MiR-106a-5p targets PFKFB3 and improves sepsis through regulating macrophage pyroptosis and inflammatory response.

The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) is a critical regulator of glycolysis and plays a key role in modulating the inflammatory response, thereby contributing to the development of inflammatory diseases such as sepsis. Despite its importance, the development of strategies to target PFKFB3 in the context of sepsis remains challenging. In this study, we employed a microRNA-based approach to decrease PFKFB3 expression. Through multiple meta-analyses, we observed a downregulation of miR-106a-5p expression and an upregulation of PFKFB3 expression in clinical sepsis samples. These changes were also confirmed in blood monocytes from patients with early sepsis and from a mouse model of lipopolysaccharide (LPS)-induced sepsis. Overexpression of miR-106a-5p significantly decreased the LPS-induced increase in glycolytic capacity, inflammatory response, and pyroptosis in macrophages. Mechanistically, we identified PFKFB3 as a direct target protein of miR-106a-5p and demonstrated its essential role in LPS-induced pyroptosis and inflammatory response in macrophages. Furthermore, treatment with agomir-miR-106a-5p conferred a protective effect in an LPS mouse model of sepsis, but this effect was attenuated in myeloid-specific Pfkfb3 knockout mice. These findings indicate that miR-106a-5p inhibits macrophage pyroptosis and inflammatory response in sepsis by regulating PFKFB3-mediated glucose metabolism, representing a potential therapeutic option for the treatment of sepsis.

PAHs removal by soil washing with thiacalix[4]arene tetrasulfonate.

Remediating soil contaminated with polycyclic aromatic hydrocarbons (PAHs) presents a significant environmental challenge due to their toxic and carcinogenic properties. Traditional PAHs remediation methods-chemical, thermal, and bioremediation-along with conventional soil-washing agents like surfactants and cyclodextrins face challenges of cost, ecological harm, and inefficiency. Here we show an effective and environmentally friendly calixarene derivative for PAHs removal through soil washing. Thiacalix[4]arene tetrasulfonate (TCAS) has a unique molecular structure of a sulfonate group and a sulfur atom, which enhances its solubility and facilitates selective binding with PAHs. It forms host-guest complexes with PAHs through π-π stacking, OH-π interactions, hydrogen bonding, van der Waals forces, and electrostatic interactions. These interactions enable partial encapsulation of PAH molecules, aiding their desorption from the soil matrix. Our results show that a 0.7% solution of TCAS can extract approximately 50% of PAHs from contaminated soil while preserving soil nutrients and minimizing adverse environmental effects. This research unveils the pioneering application of TCAS in removing PAHs from contaminated soil, marking a transformative advancement in resource-efficient and sustainable soil remediation strategies.

The inactivation of tolC sensitizes Escherichia coli to perturbations in lipopolysaccharide transport.

The Escherichia coli outer membrane channel TolC complexes with several inner membrane efflux pumps to export compounds across the cell envelope. All components of these complexes are essential for robust efflux activity, yet E. coli is more sensitive to antimicrobial compounds when tolC is inactivated compared to the inactivation of genes encoding the inner membrane drug efflux pumps. While investigating these susceptibility differences, we identified a distinct class of inhibitors targeting the core-lipopolysaccharide translocase, MsbA. We show that tolC null mutants are sensitized to structurally unrelated MsbA inhibitors and msbA knockdown, highlighting a synthetic-sick interaction. Phenotypic profiling revealed that tolC inactivation induced cell envelope softening and increased outer membrane permeability. Overall, this work identified a chemical probe of MsbA, revealed that tolC is associated with cell envelope mechanics and integrity, and highlighted that these findings should be considered when using tolC null mutants to study efflux deficiency.

Endothelial NLRP3 inflammasome regulation in atherosclerosis.

AIM: The activation of Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in endothelial cells (ECs) contributes to vascular inflammation in atherosclerosis. Considering the high glycolytic rate of ECs, we delineated whether and how glycolysis determines endothelial NLRP3 inflammasome activation in atherosclerosis. METHODS AND RESULTS: Our results demonstrated a significant upregulation of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), a key regulator of glycolysis, in human and mouse atherosclerotic endothelium, which positively correlated with NLRP3 levels. Atherosclerotic stimuli upregulated endothelial PFKFB3 expression via sterol regulatory element binding protein 2 (SREBP2) transactivation. EC-selective haplodeficiency of Pfkfb3 in Apoe-/- mice resulted in reduced endothelial NLRP3 inflammasome activation and attenuation of atherogenesis. Mechanistic investigations revealed that PFKFB3-driven glycolysis increased the NADH content and induced oligomerization of C-terminal binding protein 1 (CtBP1), an NADH-sensitive transcriptional co-repressor. The monomer form, but not the oligomer form, of CtBP1 was found to associate with the transcriptional repressor Forkhead box P1 (FOXP1) and acted as a transrepressor of inflammasome components, including NLRP3, caspase-1, and interleukin-1ß (IL-1ß). Interfering with NADH-induced CtBP1 oligomerization restored its binding to FOXP1 and inhibited the glycolysis-dependent upregulation of NLRP3, Caspase-1, and IL-1ß. Additionally, EC-specific overexpression of NADH-insensitive CtBP1 alleviates atherosclerosis. CONCLUSIONS: Our findings highlight the existence of a glycolysis-dependent NADH/CtBP/FOXP1-transrepression pathway that regulates endothelial NLRP3 inflammasome activation in atherogenesis. This pathway represents a potential target for selective PFKFB3 inhibitors or strategies aimed at disrupting CtBP1 oligomerization to modulate atherosclerosis.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

Size, distribution, and vulnerability of the global soil inorganic carbon.

Global estimates of the size, distribution, and vulnerability of soil inorganic carbon (SIC) remain largely unquantified. By compiling 223,593 field-based measurements and developing machine-learning models, we report that global soils store 2305 ± 636 (±1 SD) billion tonnes of carbon as SIC over the top 2-meter depth. Under future scenarios, soil acidification associated with nitrogen additions to terrestrial ecosystems will reduce global SIC (0.3 meters) up to 23 billion tonnes of carbon over the next 30 years, with India and China being the most affected. Our synthesis of present-day land-water carbon inventories and inland-water carbonate chemistry reveals that at least 1.13 ± 0.33 billion tonnes of inorganic carbon is lost to inland-waters through soils annually, resulting in large but overlooked impacts on atmospheric and hydrospheric carbon dynamics.

Surgical treatment for pelvic haemophilic pseudotumour: a retrospective analysis of 21 cases.

Background: Due to the rarity of pelvic haemophilic pseudotumour (PHPT) and demanding surgical technique for PHPT excision, no study reports the mid-term follow-up outcomes of surgical treatment of PHPT in a relatively large cohort. PHPT with varying degrees of bony pelvic involvement and infection status necessitates different operative procedures, yet there is currently no classification system for PHPT based on surgical practice. Methods: The study was conducted between June 25, 2004 and July 18, 2023, in Peking Union Medical College Hospital and Nanfang Hospital in China. We performed a retrospective analysis involving 21 patients with 24 PHPTs with a mean follow-up period of 7.1 years. The demographic information, PHPT characteristics, surgical data, and perioperative complications were analysed. Findings: 21 consecutive male patients with 24 PHPTs (21 primary PHPTs and three recurrent PHPTs) that underwent surgical treatment were involved in the study. A classification system including four subtypes was introduced as (I) PHPT confined to soft tissue; (II) PHPT involving bony pelvic without pelvic discontinuity; (III) PHPT causing pelvic discontinuity; (IV) Infectious PHPT. Of the 24 PHPTs, 11 (45.8%) were identified as Type I, five (20.8%) as Type II, three (12.5%) as Type III, and five (20.8%) as Type IV. At the time of surgery, the patients had a mean age of 37.0 ± 9.5 years (Range, 24-52 years). The mean maximum diameter of PHPTs upon surgery was 17.0 ± 7.7 cm (Range, 4.3-40.0 cm). The mean surgical duration was 192 ± 77 min (Range, 60-330 min) and the median intraoperative blood loss was 400 mL (IQR, 225-950 mL, Range, 100-3000 mL). One patient (4.8%) underwent intraoperative cardiopulmonary arrest and expired the following week. Four PHPTs (16.7%) presented postoperative wound infections and poor wound healing. During the follow-up period, five PHPTs (20.8%) experienced pseudotumour recurrence. Interpretation: Our findings suggest that surgical treatment for PHPTs is feasible and relatively safe. Symptomatic and progressive PHPTs should undergo surgical intervention as early as possible to minimise the surgical risks. Intraoperative use of abundant gelatin sponges in PHPT excision draws attention to severe embolism complications. Funding: There are no sources of funding for this manuscript.

Clinical outcome and survival rate of condylar constrained knee prosthesis in revision total knee arthroplasty: an average nine point six year follow-up.

PURPOSE: Condylar constrained knee prostheses (CCK) are increasingly used in revision total knee arthroplasty (rTKA), but the clinical effectiveness and long-term survival remain a debate. The purpose of this study is to report the long-term clinical and radiographic outcome, implant survival rate, and surgical safety of revision total knee arthroplasty with condylar constrained knee prosthesis. METHODS: A retrospective cohort study was performed on patients undergoing rTKA with CCK. The cases who received rTKA with CCK from January 2005 to January 2022 were selected. The duration of operation, the estimated perioperative blood loss, and the intraoperative blood transfusion rate were recorded to evaluate surgical safety. The pain visual analog scale (VAS), range of motion (ROM), the Hospital for Special Surgery (HSS) score, the Knee Society Score (KSS), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and the Oxford knee score (OKS) was recorded to assess clinical outcome. Standard anteroposterior, lateral, skyline and long-standing AP radiographs of the lower limbs were conducted to assess radiographic outcome. Implant survival was analyzed by Kaplan-Meier survival estimates. RESULTS: Fifty-five cases were followed up for an average of 9.6 years (1-18 years), including 16 males and 38 females, with an average age of 66 and an average BMI of 26.9 kg/m2. The  main reasons for revision were periprosthetic infection (32 knees, 58.2%) and aseptic loosening (13 knees, 23.6%). The duration of operation was 149 ± 56.2 min. The perioperative blood loss was 973.6 ± 421.6 ml. At the last follow-up, VAS (8.0 ± 1.1 to 1.3 ± 1.4), ROM (82.7° ± 26.1° to 108.4° ± 11.8°), HSS (45.0 ± 10.4 to 85.3 ± 8.6), KSKS (38.4 ± 12.1 to 88.5 ± 12.0), KSFS (19.6 ± 12.9 to 68.8 ± 15.1), WOMAC (67.9 ± 12.5 to 14.4 ± 9.5), and OKS (9.9 ± 4.2 to 41.6 ± 7.7) were significantly improved (P < 0.001). A total of five complications were observed, all of which were periprosthetic infection. Non-progressive radiolucent lines were observed in 26 knees (47.3%). The 10-year survival rate for no operation was 96.0%. The ten year survival rate for no revision was 98.0%. CONCLUSION: The use of CCK prosthesis for rTKA can achieve good long-term efficacy and prosthesis survival.

Impact of intraosseous regional administration of tranexamic acid in total knee arthroplasty on perioperative blood loss: a protocol for a randomised controlled trial.

INTRODUCTION: Total knee arthroplasty (TKA) is a common surgical intervention to treat joint diseases. However, TKA is associated with significant blood loss. Tranexamic acid (TXA) has been used to reduce perioperative bleeding and postoperative blood transfusion. This study aims to explore the effectiveness and safety of intraosseous regional administration (IORA) of TXA in TKA and compare differences in perioperative blood loss between IORA of TXA, intravenous infusion of TXA, and combined IORA and intravenous infusion of TXA. METHODS AND ANALYSIS: This randomised controlled trial will enrol 105 patients with osteoarthritis who meet the inclusion criteria for unilateral TKA. Patients were randomly divided into three groups using the random number table method. Group A received 1.0 g of TXA via IORA, group B received 1.0 g of TXA via intravenous infusion 15 min prior to the tourniquet release, and group C received both IORA of 1.0 g of TXA and intravenous infusion of 1.0 g of TXA. The primary outcome measure is perioperative total blood loss. Secondary outcomes include bleeding events, venous thromboembolism events, inflammation reactions, other complications and knee function assessments. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Peking Union Medical College Hospital and registered in the Chinese Clinical Trial Registry. Informed consent will be obtained from all the patients before enrolment. The trial will be conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The results of this study will be disseminated through peer-reviewed publications, conference presentations and social media platforms. The findings will provide valuable insights into the use of IORA of TXA in TKA and may lead to the development of new strategies for perioperative blood management in joint replacement surgery. TRIAL REGISTRATION NUMBER: The Ethics Committee of Peking Union Medical College Hospital (approval number: K2371); Chinese Clinical Trial Registry (trial registration number: ChiCTR2200066293).

NanoSHP099-Targeted SHP2 Inhibition Boosts Ly6Clow Monocytes/Macrophages Differentiation to Accelerate Thrombolysis.

Tumor-associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

SLCO4A1, as a novel prognostic biomarker of non­small cell lung cancer, promotes cell proliferation and migration.

Solute carrier organic anion transporter family member 4A1 (SLCO4A1) is a membrane transporter protein. The role of this molecule in non­small cell lung cancer (NSCLC) remains unclear. Bulk sequencing was carried out using early­stage NSCLC tissues with lymph node metastasis to identify SLCO4A1 that influences NSCLC cell proliferation, metastasis and prognosis. The in vitro functional assays carried out included the following: Cell Counting Kit­8, plate colony formation, Transwell and wound healing assays. The molecular techniques used included reverse transcription­quantitative PCR, western blotting and immunohistochemistry. The present study revealed the role of SLCO4A in NSCLC. SLCO4A1 was found to be expressed at high levels in NSCLC tissues and cells, and promotes cell proliferation, migration and invasion. Kaplan­Meier survival analysis indicated that patients with NSCLC and high expression of SLCO4A1 had a poor prognosis. SLCO4A was revealed to regulate the expression of the proliferation­related proteins Ki­67 and PCNA, and that of the extracellular matrix proteins vimentin and E­cadherin. Mechanistically, SLCO4A1 may affect the MAPK signaling pathway to promote NSCLC cell proliferation, migration and invasion. In addition, bioinformatics analysis demonstrated a strong association between SLCO4A1 and tumor infiltrating immune cells, highlighting its critical role in immune therapies such as immune checkpoint inhibitor treatment of patients with NSCLC.

Strain-modulated Ru-O Covalency in Ru-Sn Oxide Enabling Efficient and Stable Water Oxidation in Acidic Solution.

RuO2 is one of the benchmark electrocatalysts used as the anode material in proton exchange membrane water electrolyser. However, its long-term stability is compromised due to the participation of lattice oxygen and metal dissolution during oxygen evolution reaction (OER). In this work, weakened covalency of Ru-O bond was tailored by introducing tensile strain to RuO6 octahedrons in a binary Ru-Sn oxide matrix, prohibiting the participation of lattice oxygen and the dissolution of Ru, thereby significantly improving the long-term stability. Moreover, the tensile strain also optimized the adsorption energy of intermediates and boosted the OER activity. Remarkably, the RuSnOx electrocatalyst exhibited excellent OER activity in 0.1 M HClO4 and required merely 184 mV overpotential at a current density of 10 mA cm-2 . Moreover, it delivered a current density of 10 mA cm-2 for at least 150 h with negligible potential increase. This work exemplifies an effective strategy for engineering Ru-based catalysts with extraordinary performance toward water splitting.

Correlation Between Diaphragmatic Excursion and Exercise Tolerance Improvement Following Pulmonary Rehabilitation in Patients with Chronic Obstructive Pulmonary Disease-Obstructive Sleep Apnea Overlap Syndrome.

Purpose: We assess the predictive value of diaphragm excursion (DE) in enhancing exercise tolerance following pulmonary rehabilitation (PR) among patients with COPD-OSA overlap syndrome. Material and Methods: This prospective cohort study enrolled 63 patients diagnosed with COPD-OSA overlap syndrome who actively participated in a PR program from January 2021 to May 2023. Among these, 58 patients successfully completed the 20-week PR program, with exercise tolerance assessed through the measurement of six-minute walk distance (6MWD), and DE evaluated by ultrasonography. The responder to PR in terms of exercise ability was defined as a patient who showed an increase of >30m in 6MWD. The cutoff value for predicting PR response based on DE was determined using receiver operating characteristic (ROC) curves. Results: Following the PR program, significant improvements were observed in mMRC, 6MWD, DE during deep breathing, and diaphragm thickness fraction (DTF). Of the participants, 33 patients (57%) were classified as responders, while 25 patients (43%) were considered non-responders. Baseline values of FEV1% predicted, 6MWD, DE during deep breathing, DTF, and PaO2 exhibited a significant elevation in responders as compared to non-responders. The changes of 6MWD were positively associated with the baseline values of DTF and DE during deep breathing, FEV1% predicted and PaO2, while negatively correlated with baseline value of mMRC. The predictive performance in terms of the area under the ROC curve for determining responder's DTF was found to be 0.769, accompanied by a sensitivity of 85% and specificity of 68%, using a cutoff value at 17.26%. Moreover, it was observed that DE during deep breathing could predict the area under the ROC curve for responders to be 0.753, with a sensitivity of 91% and specificity of 56% at a cutoff value of 3.61cm. Conclusion: Diaphragm excursion serves as a valuable predictor for determining the enhancement of exercise tolerance following PR in patients with COPD-OSA overlap syndrome. Trial Registration: ChiCTR1800020257, www.chictr.org.cn/index.aspx.

Short-Term but Not Long-Term Knee Symptoms and Functional Improvements of Tissue Engineering Strategy for Meniscus Defects: A Systematic Review of Clinical Studies.

PURPOSE: To investigate the up-to-date clinical outcomes of tissue-engineered meniscus implants for meniscus defects. METHODS: A search was performed by 3 independent reviewers on PubMed, MEDLINE, EMBASE, and Cochrane from 2016 to June 18, 2023, with the term "meniscus" with all the following terms: "scaffolds," "constructs," "implant," and "tissue engineering." Inclusion criteria included "Clinical trials" and "English language articles" that involved isolated meniscus tissue engineering strategies for meniscus injuries. Only Level I to IV clinical studies were considered. The modified Coleman Methodology score was used for quality analysis of included clinical trials. The Methodological Index for Non-Randomized Studies was employed for analysis of the risk of study bias and methodological quality. RESULTS: The search identified 2,280 articles, and finally 19 original clinical trials meeting the inclusion criteria were included. Three types of tissue-engineered meniscus implants (CMI-Menaflex, Actifit, and NUsurface) have been clinically evaluated for meniscus reconstruction. Lack of standardized outcome measures and imaging protocols limits comparison between studies. CONCLUSIONS: Tissue-engineered meniscus implants can provide short-term knee symptom and function improvements, but no implants have been shown to propose significant long-term benefits for meniscus defects. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies.

The impact of COVID-19 on hip and knee arthroplasty surgical volume in China.

PURPOSE: The reduction of hip and knee arthroplasty surgical volume has been reported in many countries during the COVID-19 pandemic. In China, there is no national joint registry system and the impact of COVID-19 towards surgical volume remains unclear. The aim of this study was to investigate the hip and knee arthroplasty surgical volume in China during the pandemic and evaluate its change trends. METHODS: Annual sale numbers of prostheses used in total knee arthroplasty (TKA), total hip arthroplasty (THA), and femoral head replacement (FHR) from 2011 to 2021 was collected from providers registered in National Medical Products Administration (NMPA). Annual surgical volume of TKA, THA, FHR, unicompartmental knee arthroplasty (UKA), and revision of hip/knee arthroplasty (RJA) was collected from member hospitals of Beijing Joint Society (BJS). We used linear regression to estimate the loss of surgical volume. Annual surgical volume obtained from Britain and Australian joint registries were used to make comparison. RESULTS: In China, the surgical volume of THA/FHR, TKA, and UKA in 2020 all decreased compared to the predicted value, with a reduction of 82,525 cases (13.46%), 165,178 cases (33.50%), and 151 cases (0.65%), respectively. All the three procedures showed significant recovery in 2021. The surgical volumes of THA/FHR and UKA were 68,813 and 9402 cases higher than predicted levels, respectively, while TKA volume remained slightly below the predicted level. The regional statistics in Beijing showed similar change mode. In 2020, the surgical volume of THA/FHR, TKA, FHR, and UKA all decreased compared to the predicted value, with a reduction of 5031 cases (43.37%), 5290 cases (40.69%), 620 cases (29.18%), and 925 cases (39.11%), respectively. In 2021, with the exception of FHR, the number of these procedures increased compared to 2020, but remained below the predicted value. Compared with the data from Britain and Australia, China experienced less reduction and faster recovery in the proportions of elderly people (> 65 years old) who undergo hip and knee arthroplasty during the COVID-19 pandemic. CONCLUSION: During the COVID-19 pandemic, although hip and knee arthroplasty surgical volume in China showed a similar "restoration-recovery" change pattern with other countries, China took fewer losses in this field.

Par3L, a polarity protein, promotes M1 macrophage polarization and aggravates atherosclerosis in mice via p65 and ERK activation.

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.

Design and Discovery of Novel NLRP3 Inhibitors and PET Imaging Radiotracers Based on a 1,2,3-Triazole-Bearing Scaffold.

The NOD-like receptor (NLR) family pyrin-domain-containing 3 (NLRP3) inflammasome, an essential component of the innate immune system, has been emerging as a viable drug target and a potential biomarker for human diseases. In our efforts to develop novel small molecule NLRP3 inhibitors, a 1-(5-chloro-2-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole scaffold was designed via a rational approach based on our previous leads. Structure-activity relationship studies and biophysical studies identified a new lead compound 8 as a potent (IC50: 0.55 ± 0.16 µM), selective, and direct NLRP3 inhibitor. Positron emission tomography (PET) imaging studies of [11C]8 demonstrated its rapid and high brain uptake as well as fast washout in mice and rhesus macaque. Notably, plasma kinetic analysis of this radiotracer from the PET/magnetic resonance imaging studies in rhesus macaque suggested radiometabolic stability. Collectively, our data not only encourage further studies of this lead compound but also warrant further optimization to generate additional novel NLRP3 inhibitors and suitable central nervous system PET radioligands with translational promise.

Objective Measures of Gaze Behaviors and the Visual Environment during Near-Work Tasks in Young Adult Myopes and Emmetropes.

Purpose: To objectively quantify near-work gaze behaviors and the visual environment during reading tasks performed on a smartphone and on paper in both indoor and outdoor environments in myopes and emmetropes. Methods: A novel wearable gaze and viewing distance tracking device was used to quantify near-work gaze behaviors (focusing demand) and the visual environment (20° peripheral scene relative defocus) during a series of reading tasks. Data from nine myopes (mean age, 21 ± 1.4 years) and 10 emmetropes (21 ± 0.8 years) were analyzed. Five-minute reading tasks (matched for font type and size) were performed under four conditions: reading from a smartphone indoors, paper indoors, smartphone outdoors, and paper outdoors. Results: A significantly greater focusing demand (closer viewing distance) was found with smartphone-based reading (mean, 3.15 ± 0.74 D) compared to paper-based reading (2.67 ± 0.48 D) (P < 0.001), with the differences being greatest for myopic participants (P = 0.04). Smartphone reading was also associated with greater peripheral scene relative myopic defocus (P < 0.001). Although near-work behaviors were similar between environments, significantly more relative myopic defocus was found at the start of the paper-based task when performed outdoors compared to indoors (P = 0.02). Conclusions: Significant differences in focusing demand and scene relative defocus within a 20° field were found to be associated with reading tasks performed on a smartphone and paper in indoor and outdoor environments. Translational Relevance: These findings highlight the complex interaction between near-work behaviors and the visual environment and demonstrate that factors of potential importance to myopia development vary between paper-based and smartphone-based near tasks.

Accelerated Discovery of Targeted Environmentally Friendly A(II)B(I)X3-Type Three-Dimensional Hybrid Organic-Inorganic Perovskites for Potential Light Harvesting via Machine Learning.

The engineered hybrid organic-inorganic perovskites (HOIPs) with outstanding multifunctionalities have realized overarching targeted-driven applications and thus aroused intense research interest. The emergence of three-dimensional (3D) A(II)B(I)X3-type HOIPs in 2018 brought a breakthrough to extend the 3D perovskite family and successfully realized prominent ferroelectricity at the same time. Here, we focus on these new-type HOIPs to perform machine-learning (ML)-based molecular design to screen promising candidates for versatile light harvesting, involving photovoltaics (77 ones), water splitting (216 ones), and photodetection (178 ones), out of 3180 A(II)B(I)X3 perovskites in total. These candidates await future experimental synthesis and characterization. Our high-throughput ML-based screening of 3D A(II)B(I)X3 HOIPs would enrich the material inventory by successfully introducing a class of new 3D HOIPs to realize property-oriented light harvesting and additional versatile energy harvesting due to their potential multifunctionalities such as ferroelectricity and electrocaloricity.

AKAP12 inhibits esophageal squamous carcinoma cell proliferation, migration, and cell cycle via the PI3K/AKT signaling pathway.

Esophageal squamous cell carcinoma (ESCC) consistently ranks as one of the most challenging variants of squamous cell carcinomas, primarily due to the lack of effective early detection strategies. We herein aimed to elucidate the underlying mechanisms and biological role associated with A-kinase anchoring protein 12 (AKAP12) in the context of ESCC. Bioinformatic analysis had revealed significantly lower expression level of AKAP12 in ESCC tissue samples than in their non-cancerous counterparts. To gain deeper insights into the potential role of AKAP12 in the progression of ESCC, we conducted a single-gene set enrichment analysis of AKAP12 on ESCC datasets. Our findings suggested that AKAP12 exhibits functions inhibiting cell cycle progression, tumor proliferation, and epithelial-mesenchymal transition. To further validate our findings, we subjected ESCC cell lines to AKAP12 overexpression using CRISPR/Cas9-SAM. In vitro analyses demonstrated that increased expression of AKAP12 significantly reduced cell proliferation, migration, and cell cycle progression. Simultaneously, genes associated with this biological role undergo corresponding regulatory shifts. These observations provided valuable insights into the biological role played by AKAP12 in ESCC progression. In summary, AKAP12 shows promise as a new potential biomarker for early ESCC diagnosis, offering potential advantages for subsequent therapeutic intervention and disease management.