Two fundamentally different mechanisms by which unconscious information impairs behavioral performance: Evidence from fMRI and computational modeling.

It is increasingly clear that unconscious information impairs the performance of the corresponding action when the instruction to act is delayed. However, whether this impairment occurs at the response level or at the perceptual level remains controversial. This study used fMRI and a computational model with a pre-post design to address this elusive issue. The fMRI results showed that when the unconscious information containing strong stimulus-response associations was irrelevant to subsequent stimuli, the precuneus in the parietal lobe, which is thought to be involved in sensorimotor processing, was activated. In contrast, when the unconscious information was relevant to subsequent stimuli, regardless of the strength of the stimulus-response associations, some regions in the occipital and temporal cortices, which are thought to be involved in visual perceptual processing, were activated. In addition, the percent signal change in the regions of interest associated with motor inhibition was modulated by compatibility in the irrelevant but not in the relevant stimuli conditions. Modeling of behavioral data further supported that the irrelevant and relevant stimuli conditions involved fundamentally different mechanisms. Our finding reconciles the debate about the mechanism by which unconscious information impairs action performance and has important implications for understanding of unconscious cognition.

Windbreak and sand fixation service flow simulation in the terminal lake basin of inland rivers in arid regions: A case study of the Aral Sea basin.

Research on windbreak and sand fixation (WSF) services aids in soil conservation, and ecological protection. Over the past 50 years, the Aral Sea's shrinkage has intensified wind erosion, leading to significant sand and dust emissions in Central Asia (CA). This study uses the Revised wind erosion equation (RWEQ) model and the hybrid single particle Lagrangian integrated trajectory model (HYSPLIT) model to simulate the spatiotemporal variation pattern of WSF services in the Aral Sea basin (ASB). From the perspective of sand and dust transmission paths, the flow trajectory and benefit areas of WSF services are identified, the spatiotemporal correlation between the WSF service supply areas and benefit areas is established, and the potential impact of WSF services on beneficiary areas is quantitatively assessed. The results show the amount of wind erosion and the amount of WSF in the ASB from 2000 to 2019 showed a fluctuating trend of "first increasing and then decreasing". In terms of spatial distribution, areas with large amounts of WSF are mainly distributed in the lower reaches of the Syr Darya River and the sand dunes in the northwest of the Kizilkum Desert. WSF services mainly flow through the Kizilkum Desert, Karakum Desert, Moyinkum Desert, Kazakh Hills, and the Junggar Basin and Tarim Basin in China. Generally, it flows to the northeast and southwest. In the past 20 years, the largest areas benefiting from the flow of WSF services are mainly distributed in Uzbekistan, Kyrgyzstan, and Tajikistan. The trajectory distribution frequency shows a decreasing trend from the center to the periphery. The grassland areas constituted the largest beneficiary areas in the ASB of CA, with both the beneficiary population and real GDP exhibiting an upward trend. This study holds significant importance for enhancing the management of ecosystem services in sandy regions and for establishing ecological compensation mechanisms.

Folic acid and S-adenosylmethionine reverse Homocysteine-induced Alzheimer's disease-like pathological changes in rat hippocampus by modulating PS1 and PP2A methylation levels.

BACKGROUND: Abnormally elevated homocysteine (Hcy) is recognized as a biomarker and risk factor for Alzheimer's disease (AD). However, the underlying mechanisms by which Hcy affects AD are still unclear. OBJECTIVES: This study aimed to elucidate the effects and mechanisms by which Hcy affects AD-like pathological changes in the hippocampus through in vivo and in vitro experiments, and to investigate whether folic acid (FA) and S-adenosylmethionine (SAM) supplementation could improve neurodegenerative injuries. METHODS: In vitro experiments hippocampal neurons of rat were treated with Hcy, FA or SAM for 24 h; while the hyperhomocysteinemia (HHcy) in Wistar rats was established by intraperitoneal injection of Hcy, and FA was added to feed. The expression of ß-amyloid (Aß), phosphorylated tau protein, presenilin 1 (PS1) at the protein level and the activity of protein phosphatase 2A (PP2A) were detected, the immunopositive cells for Aß and phosphorylated tau protein in the rat hippocampus were also evaluated by immunohistochemical staining. RESULTS: FA and SAM significantly repressed Hcy-induced AD-like pathological changes in the hippocampus, including the increased tau protein phosphorylation at Ser214, Ser396 and the expression of Aß42. In addition, Hcy-induced PS1 expression increased at the protein level and PP2A activity decreased, while FA and SAM were able to retard that. CONCLUSIONS: The increase in PS1 expression and decrease in PP2A activity may be the mechanisms underlying the Hcy-induced AD-like pathology. FA and SAM significantly repressed the Hcy-induced neurodegenerative injury by modulating PS1 and PP2A methylation levels.

Monodisperse Manganese-Vanadium-Oxo Clusters with Extraordinary Lithium Storage.

Although possessing well-defined nanostructures and excellent multi-electron redox properties, polyoxometalate clusters have poor intrinsic electrical conductivity and are prone to aggregation due to large surface energy, which makes them difficult to be fully utilized when applying as electrode materials for lithium-ion batteries. In this paper, monodisperse K7MnV13O38 (MnV13) clusters are achieved by rationally utilizing nano-sized high conductive carbon dots (CDs) as stabilizers. Benefiting from the fully exposed redox sites of MnV13 clusters (high utilization rate) and sufficient interfaces with carbon dots (extra interfacial energy storage), the optimized MnV13/10CDs anode delivers a high discharge capacity up to 1348 mAh g-1 at a current density of 0.1 A g-1 and exhibits superb rate/cycling capabilities. Density functional theory (DFT) calculations verify that ionic archway channels are formed between MnV13 and CDs, eliminating the bandgap and greatly improving the electron/ion conductivity of MnV13 and CDs. This paper paves a brand-new way for synthesis of monodisperse clusters and maximization of extra interfacial energy storage.

Ephedra sinica polysaccharide regulate the anti-inflammatory immunity of intestinal microecology and bacterial metabolites in rheumatoid arthritis.

Introduction: Ephedra sinica polysaccharide (ESP) exerts substantial therapeutic effects on rheumatoid arthritis (RA). However, the mechanism through which ESP intervenes in RA remains unclear. A close correlation has been observed between enzymes and derivatives in the gut microbiota and the inflammatory immune response in RA. Methods: A type II collagen-induced arthritis (CIA) mice model was treated with Ephedra sinica polysaccharide. The therapeutic effect of ESP on collagen-induced arthritis mice was evaluated. The anti-inflammatory and cartilage-protective effects of ESP were also evaluated. Additionally, metagenomic sequencing was performed to identify changes in carbohydrate-active enzymes and resistance genes in the gut microbiota of the ESP-treated CIA mice. Liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry were performed to observe the levels of serum metabolites and short-chain fatty acids in the gut. Spearman's correlational analysis revealed a correlation among the gut microbiota, antibiotic-resistance genes, and microbiota-derived metabolites. Results: ESP treatment significantly reduced inflammation levels and cartilage damage in the CIA mice. It also decreased the levels of pro-inflammatory cytokines interleukin (IL)-6, and IL-1-ß and protected the intestinal mucosal epithelial barrier, inhibiting inflammatory cell infiltration and mucosal damage. Here, ESP reduced the TLR4, MyD88, and TRAF6 levels in the synovium, inhibited the p65 expression and pp65 phosphorylation in the NF-κB signaling pathway, and blocked histone deacetylase (HDAC1 and HDAC2) signals. ESP influenced the gut microbiota structure, microbial carbohydrate-active enzymes, and microbial resistance related to resistance genes. ESP increased the serum levels of L-tyrosine, sn-glycero-3-phosphocholine, octadecanoic acid, N-oleoyl taurine, and decreased N-palmitoyl taurine in the CIA mice. Conclusion: ESP exhibited an inhibitory effect on RA. Its action mechanism may be related to the ability of ESP to effectively reduce pro-inflammatory cytokines levels, protect the intestinal barrier, and regulate the interaction between mucosal immune systems and abnormal local microbiota. Accordingly, immune homeostasis was maintained and the inhibition of fibroblast-like synoviocyte (FLS) proliferation through the HDAC/TLR4/NF-κB pathway was mediated, thereby contributing to its anti-inflammatory and immune-modulating effects.

CAP2 contributes to Parkinson's disease diagnosed by neutrophil extracellular trap-related immune activity.

Introduction: Neutrophil extracellular traps (NETs) constitute a crucial element of the immune system, and dysfunction in immune responses is implicated in the susceptibility and progression of Parkinson's disease (PD). Nevertheless, the mechanism connecting PD and NETs remains unclear. This study aims to uncover potential NETs-related immune biomarkers and elucidate their role in PD pathogenesis. Methods: Through differential gene analysis of PD and NETs in GSE7621 datasets, we identified two PD subtypes and explored potential biological pathways. Subsequently, using ClusterWGCNA, we pinpointed pertinent genes and developed clinical diagnostic models. We then optimized the chosen model and evaluated its association with immune infiltration. Validation was conducted using the GSE20163 dataset. Screening the single-cell dataset GSE132758 revealed cell populations associated with the identified gene. Results: Our findings identified XGB as the optimal diagnostic model, with CAP2 identified as a pivotal gene. The risk model effectively predicted overall diagnosis rates, demonstrating a robust correlation between infiltrating immune cells and genes related to the XGB model. Discussion: In conclusions, we identified PD subtypes and diagnostic genes associated with NETs, highlighting CAP2 as a pivotal gene. These findings have significant implications for understanding potential molecular mechanisms and treatments for PD.

Mechanism insight into the high-efficiency catalytic killing of E. coli by metal-phenolic network as a nanozyme.

Glutathione (GSH) as an antioxidant greatly attenuates the reactive oxygen species (ROS) treatment strategy based on peroxidase-activity nanozymes. Therefore, nanozymes with multiple properties that generate ROS and further GSH-depletion functions would be of great benefit to improve antimicrobial efficacy. Herein, focusing on the green, safe and abundant functional prospects of metal-phenolic networks (MPNs) and the strong prospect of biomedical applications, we have synthesized copper tannic acid (CuTA) nanozymes with dual functional properties similar to peroxidase-like activity and GSH depletion. CuTA can catalyze the decomposition of H2O2 to hydroxyl radicals (˙OH). In addition, CuTA nanozymes can efficiently deplete available GSH, thus enhancing ROS-mediated antimicrobial therapy. The antibacterial results show that CuTA has an excellent antibacterial effect against E. coli.

Correction to "Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy".

[This corrects the article DOI: 10.1021/acscentsci.3c01310.].

Impact of relative and absolute values on orienting attention in time.

Reward has been known to render the reward-associated stimulus more salient to block effective attentional orienting in space. However, whether and how reward influences goal-directed attention in time remains unclear. Here, we used a modified attentional cueing paradigm to explore the effect of reward on temporal attention, in which the valid targets were given a low monetary reward and invalid targets were given a high monetary reward. The results showed that the temporal cue validity effect was significantly smaller when the competitive reward structure was employed (Experiment 1), and we ruled out the possibility that the results were due to the practice effect (Experiment 2a) or a reward-promoting effect (Experiment 2b). When further strengthening the intensity of the reward from 1:10 to 1:100 (Experiment 3), we found a similar pattern of results to those in Experiment 1. These results suggest that reward information which was based on relative instead of absolute values can weaken, but not reverse, the orienting attention in time.

Deep learning empowers photothermal microscopy with super-resolution capabilities.

In the past two decades, photothermal microscopy (PTM) has achieved sensitivity at the level of a single particle or molecule and has found applications in the fields of material science and biology. PTM is a far-field imaging method; its resolution is restricted by the diffraction limits. In our previous work, the modulated difference PTM (MDPTM) was proposed to improve the lateral resolution, but its resolution improvement was seriously constrained by information loss and artifacts. In this Letter, a deep learning approach of the cycle generative adversarial network (Cycle GAN) is employed for further improving the resolution of PTM, called DMDPTM. The point spread functions (PSFs) of both PTM and MDPTM are optimized and act as the second generator of Cycle GAN. Besides, the relationship between the sample's volume and the photothermal signal is utilized during dataset construction. The images of both PTM and MDPTM are utilized as the inputs of the Cycle GAN to incorporate more information. In the simulation, DMDPTM quantitatively distinguishes a distance of 60 nm between two nanoparticles (each with a diameter of 60 nm), demonstrating a 4.4-fold resolution enhancement over the conventional PTM. Experimentally, the super-resolution capability of DMDPTM is verified by restored images of Au nanoparticles, achieving the resolution of 114 nm. Finally, the DMDPTM is successfully employed for the imaging of carbon nanotubes. Therefore, the DMDPTM will serve as a powerful tool to improve the lateral resolution of PTM.

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy.

The Stimulator of Interferon Genes (STING) pathway is a promising target for cancer immunotherapy. Despite recent advances, therapies targeting the STING pathway are often limited by routes of administration, suboptimal STING activation, or off-target toxicity. Here, we report a dendritic cell (DC)-targeted polymeric prodrug platform (polySTING) that is designed to optimize intracellular delivery of a diamidobenzimidazole (diABZI) small-molecule STING agonist while minimizing off-target toxicity after parenteral administration. PolySTING incorporates mannose targeting ligands as a comonomer, which facilitates its uptake in CD206+/mannose receptor+ professional antigen-presenting cells (APCs) in the tumor microenvironment (TME). The STING agonist is conjugated through a cathepsin B-cleavable valine-alanine (VA) linker for selective intracellular drug release after receptor-mediated endocytosis. When administered intravenously in tumor-bearing mice, polySTING selectively targeted CD206+/mannose receptor+ APCs in the TME, resulting in increased cross-presenting CD8+ DCs, infiltrating CD8+ T cells in the TME as well as maturation across multiple DC subtypes in the tumor-draining lymph node (TDLN). Systemic administration of polySTING slowed tumor growth in a B16-F10 murine melanoma model as well as a 4T1 murine breast cancer model with an acceptable safety profile. Thus, we demonstrate that polySTING delivers STING agonists to professional APCs after systemic administration, generating efficacious DC-driven antitumor immunity with minimal side effects. This new polymeric prodrug platform may offer new opportunities for combining efficient targeted STING agonist delivery with other selective tumor therapeutic strategies.

LncRNA NEAT1 promotes MPP+ induced injury of PC12 cells and accelerates the progression of Parkinson's disease in mice through FUS mediated inhibition of PI3K/AKT/mTOR signalling pathway.

Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) is involved in the progression of Parkinson's disease (PD), but the specific regulatory role needs further exploration. This study showed that the expression of NEAT1 was upregulated in the cerebrospinal fluid (CSF) and peripheral blood of patients with different stages of PD. 1-Methyl-4-phenylpyridine (MPP)-treated PC 12 cells were transfected with si-NEAT1, and MPP treatment promoted cell apoptosis, oxidative stress and inflammatory factor secretion. Si-NEAT1 reversed the effects of MPP. NEAT1 silencing eliminated the effect of MPP on the protein expression levels of LC3-II and p62/SQSTM1. By using an online bioinformatics database, Fused in Sarcoma (FUS) was confirmed to be an RNA binding protein of NEAT1, and it was highly expressed in the CSF and peripheral blood of patients with PD. Si-FUS was transfected into MPP-treated PC 12 cells to detect cell apoptosis, oxidative stress, inflammatory factor secretion and autophagy, and the results were the same as those of transfection of si-NEAT1. Furthermore, MPP treatment reduced the phosphorylation levels of PI3K, Akt and mTOR, whereas si-FUS reversed the effects of MPP. In vivo, compared with the model group, the PD mice showed reduced NEAT1 and FUS expression levels and activated PI3K pathway after being injected with si-NEAT1. The brain tissue of NEAT1-silenced PD mice had decreased inflammatory infiltration and apoptosis and increased neurological scores. In conclusion, NEAT1 is involved in PD progression through FUS-mediated inhibition of the PI3K/AKT/mTOR signalling pathway.

Constructing ultra-stable, high-energy, and flexible aqueous zinc-ion batteries using environment-friendly organic cathodes.

Due to their sustainability, environmental friendliness, high specific capacity, and rapid reaction kinetics, quinone cathodes have broad application prospects in aqueous zinc-ion batteries (AZIBs). However, conventional small-molecule quinone cathodes usually suffer from unavoidable dissolution, resulting in terrible cycling stability. Herein, based on a strategy of molecular structure optimization, calix[8]quinone (C8Q) is for the first time used as a cathode in AZIBs. By extending the structure of the classical small-molecule quinone cathode calix[4]quinone (C4Q), C8Q further adds four p-benzoquinone structural units, which significantly suppresses the dissolution of its discharge products and greatly improves the cycle stability of the cathode. Specifically, the C8Q cathode displays a discharge specific capacity of 207.2 mA h g-1 at 1 A g-1 and a long-life cycle stability (93 mA h g-1/10 A g-1/10000th). Even with a high active material loading of 11 mg cm-2, the Zn‖C8Q battery also exhibits high redox reversibility and remarkable electrochemical stability. Furthermore, the belt-shaped Zn‖C8Q battery has high stability and outstanding flexibility, indicating its promising application in flexible wearable electronic devices.

Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives.

Aberrantly elevated adenosine in the tumor microenvironment exerts its immunosuppressive functions through adenosine receptors A2AR and A2BR. Antagonism of A2AR and A2BR has the potential to suppress tumor growth. Herein, we report a systemic assessment of the effects of an indole modification at position 4, 5, 6, or 7 on both A2AR/A2BR activity and selectivity of novel 2-aminopyrimidine compounds. Substituting indole at the 4-/5-position produced potent A2AR/A2BR dual antagonism, whereas the 6-position of indole substitution gave highly selective A2BR antagonism. Molecular dynamics simulation showed that the 5-cyano compound 7ai had a lower binding free energy than the 6-cyano compound 7aj due to water-bridged hydrogen bond interactions with E169 or F168 in A2AR. Of note, dual A2AR/A2BR antagonism by compound 7ai can profoundly promote the activation and cytotoxic function of T cells. This work provided a strategy for obtaining novel dual A2AR/A2BR or A2BR antagonists by fine-tuning structural modification.

Influence of Various Heat Treatments on Microstructures and Mechanical Properties of GH4099 Superalloy Produced by Laser Powder Bed Fusion.

The microstructures and mechanical properties of a γ'-strengthened nickel-based superalloy, GH4099, produced by laser powder bed fusion, at room temperature and 900 °C are investigated, followed by three various heat treatments. The as-built (AB) alloy consists of cellular/dendrite substructures within columnar grains aligning in <100> crystal orientation. No γ' phase is observed in the AB sample due to the relatively low content of Al +Ti. Following the standard solid solution treatment, the molten pool boundaries and cellular/dendrite substructures disappear, whilst the columnar grains remain. The transformation of columnar grains to equiaxed grains occurs through the primary solid solution treatment due to the recovery and recrystallization process. After aging at 850 °C for 480 min, the carbides in the three samples distributed at grain boundaries and within grains and the spherical γ' phase whose size is about 43 nm ± 16 nm develop in the standard solid solution + aging and primary solid solution + aging samples (SA and PA samples) while the bimodal size of cubic (181 nm ± 85 nm) and spherical (43 nm ± 16 nm) γ' precipitates is presented in the primary solid solution + secondary solid solution + aging sample (PSA samples). The uniaxial tensile tests are carried out at room temperature (RT) and 900 °C. The AB sample has the best RT ductility (~51% of elongation and ~67% of area reduction). Following the three heat treatments, the samples all acquire excellent RT tensile properties (>750 MPa of yield strengths and >32% of elongations). However, clear ductility dips and intergranular fracture modes occur during the 900 °C tensile tests, which could be related to carbide distribution and a change in the deformation mechanism.

Mechanical Behavior of Bio-Inspired Honeycomb-Core Composite Sandwich Structures to Low-Velocity Dynamic Loading.

In order to improve the impact resistance of sandwich panels under low-velocity impact, the lotus leaf vein is selected as a biological prototype to design a bio-inspired honeycomb (BIH) sandwich panel. ABAQUS is used to establish and effectively verify the finite element (FE) model of the BIH sandwich panel. To systematically compare and study the mechanical properties of BIH and conventional hexagonal honeycomb sandwich panels under low-velocity impact, the maximum displacement of face-sheets, the deformation mode, the plastic energy consumption and the dynamic response curve of the impact end are presented. At the same time, the performance differences between them are revealed from the perspective of an energy absorption mechanism. Furthermore, the influence of the circumscribed circle diameter ratio of the BIH trunk to branch (γ), the thickness ratio of the trunk to branch (K) and the impact angle (θ) on impact resistance is studied. Finally, the BIH sandwich panel is further optimized by using the response surface method. It can be concluded that, compared to conventional hexagonal honeycomb sandwich panels, the addition of walls in the BIH sandwich panel reduces the maximum deformation of the rear face-sheet by 10.29% and increases plastic energy consumption by 8.02%. Properly adjusting the structural parameters can effectively enhance the impact resistance of the BIH sandwich panel.

UBE2C is a diagnosis and therapeutic biomarker involved in immune infiltration of cancers including lung adenocarcinoma.

The mechanism of action of UBE2C in lung adenocarcinoma (LUAD) and its significance in cancer diagnosis, targeted therapy and immunotherapy, even in pan-cancer, are still unclear. Several large public databases and online analysis tools were used for big data mining analysis. RNA interference technology, CCK8 assay, flow cytometry and apoptosis detection, and western blot were used for in vitro experiments. UBE2C was found to be overexpressed in various of tumors, including LUAD, and its expression level was found to be significantly related to gender, weight, tumor stage, grade and prognosis in LUAD. Downregulation of UBE2C expression induced proliferation suppression and G2/M phase arrest and cell apoptosis in LUAD cells and suppressed LUAD cell growth through inhibiting the Akt-mTOR signaling pathway. Expression level of UBE2C was negatively correlated with B cells and CD4+ T cell, and also with immune checkpoint genes in LUAD. Pan-cancer assay shown that UBE2C was significantly overexpressed in 28 cancers and was correlated with Ki-67 index in many cancers. Overexpression of UBE2C in BRCA, LUAD and MESO indicated worse Overall Survival (OS). UBE2C expression levels were positively associated with immunocyte infiltration, immune regulatory genes, immune checkpoints, TMB, MSI and MMRs in some cancers. Additionally, Single-cell functional analysis showed that UBE2C was positively correlated with cell cycle, proliferation, DNA damage, EMT, DNA repair, invasion and differentiation in some cancers. These findings suggested that UBE2C could be regarded as a latent diagnosis and prognostic biomarker and a new target for immunological therapy of cancers including LUAD.

A unilateral external fixator combined with bone transport and tibio-talar fusion for the treatment of severe postoperative infection of peri-ankle fractures: retrospective analysis of 32 cases.

BACKGROUND: To investigate the clinical effects of a unilateral external fixator combined with bone transport and tibio-talar fusion in the treatment of severe postoperative infection of peri-ankle fractures. METHODS: The clinical data of 32 patients (22 men and 10 women) with severe postoperative infection of peri-ankle fractures were retrospectively analyzed. Patients' age ranged from 26 to 62 (mean, 42 ± 9.5) years old. The types of fractures were distal tibia fracture (25 cases), distal tibia and fibula fracture (5 cases), and talus fracture (2 cases). All patients underwent treatment with unilateral external fixation combined with bone transport and tibio-talar fusion. 6 patients with severe infection received two-stage treatment involving focal debridement and external fixation, osteotomy, and bone transport. The remaining 26 patients underwent debridement, external fixation, and osteotomy simultaneously. The length of bone transport, total fixation time of the external fixator, and postoperative complications were recorded for all patients. The efficacy of the treatment was assessed using the American Association of Foot and Ankle Society (AOFAS) ankle-hindfoot score. RESULTS: Patients were followed up for 16-36 months, with an average follow-up time of 24 months. The length of tibia bone transport ranged from 5 to 15 cm, with a mean length of 8.5 cm. The external fixator was applied for 12-24 months, with an average duration of 16 months. One patient suffered from refracture at tibio-talar fusion site, and one patient had external fixation pin-tract infection. No complications, such as recurrent infections (especially the MRSA infection), poor mineralization, refracture, iatrogenic nerve damage or fusion failure, were found in the remaining patients. The preoperative AOFAS ankle-hindfoot function score was 40.0 ± 3.8 (range, 30-52) points, and it increased to 75.0 ± 3.0 (range, 67-78) points at the last follow-up. CONCLUSION: A unilateral external fixator combined with bone transport and tibio-talar fusion is an effective method for treating severe postoperative infection of peri-ankle fractures. This approach is capable of reconstructing large bone defects that remain after clearing the infected lesion. Additionally, it provides stability to the ankle, enhances ankle-hindfoot function, and improves the patient's quality of life.

Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A2 receptors.

The adenosine subfamily G protein-coupled receptors A2AR and A2BR have been identified as promising cancer immunotherapy candidates. One of the A2AR/A2BR dual antagonists, AB928, has progressed to a phase II clinical trial to treat rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of the A2AR complexed with AB928 and a selective A2AR antagonist 2-118. The structures revealed a common binding mode on A2AR, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and A2AR and A2BR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A2BR. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A2BR pocket, while 2-118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between A2BR and A2AR. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A2AR/A2BR for cancer therapy.

Association between postoperative nadir platelet count and postoperative cardiovascular complications following septal myectomy in patients with hypertrophic cardiomyopathy: a retrospective cohort study.

BACKGROUND: Platelet count is associated with cardiovascular risk and mortality in several cardiovascular diseases, but the association of the nadir platelet counts post-septal myectomy with the cardiovascular complication risk in hypertrophic obstructive cardiomyopathy patients remains unclear. METHODS: This retrospective cohort study reviewed all adult patients who underwent septal myectomy at a single tertiary referral center over a 5-year period. Postoperative nadir platelet count was defined as the lowest platelet count in the first 4 postoperative days or until hospital discharge. The composite outcome included cardiovascular death, myocardial infarction, heart failure, malignant arrhythmia, cardiac tamponade, and major bleeding events within 30 days postoperatively. Univariable and multivariable logistic regression and restricted cubic spline models were used to assess the association between postoperative nadir platelet count and the 30-day postoperative cardiovascular complication risk. RESULTS: Among the 113 enrolled patients, 23 (20.4%) developed cardiovascular events within 30 days postoperatively. The incidence of postoperative cardiovascular complications was significantly higher in patients with a nadir platelet count ≤ 99 × 109/L than in those with a nadir platelet count > 99 × 109/L (33.3% vs. 7.1%, crude risk ratio: 4.67, 95% confidence interval: 1.69-12.85, P < 0.001). Multivariable logistic regression revealed that postoperative nadir platelet count was negatively associated with 30-day postoperative cardiovascular complications (adjusted odds ratio: 0.97; 95% confidence interval: 0.95-0.99; P = 0.005) and the association was linear (Pnonlinearity = 0.058) after full adjustment. The association between nadir platelet count and cardiovascular complications within 30 days post-surgery was consistent in all predefined subgroups (Pinteraction > 0.05). CONCLUSION: The postoperative nadir platelet count was significantly associated with the 30-day post-myectomy risk of cardiovascular complications in hypertrophic obstructive cardiomyopathy patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT04275544).