A Robust In Vitro Culture Model and Generation of Memory Monocytes.

Innate monocytes can be trained or reprogrammed to adopt distinct memory states, such as low-grade inflammation and immune exhaustion, bearing fundamental relevance to the pathogenesis of both acute diseases such as sepsis as well as chronic diseases such as atherosclerosis. Therefore, it is critically important to develop a regimen for generating memory monocytes in vitro in order to better define key monocyte memory states with diverse potentials for proliferation, differentiation, and activation, as well as underlying mechanisms. Here, we describe an efficient in vitro system to propagate a large number of highly purified murine memory monocytes through sustaining bone marrow-derived monocytes with macrophage colony-stimulating factor (M-CSF, 10 ng/mL)-containing medium, together with other polarization agents such as lipopolysaccharide (LPS) for a 5-day period. This method can yield high-purity monocytes, capable of exhibiting dynamic memory behaviors upon training with various polarizing agents.

Immune Homeostasis Maintenance Through Advanced Immune Therapeutics to Target Atherosclerosis.

Atherosclerosis remains the leading cause of coronary heart disease (CHD) with enormous health and societal tolls. Traditional drug development approaches have been focused on small molecule-based compounds that aim to lower plasma lipids and reduce systemic inflammation, two primary causes of atherosclerosis. However, despite the widely available lipid-lowering and anti-inflammatory small compounds and biologic agents, CHD prevalence still remains high. Based on recent advances revealing disrupted immune homeostasis during atherosclerosis pathogenesis, novel strategies aimed at rejuvenating immune homeostasis with engineered immune leukocytes are being developed. This chapter aims to assess basic and translational efforts on these emerging strategies for the effective development of atherosclerosis treatment, as well as key challenges in this important translational field.

Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

Feasibility of sludge deep dewaterability improvement for incineration disposal by combined conditioning of freeze-thaw and sawdust.

Sludge incineration is the main strategy for sludge reduction in China. The combined conditioning of lime and chemical agents has been proven to achieve sludge dewatering by disrupting the extracellular polymeric substances (EPS) of sludge and reducing its compressibility. However, when incineration is the intended disposal purpose, this method poses challenges such as incomplete combustion, equipment corrosion, secondary pollution, and decreased calorific value of sludge cake. In contrast, freeze-thaw conditioning, coupled with sawdust as a high-calorific-value bio-waste, emerges as an efficient and clean alternative. The research investigates the synergistic effects of freeze-thaw and sawdust co-conditioning on various sludge properties, including dewaterability, compressibility, consolidation, permeability, microscopicity, and calorific value. The study reveals that the combined conditioning significantly reduces water content and compressibility while increasing void ratio, consolidation, permeability, and enhancing the calorific value of the sludge cake. Specifically, sludge cake conditioned with 60% dried solids (DS) sawdust and freeze-thaw achieved a water content (Wc) of 49.07% and a calorific value of 1422.3 kcal/kg, meeting standards for self-sustained incineration. With heat recovery, the combined conditioning generates an economic revenue of 25.1 $/t DS after deducting costs, thereby reducing the overall cost of sludge reduction treatment. This research offers a clean and practical solution for sludge incineration and reduction, demonstrating great economic value and application potential.

Pricing strategy research in the dual-channel pharmaceutical supply chain considering service.

In the context of developing a new era, the pharmaceutical supply chain market has gradually transformed from a seller's market to a buyer's market. The closer the consumers are, the greater the market pricing power, so the pharmaceutical market power of manufacturers and retailers has also changed. This study considers the effect of service on the pricing strategy of the pharmaceutical platform supply chain. The study aimed to coordinate optimization, and the coordination strategy of the pharmaceutical platform supply chain of complementary products is discussed mainly by researching the price and service factors. Various situations are studied by hypothesis and model solving. This study uses Stackelberg game decision-making. Manufacturers are at the forefront of platform supply chain decisions. The research found that the price was lower under centralized decision-making than under decentralized decision-making. Coordination between price and service levels needs attention in the pharmaceutical platform supply chain of complementary products, and the service level should be controlled within a certain range. Only by improving the service level can enterprises maximize profits, providing a theoretical basis for pharmaceutical supply chain pricing strategy research. Supply chain members must strive to improve service levels to improve medical supply consumers' (patients) psychological satisfaction level. Service levels do not fully mitigate channel conflict. Therefore, pharmaceutical complements have become a way to alleviate the conflicts in the pharmaceutical platform supply chain.

A Load-Adaptive Driving Method for a Quasi-Continuous-Wave Laser Diode.

A quasi-continuous-wave (QCW) laser diode (LD) driver is commonly used to drive diode bars and stacks designed specifically for QCW operations in solid-state lasers. Such drivers are optimized to deliver peak current and voltage pulses to LDs while maintaining low average power levels. As a result, they are widely used in laser processing devices and laser instruments. Traditional high-energy QCW LD drivers primarily use capacitors as energy storage components and pulsed constant-current sources with op-amps and power metal-oxide-semiconductor field-effect transistors (MOSFETs) as their core circuits for generating repeated constant-current pulses. The drawback of this type of driver is that the driver's output voltage needs to be manually adjusted according to the operating voltage of the load before use to maximize driver efficiency while providing a sufficient current. Another drawback is its inability to automatically adjust the output voltage to maintain high efficiency when the load changes during the driver operation. Drastic changes in the load can cause the driver to fail to function properly in extreme cases. Based on the above traditional circuit structure, this study designed a stability compensation circuit and realized a QCW LD driver for driving a GS20 diode stack with a maximum repetition rate of 100 Hz, a constant current of approximately 300 A, a load voltage of approximately 10 V, and a pulse width of approximately 300 µs. In particular, a high-efficiency, load-adaptive driving method was used with the MOSFETs in the critical saturation region (i.e., between the linear and saturated regions), controlling its power loss effectively while achieving maximum output current of the driver. The experiments demonstrated that the driver efficiency could be maintained at more than 80% when the load current varied from 50 to 300 A.

Anisotropic Growth of Covalent Inorganic Complexes to Nanoplatelets.

Colloidal II-VI semiconductor nanoplatelets (NPLs) provide a new platform in material science due to their unique growth mode and advanced optical properties. However, in contrast to the rapid development of zinc blend structured NPLs, studies on the formation of wurtzite (WZ) NPLs have been limited to the lamellar assembly of specific magic-sized nanoclusters (MSCs). Therefore, the study of new precursors is important for enriching the synthesis strategy, improving the study of two-dimensional (2D) nanocrystal growth mechanisms, and constructing complex nanostructures. Here, we demonstrated that covalent inorganic complexes (CICs), as novel functional intermediates, can be directly used to form NPLs without involving MSCs. Using in situ absorption spectra, we demonstrated that the evolution followed a pseudo-first-order kinetics (kobs = 0.02 min-1 (t1/2 = 34.7 min)). Several types of binary WZ NPLs, including CdSe, CdS, CdTe, and ZnS, have been directly prepared based on this mechanism through the anisotropic growth of CICs. In addition, CICs can also be used to prepare Mn-doped CdSe NPLs. The present study not only affords new precursors for the synthesis of WZ NPLs but also advances our understanding of the synthesis mechanism of nanocrystals.

Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis.

Monocytes can develop an exhausted memory state characterized by reduced differentiation, pathogenic inflammation, and immune suppression that drives immune dysregulation during sepsis. Chromatin alterations, notably via histone modifications, underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we show altered DNA methylation throughout the genome of exhausted monocytes, including genes implicated in immune dysregulation during sepsis and COVID-19 infection (e.g., Plac8). These changes are recapitulated in septic mice induced by cecal slurry injection. Methylation profiles developed in septic mice are maintained during ex vivo culture, supporting the involvement of DNA methylation in stable monocyte exhaustion memory. Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Our study demonstrates the significance of altered DNA methylation in the maintenance of stable monocyte exhaustion memory.

Healing an ischial tuberosity pressure ulcer in a patient with neurogenic heterotopic ossification: a case report.

Neurogenic heterotopic ossification (NHO) is widely recognised as an aberrant bone formation in soft tissue following central nervous system injury. It is most frequently associated with pain and limited movement, especially in the hip. However, it may be neglected in patients with paraplegia with a pressure ulcer (PU). We report the case of an 18-year-old male patient who presented with a hard-to-heal ischial tuberosity PU and who had undergone three operations at other hospitals during the previous six months, which had failed to repair the PU. There was a history of paraplegia as a consequence of spinal cord injury two years previously. Computed tomography and three-dimensional reconstruction showed massive heterotopic ossification (HO) in the wound bed and around the right hip. Histological findings were consistent with a diagnosis of HO. The HO around the wound was completely excised, negative pressure wound therapy was used to promote granulation, and a gluteus maximus musculocutaneous flap was used to cover the wound. We conclude that for patients with paraplegia, with a hard-to-heal PU, it should be determined whether it is associated with NHO. Surgical resection of HO surrounding the wound and improving the microcirculation are critical for repair and reconstruction of these PUs.

Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models.

Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1-KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1-KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.

Alleviation of monocyte exhaustion by BCG derivative mycolic acid.

Monocyte exhaustion with sustained pathogenic inflammation and immune-suppression, a hallmark of sepsis resulting from systemic infections, presents a challenge with limited therapeutic solutions. This study identified Methoxy-Mycolic Acid (M-MA), a branched mycolic acid derived from Mycobacterium bovis Bacillus Calmette-Guérin (BCG), as a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA effectively blocked the expansion of Ly6Chi/CD38hi/PD-L1hi monocytes induced by LPS challenges and restored the expression of immune-enhancing CD86. M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Independent of TREM2, M-MA blocks Src-STAT1-mediated inflammatory polarization and reduces the production of immune suppressors TAX1BP1 and PLAC8. Whole genome methylation analyses revealed M-MA's ability to erase the methylation memory of exhausted monocytes, particularly restoring Plac8 methylation. Together, our data suggest M-MA as an effective agent in restoring monocyte homeostasis with a therapeutic potential for treating sepsis.

Not so hidden anymore: Advances and challenges in understanding root growth under water deficits.

Limited water availability is a major environmental factor constraining plant development and crop yields. One of the prominent adaptations of plants to water deficits is the maintenance of root growth that enables sustained access to soil water. Despite early recognition of the adaptive significance of root growth maintenance under water deficits, progress in understanding has been hampered by the inherent complexity of root systems and their interactions with the soil environment. We highlight selected milestones in the understanding of root growth responses to water deficits, with emphasis on founding studies that have shaped current knowledge and set the stage for further investigation. We revisit the concept of integrated biophysical and metabolic regulation of plant growth and use this framework to review central growth-regulatory processes occurring within root growth zones under water stress at subcellular to organ scales. Key topics include the primary processes of modifications of cell wall-yielding properties and osmotic adjustment, as well as regulatory roles of abscisic acid and its interactions with other hormones. We include consideration of long-recognized responses for which detailed mechanistic understanding has been elusive until recently, for example hydrotropism, and identify gaps in knowledge, ongoing challenges, and opportunities for future research.

A follow-up study on factors affecting the recovery of patients with hypothyroidism in different selenium environments.

BACKGROUND: Hypothyroidism is a major manifestation of autoimmune thyroid diseases (AITD). We previously reported that a low selenium (Se) status was linked to an elevated prevalence of thyroid diseases. We hypothesized that Se status may also influence the restoration of thyroid function. Thus, this study aimed to investigate the factors affecting the recovery of thyroid function in patients with (sub-)clinical hypothyroidism, with a specific focus on Se status. METHODS: We conducted a 6-year prospective cohort study comparing two counties with different Se concentrations. Demographic and disease data were collected from 1,190 individuals (549 Se-adequate and 641 Se-deficient) who completed a follow-up study in 2019. In addition, urinary iodine (I) levels, thyroid function, and serum and nail Se levels were measured. Logistic regression was used to investigate the relationship between Se deficiency and recovery of thyroid function. RESULTS: Sex and smoking status was similar between the two counties studied. Thyroid function recovery rate was significantly higher in Se-deficient counties (46.0% vs. 30.6%, P = 0.008). In the multivariate analysis, our results show that female sex (odds ratio [OR] (95% confidence interval [CI]) = 1.875 (1.080-3.257), P = 0.026] and increasing age [OR (95%CI) = 1.028(1.007-1.049), P = 0.009] were associated with the recovery rate. Additionally, our study revealed that while Se status was significant in the univariate analysis, this association appeared to disappear in the multivariate analysis. CONCLUSIONS: Female sex and increasing age have unfavorable effects on the recovery of thyroid function in patients over 30 years of age with (sub-) clinical hypothyroidism.

New molecular insights into ferroptosis in lung adenocarcinoma progression and pharmacological compounds for targeted therapy.

BACKGROUND: The involvement of ferroptosis has been found in many pathological conditions of the lung. The genetic engineering of ferroptosis-related genes may provide a potential target for the treatment of lung adenocarcinoma (LUAD). METHODS: Nine ferroptosis regulators and markers were collected from FerrDb and their somatic mutations and expressions were analyzed based on The Cancer Genome Atlas (TCGA)-LUAD cohort data. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to screen genes significantly associated with ferroptosis. The ferroptosis-related gene signature was constructed using TCGA-LUAD cohort data and was verified using the GSE cohort with pooled data for GSE30219, GSE31210, GSE37745 and GSE50081. Immune microenvironment component and mutation analysis were performed for genes in the ferroptosis-related gene signature. RESULTS: All nine ferroptosis regulators and markers were differentially expressed between normal LUAD tumor tissues and adjacent normal tissues and were related to copy number variation. The expression of 1329 genes were significantly associated with nine ferroptosis regulators and markers in the TCGA-LUAD dataset, five (ALDOA, PLK1, CD47, CENPC and TMOD3) of which were integrated into a ferroptosis-related gene signature to calculate the risk score of LUAD samples, showing a significant correlation with the abundance of immune cell infiltration and the immune score. Molecular docking showed the binding activity of natural active compound quercetin to target proteins ALDOA and CD47, as well as the binding activity of aristolochic acid to PLK1 protein and TMOD3 protein. CONCLUSIONS: In the present study, a ferroptosis-related gene signature with predictive value for LUAD prognosis was constructed, in which the gene was a potential therapeutic target for LUAD. Quercetin and aristolochic acid were potential candidates for inhibiting these targets by directly binding to them and showing high affinity and strong stability.

Aberrant expression and regulatory role of histone deacetylase 9 in vascular endothelial cell injury in intracranial aneurysm.

Intracranial aneurysm (IA) is one of the most challenging cerebrovascular lesions for clinicians. The aim of this study was to investigate the abnormal expression and role of histone deacetylase 9 (HDAC9) in IA-associated injury of vascular endothelial cells (VECs). First, IA tissue and normal arterial tissue were collected and VECs were isolated from IA patients. The expression levels of HDAC9, microRNA (miR)-34a-5p, and vascular endothelial growth factor-A (VEGFA) were determined. Cell viability, proliferation, apoptosis, and migration were assessed by Cell Counting Kit-8 (CCK-8) assay, EdU staining, TUNEL staining, and transwell assay. The binding of miR-34a-5p to VEGFA was analyzed by the dual-luciferase assay, and the accumulation of HDAC9 and lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) on the miR-34a-5p promoter was detected by the chromatin immunoprecipitation assay. The results showed that HDAC9 and VEGFA were increased and miR-34a-5p was decreased in IA tissues and cells. Silencing of HDAC9 inhibited apoptosis and increased viability, proliferation, and migration of VECs, whereas overexpression of HDAC9 exerted the opposite functions. HDAC9 accumulated at the miR-34a-5p promoter to decrease miR-34a-5p expression by reducing H3 locus-specific acetylation and further promoted VEGFA expression. Knockdown of miR-34a-5p or VEGFA overexpression reversed the protective role of HDAC9 silencing in VECs injury. In conclusion, our study suggests that HDAC9 may be a therapeutic target for IA.

Different approaches for treating myopic choroidal neovascularization: a network Meta-analysis.

AIM: To evaluate the efficacy of intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF), photodynamic therapy (PDT), and laser treatment (LT) for anatomical and functional improvement in myopic choroidal neovascularization (mCNV) patients. METHODS: Two researchers independently searched PubMed, Cochrane Library, Web of Science, and other databases to screen studies comparing best-corrected vision acuity (BCVA) and foveal center thickness (FCT) changes after mCNV treatment. Post-treatment chorioretinal atrophy (CRA) is a secondary outcome indicator. The retrieval time limit is from the database construction to January 30, 2023. RESULTS: A total of 1072 eyes in 16 articles were included. In the RCTs, intravitreal bevacizumab (IVB) and intravitreal ranibizumab (IVR) were superior to PDT (MD=0.18, 95%CI: 0.02, 0.40, MD=0.18, 95%CI: 0.01, 0.42) in improving BCVA of mCNV patients (P<0.05). The relative effectiveness in improving BCVA, from high to low, appeared to be IVR, intravitreal aflibercept (IVA), IVB, LT, PDT, and sham first followed by IVA (Sham/IVA). While improving the FCT from high to low was IVA, IVR, IVB, PDT. In retrospective studies, the results of BCVA after long-term treatment showed that all the therapeutic effects from high to low was IVA, intravitreal conbercept (IVC), IVR, IVB, IVB/IVR, PDT with IVB/IVR, PDT. The effect of improving FCT was IVA, IVR, IVC, PDT, and IVB from high to low. And in the effects of improving CRA, the IVB appeared to be higher than IVR, while the PDT was the smallest, but none of the differences in the results were statistically significant. CONCLUSION: Anti-VEGF has the best effect on long-term vision improvement in mCNV patients, using IVB or IVR alone to treat mCNV may be better than IVB or IVR combined with PDT. There is no significant difference in the improvement of visual acuity, macular edema, and CRA in mCNV patients treated with any different anti-VEGF drugs.

Breeding Efficiency for Salt Tolerance in Alfalfa.

Alfalfa (Medicago sativa L.), one of the most extensively grown forage crops, is sensitive to saline soils. We measured the breeding efficiency for increased salt tolerance in alfalfa by comparing lines selected from BC79S, CS, and SII populations with their unselected parental means for forage mass and associated changes in stem length, leaf-to-stem ratio (LSR), number of nodes per stem, crude protein (CP) content, and neutral detergent fiber (NDF) content. The overall forage mass in the non-salt-stressed test (9562 kg ha-1) was greater (p < 0.001) than under salt stress (5783 kg ha-1), with a 40% production advantage. In the non-salt-stressed test, the BC79S and CS lines averaged at a 4% lower production than their parents, while SII lines had on average a 9% greater production. Conversely, in the salt-stressed test, all lines showed a 20% overall greater seasonal production than their parents. Some selected lines produced more forage mass in both the non-stressed and salt-stressed tests than their parents. The stem length, LSR, node number, CP content, and NDF content of the selected lines varied with respect to non-stressed vs. stressed, but they tended not to differ greatly from their respective parental means under either non- or salt-stressed conditions. The selection protocol provided a universal increase in forage mass under salt-stressed field conditions of the selected lines. Furthermore, we identified lines with forage mass values greater than their parental means under non- and salt-stressed field conditions.

Fenofibrate Ameliorates Retinal Pigment Epithelium Injury Induced by Excessive Fat Through Upregulation of PI3K/AKT Signaling.

Purpose: This study aimed to determine the effect and its mechanism of fenofibrate on retinal pigment epithelium (RPE) injury induced by excessive fat in vitro and in vivo. Methods: ARPE-19 cells were co-incubated with palmitic acid (PA) and fenofibric acid (the active form of fenofibrate after metabolism in vivo) and mice fed with high-fat diet (HFD) were supplemented with fenofibrate. The following methods were used: Western blot and immunofluorescent staining to determine expressions of reactive oxygen species (ROS)-associated factors and proinflammatory cytokines; electroretinogram (ERG) c-wave to evaluate RPE function; TUNEL staining to detect the apoptotic cell in RPE tissue. Additionally, ARPE19 cells were treated with PI3K/AKT inhibitor or agonist to investigate the mechanism of fenofibric acid inhibiting PA-induced RPE damage. Results: We found that the application of PA inhibited RPE cell viability in a dose-dependent manner, and increased the levels of NAPDH oxidase 4 (NOX4), 3-nitrotyrosin (3-NT), intracellular adhesion molecule-1(ICAM1), tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) at 400µM. The application of fenofibric acid resulted in the inhibition of NOX4, 3-NT, TNFα, ICAM1 and VEGF expression in ARPE-19 cells treated with PA. Moreover, wortmannin, as a selective inhibitor of PI3K/AKT pathway, abolished the effects of fenofibrate on the oxidative stress and inflammation in ARPE-19 cells. In addition, 740Y-P, a selective agonist of PI3K/AKT pathway, enhanced the protective action of fenofibrate. Meanwhile, in vivo dosing of fenofibrate ameliorated the downregulated amplitudes of ERG c-wave in HFD-fed mice and suppressed the HFD-induced oxidative injury and inflammatory response in RPE tissues. Conclusion: Our results suggested that fenofibrate ameliorated RPE cell damage induced by excessive fat in vitro and in vivo, in part, through activation of the PI3K/AKT signaling pathway.

Impact of Easing COVID-19 Restrictions on Fear of COVID-19 and Social Support Among Chinese Students: A Longitudinal Analysis.

Introduction: This longitudinal study aims to investigate the relationship between fear of COVID-19, support-seeking behaviors, and perceived social support among Chinese college students during two distinct periods of the COVID-19 pandemic: the period of strict control (time 1) and the period following a relaxation of restrictions (time 2). Methods: A total of 408 Chinese college students participated in this study. Data collection included demographic information, measures of fear of COVID-19, support-seeking behaviors, and perceived social support. Results: Fear of COVID-19 at time 1 showed a significant positive association with fear of COVID-19 at time 2. The relationship between support-seeking behavior at time 1 and fear of COVID-19 at time 2 was significantly mediated through a chain mediation effect of support-seeking behavior at time 1 and perceived social support at time 2. Discussion: This study contributes to the growing body of evidence on the psychological impacts of the COVID-19 pandemic and underscores the significance of social support in mitigating fear of COVID-19. It calls for a re-evaluation of public health policies considering their potential psychological effects and introduces new opportunities for developing psychosocial interventions.

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis.

Background: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. Methods: Systems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naïve monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE -/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE -/- mice. Results: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo . Conclusion: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.