Role of atmospheric rivers in shaping long term Arctic moisture variability.

Atmospheric rivers (ARs) reaching high-latitudes in summer contribute to the majority of climatological poleward water vapor transport into the Arctic. This transport has exhibited long term changes over the past decades, which cannot be entirely explained by anthropogenic forcing according to ensemble model responses. Here, through observational analyses and model experiments in which winds are adjusted to match observations, we demonstrate that low-frequency, large-scale circulation changes in the Arctic play a decisive role in regulating AR activity and thus inducing the recent upsurge of this activity in the region. It is estimated that the trend in summertime AR activity may contribute to 36% of the increasing trend of atmospheric summer moisture over the entire Arctic since 1979 and account for over half of the humidity trends in certain areas experiencing significant recent warming, such as western Greenland, northern Europe, and eastern Siberia. This indicates that AR activity, mostly driven by strong synoptic weather systems often regarded as stochastic, may serve as a vital mechanism in regulating long term moisture variability in the Arctic.

[Research Progress on Predictive Biomarkers of Immunotherapy Efficacy
in Non-small Cell Lung Cancer].

Lung cancer is one of the most common malignant tumors in the world, of which non-small cell lung cancer (NSCLC) is the majority. The emergence of immune checkpoint inhibitors (ICIs) has greatly changed the treatment strategy of NSCLC and improved the prognosis of patients. However, in reality, only a small number of patients can achieve long-term benefit. Therefore, the identification of reliable predictive biomarkers is essential for the selection of treatment modalities. With the development of molecular biology and genome sequencing technology in recent years, as well as the in-depth understanding of tumor and its host immune microenvironment, research on biomarkers has emerged in an endless stream. This review focuses on the predictive biomarkers of immunotherapy efficacy in NSCLC, in order to provide some guidance for precision immunotherapy.
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Predicting papillary thyroid microcarcinoma in American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) 3 nodules: radiomics analysis based on intratumoral and peritumoral ultrasound images.

Background: A subset of patients undergoing thyroid surgery for presumed benign thyroid disease presented with papillary thyroid microcarcinoma (PTMC). A non-invasive and precise method for early recognition of PTMC are urgently needed. The aim of this study was to construct and validate a nomogram that combines intratumoral and peritumoral radiomics features as well as clinical features for predicting PTMC in the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) 3 nodules using ultrasonography. Methods: A retrospective review was conducted on a cohort of 221 patients who presented with ACR TI-RADS 3 nodules. These patients were subsequently pathologically diagnosed with either PTMC or benign thyroid nodules. These patients were randomly divided into a training and test cohort with an 8:2 ratio for developing the clinical model, intratumor-region model, peritumor-region model and the combined-region model respectively. The radiomics features were extracted from ultrasound (US) images of each patient. We employed K-nearest neighbor (KNN) model as the base model for building the radiomics signature and clinical signature. Finally, a radiomics-clinical nomogram that combined intratumoral and peritumoral radiomics features as well as clinical features was developed. The prediction performance of each model was assessed by the area under the curve (AUC), sensitivity, specificity and calibration curve. Results: A total of 23 radiomics features were selected to develop radiomics models. The combined-region radiomics model showed favorable prediction efficiency in both the training dataset (AUC: 0.955) and the test dataset (AUC: 0.923). A radiomics-clinical nomogram was constructed and achieved excellent calibration and discrimination, which yielded an AUC value of 0.950, a sensitivity of 0.950 and a specificity of 0.920. Conclusions: This study proposed the nomogram that contributes to the accurate and intuitive identification of PTMC in ACR TI-RADS 3 nodules.

Boston Naming Test as a Screening Tool for Early Postoperative Cognitive Dysfunction in Elderly Patients After Major Noncardiac Surgery.

PURPOSE: The Boston naming test (BNT), as a simple, fast, and easily administered neuropsychological test, was demonstrated to be useful in detecting language function. In this study, BNT was investigated whether it could be a screening tool for early postoperative cognitive dysfunction (POCD). METHODS: This prospective observational cohort study included 132 major noncardiac surgery patients and 81 nonsurgical controls. All participants underwent a mini-mental state examination (MMSE) and BNT 1 day before and 7 days after surgery. Early POCD was assessed by reliable change index and control group results. RESULTS: Seven days after surgery, among 132 patients, POCD was detected in 30 (22.7%) patients (95% CI, 15.5%-30.0%) based on MMSE, and 45 (34.1%) patients (95% CI, 26.3%-41.9%) were found with postoperative language function decline based on BNT and MMSE. Agreement between the BNT spontaneous naming and MMSE total scoring was moderate (Kappa .523), and the sensitivity of BNT spontaneous naming for detecting early POCD was .767. Further analysis showed that areas under receiver operating characteristics curves (AUC) did not show statistically significant differences when BNT spontaneous naming (AUC .862) was compared with MMSE language functional subtests (AUC .889), or non-language functional subtests (AUC .933). CONCLUSION: This study indicates the feasibility of implementing the BNT spontaneous naming test to screen early POCD in elderly patients after major noncardiac surgery.

A multicentre, randomised, double-blind, double-dummy, parallel-controlled, phase 3 clinical trial assessing the efficacy and safety of intravenous nemonoxacin malate vs. levofloxacin for community-acquired pneumonia in adult patients.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.

Automated Design of Fault Diagnosis CNN Network for Satellite Attitude Control Systems.

Despite the dominance of unsupervised and self-supervised anomaly detection methods in the current satellite fault diagnosis domain, supervised anomaly detection offers a superior alternative for high-sensitivity detection and lightweight deployment requirements specific to subsystems or components, such as attitude control systems (ACSs). This article addresses the issues of over-design and insufficient accuracy in the CNN network design for satellite ACS fault diagnosis by introducing the modified particle swarm optimization-advanced convolution blocks-based CNN (MPSO-ACBCNN) method. First, we present the ACBCNN, a lightweight, flexible-layer CNN architecture. This architecture leverages advanced convolution blocks (ACBs), which incorporate numerous efficient design elements to enhance feature extraction capabilities within power spectral density (PSD) graphs of various fault samples, and employs classical dense connection methods to prevent the issue of gradient vanishing. Second, we devise the MPSO-ACBCNN algorithm to optimize the ACBCNN fault diagnosis architecture for specified ACS using MPSO. In MPSO-ACBCNN, several optimizations to the canonical PSO are implemented, including the fitness design that balances the tradeoff between total parameter quantity and the training effectiveness, and methods to ensure feasible solutions, etc. Finally, numerical experimental results demonstrate the effectiveness and superiority of MPSO-ACBCNN in fault diagnosis for ACS.

miR-153 promotes neural differentiation by activating the cell adhesion/Ca2+ signaling pathway and targeting ion channel activity in HT-22 cells by bioinformatic analysis.

MicroRNAs have been studied extensively in neurodegenerative diseases. In a previous study, miR-153 promoted neural differentiation and projection formation in mouse hippocampal HT-22 cells. However, the pathways and molecular mechanism underlying miR-153-induced neural differentiation remain unclear. To explore the molecular mechanism of miR-153 on neural differentiation, we performed RNA sequencing on miR-153-overexpressed HT-22 cells. Based on RNA sequencing, differentially expressed genes (DEGs) and pathways in miR-153-overexpressed cells were identified. The Database for Annotation, Visualization and Integrated Discovery and Gene Set Enrichment Analysis were used to perform functional annotation and enrichment analysis of DEGs. Targetscan predicted the targets of miR-153. The Search Tool for the Retrieval of Interacting Genes and Cytoscape, were used to construct protein-protein interaction networks and identify hub genes. Q-PCR was used to detect mRNA expression of the identified genes. The expression profiles of the identified genes were compared between embryonic days 9.5 (E9.5) and E11.5 in the embryotic mouse brain of the GDS3442 dataset. Cell Counting Kit-8 assay was used to determine cell proliferation and cellular susceptibility to amyloid ß-protein (Aß) toxicity in miR-153-overexpressed cells. The results indicated that miR-153 increased cell adhesion/Ca2+ (Cdh5, Nrcam, and P2rx4) and Bdnf/Ntrk2 neurotrophic signaling pathway, and decreased ion channel activity (Kcnc3, Kcna4, Clcn5, and Scn5a). The changes in the expression of the identified genes in miR-153-overexpressed cells were consistent with the expression profile of GDS3442 during neural differentiation. In addition, miR-153 overexpression decreased cellular susceptibility to Aß toxicity in HT-22 cells. In conclusion, miR-153 overexpression may promote neural differentiation by inducing cell adhesion and the Bdnf/Ntrk2 pathway, and regulating electrophysiological maturity by targeting ion channels. MiR-153 may play an important role in neural differentiation; the findings provide a useful therapeutic direction for neurodegenerative diseases.

Outcomes of Heart Transplantation From Donation After Circulatory Death: An Up-to-Date Systematic Meta-analysis.

BACKGROUND: Donation after circulatory death (DCD) heart transplantation (HTx) significantly expands the donor pool and reduces waitlist mortality. However, high-level evidence-based data on its safety and effectiveness are lacking. This meta-analysis aimed to compare the outcomes between DCD and donation after brain death (DBD) HTxs. METHODS: Databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were systematically searched for randomized controlled trials and observational studies reporting the outcomes of DCD and DBD HTxs published from 2014 onward. The data were pooled using random-effects models. Risk ratios (RRs) with 95% confidence intervals (CIs) were used as the summary measures for categorical outcomes and mean differences were used for continuous outcomes. RESULTS: Twelve eligible studies were included in the meta-analysis. DCD HTx was associated with lower 1-y mortality rate (DCD 8.13% versus DBD 10.24%; RR = 0.75; 95% CI, 0.59-0.96; P = 0.02) and 5-y mortality rate (DCD 14.61% versus DBD 20.57%; RR = 0.72; 95% CI, 0.54-0.97; P = 0.03) compared with DBD HTx. CONCLUSIONS: Using the current DCD criteria, HTx emerges as a promising alternative to DBD transplantation. The safety and feasibility of DCD hearts deserve further exploration and investigation.

Targeted depletion of PD-1-expressing cells induces immune tolerance through peripheral clonal deletion.

Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter. Moreover, we found that diphtheria toxin receptor (DTR)-mediated ablation of PD-1+ cells reshaped the TCR repertoire through peripheral clonal deletion of alloreactive T cells and promoted tolerance in mouse transplantation models. In addition, by using PD-1-specific depleting antibodies, we found that antibody-mediated depletion of PD-1+ cells prevented heart transplant rejection and the development of experimental autoimmune encephalomyelitis (EAE) in humanized PD-1 mice. Thus, these data suggest that PD-1 is an attractive target for peripheral clonal deletion and induction of immune tolerance.

Progress of engineered bacteria for tumour therapy.

Finding novel therapeutic modalities, improving drug delivery efficiency and targeting, and reducing the immune escape of tumor cells are currently hot topics in the field of tumor therapy. Bacterial therapeutics have proven highly effective in preventing tumor spread and recurrence, used alone or in combination with traditional therapies. In recent years, a growing number of researchers have significantly improved the targeting and penetration of bacteria by using genetic engineering technology, which has received widespread attention in the field of tumor therapy. In this paper, we provide an overview and assessment of the advancements made in the field of tumor therapy using genetically engineered bacteria. We cover three major aspects: the development of engineered bacteria, their integration with other therapeutic techniques, and the current state of clinical trials. Lastly, we discuss the limitations and challenges that are currently being faced in the utilization of engineered bacteria for tumor therapy.

Comparison of the cachexia index based on hand-grip strength (H-CXI) with the original CXI for the prediction of cancer cachexia and prognosis in patients who underwent radical colectomy for colorectal cancer.

Background and aims: The cachexia index (CXI) is a novel biomarker for estimating cancer cachexia. The cachexia index based on hand-grip strength (H-CXI) has been recently developed as a simple proxy for CXI. The present study aims to compare both the H-CXI and CXI for the prediction of cancer cachexia and postoperative outcomes in patients who underwent radical colectomy for colorectal cancer. Methods: Patients who underwent radical operations for colorectal cancer were included in this study. Cancer cachexia was diagnosed according to the international consensus outlined by Fearon et al. The cachexia index (CXI) was calculated as [skeletal muscle index (SMI) × serum albumin/neutrophil-to-lymphocyte ratio (NLR)]. The H-CXI was calculated as [hand-grip strength (HGS)/height2 × serum albumin/NLR]. The SMI was measured based on the preoperative CT images at the third lumbar vertebra (L3) level. HGS was measured before surgery. Results: From July 2014 to May 2021, a total of 1,411 patients were included in the present study, of whom 361 (25.6%) were identified as having cancer cachexia. Patients with cachexia had a lower CXI (p < 0.001) and lower H-CXI (p < 0.001) than those without cachexia. A low CXI but not low H-CXI independently predicted cancer cachexia in the multivariate analysis (OR 1.448, p = 0.024). Both a low CXI (HR 1.476, p < 0.001 for OS; HR 1.611, p < 0.001 for DFS) and low H-CXI (HR 1.369, p = 0.007 for OS; HR 1.642, p < 0.001 for DFS) were independent predictors for overall survival (OS) and disease-free survival (DFS) after adjusting for the same covariates. A low H-CXI but not low CXI was an independent risk factor for postoperative complications (OR 1.337, p = 0.044). No significant association was found between cancer cachexia and postoperative complications. Conclusion: The CXI and H-CXI exhibited better prognostic value than cancer cachexia for the prediction of postoperative outcomes in patients who underwent radical colectomy for colorectal cancer. The H-CXI was a superior index over the CXI in predicting short-term clinical outcomes, whereas the CXI demonstrated a closer correlation with Fearon's criteria for cancer cachexia. Ideal tools for the assessment of cancer cachexia should incorporate not only weight loss but also muscle mass, physical function, and inflammatory state.

Photoredox-catalyzed unsymmetrical diamination of alkenes for access to vicinal diamines.

A photoredox-catalyzed unsymmetrical diamination of alkenes by using N-aminopyridinium salts and nitriles as the amination reagents has been developed. Various vicinal diamines were obtained in moderate to excellent yields under mild reaction conditions. Furthermore, this protocol could be applied in the late-stage modification of pharmaceuticals and natural products. Preliminary mechanistic studies suggested that this methodology may undergo a radical pathway followed by a Ritter-type reaction.

Immunoassay System Based on the Technology of Time-Resolved Fluorescence Resonance Energy Transfer.

To enhance the specificity and sensitivity, cut the cost, and realize joint detection of multiple indicators, an immunoassay system based on the technology of time-resolved fluorescence resonance energy transfer (TR-FRET) was studied. Due to the FRET of the reagent, the donor probe and acceptor probe emitted specific fluorescence to enhance specificity. Long-lifetime specific fluorescence from the acceptor probe was combined with time-resolved technology to enhance sensitivity. A xenon flash lamp and a photomultiplier tube (PMT) were selected as the light source and detector, respectively. A filter-switching mechanism was placed in the light path, so the fluorescence signal from the donor and acceptor was measured alternately. The instrument's design is given, and some specificI parts are described in detail. Key technical specifications of the instrument and procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6(IL-6) were tested, and the test results were presented subsequently. The CV value of the self-designed counting module is better than 0.01%, and the instrument noises for 620 nm and 665 nm are 41.44 and 10.59, respectively. When set at 37 °C, the temperature bias (B) is 0.06 °C, and the temperature fluctuation is 0.10 °C. The CV and bias are between ±3% and 5%, respectively, when pipetting volumes are between 10 µL and 100 µL. Within the concentration range of 0.01 nM to 10 nM, the luminescence values exhibit linear regression correlation coefficients greater than 0.999. For PCT detection, when the concentration ranges from 0.02 ng/mL to 50 ng/mL, the correlation coefficient of linear fitting exceeds 0.999, and the limit of quantification is 0.096 ng/mL. For CRP and IL-6, the detection concentration ranges from 0 ng/mL to 500 ng/mL and 0 ng/mL to 20 ng/mL, respectively, with limits of quantification of 2.70 ng/mL and 2.82 ng/mL, respectively. The experimental results confirm the feasibility of the technical and instrumental solutions.

The ultrasound-based radiomics-clinical machine learning model to predict papillary thyroid microcarcinoma in TI-RADS 3 nodules.

Background: Conventional ultrasound (CUS) technology has proven to be successful in the identification of thyroid nodules. Moreover, the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) was developed for the purpose of evaluating the risk of thyroid nodules based on ultrasound imaging. Nevertheless, identifying papillary thyroid microcarcinoma (PTMC) from TI-RADS 3 nodules using this system can be difficult due to overlapping morphological features. The main objective of this study was to investigate the efficacy of a machine learning model that utilizes ultrasound-based radiomics features and clinical information in accurately predicting the presence of PTMC in TI-RADS 3 nodules. Methods: A total of 221 patients with TI-RADS 3 nodules were included, consisting of 91 cases of PTMC and 130 benign thyroid nodules. They were randomly divided into training and test cohort in an 8:2 ratio. Radiomics features were extracted from CUS images by manually outlining the targets, while clinical parameters were obtained from electronic medical records. The radiomics model, clinical model, and combined model were constructed and validated to distinguish between PTMC and benign thyroid nodules. Radiomics variables were extracted via the Pyradiomics package (V1.3.0). Moreover, least absolute shrinkage and selection operator (LASSO) regression was used for feature selection. Light Gradient Boosting Machine (LightGBM) was employed to build both radiomics and clinical models. Ultimately, a radiomics-clinical model, which fused radiomics features with clinical information, was developed. Results: Among a total of 1,477 radiomics features, fifteen features that were found to be associated with PTMC through univariate analysis and LASSO regression were selected for the development of the radiomics model. The combined "radiomics-clinical" model demonstrated superior diagnostic accuracy compared to the clinical model for distinguishing PTMC in both the training dataset [area under receiver operating curve (AUC): 0.975 vs. 0.845] and the validation dataset (AUC: 0.898 vs. 0.811). We constructed a radiomics-clinical nomogram, and the clinical applicability was confirmed through decision curve analysis. Conclusions: Utilizing an ultrasound-based radiomics approach has proven to be effective in predicting PTMC in patients with TI-RADS 3 nodules.

Vascular plant communities and biocrusts act as controlling factors in mitigating soil erosion on the Great Wall in a semi-humid area of Northwestern China.

The Great Wall, a World Heritage Site and a vertical wall habitat, is under threat of soil erosion. The role of vascular plants and biocrust in controlling soil erosion has attracted attention, yet our knowledge of the underlying mechanism is limited, and there is a lack of systematic strategies for erosion prevention and control. In this study, we quantified the vascular plant community functional composition (including species diversity, functional diversity, and community-weighted mean), biocrust coverage, and soil erosion levels associated with seven different zones (lower, middle, and upper zones on East and West faces, plus wall crest) of the Great Wall. We then employed a combination of linear regression analysis, random forest model, and structural equation model to evaluate the individual and combined effects, as well as the direction and relative importance of these factors in reducing soil erosion. The results indicated that the vascular plant species richness, species diversity, functional richness, community-weighted mean, and moss crust coverage decreased significantly from the crest to the lower zone of the Great Wall (P < 0.05), and were negatively correlated with the soil erosion area and depth on both sides of the Great Wall (P < 0.05). This suggests that higher zones on the wall favored the colonization and growth of biocrusts and vascular plants and that biocrusts and vascular plants reduced soil erosion on the wall. Based on these findings, we propose a "restoration framework" for managing soil erosion on walls, based on biocrust and vascular plant communities (namely target species selection, plant community construction, biocrust inoculation, and maintenance of community stability), which aims to address the urgent need for more effective soil erosion prevention and control strategies on the Great Wall and provide practical methods that practitioners can utilize.

Anti-obesity effects of mulberry leaf extracts on female high-fat diet-induced obesity: Modulation of white adipose tissue, gut microbiota, and metabolic markers.

Mulberry leaves (MLs) are reported to have beneficial effects in modulating obesity in male models. However, the impact of different types of mulberry leaf extracts (MLEs) on female models, specifically their influence on adipocytes, gut microbiota, and related metabolic markers, remains poorly understood. In this study, we observed a strong correlation between the total phenolic content (TPC), antioxidant and adipocyte modulation effects of water extracted MLEs. HB-W (water-extracted baiyuwang) and HY-W (water-extracted Yueshen) demonstrated remarkable inhibition effects on adipocytes in 3 T3-L1 adipocytes model. Moreover, MLEs effectively reduced the levels of triglycerides (TG), non-esterified fatty acids (NEFA), and total cholesterol (T-CHO) in adipocytes in vitro. In vivo experiments conducted on female mice with high fat diet (HFD)-induced obesity revealed the anti-obesity effects of HB-W and HY-W, leading to a significant decrease in weight gain rates and notable influence on the ratios of adipose tissue, particularly white adipose tissue (WAT). Gene expression analysis demonstrated the up-regulation of WAT-related genes (Pla2g2a and Plac8) by HB-W, while HY-W supplementation showed beneficial effects on the regulation of blood sugar-related genes. Furthermore, both HB-W and HY-W exhibited modulatory effects on obesity-related gut microbiota (Firmicutes-to-Bacteroidetes ratio) and short chain fatty acid (SCFA) contents. Importantly, they also mitigated abnormalities in liver function and uncoupling protein 1 (UPC1) expression. Overall, our findings underscore the anti-obesity effects of MLEs in female rats with high-fat diet-induced obesity.

Polarimetric Helmholtz Stereopsis.

Helmholtz stereopsis (HS) exploits the reciprocity principle of light propagation (i.e., the Helmholtz reciprocity) for 3D reconstruction of surfaces with arbitrary reflectance. In this paper, we present the polarimetric Helmholtz stereopsis (polar-HS), which extends the classical HS by considering the polarization state of light in the reciprocal paths. With the additional phase information from polarization, polar-HS requires only one reciprocal image pair. We derive the reciprocity relationship of Mueller matrix and formulate new reciprocity constraint that takes polarization state into account. We also utilize polarimetric constraints and extend them to the case of perspective projection. For the recovery of surface depths and normals, we incorporate reciprocity constraint with diffuse/specular polarimetric constraints in a unified optimization framework. For depth estimation, we further propose to utilize the consistency of diffuse angle of polarization. For normal estimation, we develop a normal refinement strategy based on degree of linear polarization. Using a hardware prototype, we show that our approach produces high-quality 3D reconstruction for different types of surfaces, ranging from diffuse to highly specular.

MEK1/2-PKM2 Pathway Modulates the Immunometabolic Reprogramming of Proinflammatory Allograft-infiltrating Macrophages During Heart Transplant Rejection.

BACKGROUND: Emerging evidence has highlighted the role of macrophages in heart transplant rejection (HTR). However, the molecular signals modulating the immunometabolic phenotype of allograft-infiltrating macrophages (AIMs) during HTR remain unknown. METHODS: We analyzed single-cell RNA sequencing data from cardiac graft-infiltrating immunocytes to characterize the activation patterns and metabolic features of AIMs. We used flow cytometry to determine iNOS and PKM2 expression and MEK/ERK signaling activation levels in AIMs. We then generated macrophage-specific Mek1/2 knockout mice to determine the role of the MEK1/2-PKM2 pathway in the proinflammatory phenotype and glycolytic capacity of AIMs during HTR. RESULTS: Single-cell RNA sequencing analysis showed that AIMs had a significantly elevated proinflammatory and glycolytic phenotype. Flow cytometry analysis verified that iNOS and PKM2 expressions were significantly upregulated in AIMs. Moreover, MEK/ERK signaling was activated in AIMs and positively correlated with proinflammatory and glycolytic signatures. Macrophage-specific Mek1/2 deletion significantly protected chronic cardiac allograft rejection and inhibited the proinflammatory phenotype and glycolytic capacity of AIMs. Mek1/2 ablation also reduced the proinflammatory phenotype and glycolytic capacity of lipopolysaccharides + interferon-γ-stimulated macrophages. Mek1/2 ablation impaired nuclear translocation and PKM2 expression in macrophages. PKM2 overexpression partially restored the proinflammatory phenotype and glycolytic capacity of Mek1/2 -deficient macrophages. Moreover, trametinib, an Food and Drug Administration-approved MEK1/2 inhibitor, ameliorated chronic cardiac allograft rejection. CONCLUSIONS: These findings suggest that the MEK1/2-PKM2 pathway is essential for immunometabolic reprogramming of proinflammatory AIMs, implying that it may be a promising therapeutic target in clinical heart transplantation.

Am I Winning or Losing? Probing the Appraisal of Partial Wins via Response Vigor.

Attempts to obtain rewards are not always successful. Despite investing much time, effort, or money, sometimes individuals may not obtain any reward. Other times they may obtain some reward, but the obtained reward may be smaller than their initial investment, such as partial wins in gambling. It remains unclear how such ambiguous outcomes are appraised. To address this question, we systematically varied the payoffs for different outcomes in a computerized scratch card task across three experiments. To test outcome appraisal, we used response vigor as a novel proxy. In the scratch card task, participants turned three cards one by one. Depending on the turned cards, they either received an amount that was higher than the wager (win), an amount lower than the wager (partial win), or nothing (loss). Overall, participants responded to partial wins more slowly than losses, but more quickly than wins. Partial wins were therefore appraised to be better than losses, but worse than wins. Importantly, further analyses showed that outcome appraisal was not based on the net win or loss amount. Instead, participants primarily used the configuration of turned cards as a cue for the relative rank of an outcome within a specific game. Outcome appraisals thus utilize simple heuristic rules, rely on salient information (such as outcome-related cues in gambling), and are specific to a local context. Together, these factors may contribute to the misperception of partial wins as real wins in gambling. Future work may examine how outcome appraisal may be modulated by the salience of certain information, and investigate the appraisal process in contexts beyond gambling.

Interplays between plants and environmental factors determine pullout resistance on different revegetated slopes in mining areas.

Plant roots play a crucial role in enhancing soil stability and protecting slopes during ecological restoration, particularly in mining areas where external-soil spray seeding is employed. However, the relationship between plant root pullout resistance and environmental factors on different types of slopes remains unclear. In this study, we investigated the interactions between the pullout resistance of a dominant species, Artemisia gmelinii, and environmental factors on three slope types (rocky, geotechnical, and soil) using multi-group structural equation modeling. Our findings reveal that the pullout resistance of plant roots was strongly influenced by various factors, including but not limited to biological factors such as plant height and biomass. It showed a positive correlation between soil silt content and soil nutrient levels. Notably, the pullout resistance on soil slopes was significantly higher than on rocky slopes. Furthermore, the impact of soil nutrients and texture on pullout resistance was more pronounced on geotechnical and soil slopes compared to rocky slopes. Multi-group structural equation modeling highlighted that among all environmental factors, slope gradient and underground biomass had the most significant influence on pullout resistance across all slope types. Specifically, slope gradient had a greater effect on soil slopes, whereas underground biomass played a more prominent role on rocky and geotechnical slopes. Overall, our study suggests that when implementing external-soil spray seeding in mining areas, it is crucial to consider the interplay between plant roots and environmental factors, including slope properties. This holistic approach is crucial for maximizing the effectiveness of plants in slope protection during eco-engineering projects.