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The downscaling of electronic devices requires rechargeable microbatteries with enhanced energy and power densities. Here, we evaluate self-assembled vertically aligned nano-composite (VAN) thin films as a platform to create high-performance three-dimensional (3D) microelectrodes. This study focuses on controlling the VAN formation to enable interface engineering between the LiMn2O4 cathode and the (Li,La)TiO3 solid electrolyte. Electrochemical analysis in a half cell against lithium metal showed the absence of sharp redox peaks due to the confinement in the electrode pillars at the nanoscale. The (100)-oriented VAN thin films showed better rate capability and stability during extensive cycling due to the better alignment to the Li-diffusion channels. However, an enhanced pseudocapacitive contribution was observed for the increased total surface area within the (110)-oriented VAN thin films. These results demonstrate for the first time the electrochemical behavior of cathode-electrolyte VANs for lithium-ion 3D microbatteries while pointing out the importance of control over the vertical interfaces.

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment. ispartof: J Clin Invest vol:133 issue:12 pages:e163105- ispartof: location:United States status: Published online

This study aimed to compare the effects of four resistance exercise orders on muscular strength, body composition, functional fitness, cardiovascular risk factors, and mental health parameters in trained older women.The intervention lasted 63 wk. Sixty-one physically independent women (60 yr) after completing a 12-wk resistance training (RT) preconditioning phase were randomized into four different exercise orders groups to perform 12 wk of RT: multijoint to single-joint and upper- to lower-body, single-joint to multijoint and upper- to lower-body, multijoint to single-joint and lower- to upper-body, and single-joint to multijoint and lower- to upper-body. This was followed by a 12-wk detraining period and another 12-wk RT in which exercise orders were crossed over between MJ-SJ and SJ-MJ conditions. Body composition (dual-energy x-ray absorptiometry), muscular strength (one-repetition maximum tests), functional fitness (gait speed, walking agility, 30-s chair stand, and 6-min walk tests), cardiovascular risk factors (glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, advanced oxidation protein product, total radical-trapping antioxidant parameter, and nitric oxide), depressive (Geriatric Depression Scale) and anxiety symptoms (Beck Anxiety Inventory), and cognitive performance (Montreal Cognitive Assessment, Trail Making, verbal fluency, and Stroop test) were analyzed.After the final training period, all groups presented significant improvements ( P0.05) in almost all analyzed variables (muscular strength, body composition, functional tests, blood biomarkers, and mental health parameters), without significant difference among exercise orders.Our results suggest that RT exercise orders in which MJ, SJ, upper, or lower-body exercises are performed first have similar effects on health parameters in trained older women.

Mixed modes observed in red giants allow for investigation of the stellar interior structures. One important feature in these structures is the buoyancy spike caused by the discontinuity of the chemical gradient left behind during the first dredge-up. The buoyancy spike emerges at the base of the convective zone in low-luminosity red giants and later becomes a glitch when the g-mode cavity expands to encompass the spike. Here, we study the impact of the buoyancy spike on the dipolar mixed modes using stellar models with different properties. We find that the applicability of the asymptotic formalisms for the coupling factor, q, varies depending on the location of the evanescent zone, relative to the position of the spike. Significant deviations between the value of q inferred from fitting the oscillation frequencies and either of the formalisms proposed in the literature are found in models with a large frequency separation in the interval 5 to 15 microHz, with evanescent zones located in a transition region which may be thin or thick. However, it is still possible to reconcile q with the predictions from the asymptotic formalisms, by choosing which formalism to use according to the value of q. For stars approaching the luminosity bump, the buoyancy spike becomes a glitch and strongly affects the mode frequencies. Fitting the frequencies without accounting for the glitch leads to unphysical variations in the inferred q, but we show that this is corrected when properly accounting for the glitch in the fitting., Comment: 21 pages, 10 figures

PurposeThis paper studies the dynamics and elasticities of house prices in Spain and Portugal (Iberia) at the Metropolitan Statistical Area (MSA) level, addressing panel regression problems such as heterogeneity and cross-sectional dependence between MSA.Design/methodology/approachThe authors develop a two steps study. First, five distinct estimation methodologies are applied to estimate the long-term house price equilibrium of the Iberian MSA house market: Mean Group (MG), Fully Modified Ordinary Least Square (FMOLS) MG (FMOLS-MG), FMOLS Augmented MG (FMOLS-AMG), Common Correlated Effects MG (CCEMG) and Dynamic CCEMG (DCCEMG). FMOLS-AMG is found to be the best estimator for the long-term model. Second, an additional five distinct estimation methodologies are applied to estimate the short-term house price dynamics using the long-term FMOLS-AMG estimated price in the error-correction term of the short-term dynamic house price model: OLS Fixed Effects (FE), OLS Random Effects (RE), MG, CCEMG and DCCEMG. DCCEMG is found to be the best estimator for the short-term model.FindingsThe results show that in the long run Iberian house prices are inelastic to aggregate income (0.227). This is a much lower elasticity than what was previously found in US MSA house price studies, suggesting that there are other factors explaining Iberian house prices. According to our study, coastal MSA presents an inelastic housing supply and a price to income elasticity close to one, whereas inland MSA are shown to have an elastic supply and a non-significant price to income elasticity. Spatial differences are important and cross-section dependence is prevalent, affecting estimates in conventional methodologies that do not account for these limitations, such as OLS-FE and OLS-RE. Momentum and mean reversion are the main determinants of short-term dynamics.Practical implicationsRecent econometric advances that account for slope heterogeneity and cross-section dependence produce more accurate estimates than conventional panel estimation methodologies. The results suggest that house markets should be analyzed at the metropolitan level, not at the national level and that there are significant differences between short-term and long-term house price determinants.Originality/valueTo the best of the authors' knowledge, this is the first study applying recent econometric advances to the Iberian MSA house market.

Nunes, JP, Marcori, AJ, Ribeiro, AS, Cunha, PM, Kassiano, W, Costa, BDV, Aguiar, AF, Nakamura, M, Mayhew, JL, and Cyrino, ES. Differential responsiveness for strength gain between limbs after resistance training in older women: Impact on interlimb asymmetry reduction. J Strength Cond Res 36(11): 3209-3216, 2022-The present study compared strength responses between preferred (PREF) and nonpreferred (N-PREF) legs in older women. Muscular strength was measured unilaterally using an isokinetic dynamometer and was analyzed for reproducibility scores, acute performance, and responsiveness to a resistance training (RT) program. One hundred eleven women (aged ≥60 years) performed 12 weeks of whole-body RT (3 times a week; 4 lower-body exercises). Reproducibility scores (intraclass correlation coefficient ≥0.920; following test-retests in part of the sample at pretraining; n = 19), average acute performances, and average strength gains (PREF = ∼6.9%; N-PREF = ∼7.2%) were similar between legs (p0.05). However, the individual analyses showed that some subjects were considered responders to strength gains in 1 leg, whereas nonresponders in the other. Nonetheless, when considering the responses in all strength tests, most subjects (91%) were considered responder to at least 1 measure. In addition, it was observed that the strength ratio between PREF/N-PREF legs was altered for those who presented some asymmetry at baseline, as the limbs became more symmetrical in all strength measures after the RT. In conclusion, we observed that some older women may have different levels of strength between legs; however, a traditional 12-week RT program with bilateral exercises can reduce such asymmetry by inducing greater strength gains in the weaker leg.

Malnutrition is frequently identified in patients with advanced chronic liver disease (ACLD), and its early identification is necessary for effective nutrition treatment. The aim of this study was to develop and validate a tool for specific nutrition evaluation of patients with ACLD (SNE-ACLD).SNE-ACLD was developed by consensus among experts using Delphi technique. The initial proposal for the SNE-ACLD had six domains (history of weight loss, changes in food intake, gastrointestinal symptoms, changes in functional capacity, presence of complications of liver disease, and a nutrition-focused physical examination) and 11 items. Fifteen experts participated in content validation. In a cross-sectional study design, the new tool was applied to 129 inpatients and outpatients from a gastrohepatology unit. Nutrition status was evaluated with SNE-ACLD and subjective global assessment by one researcher. Content validation and semantic analysis were obtained by content validity index. To verify accuracy of SNE-ACLD, the sensitivity, specificity, Youden index, and area under the receiver operating characteristic curve (AUC) were calculated.After five evaluative sequences conducted by experts, experts excluded the domain for history of weight loss and its respective item. The final version of SNE-ACLD consists of five domains and 10 items. The new instrument showed good accuracy in identifying any level of malnutrition (AUC = 0.83; 95% CI, 0.76-0.91) and severe malnutrition (AUC = 0.90; 95% CI, 0.79-1.00).SNE-ACLD can be used in nutrition assessment of patients with liver disease. Future works should investigate its agreement with other methods and its predictive value.

Oxidative stress plays a key role in the initiation and progression of metabolic diseases, including obesity. Preventing the accumulation of reactive oxygen species and oxidative damage to macromolecules is a beneficial strategy for reducing comorbidities associated with obesity. Fruits from the Spondias genus are known for their antioxidant activity, but they are not available year-round due to their seasonality. In this context, we investigated the antioxidant activity and identified the chemical constituents of the aqueous extract of the stem bark of Spondias purpurea L. (EBSp). Additionally, we evaluated the effect of EBSp consumption on metabolic parameters in mice with obesity induced by a high-fat diet. Chemical analyses revealed 19 annotated compounds from EBSp, including flavan-3-ols, proanthocyanidins, methoxylated coumarin, and gallic and ellagic acids, besides other phenolic compounds. In vitro, EBSp showed antioxidant activity through the scavenging of the free radicals and the protection of macromolecules against oxidative damage. Cellular assays revealed that EBSp reduced the levels of malondialdehyde produced by erythrocytes exposed to the oxidizing agent AAPH. Flow cytometry studies showed that EBSp reduced reactive oxygen species levels in human peripheral blood mononuclear cells treated with hydrogen peroxide. Obese mice treated with EBSp (400 mg.kg-1) for 60 days showed reduced levels of malondialdehyde in the heart, liver, kidneys, and nervous system. The total cholesterol levels in mice treated with EBSp reached levels similar to those after treatment with the drug simvastatin. Together, the results show that the combination of the different phenolic compounds in S. purpurea L. bark promotes antioxidant effects in vitro and in vivo, resulting in cytoprotection in the context of oxidative stress associated with obesity and a reduction in hypercholesterolemia. From a clinical perspective, the reduction in oxidative stress in obese individuals contributes to the reduction in the emergence of comorbidities associated with this metabolic syndrome.

Occurrence of hyperglycemia upon infection is associated with worse clinical outcome in COVID-19 patients. However, it is still unknown whether SARS-CoV-2 directly triggers hyperglycemia. Herein, we interrogated whether and how SARS-CoV-2 causes hyperglycemia by infecting hepatocytes and increasing glucose production. We performed a retrospective cohort study including patients that were admitted at a hospital with suspicion of COVID-19. Clinical and laboratory data were collected from the chart records and daily blood glucose values were analyzed to test the hypothesis on whether COVID-19 was independently associated with hyperglycemia. Blood glucose was collected from a subgroup of nondiabetic patients to assess pancreatic hormones. Postmortem liver biopsies were collected to assess the presence of SARS-CoV-2 and its transporters in hepatocytes. In human hepatocytes, we studied the mechanistic bases of SARS-CoV-2 entrance and its gluconeogenic effect. SARS-CoV-2 infection was independently associated with hyperglycemia, regardless of diabetic history and beta cell function. We detected replicating viruses in human hepatocytes from postmortem liver biopsies and in primary hepatocytes. We found that SARS-CoV-2 variants infected human hepatocytes in vitro with different susceptibility. SARS-CoV-2 infection in hepatocytes yields the release of new infectious viral particles, though not causing cell damage. We showed that infected hepatocytes increase glucose production and this is associated with induction of PEPCK activity. Furthermore, our results demonstrate that SARS-CoV-2 entry in hepatocytes occurs partially through ACE2- and GRP78-dependent mechanisms. SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK-dependent gluconeogenic effect in these cells that potentially is a key cause of hyperglycemia in infected patients.

Supplementary Figure from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

Supplementary Data from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti–PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Supplementary material and methods

Generation of myeloid cell-specific TLR4 knockout mice

Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity. In vitro, paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre+/−/TLR4fl/fl), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment.Significance: This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg. Cancer Res; 78(20); 5891–900. ©2018 AACR.See related commentary by Garassino et al., p. 5729

Solid Phase Microextraction (SPME) is an effective, cost-saving, versatile and easily automated solvent-free extraction technique that has become prevalent in the extraction and pre-concentration steps both for analytical procedures for compounds related to aroma and flavors/off-flavors in foods and beverages, as well as in the determination of exogenous contaminants in these samples. Among them, especially relevant is its application to the characterization of beers – the most popular alcoholic beverage in the world, produced after the action of yeasts over malted cereals and seasoned with hops. Therefore, in this chapter we discuss the application of SPME to the assessment of trace constituents in beers and their main ingredients.

Background COVID-19 is characterized by severe acute lung injury, which is associated with neutrophil infiltration and the release of neutrophil extracellular traps (NETs). COVID-19 treatment options are scarce. Previous work has shown an increase in NETs release in the lung and plasma of COVID-19 patients suggesting that drugs that prevent NETs formation or release could be potential therapeutic approaches for COVID-19 treatment. Methods Here, we report the efficacy of NET-degrading DNase I treatment in a murine model of COVID-19. SARS-CoV-2-infected K18-hACE2 mice were performed for clinical sickness scores and lung pathology. Moreover, the levels of NETs were assessed and lung injuries were by histopathology and TUNEL assay. Finally, the injury in the heart and kidney was assessed by histopathology and biochemical-specific markers. Results DNase I decreased detectable levels of NETs, improved clinical disease, and reduced lung, heart, and kidney injuries in SARS-CoV-2-infected K18-hACE2 mice. Furthermore, our findings indicate a potentially deleterious role for NETs lung tissue in vivo and lung epithelial (A549) cells in vitro, which might explain part of the pathophysiology of severe COVID-19. This deleterious effect was diminished by the treatment with DNase I. Conclusions Together, our results support the role of NETs in COVID-19 immunopathology and highlight NETs disruption pharmacological approaches as a potential strategy to ameliorate COVID-19 clinical outcomes.

BACKGROUND: Retrospective studies report that visualisation of the liver may be severely limited using ultrasound (US), potentially contributing to diminished sensitivity for detection of hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, but there are limited prospective data. AIMS: To compare liver visualisation scores prospectively for US and abbreviated hepatobiliary phase (HBP) magnetic resonance imaging (AMRI) in a cohort of participants with NAFLD cirrhosis and a clinical indication for HCC surveillance. METHODS: This prospective multicenter study included 54 consecutive participants (67% women) with NAFLD cirrhosis who underwent contemporaneous US as well as HBP-AMRI with gadoxetic acid. Primary outcome was the proportion of imaging examinations with severe limitations in liver visualisation (visualisation score C) compared head-to-head between US and AMRI. RESULTS: The mean (± standard deviation) age was 63.3 years (±8.4) and body mass index was 32.0 kg/m(2) (±6.0). Nineteen participants (35%) had severe visualisation limitations on US, compared with 10 (19%) with AMRI, p < 0.0001. Nine (17%) participants had

The immune synapse (IS) is a cell-cell interaction platform critical in lymphocyte activation by specific antigens. Despite of B cells being able to also respond to soluble antigens, in particular thein vivoimportance of the IS and surface-tethered antigen recognition has strongly emerged in the recent years. The IS serves as a dynamic hub for multiple cellular actions but the molecular details of these functions, especially beyond the B cell antigen receptor (BCR) signalling, remain poorly understood. Here, to address the lack in the systems level understanding of the IS, we setup methodology for comprehensive investigation of the composition of the primary mouse B cells’ IS at proteome level. Utilizing functionalized magnetic beads to mimic antigen presenting cells and trigger IS formation on them, we developed a method to specifically and robustly extract the cell adhesions on the beads, namely the IS or transferrin receptor mediated adhesion as a control. Our data revealed 661 proteins exclusively present in the IS at 15 minutes after BCR engagement, 13 exclusively in the control adhesions and 365 proteins shared between the samples. We got strong coverage of the known components of the IS as well as identified a plethora of unknown proteins and functional pathways with hitherto unknown roles in B cell IS. Thus, in this work, we validated the IS isolation method as a valuable tool to study early B cell activation by surface-bound antigens as well as unveil several novel proteins and pathways suggestive of new functional aspects in the IS.