T cell cascade regulation initiates systemic antitumor immunity through living drug factory of anti-PD-1/IL-12 engineered probiotics.

Immune checkpoint blockade (ICB) has revolutionized cancer therapy but only works in a subset of patients due to the insufficient infiltration, persistent exhaustion, and inactivation of T cells within a tumor. Herein, we develop an engineered probiotic (interleukin [IL]-12 nanoparticle Escherichia coli Nissle 1917 [INP-EcN]) acting as a living drug factory to biosynthesize anti-PD-1 and release IL-12 for initiating systemic antitumor immunity through T cell cascade regulation. Mechanistically, INP-EcN not only continuously biosynthesizes anti-PD-1 for relieving immunosuppression but also effectively cascade promote T cell activation, proliferation, and infiltration via responsive release of IL-12, thus reaching a sufficient activation threshold to ICB. Tumor targeting and colonization of INP-EcNs dramatically increase local drug accumulations, significantly inhibiting tumor growth and metastasis compared to commercial inhibitors. Furthermore, immune profiling reveals that anti-PD-1/IL-12 efficiently cascade promote antitumor effects in a CD8+ T cell-dependent manner, clarifying the immune interaction of ICB and cytokine activation. Ultimately, such engineered probiotics achieve a potential paradigm shift from T cell exhaustion to activation and show considerable promise for antitumor bio-immunotherapy.

A Silver Nanocluster Assembled by a Superatomic Building Unit.

A unique assembly of a two-electron superatom, [Ag10{S2P(OiPr)2}8], as a primary building unit in the construction of a supramolecule [Ag10{S2P(OiPr)2}8]2(µ-4,4'-bpy) through a 4,4'-bipyridine (4,4'-bpy) linker is reported. This approach is facilitated by an open site in the structure that allows for effective pairing. The assembled structure demonstrates a minimal solvatochromic shift across organic solvents with variable polarities, highlighting the influence of self-assembly on the photophysical properties of silver nanoclusters.

Hydride-doped coinage metal superatoms and their catalytic applications.

Superatomic constructs have been identified as a critical component of future technologies. The isolation of coinage metal superatoms relies on partially reducing metallic frameworks to accommodate the mixed valent state required to generate a superatom. Controlling this reduction requires careful consideration in reducing the agent, temperature, and the ligand that directs the self-assembly process. Hydride-based reducing agents dominate the synthetic wet chemical routes to coinage metal clusters. However, within this category, a unique subset of superatoms that retain a hydride/s within the nanocluster post-reduction have emerged. These stable constructs have only recently been characterized in the solid state and have highly unique structural features and properties. The difficulty in identifying the position of hydrides in electron-rich metallic constructs requires the combination and correlation of several analytical methods, including ESI-MS, NMR, SCXRD, and DFT. This text highlights the importance of NMR in detecting hydride environments in these superatomic systems. Added to the complexity of these systems is the dual nature of the hydride, which can act as metallic hydrogen in some cases, resulting in entirely different physical properties. This review includes all hydride-doped superatomic nanoclusters emphasizing synthesis, structure, and catalytic potential.

Doping effect on a two-electron silver nanocluster.

This study investigates the effects of metal addition and doping of a 2-electron silver superatom, [Ag10{S2P(OiPr)2}8] (Ag10). When Ag+ is added to Ag10 in THF solution, [Ag11{S2P(OiPr)2}8(OTf)] (Ag11) is rapidly formed almost quantitatively. When the same method is used with Cu+, a mixture of alloys, [CuxAg11-x{S2P(OiPr)2}8]+ (x = 1-3, CuxAg11-x), is obtained. In contrast, introducing Au+ to Ag10 leads to decomposition. The structural and compositional analysis of Ag11 was characterized by single-crystal X-ray diffraction (SCXRD), ESI-MS, NMR spectroscopy, and DFT calculations. While no crystal structure was obtained for CuxAg11-x, DFT calculations provide insights into potential sites for copper location. The absorption spectrum exhibits a notable blue shift in the low-energy band after copper doping, contrasting with that of the slight shift observed in 8-electron Cu-doped Ag nanoclusters. Ag11 and CuxAg11-x are strongly emissive at room temperature, and solvatochromism across different organic solvents is highlighted. This study underscores the profound influence of metal addition and doping on the structural and optical properties of silver nanoclusters, providing important contributions to understanding the nanoclusters and their photophysical behaviors.

Combined bioinformatics and machine learning methodologies reveal prognosis-related ceRNA network and propose ABCA8, CAT, and CXCL12 as independent protective factors against osteosarcoma.

BACKGROUND: Aberrant circular RNA (circRNA) acts as an oncogene or suppressor during neoplasm initiation and development. However, the functions of most circRNAs in osteosarcoma (OS) remain unclear. OBJECTIVES: We aimed to investigate the expression, molecular functions and mechanisms underlying circRNAs in OS. MATERIAL AND METHODS: Network interaction, pathway enrichment and regression analyses were performed to determine differentially expressed (DE) circRNAs, microRNAs (miRNAs) and messenger RNAs (mRNAs). We constructed competitive endogenous RcodeNA (ceRNA) networks and integrated patient clinical data to analyze the relationship between the networks and prognosis. The circRNA, miRNA and mRNA data were retrieved from Gene Expression Omnibus (GEO) microarray datasets. A circRNA-miRNA-mRNA interaction network was established and visualized using miRNet. Protein interactions were investigated using STRING and Cytoscape, and hub genes were identified using the MCODE plug-in. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway analyses were performed to determine the DEmRNAs. LIMMA and RobustRankAggreg were used to screen for DERNAs. Node genes in the interaction network were analyzed using least absolute shrinkage and selection operator (LASSO) and Cox regression to obtain OS-related ceRNA networks. RESULTS: We identified 9 DEcircRNAs, 243 DEmiRNAs and 211 DEmRNAs. We found that a ceRNA subnetwork, based on 1 circRNA, 1 miRNA and 8 mRNAs, was closely associated with OS prognosis. Integrating the proportional hazards model and survival analysis revealed 3 independent protective factors: adenosine triphosphate (ATP)-binding cassette sub-family A member 8 (ABCA8), catalase (CAT) and C-X-C motif chemokine ligand 12 (CXCL12). CONCLUSIONS: Our study provides novel insights into circRNA-related ceRNA networks and identifies potential prognostic biomarkers of OS.

Efficacy of Oral Appliance for Mild, Moderate, and Severe Obstructive Sleep Apnea: A Meta-analysis.

OBJECTIVE: Oral appliances (OA) are the recommended first-line option for mild-to-moderate obstructive sleep apnea (OSA)-hypopnea. However, there is a lack of evidence to compare the effectiveness of OA in different severities of OSA. The purpose of this study was to investigate the therapeutic effects of preferred OA (tongue retention devices [TRD] and mandibular advancement device [MAD]) in different severities of OSA. DATA SOURCES: PubMed/MEDLINE, The Cochrane Library, and Web of Science. REVIEW METHODS: Concentrating on the efficacy of OA, 2 authors searched 3 databases up to November 10, 2022, independently and systematically, following the requirements and steps of the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Ultimately, 42 studies with 2265 patients met the criteria for inclusion in OA. Overall, the apnea-hypopnea index improved by 48% (5.6), 67% (14.92), and 62% (32.1) in mild, moderate, and severe OSA, respectively. Subgroup analysis showed a significant difference between MAD and TRD efficacy in mild OSA (58% vs 21%). However, no significant difference was seen between MAD and TRD efficacy in moderate (67% vs 66%) and severe OSA (66% vs 51%). There was no significant difference across groups in the Epworth Sleepiness Scale, oxygen desaturation index (ODI), and lowest oxygen saturation (LSAT). CONCLUSION: Overall, both TRD and MAD are effective treatments for moderate and severe OSA. MAD is efficacious in mild OSA, while TRD requires further validation. Furthermore, mild-moderate and severe OSA received similar improvements in sleepiness, ODI, and LSAT. This study complements the evidence for the efficacy of OA.

Associations Between Sleep Spindle Metrics, Age, Education and Executive Function in Young Adult and Middle-Aged Patients with Obstructive Sleep Apnea.

Purpose: This study aimed to investigate the association between sleep spindle metrics and executive function in individuals with obstructive sleep apnea (OSA). Furthermore, we examined the association of age and education on executive function. Patients and Methods: A total of 230 (40.90 ± 8.83 years, F/M = 45/185) participants were enrolled. Overnight electroencephalogram (C3-M2) recording detected sleep spindles by a novel U-Net-type neural network that integrates temporal information with time-frequency images. Sleep spindle metrics, including frequency (Hz), overall density (events/min), fast density (events/min), slow density (events/min), duration (sec) and amplitude (µV), were measured. Executive function was assessed using standardized neuropsychological tests. Associations between sleep spindle metrics, executive function, and demographic factors were analyzed using multivariate linear regression. Results: In fully adjusted linear regression models, higher overall sleep spindle density (TMT-A, B=-1.279, p=0.009; TMT-B, B=-1.813, p=0.008), fast sleep spindle density (TMT-A, B=-1.542, p=0.048; TMT-B, B=-2.187, p=0.036) and slow sleep spindle density (TMT-A, B=-1.731, p=0.037; TMT-B, B=-2.449, p=0.034) were associated with better executive function. And the sleep spindle duration both during N2 sleep time (TMT-A, B=-13.932, p=0.027; TMT-B, B=-19.001, p=0.034) and N3 sleep time (TMT-B, B=-29.916, p=0.009; Stroop-incongruous, B=-21.303, p=0.035) was independently associated with better executive function in this population. Additionally, age and education were found to be highly associated with executive function. Conclusion: Specific sleep spindle metrics, higher overall density, fast density and slow density during N2 sleep time, and longer duration during N2 and N3 sleep time, are independent and sensitive indicators of better executive function in young adult and middle-aged patients with OSA. Further research is needed to explore the underlying mechanisms and clinical implications of these findings.

Hydride-Containing Pt-doped Cu-rich Nanoclusters: Synthesis, Structure, and Electrocatalytic Hydrogen Evolution.

A structurally precise hydride-containing Pt-doped Cu-rich nanocluster [PtH2 Cu14 {S2 P(Oi Pr)2 }6 (CCPh)6 ] (1) has been synthesized. It consists of a bicapped icosahedral Cu14 cage that encapsulates a linear PtH2 unit. Upon the addition of two equivalents of CF3 COOH to 1, two hydrido clusters are isolated. These clusters are [PtHCu11 {S2 P(Oi Pr)2 }6 (CCPh)4 ] (2), which is a vertex-missing Cu11 cuboctahedron encaging a PtH moiety, and [PtH2 Cu11 {S2 P(Oi Pr)2 }6 (CCPh)3 ] (3), a distorted 3,3,4,4,4-pentacapped trigonal prismatic Cu11 cage enclosing a PtH2 unit. The electronic structure of 2, analyzed by Density Functional Theory, is a 2e superatom. The electrocatalytic activities of 1-3 for hydrogen evolution reaction (HER) were compared. Notably, Cluster 2 exhibited an exceptionally excellent HER activity within metal nanoclusters, with an onset potential of -0.03 V (at 10 mA cm-2 ), a Tafel slope of 39 mV dec-1 , and consistent HER activity throughout 3000 cycles in 0.5 M H2 SO4 . Our study suggests that the accessible central Pt site plays a crucial role in the remarkable HER activity and may provide valuable insights for establishing correlations between catalyst structure and HER activity.

Locating Interstitial Hydrides in MH2@Cu14 (M = Cu, Ag) Clusters by Single-Crystal X-ray Diffraction.

Two structures, [Cu15H2(S2CNnBu2)6(C≡CPh)6][CuCl2] (1) and [AgH2Cu14{S2P(OiPr)2}6(C≡CPh)6][PF6] (2), are characterized by X-ray crystallography with high-quality single crystals. The position of interstitial hydrides can be accurately located. In addition, the refinement of the hydrides with anisotropic displacement parameters (ADPs) was successful. The distances between the central atom and copper atoms, as well as the distances within the metal cages surrounding the hydrides, are analyzed and compared with similar MH2@Cu14 (M = Cu, Ag, Pd) compounds. This work provides a thoughtful and accurate assessment of the considerations and challenges associated with anisotropic refinement for H atoms, particularly in X-ray data collection.

Hydride Doping Effects on the Structure and Properties of Eight-Electron Rh/Ag Superatoms: The [RhHx@Ag21-x{S2P(OnPr)2}12] (x = 0-2) Series.

Three hitherto unknown eight-electron rhodium/silver alloy nanoclusters, [RhAg21{S2P(OnPr)2}12] (1), [RhHAg20{S2P(OnPr)2}12] (2), and [RhH2Ag19{S2P(OnPr)2}12] (3), have been isolated and fully characterized. Cluster 1 contains a regular Rh@Ag12 icosahedral core, whereas 2 and 3 exhibit distorted RhH@Ag12 and RhH2@Ag12 icosahedral cores. The single-crystal neutron structure of 2 located the encapsulated hydride at the center of an enlarged RhAg3 tetrahedron. A similar position was found by neutron diffraction for one of the hydrides in 3, whereas the other hydride is trigonally coordinated to Rh and an elongated Ag-Ag edge. The solid-state structures of 1-3 possess C1 symmetry due to the asymmetric arrangement of the surrounding capping Ag atoms. Our investigation shows that the insertion of one hydride dopant provokes the elimination of one capping silver atom on the cluster surface, resulting in the general formula [RhHx@Ag21-x{S2P(OnPr)2}12] (x = 0-2), which maintains the same number of cluster electrons as well as neutral charge. Clusters 1-3 exhibit an intense emission band in the NIR region. Contrarily to their PdAg21 and PdHAg20 relatives, the 4d orbitals of the encapsulated heterometal are somewhat involved in the optical processes.

Galvanic replacement-induced introduction of a heteroligand into bimetallic and trimetallic nanoclusters.

Heteroleptic 8-electron silver-rich alloy nanoclusters, [Au@Au4Ag12(dtp)7(PPh3)4]2+ (1) and [Pt@Au4Ag11(dtp)7(PPh3)4] (2), were successfully synthesized via a galvanic replacement reaction of 1,1-dithiolate-protected M@Ag20 (M = Au and Pt) nanoclusters with Au(I)-phosphine salts, leading to the alteration of the cluster nuclearity and geometry of shell skeletons but retaining the same 8-electron count.

Unusual core engineering on a copper hydride nanoball.

A neutral polyhydrido copper cluster, [Cu27H15{S2CNnBu2}12] (abbreviated as [Cu27H15]), was prepared by the reaction of dithiocarbamates (dtc), Cu(I) salts and NaBH4. The isolated cluster provides insights into core engineering, demonstrating its novel ability to reversibly add or remove one copper atom from the cluster core. Single-crystal X-ray analysis reveals that the new core-shell structure exhibits a Cu24 rhombicuboctahedral outer cage and an inner Cu3 triangular kernel. The two core-shell clusters, [Cu27H15{S2CNnBu2}12] and previously published [Cu28H15(S2CNnBu2)12]+ (abbreviated as [Cu28H15]+), are only differentiated by one copper atom in their inner core. Importantly, we demonstrate core engineering with the controllable reversible transition between an irregular Cu4 tetrahedron and a Cu3 triangle, whilst maintaining their outer Cu24 shell intact. The 15 hydride atoms in [Cu27H15], coordinated in three different modes, are co-incident with the hydride positions in [Cu28H15]+. The degradation of [Cu27H15] in solution or the addition of one eq. of Cu(I) ions leads to the conversion of [Cu27H15] into [Cu28H15]+, while the reverse transformation can be achieved by the addition of either formic acid or a reducing agent to [Cu28H15]+. A dicationic species was observed in the ESI mass spectrum, and the composition is formulated as [Cu56H30(S2CNnBu2)24]2+, a dimer of [Cu27H15(S2CNnBu2)12 + Cu+]22+. The dimeric species was further explored by DFT calculations, suggesting that the lowest energy structure consists of a [Cu28H15]+ and a [Cu27H15] cluster connected through one Cu+ atom bridge. As a result, [Cu27H15] is considered an intermediate species in the formation of the more stable [Cu28H15]+ nanoball.

Superatom Pruning by Diphosphine Ligands as a Chemical Scissor.

A two-electron silver superatom, [Ag6{S2P(OiPr)2}4(dppm)2] (1), was synthesized by adding dppm (bis(diphenylphosphino)methane) into [Ag20{S2P(OiPr)2}12] (8e). It was characterized by single-crystal crystallography, multinuclear NMR spectroscopy, electrospray ionization-mass spectrometry, density functional theory (DFT), and time-dependent DFT calculations. The added dppm ligands, which carry out the nanocluster-to-nanocluster transformation, act as a chemical scissor to prune the nanocluster geometrically from an icosahedron-based Ag20 nanocluster (NC) to an octahedral Ag6 NC and electronically from eight-electron to two-electron. Eventually, dppm was involved in the protective shell to form a new heteroleptic NC. The temperature-dependent NMR spectroscopy confirms its fluxional behavior, showing the fast atomic movement at ambient temperature. Compound 1 exhibits a bright yellow emission under UV irradiation at ambient temperature with a quantum yield of 16.3%. This work demonstrates a new methodology to achieve nanocluster-to-nanocluster transformation via stepwise synthesis.

Hydride-containing 2-Electron Pd/Cu Superatoms as Catalysts for Efficient Electrochemical Hydrogen Evolution.

The first hydride-containing 2-electron palladium/copper alloys, [PdHCu11 {S2 P(Oi Pr)2 }6 (C≡CPh)4 ] (PdHCu11 ) and [PdHCu12 {S2 P(Oi Pr)2 }5 {S2 PO(Oi Pr)} (C≡CPh)4 ] (PdHCu12 ), are synthesized from the reaction of [PdH2 Cu14 {S2 P(Oi Pr)2 }6 (C≡CPh)6 ] (PdH2 Cu14 ) with trifluoroacetic acid (TFA). X-ray diffraction reveals that the PdHCu11 and PdHCu12 kernels consist of a central PdH unit encapsulated within a vertex-missing Cu11 cuboctahedron and complete Cu12 cuboctahedron, respectively. DFT calculations indicate that both PdHCu11 and PdHCu12 can be considered as axially-distorted 2-electron superatoms. PdHCu11 shows excellent HER activity, unprecedented within metal nanoclusters, with an onset potential of -0.05 V (at 10 mA cm-2 ), a Tafel slope of 40 mV dec-1 , and consistent HER activity during 1000 cycles in 0.5 M H2 SO4 . Our study suggests that the accessible central Pd site is the key to HER activity and may provide guidelines for correlating catalyst structures and HER activity.

Synchronized delivery of dual-drugs for potentiating combination chemotherapy based on smart triple-responsive polymeric micelles.

Here, we combined reversible addition-fragmentation chain transfer (RAFT) polymerization and amide coupling reaction to develop a novel drug-polymer conjugate using poly(AMA-co-IMMA)-b-poly(OEGMA) (termed as PAIPO) as nanocarriers. In order to enhance cellular uptake and obtain subsequent endo/lysosomal escape capacity, the dual-drugs-conjugated prodrug was then coupled with 2,3-dimethylmaleimide (DA) moieties and implanted with imidazolyl groups, respectively. Paclitaxel (PTX) was conjugated to PAIPO via 3,3'-dithiodipropionic acid (DPA) to construct a GSH-responsive moiety, while doxorubicin (DOX) was conjugated to PAIPO via 4-formyl benzoic acid to construct a pH-responsive moiety, which synergistically enabled a synchronized and precise drug delivery. The micelles self-assembled from DOX/PTX@PAIPODA showed an ideal average diameter (163.2-178.3 nm), contributing to passive targeting by the EPR effect. Moreover, a switch of the surface Zeta potential of micelles from steady negatively charged (- 9.74 ± 0.54 mV) at pH 7.4 to positively charged (+ 6.33 ± 1.25 mV) at pH 6.5, facilitated the long blood circulation and cellular endocytosis of micelles, respectively. More importantly, in vitro studies confirmed that DAM(DOXn/PTX) exhibited a strong synergism against tumor cells, and under slightly acidic conditions (pH 6.5), the combination index (CI) values for DAM(DOX1/PTX) on HeLa and Skov-3 cells were estimated to be 0.47 and 0.49 (previous to be 0.50 and 0.56 at pH 7.4), respectively. And in vivo results showed effective tumor accumulation potential, remarkable biosafety, and biocompatibility. Combined, such synchronized delivery approach based on multi-responsive micelles might potentiate the efficacy of combination chemotherapy in clinical cancer treatment.

Cleavable collagenase-assistant nanosonosensitizer for tumor penetration and sonodynamic therapy.

Sonodynamic therapy (SDT), a combination of low-intensity ultrasound with a sonosensitizer, has been explored as a promising alternative for cancer therapy. However, condensed extracellular matrix (ECM) resulting in poor perfusion and extreme hypoxia in solid tumor potentially compromises effective SDT. Herein, we develop a novel cleavable collagenase-assistant and O2-supplied nanosonosensitizer (FePO2@HC), which is embedded through fusing collagenase (CLG) and human serum albumin (HSA), followed by encapsulating Ferric protoporphyrin (FeP) and dioxygen. As a smart carrier, HSA is stimuli-responsive and collapsed by reduced glutathione (GSH) overexpressed in tumor, resulting to the release of the components in FePO2@HC. The released CLG acting as an artificial scissor, degrades the collagen fibers in tumor, thus, breaking tumor tissue and enhancing FePO2 accumulation in tumor inner with higher than that without CLG. Simultaneously, oxygen molecules are released from FePO2 in hypoxic environment and alleviate the tumor hypoxia. As a sonosensitizer, FeP is subsequently irradiated by ultrosound wave (US) and activates surrounding dioxygen to generate amount of singlet oxygen (1O2). Contributed from the ECM-degradation, such SDT-based nanosystem with increased sonosensitizer permeability and oxygen content highly improved the tumor inhibition efficacy without toxic effects. This study presents a new paradigm for ECM depletion-based strategy of deep-seated penetration, and will expand the nanomedicine application of metalloporphyrin sonosensitizers in SDT.

Evaluation of obstructive sleep apnea: an analysis based on aberrant genes.

BACKGROUND: Obstructive sleep apnea (OSA) is an upstream disorder that frequently causes multisystem disorders. Much research has revealed the pathogenesis of OSA, but there is still a lack of research on the complications caused by OSA. METHODS: The mRNA expression and methylation dataset based on peripheral blood mononuclear cells (PBMCs) were downloaded from the Gene Expression Omnibus (GEO) database. All differential expressed genes (DEGs) were ranked using the Robust Rank Aggregation (RRA) algorithm. A weighted gene co-expression network analysis (WGCNA) was constructed. Subsequently, we used immune infiltration, enrichment analysis, and least absolute shrinkage and selection operator (LASSO) regression analysis for apnea and hypopnea index (AHI) and hypertension and excessive daytime sleepiness (EDS) and constructed diagnostic model using random forest algorithm. RESULTS: In the present study, we identified 318 DEGs in PBMCs involved in pathogenesis or continuous positive airway pressure (CPAP) therapy. Pathway enrichment identified DEGs associated with protein regulation and metabolism. Notably, through intra group analysis, we found that the immune disorder was more significant for OSA in males, non-daytime sleepy, or non-hypertensive OSA. The area under the ROC curve of model for EDS prediction is 0.889 and 0.852 for hypertension. Notably, we found that the diagnostic model had a high linear predictive value for AHI. CONCLUSIONS: Our results indicate that PBMCs are a significant component of alterations in OSA and are expected to explain the mechanism of multisystem diseases caused by OSA. The present study provides new insights for symptom evaluation, classification and treatment of OSA from the molecular level.

Causal associations between obstructive sleep apnea and COVID-19: A bidirectional Mendelian randomization study.

BACKGROUNDS: The COVID-19 pandemic has caused significant impact on human health. Whether obstructive sleep apnea (OSA) increases the risk of COVID-19 remains unclear. We sought to clarify this issue using two-sample Mendelian randomization (TSMR) analysis in large cohorts. METHODS: Bidirectional two-sample Mendelian randomization (MR) was used to evaluate the potential causality between OSA and COVID-19 by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was selected as the main approach for data analysis to estimate the possible causal effects. Alternative methods such as MR-Egger, the MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented as sensitivity analysis approaches to ensure the robustness of the results. RESULTS: All forward MR analyses consistently indicated the absence of a causal relationship between OSA and any COVID-19 phenotype. In the reverse MR analysis, the IVW mode demonstrated that severe respiratory confirmed COVID-19 was correlated with a 4.9% higher risk of OSA (OR, 1.049; 95%CI, 1.018-1.081; P = 0.002), consistent in MR-PRESSO (OR = 1.049, 95%CI 1.018-1.081, P = 0.004), weighted median (OR = 1.048, 95%CI 1.003-1.095, P = 0.035), and MR-Egger (OR = 1.083, 95%CI 1.012-1.190, P = 0.041) methods. CONCLUSIONS: There is no significant evidence supporting a causal association between OSA and any COVID phenotype, while we identified potential evidence for a causal effect of severe COVID-19 on an increased risk of OSA.

Synergistic Effect of Kokumi-Active γ-Glutamyl Peptides and l-Glutamate on Enhancing Umami Sensation and Stimulating Cholecystokinin Secretion via T1R1/T1R3 Activation in STC-1 Cells.

This study aimed to investigate the synergistic effect of γ-glutamyl peptides (γEL, γEV, and γEγEV) and l-glutamate (MSG) on the activation of the umami receptor (T1R1/T1R3) in relation to enhanced umami taste and promoted cholecystokinin (CCK) secretion. The synergy of γ-glutamyl peptides and MSG (1-15 mM, 1:1) caused a significant increase in both the umami taste score by 0.218 ± 0.015-1.216 ± 0.031 times and the CCK secretion by 41.41 ± 6.46-201.16 ± 12.91% when compared to the group treated with individual MSG. The increase in CCK secretion promoted by γ-glutamyl peptides was only reduced by 11.54 ± 0.01-45.65 ± 3.58% after adding yjr CaSR inhibitor (NPS 2143), implying that there were other receptors besides CaSR involved in the stimulation of CCK secretion. The mixture of γEγEV and MSG synergistically increased the intracellular calcium release by 111.26 ± 11.94-135.28 ± 16.60% in STC-1 and 108.47 ± 7.89-152.33 ± 26.26% in HEK 293 compared to MSG. The protein expression for T1R1/T1R3 was increased, indicating that the mixture can activate T1R1/T1R3. The amino acids V277, S147, and D190 of T1R3 can be critical for the binding of γEγEV to T1R3. This is the first report on the synergistic effect of taste-active substances on taste sensation and hormone release via taste receptor activation.

Synthesis, structural studies, and photophysical properties of heteroleptic inverse-coordination clusters.

Two series of hyper-coordinated halide-centered M12 cuboctahedral clusters, [M12(µ12-X){S2P(OnPr)2}6{CCPh}4](PF6), 1a-c and 2a-c (where M = Cu, 1; Ag, 2; X = Cl, a; Br, b; I, c), were synthesized and fully characterized by ESI-MS, multi-NMR spectroscopy, IR and UV-Vis spectroscopy, photoluminescence analysis, and single-crystal X-ray crystallography. Structures 1c, 2b, and 2c show a twelve-coordinated halide encapsulated in the M12 cage, which is stabilized by six dithiophosphate and four alkynyl ligands. Compound 2b is the first Ag(I) cluster containing a twelve-coordinated bromide. The structural features of all six clusters are highly similar, providing a comparison basis of the inverse coordination for halides. Besides, the detailed structural analysis illustrates how the inverse coordination of a halide has influenced the size of the cuboctahedral M12 framework.