Glymphatic abnormality in systemic lupus erythematosus detected by diffusion tensor image analysis along the perivascular space.

OBJECTIVES: This study aimed to evaluate the activity of the glymphatic system in systemic lupus erythematosus (SLE) by a diffusion-based method termed "Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS)", and examined its correlations with morphological changes in the brain. METHODS: In this cross-sectional study, forty-five female patients with SLE and thirty healthy controls (HCs) were included. Voxel-based and surface-based morphometric analyses were performed to examine T1 weighted images, and diffusion tensor images were acquired to determine diffusivity along the x-, y-, and z-axes in the plane of the lateral ventricle body. The ALPS-index was calculated. The differences in values between SLE patients and HC group were compared using the independent samples t test or Mann-Whitney U test. For the correlations between the ALPS-index and brain morphological parameters, partial correlation analysis and Pearson's correlation analysis were conducted. RESULTS: SLE patients showed lower values for the ALPS-index in left (1.543 ± 0.141 vs 1.713 ± 0.175, p < 0.001), right (1.428 ± 0.142 vs 1.556 ± 0.139, p < 0.001) and whole (1.486 ± 0.121 vs 1.635 ± 0.139, p < 0.001) brain compared with the HC group. The reduced ALPS-index showed significant positive correlations with gray matter loss. CONCLUSION: The non-invasive ALPS-index could serve as a sensitive and effective neuroimaging biomarker for individually quantifying glymphatic activity in patients with SLE. Glymphatic system abnormality may be involved in the pathophysiologic mechanism underlying central nervous system damage in SLE patients.

Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease.

Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps (NETs). However, the substrates of PAD4 and its exact role in inflammatory bowel disease (IBD) remain unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD. Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium (DSS)-induced colitis mouse model. scRNA-seq analysis revealed significant alterations in intestinal cell populations, with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion. Gene expression analysis highlighted pathways related to inflammation and epithelial cell function. Furthermore, we found that neutrophil-derived extracellular vesicles (EVs) carrying PAD4 were secreted into intestinal epithelial cells (IECs). Within IECs, PAD4 citrullinates mitochondrial creatine kinase 1 (CKMT1) at the R242 site, leading to reduced CKMT1 protein stability via the autophagy pathway. This action compromises mitochondrial homeostasis, impairs intestinal barrier integrity, and induces IECs apoptosis. IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis. Clinical analysis of IBD patients revealed elevated levels of PAD4, increased CKMT1 citrullination, and decreased CKMT1 expression. In summary, our findings highlight the crucial role of PAD4 in IBD, where it modulates IECs plasticity via CKMT1 citrullination, suggesting that PAD4 may be a potential therapeutic target for IBD.

Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia.

In the face of escalating metabolic disease prevalence, largely driven by modern lifestyle factors, this study addresses the critical need for novel therapeutic approaches. We have identified the sodium-coupled citrate transporter (NaCT or SLC13A5) as a target for intervention. Utilizing rational drug design, we developed a new class of SLC13A5 inhibitors, anchored by the hydroxysuccinic acid scaffold, refining the structure of PF-06649298. Among these, LBA-3 emerged as a standout compound, exhibiting remarkable potency with an IC50 value of 67 nM, significantly improving upon PF-06649298. In vitro assays demonstrated LBA-3's efficacy in reducing triglyceride levels in OPA-induced HepG2 cells. Moreover, LBA-3 displayed superior pharmacokinetic properties and effectively lowered triglyceride and total cholesterol levels in diverse mouse models (PCN-stimulated and starvation-induced), without detectable toxicity. These findings not only spotlight LBA-3 as a promising candidate for hyperlipidemia treatment but also exemplify the potential of targeted molecular design in advancing metabolic disorder therapeutics.

Sciadonic acid attenuates high-fat diet-induced bone metabolism disorders in mice.

High-fat diet (HFD) has been associated with certain negative bone-related outcomes, such as bone metabolism disruption and bone loss. Sciadonic acid (SC), one of the main nutritional and functional components of Torreya grandis seed oil, is a unique Δ5-unsaturated-polymethylene-interrupted fatty acid (Δ5-UPIFA) that has been claimed to counteract such disorders owing to some of its physiological effects. However, the role of SC in ameliorating bone metabolism disorders due to HFD remains unclear. In the present investigation, we observed that SC modulates the OPG/RANKL/RANK signaling pathway by modifying the lipid metabolic state and decreasing inflammation in mice. In turn, it could balance bone resorption and formation as well as calcium and phosphorus levels, enhance bone strength and bone mineral density (BMD), and improve its microstructure. In addition, SC could inhibit fat vacuoles in bone, reverse the phenomenon of reduced numbers and poor continuity of bone trabeculae, and promote orderly arrangement of collagen fibers and cartilage repair. This study provides some theoretical basis for SC as a dietary intervention agent to enhance bone nutrition.

Maslinic acid alleviates intervertebral disc degeneration by inhibiting the PI3K/AKT and NF-κB signaling pathways.

Intervertebral disc degeneration (IDD) is the cause of low back pain (LBP), and recent research has suggested that inflammatory cytokines play a significant role in this process. Maslinic acid (MA), a natural compound found in olive plants ( Olea europaea), has anti-inflammatory properties, but its potential for treating IDD is unclear. The current study aims to investigate the effects of MA on TNFα-induced IDD in vitro and in other in vivo models. Our findings suggest that MA ameliorates the imbalance of the extracellular matrix (ECM) and mitigates senescence by upregulating aggrecan and collagen II levels as well as downregulating MMP and ADAMTS levels in nucleus pulposus cells (NPCs). It can also impede the progression of IDD in rats. We further find that MA significantly affects the PI3K/AKT and NF-κB pathways in TNFα-induced NPCs determined by RNA-seq and experimental verification, while the AKT agonist Sc-79 eliminates these signaling cascades. Furthermore, molecular docking simulation shows that MA directly binds to PI3K. Dysfunction of the PI3K/AKT pathway and ECM metabolism has also been confirmed in clinical specimens of degenerated nucleus pulposus. This study demonstrates that MA may hold promise as a therapeutic agent for alleviating ECM metabolism disorders and senescence to treat IDD.

A root-knot nematode effector targets the Arabidopsis cysteine protease RD21A for degradation to suppress plant defense and promote parasitism.

Meloidogyne incognita is one of the most widely distributed plant-parasitic nematodes and causes severe economic losses annually. The parasite produces effector proteins that play essential roles in successful parasitism. Here, we identified one such effector named MiCE108, which is exclusively expressed within the nematode subventral esophageal gland cells and is upregulated in the early parasitic stage of M. incognita. A yeast signal sequence trap assay showed that MiCE108 contains a functional signal peptide for secretion. Virus-induced gene silencing of MiCE108 impaired the parasitism of M. incognita in Nicotiana benthamiana. The ectopic expression of MiCE108 in Arabidopsis suppressed the deposition of callose, the generation of reactive oxygen species, and the expression of marker genes for bacterial flagellin epitope flg22-triggered immunity, resulting in increased susceptibility to M. incognita, Botrytis cinerea, and Pseudomonas syringae pv. tomato (Pst) DC3000. The MiCE108 protein physically associates with the plant defense protease RD21A and promotes its degradation via the endosomal-dependent pathway, or 26S proteasome. Consistent with this, knockout of RD21A compromises the innate immunity of Arabidopsis and increases its susceptibility to a broad range of pathogens, including M. incognita, strongly indicating a role in defense against this nematode. Together, our data suggest that M. incognita deploys the effector MiCE108 to target Arabidopsis cysteine protease RD21A and affect its stability, thereby suppressing plant innate immunity and facilitating parasitism.

Systemic lupus erythematosus-related brain abnormalities in the default mode network and the limbic system: A resting-state fMRI meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an immune-mediated and multi-systemic disease which may affect the nervous system, causing neuropsychiatric SLE (NPSLE). Recent neuroimaging studies have examined brain functional alterations in SLE. However, discrepant findings were reported. This meta-analysis aims to identify consistent resting-state functional abnormalities in SLE. METHODS: PubMed and Web of Science were searched to identify candidate resting-state functional MRI studies assessing SLE. A voxel-based meta-analysis was performed using the anisotropic effect-size version of the seed-based d mapping (AES-SDM). The abnormal intrinsic functional patterns extracted from SDM were mapped onto the brain functional network atlas to determine brain abnormalities at a network level. RESULTS: Twelve studies evaluating fifteen datasets were included in this meta-analysis, comprising 572 SLE patients and 436 healthy controls (HCs). Compared with HCs, SLE patients showed increased brain activity in the bilateral hippocampus and right superior temporal gyrus, and decreased brain activity in the left superior frontal gyrus, left middle temporal gyrus, bilateral thalamus, left inferior frontal gyrus and right cerebellum. Mapping the abnormal patterns to the network atlas revealed the default mode network and the limbic system as core neural systems commonly affected in SLE. LIMITATIONS: The number of included studies is relatively small, with heterogeneous analytic methods and a risk of publication bias. CONCLUSIONS: Brain functional alterations in SLE are predominantly found in the default mode network and the limbic system. These findings uncovered a consistent pattern of resting-state functional network abnormalities in SLE which may serve as a potential objective neuroimaging biomarker.

Experimental Study on the Localized Deformation and Damage Behavior of Polymer-Bonded Explosive Simulant under Cyclic Compression.

Uniaxial cyclic compression tests were performed to investigate the compression deformation and damage of polymer-bonded explosive (PBX) simulant, particularly shear localization. The macroscopic mechanical behavior and mesoscale failure mechanisms of the PBX simulant were analyzed by optical observation and SEM scanning methods. After each cyclic compression, the specimen was scanned by X-ray computed tomography (CT), and the internal 3D deformation of the specimen was calculated using the digital volume correlation (DVC) method. The results show that the stress-strain curve of the PBX simulant exhibits five stages and coincides with the morphological changes on the surface of the specimen. The mesoscale failure mechanism is dominated by particle interface debonding and binder tearing, accompanied by a small amount of particle breakage. There are three bifurcation points (T1, T2, and T3) in the curves of the normal and shear strain components with compression strain. It was found that these bifurcation points can reflect the full progression of the specimen from inconspicuous damage to uniformly distributed damage, shear localization, and eventual macroscopic fracture. The strain invariant I1 can quantitatively and completely characterize the deformation and damage processes of the PBX simulant under cyclic compression.

Comparing perioperative outcomes between regional anesthesia and general anesthesia in patients undergoing hip fracture surgery: a systematic review and meta-analysis.

PURPOSE: Nearly all patients with hip fractures undergo surgical treatment. The use of different anesthesia techniques during surgery may influence the clinical outcomes. The optimal anesthetic technique for patients undergoing hip fracture surgery is still controversial. We performed this updated systematic review and meta-analysis to compare clinical outcomes of patients undergoing hip fracture surgery with different anesthesia techniques. SOURCE: Articles published from 2000 to May 2023 were included from MEDLINE, Embase, Web of Science, and the Cochrane Library. We included randomized controlled trials and observational studies comparing general anesthesia (GA) with regional anesthesia (RA) for the outcomes of 30-day mortality, 90-day mortality, in-hospital mortality, perioperative complications, length of hospital stay, and length of surgery in patients undergoing hip fracture surgery. Subgroup analyses were performed for the outcomes based on study design (randomized controlled trials or observational studies). We used a random-effects model for all analyses. PRINCIPAL FINDINGS: In this meta-analysis, we included 12 randomized controlled trials. There was no difference in postoperative 30-day mortality between the two groups (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.44 to 1.74; I2 = 0%). The incidence of intraoperative hypotension was lower in patients who received RA vs GA (OR, 0.52; 95% CI, 0.38 to 0.72; I2 = 0%). No significant differences were observed in 90-day mortality, in-hospital mortality, postoperative delirium, pneumonia, myocardial infarction, venous thromboembolism, length of surgery, and length of hospital stay. CONCLUSION: In this updated systematic review and meta-analysis, RA did not reduce postoperative 30-day mortality in hip fracture surgery patients compared to GA. Fewer patients receiving RA had intraoperative hypotension than those receiving GA did. Apart from intraoperative hypotension, the data showed no differences in complications between the two anesthetic techniques. STUDY REGISTRATION: PROSPERO (CRD42023411854); registered 7 April 2023.

RéSUMé: OBJECTIF: Presque toutes les personnes ayant subi une fracture de la hanche se font opérer. L'utilisation de différentes techniques d'anesthésie pendant la chirurgie peut influencer les issues cliniques. La technique d'anesthésie optimale pour la patientèle bénéficiant de chirurgie de fracture de la hanche est encore controversée. Nous avons réalisé cette mise à jour par revue systématique et méta-analyse pour comparer les issues cliniques des personnes bénéficiant d'une chirurgie de fracture de la hanche avec différentes techniques d'anesthésie. SOURCES: Les articles publiés de 2000 à mai 2023 ont été inclus à partir des bases de données MEDLINE, Embase, Web of Science et Cochrane Library. Nous avons inclus des études randomisées contrôlées et des études observationnelles comparant l'anesthésie générale (AG) à l'anesthésie régionale (AR) pour les issues de mortalité à 30 jours, de mortalité à 90 jours, de mortalité intrahospitalière, de complications périopératoires, de durée de séjour à l'hôpital et de durée de la chirurgie pour les personnes bénéficiant d'une chirurgie de fracture de la hanche. Des analyses de sous-groupes ont été réalisées pour les issues en fonction de la méthodologie utilisée (étude randomisée contrôlée ou étude observationnelle). Un modèle à effets aléatoires a été utilisé pour toutes les analyses. CONSTATATIONS PRINCIPALES: Dans cette méta-analyse, nous avons inclus 12 études randomisées contrôlées. Il n'y avait pas de différence dans la mortalité postopératoire à 30 jours entre les deux groupes (rapport de cotes [RC], 0,88; intervalle de confiance à 95 % [IC], 0,44 à 1,74; I2 = 0 %). L'incidence d'hypotension peropératoire était plus faible chez les patient·es ayant reçu une AR vs une AG (RC, 0,52; IC 95 %, 0,38 à 0,72; I2 = 0 %). Aucune différence significative n'a été observée dans les issues de mortalité à 90 jours, de mortalité intrahospitalière, de delirium postopératoire, de pneumonie, d'infarctus du myocarde, de thromboembolie veineuse, de durée de la chirurgie, et de durée du séjour à l'hôpital. CONCLUSION: Dans cette revue systématique avec méta-analyse, l'anesthésie régionale n'a pas réduit la mortalité postopératoire à 30 jours chez les personnes ayant bénéficié d'une chirurgie de fracture de la hanche par rapport à l'anesthésie générale. Une proportion moindre de patient·es ayant reçu une AR présentaient une hypotension peropératoire par rapport aux personnes ayant reçu une AG. En dehors de l'hypotension peropératoire, les données n'ont montré aucune différence dans les complications entre les deux techniques anesthésiques. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42023411854); enregistrée le 7 avril 2023.

T1 Mapping and Amide Proton Transfer Weighted Imaging for Predicting Lymph Node Metastasis in Patients with Rectal Cancer.

BACKGROUND: Accurate preoperative judgment of lymph node (LN) metastasis is a critical step in creating a treatment strategy and evaluating prognosis in rectal cancer (RC) patients. OBJECTIVE: This study aimed to explore the value of T1 mapping and amide proton transfer weighted (APTw) imaging in predicting LN metastasis in patients with rectal cancer. METHODS: In a retrospective study, twenty-three patients with pathologically confirmed rectal adenocarcinoma who underwent MRI and surgery from August 2019 to August 2021 were selected. Then, 3.0T/MR sequences included conventional sequences (T1WI, T2WI, and DWI), APTw imaging, and T1 mapping. Patients were divided into LN metastasis (group A) and non-LN metastasis groups (group B). The intra-group correlation coefficient (ICC) was used to test the inter-observer consistency. Mann-Whitney U test was used to compare the differences between the two groups. Spearman correlation analysis was performed to evaluate the correlation between T1 and APT values. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the differential performance of each parameter and their combination. The difference between AUCs was compared using the DeLong test. RESULTS: The APT value in patients with LN metastasis was significantly higher than in those without LN metastasis group (P=0.020). Also, similar results were observed for the T1 values (P=0.001). The area under the ROC curve of the APT value in the prediction of LN metastasis was 0.794; when the cutoff value was 1.73%, the sensitivity and specificity were 71.4% and 88.9%, respectively. The area under the ROC curve of the T1 value was 0.913; when the cutoff value was 1367.36 ms, the sensitivity and specificity were 78.6% and 100.0%, respectively. The area under the ROC curve of T1+APT was 0.929, with a sensitivity of 78.6% and specificity of 100.0%. CONCLUSION: APT and T1 values show great diagnostic efficiency in predicting LN metastasis in rectal cancer.

Sciadonic acid ameliorates cyclophosphamide-induced immunosuppression by modulating the immune response and altering the gut microbiota.

BACKGROUND: Cyclophosphamide (Cy) is a frequently used chemotherapeutic drug, but long-term Cy treatment can cause immunosuppression and intestinal mucosal damage. The intestinal mucosal barrier and gut flora play important roles in regulating host metabolism, maintaining physiological functions and protecting immune homeostasis. Dysbiosis of the intestinal flora affects the development of the intestinal microenvironment, as well as the development of various external systemic diseases and metabolic syndrome. RESULTS: The present study investigated the influence of sciadonic acid (SA) on Cy-induced immunosuppression in mice. The results showed that SA gavage significantly alleviated Cy-induced immune damage by improving the immune system organ index, immune response and oxidative stress. Moreover, SA restored intestinal morphology, improved villus integrity and activated the nuclear factor κB signaling pathway, stimulated cytokine production, and reduced serum lipopolysaccharide (LPS) levels. Furthermore, gut microbiota analysis indicated that SA increased t beneficial bacteria (Alistipes, Lachnospiraceae_NK4A136_group, Rikenella and Odoribacter) and decreased pathogenic bacteria (norank-f-Oscillospiraceae, Ruminococcus and Desulfovibrio) to maintain intestinal homeostasis. CONCLUSION: The present study provided new insights into the SA regulation of intestinal flora to enhance immune responses. © 2024 Society of Chemical Industry.

Chronic vascular pathogenesis results in the reduced serum Metrnl levels in ischemic stroke patients.

Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.

MMP-2 Responsive Peptide Hydrogel-Based Nanoplatform for Multimodal Tumor Therapy.

Introduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release. Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed. Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy. Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.

Flexible nanoplasmonic sensor for multiplexed and rapid quantitative food safety analysis with a thousand-times sensitivity improvement.

The accumulation of trace amounts of certain small molecules in food poses considerable human health challenges, including the potential for carcinogenesis and mutagenesis. Here, an ultrasensitive gold-platinum nanoflower-coupled metasurface plasmon resonance (MetaSPR) (APNMSPR) biosensor, based on a competitive immunoassay, was developed for the multiplexed and rapid quantitative analysis of trace small molecules in eggs, offering timely monitoring of food safety. This one-step biosensor can be integrated into either a newly designed detachable high-throughput MetaSPR chip-strip plate device or a standard 96-well plate for multiplexed small-molecule detection within a single egg. The limits of detection were 0.81, 1.12, and 1.74 ppt for florfenicol, fipronil, and enrofloxacin, respectively, demonstrating up to 1000-fold increased sensitivity and a 15-fold reduction in analysis time compared with those of traditional methods. The results obtained using the APNMSPR biosensor showed a strong correlation with those obtained using liquid chromatography-tandem mass spectrometry. The APNMSPR biosensor holds immense promise for the multiplexed, highly sensitive, and rapid quantitative analysis of small molecules for applications in food safety control, early diagnosis, and environmental monitoring.

Nomogram for predicting neutropenia in patients with esophageal, gastric, or colorectal cancer treated by chemotherapy in the first cycle.

OBJECTIVES: Development and validation of a predictive model including serum vitamin concentration to estimate the risk of chemotherapy-induced grade 3/4 neutropenia in esophageal cancer, gastric cancer, or colorectal cancer patients who receive the first cycle of chemotherapy. METHODS: Data from 535 patients treated at the Affiliated Fuyang People's Hospital of Anhui Medical University from January 1, 2020, to March 2, 2022, were used to derive the predictive model. Least absolute shrinkage and selection operator regression analysis was performed to screen potential risk characteristics, and multivariate logistic regression was utilized to investigate efficient factors associated with chemotherapy-induced neutropenia. A nomogram was constructed using this logistic model. This nomogram was then tested on a temporal validation cohort containing 212 consecutive patients. RESULTS: In the cohort of all 747 eligible patients, grade 3/4 neutropenia incidence was 45.2%. Age, Eastern Cooperative Oncology Group-performance status, neutrophil count, serum albumin, and hemoglobin data were entered into the final model. The performance of the final predictive nomogram was assessed by the area under the receiver operating characteristic curve in both the development and validation datasets. The calibration curves indicated that the estimated risks were accurate. Decision curve analysis for the predictive model exhibited improved clinical practicality. CONCLUSION: In the present study, we established an accessible risk predictive model and identified valuable serum vitamin concentration parameters associated with chemotherapy-induced neutropenia. The predictive model may improve the grade 3/4 neutropenia risk prediction in patients with gastrointestinal malignancies who receive oxaliplatin- and fluoropyrimidine-based chemotherapy and help physicians make appropriate decisions for disease management.

Activation of TAZ by XMU-MP-1 inhibits osteoclastogenesis and attenuates ovariectomy-induced cancellous bone loss.

Osteoporosis is a metabolic bone loss disorder usually accompanied by overactivated osteoclast formation and increased bone resorption. Transcriptional co-activator with PDZ-binding motif (TAZ) is an emerging potential target for the treatment of osteoporosis. Our previous research showed that TAZ overexpression inhibited osteoclast formation while TAZ silencing had the opposite effect. In addition, TAZ knockout in mouse osteoclasts induced osteoporosis in animal experiments. XMU-MP-1 (XMU) is a selective MST1/2 inhibitor that can theoretically activate TAZ; however, its effect on osteoporosis remains unknown. In this study, we found that XMU treatment significantly increased TAZ expression in osteoclasts and inhibited osteoclast formation in vitro; however, this inhibitory effect was eliminated after the deletion of TAZ. Furthermore, XMU treatment upregulated TAZ expression in osteoclasts and alleviated ovariectomy (OVX)-induced osteoporosis in bilateral OVX mouse models. These findings suggest that XMU can effectively activate TAZ and that pharmacological activation of TAZ may be a promising option for the treatment of osteoporosis.

Facet joint tropism, pelvic incidence and intervertebral height index: associations with facet joint osteoarthritis in lumbar spinal stenosis.

BACKGROUND CONTEXT: Facet joint osteoarthritis (FJOA) is associated with lumbar disc degeneration and has a significant role in the development of lumbar spinal stenosis (LSS). The relationship between various radiographic parameters and the grade of FJOA is not well understood. PURPOSE: To explore radiographical parameters associated with FJOA in LSS without lumbar dynamic instability. STUDY DESIGN: Retrospective study analysis. PATIENT SAMPLE: A total of 122 patients diagnosed with LSS who visited our hospital between January 2015 and July 2022. OUTCOME MEASURES: We evaluated radiographic parameters of patients at L4-5 including lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), grades of FJOA, facet joint orientation (FO), facet joint tropism (FT), intervertebral height index (IHI) and the relative cross-sectional area (RCSA) of paraspinal muscles. METHODS: Patients diagnosed with LSS between January 2015 and July 2022 were enrolled. Demographic characteristics and radiographic parameters were collected. Spinopelvic parameters were measured through the preoperative lateral image of the whole spine, including LL, PI, pelvic tilt, and sacral slope. Lumbar computed tomography scan and magnetic resonance imaging were collected to measure the FO, FT, IHI, and the RCSA of paraspinal muscles respectively. Patients were divided into three groups according to the severity of FJOA graded by the Weishaupt classification: grade 0 and grade 1 were group A, grade 2 were group B, and grade 3 were group C. All variables were compared among the three groups, while the relationship between parameters and grades of FJOA were also analyzed. RESULTS: A total of 122 patients were included. PI was significantly greater in group C compared to group A (p = 0.025) and group B (p=0.022). FT was significantly greater in group C compared to group A (p<.001) and group B (p<.001). The RCSA of multifidus in group A were significantly greater than that in group B (p=0.02) and C (p=0.002). Additionally, FO in group C were significantly lower than group A (p<.001) and group B (p=0.028). The IHI in group C was significantly lower than group A (p=0.017). The correlation analysis indicated that grades of FJOA was positively related to Age, BMI (body mass index), PI, LL and FT, while negatively related to IHI, FO, RCSA of multifidus and RCSA of psoas major. Furthermore, the logistics regression showed that FT, PI, and IHI were important influence factors for FJOA. CONCLUSIONS: The current study confirmed that FT, PI and IHI were significantly associated with grades of FJOA at L4-5. Additionally, longitudinal studies are needed to understand the causal relationship between these parameters and FJOA.

FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two ß regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no experimental data show the relationship between FARSB and HCC progression. We found that the high expression of FARSB in liver cancer is closely related to patients' low survival and poor prognosis. In liver cancer cells, the mRNA and protein expression levels of FARSB are increased and promote cell proliferation and migration. Mechanistically, FARSB activates the mTOR complex 1 (mTORC1) signaling pathway by binding to the component Raptor of the mTORC1 complex to play a role in promoting cancer. In addition, we found that FARSB can inhibit erastin-induced ferroptosis by regulating the mTOR signaling pathway, which may be another mechanism by which FARSB promotes HCC progression. In summary, FARSB promotes HCC progression and is associated with the poor prognosis of patients. FARSB is expected to be a biomarker for early screening and treatment of HCC.

MiR-29b Downregulation by p53/Sp1 Complex Plays a Critical Role in Bleb Scar Formation After Glaucoma Filtration Surgery.

Purpose: To investigate the function and mechanism of tumor protein p53 in pathological scarring after glaucoma filtration surgery (GFS) using human Tenon's fibroblasts (HTFs) and a rabbit GFS model. Methods: The expression of p53 in bleb scarring after GFS and transforming growth factor-ß (TGF-ß)-induced HTFs (myofibroblasts [MFs]) was examined by western blot and immunochemical analysis. The interaction between p53 and specificity protein 1 (Sp1) was investigated by immunoprecipitation. The role of p53 and Sp1 in the accumulation of collagen type I alpha 1 chain (COL1A1) and the migration of MFs was evaluated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), wound healing, and Transwell assay. The regulatory mechanisms among p53/Sp1 and miR-29b were detected via qRT-PCR, western blot, luciferase reporter assay, and chromatin immunoprecipitation assay. The therapeutic effect of mithramycin A, a specific inhibitor of Sp1, on scarring formation was evaluated in a rabbit GFS model. Results: p53 was upregulated in bleb scar tissue and MFs. p53 and Sp1 form a transcription factor complex that induces the accumulation of COL1A1 and promotes the migration of MFs through downregulation of miR-29b, a known suppressor of COL1A1. The p53/Sp1 axis inhibits miR-29b expression by the direct binding promoter of the miR-29b gene. Mithramycin A treatment attenuated bleb scar formation in vivo. Conclusions: The p53/Sp1/miR-29b signaling pathway plays a critical role in bleb scar formation after GFS. This pathway could be targeted for therapeutic intervention of pathological scarring after GFS. Translational Relevance: Our research indicates that inhibition of p53/Sp1/miR-29b is a promising therapeutic strategy for preventing post-GFS pathological scarring.

Explainable cross-task adaptive transfer learning for motor imagery EEG classification.

Objective. In the field of motor imagery (MI) electroencephalography (EEG)-based brain-computer interfaces, deep transfer learning (TL) has proven to be an effective tool for solving the problem of limited availability in subject-specific data for the training of robust deep learning (DL) models. Although considerable progress has been made in the cross-subject/session and cross-device scenarios, the more challenging problem of cross-task deep TL remains largely unexplored.Approach. We propose a novel explainable cross-task adaptive TL method for MI EEG decoding. Firstly, similarity analysis and data alignment are performed for EEG data of motor execution (ME) and MI tasks. Afterwards, the MI EEG decoding model is obtained via pre-training with extensive ME EEG data and fine-tuning with partial MI EEG data. Finally, expected gradient-based post-hoc explainability analysis is conducted for the visualization of important temporal-spatial features.Main results. Extensive experiments are conducted on one large ME EEG High-Gamma dataset and two large MI EEG datasets (openBMI and GIST). The best average classification accuracy of our method reaches 80.00% and 72.73% for OpenBMI and GIST respectively, which outperforms several state-of-the-art algorithms. In addition, the results of the explainability analysis further validate the correlation between ME and MI EEG data and the effectiveness of ME/MI cross-task adaptation.Significance. This paper confirms that the decoding of MI EEG can be well facilitated by pre-existing ME EEG data, which largely relaxes the constraint of training samples for MI EEG decoding and is important in a practical sense.