upon voltage application. The CEI/electrolyte interface is shielded from potential changes by the electronically insulating CEI; therefore, structural changes in the EDL are restricted. This supports the prevailing understanding that the CEI layer defines the rates of solvation/de‐solvation and adsorption/desorption reactions of lithium ions.

Abstract Parkinson’s disease (PD) is pathologically characterized by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra and other brain regions, although the role of Lewy bodies remains elusive. Constipation usually precedes the motor symptoms in PD, which is in accordance with the notion that α-synuclein fibrils start from the intestinal neural plexus and ascend to the brain in at least half of PD patients. The gut microbiota is likely to be involved in intestinal and brain pathologies. Analyses of the gut microbiota in PD, rapid-eye-movement sleep behavior disorder, and dementia with Lewy bodies suggest three pathological pathways. First, Akkermansia, which is increased in PD, degrades the intestinal mucus layer and increases intestinal permeability, which triggers inflammation and oxidative stress in the intestinal neural plexus. Second, decreased short-chain fatty acids (SCFAs)-producing bacteria in PD reduce the number of regulatory T cells. Third, SCFAs also aggravate microglial activation with an unelucidated pathway. In addition, in dementia with Lewy bodies (DLB), which is another form of α-synucleinopathies, increased genera, Ruminococcus torques and Collinsella, may mitigate neuroinflammation in the substantia nigra by increasing secondary bile acids. Interventions for the gut microbiota and their metabolites may potentially delay or mitigate the development and progression of PD and other Lewy body diseases.

Abstract Gut microbiota and fecal bile acids were analyzed in 278 patients with α-synucleinopathies, which were comprised of 28 patients with dementia with Lewy bodies (DLB), 224 patients with Parkinson’s disease (PD), and 26 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Similarly to PD, short-chain fatty acids-producing genera were decreased in DLB. Additionally, Ruminococcus torques and Collinsella were increased in DLB, which were not changed in PD. Random forest models to differentiate DLB and PD showed that high Ruminococcus torques and high Collinsella, which presumably increase intestinal permeability, as well as low Bifidobacterium, which are also observed in Alzheimer’s disease, were predictive of DLB. As Ruminococcus torques and Collinsella are also major secondary bile acids-producing bacteria, we quantified fecal bile acids and found that the production of ursodeoxycholic acid (UDCA) was high in DLB. Increased UDCA in DLB may mitigate neuroinflammation at the substantia nigra, whereas neuroinflammation may not be critical at the neocortex. Theraeutic intervention to increase Bifidobacteirum and its metabolites may retard the development and progression of DLB.

A thin-film battery composed of a LiFePO4 cathode/Li3PO4 electrolyte/Li anode was fabricated on a Pt/Ti/Si (PTS) substrate via RF magnetron sputtering. The amorphous Li3PO4 film was densely stacked on a 60 nm-thick LiFePO4 film, which provided a suitable reaction field for understanding the electrochemical properties of LiFePO4 at the interface with the solid electrolyte. The LiFePO4 cathode film exhibited highly reversible lithium desertion/insertion at the interface at room temperature and 60 °C, without any side reactions. An irreversible oxidation reaction occurred during the initial charging process at 100 °C, leading to an increase in the charge-transfer resistance of the LiFePO4/Li3PO4 interface with no significant decrease in the lithium desertion/insertion capacity of LiFePO4. This result suggests the formation of a resistive interphase via the decomposition of Li3PO4 at 100 °C. A severe decrease in capacity is observed at 125 °C, which indicates the LiFePO4-side interface contributed to the side reactions. The film battery exhibits a severe decrease in capacity at 125 °C.

Abstract To elucidate the relevance of gut dysbiosis in Parkinson’s disease (PD) in disease progression, we made random forest models to predict the progression of PD in two years by gut microbiota in 165 PD patients. The area under the receiver operating characteristic curves (AUROCs) of gut microbiota-based models for Hoehn & Yahr (HY) stages 1 and 2 were 0.799 and 0.705, respectively. Similarly, gut microbiota predicted the progression of Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III scores in an early stage of PD with AUROC = 0.728. Decreases of short-chain fatty acid-producing genera, Fusicatenibacter, Faecalibacterium, and Blautia, as well as an increase of mucin-degrading genus Akkermansia, predicted accelerated disease progression. The four genera remained unchanged in two years in PD, indicating that the taxonomic changes were not the consequences of disease progression. PD patients with marked gut dysbiosis may thus be destined to progress faster than those without gut dysbiosis.

The electronic structure evolution within a battery during cycling can provide crucial cues for its optimization, but insights on operando band structures are extremely challenging to obtain. Here, the authors determine the overall band structure of a model thin-film solid-state lithium battery via operando hard X-ray photoelectron spectroscopy, considering the cathode and anode sides.

Abstract Background The human microbiome forms very complex communities that consist of hundreds to thousands of different microorganisms that not only affect the host, but also participate in disease processes. Several state-of-the-art methods have been proposed for learning the structure of microbial communities and to investigate the relationship between microorganisms and host environmental factors. However, these methods were mainly designed to model and analyze single microbial communities that do not interact with or depend on other communities. Such methods therefore cannot comprehend the properties between interdependent systems in communities that affect host behavior and disease processes. Results We introduce a novel hierarchical Bayesian framework, called BALSAMICO (BAyesian Latent Semantic Analysis of MIcrobial COmmunities), which uses microbial metagenome data to discover the underlying microbial community structures and the associations between microbiota and their environmental factors. BALSAMICO models mixtures of communities in the framework of nonnegative matrix factorization, taking into account environmental factors. We proposes an efficient procedure for estimating parameters. A simulation then evaluates the accuracy of the estimated parameters. Finally, the method is used to analyze clinical data. In this analysis, we successfully detected bacteria related to colorectal cancer. Conclusions These results show that the method not only accurately estimates the parameters needed to analyze the connections between communities of microbiota and their environments, but also allows for the effective detection of these communities in real-world circumstances.

Oxygen reduction and evolution reactions (ORR and OER, respectively) of perovskite-type La0.8Sr0.2CoO3 were characterized using two-dimensional model electrodes with different reaction planes (001), (110), and (111). Synthesized by pulsed laser deposition, these thin (30 nm) and flat (roughness < 1 nm) electrodes can reveal the reaction plane dependence of the ORR activity. From steady-state polarization measurements in KOH (aq.), the ORR activity was the highest on the (001) film during the first ORR/OER cycle, and it decreased significantly during the second cycle. In-situ synchrotron X-ray diffraction clarified crystal structure changes in the bulk and surface regions of La0.8Sr0.2CoO3, and these changes are associated with forming oxygen defects during the initial electrochemical process. Furthermore, the La0.8Sr0.2CoO3 surface partially decomposed upon reacting with the aqueous solution, as clarified by hard X-ray photoemission spectroscopy. Therefore, the interfacial structures formed in the electrochemical reaction field is important for enhancing ORR and OER activities.

Abstract Background One of the major challenges in microbial studies is detecting associations between microbial communities and a specific disease. A specialized feature of microbiome count data is that intestinal bacterial communities form clusters called as “enterotype”, which are characterized by differences in specific bacterial taxa, making it difficult to analyze these data under health and disease conditions. Traditional probabilistic modeling cannot distinguish between the bacterial differences derived from enterotype and those related to a specific disease. Results We propose a new probabilistic model, named as ENIGMA (Enterotype-like uNIGram mixture model for Microbial Association analysis), which can be used to address these problems. ENIGMA enabled simultaneous estimation of enterotype-like clusters characterized by the abundances of signature bacterial genera and the parameters of environmental effects associated with the disease. Conclusion In the simulation study, we evaluated the accuracy of parameter estimation. Furthermore, by analyzing the real-world data, we detected the bacteria related to Parkinson’s disease. ENIGMA is implemented in R and is available from GitHub (https://github.com/abikoushi/enigma).

The mortality rates of COVID-19 vary widely across countries, but the underlying mechanisms remain unelucidated. We aimed at the elucidation of relationship between gut microbiota and the mortality rates of COVID-19 across countries. Raw sequencing data of 16S rRNA V3-V5 regions of gut microbiota in 953 healthy subjects in ten countries were obtained from the public database. We made a generalized linear model (GLM) to predict the COVID-19 mortality rates using gut microbiota. GLM revealed that low genus Collinsella predicted high COVID-19 mortality rates with a markedly low p-value. Unsupervised clustering of gut microbiota in 953 subjects yielded five enterotypes. The mortality rates were increased from enterotypes 1 to 5, whereas the abundances of Collinsella were decreased from enterotypes 1 to 5 except for enterotype 2. Collinsella produces ursodeoxycholate. Ursodeoxycholate was previously reported to inhibit binding of SARS-CoV-2 to angiotensin-converting enzyme 2; suppress pro-inflammatory cytokines like TNF-α, IL-1β, IL-2, IL-4, and IL-6; have antioxidant and anti-apoptotic effects; and increase alveolar fluid clearance in acute respiratory distress syndrome. Ursodeoxycholate produced by Collinsella may prevent COVID-19 infection and ameliorate acute respiratory distress syndrome in COVID-19 by suppressing cytokine storm syndrome.

ABSTRACT Gut dysbiosis has been repeatedly reported in Parkinson’s disease (PD) but only once in idiopathic rapid-eye-movement sleep behavior disorder (iRBD) from Germany. Abnormal aggregation of α-synuclein fibrils causing PD possibly starts from the intestine, although this is still currently under debate. iRBD patients frequently develop PD. Early-stage gut dysbiosis that is causally associated with PD is thus expected to be observed in iRBD. We analyzed gut microbiota in 26 iRBD patients and 137 controls by 16S rRNA sequencing (16S rRNA-seq). Our iRBD data set was meta-analyzed with the German iRBD data set and was compared with gut microbiota in 223 PD patients. Unsupervised clustering of gut microbiota by LIGER, a topic model-based tool for single-cell RNA sequencing (RNA-seq) analysis, revealed four enterotypes in controls, iRBD, and PD. Short-chain fatty acid (SCFA)-producing bacteria were conserved in an enterotype observed in controls and iRBD, whereas they were less conserved in enterotypes observed in PD. Genus Akkermansia and family Akkermansiaceae were consistently increased in both iRBD in two countries and PD in five countries. Short-chain fatty acid (SCFA)-producing bacteria were not significantly decreased in iRBD in two countries. In contrast, we previously reported that recognized or putative SCFA-producing genera Faecalibacterium, Roseburia, and Lachnospiraceae ND3007 group were consistently decreased in PD in five countries. In α-synucleinopathy, increase of mucin-layer-degrading genus Akkermansia is observed at the stage of iRBD, whereas decrease of SCFA-producing genera becomes obvious with development of PD. IMPORTANCE Twenty studies on gut microbiota in PD have been reported, whereas only one study has been reported on iRBD from Germany. iRBD has the highest likelihood ratio to develop PD. Our meta-analysis of iRBD in Japan and Germany revealed increased mucin-layer-degrading genus Akkermansia in iRBD. Genus Akkermansia may increase the intestinal permeability, as we previously observed in PD patients, and may make the intestinal neural plexus exposed to oxidative stress, which can lead to abnormal aggregation of prion-like α-synuclein fibrils in the intestine. In contrast to PD, SCFA-producing bacteria were not decreased in iRBD. As SCFA induces regulatory T (Treg) cells, a decrease of SCFA-producing bacteria may be a prerequisite for the development of PD. We propose that prebiotic and/or probiotic therapeutic strategies to increase the intestinal mucin layer and to increase intestinal SCFA potentially retard the development of iRBD and PD.

The establishment of three-electrode cells for all-solid-state lithium-ion batteries is an important issue to clarify the electrochemical behavior of the battery components and solve problems for the practical applications. Here we prepared an all-solid-state three-electrode cell with a chemically-reduced Li4Ti5O12 reference electrode and investigated electrochemical properties of a LiCoO2 composite electrode in a Li-In|Li10GeP2S12|LiCoO2 cell. Plateau potentials in charge-discharge curves were coincident with reported values. Cell impedance measured with two-electrode configuration agreed well with the sum of the impedances of the positive and the negative electrodes measured with the reference electrode. These results show that chemically-reduced Li4Ti5O12 reference electrode was worked as a Li7Ti5O12|Li4Ti5O12 reference electrode and electrochemical properties of the LiCoO2 electrode and the Li-In electrode were separated. From the temperature and the state of charge dependences of LiCoO2 impedance, resistances related to interface or interphase and charge-transfer reaction were identified. These results show that all-solid-state cells with chemically-reduced Li4Ti5O12 reference electrodes are promising candidates for three-electrode cells for all-solid-state lithium-ion battery systems.

A combinatorial synthesis system consisting of co-sputtering multiple radio frequency (RF) cathodes was developed to investigate the presence of new amorphous solid electrolytes in a pseudo-ternary Li3PO4-Li4SiO4-LiAlO2 system. Oxynitride solid-electrolyte films were synthesized under an N2 atmosphere by reactive RF sputtering with cathodes made of different materials, such as Li3PO4, Li4SiO4, and LiAlO2 installed at different positions in the chamber. The formation of amorphous films with no grains and a continuous atomic distribution was confirmed using scanning electron microscopy and energy-dispersive X-ray spectroscopy. In a single synthesis, we fabricated an oxynitride solid-electrolyte film, in which the composition range of the components was approximately one-eighth that in the corresponding pseudo-ternary system. The highest Li-ion conductivity of 3.1 × 10−6 S cm−1 was obtained for the LiPSiAlON film with a composition ratio of LiPON : LiSiON : LiAlON = 48.5 : 33.9 : 17.6. The different bonding states of O and N in the LiPSiAlON film doped with P, Si, and Al were examined using X-ray photoemission spectroscopy. The ionic conductivity was improved by the mixed anion effect. The combinatorial synthesis enables the efficient optimization of the chemical composition and facilitates the development of highly conductive amorphous solid electrolytes.

K2NiF4-type oxides are expected to be potential lithium-ion conductors because they have a structure similar to that of perovskites, which provide a reasonably flexible framework for accommodating defects such as charge carriers within the lattice. However, the K2NiF4-type structure as a framework for lithium conductors is scarcely reported. This article presents the preparation of Sr(La1−xLi3x)ScO4 with a K2NiF4 structure by a solid-state reaction at a high pressure of 2 GPa, and elucidates its lithium-ion-conducting properties. Sr(La1−xLi3x)ScO4 forms solid solutions in the x range of 0.05–0.20. Its orthorhombic lattice expands with lithium doping, indicating the incorporation of lithium ions as interstitial species in the structure. The highly doped samples exhibit high ionic conductivities (e.g., 4.66 × 10−6 S cm−1 at 250 °C for x = 0.15 and 4.29 × 10−2 S cm−1 at 375 °C for x = 0.2) with an activation energy of ∼100 kJ mol−1. The samples show an abnormal increase in the ionic conductivity at ∼300 °C, possibly due to the increase in the orthorhombicity of Sr(La1−xLi3x)ScO4. As the electronic conductivities of the developed oxide materials are a few orders of magnitude lower than their total conductivities, they can be used as solid electrolytes in all-solid-state lithium batteries. The study reveals that K2NiF4-type oxides are attractive candidates for developing novel lithium-ion conductors.

Abstract Background Establishing the relationship between microbiota and specific diseases is important but requires appropriate statistical methodology. A specialized feature of microbiome count data is the presence of a large number of zeros, which makes it difficult to analyze in case-control studies. Most existing approaches either add a small number called a pseudo-count or use probability models such as the multinomial and Dirichlet-multinomial distributions to explain the excess zero counts, which may produce unnecessary biases and impose a correlation structure taht is unsuitable for microbiome data. Results The purpose of this article is to develop a new probabilistic model, called BERnoulli and MUltinomial Distribution-based latent Allocation (BERMUDA), to address these problems. BERMUDA enables us to describe the differences in bacteria composition and a certain disease among samples. We also provide a simple and efficient learning procedure for the proposed model using an annealing EM algorithm. Conclusion We illustrate the performance of the proposed method both through both the simulation and real data analysis. BERMUDA is implemented with R and is available from GitHub (https://github.com/abikoushi/Bermuda).

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. Patients with MSA show various phenotypes during the course of their illness, including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. Patients with MSA sometimes present with isolated autonomic failure or motor symptoms/ signs. The median duration from onset to the concomitant appearance of motor and autonomic symptoms is approximately 2 years but can range up to 14 years. As the presence of both motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. In contrast, patients with MSA may show severe autonomic failure and die before the presentation of motor symptoms/signs, which are currently required for the diagnosis of MSA. Recent studies have also revealed that patients with MSA may show nonsupporting features of MSA such as dementia, hallucinations, and vertical gaze palsy. To establish early diagnostic criteria and clinically definitive categorization for the successful development of disease-modifying therapy or symptomatic interventions for MSA, research should focus on the isolated phase and atypical symptoms to develop specific clinical, imaging, and fluid biomarkers that satisfy the requirements for objectivity, for semi- or quantitative measurements, and for uncomplicated, worldwide availability. Several novel techniques, such as automated compartmentalization of the brain into multiple parcels for the quantification of gray and white matter volumes on an individual basis and the visualization of α-synuclein and other candidate serum and cerebrospinal fluid biomarkers, may be promising for the early and clinically definitive diagnosis of MSA.

Perovskite-type lithium ionic conductors were explored in the (LixLa1−x/3)ScO3 system following their syntheses via a high-pressure solid-state reaction. Phase identification indicated that a solid solution with a perovskite-type structure was formed in the range 0 ≤ x < 0.6. When x = 0.45, (Li0.45La0.85)ScO3 exhibited the highest ionic conductivity and a low activation energy. Increasing the loading of lithium as an ionic diffusion carrier expanded the unit cell volume and contributed to the higher ionic conductivity and lower activation energy. Cations with higher oxidation numbers were introduced into the A/B sites to improve the ionic conductivity. Ce4+ and Zr4+ or Nb5+ dopants partially substituted the A-site (La/Li) and B-site Sc, respectively. Although B-site doping produced a lower ionic conductivity, A-site Ce4+ doping improved the conductive properties. A perovskite-type single phase was obtained for (Li0.45La0.78Ce0.05)ScO3 upon Ce4+ doping, providing a higher ionic conductivity than (Li0.45La0.85)ScO3. Compositional analysis and crystal-structure refinement of (Li0.45La0.85)ScO3 and (Li0.45La0.78Ce0.05)ScO3 revealed increased lithium contents and expansion of the unit cell upon Ce4+ co-doping. The highest ionic conductivity of 1.1 × 10−3 S cm−1 at 623 K was confirmed for (Li0.4Ce0.15La0.67)ScO3, which is more than one order of magnitude higher than that of the (LixLa1−x/3)ScO3 system.

Oral administration of hydrogen water ameliorates Parkinson's disease (PD) in rats, mice, and humans. We previously reported that the number of putative hydrogen-producing bacteria in intestinal microbiota is low in PD compared to controls. We also reported that the amount of hydrogen produced by ingestion of lactulose is low in PD patients. The decreased hydrogen production by intestinal microbiota may be associated with the development and progression of PD. We measured the amount of hydrogen production using gas chromatography by seven bacterial strains, which represented seven major intestinal bacterial groups/genera/species. Blautia coccoides and Clostridium leptum produced the largest amount of hydrogen. Escherichia coli and Bacteroides fragilis constituted the second group that produced hydrogen 34- to 93-fold lower than B. coccoides. Bifidobacterium pseudocatenulatum and Atopobium parvulum constituted the third group that produced hydrogen 559- to 2164-fold lower than B. coccoides. Lactobacillus casei produced no detectable hydrogen. Assuming that taxonomically neighboring strains have similar hydrogen production, we simulated hydrogen production using intestinal microbiota that we previously reported, and found that PD patients produce a 2.2-fold lower amount of intestinal hydrogen compared to controls. The lower amount of intestinal hydrogen production in PD was also simulated in cohorts of two other countries. The number of hydrogen-producing intestinal bacteria may be associated with the development and progression of PD. Further studies are required to prove its beneficial effect.

Severe hyposmia is a risk factor of dementia in Parkinson's disease (PD), while the underlying functional connectivity (FC) and brain volume alterations in PD patients with severe hyposmia (PD-SH) are unclear.We examined voxel-based morphometric and resting state functional magnetic resonance imaging findings in 15 cognitively normal PD-SH, 15 cognitively normal patients with PD with no/mild hyposmia (PD-N/MH), and 15 healthy controls (HCs).Decreased gray matter volume (GMV) was observed in the bilateral cuneus, right associative visual area, precuneus, and some areas in anterior temporal lobes in PD-SH group compared to HCs. Both the PD-SH and PD-N/MH groups showed increased GMV in the bilateral posterior insula and its surrounding regions. A widespread significant decrease in amygdala FC beyond the decreased GMV areas and olfactory cortices were found in the PD-SH group compared with the HCs. Above all, decreased amygdala FC with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of Addenbrooke's Cognitive Examination-Revised scores and severity of hyposmia in all participants. Canonical resting state networks exhibited decreased FC in the precuneus and left executive control networks but increased FC in the primary and high visual networks of patients with PD compared with HCs. Canonical network FC to other brain regions was enhanced in the executive control, salience, primary visual, and visuospatial networks of the PD-SH.PD-SH showed extensive decreased amygdala FC. Particularly, decreased FC between the amygdala and inferior parietal lobule, lingual gyrus, and fusiform gyrus were associated with the severity of hyposmia and cognitive performance. In contrast, relatively preserved canonical networks in combination with increased FC to brain regions outside of canonical networks may be related to compensatory mechanisms, and preservation of brain function.

We previously reported gut dysbiosis in patients with Parkinson's disease (PD).The aim of this study is to examine whether gut dysbiosis correlates with the progression of PD.We examined changes in gut microbiota and demographic features in 2 years in 36 PD patients.A change of total UPDRS scores in 2 years was predicted by the counts of Bifidobacterium and Atopobium cluster at year 0 with a correlation coefficient of 0.52. Correlation analysis additionally revealed that low counts of Bifidobacterium and Bacteroides fragilis at year 0 were associated with worsening of UPDRS I scores in 2 years. In addition, low counts of Bifidobacterium at year 0 were associated with worsening of hallucinations/delusions in 2 years. Similarly, low counts of B. fragilis at year 0 were associated with worsening of motivation/initiative in 2 years. The patients were evenly divided into the deteriorated and stable groups based on the degree of worsening of total UPDRS scores. The deteriorated group had lower counts of Bifidobacterium, B. fragilis, and Clostridium leptium than the stable group at year 0 but not at year 2, suggesting that the deteriorated group may demonstrate accelerated lowering of these bacteria at year 0.The total counts of intestinal bacterial decrease in the course of PD progression. Temporal profiles of lowering of bacterial counts are likely to be different from bacteria to bacteria, and also between the deteriorating and stable groups, which may be able to be exploited to differentiate patients with rapidly and slowly progressive PD pathology.

Lithium superionic conductors with the Li10GeP2S12 (LGPS)-type structure are promising materials for use as solid electrolytes in next-generation lithium batteries. A novel member of the LGPS family, Li9.42Si1.02P2.1S9.96O2.04, and its solid solutions were synthesised by quenching from 1273 K in the Li2S–P2S5–SiO2 pseudoternary system. The material exhibited an ionic conductivity as high as 3.2×10−4 S cm−1 at 298 K, as well as the high electrochemical stability to lithium metal, which was improved by the introduction of oxygen into the LGPS-type structure. An all-solid-state cell with a lithium metal anode and Li9.42Si1.02P2.1S9.96O2.04 as the separator showed excellent performance with a high coulomb efficiency of 100%. Thus, oxygen doping is an effective way of improving the electrochemical stability of LGPS-type structure.

The intestine is one of the first affected organs in Parkinson's disease (PD). PD subjects show abnormal staining for Escherichia coli and α-synuclein in the colon.We recruited 52 PD patients and 36 healthy cohabitants. We measured serum markers and quantified the numbers of 19 fecal bacterial groups/genera/species by quantitative RT-PCR of 16S or 23S rRNA. Although the six most predominant bacterial groups/genera/species covered on average 71.3% of total intestinal bacteria, our analysis was not comprehensive compared to metagenome analysis or 16S rRNA amplicon sequencing.In PD, the number of Lactobacillus was higher, while the sum of analyzed bacteria, Clostridium coccoides group, and Bacteroides fragilis group were lower than controls. Additionally, the sum of putative hydrogen-producing bacteria was lower in PD. A linear regression model to predict disease durations demonstrated that C. coccoides group and Lactobacillus gasseri subgroup had the largest negative and positive coefficients, respectively. As a linear regression model to predict stool frequencies showed that these bacteria were not associated with constipation, changes in these bacteria were unlikely to represent worsening of constipation in the course of progression of PD. In PD, the serum lipopolysaccharide (LPS)-binding protein levels were lower than controls, while the levels of serum diamine oxidase, a marker for intestinal mucosal integrity, remained unchanged in PD.The permeability to LPS is likely to be increased without compromising the integrity of intestinal mucosa in PD. The increased intestinal permeability in PD may make the patients susceptible to intestinal dysbiosis. Conversely, intestinal dysbiosis may lead to the increased intestinal permeability. One or both of the two mechanisms may be operational in development and progression of PD.

In repetitive measurements of flow-mediated dilatation (FMD), the duration of the interval between measurements remains controversial. In this pilot study, we conducted three sequential measurements of low-flow-mediated constriction (L-FMC), FMD and flow-mediated total dilation (FMTD; L-FMC+ FMD) at baseline and intervals of 15 and 60 min in 30 healthy males. FMD15, L-FMC15, and FMTD15 were significantly lower than the respective first measurements, but all indices showed full recovery at 60 min in all subjects. The baseline diameter was slightly increased at 15 min and restored at 60 min, but the maximum diameter, and the baseline and reactive flow velocity unchanged. We examined the relationship between recovery rate of FMTD at 15 min (FMTD-R) and cardio-ankle vascular index (CAVI). Univariate analysis showed moderate correlation between FMTD-R, and CAVI and L-FMC0. Patients were divided according to FMTD-R value; the low-FMTD-R group [below the median value (-26.2%)] included a significantly higher proportion of smokers and higher CAVI values than the high-FMTD-R group. The reproducibility of FMTD and FMTD-R was evaluated in another group of 25 healthy subjects. The range of variation across measurements was 1.1% for FMTD and 4.6% for FMTD-R; with intraclass correlation coefficients of 0.93 and 0.95, respectively. The present study demonstrated blunted recovery of FMD within 15 min, suggesting the need for selection of a more adequate interval between measurements to avoid underestimation of FMD in subsequent measurements. The findings demonstrated the reproducibility of FMTD-R and FMTD measurements, and that FMTD-R might be involved in arterial stiffness and early vascular impairment in the healthy subjects.

Mechanical properties of Li10.35Ge1.35P1.65S12 (LGPS) solid electrolytes with different grain sizes were investigated via indentation tests. Hand-milled LGPS (HM LGPS, d50: 1.32 μm) and wet-milled LGPS (WM LGPS, d50: 0.46 μm) powders were uniaxially pressed to obtain pellet samples. The HM LGPS and WM LGPS pellets had a similar bulk density of 1.63 g cm-3. At the initial loading/unloading, the WM LPGS pellet showed a large deformation owing to a decrease in cavities compared with the HM LGPS. In the subsequent cycles, both pellets exhibited elastic deformation behavior in the pressure range up to 20 N. The elastic modulus and relative residual depth of HM LGPS and WM LGPS were 21.7 GPa and 15.0 GPa and 0.75 and 0.71, respectively. This result revealed that WM LGPS is more elastically deformable and less plastically deformable than HM LGPS, which could be associated with the grain boundary strengthening interpreted by the Hall-Petch relation. Based on these mechanical properties, the superior cycle stability at the In-Li electrode/WM LGPS electrolyte interface during charging/discharging was discussed. Controlling the mechanical properties of sulfide solid electrolytes by the grain size is important for suppressing physical degradation in all-solid-state batteries. [ABSTRACT FROM AUTHOR]