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In Alzheimer’s disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer’s patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

The treatment landscape of acute myeloid leukemia (AML) is evolving, with promising therapies entering clinical translation, yet patient responses remain heterogeneous, and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy makeup from bulk transcriptomes of more than 1,000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor and mature cell types. Leukemia hierarchy composition was associated with functional, genomic and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP and Intermediate. Critically, variation in hierarchy composition along the Primitive versus GMP or Primitive versus Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A seven-gene biomarker derived from the Primitive versus Mature axis was associated with response to 105 investigational drugs. Cellular hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML. A novel gene expression classifier of AML heterogeneity captures patient-specific variation in leukemia cell composition and predicts clinical responses to treatment.

Continuous supply of immune cells throughout life relies on the delicate balance in the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production and unexpected stress conditions. Here we identified distinct subsets of human long-term (LT)-HSCs that responded differently to regeneration-mediated stress: an immune checkpoint ligand CD112 lo subset that exhibited a transient engraftment restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112 hi subset that responded rapidly. This functional heterogeneity and CD112 expression are regulated by INKA1 through direct interaction with PAK4 and SIRT1, inducing epigenetic changes and defining an alternative state of LT-HSC quiescence that serves to preserve self-renewal and regenerative capacity upon regeneration-mediated stress. Collectively, our data uncovered the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that balances blood cell demands with preserving a stem cell reservoir. Dick and colleagues identify human LT-HSC subsets with distinct quiescent states. They link these differences to INKA1-mediated downregulation of the transmembrane protein CD112 and its interaction with the protein deacetylase SIRT1. INKA1 is inversely correlated with the histone H4K16Ac mark, which then distinguishes ‘latent’ CD112 lo LT-HSCs from CD112 hi LT-HSCs that are more readily activated in response to hematopoietic stress.

The energy loss functions (ELFs) of Fe and Ni have been derived from measured reflection electron energy loss spectroscopy (REELS) spectra by a reverse Monte Carlo analysis in our previous work. In this work, we present further improvements of ELFs for these metals. For Fe, we have updated ELFs at primary electron energies of 2 keV and 3 keV in a wider photon energy region (0–180 eV) with a better accuracy, which is verified by sum rules. Regarding to Ni, we supplement the ELF at primary energy of 5 keV and we also improve the data accuracy at 3 keV. Applying these new and more accurate ELFs we present the optical constants and dielectric functions for the two metals. The improvements were highlighted by comparing our present results with the previous data.

We present multi-model global datasets of nitrogen and sulfate deposition covering time periods from 1850 to 2100, calculated within the Atmospheric Chemistry and Climate Model Intercomparison Project (ACCMIP). The computed deposition fluxes are compared to surface wet deposition and ice core measurements. We use a new dataset of wet deposition for 2000–2002 based on critical assessment of the quality of existing regional network data. We show that for present day (year 2000 ACCMIP time slice), the ACCMIP results perform similarly to previously published multi-model assessments. For this time slice, we find a multi-model mean deposition of approximately 50 Tg(N) yr−1 from nitrogen oxide emissions, 60 Tg(N) yr−1 from ammonia emissions, and 83 Tg(S) yr−1 from sulfur emissions. The analysis of changes between 1980 and 2000 indicates significant differences between model and measurements over the United States but less so over Europe. This difference points towards a potential misrepresentation of 1980 NH3 emissions over North America. Based on ice core records, the 1850 deposition fluxes agree well with Greenland ice cores, but the change between 1850 and 2000 seems to be overestimated in the Northern Hemisphere for both nitrogen and sulfur species. Using the Representative Concentration Pathways (RCPs) to define the projected climate and atmospheric chemistry related emissions and concentrations, we find large regional nitrogen deposition increases in 2100 in Latin America, Africa and parts of Asia under some of the scenarios considered. Increases in South Asia are especially large, and are seen in all scenarios, with 2100 values more than double their 2000 counterpart in some scenarios and reaching > 1300 mg(N) m−2 yr−1 averaged over regional to continental-scale regions in RCP 2.6 and 8.5, ~ 30–50% larger than the values in any region currently (circa 2000). However, sulfur deposition rates in 2100 are in all regions lower than in 2000 in all the RCPs. The new ACCMIP multi-model deposition dataset provides state-of-the-science, consistent and evaluated time slice (spanning 1850–2100) global gridded deposition fields for use in a wide range of climate and ecological studies.

We present a combined experimental and theoretical work to obtain the energy loss function (ELF) or the excitation spectrum of samarium in the energy loss range between 3 and 200 eV. At low loss energies, the plasmon excitation is clearly identified and the surface and bulk contributions are distinguished. For the precise analysis the frequency-dependent energy loss function and the related optical constants ( n and k ) of samarium were extracted from the measured reflection electron energy loss spectroscopy (REELS) spectra by the reverse Monte Carlo method. The ps - and f -sum rules with final ELF fulfils the nominal values with 0.2% and 2.5% accuracy, respectively. It was found that a bulk mode locates at 14.2 eV with the peak width ~6 eV and the corresponding broaden surface plasmon mode locates at energies of 5-11 eV.

Present day tropospheric ozone and its changes between 1850 and 2100 are considered, analysing 15 global models that participated in the Atmospheric Chemistry and Climate Model Intercomparison Project (ACCMIP). The ensemble mean compares well against present day observations. The seasonal cycle correlates well, except for some locations in the tropical upper troposphere. Most (75 %) of the models are encompassed with a range of global mean tropospheric ozone column estimates from satellite data, but there is a suggestion of a high bias in the Northern Hemisphere and a low bias in the Southern Hemisphere, which could indicate deficiencies with the ozone precursor emissions. Compared to the present day ensemble mean tropospheric ozone burden of 337 ± 23 Tg, the ensemble mean burden for 1850 time slice is ~30% lower. Future changes were modelled using emissions and climate projections from four Representative Concentration Pathways (RCPs). Compared to 2000, the relative changes in the ensemble mean tropospheric ozone burden in 2030 (2100) for the different RCPs are: −4% (−16%) for RCP2.6, 2% (−7%) for RCP4.5, 1% (−9%) for RCP6.0, and 7% (18%) for RCP8.5. Model agreement on the magnitude of the change is greatest for larger changes. Reductions in most precursor emissions are common across the RCPs and drive ozone decreases in all but RCP8.5, where doubled methane and a 40–150% greater stratospheric influx (estimated from a subset of models) increase ozone. While models with a high ozone burden for the present day also have high ozone burdens for the other time slices, no model consistently predicts large or small ozone changes; i.e. the magnitudes of the burdens and burden changes do not appear to be related simply, and the models are sensitive to emissions and climate changes in different ways. Spatial patterns of ozone changes are well correlated across most models, but are notably different for models without time evolving stratospheric ozone concentrations. A unified approach to ozone budget specifications and a rigorous investigation of the factors that drive tropospheric ozone is recommended to help future studies attribute ozone changes and inter-model differences more clearly.

Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. Epigenetic deregulation contributes to AML pathogenesis. KDM6 proteins are histone-3-lysine-27-demethylases that play context-dependent roles in AML. We inform that KDM6-demethylase function critically regulates DNA-damage-repair-(DDR) gene expression in AML. Mechanistically, KDM6 expression is regulated by genotoxic stress, with deficiency of KDM6A-(UTX) and KDM6B-(JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations are implicated in chemoresistance, although a significant percentage of relapsed-AML has upregulated KDM6A. Olaparib treatment reduced engraftment of KDM6A-mutant-AML-patient-derived xenografts, highlighting synthetic lethality using Poly-(ADP-ribose)-polymerase-(PARP)-inhibition. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, BCL2A1 associates with venetoclax resistance, and KDM6A loss was accompanied with a downregulated BCL2A1. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support of a novel combination therapy for AML based on subtype-heterogeneity, and establishes KDM6A as a molecular regulator for determining therapeutic efficacy.

Purpose: To investigate the differential clinical significance of fractional concentration of exhaled nitric oxide measured at a flow rate of 200 mL/s (FENO200) and concentration of nitric oxide in alveolar (CANO) in asthma, chronic obstructive pulmonary disease (COPD) or asthma-COPD Overlap (ACO).Methods: A total of 178 patients were included, with 82 patients in asthma group, 47 patients in COPD group and 49 patients in ACO group. Data for demographic data, spirometry and exhaled nitric oxide were collected for comparative analysis, correlation analysis and discriminant canonical analysis.Results: The values of FENO200 in asthma, COPD and ACO groups were 11.0(7.0– 22.3), 8.0(6.0– 11.0) and 9.0(6.5– 19.5) ppb, respectively. In the asthma group, FENO200 exhibited negative correlations with FEV1/FVC, MMEF and MEF50. No significant correlation was observed between CANO and pulmonary function parameters. In the COPD group, both FENO200 and CANO showed negative correlation with pulmonary function parameters including FVC, FEV1, PEF, MMEF, MEF75, MEF50. In the ACO group, FENO200 demonstrated no significant correlation with pulmonary function parameters, while CANO was correlated with FEV1, PEF, MMEF and MEF50. In COPD group, ΔFEV1 in the bronchodilator test was correlated with FENO200. As for the ACO group, ΔFEV1 was correlated with CANO. In the discriminant canonical analysis, four parameters including gender, age, MEF75 and FENO50 discriminated between the three groups of asthma, COPD and ACO.Conclusion: In asthma, COPD and ACO, FENO200 has demonstrated a robust correlation with CANO. Elevated FENO200 levels are predominantly indicative of pulmonary function impairment in asthma and COPD, whereas elevated CANO levels are mainly correlated with pulmonary function impairment in COPD and ACO. Compared with FENO200 and CANO, FENO50 may have a better discriminatory ability in distinguishing asthma, COPD and ACO.

In recent years there has been increased interest in Bi-containing solders to improve the reliability of electronics and drive down processing temperatures. When the Bi content is more than ~ 2 wt% in Sn–Ag–Cu–Bi and Sn–Cu–Ni–Bi solders, (Bi) phase forms by a non-equilibrium eutectic reaction and also precipitates in the solid state. Here, we study the development of bismuth plates during room temperature storage in a range of Bi-containing solders. It is shown that Bi plates precipitate with one of two (Bi)–βSn orientation relationships (ORs). During coarsening the OR with the better lattice match grows at the expense of the other, leading to a single OR. The plate coarsening kinetics scale with the cube root of holding time and are relatively rapid, with plates exceeding 1 µm in length within 1 day at room temperature. Prolonged room temperature storage of more than 1 year resulted in Bi accumulation in 5–20 µm (Bi) particles at βSn grain boundaries.