A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene.

In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant allele of glr-3 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons express GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery.

Preclinical efficacy of potent and selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias.

The interaction between menin and histone-lysine N-methyltransferase 2A (KMT2A) is a critical dependency for KMT2A- or nucleophosmin 1 (NPM1)-altered leukemias and an emerging opportunity for therapeutic development. JNJ-75276617 is a novel, orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between menin and KMT2A. In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) AML cells, JNJ-75276617 inhibited the association of the menin-KMT2A complex with chromatin at target gene promoters, resulting in reduced expression of several menin-KMT2A target genes, including MEIS1 and FLT3. JNJ-75276617 displayed potent anti-proliferative activity across several AML and ALL cell lines and patient samples harboring KMT2A- or NPM1-alterations in vitro. In xenograft models of AML and ALL, JNJ-75276617 reduced leukemic burden and provided a significant dose-dependent survival benefit accompanied by expression changes of menin-KMT2A target genes. JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice. Interestingly, JNJ-75276617 showed potent anti-proliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A co-crystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory (R/R) acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).

Stress-dependent activation entropy in thermally activated cross-slip of dislocations.

Cross-slip of screw dislocations in crystalline solids is a stress-driven thermally activated process essential to many phenomena during plastic deformation, including dislocation pattern formation, strain hardening, and dynamic recovery. Molecular dynamics (MD) simulation has played an important role in determining the microscopic mechanisms of cross-slip. However, due to its limited timescale, MD can only predict cross-slip rates in high-stress or high-temperature conditions. The transition state theory can predict the cross-slip rate over a broad range of stress and temperature conditions, but its predictions have been found to be several orders of magnitude too low in comparison to MD results. This discrepancy can be expressed as an anomalously large activation entropy whose physical origin remains unclear. Here, we resolve this discrepancy by showing that the large activation entropy results from anharmonic effects, including thermal softening, thermal expansion, and soft vibrational modes of the dislocation. We expect these anharmonic effects to be significant in a wide range of stress-driven thermally activated processes in solids.

Facile and Widely Applicable Route to Self-Adaptive Emissivity Modulation: Energy-Saving Demonstration with Transparent Wood.

The cooling power provided by radiative cooling is unwanted during cold hours. Therefore, self-adaptive regulation is desired for radiative cooling, especially in all-weather applications. However, current routes for radiative cooling regulation are constrained by substrates and complicated processing. Here, self-adaptive radiative cooling regulation on various potential substrates (transparent wood, PET, normal glass, and cement) was achieved by a Fabry-Perot structure consisting of a silver nanowires (AgNWs) bottom layer, PMMA spacer, and W-VO2 top layer. The emissivity-modulated transparent wood (EMTW) exhibits an emissivity contrast of 0.44 (ε8-13-L = ∼0.19 and ε8-13-H = ∼0.63), which thereby yields considerable energy savings across different climate zones. The emissivity contrast can be adjusted by varying the spinning parameters during the deposition process. Positive emissivity contrast was also achieved on three other industrially relevant substrates via this facile and widely applicable route. This proves the great significance of the approach to the promotion and wide adoption of radiative cooling regulation concept in the built environment.

Compact In Situ Electrochemical NMR with Wireless and Anti-interference Strategy in Multiscenario Applications.

The integration of electrochemistry with nuclear magnetic resonance (NMR) spectroscopy recently offers a powerful approach to understanding oxidative metabolism, detecting reactive intermediates, and predicting biological activities. This combination is particularly effective as electrochemical methods provide excellent mimics of metabolic processes, while NMR spectroscopy offers precise chemical analysis. NMR is already widely utilized in the quality control of pharmaceuticals, foods, and additives and in metabolomic studies. However, the introduction of additional and external connections into the magnet has posed challenges, leading to signal deterioration and limitations in routine measurements. Herein, we report an anti-interference compact in situ electrochemical NMR system (AICISENS). Through a wireless strategy, the compact design allows for the independent and stable operation of electrochemical NMR components with effective interference isolation. Thus, it opens an avenue toward easy integration into in situ platforms, applicable not only to laboratory settings but also to fieldwork. The operability, reliability, and versatility were validated with a series of biomimetic assessments, including measurements of microbial electrochemical systems, functional foods, and simulated drug metabolisms. The robust performance of AICISENS demonstrates its high potential as a powerful analytical tool across diverse applications.

Mechanism of Thermoelectric Performance Enhancement in CaMg2 Bi2 -Based Materials with Different Cation Site Doping.

Chemical bonds determine electron and phonon transport in solids. Tailoring chemical bonding in thermoelectric materials causes desirable or compromise thermoelectric transport properties. In this work, taking an example of CaMg2 Bi2 with covalent and ionic bonds, density functional theory calculations uncover that element Zn, respectively, replacing Ca and Mg sites cause the weakness of ionic and covalent bonding. Electrically, Zn doping at both Ca and Mg sites increases carrier concentration, while the former leads to higher carrier concentration than that of the latter because of its lower vacancy formation energy. Both doping types increase density-of-state effective mass but their mechanisms are different. The Zn doping Ca site induces resonance level in valence band and Zn doping Mg site promotes orbital alignment. Thermally, point defect and the change of phonon dispersion introduced by doping result in pronounced reduction of lattice thermal conductivity. Finally, combining with the further increase of carrier concentration caused by Na doping and the modulation of band structure and the decrease of lattice thermal conductivity caused by Ba doping, a high figure-of-merit ZT of 1.1 at 823 K in Zn doping Ca sample is realized, which is competitive in 1-2-2 Zintl phase thermoelectric systems.

Biomimetic Multifunctional Graphene-Based Coating for Thermal Management, Solar De-Icing, and Fire Safety: Inspired from the Antireflection Nanostructure of Compound Eyes.

Due to the ubiquitous and inexhaustible solar source, photothermal materials have gained considerable attention for their potential in heating and de-icing. Nevertheless, traditional photothermal materials, exemplified by graphene, frequently encounter challenges emanating from their elevated reflectance. Inspired by ocular structures, this study uses the Fresnel equation to enhance the photo-thermal conversion efficiency of graphene by introducing a polydimethylsiloxane (PDMS)/silicon dioxide (SiO2) coating, which reduces the light reflectance (≈20%) through destructive interference. The designed coating achieves an equilibrium temperature of ≈77 °C at one sun and a quick de-icing in ≈65 s, all with a thickness of 5 µm. Simulations demonstrate that applying this coating to high-rise buildings results in energy savings of ≈31% in winter heating. Furthermore, the combination of PDMS/SiO2 and graphene confers a notable enhancement in thermal stability through a synergistic flame-retardant mechanism, effectively safeguarding polyurethane against high temperatures and conflagrations, leading to marked reduction of 58% and 28% in heat release rate and total heat release. This innovative design enhances the photo-thermal conversion, de-icing function, and flame retardancy of graphene, thereby advancing its applications in outdoor equipment, high-rise buildings, and aerospace vessels.

Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque.

BACKGROUND: The heightened risk of cardiovascular and cerebrovascular events is associated with the increased instability of atherosclerotic plaques. However, the lack of effective diagnostic biomarkers has impeded the assessment of plaque instability currently. This study was aimed to investigate and identify hub genes associated with unstable plaques through the integration of various bioinformatics tools, providing novel insights into the detection and treatment of this condition. METHODS: Weighted Gene Co-expression Network Analysis (WGCNA) combined with two machine learning methods were used to identify hub genes strongly associated with plaque instability. The cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method was utilized to assess immune cell infiltration patterns in atherosclerosis patients. Additionally, Gene Set Variation Analysis (GSVA) was conducted to investigate the potential biological functions, pathways, and mechanisms of hub genes associated with unstable plaques. To further validate the diagnostic efficiency and expression of the hub genes, immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were performed on collected human carotid plaque and blood samples. Immunofluorescence co-staining was also utilized to confirm the association between hub genes and immune cells, as well as their colocalization with mitochondria. RESULTS: The CIBERSORT analysis demonstrated a significant decrease in the infiltration of CD8 T cells and an obvious increase in the infiltration of M0 macrophages in patients with atherosclerosis. Subsequently, two highly relevant modules (blue and green) strongly associated with atherosclerotic plaque instability were identified. Through intersection with mitochondria-related genes, 50 crucial genes were identified. Further analysis employing least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) algorithms revealed six hub genes significantly associated with plaque instability. Among them, NT5DC3, ACADL, SLC25A4, ALDH1B1, and MAOB exhibited positive correlations with CD8 T cells and negative correlations with M0 macrophages, while kynurenine 3-monooxygenas (KMO) demonstrated a positive correlation with M0 macrophages and a negative correlation with CD8 T cells. IHC and RT-qPCR analyses of human carotid plaque samples, as well as ELISA analyses of blood samples, revealed significant upregulation of KMO and MAOB expression, along with decreased ALDH1B1 expression, in both stable and unstable samples compared to the control samples. However, among the three key genes mentioned above, only KMO showed a significant increase in expression in unstable plaque samples compared to stable plaque samples. Furthermore, the expression patterns of KMO in human carotid unstable plaque tissues and cultured mouse macrophage cell lines were assessed using immunofluorescence co-staining techniques. Finally, lentivirus-mediated KMO silencing was successfully transduced into the aortas of high-fat-fed ApoE-/- mice, with results indicating that KMO silencing attenuated plaque formation and promoted plaque stability in ApoE-/- mice. CONCLUSIONS: The results suggest that KMO, a mitochondria-targeted gene associated with macrophage cells, holds promise as a valuable diagnostic biomarker for assessing the instability of atherosclerotic plaques.

1,25(OH)2 D3 inhibits Lewis lung cancer cell migration via NHE1-sensitive metabolic reprograming.

High prevalence and metastasis rates are characteristics of lung cancer. Glycolysis provides energy for the development and metastasis of cancer cells. The 1,25-dihydroxy vitamin D3 (1,25(OH)2 D3 ) has been linked to reducing cancer risk and regulates various physiological functions. We hypothesized that 1,25(OH)2 D3 could be associated with the expression and activity of Na+ /H+ exchanger isoform 1 (NHE1) of Lewis lung cancer cells, thus regulating glycolysis as well as migration by actin reorganization. Followed by online public data analysis, Vitamin D3 receptor, the receptor of 1,25(OH)2 D3 has been proved to be abundant in lung cancers. We demonstrated that 1,25(OH)2 D3 treatment suppressed transcript levels, protein levels, and activity of NHE1 in LLC cells. Furthermore, 1,25(OH)2 D3 treatment resets the metabolic balance between glycolysis and OXPHOS, mainly including reducing glycolytic enzymes expression and lactate production. In vivo experiments showed the inhibition effects on tumor growth as well. Therefore, we concluded that 1,25(OH)2 D3 could amend the NHE1 function, which leads to metabolic reprogramming and cytoskeleton reconstruction, finally inhibits the cell migration.

Retroperitoneoscopic Clampless, Sutureless Hybrid Therapy in the Management of Renal Hilar Tumors.

OBJECTIVE: We aimed to investigate the outcomes and feasibility of a retroperitoneoscopic clampless, sutureless hybrid technique in the management of renal hilar tumors. METHODS: A retrospective cohort of consecutive patients with renal hilar tumors who received retroperitoneoscopic clampless, sutureless hybrid therapy between January 2017 and April 2021 was included. The hybrid surgical technique involved microwave ablation (MWA), followed by clampless tumor enucleation and sutureless hemostasis. Surgical, pathological, and oncological outcomes were recorded and analyzed. RESULTS: Sixty patients were included in this study. The median tumor size was 3.5 cm (2-5), the median RENAL score was 7 (range 6-10), the median operative time was 110 min (70-130), and the median estimated blood loss was 80 mL (30-130). The median length of postoperative hospital stay was 3 days (2-4), and no warm ischemia time was observed, except in one patient who required conversion to conventional on-clamp laparoscopic partial nephrectomy (LPN) with a 10 min warm ischemia time. Three minor complications (Clavien-Dindo grade I) and one major complication (Clavien-Dindo grade III) were recorded postoperatively. Thus far, no blood transfusions have been required. Renal dysfunction or tumor recurrence did not occur within a median follow-up of 45 months. CONCLUSION: The retroperitoneoscopic hybrid technique involving MWA, clampless tumor enucleation, and sutureless hemostasis is a feasible and safe option for the management of selective renal hilar tumors. Complete tumor removal with maximal renal function preservation can be achieved, with a low complication rate.

ERBB3 deficiency causes a multisystemic syndrome in human patient and zebrafish.

The Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598), while a recent study reported six additional patients carrying ERBB3 variants which exhibited distinct clinical features with evident intestinal dysmotility (OMIM 243180). The potential connection between these phenotypes remains unknown, and the ERBB3-related phenotype spectrum needs to be better characterized. Here, we described a patient presenting with a multisystemic syndrome including skip segment Hirschsprung disease, bilateral clubfoot deformity, and cardiac defect. Trio-whole exome sequencing revealed a novel compound heterozygous variant (c.1914-7C>G; c.2942_2945del) in the patient's ERBB3 gene. RT-PCR and in vitro minigene analysis demonstrated that variant c.1914-7C>G caused aberrant mRNA splicing. Both variants resulted in premature termination codon and complete loss of ERBB3 function. erbb3b knockdown in zebrafish simultaneously caused a reduction in enteric neurons in the distal intestine, craniofacial cartilage defects, and micrognathia, which phenotypically mimics ERBB3-related intestinal dysmotility and some features of lethal congenital contracture syndrome in human patients. These findings provide further patient and animal evidence supporting that ERBB3 deficiency causes a complex syndrome involving multiple systems with phenotypic variability among distinct individuals.

Involvement of brassinosteroids and abscisic acid in spikelet degeneration in rice under soil drying during meiosis.

Spikelet degeneration in rice (Oryza sativa L.) is a serious physiological defect, and can be regulated by soil moisture status and phytohormones. This study investigated the possibility that brassinosteroids (BRs) in collaboration with abscisic acid (ABA) are involved in mediating the effect of soil drying during meiosis on spikelet degeneration in rice. Three rice cultivars were field grown and three irrigation regimes including well watered (WW), moderate soil drying (MD), and severe soil drying (SD) were imposed during meiosis. MD significantly decreased spikelet degeneration in comparison with WW, due mainly to the alleviation in oxidative damage via enhancing ascorbate-glutathione (AsA-GSH) cycle activity in young panicles, and SD exhibited the opposite effects. Enhanced AsA-GSH cycle strength, decreased oxidative stress, and spikelet degeneration rate were closely associated with the synergistically elevated BR and ABA levels in young panicles in MD. In contrast, low BR and excessive ABA levels led to an increase in spikelet degeneration in SD. The three cultivars exhibited the same tendencies. The intrinsic link among AsA-GSH cycle, oxidative stress, spikelet degeneration rate, and BR and ABA levels was further verified by using transgenic rice lines and chemical regulators. BRs or ABA play a unique role in regulating spikelet degeneration. Synergistically increased BR and ABA levels in MD could work together to strengthen AsA-GSH cycle activity, leading to a reduction in oxidative damage and spikelet degeneration. On the other hand, a severe imbalance between low BR and excessive ABA levels may have contributed to the opposite effects in SD.

A prediction model of elderly hip fracture mortality including preoperative red cell distribution width constructed based on the random survival forest (RSF) and Cox risk ratio regression.

An independent correlation between pre-RDW and 1-year mortality after surgery in elderly hip fracture can be used to predict mortality in elderly hip fracture patients and has predictive significance in anemia patients. With further research, a treatment algorithm can be developed to potentially identify patients at high risk of preoperative mortality. INTRODUCTION: Red blood cell distribution width (RDW) is an independent predictor of various disease states in elderly individuals, but its association with the prognosis of elderly hip fracture patients is controversial. This study aimed to evaluate the prognostic value of RDW in such patients, construct a prediction model containing RDW using random survival forest (RSF) and Cox regression analysis, and compare RDW in patients with and without anemia. METHODS: We retrospectively analyzed the data of elderly patients who underwent hip fracture surgery, selected the best variables using RSF, stratified the independent variables by Cox regression analysis, constructed a 1-year mortality prediction model of elderly hip fracture with RDW, and conducted internal validation and external validation. RESULTS: Two thousand one hundred six patients were included in this study. The RSF algorithm selects 12 important influencing factors, and Cox regression analysis showed that eight variables including preoperative RDW (pre-RDW) were independent risk factors for death within 1-year after hip fracture surgery in elderly patients. Stratified analysis showed that pre-RDW was still independently associated with 1-year mortality in the non-anemia group and not in the anemia group. The nomogram prediction model had high differentiation and fit, and the prediction model constructed by the total cohort of patients was also used for validation of patients in the anemia patients and obtained good clinical benefits. CONCLUSION: An independent correlation between pre-RDW and 1-year mortality after surgery in elderly hip fracture can be used to predict mortality in elderly hip fracture patients and has predictive significance in anemia patients.

Impaired FXR-CPT1a signaling contributes to parenteral nutrition-induced villus atrophy in short-bowel syndrome.

Parenteral nutrition (PN)-induced villus atrophy is a major cause of intestinal failure (IF) for children suffering from short bowel syndrome (SBS), but the precise mechanism remains unclear. Herein, we report a pivotal role of farnesoid X receptor (FXR) signaling and fatty acid oxidation (FAO) in PN-induced villus atrophy. A total of 14 pediatric SBS patients receiving PN were enrolled in this study. Those patients with IF showed longer PN duration and significant intestinal villus atrophy, characterized by remarkably increased enterocyte apoptosis concomitant with impaired FXR signaling and decreased FAO genes including carnitine palmitoyltransferase 1a (CPT1a). Likewise, similar changes were found in an in vivo model of neonatal Bama piglets receiving 14-day PN, including villus atrophy and particularly disturbed FAO process responding to impaired FXR signaling. Finally, in order to consolidate the role of the FXR-CPT1a axis in modulating enterocyte apoptosis, patient-derived organoids (PDOs) were used as a mini-gut model in vitro. Consequently, pharmacological inhibition of FXR by tauro-ß-muricholic acid (T-ßMCA) evidently suppressed CPT1a expression leading to reduced mitochondrial FAO function and inducible apoptosis. In conclusion, impaired FXR/CPT1a axis and disturbed FAO may play a pivotal role in PN-induced villus atrophy, contributing to intestinal failure in SBS patients.

Targeted metabolomics unravels altered phenylalanine levels in piglets receiving total parenteral nutrition.

Parenteral nutrition, received by many patients with intestinal failure, can induce hepatobiliary complications, which is termed as parenteral nutrition-associated liver disease (PNALD). The spectrum of PNALD ranges from cholestasis and steatosis to fibrosis and cirrhosis. Although many factors contribute to the pathogenesis of PNALD, the underlying mechanisms remain unclear. In this study, we performed targeted metabolomics to characterize the metabolomic profile in neonatal piglets receiving total parenteral nutrition (TPN) or enteral nutrition (EN) for 1 or 2 weeks. Overall, the metabolomic signature of TPN groups differed from EN groups at both time points. Among the 20 acylcarnitines identified, a majority of them were significantly reduced in TPN groups. KEGG pathway analysis showed that phenylalanine metabolism-associated pathways were dysregulated accompanied by more progressive liver steatosis associated with TPN. Next, we evaluated phenylalanine catabolism and its association with fatty acid oxidation in piglets and rats with PNALD. We showed that the hepatic expression of phenylalanine-degrading enzyme phenylalanine hydroxylase (PAH) was reduced and systemic phenylalanine levels were increased in both animal models of PNALD. Moreover, carnitine palmitoyltransferase 1A, a central regulator of fatty acid oxidation, was downregulated and its expression was negatively correlated with phenylalanine levels in TPN-fed animals. To explore the effects of phenylalanine accumulation on lipid metabolism, we treated HepG2 cells with phenylalanine co-cultured with sodium palmitate or soybean oil emulsion to induce lipid accumulation. We found that phenylalanine treatment exacerbated lipid accumulation by inhibiting fatty acid oxidation without affecting fatty acid synthesis. In summary, our findings establish a pathogenic role of increased phenylalanine levels in driving liver steatosis, linking dysregulation of phenylalanine catabolism with lipid accumulation in the context of PNALD.

A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting Treg differentiation.

Recent evidence has revealed that small polypeptides (containing fewer than 100 amino acids) can be translated from noncoding RNAs (ncRNAs), which are usually defined as RNA molecules that do not encode proteins. However, studies on functional products translated from primary transcripts of microRNA (pri-miRNA) are quite limited. Here, we describe a peptide termed miPEP31 that is encoded by pri-miRNA-31. miPEP31 is highly expressed in Foxp3+ regulatory T cells (Tregs ) and significantly promotes the differentiation of Tregs without affecting their inhibitory ability. Our results show that miPEP31 is a cell-penetrating peptide both in vitro and in vivo. miPEP31 downregulates miR-31 expression, enhances peripheral Treg induction, and dramatically suppresses experimental autoimmune encephalomyelitis. Mechanistically, we show that miPEP31 acts as a transcriptional repressor inhibiting the expression of miRNA-31, a negative regulator of Tregs . Our results reveal an indispensable role of miPEP31 in maintaining immune homeostasis by promoting Treg differentiation and also present a potential therapeutic peptide for modulating miRNA expression and treating autoimmune diseases.

Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway.

AIM: To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). METHODS: Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. RESULTS: The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1ß) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. CONCLUSION: We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

Preoperative prediction of disease-free survival in pancreatic ductal adenocarcinoma patients after R0 resection using contrast-enhanced CT and CA19-9.

OBJECTIVES: To investigate the efficiency of a combination of preoperative contrast-enhanced computed tomography (CECT) and carbohydrate antigen 19-9 (CA19-9) in predicting disease-free survival (DFS) after R0 resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: A total of 138 PDAC patients who underwent curative R0 resection were retrospectively enrolled and allocated chronologically to training (n = 91, January 2014-July 2019) and validation cohorts (n = 47, August 2019-December 2020). Using univariable and multivariable Cox regression analyses, we constructed a preoperative clinicoradiographic model based on the combination of CECT features and serum CA19-9 concentrations, and validated it in the validation cohort. The prognostic performance was evaluated and compared with that of postoperative clinicopathological and tumor-node-metastasis (TNM) models. Kaplan-Meier analysis was conducted to verify the preoperative prognostic stratification performance of the proposed model. RESULTS: The preoperative clinicoradiographic model included five independent prognostic factors (tumor diameter on CECT > 4 cm, extrapancreatic organ infiltration, CECT-reported lymph node metastasis, peripheral enhancement, and preoperative CA19-9 levels > 180 U/mL). It better predicted DFS than did the postoperative clinicopathological (C-index, 0.802 vs. 0.787; p < 0.05) and TNM (C-index, 0.802 vs. 0.711; p < 0.001) models in the validation cohort. Low-risk patients had significantly better DFS than patients at the high-risk, defined by the model preoperatively (p < 0.001, training cohort; p < 0.01, validation cohort). CONCLUSIONS: The clinicoradiographic model, integrating preoperative CECT features and serum CA19-9 levels, helped preoperatively predict postsurgical DFS for PDAC and could facilitate clinical decision-making. CLINICAL RELEVANCE STATEMENT: We constructed a simple model integrating clinical and radiological features for the prediction of disease-free survival after curative R0 resection in patients with pancreatic ductal adenocarcinoma; this novel model may facilitate preoperative identification of patients at high risk of recurrence and metastasis that may benefit from neoadjuvant treatments. KEY POINTS: • Existing clinicopathological predictors for prognosis in pancreatic ductal adenocarcinoma (PDAC) patients who underwent R0 resection can only be ascertained postoperatively and do not allow preoperative prediction. • We constructed a clinicoradiographic model, using preoperative contrast-enhanced computed tomography (CECT) features and preoperative carbohydrate antigen 19-9 (CA19-9) levels, and presented it as a nomogram. • The presented model can predict disease-free survival (DFS) in patients with PDAC better than can postoperative clinicopathological or tumor-node-metastasis (TNM) models.

Achieving Superior Electromagnetic-Absorbing Performances in the Hexagonal Flake BaFe12O19@PVDF Composites.

Combining magnetic and dielectric materials to form a composite can significantly improve its impedance matching and electromagnetic wave absorption performance. Furthermore, composite materials with a core-shell structure hold promise in meeting the demand for lightweight and highly electromagnetic-absorbing properties. In this study, uniform hexagonal flake barium ferrite (BaFe12O19) was prepared using the hydrothermal method. Subsequently, BaFe12O19@PVDF composites were synthesized by the sol-gel method. By adjusting the mass ratio of BaFe12O19 and PVDF, the shell size of the BaFe12O19@PVDF composite material was controlled, and its electromagnetic absorption performance was enhanced. The shell thickness of BaFe12O19@PVDF is 19.64 nm when the BaFe12O19: PVDF mass ratio is 1:1.0, and the optimal impedance matching is obtained at 13.4 GHz. Meanwhile, at a thickness of 1.5 mm, the minimum reflection loss (RLmin) reached -58.04 dB, and an effective absorption bandwidth (EAB) (RL ≤ -10 dB) of 5.53 GHz was achieved within the frequency range of 11.65 to 15.63 GHz and from 16.36 to 17.91 GHz. Besides, the composites with a matching thickness of 3.5 mm show a maximum EAB of 15.90 GHz when the mass ratio of BaFe12O19 to PVDF is 1:1.2. Within the frequency range of 2-18 GHz, the coverage of reflection loss less than -10 dB is 99.38%, almost achieving full coverage. These results demonstrate that BaFe12O19@PVDF composites exhibit excellent electromagnetic-absorbing performances, making them an excellent candidate for electromagnetic wave absorption in 5G communications.

Sodium houttuyfonate Modulates the Lung Th1/Th2 Balance and Gut Microbiota to Protect Against Pathological Changes in Lung of Ovalbumin-induced Asthmatic mice.

OBJECTIVE: The gut-lung axis involves microbial and product interactions between the lung and intestine. Antibiotics for chronic asthma can cause intestinal dysbiosis, disrupting this axis. Sodium houttuyfonate (SH) has diverse biological activities, including modifying gut microbiota, antibacterial, and anti-inflammatory. This study aims to explore the relationship between SH, CD4+ T cells, and gut microbiota. METHODS: Allergic asthma was experimentally induced in mice through injection and inhalation of ovalbumin. After the administration of different amounts of SH, ELISA was utilized to ascertain the levels of inflammatory cytokines in the serum, flow cytometry was used to examine the levels of Th1/Th2 cytokines in CD4+ cells from lung tissues. The expression of T-bet and GATA3 in lung tissue was determined by Western blotting and quantitative real-time PCR assay. Gut microbiota was determined by 16S rRNA gene sequencing. RESULTS: The results showed that SH can alleviate pulmonary injury in asthmatic mice, reducing serum levels of IL-4, IL-5, and IL-13 while simultaneously increasing IFN-γ. Furthermore, SH has been observed to modulate the balance of Th1/Th2 cells by up-regulating the mRNA and protein expression of T-bet but down-regulating GATA3 in the lung tissues of asthmatic mice, thereby promoting the differentiation of Th1 cells. Additionally, SH can regulate the variety and composition of gut microbiota especially genus Akkermansia in asthmatic mice. CONCLUSION: SH can alleviate asthma through the regulation of Th1/Th2 cells and gut microbiota.