APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

Ligand-induced conformational changes in protein molecules detected by sum-frequency generation.

We present the first demonstration of ligand-induced conformational changes in a biological molecule, a protein, by sum-frequency generation (SFG). Constructs of KRasG12D protein were prepared by selectively deuterating residues of a single amino acid type using isotope-labeled amino acids and cell-free protein synthesis. By attaching labeled protein to a supported bilayer membrane via a His-tag to Ni-NTA-bearing lipids, we ensured that single layers of ordered molecules were formed while preserving the protein's native structure. Exceptionally large SFG amide I signals were produced in both labeled and unlabeled proteins, demonstrating a high degree of orientational order upon attachment to the bilayer. Deuterated protein also produced SFG signals in the CDx spectral region, which were not present in the unlabeled protein. The CDx signals were measured before and after binding a peptide inhibitor, KRpep-2d, revealing shifts in SFG intensity due to conformational changes at the labeled sites. In particular, peaks associated with CDx stretching vibrations for alanine, valine, and glycine changed substantially in amplitude upon inhibitor binding. By inspection of the crystal structure, these three residues are uniquely colocated on the protein surface in and near the nucleotide binding site, which is in allosteric communication with the site of peptide inhibitor binding, suggesting an approach to identify a ligand's binding site. The technique offers a highly sensitive, nonperturbative method of mapping ligand-induced conformational changes and allosteric networks in biological molecules for studies of the relationship between structure and function and mechanisms of action in drug discovery.

Coordination and diffusion in glyoxal-based electrolytes for potassium-ion batteries.

Glyoxal-based electrolytes have been identified as promising for potassium-ion batteries (PIBs). Here we investigate the properties of electrolytes containing bis(fluorosulfonyl)imide (KFSI) in 1,1,2,2-tetra-ethoxy-ethane (tetra-ethyl-glyoxal, TEG) using density functional theory (DFT) calculations, Raman spectroscopy, and impedance spectroscopy. The coordination and configuration of the complexes possible to arise from coordination of the K+ ions by FSI and TEG were investigated both from an energetic point of view as well as qualitatively determined via comparing experimental and artificial Raman spectra. Overall, the K+ coordination depends heavily on the electrolyte composition with contributions both from FSI and TEG. Energetically the coordination by both the trans FSI anion conformer and the TEG solvent with four z-chain conformation is preferrable. From the spectroscopy we find that at lower concentrations, the predominant coordination is by TEG, whereas at higher concentrations, K+ is coordinated mostly by FSI. Concerning the diffusion of ions, investigated by impedance spectroscopy, show that the diffusion of the potassium salt is faster as compared to lithium and sodium salts in comparable electrolytes.

Pyrrolidium- and Imidazolium-Based Ionic Liquids and Electrolytes with Flexible Oligoether Anions.

A new class of fluorine-free ionic liquids (ILs) and electrolytes based on aliphatic flexible oligoether anions, 2-(2-methoxyethoxy)acetate (MEA) and 2-[2-(2-methoxyethoxy)ethoxy]acetate (MEEA), coupled with pyrrolidinium and imidazolium cations is introduced. For the ILs with MEEA anions, Li+ conducting electrolytes are created by doping the ILs with 30 mol % of LiMEEA. The structural flexibility of the oligoether functionality in the anion results in glass transition temperatures (Tg) as low as -60 °C for the neat ILs and the electrolytes. The imidazolium-based ILs and electrolytes reveal better thermal stabilities but higher Tg and lower electrochemical stabilities than the corresponding pyrrolidinium-based analogues. All neat ILs show comparable transport properties for the cations and these decrease by the addition of lithium salt - the pyrrolidinium-based electrolyte being affected the most.

Artificial Intelligence Applied to Battery Research: Hype or Reality?

This is a critical review of artificial intelligence/machine learning (AI/ML) methods applied to battery research. It aims at providing a comprehensive, authoritative, and critical, yet easily understandable, review of general interest to the battery community. It addresses the concepts, approaches, tools, outcomes, and challenges of using AI/ML as an accelerator for the design and optimization of the next generation of batteries─a current hot topic. It intends to create both accessibility of these tools to the chemistry and electrochemical energy sciences communities and completeness in terms of the different battery R&D aspects covered.

Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease.

BACKGROUND: The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease. METHODS: We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality. RESULTS: No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively). CONCLUSIONS: In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).

Ionic Liquids and Electrolytes with Flexible Aromatic Anions.

Five new n-tetrabutylphosphonium (P4444 )+ cation-based ionic liquids (ILs) with oligoether substituted aromatic carboxylate anions have been synthesized. The nature and position of the oligoether chain affect thermal stability (up to 330 °C), phase behaviour (Tg <-55 °C) and ion transport. Furthermore, with the aim of application in lithium batteries, electrolytes were created for two of the ILs by 10 mol% doping using the corresponding Li-salts. This affects the ion diffusion negatively, from being higher and equal for cations and anions to lower for all ions and unequal. This is due to the stronger ionic interactions and formation of aggregates, primarily between the Li+ ions and the carboxylate group of the anions. Electrochemically, the electrolytes have electrochemical stability windows up to 3.5 V, giving some promise for battery application.

Structurally flexible pyrrolidinium- and morpholinium-based ionic liquid electrolytes.

Ion transport measures and details as well as physico-chemical and electrochemical properties are presented for a small set of structurally flexible pyrrolidinium (Pyrr) and morpholinium (Morph) cation-based ionic liquids (ILs), all with oligoether phosphate-based anions. All have high thermal stabilities, low glass transition temperatures, and wide electrochemical stability windows, but rather moderate ionic conductivities, where both the anions and the cations of the Pyrr-based ILs diffuse faster than those of the Morph-based ILs. Overall, the Pyrr-based ILs show significantly more promise as high-temperature supercapacitor electrolytes, rendering a specific capacitance of 164 F g-1 at 1 mV s-1, a power density of 609 W kg-1 and a specific energy density of 27 W h kg-1 at 90 °C in a symmetric graphite supercapacitor.

Aromatic heterocyclic anion based ionic liquids and electrolytes.

Five new ionic materials comprising fluorine-free aromatic heterocyclic anions based on pyridine and pyrazine combined with a common n-tetrabutylphosphonium cation, (P4444)+, result in two room temperature ionic liquids (RTILs), one semi-solid, and two organic ionic plastic crystals (OIPCs) with melting points >20 °C. The OIPCs showed a plastic crystalline phase, multiple solid-solid transitions, and plastic crystalline and melt phases. For both the neat RTILs and the Li+ conducting electrolytes, the nature and strength of the ion-ion interactions mainly depend on the position of the nitrogen atom with respect to the carboxylate group in the anions. Furthermore, for the RTILs the ionic conductivity is effected by the electronic structure and flexibility of the ions and the anions diffuse faster than the (P4444)+ cation, but are slowed down in the electrolytes due to the strong electrostatic interactions between the carboxylate group of the anions and the Li+, as shown both experimentally and computationally. Overall, this study describes the effect of structural tuning of aromatic anions on the ion-ion interactions and introduces new ionic materials with promising properties to be used as solid and liquid electrolytes in energy storage devices.

Structural insight into allosteric modulation of protease-activated receptor 2.

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.

Cardiovascular Disease Risk in Rural Adults: A Pilot Intervention Study Using Registered Nurse/Community Health Worker Teams.

BACKGROUND: Cardiovascular disease (CVD) risk reduction programs led by a nurse/community health worker team are effective in urban settings. This strategy has not been adequately tested in rural settings. OBJECTIVE: A pilot study was conducted to examine the feasibility of implementing an evidence-based CVD risk reduction intervention adapted to a rural setting and evaluate the potential impact on CVD risk factors and health behaviors. METHODS: A 2-group, experimental, repeated-measures design was used; participants were randomized to a standard primary care group (n = 30) or an intervention group (n = 30) where a registered nurse/community health worker team delivered self-management strategies in person, by phone, or by videoconferencing. Outcomes were measured at baseline and at 3 and 6 months. A sample of 60 participants was recruited and retained in the study. RESULTS: In-person (46.3%) and telephone (42.3%) meetings were used more than the videoconferencing application (9%). Mean change at 3 months differed significantly between the intervention and control groups for CVD risk (-1.0 [95% confidence interval (CI), -3.1 to 1.1] vs +1.4 [95% CI, -0.4 to 3.3], respectively), total cholesterol (-13.2 [95% CI, -32.1 to 5.7.] vs +21.0 [95% CI, 4.1-38.1], respectively), and low-density lipoprotein (-11.5 [95% CI, -30.8 to 7.7] vs +19.6 [95% CI, 1.9-37.2], respectively). No between-group differences were seen in high-density lipoprotein, blood pressure, or triglycerides. CONCLUSIONS: Participants receiving the nurse/community health worker-delivered intervention improved their risk CVD profiles, total cholesterol, and low-density lipoprotein levels at 3 months. A larger study to explore the intervention impact on CVD risk factor disparities experienced by rural populations is warranted.

Disparities in Access to Radiation Therapy by Race and Ethnicity in the United States With Focus on American Indian/Alaska Native People.

OBJECTIVES: Striking disparities in access to radiation therapy (RT) exist, especially among racial and ethnic-minority patients. We analyzed census block group data to evaluate differences in travel distance to RT as a function of race and ethnicity, socioeconomic status, and rurality. METHODS: The Directory of Radiotherapy Centers provided the addresses of facilities containing linear accelerators for RT. We classified block groups as majority (≥ 50%) American Indian/Alaska Native (AI/AN), black, white, Asian, no single racial majority, or Hispanic regardless of race. We used the Area Deprivation Index to classify deprivation and Rural-Urban Commuting Area codes to classify rurality. Generalized linear mixed models tested associations between these factors and distance to nearest RT facility. RESULTS: Median distance to nearest RT facility was 72 miles in AI/AN-majority block groups, but 4 to 7 miles in block groups with non-AI/AN majorities. Multivariable models estimated that travel distances in AI/AN-majority block groups were 39 to 41 miles longer than in areas with non-AI/AN majorities. Travel distance was 1.3 miles longer in the more deprived areas versus less deprived areas and 16 to 32 miles longer in micropolitan, small town, and rural areas versus metropolitan areas. CONCLUSIONS: Cancer patients in block groups with AI/AN-majority populations, nonmetropolitan location, and low socioeconomic status experience substantial travel disparities in access to RT. Future research with more granular community- and individual-level data should explore the many other known barriers to access to cancer care and their relationship to the barriers posed by distance to RT care.

Achievements, Challenges, and Prospects of Calcium Batteries.

This Review flows from past attempts to develop a (rechargeable) battery technology based on Ca via crucial breakthroughs to arrive at a comprehensive discussion of the current challenges at hand. The realization of a rechargeable Ca battery technology primarily requires identification and development of suitable electrodes and electrolytes, which is why we here cover the progress starting from the fundamental electrode/electrolyte requirements, concepts, materials, and compositions employed and finally a critical analysis of the state-of-the-art, allowing us to conclude with the particular roadblocks still existing. As for crucial breakthroughs, reversible plating and stripping of calcium at the metal-anode interface was achieved only recently and for very specific electrolyte formulations. Therefore, while much of the current research aims at finding suitable cathodes to achieve proof-of-concept for a full Ca battery, the spectrum of electrolytes researched is also expanded. Compatibility of cell components is essential, and to ensure this, proper characterization is needed, which requires design of a multitude of reliable experimental setups and sometimes methodology development beyond that of other next generation battery technologies. Finally, we conclude with recommendations for future strategies to make best use of the current advances in materials science combined with computational design, electrochemistry, and battery engineering, all to propel the Ca battery technology to reality and ultimately reach its full potential for energy storage.

Structural analysis of the LDL receptor-interacting FERM domain in the E3 ubiquitin ligase IDOL reveals an obscured substrate-binding site.

Hepatic abundance of the low-density lipoprotein receptor (LDLR) is a critical determinant of circulating plasma LDL cholesterol levels and hence development of coronary artery disease. The sterol-responsive E3 ubiquitin ligase inducible degrader of the LDLR (IDOL) specifically promotes ubiquitination and subsequent lysosomal degradation of the LDLR and thus controls cellular LDL uptake. IDOL contains an extended N-terminal FERM (4.1 protein, ezrin, radixin, and moesin) domain, responsible for substrate recognition and plasma membrane association, and a second C-terminal RING domain, responsible for the E3 ligase activity and homodimerization. As IDOL is a putative lipid-lowering drug target, we investigated the molecular details of its substrate recognition. We produced and isolated full-length IDOL protein, which displayed high autoubiquitination activity. However, in vitro ubiquitination of its substrate, the intracellular tail of the LDLR, was low. To investigate the structural basis for this, we determined crystal structures of the extended FERM domain of IDOL and multiple conformations of its F3ab subdomain. These reveal the archetypal F1-F2-F3 trilobed FERM domain structure but show that the F3c subdomain orientation obscures the target-binding site. To substantiate this finding, we analyzed the full-length FERM domain and a series of truncated FERM constructs by small-angle X-ray scattering (SAXS). The scattering data support a compact and globular core FERM domain with a more flexible and extended C-terminal region. This flexibility may explain the low activity in vitro and suggests that IDOL may require activation for recognition of the LDLR.

CHAMPION: Chalmers hierarchical atomic, molecular, polymeric and ionic analysis toolkit.

We present CHAMPION (Chalmers hierarchical atomic, molecular, polymeric, and ionic analysis toolkit): a software developed to automatically detect time-dependent bonds between atoms based on their dynamics, classify the local graph topology around them, and analyze the physicochemical properties of these topologies by statistical physics. In stark contrast to methodologies where bonds are detected based on static conditions such as cut-off distances, CHAMPION considers pairs of atoms to be bound only if they move together and act as a bound pair over time. Furthermore, the time-dependent global bond graph is possible to split into dynamically shifting connected components or subgraphs around a certain chemical motif and thereby allow the physicochemical properties of each such topology to be analyzed by statistical physics. Applicable to condensed matter and liquids in general, and electrolytes in particular, this allows both quantitative and qualitative descriptions of local structure, as well as dynamical processes such as speciation and diffusion. We present here a detailed overview of CHAMPION, including its underlying methodology, implementation, and capabilities.

Spectroscopic and Computational Study of Boronium Ionic Liquids and Electrolytes.

Boronium cation-based ionic liquids (ILs) have demonstrated high thermal stability and a >5.8 V electrochemical stability window. Additionally, IL-based electrolytes containing the salt LiTFSI have shown stable cycling against the Li metal anode, the "Holy grail" of rechargeable lithium batteries. However, the basic spectroscopic characterisation needed for further development and effective application is missing for these promising ILs and electrolytes. In this work, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and density functional theory (DFT) calculations are used in combination to characterise four ILs and electrolytes based on the [NNBH2 ]+ and [(TMEDA)BH2 ]+ boronium cations and the [FSI]- and [TFSI]- anions. By using this combined experimental and computational approach, proper understanding of the role of different ion-ion interactions for the Li cation coordination environment in the electrolytes was achieved. Furthermore, the calculated vibrational frequencies assisted in the proper mode assignments for the ILs and in providing insights into the spectroscopic features expected at the interface created when they are adsorbed on a Li(001) surface. A reproducible synthesis procedure for [(TMEDA)BH2 ]+ is also reported. The fundamental findings presented in this work are beneficial for any future studies that utilise IL based electrolytes in next generation Li metal batteries.

Boosting Rechargeable Batteries R&D by Multiscale Modeling: Myth or Reality?

This review addresses concepts, approaches, tools, and outcomes of multiscale modeling used to design and optimize the current and next generation rechargeable battery cells. Different kinds of multiscale models are discussed and demystified with a particular emphasis on methodological aspects. The outcome is compared both to results of other modeling strategies as well as to the vast pool of experimental data available. Finally, the main challenges remaining and future developments are discussed.

Examining Perceptions of Spanish Language Health Information Among Hispanics Living in the United States: A Qualitative Study Assessing Videos, Brochures, and Websites.

BACKGROUND: Nationally, Hispanics experience health disparities manifested as a higher prevalence of chronic diseases in comparison to non-Hispanic Whites. Factors that influence health disparities in this population include inadequate dissemination of culturally and linguistically appropriate health information. METHOD: Our qualitative analysis is based on data obtained from three focus groups with Spanish-speaking Hispanic adults conducted at a clinic in Nebraska. Participants were asked about their perceptions of health information in the form of videos, brochures, and websites. We followed the consolidated criteria for reporting qualitative research and used the theoretical framework of content analysis. RESULTS: For videos, attributes associated with higher levels of trust included a friendly health professional, the logo or name of a health care institute, and a reference specifying "se habla Español." For brochures, attributes associated with trust included use of visual aids, use of numerous colors and big font sizes, the year of printing, and a health care agency logo. For websites, characteristics associated with trust were inclusion of plain language, use of pictures and videos, and date of last update. In all focus groups, participants perceived the use of mixed English/Spanish language in health information from pamphlets and websites as unprofessional. The use of unknown governmental logos in health promotional videos and websites was perceived as untrustworthy information. CONCLUSIONS: Spanish-speaking Hispanics prefer health information supported by a health care agency or delivered by a health care professional. Health communication strategies should avoid the use of mixed English/Spanish language in sensitive information especially when combined with governmental logos.

High-Performant All-Organic Aqueous Sodium-Ion Batteries Enabled by PTCDA Electrodes and a Hybrid Na/Mg Electrolyte.

Aqueous sodium-ion batteries (ASIBs) are aspiring candidates for low environmental impact energy storage, especially when using organic electrodes. In this respect, perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) is a promising anode active material, but it suffers from extensive dissolution in conventional aqueous electrolytes. As a remedy, we here present a novel aqueous electrolyte, which inhibits the PTCDA dissolution and enables their use as all-organic ASIB anodes with high capacity retention and Coulombic efficiencies. Furthermore, the electrolyte is based on two, hence "hybrid", inexpensive and non-fluorinated Na/Mg-salts, it displays favourable physico-chemical properties and an electrochemical stability window >3 V without resorting to the extreme salt concentrations of water-in-salt electrolytes. Altogether, this paves the way for ASIBs with both relatively high energy densities, inexpensive total cell chemistries, long-term sustainability, and improved safety.

Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes.

MOTIVATION: Medulloblastoma (MB) is a brain cancer predominantly arising in children. Roughly 70% of patients are cured today, but survivors often suffer from severe sequelae. MB has been extensively studied by molecular profiling, but often in small and scattered cohorts. To improve cure rates and reduce treatment side effects, accurate integration of such data to increase analytical power will be important, if not essential. RESULTS: We have integrated 23 transcription datasets, spanning 1350 MB and 291 normal brain samples. To remove batch effects, we combined the Removal of Unwanted Variation (RUV) method with a novel pipeline for determining empirical negative control genes and a panel of metrics to evaluate normalization performance. The documented approach enabled the removal of a majority of batch effects, producing a large-scale, integrative dataset of MB and cerebellar expression data. The proposed strategy will be broadly applicable for accurate integration of data and incorporation of normal reference samples for studies of various diseases. We hope that the integrated dataset will improve current research in the field of MB by allowing more large-scale gene expression analyses. AVAILABILITY AND IMPLEMENTATION: The RUV-normalized expression data is available through the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) and can be accessed via the GSE series number GSE124814. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.