Diversification of von Willebrand Factor A and Chitin-Binding Domains in Pif/BMSPs Among Mollusks.

Pif is a shell matrix protein (SMP) identified in the nacreous layer of Pinctada fucata (Pfu) comprised two proteins, Pif97 and Pif 80. Pif97 contains a von Willebrand factor A (VWA) and chitin-binding domains, whereas Pif80 can bind calcium carbonate crystals. The VWA domain is conserved in the SMPs of various mollusk species; however, their phylogenetic relationship remains obscure. Furthermore, although the VWA domain participates in protein-protein interactions, its role in shell formation has not been established. Accordingly, in the current study, we investigate the phylogenetic relationship between PfuPif and other VWA domain-containing proteins in major mollusk species. The shell-related proteins containing VWA domains formed a large clade (the Pif/BMSP family) and were classified into eight subfamilies with unique sequential features, expression patterns, and taxa diversity. Furthermore, a pull-down assay using recombinant proteins containing the VWA domain of PfuPif 97 revealed that the VWA domain interacts with five nacreous layer-related SMPs of P. fucata, including Pif 80 and nacrein. Collectively, these results suggest that the VWA domain is important in the formation of organic complexes and participates in shell mineralisation.

Formation Processes of a Solid Electrolyte Interphase at a Silicon/Sulfide Electrolyte Interface in a Model All-Solid-State Li-Ion Battery.

Understanding the electrochemical reactions at the interface between a Si anode and a solid sulfide electrolyte is essential in improving the cycle stabilities of Si anodes in all-solid-state batteries (ASSBs). Highly dense Si films with very low roughnesses of <1 nm were fabricated at room temperature via cathodic arc plasma deposition, which led to the formation of a Si/sulfide electrolyte model interface. Li (de)alloying through the model interface hardly occurred during the first cycle, whereas it proceeded stably in subsequent cycles. Hard X-ray photoelectron spectroscopy and neutron reflectometry directly revealed that the reduction or oxidation of the interfacial component or Li3PS4 electrolyte occurred during the first cycle. Consequently, an interfacial layer with a thickness of 13 nm and primarily composed of Li2S, SiS2, and P2S5 glasses was formed during the first cycle. The interfacial layer acted as a Li-conductive, electron-insulating solid electrolyte interphase (SEI) that provided reversible (de)lithiation. Our model interface directly demonstrates the electrochemical reaction processes at the Si/Li3PS4 interface and provides insights into the structures and electrochemical properties of SEIs to activate the (de)lithiation of Si anodes using a sulfide electrolyte.

Clinical Efficacy of Neurotropin for Lumbar Spinal Stenosis with Low Back Pain.

PURPOSE: We compared the clinical effects of Neurotropin, limaprost alfadex, and a combination of both drugs for lumbar spinal stenosis (LSS) with low back pain (LBP). METHODS: We conducted a multicenter, randomized, active-controlled, open-label trial from March 2021 to May 2022. Participants were patients diagnosed with LSS by MRI and were randomly assigned to three groups: Neurotropin/limaprost combination (NL group), Neurotropin (N group), and limaprost group (L group). Participants received the drugs administered orally for 12 weeks, and each examination and observation was performed before any drug administration and every 2 weeks thereafter. We recorded age, sex, height, weight, duration of symptoms, intermittent claudication distance, level of stenosis in MRI, and concomitant analgesics as examination items in the trial period. Items measured during the trial were visual analog scale (VAS) score (mm) for LBP, leg pain and numbness, walking activity (walking speed, stride length), standing balance (3 m Timed Up-and-Go (TUG) Test results, Five Times Sit-to-Stand Test (FTSST) results), LBP/Quality of Life (QOL)-related scores (Oswestry Disability Index (ODI), Euro QOL 5-Dimensions 5-Level (EQ-5D-5L), Roland-Morris Disability Questionnaire (RDQ)), psychological factors (Pain catastrophizing scale (PCS) and Pain Self-Efficacy Questionnaire (PSEQ) scores), and adverse events. Each item was evaluated using changes at each visit (weeks 2-12) from baseline value before drug administration (week 0), and changes were considered significant when p < 0.05. RESULTS: We included results from 64 patients in the present study; 24 were assigned to the NL group (mean age 71.2 years), 20 to the N group (mean age 76.2 years), and 20 to the L group (mean age 74.4 years). There were no significant differences between the three groups in patient characteristics, concomitant analgesics, or baseline VAS score, gait balance, or QOL-related scores (p ≥ 0.05). The VAS and leg pain scores were significantly improved in Group L, and LBP was improved significantly in Group N. QOL and ODI scores improved significantly in the NL and L groups, EQ-5D score improved significantly in the L group, and RDQ score improved significantly in all groups (p < 0.05). Psychological factor and PCS scores improved significantly in the NL and L groups (p < 0.05). Walking speed and stride length were improved significantly in the NL and N groups (p < 0.05). TUG/FTSST scores were improved significantly in all groups (p < 0.05). Leg pain VAS score was improved significantly (p < 0.05) in the L group compared with the NL group after 6 and 12 weeks of administration, and LBP VAS was improved significantly in the N group after 6 weeks compared with the NL group (p < 0.05). Walking speed was significantly improved in the NL group after 2 weeks compared with the N group and improved significantly in the NL group after 6 weeks (p < 0.05) compared with the L group. RDQ was decreased significantly in the L group compared with the NL group after 8 weeks (p < 0.05). CONCLUSIONS: Combined use of Neurotropin and limaprost showed an additional effect on walking speed compared with single drug administration. Neurotropin may contribute to the improvement of low back pain, walking speed/stride length, and standing balance. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031200282).

Evolution of nacre- and prisms-related shell matrix proteins in the pen shell, Atrina pectinata.

The molluscan shell is a good model for understanding the mechanisms underlying biomineralization. It is composed of calcium carbonate crystals and many types of organic molecules, such as the matrix proteins, polysaccharides, and lipids. The pen shell Atrina pectinata (Pterioida, Pinnidae) has two shell microstructures: an outer prismatic layer and an inner nacreous layer. Similar microstructures are well known in pearl oysters (Pteriidae), such as Pinctada fucata, and many kinds of shell matrix proteins (SMPs) have been identified from their shells. However, the members of SMPs that consist of the nacreous and prismatic layers of Pinnidae bivalves remain unclear. In this study, we identified 114 SMPs in the nacreous and prismatic layers of A. pectinata, of which only seven were found in both microstructures. 54 of them were found to bind calcium carbonate. Comparative analysis of nine molluscan shell proteomes showed that 69 of 114 SMPs of A. pectinata were found to have sequential similarity with at least one or more SMPs of other molluscan species. For instance, nacrein, tyrosinase, Pif/BMSP-like, chitinase (CN), chitin-binding proteins, CD109, and Kunitz-type serine proteinase inhibitors are widely shared among bivalves and gastropods. Our results provide new insights for understanding the complex evolution of SMPs related to nacreous and prismatic layer formation in the pteriomorph bivalves.

New treatment strategy for chronic low back pain with alpha wave neurofeedback.

The lifetime prevalence of low back pain is 83%. Since there is a lack of evidence for therapeutic effect by cognitive behavioral therapy (CBT) or physical therapy (PT), it is necessary to develop objective physiological indexes and effective treatments. We conducted a prospective longitudinal study to evaluate the treatment effects of CBT, PT, and neurofeedback training (NFT) during alpha wave NFT. The early-chronic cases within 1 year and late-chronic cases over 1 year after the diagnosis of chronic low back pain were classified into six groups: Controls, CBTs, PTs, NFTs, CBT-NFTs, PT-NFTs. We evaluated the difference in EEG, psychosocial factors, scores of low back pain before/after the intervention. Therapeutic effect was clearly more effective in the early-chronic cases. We found that the intensity of alpha waves increased significantly after therapeutic intervention in the NFT groups, but did not have the main effect of reducing low back pain; the interaction between CBT and NFT reduced low back pain. Factors that enhance therapeutic effect are early intervention, increased alpha waves, and self-efficacy due to parallel implementation of CBT/PT and NFT. A treatment protocol in which alpha wave neurofeedback training is subsidiarily used with CBT or PT should be developed in the future.

Evolution of Epidermal Growth Factor (EGF)-like and Zona Pellucida Domains Containing Shell Matrix Proteins in Mollusks.

Several types of shell matrix proteins (SMPs) have been identified in molluskan shells. Their diversity is the consequence of various molecular processes, including domain shuffling and gene duplication. However, the evolutionary origin of most SMPs remains unclear. In this study, we investigated the evolutionary process EGF-like and zona pellucida (ZP) domains containing SMPs. Two types of the proteins (EGF-like protein (EGFL) and EGF-like and ZP domains containing protein (EGFZP)) were found in the pearl oyster, Pinctada fucata. In contrast, only EGFZP was identified in the gastropods. Phylogenetic analysis and genomic arrangement studies showed that EGFL and EGFZP formed a clade in bivalves, and their encoding genes were localized in tandem repeats on the same scaffold. In P. fucata, EGFL genes were expressed in the outer part of mantle epithelial cells are related to the calcitic shell formation. However, in both P. fucata and the limpet Nipponacmea fuscoviridis, EGFZP genes were expressed in the inner part of the mantle epithelial cells are related to aragonitic shell formation. Furthermore, our analysis showed that in P. fucata, the ZP domain interacts with eight SMPs that have various functions in the nacreous shell mineralization. The data suggest that the ZP domain can interact with other SMPs, and EGFL evolution in pterimorph bivalves represents an example of neo-functionalization that involves the acquisition of a novel protein through gene duplication.

Dimorphic life cycle through transverse division in burrowing hard coral Deltocyathoides orientalis.

The azooxanthellate solitary scleractinian Deltocyathoides orientalis (family Turbinoliidae), which has bowl-shaped costate corallites, exhibits burrowing behavior on soft substrates and can adapt to an infaunal mode of life. Here, we describe previously unknown aspects of their life history and asexual mode of reproduction based on morphological and molecular phylogenetic analyses. The findings reveal that (1) D. orientalis exhibits asexual reproduction by transverse division; (2) smaller bowl-shaped costate anthocyathus derived from cylindrical to tympanoid anthocaulus were attached to hard substrates, including shell fragments and gravels on soft substrates; and (3) anthocyathus only reproduce sexually after division, and anthocaulus was found to regrow and repeatedly produce anthocyathi through transverse division. The bowl-shaped corallum morphology of the anthocyathus just after division might reduce the time required for skeletal formation to enable infaunal adaption after transverse division. Immediately after division, D. orientalis can smoothly shift to a burrowing lifestyle that efficiently utilizes soft-substrate environments, thus increasing its survival rate. The morphological formation of prospective anthocyathus in the anthocaulus stage is consequently thought to involve an increase in clonal individuals as well as adaptations for a burrowing free-living mode of life in the anthocyathus stage.

Oxygen saturation targets in pediatric respiratory disease.

BACKGROUND: The present study aimed to assess the appropriate oxygen saturation target in patients with pediatric respiratory diseases by lowering the oxygen saturation target from SpO2 94% to 90%. No previous study has explored appropriate oxygen saturation targets in respiratory diseases other than bronchiolitis. METHODS: The present, prospective, single-arm intervention trial enrolled pediatric inpatients with bronchiolitis, bronchitis, pneumonia, and asthma. The oxygen saturation target was lowered from SpO2 94% to 90% after the patients' general condition improved. The patients continued to be observed for 12 h after achieving SpO2 94%. The duration from the first cut-off point (SpO2 90% for 12 h without oxygen) to the second cut-off point (SpO2 94% for 12 h) was then evaluated. RESULTS: In total, 248 patients completed the study. Patients with bronchiolitis, bronchitis, pneumonia, and asthma had an interval between the two cut-off points of 23.9, 15.5, 19.1, and 13.8 h, respectively, (mean 17.2 h; 95% confidence interval 15.0-19.5). CONCLUSIONS: In generally healthy children, setting the oxygen saturation target at SpO2 90% after confirming improvement in their general condition was safe. The time required for increasing SpO2 from 90% to 94% was longest in the patients with bronchiolitis.

[Stanford Type A Acute Aortic Dissection Complicated by Takotsubo Cardiomyopathy:Report of a Case].

No case report about takotsubo cardiomyopathy with Stanford type A acute dissection is present in the literature. Here we report a case of takotsubo cardiomyopathy that was diagnosed following Stanford type A acute aortic dissection. A 65-year-old man was admitted with dyspnea. He had experienced acute chest pain 10 days prior. Computed tomography (CT) confirmed Stanford type A aortic dissection and primary entry tear in the proximal aortic arch with a thrombosed false lumen in the ascending aorta. Echocardiography revealed takotsubo-like wall motion, with an ejection fraction (EF) of 20%. Electrocardiography (ECG) showed ST-segment elevation in V2-V3. Subsequently, coronary artery disease was excluded by coronary CT. After 1 month, ECG findings and EF appeared normal. Thirty-five days after admission, aortic arch replacement was performed with the frozen elephant trunk technique. The patient's postoperative course was uneventful. Takotsubo cardiomyopathy should be considered as a possible complication of acute aortic dissection with ST-segment elevation.

Reaction Mechanism of Li2MnO3 Electrodes in an All-Solid-State Thin-Film Battery Analyzed by Operando Hard X-ray Photoelectron Spectroscopy.

Li2MnO3 is a promising cathode candidate for Li-ion batteries because of its high discharge capacity; however, its reaction mechanism during cycling has not been sufficiently explicated. Observations of Mn and O binding energy shifts in operando hard X-ray photoelectron spectroscopy measurements enabled us to determine the charge-compensation mechanism of Li2MnO3. The O 1s peak splits at an early stage during the first charge, and the concentration of lower-valence O changes reversibly with cycling, indicating the formation of a low-valence O species that intrinsically participates in the redox reaction. The O 1s peak-splitting behavior, which indicates the number of valences of O in Li2MnO3, is supported by the computational results for an O3 to O1 structural transition. This is in agreement with the results of our previous study, wherein we confirmed this O3 to O1 transition based on in situ surface X-ray diffraction analysis, X-ray photoelectron spectroscopy, and first-principles formation energy calculations.

De novo design of a nanopore for single-molecule detection that incorporates a ß-hairpin peptide.

The amino-acid sequence of a protein encodes information on its three-dimensional structure and specific functionality. De novo design has emerged as a method to manipulate the primary structure for the development of artificial proteins and peptides with desired functionality. This paper describes the de novo design of a pore-forming peptide, named SV28, that has a ß-hairpin structure and assembles to form a stable nanopore in a bilayer lipid membrane. This large synthetic nanopore is an entirely artificial device for practical applications. The peptide forms multidispersely sized nanopore structures ranging from 1.7 to 6.3 nm in diameter and can detect DNAs. To form a monodispersely sized nanopore, we redesigned the SV28 by introducing a glycine-kink mutation. The resulting redesigned peptide forms a monodisperse pore with a diameter of 1.7 nm leading to detection of a single polypeptide chain. Such de novo design of a ß-hairpin peptide has the potential to create artificial nanopores, which can be size adjusted to a target molecule.

Operando analysis of electronic band structure in an all-solid-state thin-film battery.

Material characterization that informs research and development of batteries is generally based on well-established ex situ and in situ experimental methods that do not consider the band structure. This is because experimental extraction of structural information for liquid-electrolyte batteries is extremely challenging. However, this hole in the available experimental data negatively affects the development of new battery systems. Herein, we determined the entire band structure of a model thin-film solid-state battery with respect to an absolute potential using operando hard X-ray photoelectron spectroscopy by treating the battery as a semiconductor device. We confirmed drastic changes in the band structure during charging, such as interfacial band bending, and determined the electrolyte potential window and overpotential location at high voltage. This enabled us to identify possible interfacial side reactions, for example, the formation of the decomposition layer and the space charge layer. Notably, this information can only be obtained by evaluating the battery band structure during operation. The obtained insights deepen our understanding of battery reactions and provide a novel protocol for battery design.

Hydrophilic Shell Matrix Proteins of Nautilus pompilius and the Identification of a Core Set of Conchiferan Domains.

Despite being a member of the shelled mollusks (Conchiferans), most members of extant cephalopods have lost their external biomineralized shells, except for the basally diverging Nautilids. Here, we report the result of our study to identify major Shell Matrix Proteins and their domains in the Nautilid Nautilus pompilius, in order to gain a general insight into the evolution of Conchiferan Shell Matrix Proteins. In order to do so, we performed a multiomics study on the shell of N. pompilius, by conducting transcriptomics of its mantle tissue and proteomics of its shell matrix. Analyses of obtained data identified 61 distinct shell-specific sequences. Of the successfully annotated 27 sequences, protein domains were predicted in 19. Comparative analysis of Nautilus sequences with four Conchiferans for which Shell Matrix Protein data were available (the pacific oyster, the pearl oyster, the limpet and the Euhadra snail) revealed that three proteins and six protein domains were conserved in all Conchiferans. Interestingly, when the terrestrial Euhadra snail was excluded, another five proteins and six protein domains were found to be shared among the four marine Conchiferans. Phylogenetic analyses indicated that most of these proteins and domains were probably present in the ancestral Conchiferan, but employed in shell formation later and independently in most clades. Even though further studies utilizing deeper sequencing techniques to obtain genome and full-length sequences, and functional analyses, must be carried out in the future, our results here provide important pieces of information for the elucidation of the evolution of Conchiferan shells at the molecular level.

Characteristics of Early-Onset Dementia in Chiba Prefecture, Japan: A Multicenter Survey.

INTRODUCTION: Early-onset dementia (EOD), defined as dementia onset before the age of 65 years, is relatively rare, but its social impacts are significant. This study aimed to characterize the diagnosis and clinical and social status of EOD subjects in the 11 dementia centers in Chiba Prefecture, Japan. METHODS: A retrospective 1-year survey was conducted. Collected data included clinical diagnosis, age at onset, age at survey, neuropsychological test, family history, employment, and living status. RESULTS: We identified 208 EOD subjects, including 123 (59.4%), 24 (11.6%), 21 (10.1%), 17 (8.2%), and 10 (4.8%) with Alzheimer's disease (AD), vascular dementia, frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies/Parkinson's disease dementia, and alcohol-related dementia, respectively. The Mini-Mental State Examination (MMSE) score <24 was observed in 50-75% of patients and was not correlated with disease duration. Twenty-four (16.4%) subjects had positive family history of EOD. EOD subjects were at risk of early retirement, and 133 subjects lived with their family, in whom 64 (30.8%) lived with their child. CONCLUSION: In dementia centers, AD, FTLD, and Lewy body dementia had relatively large proportion. Employment, economy, and social supports are urgently needed for EOD subjects and their family.

Cognitive Impairment in Multiple System Atrophy Is Related to White Matter Damage Detected by the T1-Weighted/T2-Weighted Ratio.

INTRODUCTION: This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. METHODS: The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. RESULTS: MSA patients showed a higher white matter sT1w/T2w ratio value than controls (p < 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (r = 0.377, p = 0.021) and the Addenbrooke's cognitive examination III score (r = -0.438, p = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (p = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. CONCLUSION: The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients.

Neuropsychiatric Symptoms in Parkinson's Disease After Subthalamic Nucleus Deep Brain Stimulation.

Background: Indications for subthalamic nucleus deep brain stimulation (STN-DBS) surgery are determined basically by preoperative motor function; however, postoperative quality of life (QOL) is not necessarily associated with improvements in motor symptoms, suggesting that neuropsychiatric symptoms might be related to QOL after surgery in patients with Parkinson's disease. Objectives: We aimed to examine temporal changes in neuropsychiatric symptoms and their associations with QOL after STN-DBS. Materials and Methods: We prospectively enrolled a total of 61 patients with Parkinson's disease (mean age = 65.3 ± 0.9 years, mean disease duration = 11.9 ± 0.4 years). Motor function, cognitive function, and neuropsychiatric symptoms were evaluated before and after DBS surgery. Postoperative evaluation was performed at 3 months, 1 year, and 3 years after surgery. Results: Of the 61 participants, 54 completed postoperative clinical evaluation after 3 months, 47 after 1 year, and 23 after 3 years. Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. Non-motor symptoms such as impulsivity and the Unified PD Rating Scale (UPDRS) part I score were associated with QOL after STN-DBS. Conclusions: Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. The UPDRS part I score and higher impulsivity might be associated with QOL after STN-DBS.

Effects of Nintendo Ring Fit Adventure Exergame on Pain and Psychological Factors in Patients with Chronic Low Back Pain.

Objective: In recent years, there has been an increase in research on the therapeutic effects of exergaming, but there have been few studies on these types of interventions for chronic low back pain. In this study, we hypothesized that the Nintendo Ring Fit Adventure (RFA) exergame would be effective for patients with chronic low back pain, and we conducted a randomized prospective longitudinal study. Materials and Methods: Patients with chronic low back pain were included in this study. Twenty randomly selected patients (9 males and 11 females, mean age 49.3 years) were included in the RFA group, and RFA exergaming was performed once a week for 40 minutes for 8 weeks. Twenty patients (12 males and 8 females, mean age 55.60 years) served as the control group and received oral treatment for 8 weeks. Pain and psychological scores (pain self-efficacy, pain catastrophizing, and kinesiophobia) were measured and analyzed before and after 8 weeks of treatment in both groups. Results: In the RFA group, low back pain, buttock pain, and pain self-efficacy were significantly improved after 8 weeks of RFA exergaming, but there was no significant improvement in lower limb numbness, pain catastrophizing, or kinesiophobia. In the control group, no significant improvement was observed after 8 weeks of oral treatment. Conclusion: RFA exergaming increased pain self-efficacy and reduced pain in patients with chronic low back pain. Future treatment protocols should be developed to improve pain self-efficacy. Approval code: 2894, School of Medicine, Chiba University.

Background factors for chronic low back pain resistant to cognitive behavioral therapy.

This study examined the factors that inhibit the therapeutic effects of cognitive behavioral therapy (CBT) and clarify the adaptation judgment criteria of CBT. We included patients with chronic low back pain and allocated them to the adaptation (with visual analog scale [VAS] improvement) or non-adaptation group (without VAS improvement). The patients were analyzed using various psychological tests. CBT improved depressive symptoms and catastrophic thinking; however, they were not correlated with the VAS and did not directly affect low back pain improvement. The non-adaptation group showed an unexplainable/vague sense of anxiety; an excessive focus on searching for pain; a strong intimacy desire; a strong tendency of medical dependency; and fantasy or distortion of the actual experience, especially self-image. Moreover, the patients showed a low ability to objectively express or attribute meaning to pain due to poor language skills, attention-deficit hyperactivity disorder, and emotional value judgment. Individuals with the aforementioned characteristics of pre-CBT psychological tests should select a different treatment approach given the high poor-adaption possibility. Even patients with depressive or anxious symptoms are not necessarily adaptable for CBT. Therefore, pre-CBT tests for treatment suitability are necessary. Future studies should establish a protocol for psychotherapy suitable for the non-adaptation group.

Reactions of the Li2MnO3 Cathode in an All-Solid-State Thin-Film Battery during Cycling.

We evaluated the structural change of the cathode material Li2MnO3 that was deposited as an epitaxial film with an (001) orientation in an all-solid-state battery. We developed an in situ surface X-ray diffraction (XRD) technique, where X-rays are incident at a very low grazing angle of 0.1°. An X-ray with wavelength of 0.82518 Å penetrated an ∼2 µm-thick amorphous Li3PO4 solid-state electrolyte and ∼1 µm-thick metal Li anode on the Li2MnO3 cathode. Experiments revealed a structural change to a high-capacity (activated) phase that proceeded gradually and continuously with cycling. The activated phase barely showed any capacity fading. First-principles calculations suggested that the activated phase has O1 stacking, which is attained by first delithiating to an intermediate phase with O3 stacking and tetrahedral Li. This intermediate phase has a low Li migration barrier path in the [001] direction, but further delithiation causes an energetically favorable and irreversible transition to the O1 phase. We propose a mechanism of structural change with cycling: charging to a high voltage at a sufficiently low Li concentration typically induces irreversible transition to a phase detrimental to cycling that could, but not necessarily, be accompanied by the dissolution of Mn and/or the release of O into the electrolyte, while a gradual irreversible transition to an activated phase happens at a similar Li concentration under a lower voltage.