IRF8 maintains mononuclear phagocyte and neutrophil function in acute kidney injury.

Immune cells are key players in acute tissue injury and inflammation, including acute kidney injury (AKI). Their development, differentiation, activation status, and functions are mediated by a variety of transcription factors, such as interferon regulatory factor 8 (IRF8) and IRF4. We speculated that IRF8 has a pathophysiologic impact on renal immune cells in AKI and found that IRF8 is highly expressed in blood type 1 conventional dendritic cells (cDC1s), monocytes, monocyte-derived dendritic cells (moDCs) and kidney biopsies from patients with AKI. In a mouse model of ischemia‒reperfusion injury (IRI)-induced AKI, Irf8 -/- mice displayed increased tubular cell necrosis and worsened kidney dysfunction associated with the recruitment of a substantial amount of monocytes and neutrophils but defective renal infiltration of cDC1s and moDCs. Mechanistically, global Irf8 deficiency impaired moDC and cDC1 maturation and activation, as well as cDC1 proliferation, antigen uptake, and trafficking to lymphoid organs for T-cell priming in ischemic AKI. Moreover, compared with Irf8 +/+ mice, Irf8 -/- mice exhibited increased neutrophil recruitment and neutrophil extracellular trap (NET) formation following AKI. IRF8 primarily regulates cDC1 and indirectly neutrophil functions, and thereby protects mice from kidney injury and inflammation following IRI. Our results demonstrate that IRF8 plays a predominant immunoregulatory role in cDC1 function and therefore represents a potential therapeutic target in AKI.

Macrophage based drug delivery: Key challenges and strategies.

As a natural immune cell and antigen presenting cell, macrophages have been studied and engineered to treat human diseases. Macrophages are well-suited for use as drug carriers because of their biological characteristics, such as excellent biocompatibility, long circulation, intrinsic inflammatory homing and phagocytosis. Meanwhile, macrophages' uniquely high plasticity and easy re-education polarization facilitates their use as part of efficacious therapeutics for the treatment of inflammatory diseases or tumors. Although recent studies have demonstrated promising advances in macrophage-based drug delivery, several challenges currently hinder further improvement of therapeutic effect and clinical application. This article focuses on the main challenges of utilizing macrophage-based drug delivery, from the selection of macrophage sources, drug loading, and maintenance of macrophage phenotypes, to drug migration and release at target sites. In addition, corresponding strategies and insights related to these challenges are described. Finally, we also provide perspective on shortcomings on the road to clinical translation and production.

[K2(Bi@Pd12@Bi20)]4-: An Endohedral Inorganic Fullerene with Spherical Aromaticity.

Inorganic fullerene clusters have attracted widespread attention due to their highly symmetrical geometric structures and intrinsic electronic properties. However, cage-like clusters composed of heavy metal elements with high symmetry are rarely reported, and their synthesis is also highly challenging. In this study, we present the synthesis of a [K2(Bi@Pd12@Bi20)]4- cluster that incorporates a {Bi20} cage with pseudo-Ih symmetry, making it the largest main group metal cluster compound composed of the bismuth element to date. Magnetic characterization and theoretical calculations suggest that the spin state of the overall cluster is a quartet. Quantum chemical calculations reveal that the [Bi20]3- cluster has a similar electronic configuration to C606- and the [Bi@Pd12@Bi20]6- cluster exhibits a unique open-shell aromatic character.

2D Janus Polarization Functioned by Mechanical Force.

2D polarization materials have emerged as promising candidates for meeting the demands of device miniaturization, attributed to their unique electronic configurations and transport characteristics. Although the existing inherent and sliding mechanisms are increasingly investigated in recent years, strategies for inducing 2D polarization with innovative mechanisms remain rare. This study introduces a novel 2D Janus state by modulating the puckered structure. Combining scanning probe microscopy, transmission electron microscopy, and density functional theory calculations, this work realizes force-triggered out-of-plane and in-plane dipoles with distorted smaller warping in GeSe. The Janus state is preserved after removing the external mechanical perturbation, which could be switched by modulating the sliding direction. This work offers a versatile method to break the space inversion symmetry in a 2D system to trigger polarization in the atomic scale, which may open an innovative insight into configuring novel 2D polarization materials.

An oleanic acid decorated gold nanorod for highly efficient inhibition of hemagglutinin and visible rapid detection of the influenza virus.

Accurate diagnosis and effective antiviral treatments are urgently needed for the prevention and control of flu caused by influenza viruses. In this study, a novel oleanic acid (OA) functionalized gold nanorod OA-AuNP was prepared through a convenient ligand-exchange reaction. As hemagglutinin (HA) on the viral surface binds strongly to the multiple OA molecules on the surface of the nanoparticle, the prepared OA-AuNP was found to exhibit potent antiviral activity against a wide range of influenza A virus strains. Furthermore, the change in color resulting from the specific binding between HA and OA and the resultant aggregation of the OA-AuNP can be visually observed or measured by UV-vis spectra with a detection limit of 2 and 0.18 hemagglutination units (HAU), respectively, which is comparable to the commercially available influenza colloid gold rapid diagnostic kits. These findings demonstrate the potential of the OA-AuNP for the development of novel multivalent antiviral conjugates and the diagnosis of influenza virus.

Interactions between plants and bacterial communities for phytoremediation of petroleum-contaminated soil.

Plants can stimulate the microbes to degrade ubiquitous petroleum hydrocarbons (PHCs), which has prompted a novel view on rhizoremediation. In the present study, the degradation rate of PHCs was investigated and 16S rRNA gene analysis was performed to investigate the PHC-degrading bacteria in petroleum-contaminated soil with different plants. Mirabilis jalapa (M. jalapa) has a higher PHC degradation rate than Lolium perenne (L. perenne) under petroleum contamination. The bacterial diversity in rhizospheric soil was decreased but the relative abundance of Actinobacteriota, Proteobacteria, and Candidatus Saccharibacteria were significant increased on 45 days petroleum-contaminated rhizospheric soil. In addition, the relative expression of PHC degradation-related genes, the content of malic acid and citric acid of the root exudates in the two plants was significantly increased in response to petroleum stress. The content of citric acid increased 11.9 times in M. jalapa and 3.4 times in L. perenne, respectively, in response to petroleum stress. These results indicate that M. jalapa changes the hydrocarbon-degrading microbial community to enhance the degradation of PHCs by root exudates and phytostimulation.

Region-Specific CD16+ Neutrophils Promote Colorectal Cancer Progression by Inhibiting Natural Killer Cells.

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro-tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF-κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region-specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16-knockout reverses the pro-tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region-specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC.

Extension and Fusion of Cyclic Polyantimony Units.

The synthesis and characterization of a series of polyantimony anionic clusters are reported. The products [(NbCp)2Sb10]2-, [MSb13]3- (M = Ru/Fe), and [MSb15]3- (M = Ru/Fe) were isolated as either K(18-crown-6) or K([2.2.2]-crypt) salts. The Sb10 ring contained in the [(NbCp)2Sb10]2- cluster can be viewed as an extension of two envelope-like cyclo-Sb5 units and represents by far the largest monocyclic all-antimony species. The clusters [MSb13]3- and [MSb15]3- (M = Ru/Fe) illustrate the variability of crown-like Sb8 ring motifs and reveal the fusion of different antimony fragments featuring unique Sb-Sb chain-like units. The reported synthetic approaches involve the fabrication of a variety of distinctive polyantimony anionic clusters, enhancing our understanding of the coordination chemistry of heavier group 15 elements.

A Biomimetic Fibrous Composite Scaffold with Nanotopography-Regulated Mineralization for Bone Defect Repair.

The effective regeneration of large bone defects via bone tissue engineering is challenging due to the difficulty in creating an osteogenic microenvironment. Inspired by the fibrillar architecture of the natural extracellular matrix, we developed a nanoscale bioengineering strategy to produce bone fibril-like composite scaffolds with enhanced osteogenic capability. To activate the surface for biofunctionalization, self-adaptive ridge-like nanolamellae were constructed on poly(ε-caprolactone) (PCL) electrospinning scaffolds via surface-directed epitaxial crystallization. This unique nanotopography with a markedly increased specific surface area offered abundant nucleation sites for Ca2+ recruitment, leading to a 5-fold greater deposition weight of hydroxyapatite than that of the pristine PCL scaffold under stimulated physiological conditions. Bone marrow mesenchymal stem cells (BMSCs) cultured on bone fibril-like scaffolds exhibited enhanced adhesion, proliferation, and osteogenic differentiation in vitro. In a rat calvarial defect model, the bone fibril-like scaffold significantly accelerated bone regeneration, as evidenced by micro-CT, histological histological and immunofluorescence staining. This work provides the way for recapitulating the osteogenic microenvironment in tissue-engineered scaffolds for bone repair.

Structuring restricted amorphous molecular chains in the reinforced cellulose film by uniaxial stretching.

The construction of the preferred orientation structure by stretching is an efficient strategy to fabricate high-performance cellulose film and it is still an open issue whether crystalline structure or amorphous molecular chain is the key factor in determining the enhanced mechanical performance. Herein, uniaxial stretching with constant width followed by drying in a stretching state was carried out to cellulose hydrogels with physical and chemical double cross-linking networks, achieving high-performance regenerated cellulose films (RCFs) with an impressive tensile strength of 154.5 MPa and an elastic modulus of 5.4 GPa. The hierarchical structure of RCFs during uniaxial stretching and drying was systematically characterized from micro- to nanoscale, including microscopic morphology, crystalline structure as well as relaxation behavior at a molecular level. The two-dimensional correlation spectra of dynamic mechanical analysis and Havriliak-Negami fitting results verified that the enhanced mechanical properties of RCFs were mainly attributed to the stretch-induced tight packing and restricted relaxation of amorphous molecular chains. The new insight concerning the contribution of molecular chains in the amorphous region to the enhancement of mechanical performance for RCFs is expected to provide valuable guidance for designing and fabricating high-performance eco-friendly cellulose-based films.

Biomimetic Mineralized 3D-Printed Polycaprolactone Scaffold Induced by Self-Adaptive Nanotopology to Accelerate Bone Regeneration.

Three-dimensional (3D)-printed biodegradable polymer scaffolds are at the forefront of personalized constructs for bone tissue engineering. However, it remains challenging to create a biological microenvironment for bone growth. Herein, we developed a novel yet feasible approach to facilitate biomimetic mineralization via self-adaptive nanotopography, which overcomes difficulties in the surface biofunctionalization of 3D-printed polycaprolactone (PCL) scaffolds. The building blocks of self-adaptive nanotopography were PCL lamellae that formed on the 3D-printed PCL scaffold via surface-directed epitaxial crystallization and acted as a linker to nucleate and generate hydroxyapatite crystals. Accordingly, a uniform and robust mineralized layer was immobilized throughout the scaffolds, which strongly bound to the strands and had no effect on the mechanical properties of the scaffolds. In vitro cell culture experiments revealed that the resulting scaffold was biocompatible and enhanced the proliferation and osteogenic differentiation of mouse embryolous osteoblast cells. Furthermore, we demonstrated that the resulting scaffold showed a strong capability to accelerate in vivo bone regeneration using a rabbit bone defect model. This study provides valuable opportunities to enhance the application of 3D-printed scaffolds in bone repair, paving the way for translation to other orthopedic implants.

[Pollution Characteristics and Source Analysis of Soil Heavy Metal in Coal Mine Area near the Yellow River in Shandong].

To explore the pollution characteristics and source of soil heavy metal in a coal mine area near the Yellow River in Shandong, the geo-accumulation index method and improved Nemerow pollution index method were used to evaluate the pollution characteristics of soil heavy metal. The absolute principal component-multiple linear regression model (APCS-MLR) was used to quantitatively analyze the source of soil heavy metal, and the spatial distribution of Hg and Cd were analyzed using the Kriging spatial difference method in ArcGIS. The result accuracy of the APCS-MLR model was further verified. The results showed that:The measured contents of soil heavy metal Cu, Zn, Pb, Cr, Cd, Ni, As, and Hg all exceeded the normal site, among which, Hg and Cd exceeded the background values of soil elements in Shandong. The coefficient of variation (CV) of Hg was higher than 0.500, indicating significant spatial heterogeneity. Moreover, the correlation between Hg and other heavy metals was generally low, and the possibility of the same pollution source was small. The results of the geo-accumulation index and improved Nemerow pollution index showed that the overall soil heavy metal pollution was at a moderate level, among which the Hg pollution level was the highest, and its maximum value was at a slanted-heavy pollution level; Cu, Cd, and As in soil caused local pollution, which were at a slanted-light pollution level. Soil heavy metal pollution was closely related to mining activities, rehabilitation, and engineering construction in the coal mine area. The two major pollution sources of soil heavy metal in the research area were the compound source of the parent material and industrial and mining transportation sources (known source 1) and the compound source of atmospheric sedimentation and coal production (known source 2), the contribution rates of which were 76.705% and 16.171%, respectively. The results of the APCS-MLR model were shown to be reliable by analyzing the content distribution of Hg and Cd using the Kriging space difference mode. This research can provide scientific basis for the precise control and improvement of soil heavy metal pollution, ensuring the safety of food and agricultural products and improving the quality of the ecological environment in the coal mine area in the Shandong section of the Yellow River Basin.

Long-term outcomes of 1-2 cm rectal neuroendocrine tumors after local excision or radical resection: A population-based multicenter study.

Objectives: Studies on rectal neuroendocrine tumors (R-NETs) that are 1-2 cm in size are limited, and the optimal treatment for these tumors is not well established. Methods: Data from patients with primary localized R-NETs 1-2 cm in size were retrospectively collected from 17 large-scale referral medical centers in China. Long-term prognosis, quality of life (QOL), and fecal incontinence were evaluated, and the effects of local excision (LE) or radical resection (RR) were elucidated using propensity score matching (PSM). Results: A total of 272 patients were included in this study; 233 underwent LE, and the remaining 39 underwent RR. Patients in the LE group showed lower tumor location, fewer postoperative Clavien-Dindo III-V complications, more G1 tumors, and lower tumor stage. There were no significant differences in the relapse-free survival or overall survival (OS) between the LE and RR groups after PSM. Patients in the LE group reported superior physical, role, emotional, social, and cognitive functions, global QOL, and Wexner fecal incontinence scores compared with those in the RR group (all P < 0.050). Eighteen (6.6%) patients had lymph node metastases. Multivariable analysis revealed that tumor location (odds ratio [OR] = 3.19, 95% confidence interval [CI] 1.04-10.07, P = 0.010), neutrophil-to-lymphocyte ratio (NLR) > 1.80 (OR = 4.50, 1.46-15.89, P = 0.012), and T3-T4 (OR = 36.31, 95% CI 7.85-208.62, P < 0.001) were independent risk factor for lymph node metastasis. Conclusions: R-NETs measuring 1-2 cm generally have a favorable prognosis, and there is no difference in postoperative survival between LE and RR. For patients without lymph node metastasis, LE should be the preferred choice; however, for patients with a higher tumor location, preoperative NLR >1.8 or T3/T4 tumors, RR should be considered.

Iron biology.

Iron is a fundamental element for biological life, starting from bacteria till humans. Iron is essential for cell function and survival, energy production and metabolism, whereas increased levels cause oxidative stress. It is also a constituent of haemoglobin and thus it is necessary for oxygen transportation through the body. Given these multiple functions, the regulation of iron metabolism is complex and tight coupled with oxygen homeostasis at tissue and cellular levels, thanks to the interaction with the hypoxia inducible factor (HIF) system. In patients with chronic kidney disease (CKD), iron deficiency significantly contributes to anaemia development. This frequently overlaps with chronic inflammation, causing iron- restricted erythropoiesis. To add further complexity, metabolic hyperferritinemia may, on one side, increase the risk for CKD and, on the other, overlaps with functional iron deficiency. Excessive intracellular iron in certain cell types during CKD can also mediate cellular death (called ferroptosis), and contribute to the pathogenesis of kidney damage, atherosclerosis and vascular calcifications. This review is aimed at broadening the perspective of iron metabolism in the setting of CKD not just as a contributor to anaemia in CKD patients, but also as an important player with an impact on cell metabolism, renal fibrosis, and the cardiovascular system.

The PHYB-FOF2-VOZ2 module functions to fine-tune flowering in response to changes in light quality by modulating FLC expression in Arabidopsis.

Proper timing of flowering under different environmental conditions is critical for plant propagation. Light quality is a pivotal environmental cue that plays a critical role in flowering regulation. Plants tend to flower late under light with a high red (R)/far-red (FR) light ratio but early under light with a low R/FR light ratio. However, how plants fine-tune flowering in response to changes in light quality is not well understood. Here, we demonstrate that F-box of Flowering 2 (FOF2), an autonomous pathway-related regulator, physically interacts with VASCULAR PLANT ONE-ZINC FINGER 1 and 2 (VOZ1 and VOZ2), which are direct downstream factors of the R/FR light receptor phytochrome B (PHYB). We show that PHYB physically interacts with FOF2, mediates stabilization of the FOF2 protein under FR light and end-of-day FR light, and enhances FOF2 binding to VOZ2, which leads to degradation of VOZ2 by SCFFOF2 E3 ligase. By contrast, PHYB mediates degradation of FOF2 protein under R light and end-of-day R light. Genetic interaction studies demonstrated that FOF2 functions downstream of PHYB to promote FLC expression and inhibit flowering under both high R/FR light and simulated shade conditions, processes that are partially dependent on VOZ proteins. Taken together, our findings suggest a novel mechanism whereby plants fine-tune flowering time through a PHYB-FOF2-VOZ2 module that modulates FLC expression in response to changes in light quality.

Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway.

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1ß⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn's disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn's disease.

Intrathecal Anesthesia Prevents Ventricular Arrhythmias in Rats with Myocardial Ischemia/Reperfusion.

INTRODUCTION: Ventricular arrhythmia is commonly provoked by acute cardiac ischemia through sympathetic exaggeration and is often resistant to anti-arrhythmic therapies. Thoracic epidural anesthesia has been reported to terminate fatal ventricular arrhythmia; however, its underlying mechanism is unknown. METHODS: Rats were randomly divided into four groups: sham, sham plus bupivacaine, ischemia/reperfusion (IR), and IR plus bupivacaine groups. Bupivacaine (1 mg/mL, 0.05 mL/100 g body weight) was injected intrathecally into the L5-L6 intervertebral space prior to establishing a myocardial IR rat model. Thereafter, cardiac arrhythmia, cardiac function, myocardial injury, and electrical activities of the heart and spinal cord were evaluated. RESULTS: Intrathecal bupivacaine inhibited spinal neural activity, improved heart rate variability, reduced ventricular arrhythmia score, and ameliorated cardiac dysfunction in IR rats. Furthermore, intrathecal bupivacaine attenuated cardiac injury and myocardial apoptosis and regulated cardiomyocyte autophagy and connexin-43 distribution during myocardial IR. CONCLUSION: Our results indicate that intrathecal bupivacaine blunts spinal neural activity to prevent cardiac arrhythmia and dysfunction induced by IR and that this anti-arrhythmic activity may be associated with regulation of autonomic balance, myocardial apoptosis and autophagy, and cardiac gap junction function.

The Association between Obstructive Sleep Apnea and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Utilizing summary-level data from large-scale genome-wide association studies in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighted was used as the primary method for MR analysis. In addition, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. RESULTS: The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. CONCLUSION: Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction.

[Traditional Chinese medicine preparations in medical institutions: current situation and inspirations on research and development of new traditional Chinese medicine preparations].

Traditional Chinese medicine(TCM) preparations in medical institutions embody the characteristics of TCM and are the source for the development of new TCM drugs. This study summarizes the current situation, existing problems, and development trends of the TCM preparations in medical institutions in 31 provinces across China. Furthermore, this paper puts forward the development path of new TCM preparations based on the requirements of registration and management regulations of TCM preparations, providing new ideas for promoting the inheritance, innovation, and development of TCM.