A sodium-ion sulfide solid electrolyte with unprecedented conductivity at room temperature.

Solid electrolytes are key materials to enable solid-state rechargeable batteries, a promising technology that could address the safety and energy density issues. Here, we report a sulfide sodium-ion conductor, Na2.88Sb0.88W0.12S4, with conductivity superior to that of the benchmark electrolyte, Li10GeP2S12. Partial substitution of antimony in Na3SbS4 with tungsten introduces sodium vacancies and tetragonal to cubic phase transition, giving rise to the highest room-temperature conductivity of 32 mS cm-1 for a sintered body, Na2.88Sb0.88W0.12S4. Moreover, this sulfide possesses additional advantages including stability against humid atmosphere and densification at much lower sintering temperatures than those (>1000 °C) of typical oxide sodium-ion conductors. The discovery of the fast sodium-ion conductors boosts the ongoing research for solid-state rechargeable battery technology with high safety, cost-effectiveness, large energy and power densities.

Correction: Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication.

Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models. The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation of an erythroid leukemia lineage into granulomonocytic-like lineage cells. In addition, pevonedistat-induced rereplication stress during the S phase was greatly augmented by concomitant treatment with T-3775440, as reflected by the increased induction of apoptosis. We further demonstrated that the combination treatment was markedly effective in subcutaneous tumor xenograft models as well as in a disseminated model of AML, leading to tumor eradication or prolonged survival in T-3775440/pevonedistat cotreated mice. Our findings indicate the therapeutic potential of the combination of LSD1 inhibitors and pevonedistat for the treatment of AML.

A molecular dynamics study of nuclear quantum effect on diffusivity of hydrogen molecule.

In this paper, the nuclear quantum effect of the hydrogen molecule on its diffusivity was analyzed using the molecular dynamics (MD) method. The centroid MD (CMD) method was applied to reproduce the time evolution of the molecules. The diffusion coefficient of hydrogen was calculated using the Green-Kubo method over a wide temperature region, and the temperature dependence of the quantum effect of the hydrogen molecule on its diffusivity was addressed. The calculated results were compared with classical MD results based on the principle of corresponding state (PCS). It was confirmed that the difference in the diffusion coefficient calculated in the CMD and classical MD methods was small, and the PCS appears to be satisfied on the temperature dependence of the diffusion coefficient, even though the quantum effect of the hydrogen molecules was taken into account. It was clarified that this result did not suggest that the quantum effect on the diffusivity of the hydrogen molecule was small but that the two changes in the intermolecular interaction of hydrogen due to the quantum effect offset each other. Moreover, it was found that this tendency was related to the temperature dependence of the ratio of the kinetic energy of the quantum fluctuational motion to the classical kinetic energy.

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling.

Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.

Predictive Factors Associated with Oral Intake Ability in Gastrostomy Patients Under Long-Term Care.

OBJECTIVE: To determine the physical indicators associated with oral intake status and swallowing function in gastrostomy patients under long-term care. DESIGN: Cross-sectional study. SETTING: Thirty-one hospitals that perform gastrostomy insertion, replacement and management. PARTICIPANTS: A total of 117 respondents from 31 hospitals in Japan underwent gastrostomy tube replacement and management between September 2012 and January 2014. Each participant underwent a gastrostomy at least 6 months prior to the study, and received long-term care either at home, a care facility, or a hospital. MEASUREMENTS: We conducted a questionnaire survey at Japanese hospitals and used the data obtained from 117 respondents for analysis. The survey was conducted using a questionnaire form that collected information about the following items: oral intake status, sex, age, disease history, number of days elapsed since gastrostomy, residence status, modified Rankin Scale score, consciousness, oral hygiene status, articulation and phonation, voluntary saliva swallow, Modified Water Swallow Test, and Food Test. RESULTS: Results revealed significant differences in modified Rankin Scale scores, sputum production, articulation and phonation, and voluntary saliva swallowing between patients who were orally fed and those who were not. Moreover, sputum production and voluntary saliva swallowing were strongly associated with oral intake status. Finally, sputum production, articulation and phonation, and voluntary saliva swallowing were strongly associated with swallowing function test results. CONCLUSION: Results from this study suggested that sputum production, articulation and phonation, and voluntary saliva swallowing could be used as indicators for estimating oral intake status and swallowing function in gastrostomy patients under long-term care.

Inter-rater and intra-rater reliability outcomes of a rapid bacteria counting system with pressure ulcer samples.

OBJECTIVE: Evaluating bacterial load in pressure ulcers (PUs) is key to combat infection; therefore, using technologies to measure bacterial count can be particularly useful. A rapid bacteria counting system was recently developed and introduced to the wound care field. However, its reliability was not established. This cross-sectional study aimed to evaluate the inter-rater and intra-rater reliability of bacterial count using this rapid counting system. METHOD: We took bacterial swabs from patients with category I or greater PUs to assess inter- and intra-rater reliability. An assessor swabbed the longest axis of the PU once and bacterial counts were measured using a rapid bacteria counting system. To confirm the inter-rater and intra-rater reliability, intraclass correlation coefficients (ICCs) were calculated. RESULTS: We took 63 and 57 pairs of bacterial counts from 13 patients with 16 category I or greater PUs to assess inter- and intra-rater reliability, respectively. Overall ICCs [95% confidence intervals (CI)] for the bacterial counts were 0.83 [0.73-0.90, p<0.001, inter-rater reliability, n=63], and 0.89 [0.82-0.94, p< 0.001, intra-rater reliability, n=57]. CONCLUSION: A high level of reliability for counting bacterial numbers in PU sites was confirmed. The results should encourage clinicians and researchers to use this type of device for the real-time assessment of wound bacterial bioburden at the patient's bedside.

Publisher's Note: Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen [Phys. Rev. Lett. 117, 082503 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.082503.

Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen.

We present an improved search for neutrinoless double-beta (0νßß) decay of ^{136}Xe in the KamLAND-Zen experiment. Owing to purification of the xenon-loaded liquid scintillator, we achieved a significant reduction of the ^{110m}Ag contaminant identified in previous searches. Combining the results from the first and second phase, we obtain a lower limit for the 0νßß decay half-life of T_{1/2}^{0ν}>1.07×10^{26} yr at 90% C.L., an almost sixfold improvement over previous limits. Using commonly adopted nuclear matrix element calculations, the corresponding upper limits on the effective Majorana neutrino mass are in the range 61-165 meV. For the most optimistic nuclear matrix elements, this limit reaches the bottom of the quasidegenerate neutrino mass region.

Mammary transcriptome analysis of lactating dairy cows following administration of bovine growth hormone.

The galactopoietic effect of growth hormone (GH) in lactating ruminants is well established; however the mechanisms that mediate these effects are not well understood. The first objective of this study was to determine the effect of GH on the synthesis of the major casein and whey proteins. The second objective was to identify the genes and pathways that may be involved in mediating the effect of GH on milk synthesis. A single subcutaneous injection of a commercially available slow release formulation of GH (Lactatropin®), or physiological saline solution (control) was administered to non-pregnant dairy cows (n=4/group) in mid-late lactation. Milk samples were collected for composition analysis and mammary lobulo-alveolar tissue was collected postmortem 6 days post injection. Gene expression profiles were evaluated using either a 22 000 bovine complementary DNA microarray or quantitative PCR (qPCR), and microarrays were validated by qPCR. The yield of all the major casein and whey proteins was increased 32% to 41% in GH-treated cows, with the exception of α-lactalbumin yield which was elevated by 70% relative to controls. Treatment with GH treatment tended to increase the concentration of α-lactalbumin but had no effect on the concentration of any of the major milk proteins. Messenger RNA (mRNA) abundance of the major whey and casein genes, with the exception of α-s2-casein, was increased in response to GH compared with controls, which is consistent with the positive effect of GH on milk production. Treatment with GH treatment influenced the mRNA abundance of genes involved in cell growth and proliferation, transcriptional and translational regulation, actin cytoskeleton signalling, lipid metabolism and cell death. This study has provided new insights into the cell signalling that may be involved in mediating the effect of GH on milk production in the mammary gland of lactating dairy cows.

Use of smartphone attached mobile thermography assessing subclinical inflammation: a pilot study.

OBJECTIVE: To verify the reliability and validity of FLIR ONE, a device connected to a smartphone, for the assessment of inflammation based on relative temperature increase compared with the thermography routinely used in pressure ulcer (PU) and diabetic foot assessment. METHOD: Participants in this pilot cross-sectional observational study were recruited from the patients in the PU team rounds and the diabetic foot outpatient clinic at the university hospital in January 2015. Cohen's kappa coefficient with its 95% confidence intervals was used to evaluate the criterion-related validity and inter- and intra-rater reliability for the thermal imaging assessment. For assessing criterion-related validity, a hand-held high-end infrared thermography device was used to provide reference data. Comparison of thermal images between the smartphone-connected device and the hand-held device was performed with both a 'predetermined range' and an 'automatically-set range.' For assessing inter-rater reliability, two assessors evaluated the thermal images taken by the mobile thermography. For assessing intra-rater reliability, one assessor evaluated the thermal images twice. The thermal images were shown to the assessors at random. RESULTS: Among 16 thermal images obtained from eight patients, kappa coefficients for each value were as follows: for the predetermined range and automatically-set range, respectively, the criterion-related validity was 1.00 (95% confidence interval 1.00-1.00) and 1.00 (95% confidence interval 1.00-1.00); the inter-rater reliability was 1.00 (95% confidence interval 1.00-1.00) and 1.00 (95% confidence interval 1.00-1.00); and the intra-rater reliability was 1.00 (95% confidence interval 1.00-1.00) and 1.00 (95% confidence interval 1.00-1.00). CONCLUSION: This pilot study suggests that FLIR ONE can work as an alternative device for assessing subclinical inflammation in PUs and the diabetic foot in clinical settings. Our results may facilitate clinicians in accepting the routine use of thermal imaging assessment at the patients' bedside.

Calcium-dependent intracellular signal pathways in primary cultured adipocytes and ANK3 gene variation in patients with bipolar disorder and healthy controls.

Bipolar disorder (BD) is a chronic psychiatric disorder of public health importance affecting >1% of the Swedish population. Despite progress, patients still suffer from chronic mood switches with potential severe consequences. Thus, early detection, diagnosis and initiation of correct treatment are critical. Cultured adipocytes from 35 patients with BD and 38 healthy controls were analysed using signal pathway reporter assays, that is, protein kinase C (PKC), protein kinase A (PKA), mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)), Myc, Wnt and p53. The levels of activated target transcriptional factors were measured in adipocytes before and after stimulation with lithium and escitalopram. Variations were analysed in the loci of 25 different single-nucleotide polymorphisms (SNPs). Activation of intracellular signals in several pathways analysed were significantly higher in patients than in healthy controls upon drug stimulation, especially with escitalopram stimulation of PKC, JNK and Myc, as well as lithium-stimulated PKC, whereas no meaningful difference was observed before stimulation. Univariate analyses of contingency tables for 80 categorical SNP results versus diagnoses showed a significant link with the ANK3 gene (rs10761482; likelihood ratio χ(2)=4.63; P=0.031). In a multivariate ordinal logistic fit for diagnosis, a backward stepwise procedure selected ANK3 as the remaining significant predictor. Comparison of the escitalopram-stimulated PKC activity and the ANK3 genotype showed them to add their share of the diagnostic variance, with no interaction (15% of variance explained, P<0.002). The study is cross-sectional with no longitudinal follow-up. Cohorts are relatively small with no medication-free patients, and there are no 'ill patient' controls. It takes 3 to 4 weeks of culture to expand adipocytes that may change epigenetic profiles but remove the possibility of medication effects. Abnormalities in the reactivity of intracellular signal pathways to stimulation and the ANK3 genotype may be associated with pathogenesis of BD. Algorithms using biological patterns such as pathway reactivity together with structural genetic SNP data may provide opportunities for earlier detection and effective treatment of BD.

Indocyanine Green Lymphography Findings in Primary Leg Lymphedema.

OBJECTIVES: Indocyanine green (ICG) lymphography has been reported to be useful for the evaluation of secondary lymphedema, but no study has reported characteristic findings of ICG lymphography in primary lymphedema. This study aimed to classify characteristic ICG lymphography patterns in primary lymphedema. METHODS: The study was a retrospective observational study. Thirty one primary lower extremity lymphedema (LEL) patients with a total of 62 legs were studied. ICG lymphography patterns were categorized according to the visibility of lymphatics and dermal backflow (DB) extension. Clinical demographics were compared with categorized ICG lymphography patterns. RESULTS: All symptomatic legs showed abnormal patterns, and all asymptomatic legs showed normal patterns on ICG lymphography. Abnormal lymphographic patterns could be classified into proximal DB (PDB), distal DB (DDB), less enhancement (LE), and no enhancement (NE) patterns. There were significant differences between PDB (16 patients), DDB (6 patients), LE (4 patients), and NE patterns (5 patients) in age (37.3 ± 18.3 vs. 61.8 ± 19.2 vs. 50.8 ± 27.7 vs. 29.2 ± 18.0 years, p = .035), onset of edema (23.9 ± 19.4 vs. 46.8 ± 27.0 vs. 43.0 ± 31.3 vs. 6.6 ± 14.2 years, p = .020), laterality (bilateral; 18.8% vs. 66.7% vs. 75.0% vs. 0%, p » .016), cellulitis history(56.3% vs. 100% vs. 25.0% vs. 0%, p » .007), and LEL index (292.2 ± 32.8 vs. 254.2 ± 28.6 vs. 243.3 ± 9.4 vs. 295.2 ± 44.8, p = .016). CONCLUSIONS: ICG lymphography findings in primary lymphedema could be classified into four patterns withdifferent patient characteristics.

TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.

Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.