Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The tumor microenvironment (TME) contributes to the poor response of patients with HCC to current therapies, while tumor vascular endothelial cells (ECs) are fundamental TME components that significantly contribute to tumor progression. However, the specific functions and mechanisms of tumor vascular ECs in HCC remain unclear. METHODS: We screened and validated diacylglycerol kinase gamma (DGKG) hyper-expression specifically in HCC tumor vascular ECs. Single-cell RNA-sequencing, cytometry by time-of-flight, and in vitro and in vivo studies were performed to investigate the functions of endothelial DGKG. Multiplexed immunohistochemistry staining and flow cytometry were used to evaluate changes in the TME. RESULTS: Functionally, endothelial DGKG promotes tumor angiogenesis and immunosuppressive regulatory T-cell differentiation in HCC. Of significance, we found that HIF-1α activates DGKG transcription by directly binding to its promoter region under hypoxia. Upregulated DGKG promotes HCC progression by recruiting ubiquitin specific peptidase 16 to facilitate ZEB2 deubiquitination, which increases TGF-ß1 secretion, thus inducing tumor angiogenesis and regulatory T-cell differentiation. Importantly, targeting endothelial DGKG potentiated the efficiency of dual blockade of PD-1 and VEGFR-2. CONCLUSION: Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immune evasion via the ZEB2/TGF-ß1 axis, suggesting EC-specific DGKG as a potential therapeutic target for HCC. IMPACT AND IMPLICATIONS: Here, we reported that hypoxia-induced endothelial cell-specific DGKG hyper-expression promotes angiogenesis and immune evasion in HCC by recruiting USP16 for K48-linked deubiquitination and inducing the subsequent stabilization of ZEB2, leading to increased TGF-ß1 secretion. Most importantly, endothelial DGKG inhibition greatly improved the efficacy of the dual combination of anti-VEGFR2 and anti-PD-1 treatment in a mouse HCC model, significantly inhibiting the malignant progression of HCC and improving survival. This preclinical study supports the targeting of endothelial DGKG as a potential strategy for precision HCC treatment.

Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer.

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMBhighCNAhigh, as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer.

The mitochondrial carboxylase PCCA interacts with Listeria monocytogenes phospholipase PlcB to modulate bacterial survival.

Listeria monocytogenes, a prominent foodborne pathogen responsible for zoonotic infections, owes a significant portion of its virulence to the presence of the phospholipase PlcB. In this study, we performed an in-depth examination of the intricate relationship between L. monocytogenes PlcB and host cell mitochondria, unveiling a novel participant in bacterial survival: the mitochondrial carboxylase propionyl-coenzyme A carboxylase (PCCA). Our investigation uncovered previously unexplored levels of interaction and colocalization between PCCA and PlcB within host cells, with particular emphasis on the amino acids 504-508 of PCCA, which play a pivotal role in this partnership. To assess the effect of PCCA expression on L. monocytogenes proliferation, PCCA expression levels were manipulated by siRNA-si-PCCA or pCMV-N-HA-PCCA plasmid transfection. Our findings demonstrated a clear inverse correlation between PCCA expression levels and the proliferation of L. monocytogenes. Furthermore, the effect of L. monocytogenes infection on PCCA expression was investigated by assessing PCCA mRNA and protein expression in HeLa cells infected with L. monocytogenes. These results indicate that L. monocytogenes infection did not significantly alter PCCA expression. These findings led us to propose that PCCA represents a novel participant in L. monocytogenes survival, and its abundance has a detrimental impact on bacterial proliferation. This suggests that L. monocytogenes may employ PlcB-PCCA interactions to maintain stable PCCA expression, representing a unique pro-survival strategy distinct from that of other intracellular bacterial pathogens. IMPORTANCE: Mitochondria represent attractive targets for pathogenic bacteria seeking to modulate host cellular processes to promote their survival and replication. Our current study has uncovered mitochondrial carboxylase propionyl-coenzyme A carboxylase (PCCA) as a novel host cell protein that interacts with L. monocytogenes PlcB. The results demonstrate that PCCA plays a negative regulatory role in L. monocytogenes infection, as heightened PCCA levels are associated with reduced bacterial survival and persistence. However, L. monocytogenes may exploit the PlcB-PCCA interaction to maintain stable PCCA expression and establish a favorable intracellular milieu for bacterial infection. Our findings shed new light on the intricate interplay between bacterial pathogens and host cell mitochondria, while also highlighting the potential of mitochondrial metabolic enzymes as antimicrobial agents.

miR-708-5p deficiency involves the degeneration of mandibular condylar chondrocytes via the TLR4/NF-κB pathway.

OBJECTIVE: Ageing and aberrant biomechanical stimulation are two major risk factors for osteoarthritis (OA). One of the main characteristics of aged cartilage is cellular senescence. One of the main characteristics of osteoarthritic joints is cartilage degeneration. The cells in the temporomandibular joint (TMJ) cartilage are zonally arranged. The deep zone cells are differentiated from the superficial zone cells (SZCs). The purpose of the present study was to investigate whether degenerative shear stress (SS) stimulates the senescence programme in TMJ SZCs, and to determine which miRNA is involved in this process. METHOD: SZCs were isolated from the TMJ condyles of 3-week-old rats and treated with continuous passaging or SS. RNA sequencing was conducted to identify miRNA(s) that overlap with those involved in the replication senescence process and the SS-induced degeneration programme. Unilateral anterior crossbite (UAC), which is TMJ-OA inducible, was applied to 2-month-old and 12-month-old mice for 3 weeks. The effect of TMJ local injection of agomiR-708-5p was evaluated histologically. RESULTS: Both replication and SS treatment induced SZC senescence. miR-708-5p was identified. Knocking down miR-708-5p in SS-treated SZCs led to more severe senescence by alleviating the inhibitory impact of miR-708-5p on the TLR4/NF-κB pathway. miR-708-5p expression in mouse TMJ cartilage decreased with age. UAC induced more severe osteoarthritic cartilage lesions in 12-month-old mice than in 2-month-old mice. Injection of agomiR-708-5p suppressed UAC-induced osteoarthritic cartilage lesions. CONCLUSIONS: Age-related miR-708-5p deficiency is involved in the mechanically stimulated OA process. Intra-articular administration of agomiR-708-5p is a promising new strategy for OA treatment.

Expression profiling and function analysis identified new genes regulating cumulus expansion and apoptosis.

Studies on the mechanisms behind cumulus expansion and cumulus cell (CC) apoptosis are essential for understanding the mechanisms for oocyte maturation. Genes expressed in CCs might be used as markers for competent oocytes and/or embryos. In this study, both in vitro (IVT) and in vivo (IVO) mouse oocyte models with significant difference in cumulus expansion and CC apoptosis were used to identify and validate new genes regulating cumulus expansion and CC apoptosis of mouse oocytes. We first performed mRNA sequencing and bioinformatic analysis using the IVT oocyte model to identify candidate genes. We then analyzed functions of the candidate genes by RNAi or gene overexpression to select the candidate cumulus expansion and CC apoptosis-regulating genes. Finally, we validated the cumulus expansion and CC apoptosis-regulating genes using the IVO oocyte model. The results showed that while Spp1, Sdc1, Ldlr, Ezr and Mmp2 promoted, Bmp2, Angpt2, Edn1, Itgb8, Cxcl10 and Agt inhibited cumulus expansion. Furthermore, Spp1, Sdc1 and Ldlr inhibited CC apoptosis. In conclusion, by using both IVT and IVO oocyte models, we have identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos and for elucidating the molecular mechanisms behind oocyte maturation.

Remote ischemic conditioning reduces adverse events in patients with acute ischemic stroke complicating acute myocardial infarction: a randomized controlled trial.

BACKGROUND: Acute ischemic stroke (AIS) complicating an acute myocardial infarction (AMI) is not uncommon, but can severely worsen the clinical prognosis. This study aimed to investigate whether remote ischemic conditioning (RIC) could provide clinical benefits to patients with AIS complicating AMI. METHODS: Subjects with AIS complicating AMI were recruited in this double-blind, randomized, controlled trial; assigned to the RIC and sham groups; and respectively underwent twice daily RIC and sham RIC for 2 weeks. All subjects received standard medical therapy. The primary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCEs) within 3 months after enrollment. MACCEs comprise of death from all causes, unstable anginas, AMI, acute ischemic strokes, and transient ischemic attacks. RESULTS: Eighty subjects were randomly assigned; 37 patients in the RIC group and 40 patients in the sham-RIC group completed the 3-month follow-up and were included in the final analysis. Both RIC and sham RIC procedures were well tolerated. At 3-month follow-up, 11 subjects (29.7%) in the RIC group experienced MACCEs compared to 21 (52.5%) in the sham group (hazard ratio [HR], 0.396; 95% confidence interval, 0.187-0.838; adjusted p < 0.05). Six subjects (16.2%) in the RIC group had died at the 3-month follow up, significantly lower than the 15 (37.5%) deaths in the sham group (adjusted HR 0.333; 95% CI 0.126-0.881; p = 0.027). Seventeen subjects (45.9%) in the RIC group and 6 subjects (15.0%) in the sham group achieved functional independence (mRS score ≤ 2) at 3-month follow-up (adjusted OR 12.75; 95% CI 2.104-77.21; p = 0.006). CONCLUSIONS: Among patients with acute ischemic stroke complicating acute myocardial infarction, treatment with remote ischemic conditioning decreased the major adverse cardiac and cerebrovascular events and improved functional outcomes at 90 days. TRIAL REGISTRATION: URL: www. CLINICALTRIALS: gov . Unique identifier: NCT03868007. Registered 8 March 2019.

Circulating microRNA-33b levels are associated with the presence and severity of coronary heart disease.

MicroRNA-33b (miR-33b) affected various biological pathways in regulating cholesterol homeostasis which may link to the pathogenesis of atherosclerotic lesions. However, whether this marker is associated with the presence and severity of coronary heart disease (CHD) is undetermined. We aim to explore the diagnostic value of circulating miR-33b level in the presence and severity of CHD. Altogether 320 patients were enrolled, including 240 patients diagnosed with CHD while 80 were classified as controls after CAG examination. Circulating miR-33b level was analyzed in all subjects, the Gensini score was calculated to assess the severity of stenotic lesions. The association between miR-33b and the presence and severity of CHD was analyzed, and the diagnostic potential of miR-33b of CHD was performed by the receiver operating characteristic (ROC) analysis. The CHD group had higher miR-33b levels (p < 0.001), and the miR-33b content significantly elevated following an increasing Gensini score (p for trend < 0.001). After adjustments for potential risk factors, such as several blood lipid markers, miR-33b remained a significant determinant for CHD (p < 0.001). ROC analysis disclosed that the AUC was 0.931. The optimal cutoff value of miR-33b was with a sensitivity of 81.3% and a specificity of 98.7% in differentiating CHD. It can prognosticate that the higher level of miR-33b was linked to increased severity of disease in CHD patients. Thus, the application of this marker might assist in the diagnosis and classification of CHD patients. Nevertheless, additional studies with larger sample sizes will be required to verify these results.

DegU-mediated suppression of carbohydrate uptake in Listeria monocytogenes increases adaptation to oxidative stress.

The foodborne bacterial pathogen Listeria monocytogenes exhibits remarkable survival capabilities under challenging conditions, severely threatening food safety and human health. The orphan regulator DegU is a pleiotropic regulator required for bacterial environmental adaptation. However, the specific mechanism of how DegU participates in oxidative stress tolerance remains unknown in L. monocytogenes. In this study, we demonstrate that DegU suppresses carbohydrate uptake under stress conditions by altering global transcriptional profiles, particularly by modulating the transcription of the phosphoenolpyruvate-carbohydrate phosphotransferase system (PTS)-related genes, such as ptsH, ptsI, and hprK. Specifically, in the absence of degU, the transcripts of ptsI are significantly upregulated and those of hprK are significantly downregulated in response to copper ion-induced stress. Overexpression of ptsI significantly increases bacterial growth in vitro, while overexpression of hprK leads to a decrease in growth. We further demonstrate that DegU directly senses oxidative stress, downregulates ptsI transcription, and upregulates hprK transcription. Additionally, through an electrophoretic mobility shift assay, we demonstrate that DegU directly regulates the transcription of ptsI and hprK by binding to specific regions within their respective promoter sequences. Notably, the putative pivotal DegU binding sequence for ptsI is located from 38 to 68 base pairs upstream of the ptsH transcription start site (TSS), whereas for hprK, it is mapped from 36 to 124 base pairs upstream of the hprK TSS. In summary, we elucidate that DegU plays a significant role in suppressing carbohydrate uptake in response to oxidative stress through the direct regulation of ptsI and hprK.ImportanceUnderstanding the adaptive mechanisms employed by Listeria monocytogenes in harsh environments is of great significance. This study focuses on investigating the role of DegU in response to oxidative stress by examining global transcriptional profiles. The results highlight the noteworthy involvement of DegU in this stress response. Specifically, DegU acts as a direct sensor of oxidative stress, leading to the modulation of gene transcription. It downregulates ptsI transcription while it upregulates hprK transcription through direct binding to their promoters. Consequently, these regulatory actions impede bacterial growth, providing a defense mechanism against stress-induced damage. These findings gained from this study may have broader implications, serving as a reference for studying adaptive mechanisms in other pathogenic bacteria and aiding in the development of targeted strategies to control L. monocytogenes and ensure food safety.

Atypical primary central nervous system lymphoma and glioblastoma: multiparametric differentiation based on non-enhancing volume, apparent diffusion coefficient, and arterial spin labeling.

OBJECTIVES: To evaluate the multiparametric diagnostic performance with non-enhancing tumor volume, apparent diffusion coefficient (ADC), and arterial spin labeling (ASL) to differentiate between atypical primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM). METHODS: One hundred and fifty-eight patients with pathologically confirmed typical PCNSL (n = 59), atypical PCNSL (hemorrhage, necrosis, or heterogeneous contrast enhancement, n = 29), and GBM (n = 70) were selected. Relative minimum ADC (rADCmin), mean (rADCmean), maximum (rADCmax), and rADCmax-min (rADCdif) were obtained by standardization of the contralateral white matter. Maximum cerebral blood flow (CBFmax) was obtained according to the ASL-CBF map. The regions of interests (ROIs) were manually delineated on the inner side of the tumor to further generate a 3D-ROI and obtain the non-enhancing tumor (nET) volume. The area under the curve (AUC) was used to evaluate the diagnostic performance. RESULTS: Atypical PCNSLs showed significantly lower rADCmax, rADCmean, and rADCdif than that of GBMs. GBMs showed significantly higher CBFmax and nET volume ratios than that of atypical PCNSLs. Combined three-variable models with rADCmean, CBFmax, and nET volume ratio were superior to one- and two-variable models. The AUC of the three-variable model was 0.96, and the sensitivity and specificity were 90% and 96.55%, respectively. CONCLUSION: The combined evaluation of rADCmean, CBFmax, and nET volume allowed for reliable differentiation between atypical PCNSL and GBM. KEY POINTS: • Atypical PCNSL is easily misdiagnosed as glioblastoma, which leads to unnecessary surgical resection. • The nET volume, ADC, and ASL-derived parameter (CBF) were lower for atypical PCNSL than that for glioblastoma. • The combination of multiple parameters performed well (AUC = 0.96) in the discrimination between atypical PCNSL and glioblastoma.

The effect of O-antigen length determinant wzz on the immunogenicity of Salmonella Typhimurium for Escherichia coli O2 O-polysaccharides delivery.

Attenuated Salmonella Typhimurium is a promising antigen delivery system for live vaccines such as polysaccharides. The length of polysaccharides is a well-known key factor in modulating the immune response induced by glycoconjugates. However, the relationship between the length of Lipopolysaccharide (LPS) O-antigen (OAg) and the immunogenicity of S. Typhimurium remains unclear. In this study, we assessed the effect of OAg length determined by wzzST on Salmonella colonization, cell membrane permeability, antimicrobial activity, and immunogenicity by comparing the S. Typhimurium wild-type ATCC14028 strain to those with various OAg lengths of the ΔwzzST mutant and ΔwzzST::wzzECO2. The analysis of the OAg length distribution revealed that, except for the very long OAg, the short OAg length of 2-7 repeat units (RUs) was obtained from the ΔwzzST mutant, the intermediate OAg length of 13-21 RUs was gained from ΔwzzST::wzzECO2, and the long OAg length of over 20 RUs was gained from the wild-type. In addition, we found that the OAg length affected Salmonella colonization, cell permeability, and antibiotic resistance. Immunization of mice revealed that shortening the OAg length by altering wzzST had an effect on serum bactericidal ability, complement deposition, and humoral immune response. S. Typhimurium mutant strain ΔwzzST::wzzECO2 possessed good immunogenicity and was the optimum option for delivering E. coli O2 O-polysaccharides. Furthermore, the attenuated strain ATCC14028 ΔasdΔcrpΔcyaΔrfbPΔwzzST::wzzECO2-delivered E. coli O2 OAg gene cluster outperforms the ATCC14028 ΔasdΔcrpΔcyaΔrfbP in terms of IgG eliciting, cytokine expression, and immune protection in chickens. This study sheds light on the role of OAg length in Salmonella characteristics, which may have a potential application in optimizing the efficacy of delivered polysaccharide vaccines.

Perioperative Brain Injury in Children with Aortic Arch Anomalies: A Retrospective Study of Risk Factors and Outcomes.

Complex pediatric cardiac disease is associated with brain impairment and neurodevelopmental disorders, particularly in patients requiring cardiac surgery for aortic arch anomalies. This study examines the incidence, risk factors, and outcomes of perioperative brain injury in children undergoing aortic arch repair who had aortic arch anomalies. A total of 145 children with aortic arch anomalies in our center undergoing aortic arch repair between January 2014 and December 2022 were enrolled. There were 129 (89.0%) with coarctation of the aorta (COA) and 16 (9.7%) with interrupted aortic arch (IAA). Risk factor analysis of brain injuries was done using perioperative imaging and included symptoms of hemorrhagic stroke, arterial ischemic stroke, white matter injury, cerebral sinus venous thrombosis, and other pathologies. Preoperatively, 50/145 (34.5%) patients had brain injuries. Multivariate analysis showed that an increased risk of hemorrhagic stroke was associated with newborns (odds ratio [OR], 2.09 [95% CI 0.08-3.50]), isolated COA (OR, 3.69 [95% CI 1.23-7.07]), mechanical ventilation (MV) ([OR, 2.56 [95% CI 1.25-4.03]), and sepsis (OR, 1.73 [95% CI 0.46-3.22]). Newborns ([OR, 1.91 [95% Cl 0.58-3.29]) and weight-for-age z score ([OR, -0.45 [95% CI -0.88 to -0.1]) were associated with an increased risk of white matter injury. New postoperative brain injuries were present in 12.9% of the patients (16/124). Deep hypothermic circulatory arrest (DHCA) was associated with new postoperative brain injuries compared with deep hypothermic low-flow (DHLF) plus antegrade cerebral perfusion (ACP) (([OR, 2.67 [95% CI, 0.58-5.75])). Isolated COA was almost associated with new postoperative brain injuries (OR, 1.13 [95% CI, -0.04 to 2.32]). Children diagnosed with isolated COA appeared to have a higher risk of perioperative brain injury, but the underlying mechanisms are still unclear. We focused on the intrinsic mechanism by which changes in hemodynamics caused by COA result in perioperative brain injury. Further research will be needed to optimize the personalized treatment and cerebral perfusion techniques for complex pediatric cardiac surgery.

Aberrant Spontaneous Brain Activity and its Association with Cognitive Function in Non-Obese Nonalcoholic Fatty Liver Disease: A Resting-State fMRI Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been proven to be associated with an increased risk of cognitive impairment and dementia, and this association is more significant in non-obese NAFLD populations, but its pathogenesis remains unclear. Our study aimed to explore the abnormalities of spontaneous brain activity in non-obese NAFLD patients by resting-state fMRI (RS-fMRI) and their relationship with cognitive function. METHODS: 19 non-obese NAFLD, 25 obese NAFLD patients, and 20 healthy controls (HC) were enrolled. All subjects underwent RS-fMRI scan, psychological scale assessment, and biochemical examination. After RS-fMRI data were preprocessed, differences in low-frequency fluctuation amplitude (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were compared among the three groups. Furthermore, the relationship between RS-fMRI indicators and cognitive and clinical indicators were performed using correlation analysis. RESULTS: The cognitive function was declined in both NAFLD groups. Compared with obese NAFLD patients, non-obese NAFLD patients showed increased ALFF and ReHo in the left middle temporal gyrus (MTG), increased ReHo in the sensorimotor cortex and reduced FC between left MTG and right inferior frontal gyrus (IFG). Compared with HC, non-obese NAFLD patients showed increased ALFF and ReHo in the left calcarine cortex and fusiform gyrus (FG), decreased ALFF in the bilateral cerebellum, and reduced FC between left FG and right IFG and left angular gyrus. In addition to the same results, obese patients showed increased activity in different regions of the bilateral cerebellum, while decreased ALFF in the right superior frontal gyrus and ReHo in the right orbitofrontal cortex (OFC). Correlation analysis showed that in non-obese patients, the ALFF values in the FG and the FC values between the left MTG and the right IFG were associated with cognitive decline, insulin resistance, and fasting glucose disorder. CONCLUSIONS: Non-obese NAFLD patients showed abnormal local spontaneous activity and FC in regions involved in the sensorimotor, temporo-occipital cortex, cerebellum, and reward system (such as OFC), some of which may be the potential neural mechanism difference from obese NAFLD patients. In addition, the temporo-occipital cortex may be a vulnerable target for cognitive decline in non-obese NAFLD patients.

Association analysis of PLIN2 gene polymorphisms and lambing performance in Qianbei Ma goats.

Qianbei Ma goats are one of the three most valued local goat breeds in Guizhou, China; furthermore, it has lower litter size performance. The purpose of this study was to explore the correlation between SNP (single-nucleotide polymorphisms) of PLIN2 gene and lambing performance. The bioinformatics analysis, DNA sequencing, RT-qPCR and correlation analysis methods were used to analyse the evolutionary relationship of PLIN2 protein in 13 species, to detect the expression pattern of PLIN2 gene in the gonad axis of Qianbei sheep, to explore the dominant genotype of PLIN2 related to lambing traits and to screen molecular markers related to lambing performance to guide the breeding of Qianbei Ma goats. Results showed that the Qianbei Ma goat PLIN2 protein had the closest genetic relationship with sheep and the furthest from mice, there were significant or extremely significant differences in the expression levels of the PLIN2 gene in the gonadal axis of the mothers of single- and multi-lamb groups. Compared with the reference sequence, four SNPs were found, which were g.1006 C → A and g.1171 A → G in the first and second intron regions of the PLIN2 gene, g.8514 C → T in the exon 8 region and g.9122 A → T in the 3'UTR. The correlation analysis showed that g.1006 C → A, g.8514 C → T and g.9122 A → T had significant indigenous effects on the lambing performance of Qianbei Ma goats (p < .05). The number of third births for diploid H2H5 was significantly higher than that of diploid H1H2, and the number of first to third births for diploid H2H5 was large and stable. The results showed that PLIN2 gene could be used as a candidate gene related to lambing traits of Qianbei Ma goat.

Reconstructed magnetic resonance image-based effusion volume assessment for temporomandibular joint arthralgia.

BACKGROUND: Joint effusion is often noticed in magnetic resonance image (MRI) and its diagnostic value for arthralgia of the temporomandibular joint (TMJ) remains obscure. OBJECTIVE: To develop a method for quantitatively evaluating the joint effusion revealed in MRI and its diagnostic value for arthralgia of the TMJ. METHODS: Two-hundreds and twenty-eight TMJs, 101 with arthralgia (Group P) and 105 without (Group NP) from 103 patients, and 22 TMJs (Group CON) from 11 asymptomatic volunteers were examined by using MRI. The effusion volume was measured after constructing a three-dimensional structure of the joint effusion revealed in MRI by using the ITK-SNAP software. The diagnostic capabilities of the effusion volume on arthralgia were evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: Totally 146 joints showed MRI signs of joint effusion, including nine joints from Group CON. However, the medium volume was greater in Group P (66.65 mm3 ), but was much similar in Group CON (18.33 mm3 ) to Group NP (27.12 mm3 ). The effusion volume larger than 38.20 mm3 was validated to discriminate Group P from Group NP. The AUC value was 0.801 (95% CI 0.728 to 0.874), with a sensitivity of 75% and specificity of 78.9%. The median volume of the joint effusion was larger in those with than without bone marrow oedema, osteoarthritis, Type-III disc configurations, disc displacement and higher signal intensity of the retrodiscal tissue (all, p < .05). CONCLUSION: The present method for evaluate joint effusion volume well discriminated painful TMJs from non-pain ones.

Effect of ultrasound-supported wound debridement in subjects with diabetic foot ulcers: A meta-analysis.

A meta-analysis study to assess the effect of ultrasound-supported wound debridement (USSD) in subjects with diabetic foot ulcer (DFU). A comprehensive literature examination till January 2023 was implemented and 1873 linked studies were appraised. The picked studies contained 577 subjects with DFUs in the studies' baseline, 282 of them were using USSD, 204 were using standard care, and 91 were using a placebo. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of USSD in subjects with DFUs by the dichotomous styles and a fixed or random effect model. The USSD applied to DFU caused a significantly higher wound healing rate compared with the standard care (OR, 3.08; 95% CI, 1.94-4.88, P < .001) with no heterogeneity (I2  = 0%) and the placebo (OR, 7.61; 95% CI, 3.11-18.63, P = .02) with no heterogeneity (I2  = 0%). The USSD applied to DFUs caused a significantly higher wound healing rate compared with the standard care and the placebo. Though precautions should be taken when commerce with the consequences as all of the picked studies for this meta-analysis was with low sample sizes.

Glaucocalyxin a prevents hypoxia-induced epithelial-mesenchymal transition in human gastric cancer cells through the PI3K/Akt signaling pathway.

Hypoxia is a frequent occurrence in most solid tumors and associated with multiple cancer progression. Glaucocalyxin A (GLA) has been found to exhibit anti-tumor effect in several types of cancer, except gastric cancer (GC). The present study aimed to evaluate the function of GLA in GC and explore the underlying mechanism under hypoxia condition. Our results showed that GLA suppressed cell viability of MGC-803 cells in both normoxic or hypoxic conditions. MGC-803 cells were more sensitive to GLA in hypoxic condition. GLA attenuated hypoxia-induced migration and invasion of GC cells. Western blot assay proved that GLA elevated E-cadherin expression, as well reduced N-cadherin and vimentin expressions in hypoxia-induced GC cells. Moreover, we also found that GLA suppressed the expression of HIF-1α in both mRNA and protein levels. Furthermore, GLA blocked hypoxia-induced activation of PI3K/Akt pathway in GC cells. Notably, insulin like growth factor 1 (IGF-1), an activator of PI3K/Akt pathway, reversed the effects of GLA on cell migration, invasion and EMT in hypoxia-treated MGC-803 cells. In conclusion, these findings demonstrated that GLA exerted inhibitory effects on cell migration, invasion and epithelial to mesenchymal transition (EMT) via the PI3K/Akt signaling pathway in GC cells.

Optimal Convergence Analysis of Two-Level Nonconforming Finite Element Iterative Methods for 2D/3D MHD Equations.

Several two-level iterative methods based on nonconforming finite element methods are applied for solving numerically the 2D/3D stationary incompressible MHD equations under different uniqueness conditions. These two-level algorithms are motivated by applying the m iterations on a coarse grid and correction once on a fine grid. A one-level Oseen iterative method on a fine mesh is further studied under a weak uniqueness condition. Moreover, the stability and error estimate are rigorously carried out, which prove that the proposed methods are stable and effective. Finally, some numerical examples corroborate the effectiveness of our theoretical analysis and the proposed methods.

Simvastatin protects heart function and myocardial energy metabolism in pulmonary arterial hypertension induced right heart failure.

The favorable effect of simvastatin on pulmonary arterial hypertension (PAH) has been well defined despite the unknown etiology of PAH. However, whether simvastatin exerts similar effects on PAH induced right heart failure (RHF) remains to be determined. We aimed to investigate the function of simvastatin in PAH induced RHF. Rats in the RHF and simvastatin groups were injected intraperitoneally with monocrotaline to establish PAH-induced RHF model. The expression of miR-21-5p in rat myocardium was detected and miR-21-5p expression was inhibited using antagomiRNA. The effect of simvastatin on hemodynamic indexes, ventricular remodeling of myocardial tissues, myocardial energy metabolism, and calmodulin was explored. Dual-luciferase reporter system was used to verify the binding relationship between miR-21-5p and Smad7. In addition, the regulatory role of simvastatin in Smad7, TGFBR1 and Smad2/3 was investigated. Simvastatin treatment improved hemodynamic condition, myocardial tissue remodeling, and myocardial energy metabolism, as well as increasing calmodulin expression in rats with PAH-induced RHF. After simvastatin treatment, the expression of miR-21-5p in myocardium of rats was decreased significantly. miR-21-5p targeted Smad7 and inhibited the expression of Smad7. Compared with RHF rats, the expressions of TGFBR1 and Smad2/3 in myocardium of simvastatin-treated rats were decreased significantly. Collectively, we provided evidence that simvastatin can protect ATPase activity and maintain myocardial ATP energy reserve through the miR-21-5p/Smad/TGF-ß axis, thus ameliorating PAH induced RHF.

Comparing the characteristics and predicting the survival of patients with head and neck melanoma versus body melanoma: a population-based study.

BACKGROUND: Previous studies reported cutaneous melanoma in head and neck (HNM) differed from those in other regions (body melanoma, BM). Individualized tools to predict the survival of patients with HNM or BM remain insufficient. We aimed at comparing the characteristics of HNM and BM, developing and validating nomograms for predicting the survival of patients with HNM or BM. METHODS: The information of patients with HNM or BM from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The HNM group and BM group were randomly divided into training and validation cohorts. We used the Kaplan-Meier method and multivariate Cox models to identify independent prognostic factors. Nomograms were developed via the rms and dynnom packages, and were measured by the concordance index (C-index), the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and calibration plots. RESULTS: Of 70,605 patients acquired, 21% had HNM and 79% had BM. The HNM group contained more older patients, male sex and lentigo maligna melanoma, and more frequently had thicker tumors and metastases than the BM group. The 5-year cancer-specific survival (CSS) and overall survival (OS) rates were 88.1 ± 0.3% and 74.4 ± 0.4% in the HNM group and 92.5 ± 0.1% and 85.8 ± 0.2% in the BM group, respectively. Eight variables (age, sex, histology, thickness, ulceration, stage, metastases, and surgery) were identified to construct nomograms of CSS and OS for patients with HNM or BM. Additionally, four dynamic nomograms were available on web. The internal and external validation of each nomogram showed high C-index values (0.785-0.896) and AUC values (0.81-0.925), and the calibration plots showed great consistency. CONCLUSIONS: The characteristics of HNM and BM are heterogeneous. We constructed and validated four nomograms for predicting the 3-, 5- and 10-year CSS and OS probabilities of patients with HNM or BM. These nomograms can serve as practical clinical tools for survival prediction and individual health management.

Expression and localization of Sox10 during hair follicle morphogenesis and induced hair cycle.

Sox transcription factors play many diverse roles during development, including regulating stem cell states, directing differentiation, and influencing the local chromatin landscape. Sox10 has been implicated in the control of stem/progenitor activity and epithelial-mesenchymal transition, yet it has not been studied in relation to the hair follicle cycle or hair follicle stem cell (HFSC) control. To elucidate the role of Sox10 in hair follicle cycle control, we performed immunohistochemical and immunofluorescence analysis of its expression during hair morphogenesis, the postnatal hair cycle, and the depilation-induced murine hair follicle cycle. During hair follicle morphogenesis, Sox10 was expressed in the hair germ and peg. In telogen, we detected nuclear Sox10 in the hair bulge and germ cell cap, where HFSCs reside, while in anagen and catagen, Sox10 was detected in the epithelial portion, such as the strands of keratinocytes, the outer root sheath (ORS) in anagen, and the regressed epithelial strand of hair follicle in catagen. These results suggest that Sox10 may be involved in early hair follicle morphogenesis and postnatal follicular cycling.