Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis.

ABSTRACT: Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

[Assessment of the lagging effect of vegetation response and loss probability in the Pearl River basin under drought stress]. / å¹²æ—±èƒè¿«ä¸‹ç æ±ŸæµåŸŸæ¤è¢«å“åº”çš„æ»žåŽæ•ˆåº”åŠæŸå¤±æ¦‚çŽ‡è¯„ä¼°.

We quantified the lag time of vegetation response to drought in the Pearl River basin (PRB) based on the standardized precipitation evapotranspiration index (SPEI) and normalized difference vegetation index (NDVI), and constructed a vegetation loss probability model under drought stress based on the Bayesian theory and two-dimensional joint distribution. We further quantitatively evaluated the spatial variations of loss probability of four vegetation types (evergreen broadleaf forest, mixed forest, grassland, and cropland) under different drought intensities. The results showed that the drought risk in eastern West River, the upper reaches of North River and East River, and southern Pearl River Delta was obviously higher than that in other regions during 1982-2020. The response time of vegetation to drought in high-altitude areas in the upper reaches of PRB (mostly<3 month) was generally shorter than that in low altitude areas (>8 month). Drought exacerbated the probability of vegetation loss, with higher vulnerability of mixed forest than the other three vegetation types. The loss probability of vegetation was lower in northwestern PRB than that in central PRB.

Cross-shore parallel tidal channel systems formed by alongshore currents.

Parallel tidal channel systems, characterized by commonly cross-shore orientation and regular spacing, represent a distinct class of tidal channel networks in coastal environments worldwide. Intriguingly, these cross-shore oriented channel systems can develop in environments dominated by alongshore tidal currents, for which the mechanisms remain elusive. Here, we combine remote sensing imagery analysis and morphodynamic simulations to demonstrate that the deflection of alongshore tidal currents at transitions in bed elevation determines the characteristic orientation of the parallel tidal channels. Numerical results reveal that sharp changes in bed elevation lead to nearly 90-degree intersection angles, while smoother transitions in bed profiles result in less perpendicular channel alignments. These findings shed light on the potential manipulation of tidal channel patterns in coastal wetlands, thus equipping coastal managers with a broader range of strategies for the sustainable management of these vital ecosystems in the face of climate change and sea level rise.

The correlation between menstrual characteristics and fertility in women of reproductive age: a systematic review and meta-analysis.

IMPORTANCE: Menstruation serves as an indicator of women's reproductive well-being and plays a pivotal role in their fertility; nevertheless, there remains an ongoing debate regarding the epidemiological evidence linking menstrual characteristics and fertility. OBJECTIVE: To explore the correlation between menstrual characteristics and fertility in women of reproductive age. DATA SOURCES: A comprehensive literature search was conducted using PubMed, Embase, Web of Science, and Cochrane libraries to identify research articles published up until 9 February 2024. STUDY SELECTION AND SYNTHESIS: We included all studies in which the relationship between menstrual characteristics and pregnancy rates among women of reproductive age was investigated. We excluded studies involving the administration of oral contraceptives, application of assisted reproductive technologies, and individuals with a documented history of infertility or partners with a known history of infertility. MAIN OUTCOMES: Clinical pregnancy and miscarriage. RESULTS: This meta-analysis was composed of nine studies involving a total of 399,966 women, and the evidential quality derived from these studies was deemed to be high with a low risk of bias. Compared with a normal menstrual cycle length (2532 days), the impact of a short (<25 days) or long (>32 days) menstrual cycle on a woman's pregnancy was relatively insignificant (OR=0.81, CI [0.65, 1.01], I2=68%; OR=0.89, CI [0.75, 1.06], I2=60%, respectively); however, a change in cycle length may increase the risk of miscarriage (RR=1.87, CI [1.11, 3.15], I2=0%; RR=1.66, CI [1.07, 2.57], I2=43%, respectively). In comparison to women experiencing menarche at a typical age (1214 years), those with a late age at menarche (>14 years) exhibited a decreased likelihood of pregnancy (OR=0.92, CI [0.91, 0.93], I2=0%); and compared with women experiencing a normal duration of menstrual bleeding (47 days), those with a short duration of menstrual bleeding (<4 days) exhibited reduced fertility potential (OR=0.86, CI [0.84, 0.88], I2=29%). CONCLUSION AND RELEVANCE: Short and long menstrual cycle lengths may elevate women's susceptibility to spontaneous abortion, whereas late age at menarche and short duration of menstrual bleeding appear to be linked to diminished fertility among women of reproductive age.

Microbial remediation of petroleum-contaminated soil focused on the mechanism and microbial response: a review.

The environmental pollution caused by petroleum hydrocarbons has received considerable attention in recent years. Microbial remediation has emerged as the preferred method for the degradation of petroleum hydrocarbons, which is experiencing rapid development driven by advancements in molecular biology. Herein, the capacity of different microorganisms used for crude oil bioremediation was reviewed. Moreover, factors influencing the effectiveness of microbial remediation were discussed. Microbial remediation methods, such as bioaugmentation, biostimulation, and bioventilation, are summarized in this review. Aerobic and anaerobic degradation mechanisms were reviewed to elucidate the metabolic pathways involved. The impacts of petroleum hydrocarbons on microorganisms and the environment were also revealed. A brief overview of synthetic biology and a unique perspective of technique combinations were presented to provide insight into research trends. The challenges and future outlook were also presented to stimulate contemplation of the mechanisms involved and the development of innovative techniques.

Restoring colistin sensitivity in colistin-resistant Salmonella and Escherichia coli: combinatorial use of berberine and EDTA with colistin.

The appearance and prevalence of multidrug-resistance (MDR) Gram-negative bacteria (GNB) have limited our antibiotic capacity to control bacterial infections. The clinical efficacy of colistin (COL), considered as the "last resort" for treating GNB infections, has been severely hindered by its increased use as well as the emergence and prevalence of mobile colistin resistance (MCR)-mediated acquired drug resistance. Identifying promising compounds to restore antibiotic activity is becoming an effective strategy to alleviate the crisis of increasing MDR. We first demonstrated that the combination of berberine (BBR) and EDTA substantially restored COL sensitivity against COL-resistant Salmonella and Escherichia coli. Molecular docking indicated that BBR can interact with MCR-1 and the efflux pump system AcrAB-TolC, and BBR combined with EDTA downregulated the expression level of mcr-1 and tolC. Mechanically, BBR combined with EDTA could increase bacterial membrane damage, inhibit the function of multidrug efflux pump, and promote oxidative damage, thereby boosting the action of COL. In addition, transcriptome analysis found that the combination of BBR and EDTA can accelerate the tricarboxylic acid cycle, inhibit cationic antimicrobial peptide (CAMP) resistance, and attenuate Salmonella virulence. Notably, the combination of BBR and EDTA with COL significantly reduced the bacterial load in the liver and spleen of a mice model infected with Salmonella. Our findings revealed that BBR and EDTA can be used as adjuvants collectively with COL to synergistically reverse the COL resistance of bacteria. IMPORTANCE: Colistin is last-resort antibiotic used to treat serious clinical infections caused by MDR bacterial pathogens. The recent emergence of transferable plasmid-mediated COL resistance gene mcr-1 has raised the specter of a rapid worldwide spread of COL resistance. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. Our research showed that berberine combined with EDTA effectively reversed COL resistance both in vivo and in vitro through multiple modes of action. The discovery of berberine in combination with EDTA as a new and safe COL adjuvant provides a therapeutic regimen for combating Gram-negative bacteria infections. Our findings provide a potential therapeutic option using existing antibiotics in combination with antibiotic adjuvants and address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling.

BACKGROUND AND AIM: Clinically, septic males tend to have higher mortality rates, but it is unclear if this is due to sex differences in cardiac dysfunction, possibly influenced by hormonal variations. Cardiac dysfunction significantly contributes to sepsis-related mortality, primarily influenced by metabolic imbalances. Peroxisome proliferator-activated receptor delta (PPARδ) is a key player in cardiac metabolism and its activation has been demonstrated to favor sepsis outcomes. While estradiol (E2) is abundant and beneficial in females, its impact on PPARδ-mediated metabolism in the heart with regards to sex during sepsis remains unknown. METHODS AND RESULTS: Here, we unveil that while sepsis diminishes PPARδ nuclear translocation and induces metabolic dysregulation, oxidative stress, apoptosis and dysfunction in the heart thereby enhancing mortality, these effects are notably more pronounced in males than females. Mechanistic experiments employing ovariectomized(OVX) mice, E2 administration, and G protein-coupled estrogen receptor 1(GPER-1) knockout (KO) mice revealed that under lipopolysaccharide (LPS)-induced sepsis, E2 acting via GPER-1 enhances cardiac electrical activity and function, promotes PPARδ nuclear translocation, and subsequently ameliorates cardiac metabolism while mitigating oxidative stress and apoptosis in females. Furthermore, PPARδ specific activation using GW501516 in female GPER-1-/- mice reduced oxidative stress, ultimately decreasing NLRP3 expression in the heart. Remarkably, targeted GPER-1 activation using G1 in males mirrors these benefits, improving cardiac electrical activity and function, and ultimately enhancing survival rates during LPS challenge. By employing NLRP3 KO mice, we demonstrated that the targeted GPER-1 activation mitigated injury, enhanced metabolism, and reduced apoptosis in the heart of male mice via the downregulation of NLRP3. CONCLUSION: Our findings collectively illuminate the sex-specific cardiac mechanisms influencing sepsis mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in sepsis-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact.

The Influencing Factors of Frailty and Quality of Life in Elderly Patients After Spinal Surgery.

Background: To study the related factors of frailty and quality of life in elderly patients after spinal surgery. Methods: The anxiety, depression, frailty, and quality of life of all patients were assessed by the Anxiety screening scale (GAD-7), Depression screening scale (PHQ-9), Frailty screening scale (FRAIL), and European five-dimensional health scale (EQ-5D-5L) 1 day before surgery (DAY-0). A numeric rating scale (NRS) was used to evaluate patients' pain during activities on the 1st day (POD-1), 3rd day (POD-3), and 30th day (POD-30) after operation. FRAIL scale and EQ-5D-5L were used to evaluate patients' frailty and quality of life on POD-30 and 90th day (POD-90) after the operation. Results: There were significant differences in age, body mass index (BMI), preoperative serum albumin level (ALB), and NRS score on POD-1 between the two groups (P<0.05). Age and PHQ-9 score were positively correlated with EQ-5D-5L score (P<0.05, r Age=0.245, rPHQ-9=0.217), and preoperative ALB level was negatively correlated with EQ-5D-5L score (P<0.05, r ALB=-0.274). Conclusion: The older the age, the larger the BMI and the higher the NRS score on the first day after surgery, the more prone to frailty in elderly patients after spinal surgery; The older age and the lower the preoperative ALB level, the worse the quality of life in elderly patients after spinal surgery.

Improvement of Phased Antenna Array Applied in Focused Microwave Breast Hyperthermia.

Focused microwave breast hyperthermia (FMBH) employs a phased antenna array to perform beamforming that can focus microwave energy at targeted breast tumors. Selective heating of the tumor endows the hyperthermia treatment with high accuracy and low side effects. The effect of FMBH is highly dependent on the applied phased antenna array. This work investigates the effect of polarizations of antenna elements on the microwave-focusing results by simulations. We explore two kinds of antenna arrays with the same number of elements using different digital realistic human breast phantoms. The first array has all the elements' polarization in the vertical plane of the breast, while the second array has half of the elements' polarization in the vertical plane and the other half in the transverse plane, i.e., cross polarization. In total, 96 sets of different simulations are performed, and the results show that the second array leads to a better focusing effect in dense breasts than the first array. This work is very meaningful for the potential improvement of the antenna array for FMBH, which is of great significance for the future clinical applications of FMBH. The antenna array with cross polarization can also be applied in microwave imaging and sensing for biomedical applications.

Leptin receptor Gln223Arg and Lys109Arg polymorphisms may be associated with HBV-related hepatocellular carcinoma risk: A system review and meta-analysis.

Increasing evidence has suggested a strong association of hepatocellular carcinoma (HCC) susceptibility and Gln223Arg (rs1137101) and Lys109Arg (rs1137100) polymorphisms in leptin receptor (LEPR) genes. To provide a quantitative assessment for such correlation, we reviewed all related systems and conducted meta-analysis for case and control researches. A literature search of Web of Science, EMBASE, PubMed, Scopus as well as China National Knowledge Infrastructure databases was collected. 95% confidence intervals (95% CIs) together with odds ratios (ORs) were calculated. Five case-control researches consisting of 1323 cases and 1919 control cases were incorporated into meta-analysis. Researches indicated A-allelic and AA genotype of rs1137101 were substantially related to boosted susceptibility of hepatitis B virus (HBV)-related HCC (mutant model, OR = 1.81, 95% CI = 1.36-2.41, p < .001; allelic model, OR = 1.55, 95% CI = 1.32-1.83, p < .001). On the contrary, we observed GG genotype of rs1137101 substantially related to reduced risk of HBV-related HCC (wild model, OR 0.59, 95%CI = 0.46-0.75, p < .001). We observed AA genotype of rs1137100 relevant to boosted HCC risk (mutant model, OR = 1.51, 95%CI = 1.14-2.01, p = .005) as well as in those with HBV-related HCCs (homozygous model, OR = 2.12, 95%CI = 1.49-3.02, p < .001; mutant model, OR = 1.67, 95%CI = 1.23-2.26, p = .001). G-allele and AA genotype of rs1137101 might be in connection with boosted HBV-related HCC susceptibility, and wild-type GG genotype might prevent diseases. AA genotype of rs1137100 might also improve HBV-related HCC susceptibility. Such conclusions ought to be validated by larger and better-designed researches.

Effect of Copper Surface Roughness on the High-Temperature Structural Stability of Single-Layer-Graphene.

Graphene (Gr) has shown great potential in the field of oxidation protection for metals. However, numerous studies have shown that Gr will suffer structural degradation on metal surface during high-temperature oxidation, which significantly limited the effectiveness of their oxidation protection. Therefore, understanding the degradation mechanism of Gr is of great interest to enhance their structural stability. Here, the effect of copper (Cu) surface roughness on the high-temperature structural stability of single-layer graphene (SLG) was examined using Cu covered with SLG as a model material. SLG/Cu with different roughness values was obtained via high-temperature annealing of the model material. After high-temperature oxidation at 500 °C, Raman spectra analysis showed that the defect density of the oxidized SLG increased from 41% to 81% when the surface roughness varied from 37 nm to 81 nm. Combined with density functional theory calculations, it was found that the lower formation energy of the C-O bond on rough Cu surfaces (0.19 eV) promoted the formation of defects in SLG. This study may provide guidance for improving the effectiveness of SLG for the oxidation protection of metallic materials.

Flexible calorimetric flow sensor with unprecedented sensitivity and directional resolution for multiple flight parameter detection.

The accurate perception of multiple flight parameters, such as the angle of attack, angle of sideslip, and airflow velocity, is essential for the flight control of micro air vehicles, which conventionally rely on arrays of pressure or airflow velocity sensors. Here, we present the estimation of multiple flight parameters using a single flexible calorimetric flow sensor featuring a sophisticated structural design with a suspended array of highly sensitive vanadium oxide thermistors. The proposed sensor achieves an unprecedented velocity resolution of 0.11 mm·s-1 and angular resolution of 0.1°. By attaching the sensor to a wing model, the angles of attack and slip were estimated simultaneously. The triaxial flight velocities and wing vibrations can also be estimated by sensing the relative airflow velocity due to its high sensitivity and fast response. Overall, the proposed sensor has many promising applications in weak airflow sensing and flight control of micro air vehicles.

Observation of the effect of hypothermia therapy combined with optimized nursing on brain protection after cardiopulmonary resuscitation: A retrospective case-control study.

This study aimed to investigate the impact of optimized emergency nursing in conjunction with mild hypothermia nursing on neurological prognosis, hemodynamics, and complications in patients with cardiac arrest. A retrospective analysis was conducted on the medical records of 124 patients who received successful cardiopulmonary resuscitation (CPR) at Fujian Provincial Hospital South Branch. The patients were divided into control and observation groups, each consisting of 62 cases. The brain function of both groups was assessed using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale. Additionally, serum neuron-specific enolase level was measured in both groups. The vital signs and hemodynamics of both groups were analyzed, and the complications and satisfaction experienced by the 2 groups were compared. The experimental group exhibited significantly improved neurological function than the control group (P < .05). Furthermore, the heart rate in the experimental group was significantly lower than the control group (P < .05). However, no significant differences were observed in blood oxygen saturation, mean arterial pressure, central venous pressure, and systolic blood pressure between the 2 groups (P > 0.05). Moreover, the implementation of optimized nursing practices significantly reduced complications and improved the quality of life and satisfaction of post-CPR patients (P < .05). The integration of optimized emergency nursing practices in conjunction with CPR improves neurological outcomes in patients with cardiac arrest.

FNeXter: A Multi-Scale Feature Fusion Network Based on ConvNeXt and Transformer for Retinal OCT Fluid Segmentation.

The accurate segmentation and quantification of retinal fluid in Optical Coherence Tomography (OCT) images are crucial for the diagnosis and treatment of ophthalmic diseases such as age-related macular degeneration. However, the accurate segmentation of retinal fluid is challenging due to significant variations in the size, position, and shape of fluid, as well as their complex, curved boundaries. To address these challenges, we propose a novel multi-scale feature fusion attention network (FNeXter), based on ConvNeXt and Transformer, for OCT fluid segmentation. In FNeXter, we introduce a novel global multi-scale hybrid encoder module that integrates ConvNeXt, Transformer, and region-aware spatial attention. This module can capture long-range dependencies and non-local similarities while also focusing on local features. Moreover, this module possesses the spatial region-aware capabilities, enabling it to adaptively focus on the lesions regions. Additionally, we propose a novel self-adaptive multi-scale feature fusion attention module to enhance the skip connections between the encoder and the decoder. The inclusion of this module elevates the model's capacity to learn global features and multi-scale contextual information effectively. Finally, we conduct comprehensive experiments to evaluate the performance of the proposed FNeXter. Experimental results demonstrate that our proposed approach outperforms other state-of-the-art methods in the task of fluid segmentation.

Upregulation of outer membrane porin gene ompC contributed to enhancement of azithromycin susceptibility in multidrug-resistant Escherichia coli.

The outer membrane (OM) in gram-negative bacteria contains proteins that regulate the passive or active uptake of small molecules for growth and cell function, as well as mediate the emergence of antibiotic resistance. This study aims to explore the potential mechanisms for restoring bacteria to azithromycin susceptibility based on transcriptome analysis of bacterial membrane-related genes. Transcriptome sequencing was performed by treating multidrug-resistant Escherichia coli T28R with azithromycin or in combination with colistin and confirmed by reverse transcription-quantitative PCR (RT-qPCR). Azithromycin enzyme-linked immunosorbent assay (ELISA) test, ompC gene overexpression, and molecular docking were utilized to conduct the confirmatory research of the potential mechanisms. We found that colistin combined with azithromycin led to 48 differentially expressed genes, compared to azithromycin alone, such as downregulation of tolA, eptB, lpxP, and opgE and upregulation of ompC gene. Interestingly, the addition of colistin to azithromycin differentially downregulated the mph(A) gene mediating azithromycin resistance, facilitating the intracellular accumulation of azithromycin. Also, overexpression of the ompC elevated azithromycin susceptibility, and colistin contributed to further suppression of the Mph(A) activity in the presence of azithromycin. These findings suggested that colistin firstly enhanced the permeability of bacterial OM, causing intracellular drug accumulation, and then had a repressive effect on the Mph(A) activity along with azithromycin. Our study provides a novel perspective that the improvement of azithromycin susceptibility is related not only to the downregulation of the mph(A) gene and conformational remodeling of the Mph(A) protein but also the upregulation of the membrane porin gene ompC.IMPORTANCEUsually, active efflux via efflux pumps is an important mechanism of antimicrobial resistance, such as the AcrAB-TolC complex and MdtEF. Also, bacterial porins exhibited a substantial fraction of the total number of outer membrane proteins in Enterobacteriaceae, which are involved in mediating the development of the resistance. We found that the upregulation or overexpression of the ompC gene contributed to the enhancement of resistant bacteria to azithromycin susceptibility, probably due to the augment of drug uptakes caused and the opportunity of Mph(A) function suppressed by azithromycin with colistin. Under the combination of colistin and azithromycin treatment, OmpC exhibited an increased selectivity for cationic molecules and played a key role in the restoral of the antibiotic susceptibility. Investigations on the regulation of porin expression that mediated drug resistance would be important in clinical isolates treated with antibiotics.

CD73/adenosine axis exerts cardioprotection against hypobaric hypoxia-induced metabolic shift and myocarditis in a sex-dependent manner.

BACKGROUND: Clinical and experimental studies have shown that the myocardial inflammatory response during pathological events varies between males and females. However, the cellular and molecular mechanisms of these sex differences remain elusive. CD73/adenosine axis has been linked to anti-inflammatory responses, but its sex-specific cardioprotective role is unclear. The present study aimed to investigate whether the CD73/adenosine axis elicits sex-dependent cardioprotection during metabolic changes and myocarditis induced by hypobaric hypoxia. METHODS: For 7 days, male and female mice received daily injections of the CD73 inhibitor adenosine 5'- (α, ß-methylene) diphosphate (APCP) 10 mg/kg/day while they were kept under normobaric normoxic and hypobaric hypoxic conditions. We evaluated the effects of hypobaric hypoxia on the CD73/adenosine axis, myocardial hypertrophy, and cardiac electrical activity and function. In addition, metabolic homeostasis and immunoregulation were investigated to clarify the sex-dependent cardioprotection of the CD73/adenosine axis. RESULTS: Hypobaric hypoxia-induced cardiac dysfunction and adverse remodeling were more pronounced in male mice. Also, male mice had hyperactivity of the CD73/adenosine axis, which aggravated myocarditis and metabolic shift compared to female mice. In addition, CD73 inhibition triggered prostatic acid phosphatase ectonucleotidase enzymatic activity to sustain adenosine overproduction in male mice but not in female mice. Moreover, dual inhibition prostatic acid phosphatase and CD73 enzymatic activities in male mice moderated adenosine content, alleviating glycolytic shift and proinflammatory response. CONCLUSION: The CD73/adenosine axis confers a sex-dependent cardioprotection. In addition, extracellular adenosine production in the hearts of male mice is influenced by prostatic acid phosphatase and tissue nonspecific alkaline phosphatase.

Combining bulk and scRNA-seq to explore the molecular mechanisms governing the distinct efferocytosis activities of a macrophage subpopulation in PDAC.

Pancreatic ductal adenocarcinoma (PDAC), a very aggressive tumour, is currently the third leading cause of cancer-related deaths. Unfortunately, many patients face the issue of inoperability at the diagnostic phase leading to a quite dismal prognosis. The onset of metastatic processes has a crucial role in the elevated mortality rates linked to PDAC. Individuals with metastatic advances receive only palliative therapy and have a grim prognosis. It is essential to carefully analyse the intricacies of the metastatic process to enhance the prognosis for individuals with PDAC. Malignancy development is greatly impacted by the process of macrophage efferocytosis. Our current knowledge about the complete range of macrophage efferocytosis activities in PDAC and their intricate interactions with tumour cells is still restricted. This work aims to resolve communication gaps and pinpoint the essential transcription factor that is vital in the immunological response of macrophage populations. We analysed eight PDAC tissue samples sourced from the gene expression omnibus. We utilized several software packages such as Seurat, DoubletFinder, Harmony, Pi, GSVA, CellChat and Monocle from R software together with pySCENIC from Python, to analyse the single-cell RNA sequencing (scRNA-seq) data collected from the PDAC samples. This study involved the analysis of a comprehensive sample of 22,124 cells, which were classified into distinct cell types. These cell types encompassed endothelial and epithelial cells, PDAC cells, as well as various immune cells, including CD4+ T cells, CD8+ T cells, NK cells, B cells, plasma cells, mast cells, monocytes, DC cells and different subtypes of macrophages, namely C0 macrophage TGM2+, C1 macrophage PFN1+, C2 macrophage GAS6+ and C3 macrophage APOC3+. The differentiation between tumour cells and epithelial cells was achieved by the implementation of CopyKat analysis, resulting in the detection and categorization of 1941 PDAC cells. The amplification/deletion patterns observed in PDAC cells on many chromosomes differ significantly from those observed in epithelial cells. The study of Pseudotime Trajectories demonstrated that the C0 macrophage subtype expressing TGM2+ had the lowest level of differentiation. Additionally, the examination of gene set scores related to efferocytosis suggested that this subtype displayed higher activity during the efferocytosis process compared to other subtypes. The most active transcription factors for each macrophage subtype were identified as BACH1, NFE2, TEAD4 and ARID3A. In conclusion, the examination of human PDAC tissue samples using immunofluorescence analysis demonstrated the co-localization of CD68 and CD11b within regions exhibiting the presence of keratin (KRT) and alpha-smooth muscle actin (α-SMA). This observation implies a spatial association between macrophages, fibroblasts, and epithelial cells. There is variation in the expression of efferocytosis-associated genes between C0 macrophage TGM2+ and other macrophage cell types. This observation implies that the diversity of macrophage cells might potentially influence the metastatic advancement of PDAC. Moreover, the central transcription factor of different macrophage subtypes offers a promising opportunity for targeted immunotherapy in the treatment of PDAC.

A Highly Sensitive Deep-Sea Hydrodynamic Pressure Sensor Inspired by Fish Lateral Line.

Hydrodynamic pressure sensors offer an auxiliary approach for ocean exploration by unmanned underwater vehicles (UUVs). However, existing hydrodynamic pressure sensors often lack the ability to monitor subtle hydrodynamic stimuli in deep-sea environments. In this study, we present the development of a deep-sea hydrodynamic pressure sensor (DSHPS) capable of operating over a wide range of water depths while maintaining exceptional hydrodynamic sensing performance. The DSHPS device was systematically optimized by considering factors such as piezoelectric polyvinylidene fluoride-trifluoroethylene/barium titanate [P(VDF-TrFE)/BTO] nanofibers, electrode configurations, sensing element dimensions, integrated circuits, and packaging strategies. The optimized DSHPS exhibited a remarkable pressure gradient response, achieving a minimum pressure difference detection capability of approximately 0.11 Pa. Additionally, the DSHPS demonstrated outstanding performance in the spatial positioning of dipole sources, which was elucidated through theoretical charge modeling and fluid-structure interaction (FSI) simulations. Furthermore, the integration of a high Young's modulus packaging strategy inspired by fish skull morphology ensured reliable sensing capabilities of the DSHPS even at depths of 1000 m in the deep sea. The DSHPS also exhibited consistent and reproducible positioning performance for subtle hydrodynamic stimulus sources across this wide range of water depths. We envision that the development of the DSHPS not only enhances our understanding of the evolutionary aspects of deep-sea canal lateral lines but also paves the way for the advancement of artificial hydrodynamic pressure sensors.

PML-mediated nuclear loosening permits immunomodulation of mesenchymal stem/stromal cells under inflammatory conditions.

Nuclear configuration plays a critical role in the compartmentalization of euchromatin and heterochromatin and the epigenetic regulation of gene expression. Under stimulation by inflammatory cytokines IFN-γ and TNF-α, human mesenchymal stromal cells (hMSCs) acquire a potent immunomodulatory function enabled by drastic induction of various effector genes, with some upregulated several magnitudes. However, whether the transcriptional upregulation of the immunomodulatory genes in hMSCs exposed to inflammatory cytokines is associated with genome-wide nuclear reconfiguration has not been explored. Here, we demonstrate that hMSCs undergo remarkable nuclear reconfiguration characterized by an enlargement of the nucleus, downregulation of LMNB1 and LMNA/C, decondensation of heterochromatin, and derepression of repetitive DNA. Interestingly, promyelocytic leukaemia-nuclear bodies (PML-NBs) were found to mediate the nuclear reconfiguration of hMSCs triggered by the inflammatory cytokines. Significantly, when PML was depleted, the immunomodulatory function of hMSCs conferred by cytokines was compromised, as reflected by the attenuated expression of effector molecules in hMSCs and their failure to block infiltration of immune cells to lipopolysaccharide (LPS)-induced acute lung injury. Our results indicate that the immunomodulatory function of hMSCs conferred by inflammatory cytokines requires PML-mediated chromatin loosening.