Single cell transcriptome analysis identified a unique neutrophil type associated with Alzheimer's disease.

BACKGROUND: Neutrophils play an essential role in Alzheimer's disease (AD) pathology. However, the extent of their heterogeneity remains poorly explored, particularly in the context of developing novel therapies targeting these cells. RESULTS: We investigate the population structure of neutrophils purified from peripheral blood samples of AD mice. Utilizing single cell RNA sequencing, we comprehensively map neutrophil populations into six distinct clusters and find that the Neu-5 subset is specially enriched in AD mice. This subset exhibits fewer specific granules and a lower mature score. Gene ontology (GO) analysis reveals that genes involved in cytokine-mediated signaling are downregulated in the Neu-5 cluster. Furthermore, we identify the Ccrl2 gene is specifically upregulated in this subgroup, which is confirmed by flow cytometry in AD mice. Finally, immunohistochemical staining indicates that CCRL2 protein is increased in the brains of AD mice. CONCLUSIONS: We identify a unique CCRL2 positive neutrophil cluster, that is specifically enriched in the peripheral blood of AD mice.

Structure-Based Optimization of Novel Sterol 24-C-Methyltransferase Inhibitors for the Treatment of Candida albicans Infections.

Interfering with sterol biosynthesis is an important strategy for developing safe and effective antifungal drugs. We previously identified compound H55 as an allosteric inhibitor of the fungal-specific C-24 sterol methyltransferase Erg6 for treating Candida albicans infections. Herein, 62 derivatives of H55 were designed and synthesized based on target-ligand interactions to identify more active candidates. Among them, d28 displayed the most potent antivirulence ability (MHIC50 = 0.25 µg/mL) by targeting Erg6, exhibiting an 8-fold increase in potency compared with H55. Moreover, d28 significantly outperformed H55 in inhibiting cell adhesion and biofilm formation, and exhibited minimal cytotoxicity and negligible potential to induce drug resistance. Of note, the coadministration of d28 and other sterol biosynthesis inhibitors, such as tridemorph or terbinafine, demonstrated a strong synergistic antifungal action in vitro and in vivo in a murine skin infection model. These results support the potential application of d28 in the treatment of C. albicans infections.

Custom-tailored hole transport layer using oxalic acid for high-quality tin-lead perovskites and efficient all-perovskite tandems.

All-perovskite tandem solar cells (TSCs) have exhibited higher efficiencies than single-junction perovskite solar cells (PSCs) but still suffer from the unsatisfactory performance of low-bandgap (LBG) tin-lead (Sn-Pb) subcells. The inherent properties of PEDOT:PSS are crucial to high-performance Sn-Pb perovskite films and devices; however, the underlying mechanism has not been fully explored and revealed. Here, we report a facile oxalic acid treatment of PEDOT:PSS (OA-PEDOT:PSS) to precisely regulate its work function and surface morphology. OA-PEDOT:PSS shows a larger work function and an ordered reorientation and fiber-shaped film morphology with efficient hole transport pathways, leading to the formation of more ideal hole-selective contact with Sn-Pb perovskite for suppressing interfacial nonradiative recombination losses. Moreover, OA-PEDOT:PSS induces (100) preferred orientation growth of perovskite for higher-quality Sn-Pb films. Last, the OA-PEDOT:PSS-tailored LBG PSC yields an impressive efficiency of up to 22.56% (certified 21.88%), enabling 27.81% efficient all-perovskite TSC with enhanced operational stability.

Fe3O4-Incorporated Metal-Organic Framework for Chemo/Ferroptosis Synergistic Anti-Tumor via the Enhanced Chemodynamic Therapy.

Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell zeolitic imidazolate framework-8 (ZIF-8)@Fe3O4 as a therapeutic platform is proposed. Carboxymethyl cellulose (CMC) is used as a stabilizer of Fe3O4, which is then decorated on the surface of ZIF-8 via the electrostatic interaction and serves as an efficient Fenton reaction trigger. Meanwhile, the pH-responsive ZIF-8 scaffold acts as a container to encapsulate the chemotherapeutic drug doxorubicin (DOX). The obtained DOX-ZIF-8@Fe3O4/CMC (DZFC) nanoparticles concomitantly accelerate DOX release and generate more hydroxyl radicals by targeting the lysosomes in cancer cells. In vitro and in vivo studies verify that the DZFC nanoparticles trigger glutathione peroxidase 4 (GPX4)-dependent ferroptosis via the activation of the c-Jun N-terminal kinases (JNK) signaling pathway, following to achieve the chemo/ferroptosis synergistic anti-tumor efficacy. No marked toxic effects are detected during DZFC treatment in a tumor-bearing mouse model. This composite nanoparticle remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theragnostic nanomedicines.

Mechanistic Understanding of Oxidation of Tin-based Perovskite Solar Cells and Mitigation Strategies.

Tin (Sn)-based perovskites as the most promising absorber materials for lead-free perovskite solar cells (PSCs) have achieved the record efficiency of over 14 %. Although suppressing the oxidation of Sn-based perovskites is a frequently concerned topic for Sn-based PSCs, many studies have given vague explanations and the mechanisms are still under debate. This is in principal due to the lack of an in-depth understanding of various and complex intrinsic and extrinsic factors causing the oxidation process. In this context, we critically review the chemical mechanism of facile oxidation of Sn-based perovskites and differentiate its detrimental effects at material- and device-level. More importantly, we classify and introduce the intrinsic factors (raw materials and solvent of perovskite precursors) and extrinsic factors (exposure to neutral oxygen and superoxide) causing the oxidation with their corresponding anti-oxidation improvement methods. The presented comprehensive understanding and prospect of the oxidation provide insightful guidance for suppressing the oxidation in Sn-based PSCs "from the beginning to the end".

Tumor selective self-assembled nanomicelles of carbohydrate-epothilone B conjugate for targeted chemotherapy.

Epothilone B (Epo B) is a potent antitumor natural product with sub-nanomolar anti-proliferation action against several human cancer cells. However, poor selectivity to tumor cells and unacceptable therapeutic windows of Epo B and its analogs are the major obstacles to their development into clinical drugs. Herein, we present self-assembled nanomicelles based on an amphiphilic carbohydrate-Epo B conjugate that is inactive until converted to active Epo B within the tumor. Four Epo B-Rhamnose conjugates linked via two linkers containing a disulfide bond that is sensitive to GSH were synthesized. Conjugate 34 can self-assemble into nanomicelles with a high concentration of Rha on the surface, allowing for better tumor targeting. After internalization by cancer cells, the disulfide bond can be cleaved in the presence of high levels of GSH to release active Epo B, thereby exhibiting significant anticancer efficiency and selectivity in vitro and in vivo.

Borenium-ion-catalyzed hydrogenation of arenes.

Non-metal-catalyzed hydrogenation of arenes represents a sustainable and environment-friendly approach for the synthesis of cyclohexane derivatives. Herein, we report the development of a borenium-ion catalyst system which can hydrogenate a number of monocyclic arenes. Additionally, this metal-free catalytic system allows selective partial or full hydrogenation of naphthalene and anthracene by modification of the reaction conditions. Our mechanism studies suggest that the borenium-arene-mediated H2 splitting takes place before the rate-limiting step and the hydride transfer between the resulting neutral borane and protonated arene is likely the rate-limiting step in the catalytic process.

Improved Carrier Management via a Multifunctional Modifier for High-Quality Low-Bandgap Sn-Pb Perovskites and Efficient All-Perovskite Tandem Solar Cells.

All-perovskite tandem solar cells (TSCs) hold great promise in terms of ultrahigh efficiency, low manufacturing cost, and flexibility, stepping forward to the next-generation photovoltaics. However, their further development is hampered by the relatively low performance of low-bandgap (LBG) tin (Sn)-lead (Pb) perovskite solar cells (PSCs). Improving the carrier management, including suppressing trap-assisted non-radiative recombination and promoting carrier transfer, is of great significance to enhance the performance of Sn-Pb PSCs. Herein, a carrier management strategy is reported for using cysteine hydrochloride (CysHCl) simultaneously as a bulky passivator and a surface anchoring agent for Sn-Pb perovskite. CysHCl processing effectively reduces trap density and suppresses non-radiative recombination, enabling the growth of high-quality Sn-Pb perovskite with greatly improved carrier diffusion length of >8 µm. Furthermore, the electron transfer at the perovskite/C60 interface is accelerated due to the formation of surface dipoles and favorable energy band bending. As a result, these advances enable the demonstration of champion efficiency of 22.15% for CysHCl-processed LBG Sn-Pb PSCs with remarkable enhancement in both open-circuit voltage and fill factor. When paired with a wide-bandgap (WBG) perovskite subcell, a certified 25.7%-efficient all-perovskite monolithic tandem device is further demonstrated.

The impact of sociality and affective valence on brain activation: A meta-analysis.

Thirty years of neuroimaging reveal the set of brain regions consistently associated with pleasant and unpleasant affect in humans-or the neural reference space for valence. Yet some of humans' most potent affective states occur in the context of other humans. Prior work has yet to differentiate how the neural reference space for valence varies as a product of the sociality of affective stimuli. To address this question, we meta-analyzed across 614 social and non-social affective neuroimaging contrasts, summarizing the brain regions that are consistently activated for social and non-social affective information. We demonstrate that across the literature, social and non-social affective stimuli yield overlapping activations within regions associated with visceromotor control, including the amygdala, hypothalamus, anterior cingulate cortex and insula. However, we find that social processing differs from non-social affective processing in that it involves additional cortical activations in the medial prefrontal and posterior cingulum that have been associated with mentalizing and prediction. A Bayesian classifier was able to differentiate unpleasant from pleasant affect, but not social from non-social affective states. Moreover, it was not able to classify unpleasantness from pleasantness at the highest levels of sociality. These findings suggest that highly social scenarios may be equally salient to humans, regardless of their valence.

Targeting VPS41 induces methuosis and inhibits autophagy in cancer cells.

The homotypic fusion and vacuole protein sorting (HOPS) complex mediates membrane trafficking involved in endocytosis, autophagy, lysosome biogenesis, and phagocytosis. Defects in HOPS subunits are associated with various forms of cancer, but their potential as drug targets has rarely been examined. Here, we identified vacuolar protein sorting-associated protein 41 homolog (VPS41), a subunit of the HOPS complex, as a target of methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP), a natural small molecule with preferable anticancer activity. DMBP induced methuosis and inhibited autophagic flux in cancer cells by inhibiting the function of VPS41, leading to the restrained fusion of late endosomes and autophagosomes with lysosomes. Moreover, DMBP effectively inhibited metastasis in a mouse metastatic melanoma model. Collectively, the current work revealed that targeting VPS41 would provide a valuable method of inhibiting cancer proliferation through methuosis.

Factors Contributing to Sex Differences in Health-Related Quality of Life After Ischemic Stroke: BASIC (Brain Attack Surveillance in Corpus Christi) Project.

Background Women have been reported to have worse health-related quality of life (HRQoL) following stroke than men, but uncertainty exists over the reasons for the sex difference. Methods and Results We included all ischemic strokes registered with the BASIC (Brain Attack Surveillance in Corpus Christi) project (May 2010-December 2016), a population-based stroke study, who completed a 90-day outcome interview. Information on baseline characteristics was obtained from medical records and in-person interviews. HRQoL was measured by the 12-item short-form Stroke Specific Quality of Life Scale. Multivariable Tobit regression was used to estimate the mean difference in overall HRQoL scores (range, 1-5; higher indicating better HRQoL) between sexes and to identify contributing factors to the differences. We included 1061 cases with complete data on HRQoL and covariates (median age, 67 years; 51% women). In unadjusted analyses, women had poorer overall HRQoL than men (mean difference, -0.26 [95% CI, -0.40 to -0.13]). Contributors to this difference included sociodemographic/prestroke factors (eg, age, race and ethnicity, prestroke function), risk factors/comorbidities (eg, history of stroke, Alzheimer disease/dementia), and initial stroke severity. Sociodemographic/prestroke factors explained 62% of the sex difference (mean difference, -0.08 [95% CI, -0.21 to 0.04]). In a fully adjusted model that included adjustment for all confounding factors, the sex difference was eliminated and became nonsignificant (mean difference, -0.03 [95% CI, -0.16 to 0.09]). Conclusions Poorer HRQoL in women compared with men was observed and explained by the combination of sociodemographic and prestroke factors, including physical function before stroke and stroke severity. The findings suggest potential subgroups of women who might benefit from more targeted interventions before and after stroke to improve HRQoL.

Investigation on operational parameters and membrane fouling performance in treating synthetic aquaculture wastewater via forward osmosis with sucrose as draw solution.

Forward osmosis (FO), a membrane separation process driven by a natural concentration gradient, is served as a potential strategy in the aspect of wastewater treatment. In this work, a worthy attempt at aquaculture wastewater treatment using a self-made FO system was conducted, confirming it was a promising approach to treating aquaculture wastewater. Optimization of operational parameters of the FO system, including draw solution (DS) concentration, cross-flow velocity, and DS temperature, was systematically investigated to enhance the running efficiency. Different selected parameters highly influenced the water flux during the single-factor experiments, and the findings indicated that the optimal conditions were DS of 1.5 M, cross-flow velocity of 15 cm/s, and temperature of 32 °C with consideration of FO performance and economical cost. An excellent linear relationship between chemical oxygen demand (COD) changing multiples and operational parameters was obtained from experimental results, offering a great interception performance of organic contamination. On the basis of optimal operating conditions, membrane fouling experiments with different running time were conducted, and the microscopic morphology and element composition of the fouled membrane were also analyzed. The results demonstrated that a layer of cake was coated on the surface of the membrane, and the main elements in the fouling cake included C, O, Na, and S, which were highly determined by the component of the feed solution (FS) and working time. Afterward, the 60-h FO fouled membrane was cleaned under the method which combined hydraulic power and chemical agents, and the water flux recovered to 12.79 Lm-2 h-1, proving a good performance for the recovery of water flux. This investigation showed that employing sucrose as DS was effective for reducing wastewater volume, and it provided an alternative choice and a sustainable way for the separation of organic pollutants from water resources.

Experimental Study on Hydraulic Pulsation Features of Intelligent Variable Valve System for Auto Energy Saving.

The electrohydraulic valve system can realize continuous variable valve timing and lift using the flexibility of liquid. However, the existing electrohydraulic valve systems usually rely on a high-speed solenoid valve to control the on and off states of the hydraulic circuit, which pushes up the system cost. This paper introduces a continuous hydraulic variable valve timing and lift system with adjustable volume (CVVTL). Unlike the other electrohydraulic valve systems, the CVVTL does not need a high-frequency servo valve to control each valve but adjusts the valve timing and lift by controlling the system volume. However, the maximum operating speed of hydraulic variable valve systems is limited by the inherent pressure fluctuation. To relax the limit, the authors further studied the pressure fluctuation features of the CVVTL system under various conditions and summarized the harms of the fluctuation. After identifying the causes of pressure fluctuation of the CVVTL system, the authors came up with systematic countermeasures to system pressure fluctuation.

Selective Metal Chelation by a Thiosemicarbazone Derivative Interferes with Mitochondrial Respiration and Ribosome Biogenesis in Candida albicans.

Metal chelation is generally considered as a promising antifungal approach but its specific mechanisms are unclear. Here, we identify 13 thiosemicarbazone derivatives that exert broad-spectrum antifungal activity with potency comparable or superior to that of fluconazole in vitro by screening a small compound library comprising 89 thiosemicarbazone derivatives as iron chelators. Among the hits, 19ak exhibits minimal cytotoxicity and potent activity against either azole-sensitive or azole-resistant fungal pathogens. Mechanism investigations reveal that 19ak inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation, and further reduces mitochondrial membrane potential and ATP synthesis in Candida albicans. In addition, 19ak inhibits fungal ribosome biogenesis mainly by disrupting intracellular zinc homeostasis. 19ak also stimulates the activities of antioxidant enzymes and decreases reactive oxygen species formation in C. albicans, resulting in an increase in detrimental intracellular reductive stress. However, 19ak has minor effects on mammalian cells in depleting intracellular iron and zinc. Moreover, 19ak exhibits low capacity to induce drug resistance and in vivo efficacy in a Galleria mellonella infection model. These findings uncover retarded fungal mitochondrial respiration and ribosome biogenesis as downstream effects of disruption of iron and zinc homeostasis in C. albicans and provide a basis for the thiosemicarbazone 19ak in antifungal application. IMPORTANCE The increasing incidence of fungal infections and resistance to existing antifungals call for the development of broad-spectrum antifungals with novel mechanisms of action. In this study, we demonstrate that a thiosemicarbazone derivative 19ak selectively inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation and inhibits ribosome biogenesis mainly by disrupting intracellular zinc homeostasis in C. albicans. In addition, 19ak exhibits low capacity to induce fungal resistance, minimal cytotoxicity, and in vivo antifungal efficacy. This study provides the basis of thiosemicarbazone derivative 19ak as a metal chelator for the treatment of fungal infections.

Dual-readout fluorescence quenching immunochromatographic test strips for highly sensitive simultaneous detection of chloramphenicol and amantadine based on gold nanoparticle-triggered photoluminescent nanoswitch control.

Herein, a novel fluorescence quenching immunochromatographic test strip (FQICTS) for simultaneous detection of chloramphenicol (CAP) and amantadine (AMD) was developed on the basis of inner filter effect (IFE), with the combination of gold nanoparticles (AuNPs) and highly luminescent green-emitting gold nanoclusters (AuNCs) as the IFE quencher/donor pair. The AuNPs could quench the excitation light and emission light of AuNCs and achieve a high IFE efficiency due to dual spectral overlapping. Under optimal conditions, the "turn-on" mode of the AuNCs-based dual-readout FQICTS showed good linearity for CAP detection in chicken samples from 0.05 ng/g to 10 ng/g, with a limit of detection (LOD) of 0.043 ng/g. The linear range of AMD is 0.5-50 ng/g, with LOD of 0.45 ng/g. The visual LODs of CAP and AMD in "turn-on" mode were 200 and 10 times lower than that in "turn-off" mode, respectively. The "turn-on" mode of FQICTS showed high recovery for detecting CAP (82.5-94.5%) and AMD (81.9-110.7%) spiked into chicken samples. The performance and practicability of the established method were verified with commercial enzyme-immunoassay kits, and good correlations were observed. Overall, the newly developed AuNCs-based dual-readout FQICTS is a promising on-site screening tool for rapid, high-sensitivity detection of multiple food contaminants in practical applications.

Adsorption and convenient ELISA detection of sulfamethazine in milk based on MOFs pretreatment.

Metal-organic frameworks (MOFs) has excellent adsorption performance, herein, three kinds of common MOFs were used for the adsorption of sulfamethazine (SM2) in milk, then enzyme-linked immunosorbent assay (MOF-ELISA) was established. Firstly, NH2-UiO-66, NH2-MIL-101, and ZIF-8 were successfully prepared and their adsorption characteristics for SM2 were investigated. The kinetic models of the three MOFs were more in line with the pseudo-second-order adsorption kinetics, and the saturated adsorption capacity of NH2-UiO-66, NH2-MIL-101, and ZIF-8 for SM2 at 298 K were 139.64, 29.98, and 36.5 mg/g, respectively. Using three different MOFs as adsorbents, the pretreatment of milk samples could be completed within 1 h, the half inhibitory concentrations (IC50) of MOF-ELISA were 1.26, 1.86 and 2.74 ng/mL, the limit of detections (LOD) were 0.05, 0.12, and 0.19 ng/mL and the recovery rate were from 82.30% to 105.62% with the intra-day coefficient of variations (CVs) below 5.81% and inter-day CVs below 7.21%. Detection results showed good correlations with LC-MS/MS (R2 > 0.99), indicated that MOFs could effectively eliminate the interference of sample matrix, and has the potential to become a general pretreatment method for the detection of various matrices residues in food safety monitoring.

Photoredox-Catalyzed Cascade Reactions Involving Aryl Radical: Total Synthesis of (±)-Norascyronone A and (±)-Eudesmol.

Herein, we have developed two types of photoredox-catalyzed cascade reactions using diaryliodonium salts for the concise synthesis of norascyronone A and ß-eudesmol. A rationally designed photoredox-catalyzed arylation/cyclization/Friedel-Crafts cascade reaction of enone was exploited to generate the norascyronone polycyclic skeleton. A visible-light-induced radical cyclization/acyloxy-migration reaction was explored to forge the decalin skeleton of eudesmol, and mechanistic studies indicated the reaction was initiated by one-electron oxidation of the enol ester.

Xylarins A-D, Two Pairs of Diastereoisomeric Isoindoline Alkaloids from the Endolichenic Fungus Xylaria sp.

Two pairs of diastereoisomeric isoindoline alkaloids, xylarins A-D (1-4), were isolated from the endolichenic fungus Xylaria sp. Xylarins A and B (1 and 2) possess a previously undescribed 5/6/5-5/6 polycyclic scaffold, featuring a combination of a novel dihydrobenzofurone unit and an isoindoline unit, while xylarins C and D (3 and 4) contain an additional N,N-dimethylaniline at the C-3' position. Their structures were elucidated by comprehensive spectroscopic analyses combined with single-crystal X-ray diffraction and electronic circular dichroism calculations. The plausible biosynthetic pathways and gene clusters for 1-4 were proposed. Compound 1 exhibited significant antithrombotic activity.

Overnight Rostral Fluid Shifts Exacerbate Obstructive Sleep Apnea After Stroke.

Background and Purpose: Overnight shifts of fluid from lower to upper compartments exacerbate obstructive sleep apnea (OSA) in some OSA populations. Given the high prevalence of OSA after stroke, decreased mobility and use of IV fluids among hospitalized patients with stroke, and improvement in OSA in the months after stroke, we hypothesized that overnight fluid shifts occur and are associated with OSA among patients with subacute ischemic stroke. Methods: Within a population-based project, we performed overnight sleep apnea tests (ApneaLink Plus) during ischemic stroke hospitalizations. Before sleep that evening, and the following morning before rising from bed, we assessed neck and calf circumference, and leg fluid volume (bioimpedance spectroscopy). The average per subject overnight change in the 3 fluid shift measurements was calculated and compared with zero. Linear regression was used to test the crude association between each of the 3 fluid shift measurements and the respiratory event index (REI). Results: Among the 292 participants, mean REI was 24 (SD=18). Within individuals, calf circumference decreased on average by 0.66 cm (SD=0.75 cm, P<0.001), leg fluid volume decreased by a mean of 135.6 mL (SD=132.8 mL, P<0.001), and neck circumference increased by 0.20 cm (SD=1.71 cm, P=0.07). In men, when the overnight change of calf circumference was negative, an interquartile range (0.8 cm) decrease in calf circumference overnight was significantly associated with a 25.1% increase in REI (P=0.02); the association was not significant in women. The relationship between overnight change in leg fluid volume and REI was U shaped. Conclusions: This population-based, multicenter, cross-sectional study showed that in hospitalized patients with ischemic stroke, nocturnal rostral fluid shifts occurred, and 2 of the 3 measures were associated with greater OSA severity. Interventions that limit overnight fluid shifts should be tested as potential treatments for OSA among patients with subacute ischemic stroke.

Single-ion anisotropy effects on the critical behaviors of quantum entanglement and correlation in the spin-1 Heisenberg chain.

Quantum entanglement and correlations in the spin-1 Heisenberg chain with single-ion anisotropy are investigated using the quantum renormalization group method. Negativity and quantum discord (QD) are calculated with various anisotropy parameters △ and single-ion anisotropy parametersD. We focus on the relations between two abovementioned physical quantities and on transitions between the Néel, Haldane, and large-Dphases. It is found that both negativity and QD exhibit step-like patterns in different phases as the size of the system increases. Interestingly, the single-ion anisotropy parameterD, which can be modulated using nuclear electric resonance (2020Nature579205), plays an important role in tuning the quantum phase transition (QPT) of the system. Both the first partial derivative of the negativity and QD with respect toDor △ exhibit nonanalytic behavior at the phase transition points, which corresponds directly to the divergence of the correlation length. The quantum correlation critical exponents derived from negativity and QD are equal, and are the reciprocal of the correlation length exponent at each critical point. This work extends the application of quantum entanglement and correlations as tools for depicting QPTs in spin-1 systems.