Oxidative stress, malaria, sickle cell disease, and innate immunity.

Plasmodium falciparum shields from adaptive immunity in erythrocytes, but how might the innate immune system recognize infected cells? Replication by the parasite results in oxidative stress, causing surface expression of high-mannose glycans. These can act as pathogen-associated molecular patterns to stimulate phagocytosis in the spleen and the sickle cell allele enhances these responses.

Robust and Multifunctional Therapeutic Nanoparticles against Peritonitis-Induced Sepsis.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H2O2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

Electrochemical Cross-Dehydrogenative Coupling of Isochroman and Unactivated Ketones.

An unprecedented electrochemical cross-dehydrogenative coupling reaction between isochroman and unactivated ketones to directly synthesize α-substituted isochromans has been developed. This strategy provides a facile and efficient procedure to the direct activation of C(sp3)-H bond adjacent to the O atom of isochroman. The method features high atom economy, chemical oxidant-free, and mild conditions, in which methanesulfonic acid (MsOH) acts as both electrolyte and catalyst, making the process more convenient and environmentally friendly. Gram-scale experiment and synthesis of antitumor active compounds demonstrate the great potential of this protocol for practical applications.

Diverse Post-Metathesis Reactivities of Mixed Amido-Isothiocyanato Molybdenum Complexes.

Attempts to prepare mixed isothiocyanato-bis(imido) MoVI complexes led to the discovery of post-metathesis rearrangements toward three distinct products (1-3), which feature the NCS-derived chelators [N(NMe2)CS]2- (L1 in dinuclear 1 and 2) and [N(SiMe3)(NMe2)CS]- (L2 in mononuclear 3). Notably, the preparation of bidentate ligand L1 and its coordination chemistry are unprecedented. Together with computational studies, it is proposed that the putative "mono-substituted" intermediate [Mo(NtBu)2(NMe2)(NCS)] serves as the common starting point for the observed molecular transformations. Construction of the [Mo(NtBu)2(NCS)2] core was ultimately possible in the presence of additional stabilizing donors (THF or PMe3), which yielded the complexes [Mo(NtBu)2(NCS)2(THF)2] (4) and [Mo(NtBu)2(NCS)2(PMe3)2] (5).

Versatile polyphenolic platforms in regulating cell biology.

Polyphenolic materials are a class of fascinating and versatile bioinspired materials for biointerfacial engineering. In particular, due to the presence of active chemical groups, a series of unique physicochemical properties become accessible and tunable of the as-prepared polyphenolic platforms, which could delicately regulate the cell activities via cell-material contact-dependent interactions. More interestingly, polyphenols could also affect the cell behaviors via cell-material contact-independent manner, which arise due to their intrinsically functional characteristics (e.g., antioxidant and photothermal behaviors). As such, a comprehensive understanding on the relationship between material properties and desired biomedical applications, as well as the underlying mechanism at the cellular and molecular level would provide material design principles and accelerate the lab-to-clinic translation of polyphenolic platforms. In this review, we firstly give a brief overview of cell hallmarks governed by surrounding cues, followed by the introduction of polyphenolic material engineering strategies. Subsequently, a detailed discussion on cell-polyphenols contact-dependent interfacial interaction and contact-independent interaction was also carefully provided. Lastly, their biomedical applications were elaborated. We believe that this review could provide guidances for the rational material design of multifunctional polyphenols and extend their application window.

Effects of rational emotive behavior therapy on alexithymia, anxiety, depression and sleep quality of older people in nursing homes: a quasi-experimental study.

BACKGROUND: Alexithymia, a subclinical cognitive-affective impairment, is prevalent in older people and increases the risk of mental disorders. There is a vast alexithymia treatment gap, with majority of older people in nursing homes lacking access to adequate mental health care. The study aimed to evaluate the effects of rational emotive behavior therapy (REBT) on alexithymia, anxiety, depression and sleep quality of older people in nursing homes. METHODS: This quasi-experimental study was conducted with two groups (the control group and intervention) from March to November 2021. This study enrolled 86 participants, two of whom were lost to follow-up; 42 received usual care (control group) and 42 received REBT based on usual care (intervention group) in nursing homes. The older people in both groups were evaluated at baseline (T0), within one-week post-intervention (T1), and at 3-month follow-up (T3). Generalized estimating equations were used by SPSS version 26 to assess the differential change in the outcomes between the two groups. RESULTS: The intervention group shows significantly greater improvement in alexithymia than the control group at both T1 (ß = -8.167, 95%CI= -10.965, -5.368, P < 0.001) and T2 (ß=-4.119, 95%CI= -7.171, -1.067, P = 0.008). The two groups showed significant differences at both T1 and T2 in both difficulty identifying feelings and difficulty describing feelings. Compared to the control group, the intervention group shows a significant improvement in sleep quality at T2 (ß = -2.048, 95%CI=-4.004, -0.091, P = 0.040). The two groups showed significant differences at both T1 and T2 in both sleep disturbance and daytime dysfunction. For depression and anxiety, no significant differences were found between the intervention and control groups. CONCLUSIONS: REBT showed to be an effective method for improving alexithymia and sleep quality of older people in nursing homes. However, it failed to significantly alleviate anxiety and depression at least in a short-term trial. Refining this intervention may have a broader, more substantial impact on future research.

TFEB in Alzheimer's disease: From molecular mechanisms to therapeutic implications.

Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the most prevalent neurodegenerative disease worldwide. The primary pathological hallmarks of AD are the deposition of ß-amyloid plaques and neurofibrillary tangles. Autophagy, a pathway of clearing damaged organelles, macromolecular aggregates, and long-lived proteins via lysosomal degradation, has emerged as critical for proteostasis in the central nervous system (CNS). Studies have demonstrated that defective autophagy is strongly implicated in AD pathogenesis. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, enhances the expression of related genes that control autophagosome formation, lysosome function, and autophagic flux. The study of TFEB has greatly increased over the last decade, and the dysfunction of TFEB has been reported to be strongly associated with the pathogenesis of many neurodegenerative disorders, including AD. Here, we delineate the basic understanding of TFEB dysregulation involved in AD pathogenesis, highlighting the existing work that has been conducted on TFEB-mediated autophagy in neurons and other nonneuronal cells in the CNS. Additionally, we summarize the small molecule compounds that target TFEB-regulated autophagy involved in AD therapy. Our review may yield new insights into therapeutic approaches by targeting TFEB and provide a broadly applicable basis for the clinical treatment of AD.

Measurement of erythrocyte membrane mannoses to assess splenic function.

Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross-linked proteins with N-linked high-mannose glycans (HMGs). These glycans can be recognised by mannose-binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man5-9 GlcNAc2 structures. HMG levels correlated well with manual pit counts (r = 0.75-0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications.

Experimental Demonstration that No Tripartite-Nonlocal Causal Theory Explains Nature's Correlations.

Quantum theory predicts the existence of genuinely tripartite-entangled states, which cannot be obtained from local operations over any bipartite-entangled states and unlimited shared randomness. Some of us recently proved that this feature is a fundamental signature of quantum theory. The state |GHZ_{3}⟩=(|000⟩+|111⟩)/sqrt[2] gives rise to tripartite quantum correlations that cannot be explained by any causal theory limited to bipartite nonclassical common causes of any kind (generalizing entanglement) assisted with unlimited shared randomness. Hence, any conceivable physical theory that would reproduce quantum predictions will necessarily include genuinely tripartite resources. In this Letter, we verify that such tripartite correlations are experimentally achievable. We derive a new device-independent witness capable of falsifying causal theories wherein nonclassical resources are merely bipartite. Using a high-performance photonic |GHZ_{3}⟩ state with fidelities of 0.9741±0.002, we provide a clear experimental violation of that witness by more than 26.3 standard deviations, under the locality and fair sampling assumption. We generalize our Letter to the |GHZ_{4}⟩ state, obtaining correlations that cannot be explained by any causal theory limited to tripartite nonclassical common causes assisted with unlimited shared randomness.

Robust Natural Polyphenolic Adhesives against Various Harsh Environments.

Although adhesive hydrogels have been extensively explored, the development of adhesives with long-term strong adhesion capacity under various harsh environments is still met with profound challenges such as sophisticated preparation, long-term curing, and low bonding strength. Herein, a series of robust adhesive hydrogels have been developed via the polyphenol-epoxy-cross-linking (PEC) reactions between natural polyphenols (extracts) and epoxy glycidyl ethers. The as-prepared natural polyphenolic adhesive hydrogels could induce strong adhesion onto several kinds of typical substrates (i.e., wood, glass, paper, PET, PMMA, and Fe) under both dry and wet conditions based on multi-interactions. Moreover, those natural polyphenolic adhesives exhibited good low-temperature and solvent resistance performances, which could be widely used in different kinds of device repairment (i.e., chemical, petroleum, wood, metal, glass, plastic, rubber, and other industries) under different conditions. This work could provide new opportunities toward natural-inspired robust adhesives in various fields ranging from chemical transportation, industrial manufacturing, architectural design, and marine engineering to daily life.

Controlled Access to Four- and Six-Membered Palladacycles via Modifying Donor Abilities of ß-Ketiminato Ligands ("NacAcs").

The synthesis of Pd complexes of the type [PdBr(iPr2-bimy)(NacAc)] (NacAc = ß-ketiminate, iPr2-bimy = 1,3-diisopropylbenzimidazolin-2-ylidene) was attempted, in a continuing effort to quantify donor abilities of chelating ß-ketiminate ligands using the Huynh electronic parameter for bidentate donors (HEP2). Subtle variation of N-substituents on the NacAc backbone was discovered to induce a drastic change in the preferred chelating mode, in that the commonly encountered κ2-N,O-six-membered palladacycles were observed with R = Me and Et, while the unusual κ2-C,N-four-membered palladacycles were isolated with R = iPr, Cy, and tBu. Computational studies subsequently corroborated these findings, in the form of an overall exergonic six-to-four-membered ring contraction process and a lower associated activation energy for the three more electron-donating alkyl moieties. This trend in the established energy profiles can be attributed to a reduced HOMO-LUMO gap in the corresponding optimized structures of the six-membered ring complexes.

Hyposplenism and Gastrointestinal Diseases: Significance and Mechanisms.

BACKGROUND: Functional hyposplenism is a recognized complication of several gastroenterological disorders, including coeliac and inflammatory bowel diseases, and is believed to contribute to the increased infection risk seen in these disorders. SUMMARY: The mechanisms of hyposplenism are poorly understood. In this article, we review possible mechanisms underlying development of functional hyposplenism and discuss implications for its management. KEY MESSAGES: Identifying functional hyposplenism is important, as it may permit earlier recognition and treatment of serious infections through patient education and vaccination.

The ETS1-LINC00278 negative feedback loop plays a role in COL4A1/COL4A2 regulation in laryngeal squamous cell carcinoma.

The present study aimed to investigate LINC00278 expression in laryngeal squamous cell carcinoma (LSCC) and its involvement in the process of proliferation, migration, and invasion, providing a rationale for mining potential diagnostic and therapeutic targets of LSCC. Univariate and multivariate Cox regression analyses were performed to identify optimal prognostic lncRNAs. MTS, colony formation, wound healing, and Transwell invasion assays were used to determine the effects of LINC00278 overexpression on the proliferation, migration, and invasion of cancer cells. The expressions of signaling pathway-related proteins and epithelial-mesenchymal transition (EMT) marker proteins were detected using western blot. The chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to demonstrate the binding of ETS proto-oncogene 1, transcription factor (ETS1), and LINC00278 promoter region. The molecular targets of LINC00278 were identified by RNA sequencing analysis and co-expression analysis. Kaplan-Meier analysis and CIBERSORT algorithm were used to analyze survival and immune cell infiltration based on LINC00278, COL4A1, and COL4A2. Multivariate Cox regression was used to establish a six-gene prognostic model. LINC00278 expression was low in LSCC tissues, and it was significantly associated with the TNM (tumors/nodes/metastases) stage (p<0.001), lymphatic metastasis (p<0.01), and pathological differentiation (p<0.01). LINC00278 overexpression significantly reduced LSCC cell proliferation, migration, and invasion in TU686, TU177, and AMC-HN-8 cell lines. E-cadherin protein expression was increased, while N-cadherin, Vimentin, Zeb1, and Snail protein expression was decreased in the LINC00278 group, compared to the pcDNA3.1 group. Additionally, in AMC-HN-8 and FaDu cell lines, the LINC00278-treated group had significantly lower p-AKT and p-mTOR protein levels than the control group. ETS1 is a direct transcriptional regulator of the LINC00278 gene based on luciferase reporter assays and ChIP experiments. Western blot analysis demonstrated that high LINC00278 expression inhibited both ETS1 expression and phosphorylation. COL4A1/COL4A2 were identified as potential downstream targets of LINC00278. Meanwhile, the LINC00278/COL4A1/COL4A2-dominated low-risk group showed higher antigen-presenting activity and a higher immune score than the high-risk group. The findings indicated that ETS1 upregulated LINC00278 expression on the Y chromosome, which in turn inhibited LSCC growth in vivo and in vitro by inhibiting the AKT/mTOR signaling pathway via downregulation of COL4A1/COL4A2.

Merging the Non-Natural Catalytic Activity of Lipase and Electrosynthesis: Asymmetric Oxidative Cross-Coupling of Secondary Amines with Ketones.

We describe the enantioselective oxidative cross-coupling of secondary amines with ketones by combining the non-natural catalytic activity of lipase with electrosynthesis. Various 2,2-disubstituted 3-carbonyl indoles with a stereogenic quaternary carbon center were synthesized from 2-substituted indoles in yields up to 78 % with good enantio- and diastereoselectivities (up to 96 : 4 e.r. and >20 : 1 d.r.). This unprecedented protocol demonstrated that hydrolase catalysis is compatible with electrosynthesis, and the reaction can be carried out in organic solvents with a broad substrate scope and good stereoselectivity. This work provides insights into enzymatic electrosynthesis.

The red blood cell as a novel regulator of human B-cell activation.

Non-immune cells are increasingly recognized as important in regulating immunity, but the role of red blood cells (RBC) remains relatively unexplored, despite their abundance in the circulation and a cell surface rich in potential ligands. Here, we determine whether RBC influence the activation state of human B cells. Separation of RBC from peripheral blood mononuclear cells increased B-cell expression of HLA-DR/DP/DQ, whilst reconstitution reduced the levels of B-cell activation markers HLA-DR/DP/DQ, CD86, CD69 and CD40, as well as decreasing proliferative responses and IgM secretion. Inhibition of B cells required contact with RBC and was abrogated by either removal of sialic acids from RBC or blocking the corresponding lectin receptor CD22 on B cells. Chronic lymphocytic leukaemia B cells express low levels of CD22 and were less susceptible to inhibition by RBC, which may contribute to their activated phenotype. Taken together, the results identify a novel mechanism that may suppress inappropriate responsiveness of healthy B cells whilst circulating in the bloodstream.

Sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 is a rapidly internalised cell-surface antigen expressed by acute myeloid leukaemia cells.

Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 has recently been identified as a critical tumour checkpoint, augmenting the expression and function of programmed death-ligand 1. We raised a monoclonal antibody, A9E8, specific for Siglec-15 using phage display. A9E8 stained myeloid leukaemia cell lines and peripheral cluster of differentiation (CD)33+ blasts and CD34+ leukaemia stem cells from patients with acute myeloid leukaemia (AML). By contrast, there was minimal expression on healthy donor leucocytes or CD34+ stem cells from non-AML donors, suggesting targeting Siglec-15 may have significant therapeutic advantages over its fellow Siglec CD33. After binding, A9E8 was rapidly internalised (half-life of 180 s) into K562 cells. Antibodies to Siglec-15 therefore hold therapeutic potential for AML treatment.

Large-tuning-range frequency stabilization of an ultraviolet laser by an open-loop piezoelectric ceramic controlled Fabry-Pérot cavity.

We demonstrate a laser frequency stabilization method with large tuning range to stabilize a UV laser by installing piezoelectric ceramic actuators into a Fabry-Pérot cavity with an ultra-low expansion spacer. To suppress piezoelectric drift, a two-layer symmetrical structure is adopted for the piezoelectric actuator, and a 14.7 GHz tuning range is achieved. The short-term drift of the piezoelectric ceramics caused by temperature and creep is eliminated, and the long-term drift is 0.268 MHz/h when the Fabry-Pérot cavity is sealed in a chamber without a vacuum environment. The long-term frequency drift is mainly caused by stress release and is eliminated by compensating the cavity voltage with an open loop. Without the need for an external reference or a vacuum environment, the laser frequency stabilization system is greatly simplified, and it can be extended to wavelengths ranging from ultraviolet to infrared. Owing to its simplicity, stability, and large tuning range, it is applicable in cold atom and trapped ion experiments.

Protective Effects of Bone Marrow Mesenchymal Stem Cells (BMMSCS) Combined with Normothermic Machine Perfusion on Liver Grafts Donated After Circulatory Death via Reducing the Ferroptosis of Hepatocytes.

BACKGROUND To improve the quality of liver grafts from extended-criteria donors donated after circulatory death (DCD), this study explored whether bone marrow mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP) have protective effects on DCD donor livers and the effects of ferroptosis in this procedure. MATERIAL AND METHODS Twenty-four male rat DCD donor livers were randomly and averagely divided into normal, static cold storage (SCS), NMP, and NMP combined with BMMSCs groups. Liver function, bile secretion, and pathological features of DCD donor livers were detected to evaluate the protective effects of NMP and BMMSCs on DCD donor livers. Hydrogen peroxide was used to induce an oxidative stress model of hepatocyte IAR-20 cells to evaluate the protective effects of BMMSCs in vitro. RESULTS Livers treated with NMP combined with BMMSCs showed better liver function, relieved histopathological damage, reduced oxidative stress injury and ferroptosis, and the mechanism of reduction was associated with downregulation of intracellular reactive oxygen species (ROS) and free Fe²âº levels. BMMSCs showed significant protective effects on the ultrastructure of DCD donor livers and ROS-induced injury to IAR-20 cells under electron microscopy. BMMSCs also significantly improved the expression level of microtubule-associated protein 1 light chain 3 (LC3)-II in both DCD donor livers and ROS-induced injured IAR-20 cells, including upregulating the expression of ferritin. CONCLUSIONS BMMSCs combined with NMP could reduce the level of ROS and free Fe²âº in oxidative stress damaged rat DCD donor livers, potentially reduce the ferroptosis in hepatocytes, and repair both morphology and function of DCD donor livers.

The matrix metalloproteinase gene family: a significant prognostic gene lineage correlated with immune infiltrates in laryngeal squamous cell carcinoma.

This study aimed to elucidate the potential genes of the matrix metalloproteinase (MMP) family, responsible for the progression of laryngeal squamous cell carcinoma (LSCC). Besides, we ascertained the changes in common malignant behaviors in vitro by knocking down MMP1. TCGA, GEO, Oncomine, and microarray data were conducted to analyze the expression levels of MMPs and to find tissue-specific genes in LSCC. Univariate and multivariate Cox regression analyses were established in the construction of a prognostic model based on expression profiles and clinical information of LSCC in TCGA. We then comprehensively analyzed survival, co-expression network, and immune infiltration based on a prognostic model by Kaplan-Meier analysis, WGCNA, and CIBERSORT. Thereafter, qRT-PCR, proliferation, Transwell, and wound-healing assays were used to assess the accuracy of the bioinformatics data. A total of seven genes in the MMP family were identified as differentially expressed genes (DEGs) by integrating three public databases and microarray data. Additionally, multivariate Cox regression was used to establish a four-gene (MMP1/3/8/10) prognostic model, which exhibited a better predictive accuracy than the TNM (tumors/nodes/metastases) based model. The prognostic model was related to plasma cells, CD8+ T cells, follicular helper T cells, resting NK cells, and M0 macrophages infiltration. The expression of MMP1, MMP3, and MMP10 was the highest in head and neck squamous cell carcinoma (HNSC) compared to other cancer in the Oncomine and GEPIA dataset. Further, MMP1 demonstrated significant upregulation in 40 paired LSCC tissues. Eventually, MMP1 downregulation inhibited cell viability, colony formation, and cell migration in TU686 and FaDu cells. Our findings suggest that the four-gene signature might be associated with the prognosis. Further, we revealed that MMP1 is a pivotal biomarker for the biotherapy and prognostic evaluation of patients with LSCC.

Identification of MSC-AS1, a novel lncRNA for the diagnosis of laryngeal cancer.

PURPOSE: Our study was aimed to identify potential lncRNAs related to laryngeal cancer (LC) and explore their potential regulatory mechanisms. METHODS: RNA sequencing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to identify differentially expressed genes (DEGs). Receiver operating characteristic (ROC) curve analysis was performed to analyze the sensitivity and specificity of differentially expressed lncRNAs (DElncRNAs) as biomarkers. Weighted gene co-expression network analysis (WGCNA) was applied to identify co-expressed DElncRNAs and differentially expressed mRNAs (DEmRNAs) associated with clinical indicators. We performed functional enrichment analysis on target genes and constructed a lncRNA-miRNA-mRNA ceRNA network. The expression of lncRNA and mRNAs in ceRNA network were validated via RT-qPCR. RESULTS: By differential expression analyzing TCGA and GEO data, 6 up-regulated DElncRNAs were consistently identified, and their predictive performance were suggested to be considerable via ROC curve. 1998 DEmRNAs and 6 lncRNAs were involved in the construction of WGCNA network, in which the MEblue module was positively correlated with clinical stage. Functional enrichment analysis of this module suggested that the functions of DEmRNAs were closely involved in PI3K/Akt pathway. A ceRNA network composed of MSC-AS1, miR-429, COL4A1 and ITGAV was constructed. It was verified by RT-qPCR that the lncRNA and mRNAs in the ceRNA network were highly expressed in multiple LC tissues. CONCLUSIONS: This study identified lncRNA MSC-AS1 as a potential biomarker of LC. Besides, we constructed a ceRNA network, which provides a basis for the research of ceRNA in LC.