Manganese based layered oxides with modulated electronic and thermodynamic properties for sodium ion batteries

Manganese based layered oxides have received increasing attention as cathode materials for sodium ion batteries due to their high theoretical capacities and good sodium ion conductivities. However, the Jahn–Teller distortion arising from the manganese (III) centers destabilizes the host structure and deteriorates the cycling life. Herein, we report that zinc-doped Na0.833[Li0.25Mn0.75]O2 can not only suppress the Jahn–Teller effect but also reduce the inherent phase separations. The reduction of manganese (III) amount in the zinc-doped sample, as predicted by first-principles calculations, has been confirmed by its high binding energies and the reduced octahedral structural variations. In the viewpoint of thermodynamics, the zinc-doped sample has lower formation energy, more stable ground states, and fewer spinodal decomposition regions than those of the undoped sample, all of which make it charge or discharge without any phase transition. Hence, the zinc-doped sample shows superior cycling performance, demonstrating that zinc doping is an effective strategy for developing high-performance layered cathode materials

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice11Nsciescopu

Efficacy of Tandem High-Dose Chemotherapy and Autologous Stem Cell Rescue in Patients Over 1 Year of Age with Stage 4 Neuroblastoma: The Korean Society of Pediatric Hematology-Oncology Experience Over 6 Years (2000-2005)

The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival±95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2±12.4% vs. 31.3±11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients

The effect of sex and physical frailty on incident disability after 2 years among community-dwelling older adults: KFACS study

Background : This study investigated the impact of physical frailty on the development of disabilities in mobility, activities of daily living (ADL), and instrumental activities of daily living (IADL) according to sex among community-dwelling Korean older adults. Methods : We used data of 2,905 older adults aged 70-84 years from the Korean Frailty and Aging Cohort Study (KFACS) at baseline (2016-2017) and Wave 2 (2018-2019). Fried’s physical frailty phenotype was used to identify frailty. Results : After adjustment, frailty showed a higher impact for women than men on developing mobility disability (odds ratio [OR]=14.00, 95% confidence interval [CI]=4.8–40.78 vs. OR=9.89, 95% CI=4.28–22.86) and IADL disability after two years (OR=7.22, 95% CI=2.67–19.56 vs. OR=3.19, 95% CI=1.17–8.70). Pre-frailty led to mobility disability for women and men (OR=2.77, 95% CI=1.93–3.98 vs. OR=2.49, 95% CI=1.66–3.72, respectively), and IADL disability only for women (OR=3.01, 95% CI=1.28–7.09). Among the IADL components, both men and women who were prefrail or frail showed increased disability in ‘using transportation’. Among men, pre-frailty was significantly associated with disability in “going out” and “shopping”. In women, frailty was significantly associated with disability in “doing laundry,” “performing household chores,” “shopping,” and “managing money”. Conclusions : Physical frailty increased disability over 2 years for women more than men. Physical frailty increased disability in outdoor activity-related IADL components in men and household work-related IADL components in women. This study highlights the need for gender-specific policies and preventative programs for frailty, particularly restorative interventions that focus on women who are physically frail.This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), which is funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C3153), and the Research Program funded by the National Institute of Health, Korea Disease Control and Prevention Agency (2021-ER060500). The funding bodies had no role in the study design the collection, analysis and interpretation of the data; the writing of the report; or the decision to submit this article for publication

Mitochondria-Specific Accumulation of Amyloid β Induces Mitochondrial Dysfunction Leading to Apoptotic Cell Death

Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ1–42 treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ1–42-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ1–42 in HT22 cells using Aβ1–42 with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ1–42-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ1–42 accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ1–42-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ1–42 accumulation, which mimics the apoptosis process in exogenous Aβ1–42-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ1–42 accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

A Study on the Pattern Changes and Determinants of Corporate Cash Holding

This study examines what changes and impacts have brought to the corporate cash holding after the financial crisis. The main findings can be summarized by two parts. First, the recent high increase in cash holding is only found in few companies, meaning that the level of the overall ratio has not risen. Second, Korean companies tend to have a higher ratio of cash holding when they have more uncertainty about their business performances. The higher the uncertainty in overall business performances also has some effects on the cash holding patterns of the Korean companies