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Ferroptosis, a distinct type of cell death caused by iron and lipid peroxidation, has been associated with several diseases, including cardiovascular disorders. Ferrostatin-1 (Fer-1) is a known ferroptosis inhibitor, but its clinical application is limited by low efficacy and stability. In the present study, a series of Fer-1-based diamide derivatives was synthesized and evaluated to enhance ferroptosis inhibition and in vitro metabolic stability. The synthesized compounds were tested for their protective effects against Erastin-induced injury in human vascular endothelial cells (HUVECs). Among the derivatives, compound 36 exhibited the most potent anti-ferroptosis activity with an EC 50 value of 0.58 ± 0.02 µM. Remarkably, compound 36 also demonstrated superior stability in both microsomal (human and mouse) and mouse plasma assays. These findings indicated ferroptosis inhibitor 36 as a promising hit for further developing potential therapeutic drug candidates in cardiovascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: A single dose of epidural hydromorphone has been suggested as an alternative method for providing analgesia after caesarean section (CS). Nevertheless, the optimal dosage of epidural hydromorphone for postoperative pain relief following CS has yet to be determined., Methods: This trial included 30 singleton primiparous women undergoing scheduled caesarean delivery, who were recruited to determine doses of epidural hydromorphone using the modified Dixon sequential method. The initial hydromorphone dose was 0.75 mg, with adjustments based on the efficacy of the preceding participant's dose over 12 hours. Various parameters such as blood pressure, heart rate, respiratory rate, visual analog scale (VAS) pain score, postoperative adverse reactions, and patient satisfaction with analgesic effect were recorded at each time point. The VAS scores were categorized as positive (score >3) or negative (score ≤3). Participants received a single epidural injection of 0.2% ropivacaine 20 mg along with a study dose of hydromorphone. The median effective dose (ED50), 90% effective dose (ED90), and corresponding 95% confidence intervals (CIs) of hydromorphone with ropivacaine for analgesia after caesarean section were calculated using the probit method., Results: The ED90 and ED50 in our population were 1.105 mg (95% CI: 0.825-2.324 mg) and 0.659 mg (95% CI: 0.434-0.883 mg), respectively., Conclusion: Epidural hydromorphone can be safely used for postoperative analgesia in patients undergoing caesarean section, and the analgesic effect is satisfactory when the dosage is appropriate., Competing Interests: The authors declare no conflict of interest., (© 2024 Liu et al.)

The present study focuses on the design and synthesis of novel 1,4-diformyl-piperazine-based ferrostatin-1 (Fer-1) derivatives, and their evaluation against ferroptosis activity. The synthesized compounds demonstrated significant anti-ferroptosis activity in human umbilical vascular endothelial cells (HUVECs), with Compound 24 showing the highest potency. Mechanistic studies revealed that Compound 24 effectively reduced intracellular reactive oxygen species (ROS) levels, mitigated mitochondrial damage, and enhanced glutathione peroxidase 4 (GPX4) expression. Additionally, Compound 24 exhibited improved solubility and plasma stability compared to control compounds, Fer-1 and JHL-12. These findings suggest that 1,4-diformyl-piperazine-based Fer-1 derivatives hold promise as therapeutic agents for ferroptosis-associated cardiovascular diseases., (© 2024 John Wiley & Sons Ltd.)

Pain management in amphibians is an emerging field of veterinary medicine with only a limited number of analgesics studied for their efficacy. The African-clawed frog, Xenopus laevis, is a popular animal model in research due to its oocyte morphology and embryonic development. We investigated analgesic effects of 2 formulations of meloxicam (standard and extended release [ER]) along with their pharmacokinetics and potential toxicity in this species. Adult female African-clawed frogs (n = 6/group) received either standard (0.2, 0.4, 1, or 5 mg/kg) or ER meloxicam (0.6, 1.2, 3, or 15 mg/kg) injected into the dorsal lymph sac. The acetic acid test (AAT) was performed at -1, 1, 6, 12, 24, 48, and 72 h postadministration to evaluate pain response. In addition, a subset of frogs (n = 2/group) were euthanized 72 h postinjection and submitted for necropsy. There were no significant differences in AAT with both formulations compared with saline control. No signs of meloxicam-induced toxicity with either formulation was present in histology. A pharmacokinetic study was conducted for both the standard and ER formulation of meloxicam at 5 and 15 mg/kg, respectively. Results were consistent with the fact that both formulations of meloxicam were readily absorbed with the standard plasma concentrations peaking at 20.40 µg/mL at 2 h and ER plasma concentration at 30.4 µg/mL at 12 h. The elimination half-life was only determinable for standard formulation (7.74 h). According to the AAT, both formulations of meloxicam did not provide effective analgesia in adult female Xenopus laevis despite reaching high plasma concentrations.

Ferrostatin-1 (Fer-1), a first potent ferroptosis inhibitor, faces limitations in clinical use due to its low potency and metabolic instability. This study introduces a series of novel Ferrostatin-1 analogs designed to enhance plasm stability. Our design strategy focused on the modification of the 3-NH 2 of Fer-1 with benzenesulfonyl groups, resulting in analogs 9-25. Biological evaluation revealed that compound 18, with an EC 50 value of 0.57 μM, outperformed Fer-1 in inhibiting ferroptosis. It reduced intracellular ferrous ion accumulation, lipid peroxidation, and restored glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels effectively. Moreover, compound 18 exhibited favorable solubility and remarkable metabolic stability in rat plasma. These results position compound 18 as a promising candidate for developing therapeutics against ferroptosis-related diseases., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-β-carboline (THβC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THβC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THβC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Despite the record-high efficiency of GaAs solar cells, their terrestrial application is limited due to both the particularly high costs related to the required single-crystal substrates and epitaxial growth. A water-soluble lift-off layer could reduce costs by avoiding the need for toxic and dangerous etchants, substrate repolishing, and expensive process steps. Sr 3 Al 2 O 6 (SAO) is a water-soluble cubic oxide, and SrTiO 3 (STO) is a perovskite oxide, where a SAO ≈ 4 × a STO ≈ (2√2) a GaAs . Here, the pulsed laser-deposited epitaxial growth of SrTiO 3 /Sr 3 Al 2 O 6 templates on STO and Ge substrates for epitaxial GaAs growth was investigated, where SAO works as a sacrificial layer and STO protects the hygroscopic SAO during substrate transfer between deposition chambers. We identified that the SAO film quality is strongly dependent on the growth temperature and the O 2 partial pressure, where either a high T or a high P (O 2 ) improves the quality. XRD spectra of the films with optimized deposition parameters showed an epitaxial STO/SAO stack aligned to the STO (100) substrate, and TEM analysis revealed that the grown films were epitaxially crystalline throughout the thickness. The STO/SAO growth on Ge substrates at a high T with no intentional O 2 flow resulted in some nonepitaxial grains and surface pits, likely due to partial Ge oxidation. GaAs was grown by metalorganic vapor-phase epitaxy (MOVPE) on STO/SAO/STO templates. Lift-off after dissolving the sacrificial SAO in water resulted in free-standing ⟨001⟩ preferentially oriented polycrystalline GaAs., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Se alloying has enabled significantly higher carrier lifetimes and photocurrents in CdTe solar cells, but these benefits can be highly dependent on CdSe x Te 1-x processing. This work evaluates the optoelectronic, chemical, and electronic properties of thick (3 µm) undoped CdSe x Te 1-x of uniform composition and varied processing conditions (CdSe x Te 1-x evaporation rate, CdCl 2 anneal, Se content) chosen to reflect various standard device processing conditions. Sub-bandgap defect emission is observed, which increased as Se content increased and with "GrV-optimized CdCl 2 " (i.e., CdCl 2 anneal conditions used for group-V-doped devices). Low carrier lifetime is found for GrV-optimized CdCl 2 , slow CdSe x Te 1-x deposition, and low-Se films. Interestingly, all films (including CdTe control) exhibited n-type behavior, where electron density increased with Se up to an estimated ≈10 17  cm -3 . This behavior appears to originate during the CdCl 2 anneal, possibly from Se diffusion leading to anion vacancy (e.g., V Se , V Te ) and Cl Te generation., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Catecholamines (CAs) bind and activate adrenergic receptors (ARs), thus exuding a key role in cardiac adaptations to global physiological queues. Prolonged exposure to high levels of CAs promotes deleterious effects on the cardiovascular system, leading to organ dysfunction and heart failure (HF). In addition to the prominent role of ARs in inotropic and chronotropic responses, recent studies have delved into elucidating mechanisms contributing to CA toxicity and cell death. Central to this process is understanding the involvement of α1AR and βAR in cardiac remodeling and mechanisms of cellular survival. Here, we highlight the complexity of AR signaling and the fundamental need for a better understanding of its contribution to oxidative stress and cell death. This crucial informational nexus remains a barrier to the development of new therapeutic strategies for cardiovascular diseases., Competing Interests: Declaration of Interest Statement Lilly Underwood: No other financial or personal relationships to report from the authors that could influence this work. Chun-sun Jiang: No other financial or personal relationships to report from the authors that could influence this work. Joo-yeun Oh: No other financial or personal relationships to report from the authors that could influence this work. Priscila Y Sato: No other financial or personal relationships to report from the authors that could influence this work.

Spin accumulation in semiconductor structures at room temperature and without magnetic fields is key to enable a broader range of optoelectronic functionality 1 . Current efforts are limited owing to inherent inefficiencies associated with spin injection across semiconductor interfaces 2 . Here we demonstrate spin injection across chiral halide perovskite/III-V interfaces achieving spin accumulation in a standard semiconductor III-V (Al x Ga 1-x ) 0.5 In 0.5 P multiple quantum well light-emitting diode. The spin accumulation in the multiple quantum well is detected through emission of circularly polarized light with a degree of polarization of up to 15 ± 4%. The chiral perovskite/III-V interface was characterized with X-ray photoelectron spectroscopy, cross-sectional scanning Kelvin probe force microscopy and cross-sectional transmission electron microscopy imaging, showing a clean semiconductor/semiconductor interface at which the Fermi level can equilibrate. These findings demonstrate that chiral perovskite semiconductors can transform well-developed semiconductor platforms into ones that can also control spin., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses., Methods: Using structure-activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists., Results: Although in vitro potency (EC 50 ) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 μM-a 100-fold improvement over the original reference compound., Conclusions: Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito-human host interactions that lead to pathogen transmission., (© 2024. The Author(s).)

BACKGROUNDObesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.METHODSWe analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status.RESULTS524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox's regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals.CONCLUSIONObesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype.FUNDINGNIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.

Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI., Methods: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status., Results: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/ TP53 abnormal (CN-H/ TP53 abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals., Conclusion: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/ TP53 abn EC molecular subtype., Funding: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Background: Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis., Methods: ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs., Results: ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs., Conclusion: In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The Japan NBI Expert Team (JNET) classification has good diagnostic potential for colorectal diseases. We aimed to explore the diagnostic value of the JNET classification type 2B (JNET2B) criteria for colorectal laterally spreading tumors (LSTs) based on magnifying endoscopy with blue laser imaging (ME-BLI) examination., Methods: Between January 2017 and June 2023, 218 patients who were diagnosed as having JNET2B-type LSTs using ME-BLI were included retrospectively. Endoscopic images were reinterpreted to categorize the LSTs as JNET2B-low (n = 178) and JNET2B-high (n = 53) LSTs. The JNET2B-low and JNET2B-high LSTs were compared based on their histopathological and morphological classifications., Results: Among the 178 JNET2B-low LSTs, 86 (48.3%) were histopathologically classified as low-grade intraepithelial neoplasia, 54 (30.3%) as high-grade intraepithelial neoplasia (HGIN), 37 (20.8%) as intramucosal carcinoma (IMC), and one (0.6%) as superficial invasive submucosal carcinoma (SMC1). Among the 53 JNET2B-high LSTs, five (9.4%) were classified as HGIN, 28 (52.9%) as IMC, 15 (28.3%) as SMC1, and 5 (9.4%) as deep invasive submucosal carcinoma. There were significant differences in this histopathological classification between the two groups (P < 0.001). However, there was no significant difference between JNET2B-low and JNET2B-high LSTs based on their morphological classification (granular vs nongranular) or size (<20 mm vs ≥20 mm). Besides, the κ value for JNET2B subtyping was 0.698 (95% confidence interval 0.592-0.804) between the two endoscopists who reassessed the endoscopic images., Conclusion: The JNET2B subtyping of LSTs has a diagnostic potential in the preoperative setting, and may be valuable for treatment decision-making., (© 2024 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

In 2018, Nouioui et al. proposed that Bifidobacterium coryneforme was a later synonym of Bifidobacterium indicum on the basis of the digital DNA-DNA hybridization (dDDH) value (85.0%) between B. coryneforme LMG 18911 T and B. indicum LMG 11587 T . However, in the study of Scardovi et al. (1970), the type strains of B. indicum and B. coryneforme only exhibited 60% DNA-DNA hybridization value. In the present study, the genomes of B. coryneforme CGMCC 1.2279 T , B. coryneforme JCM 5819 T , B. indicum JCM 1302 T , B. indicum CGMCC 1.2275 T , B. indicum DSM 20214 T , B. indicum LMG 27437 T , B. indicum ATCC 25912 T , B. indicum KCTC 3230 T , B. indicum CCUG 34985 T , were sequenced, and the taxonomic relationship between B. coryneforme and B. indicum was re-evaluated. On the basis of the results presented here, (i) ATCC 25912 and DSM 20214 deposited by Vittorio Scardovi are two different strains; (ii) the type strain of B. indicum is ATCC 25912 T (= JCM 1302 T  = LMG 27437 T  = CGMCC 1.2275 T  = KCTC 3230 T ), and not DSM 20214 (= BCRC 14674 = CCUG 34985 = LMG 11587); (iii) B. coryneforme and B. indicum represent two different species of the genus Bifidobacterium; (iv) strain DSM 20214 (= BCRC 14674 = CCUG 34985 = LMG 11587) belongs to B. coryneforme., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Inaccurate Forrest classification may significantly affect clinical outcomes, especially in high risk patients. Therefore, this study aimed to develop a real-time deep convolutional neural network (DCNN) system to assess the Forrest classification of peptic ulcer bleeding (PUB)., Methods: A training dataset (3868 endoscopic images) and an internal validation dataset (834 images) were retrospectively collected from the 900th Hospital, Fuzhou, China. In addition, 521 images collected from four other hospitals were used for external validation. Finally, 46 endoscopic videos were prospectively collected to assess the real-time diagnostic performance of the DCNN system, whose diagnostic performance was also prospectively compared with that of three senior and three junior endoscopists., Results: The DCNN system had a satisfactory diagnostic performance in the assessment of Forrest classification, with an accuracy of 91.2% (95%CI 89.5%-92.6%) and a macro-average area under the receiver operating characteristic curve of 0.80 in the validation dataset. Moreover, the DCNN system could judge suspicious regions automatically using Forrest classification in real-time videos, with an accuracy of 92.0% (95%CI 80.8%-97.8%). The DCNN system showed more accurate and stable diagnostic performance than endoscopists in the prospective clinical comparison test. This system helped to slightly improve the diagnostic performance of senior endoscopists and considerably enhance that of junior endoscopists., Conclusion: The DCNN system for the assessment of the Forrest classification of PUB showed satisfactory diagnostic performance, which was slightly superior to that of senior endoscopists. It could therefore effectively assist junior endoscopists in making such diagnoses during gastroscopy., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP + ). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP + dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP + pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-β-carboline (THβC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC 50 values of 15.47 ± 1.31 and 19.31 ± 2.14 μM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC 50 values below 10 μM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

A novel bifidobacterium (designated F753-1 T ) was isolated from the gut of honeybee ( Apis mellifera ). Strain F753-1 T was characterized using a polyphasic taxonomic approach. Strain F753-1 T was phylogenetically related to the type strains of Bifidobacterium mizhiensis , Bifidobacterium asteroides , Bifidobacterium choladohabitans , Bifidobacterium mellis , Bifidobacterium apousia and Bifidobacterium polysaccharolyticum , having 98.4-99.8 % 16S rRNA gene sequence similarities. The phylogenomic tree indicated that strain F753-1 T was most closely related to the type strains of B. mellis and B. choladohabitans . Strain F753-1 T had the highest average nucleotide identity (94.1-94.5 %) and digital DNA-DNA hybridization (56.3 %) values with B. mellis Bin7N T . Acid production from amygdalin, d-fructose, gentiobiose, d-mannose, maltose, sucrose and d-xylose, activity of α -galactosidase, pyruvate utilization and hydrolysis of hippurate could differentiate strain F753-1 T from B. mellis CCUG 66113 T and B. choladohabitans JCM 34586 T . Based upon the data obtained in the present study, a novel species, Bifidobacterium apis sp. nov., is proposed, and the type strain is F753-1 T (=CCTCC AB 2023227 T =JCM 36562 T =LMG 33388 T ).

Introduction: Lyme disease (LD) affects ∼476,000 people each year in the United States. Symptoms are variable and include rash and flu-like symptoms. Reasons for the wide variation in disease outcomes are unknown. Powassan virus (POWV) is a tick-borne flavivirus that causes disease ranging from asymptomatic infection to encephalitis, neurologic damage, and death. POWV and LD geographic case distributions overlap, with Ixodes species ticks as the common vectors. Clinical ramifications of coinfection or sequential infection are unknown. Objectives: This study's primary objective was to determine the prevalence of POWV-reactive antibodies in sera samples collected from previously studied cohorts of individuals with self-reported LD history residing in the Northeastern United States. As a secondary objective, we studied clinical differences between people with self-reported LD history and low versus high POWV antibody levels. Methods: We used an enzyme-linked immunosorbent assay (ELISA) to quantify IgG directed at the POWV envelope (E) protein domain III in 538 samples from individuals with self-reported LD history and 16 community controls. The samples were also tested with an ELISA assay to quantify IgG directed at the POWV NS1 protein. Results: The percentage of individuals with LD history and possible evidence of POWV exposure varied depending on the assay utilized. We found no significant difference in clinical symptoms between those with low or high POWV IgG levels in the in-house assay. Congruence of the EDIII and NS1 assays was low with only 12% of those positive in the in-house EDIII ELISA testing positive in the POWV NS1 ELISA. Conclusions: The results highlight the difficulty in flavivirus diagnostic testing, particularly in the retrospective detection of flavivirus exposure. The findings suggest that a prospective study with symptomatic patients using approved clinical testing is necessary to address the incidence and clinical implications of LD and POWV co-infection or sequential infection.

Background: Sleep disturbances, which are common problems in older adults, often lead to cognitive decline and depression and may even increase mortality risk. Foot thermal therapy is a simple and safe approach for improving sleep and is associated with relatively few side effects. However, the effect of different operations of foot thermal therapy on sleep quality in older adults is inconclusive. This study aimed to access the effects of temperature, duration, and heating height of foot thermal therapy (administered through a footbath) on the subjective and objective sleep quality of older adults. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, eight databases were searched for all relevant articles published up to July 2023, and a rigorous systematic review and meta-analysis was conducted. This study was registered in the PROSPERO database (CRD42022383460). Inclusion criteria were: (1) participants with a mean age ≥60 years; (2) interventions that included foot thermal therapy; (3) a control group that received routine care but no thermal therapy; (4) outcome measurements that assessed sleep quality; and (5) the studies that utilized randomized controlled trials or quasi-experimental studies. Methodological quality was assessed using the Joanna Briggs Institute critical appraisal tools. The meta-analysis was performed using RevMan version 5.4. Results: A total of 11 studies were included. Foot thermal therapy before bedtime improved subjective sleep quality in older adults, with optimal parameters of 40°C temperature (standardized mean difference [SMD] = 0.66, 95% confidence interval [CI]: 0.33 to 0.99), ≤20-min duration (SMD = 0.66, 95% CI: 0.39 to 0.93), and 10 cm heating height (SMD = 0.78, 95% CI: 0.45 to 1.11). Subgroup analyses revealed that a temperature of 41°C-42°C can improve objective sleep latency (SMD = 0.54, 95% CI: 0.09 to 0.99). Conclusions: It is recommended to administer foot thermal therapy (40°C; ≤20 min; 10 cm above the ankle) to older adults 1 h before their bedtime. If they have trouble falling asleep, the temperature can be increased to 41°C-42°C.

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Four lactic acid bacteria, designated F690 T , F697, F790 T and F769-2, were isolated from the gut of honeybee ( Apis mellifera ). Results of 16S rRNA gene sequence analysis indicated that strains F690 T and F697 were phylogenetically related to the type strains of Lactobacillus kimbladii , Lactobacillus laiwuensis , Lactobacillus kullabergensis and Lactobacillus huangpiensis , having 99.1-99.6 % 16S rRNA gene sequence similarities; and that strains F790 T and F769-2 were most closely related to the type strain of Lactobacillus melliventris , having 99.2-99.3 % 16S rRNA gene sequence similarities. The phylogenies based on concatenated pheS , rpoA , gyrB , hsp60 , recA , rpoB and tuf sequences and based on whole genome sequences were identical to that based on 16S rRNA gene sequences. Strains F690 T and F697 exhibited the highest average nucleotide identity (ANI; 92.1-93.2 %), digital DNA-DNA hybridization (dDDH; 50-50.1 %) and average amino acid identity (AAI; 94.9-95.1 %) values with L. kimbladii Hma2N T . Strains F790 T and F769-2 had the highest ANI (93.1-94 %), dDDH (54.4 %) and AAI (94.4-94.7 %) values with L. melliventris Hma8N T . Based upon the data obtained in the present study, two novel species, Lactobacillus juensis sp. nov. and Lactobacillus rizhaonensis sp. nov., are proposed and the type strains are F690 T (=JCM 36259 T =CCTCC AB 2023131 T ) and F790 T (=JCM 36260 T =CCTCC AB 2023132 T ), respectively.

In the present study, a novel derivative, IOP-LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B-inspired indole/1,2,4-oxadiazole derivative. Our results demonstrated that IOP-LA could protect vascular endothelial cells (VECs) from oxidized low-density lipoprotein (oxLDL)-induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE -/- mice. Moreover, the protective effect of IOP-LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP-LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa-B (NF-κB) nuclear induced by oxLDL through the nuclear factor erythroid2-related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP-LA, as a new antioxidant, protects VECs from oxLDL-induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer caused by a dominant recurrent fusion of the heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). Current therapies such as chemotherapy and radiation have limited efficacy, and new treatment options are needed urgently. We have previously shown that FLC tumors are dependent on the fusion kinase DNAJB1::PRKACA, making the oncokinase an ideal drug target. mRNA degrading modalities such as antisense oligonucleotides or small interfering RNAs (siRNAs) provide an opportunity to specifically target the fusion junction. Here, we identify a potent and specific siRNA that inhibits DNAJB1::PRKACA expression. We found expression of the asialoglycoprotein receptor in FLC to be maintained at sufficient levels to effectively deliver siRNA conjugated to the GalNAc ligand. We observe productive uptake and siRNA activity in FLC patient-derived xenografts (PDX) models in vitro and in vivo. Knockdown of DNAJB1::PRKACA results in durable growth inhibition of FLC PDX in vivo with no detectable toxicities. Our results suggest that this approach could be a treatment option for FLC patients., Competing Interests: Declaration of interests T.P.P. and A.R. are employees at Ionis Pharmaceuticals., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Novel endoscopic techniques used in the treatment of gastric lesions with local submucosal fibrosis need preclinical evaluation and training due to safety limitations. Therefore, the purpose of our study was to establish an animal model of gastric local fibrotic target lesions and assess its feasibility in the evaluation and training of endoscopic techniques., Methods: In six experimental beagles, a 50% glucose solution was injected into three submucosal areas of the fundus, body, and antrum of the stomach to create gastric local fibrotic target lesions (experimental group). On post-injection day (PID) 7, the injection sites were assessed endoscopically to confirm the presence of submucosal fibrosis formation, and the dental floss clip traction assisted endoscopic submucosal dissection (DFC-ESD) procedure was performed on the gastric local fibrotic target lesions to confirm its feasibility after endoscopic observation. The normal gastric mucosa of six control beagles underwent the same procedure (control group). All the resected specimens were evaluated by histological examination., Results: All 12 beagles survived without postoperative adverse events. On PID 7, 16 ulcer changes were observed at the injection sites (16/18) under the endoscope, and endoscopic ultrasonography confirmed the local submucosal fibrosis formation in all ulcer lesions. The subsequent DFC-ESD was successfully performed on the 32 gastric target lesions, and the mean submucosal dissection time in the ulcer lesions was greater than that in the normal gastric mucosa (15.3 ± 5.6 vs. 6.8 ± 0.8 min; P < 0.001). There was no difference in rates of en bloc resection, severe hemorrhage, or perforation between the two groups. Histological analysis of the ulcer lesions showed the absence of epithelial or muscularis mucosae and extensive submucosal fibrous tissue proliferations compared with normal gastric mucosa. Overall, endoscopists had high satisfaction with the realism and feasibility of the animal model., Conclusion: We developed a novel animal model of gastric local fibrotic target lesions to simulate difficult clinical situations, which strongly appeared to be suitable for the preclinical evaluation and learning of advanced endoscopic techniques., (© 2023. The Author(s).)

Previous studies have shown that Lactobacillus futsaii (now Companilactobacillus futsaii) can be subdivided at the subspecies level. The main purpose of this study is to explore whether this is correct by using a polyphasic taxonomic approach. Lactobacillus futsaii subsp. chongqingii was proposed and effectively published in 2019. The names L. futsaii subsp. chongqingensis corrig. and Lactobacillus futsaii subsp. futsaii were not validated until March 2023. However, in the reclassification of the genus Lactobacillus by Zheng et al. in April 2020, L. futsaii was transferred to Companilactobacillus as Companilactobacillus futsaii. So Lactobacillus futsaii subsp. chongqingensis and Lactobacillus futsaii subsp. futsaii should be transferred to Companilactobacillus futsaii now. In the present study, the relationship between L. futsaii subsp. chongqingensis and L. futsaii subsp. futsaii was re-evaluated. The type strains of L. futsaii subsp. chongqingensis and L. futsaii subsp. futsaii shared identical pheS and rpoA sequences, high dDDH value, similar phenotypic characteristics and fatty acid compositions, indicating that they belonged to the same subspecies. Here, we propose to reclassify Lactobacillus futsaii subsp. chongqingensis and Lactobacillus futsaii subsp. futsaii as Companilactobacillus futsaii subsp. chongqingensis comb. nov. and Companilactobacillus futsaii subsp. futsaii comb. nov., respectively, and Companilactobacillus futsaii subsp. chongqingensis as a later heterotypic synonym of Companilactobacillus futsaii subsp. futsaii., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T 1/2  = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and C max values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: During endoscopic submucosal dissection (ESD) for gastric lesions with fibrosis, appropriate traction could provide clear submucosal dissection visualization to improve safety and efficiency of procedures. Therefore, the aim of this study was to evaluate the feasibility of magnetic ring-assisted ESD (MRA-ESD) for gastric fibrotic lesions., Method: In the eight healthy beagles, 2-3 mL of 50% glucose solution was injected into submucosal layer of the stomach to induce gastric fibrotic lesions. A week after submucosal injection, two endoscopists at different levels performed MRA-ESD or standard ESD (S-ESD) for gastric simulated lesions, respectively. The magnetic traction system consisted of external handheld magnet and internal magnetic ring. The feasibility and procedure outcomes of the magnetic traction system were mainly evaluated., Results: Forty-eight gastric simulated lesions with ulceration were confirmed to have submucosal fibrosis formation by preoperative endoscopic ultrasonography. The magnetic traction system could be easily established, only took 1.57 min, and allowed excellent submucosal visualization. The total procedure time was significantly shorter in the MRA-ESD group than in the S-ESD group for both endoscopists (mean: 46.83 vs. 25.09 min, p < 0.001), and this difference was accentuated in non-skilled endoscopist. There was significant difference between two groups in bleeding and perforation rates. Histological analysis showed the depth of resected specimens was a little deeper around the fibrotic portion in the S-ESD group (p < 0.001)., Conclusion: The magnetic ring-assisted ESD technique may be an effective and safe treatment for gastric fibrotic lesions and may shorten the endoscopic learning curve for non-skilled endoscopists., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The activation of pancreatic stellate cells (PSCs) plays a key role in the occurrence and development of chronic pancreatitis (CP) and pancreatic fibrosis, which is related to the process of epithelial-mesenchymal transition (EMT). This study was designed to investigate the effect and mechanism of Tcf21 (one of tumor suppressor genes) on pancreatic inflammation and fibrosis in vivo and in vitro., Methods: C57BL/6 male mice were intraperitoneally injected with caerulein for 6 weeks to establish CP animal model. Fixed pancreatic tissue paraffin-embedded sections were used for immunohistochemistry staining of Tcf21, fibrosis-related markers (α-SMA), interstitial markers (Vimentin) and epithelial markers (E-cadherin). Western blotting and qRT-PCR assay were performed to analyze the change of expression of the above markers after stimulation of TGF-β1 or overexpressed Tcf21 lentivirus transfection in human pancreatic stellate cells (HPSCs)., Results: The pancreatic expression of α-SMA and Vimentin of CP mice significantly increased, while the expression of Tcf21 and E-cadherin significantly decreased. TGF-β1 could promote activation and EMT process of HPSCs, and inhibited the expression of Tcf21. Overexpression of Tcf21 could significantly down-regulate the expression of α-SMA, Fibronectin and Vimentin, and up-regulated the expression of ZO-1 of HPSCs. Cell Counting Kit-8 assay and scratch wound-healing assay results showed that overexpression of Tcf21 could significantly inhibit the cell migration and proliferation of HPSCs., Conclusions: Overexpression of Tcf21 could significantly alleviate the activation, proliferation, migration of PSCs by regulating the EMT process. Tcf21 had a potential prospect of a new target for CP therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Light-induced performance changes in metal halide perovskite solar cells (PSCs) have been studied intensively over the last decade, but little is known about the variation in microscopic optoelectronic properties of the perovskite heterojunctions in a completed device during operation. Here, we combine Kelvin probe force microscopy and transient reflection spectroscopy techniques to spatially resolve the evolution of junction properties during the operation of metal-halide PSCs and study the light-soaking effect. Our analysis showed a rise of an electric field at the hole-transport layer side, convoluted with a more reduced interfacial recombination rate at the electron-transport layer side in the PSCs with an n-i-p structure. The junction evolution is attributed to the effects of ion migration and self-poling by built-in voltage. Device performances are correlated with the changes of electrostatic potential distribution and interfacial carrier dynamics. Our results demonstrate a new route for studying the complex operation mechanism in PSCs.

Pulmonary fibrosis is a progressive lung disease characterized by macrophage activation. Asbestos-induced expression of nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) in lung macrophages mediates fibrotic progression by the generation of mitochondrial reactive oxygen species (ROS), modulating mitochondrial biogenesis, and promoting apoptosis resistance; however, the mechanism(s) by which NOX4 localizes to mitochondria during fibrosis is not known. Here, we show that NOX4 localized to the mitochondrial matrix following asbestos exposure in lung macrophages via direct interaction with TIM23. TIM23 and NOX4 interaction was found in lung macrophages from human subjects with asbestosis, while it was absent in mice harboring a conditional deletion of NOX4 in lung macrophages. This interaction was localized to the proximal transmembrane region of NOX4. Mechanistically, TIM23 augmented NOX4-induced mitochondrial ROS and metabolic reprogramming to oxidative phosphorylation. Silencing TIM23 decreased mitochondrial ROS and oxidative phosphorylation. These observations highlight the important role of the mitochondrial translocase TIM23 interaction with NOX4. Moreover, this interaction is required for mitochondrial redox signaling and metabolic reprogramming in lung macrophages., Competing Interests: Conflict of interest The authors that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The etiology for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases, is unknown. Emerging evidence suggests that cellular senescence contributes importantly to AD pathophysiology, although the mechanisms underlying brain cell senescence and by which senescent cells promote neuro-pathophysiology remain unclear. In this study we show for the first time that the expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, is increased, in correlation with the increased expression of cell cycle repressors p53 and p21, in the hippocampus/cortex of senescence accelerated mouse prone 8 (SAMP8) mice and LOAD patients. Double immunostaining results show that astrocytes in the brain of LOAD patients and SAMP8 mice express higher levels of senescent markers and PAI-1, compared to astrocytes in the corresponding controls. In vitro studies further show that overexpression of PAI-1 alone, intracellularly or extracellularly, induced senescence, whereas inhibition or silencing PAI-1 attenuated H 2 O 2 -induced senescence, in primary mouse and human astrocytes. Treatment with the conditional medium (CM) from senescent astrocytes induced neuron apoptosis. Importantly, the PAI-1 deficient CM from senescent astrocytes that overexpress a secretion deficient PAI-1 (sdPAI-1) has significantly reduced effect on neurons, compared to the PAI-1 containing CM from senescent astrocytes overexpressing wild type PAI-1 (wtPAI-1), although sdPAI-1 and wtPAI-1 induce similar degree of astrocyte senescence. Together, our results suggest that increased PAI-1, intracellularly or extracellularly, may contribute to brain cell senescence in LOAD and that senescent astrocytes can induce neuron apoptosis through secreting pathologically active molecules, including PAI-1., Competing Interests: Conflicts of Interests The author has no conflict of interest to disclose, (copyright: © 2022 Jiang et al.)

Protein arginine methyltransferase 5 (PRMT5) is a major type II enzyme responsible for symmetric dimethylation of arginine (SDMA), and plays predominantly roles in human cancers, including in ovarian cancer. However, the exactly roles and underlying mechanisms of PRMT5 contributing to the progression of ovarian cancer mediated by reprogramming cell metabolism remain largely elusive. Here, we report that PRMT5 is highly expressed and correlates with poor survival in ovarian cancer. Knockdown or pharmaceutical inhibition of PRMT5 is sufficient to decrease glycolysis flux, attenuate tumor growth, and enhance the antitumor effect of Taxol. Mechanistically, we find that PRMT5 symmetrically dimethylates alpha-enolase (ENO1) at arginine 9 to promotes active ENO1 dimer formation, which increases glycolysis flux and accelerates tumor growth. Moreover, PRMT5 signals high glucose to increase the methylation modification of ENO1. Together, our data reveal a novel role of PRMT5 in promoting ovarian cancer growth by controlling glycolysis flux mediated by methylating ENO1, and highlights that PRMT5 may represent a promising therapeutic target for treating ovarian cancer., Competing Interests: The authors have declared that no competing interest exists., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose ( 18 F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and β-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia. NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.

A detailed chemical investigation of the South China Sea soft coral Sarcophyton ehrenbergi has yield seven undescribed cembranoids, namely isoehrenbergol D and sarcoehrenolides F-K embodying a rare α,β-unsaturated-lactone moiety at C-6 to C-19, along with two known related compounds, ehrenbergol D and sarcoehrenolide A. Their structures and absolute configurations were unambiguously established in the light of extensive spectroscopic data analysis, modified Mosher's method, X-ray diffraction analysis, and quantum chemical computation method. In a bioassay for α-glucosidase inhibition, ehrenbergol D was evaluated as α-glucosidase inhibitor with an IC 50 value of 13.57 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pulmonary fibrosis is characterized by stiffening of the extracellular matrix. Fibroblasts migrate in the direction of greater stiffness, a phenomenon termed durotaxis. The mechanically guided fibroblast migration could be a crucial step in the progression of lung fibrosis. In this study, we found primary human lung fibroblasts sense increasing matrix stiffness with a change of mitochondrial dynamics in favor of mitochondrial fission and increased production of ATP. Mitochondria polarize in the direction of a physiologically relevant stiffness gradient, with conspicuous localization to the leading edge, primarily lamellipodia and filopodia, of migrating lung fibroblasts. Matrix stiffness-regulated mitochondrial fission and durotactic lung fibroblast migration are mediated by a dynamin-related protein 1/mitochondrial fission factor-dependent (DRP1/MFF-dependent) pathway. Importantly, we found that the DRP1/MFF pathway is activated in fibrotic lung myofibroblasts in both human IPF and bleomycin-induced mouse lung fibrosis. These findings suggest that energy-producing mitochondria need to be sectioned via fission and repositioned in durotactic lung fibroblasts to meet the higher energy demand. This represents a potentially new mechanism through which mitochondria may contribute to the progression of fibrotic lung diseases. Inhibition of durotactic migration of lung fibroblasts may play an important role in preventing the progression of human idiopathic pulmonary fibrosis.

Purpose: Gene fusions are drivers of many pediatric tumors. In fibrolamellar hepatocellular carcinoma (FLC), a fusion of DNAJB1 and PRKACA is the dominant recurrent mutation. Expression of the DNAJB1-PRKACA fusion gene in mice results in a tumor that recapitulates FLC. However, it is not known whether transient expression of DNAJB1-PRKACA is sufficient only to trigger tumor formation or whether ongoing expression is necessary for maintenance and progression., Experimental Design: We screened short hairpin RNAs (shRNA) tiled over the fusion junction and identified several potent and specific candidates in vitro and two independent FLC patient-derived xenografts (PDX)., Results: We show that continued DNAJB1-PRKACA expression is not only required for continued tumor growth, but additionally its inhibition results in cell death. Inhibition of DNAJB1-PRKACA by an inducible shRNA in cells of PDX of FLC resulted in cell death in vitro. Induction of the shRNA inhibits FLC tumors growing in mice with no effect on xenografts from a hepatocellular carcinoma cell line engineered to express DNAJB1-PRKACA., Conclusions: Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Diabetes mellitus (DM) is a critical global health issue, affecting nearly half a billion people worldwide, with an increasing incidence rate and mortality. Type 2 diabetes is caused by the body's inability to effectively use insulin, and approximately 95% of patients have type 2 diabetes. α-glucosidase has emerged as an important therapeutic target for the treatment of type 2 diabetes. In the past years, three α-glucosidase inhibitors have been approved for clinical use, namely acarbose, voglibose, and miglitol. However, the undesirable effects associated with these carbohydrate mimic-based α-glucosidase inhibitors have limited their clinical applications. Consequently, researchers have shifted their focus towards the development of non-carbohydrate mimic α-glucosidase inhibitors that can safely and effectively manage postprandial hyperglycemia in type 2 diabetes. Herein, this article provides an overview of the synthetic α-glucosidase inhibitors, particularly those based on heterocycles, which have been reported from 2018 to 2022. This article aims to provide useful information for medicinal chemists in further developing clinically available anti-type 2 diabetes drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug acarbose (IC 50  = 258.5 μM), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC 50 value of 9.9 μM and showed higher selectivity towards α-glucosidase over α-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with α-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs compounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: PRMT5 is a major enzyme responsible for the post-translational symmetric demethylation of protein arginine residues, which has been validated as an effective therapeutic target for cancer. Thus, many nucleoside-based PRMT5 inhibitors have been reported in the past year., Objective: To discover a novel series of non-nucleoside PRMT5 inhibitors through a molecular docking-based virtual screening approach., Methods: Our in-house compound library was virtually screened using the Glide program, identifying a new PRMT5 inhibitor 1. Based on the structural similarity of hit 1, a series of structure-oriented derivatives, including 3a-3e, 7a-7g, and 12a-12f, were synthesized and selected for the inhibitory activity evaluation against PRMT5, as well as cytotoxicity against MV4-11 cell., Results: The analogs 7a-7e with benzimidazole core exhibited potent PRMT5 inhibitory activities, with 7e displaying the most potent activity with an IC 50 of 6.81 ± 0.12 μM. In the anti-proliferative assay, compound 7e showed a strong inhibitory effect on MV4-11 cell growth. Finally, the binding mode of 7e with PRMT5 was predicted to provide insights for further structural optimization., Conclusion: The newly discovered PRMT5 inhibitors have potential antitumor activity against MV4-11 cells. This work highlighted this series of 3-(1H-benzo[d]imidazol-2-yl)aniline derivatives as novel anti-cancer lead compounds targeting PRMT5, which were worthy of further investigation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Insect societies are tightly integrated, complex biological systems in which group-level properties arise from the interactions between individuals 1-4 . However, these interactions have not been studied systematically and therefore remain incompletely known. Here, using a reverse engineering approach, we reveal that unlike solitary insects, ant pupae extrude a secretion derived from the moulting fluid that is rich in nutrients, hormones and neuroactive substances. This secretion elicits parental care behaviour and is rapidly removed and consumed by the adults. This behaviour is crucial for pupal survival; if the secretion is not removed, pupae develop fungal infections and die. Analogous to mammalian milk, the secretion is also an important source of early larval nutrition, and young larvae exhibit stunted growth and decreased survival without access to the fluid. We show that this derived social function of the moulting fluid generalizes across the ants. This secretion thus forms the basis of a central and hitherto overlooked interaction network in ant societies, and constitutes a rare example of how a conserved developmental process can be co-opted to provide the mechanistic basis of social interactions. These results implicate moulting fluids in having a major role in the evolution of ant eusociality., (© 2022. The Author(s).)

Some people are more attractive to mosquitoes than others, but the mechanistic basis of this phenomenon is poorly understood. We tested mosquito attraction to human skin odor and identified people who are exceptionally attractive or unattractive to mosquitoes. These differences were stable over several years. Chemical analysis revealed that highly attractive people produce significantly more carboxylic acids in their skin emanations. Mutant mosquitoes lacking the chemosensory co-receptors Ir8a, Ir25a, or Ir76b were severely impaired in attraction to human scent, but retained the ability to differentiate highly and weakly attractive people. The link between elevated carboxylic acids in "mosquito-magnet" human skin odor and phenotypes of genetic mutations in carboxylic acid receptors suggests that such compounds contribute to differential mosquito attraction. Understanding why some humans are more attractive than others provides insights into what skin odorants are most important to the mosquito and could inform the development of more effective repellents., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Understanding phenotypic sex differences has long been a goal of biology from both a medical and evolutionary perspective. Although much attention has been paid to mean differences in phenotype between the sexes, little is known about sex differences in phenotypic variability. To gain insight into sex differences in interindividual variability at the molecular level, we analyzed RNA-seq data from 43 tissues from the Genotype-Tissue Expression project (GTEx). Within each tissue, we identified genes that show sex differences in gene expression variability. We found that these sex-differentially variable (SDV) genes are associated with various important biological functions, including sex hormone response, immune response, and other signaling pathways. By analyzing single-cell RNA sequencing data collected from breast epithelial cells, we found that genes with sex differences in gene expression variability in breast tissue tend to be expressed in a cell-type-specific manner. We looked for an association between SDV expression and Graves' disease, a well-known heavily female-biased disease, and found a significant enrichment of Graves' associated genes among genes with higher variability in females in thyroid tissue. This suggests a possible role for SDV expression in sex-biased disease. We then examined the evolutionary constraints acting on genes with sex differences in variability and found that they exhibit evidence of increased selective constraint. Through analysis of sex-biased eQTL data, we found evidence that SDV expression may have a genetic basis. Finally, we propose a simple evolutionary model for the emergence of SDV expression from sex-specific constraints., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

Neurons in visual cortical areas primary visual cortex (V1) and V4 are adaptive processors, influenced by perceptual task. This is reflected in their ability to segment the visual scene into task-relevant and task-irrelevant stimulus components and by changing their tuning to task-relevant stimulus properties according to the current top-down instruction. Differences between the information represented in each area were seen. While V1 represented detailed stimulus characteristics, V4 filtered the input from V1 to carry the binary information required for the two-alternative judgement task. Neurons in V1 were activated at locations where the behaviorally relevant stimulus was placed well outside the grating-mapped receptive field. By systematically following the development of the task-dependent signals over the course of perceptual learning, we found that neuronal selectivity for task-relevant information was initially seen in V4 and, over a period of weeks, subsequently in V1. Once the learned information was represented in V1, on any given trial, task-relevant information appeared initially in V1 responses, followed by a 12-ms delay in V4. We propose that the shifting representation of learned information constitutes a mechanism for systems consolidation of memory.