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.

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.

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".

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.

Enantioselective Total Syntheses of Manginoids†A and†C and Guignardones†A and†C.

An enantioselective synthetic approach for preparing manginoids and guignardones, two types of biogenetically related meroterpenoids, is reported. This bioinspired and divergent synthesis employs an oxidative 1,3-dicarbonyl radical-initiated cyclization and cyclodehydration of the common precursor to forge the central ring of the manginoids and guignardones, respectively, at a late stage. Key synthetic steps include silica-gel-promoted semipinacol rearrangement to form the 6-oxabicyclo[3.2.1]octane skeleton and the Suzuki-Miyaura reaction of vinyl bromide to achieve fragment coupling. This synthesis protocol enables the asymmetric syntheses of four fungal meroterpenoids from commercially available materials.

Mitophagy is involved in chromium (VI)-induced mitochondria damage in DF-1 cells.

Cr (VI), which is a common heavy metal pollutant with strong oxidizing property, exists widely in nature. Organisms can be exposed to Cr (VI) through various means. Cr (VI) causes mitochondrial dysfunction after being absorbed by cells. Whether Cr (VI) induces the selective autophagic degradation of mitochondria, which is a biological process called mitophagy, remains unclear. Mitophagy not only recycles intracellularly damaged mitochondria to compensate for nutrient deprivation but also is involved in mitochondria quality control. Thus, this study investigated whether Cr (VI) could induce mitophagy in DF-1 cells. Carbonyl cyanide m-chlorophenylhydrazone, which is a mitochondrial-uncoupling reagent that induces mitophagy, was used. DF-1 cells were incubated with different doses of Cr (VI) for varying durations. The autophagy-related proteins LC3-II and p62 levels decreased after 6 h of Cr (VI) treatment but recovered within 24 h. The mitochondrial membrane potential, which is an indicator of mitochondrial damage, was detected by flow cytometry. We found that different durations of Cr (VI) treatment induced mitochondrial mass decrease and depolarization. Furthermore, the expression of the protein translocase of outer mitochondrial membrane 20 (TOMM20), which is a mitochondrial outer membrane protein, was decreased significantly in the presence of Cr (VI). Our findings indicate that Cr (VI) may contribute to the mitochondrial morphology and function damage and may therefore lead to the autophagic clearance of mitochondria.

Pharmacokinetics and bioavailability of tildipirosin in rabbits following single-dose intravenous and intramuscular administration.

The objective of this study was to determine the pharmacokinetics of tildipirosin in rabbits after a single intravenous (i.v.) and intramuscular (i.m.) injection at a dose of 4 mg/kg. Twelve white New Zealand rabbits were assigned to a randomized, parallel trial design. Blood samples were collected prior to administration and up to 14 days postadministration. Plasma concentrations of tildipirosin were quantified using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The pharmacokinetic parameters were calculated using a noncompartmental model in WinNonlin 5.2 software. Following i.v. and i.m. administration, the elimination half-life (T1/2λ ) was 81.17 ± 9.28 and 96.68 ± 15.37 hr, respectively, and the mean residence time (MRTlast ) was 65.44 ± 10.89 and 67.06 ± 10.49 hr, respectively. After i.v. injection, the plasma clearance rate (Cl) and volume of distribution at steady state (Vdss ) were 0.28 ± 0.10 L kg-1  h-1 and 17.78 ± 5.15 L/kg, respectively. The maximum plasma concentration (Cmax ) and time to reach maximum plasma concentration (Tmax ) after i.m. administration were 836.2 ± 117.9 ng/ml and 0.33 ± 0.17 hr, respectively. The absolute bioavailability of i.m. administration was 105.4%. Tildipirosin shows favorable pharmacokinetic characteristics in rabbits, with fast absorption, extensive distribution, and high bioavailability. These findings suggest that tildipirosin might be a potential drug for the prevention and treatment of respiratory diseases in rabbits.

Divergent Total Synthesis of Euphoranginol†C, Euphoranginone†D, ent-Trachyloban-3ß-ol, ent-Trachyloban-3-one, Excoecarin†E, and ent-16α-Hydroxy-atisane-3-one.

A divergent synthetic approach to biogenetically related diterpenoids such as ent-kauranes, ent-trachylobanes, ent-beyerane, and ent-atisane has been developed. The unified synthetic route involves the De Mayo reaction to rapidly generate the bicyclo[3.2.1]-octane moiety of ent-kaurane. The key reactions also include bioinspired nucleophilic cyclopropanation generating the [3.2.1.02,7 ]-tricyclic core of ent-trachylobane and regioselective cyclopropane fragmentation furnishing ent-beyerane and ent-atisane through the nucleophilic attack and protonation of the cyclopropane ring. This strategy enables the asymmetric total syntheses of six diterpenoids from the commercially available geraniol.

Protective effects of anthocyanin against apoptosis and oxidative stress induced by arsanilic acid in DF-1 cells.

Anthocyanin is a natural plant pigment that acts as an antioxidant and scavenges free radicals. This study aimed to investigate the potential protective role of nightshade anthocyanin (NA), a natural flavonoid compound, against the arsanilic acid (ASA)-induced cell death of DF-1 cells. DF-1 cells were initially exposed to ASA, and then NA was applied to the treated cells. Cell viability, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis were examined. Results showed that NA inhibited the ASA-induced decrease in cell viability, increase in ROS, and loss of MMP in DF-1 cells. Moreover, caspase-3 activation was inhibited by ASA supplementation and NA attenuated the ASA-induced increase in the percentage of apoptotic cells. In summary, our study suggested that NA can enhance ASA-induced cytotoxicity and apoptosis, thereby providing a basis for the molecular mechanisms of NA-mediated protection.

Effects of Cr(VI)-induced calcium-sensing receptor activation on DF-1 cell pyroptosis.

This study aims to investigate the effects of Cr(VI)-induced calcium-sensing receptor (CaSR) activation on DF-1 cell pyroptosis. Previous studies show that Cr(VI) could accumulate in the body of chickens and change Ca levels. Hence, a Ca-related pathway may be an important mechanism participating in some pathological processes. Pyroptosis level, which is meditated by CaSR, increases under Cr(VI) accumulation. In the present study, pyroptosis was determined by flow cytometry to detect SYTOX blue and caspase-1 staining followed by morphological observation. Interleukin (IL)-1ß and IL-18 levels were detected by ELISA, while CaSR protein and [Ca2+]i contents were detected by Western blot and fluorescence microplate spectrophotometry, respectively. The results showed that Cr(VI) causes DF-1 cell pyroptosis in a time- and dose-dependent manner and that this effect is caspase-1 dependent. Further experiments indicated that pyroptosis could be induced by Cr(VI) and is accompanied by up-regulated [Ca2+]i content. CaSR inhibition led to decreases in pyroptosis level. Some mechanisms may be involved in Cr(VI)-triggered CaSR activation and enhance DF-1 cell pyroptosis. Taken together, the results of this study support future investigations on Cr(VI)-induced pyroptosis in DF-1 cells.

The regulatory role of COX-2 in the interaction between Cr(VI)-induced endoplasmic reticulum stress and autophagy in DF-1 cells.

Hexavalent chromium (Cr(VI)) is a common environmental pollutant. Exposure of Cr(VI) can lead to cell autophagy, but the preventive measures for diminishing Cr(VI)-induced autophagy need further study. COX-2 can be induced by several heavy metals and can lead to endoplasmic reticulum (ER) stress and autophagy; thus, COX-2, ER stress, and autophagy may be related. This study mainly investigated the role of COX-2 in the eIF2α-ATF4 pathway, which is a major pathway in cell autophagy. In this study, Cr(VI) was used as a xenobiotic to determine changes in the parameters of ER stress, autophagy, and COX-2 levels. At the same time, a clear contrast was obtained by assigning positive and negative controls of ER stress and autophagy. The results showed that during Cr(VI) invasion, the parameters of ER stress and autophagy (such as BiP, PERK, p62, LC3-II, and mTOR) were enhanced, similarly to the positive control of ER stress and/or the autophagy controls. Such enhancement is a protective mechanism for cell survival. Additionally, the COX-2 levels increased. Moreover, when COX-2 was inhibited, the PERK level remained high, whereas the LC3-II level decreased. This finding suggests that COX-2 specifically affects the interaction between ER stress and autophagy. Notably, this study reveals that Cr(VI) can induce ER stress and autophagy in DF-1 cells and that COX-2 plays an essential role in the interaction between ER stress and autophagy.

Additive- and Photocatalyst-Free Borylation of Arylazo Sulfones under Visible Light.

We developed a photocatalyst-free and additive-free, visible light induced borylation reaction using arylazo sulfones as starting material. This protocol shows some advantages such as mild conditions, simple equipment, and wide substrate scope, which gives a complementary protocol for the preparation of arylboronates.

Layer Dependence and Light Tuning Surface Potential of 2D MoS2 on Various Substrates.

Here surface potential of chemical vapor deposition (CVD) grown 2D MoS2 with various layers is reported, and the effect of adherent substrate and light illumination on surface potential of monolayer MoS2 are investigated. The surface potential of MoS2 on Si/SiO2 substrate decreases from 4.93 to 4.84 eV with the increase in the number of layer from 1 to 4 or more. Especially, the surface potentials of monolayer MoS2 are strongly dependent on its adherent substrate, which are determined to be 4.55, 4.88, 4.93, 5.10, and 5.50 eV on Ag, graphene, Si/SiO2 , Au, and Pt substrates, respectively. Light irradiation is introduced to tuning the surface potential of monolayer MoS2 , with the increase in light intensity, the surface potential of MoS2 on Si/SiO2 substrate decreases from 4.93 to 4.74 eV, while increases from 5.50 to 5.56 eV on Pt substrate. The I-V curves on vertical of monolayer MoS2 /Pt heterojunction show the decrease in current with the increase of light intensity, and Schottky barrier height at MoS2 /Pt junctions increases from 0.302 to 0.342 eV. The changed surface potential can be explained by trapped charges on surface, photoinduced carriers, charge transfer, and local electric field.

Urinary heme oxygenase-1 as a potential biomarker for early diabetic nephropathy.

BACKGROUND: Our previous study showed that increases of urinary heme oxygenase-1 (uHO-1) could be a potential biomarker indicating evaluating intrarenal oxidative damage in obstructive nephropathy. Activation of oxidative stress is an important mediator of diabetic nephropathy (DN). The aim of this study was to investigate the clinical implications of uHO-1 levels in patients with type 2 diabetes. METHODS: Eighty-four type 2 diabetic patients with normoalbuminuria (n=28), microalbuminuria (n=28), and macroalbuminuria (n=28) were included in this study. Control samples were collected from healthy volunteers (n=28) who had normal albuminuria and renal function. Urine HO-1 levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: Urinary HO-1/creatinine (cr.) levels were significantly elevated in diabetic patients with microalbuminuria and macroalbuminuria compared to those in diabetic patients with normoalbuminuria (P<0.001) and control subjects (all P<0.001). In diabetic patients with normoalbuminuria, uHO-1/cr. levels were also higher than those in controls (P<0.001). Multivariate regression analyses revealed that uHO-1/cr. levels were positively correlated to urinary albumin/creatinine ratio and inversely correlated to glomerular filtration rate. Receiver operating characteristic (ROC) curve analysis of uHO-1/cr. levels for early diagnosis and detection of DN revealed that the cut-off value of uHO-1/cr. was 4.59 ng/mg (sensitivity 75%, specificity 78.6%). CONCLUSIONS: The findings of this study indicate that increases of urine HO-1 levels can be detected in patients with type 2 diabetes before the onset of significant albuminuria, and associated with renal derangement in patients with established diabetic nephropathy. Urinary HO-1 may be used as an early biomarker for diabetic renal injury.

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.

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.

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.

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.

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.