Assessing the accuracy of CMRtools software for diagnosing liver iron overload in thalassemia patients: influencing factors and optimisation strategies.

Background: CMRtools is a software package that can be used to measure T2* values to diagnose liver iron overload, however, its accuracy in terms is affected by multiple factors, including goodness-of-fit (R2 value), the number of echo time (TE) images, and the liver iron concentration (LIC). To investigate the effects of the R2 value, the number of TE images, and the LIC on the accuracy of CMRtools software for measuring T2* values to diagnose liver iron overload (LIO). Materials and methods: CMRtools software was used to measure liver T2* values among 108 thalassemia patients via the truncation method, and the R2 values, the number of TE images, and T2* values were recorded. These values were subsequently converted into liver iron concentration (LICT) values. The LICF (derived from MRI-R2/FerriScan) was used as a reference, and the diagnostic accordance rate (DAR) was compared between R2 value subgroups, between TE image number subgroups, and between LIC subgroups. Results: The greater the R2 value was, the greater the standardized DAR (SDAR) was (p < 0.05). The SDAR are not identical between each TE image number subgroup (p > 0.05). However, the relationship between TE image number subgroups and SDAR was analysed using Spearman's correlation, and it was found to be positively correlated (rs = 0.729, p = 0.017). The SDAR are not identical between each LIC subgroup (p > 0.05), furthermore, the relationship between LIC subgroup and SDAR was found irrelevant (p = 0.747). Conclusion: The accuracy of CMRtools software for diagnosing LIO in patients with thalassemia can be improved by artificially controlling the number of TE images to be fitted and selecting higher R2 values.

Visual assessment and quantitative analysis of dual-energy CT virtual non-calcium in imaging diagnosis of multiple myeloma.

OBJECTIVE: To evaluate the reliability and diagnostic performance of dual-energy CT virtual non-calcium imaging in diagnosing bone marrow infiltration in multiple myeloma. MATERIALS AND METHODS: Seventy-two patients with multiple myeloma and ten controls were recruited. Patients received dual-energy CT and MRI while controls underwent dual-energy CT only, covering the cervical, thoracic, and lumbar spine and the pelvis. Virtual non-calcium images were compared with magnetic resonance images for confirmation and pattern classification. Fleiss Kappa analysis assessed consistency between virtual non-calcium and MRI classifications. Inter-observer agreement for virtual non-calcium and CT attenuation values was evaluated using Bland-Altman analysis. Diagnostic performances across various sites were evaluated using analysis of variance and receiver operating characteristic curve analysis. RESULTS: Dual-energy CT achieved higher consistency in classifying bone marrow infiltration in multiple myeloma than did MRI (kappa = 0.944). In the overall analysis, the mean virtual non-calcium attenuation values in the bone marrow infiltration group (- 28.3 HU; 95% confidence interval (CI), - 32.1, - 24.6) were higher than those in the non-bone marrow infiltration (- 97.5 HU; 95% CI, - 104.7, - 90.3) and control (- 89.1 HU; 95% CI, - 95.1, - 83.1; F = 172.027, P < 0.001) groups. The optimal cutoff values for virtual non-calcium attenuation varied across the overall (- 42.2 HU), cervical spine (- 21.9 HU), thoracic spine (- 42.8 HU), lumbar spine (- 56.9 HU), and pelvis (- 66.3 HU). CONCLUSION: Dual-energy CT virtual non-calcium imaging and MRI exhibited good consistency in categorising bone marrow infiltration patterns in multiple myeloma. Different virtual non-calcium attenuation value cutoffs should be used to diagnose bone marrow infiltration in various body regions.

Organ-Specific Iron Overload in Non-Transfusion-Dependent Thalassemia Patients: Insights from Quantitative MRI Evaluation.

OBJECTIVE: To elucidate the iron load in different organs of non-transfusion-dependent thalassemia (NTDT) patients using magnetic resonance imaging (MRI) T2* scan. METHODS: Thirty-four NTDT patients, including 28 NTDT iron chelation without and 6 NTDT with iron chelation, together with 15 normal controls, underwent MRI examination between December 2022 and July 2024 were enrolled in the study. Measured T2* of the pituitary gland, kidney cortex, heart, liver, pancreas, spleen. Liver and spleen volumes were evaluated. RESULTS: Of the 28 patients in NTDT without iron chelation group, 19 patients with iron overload in the liver, 9 patients with iron overload in the kidneys, and 4 patients with iron overload in the spleen. Most patients with abnormal kidney and spleen iron (76.9 %) had liver iron overload. Compared with the control group, NTDT without iron chelation patients had lower T2* in the liver, kidney, and spleen (p < 0.05). And heart T2* was correlated with kidney T2* (r = 0.480, p = 0.010) and pancreas (r = 0.411, p = 0.037). Liver T2* was correlated with spleen T2* (r = 0.479, p = 0.011). Pancreas T2* was correlated with pituitary T2* (r = -0.433, p = 0.031). CONCLUSIONS: NTDT patients exhibit significant organ-specific iron overload, particularly in the liver, kidneys, and spleen. The correlations between iron levels in different organs suggest interconnected mechanisms of iron accumulation. These findings highlight the importance of regular MRI screening to monitor and manage iron overload in NTDT patients.

Assessing the causal relationship between gut microbiota and prostate cancer: A two-sample Mendelian randomization study.

BACKGROUND: Numerous studies indicate that the gut microbiome is closely associated with prostate cancer (PCa), however, owing to various confounding factors, the causal relationship between gut microbiota and PCa remains unclear. METHODS: A 2-sample Mendelian randomization (MR) analysis utilized genome-wide association study (GWAS) data on the gut microbiota of 18,340 participants and GWAS summary statistics on PCa involving 46,3010 participants. Inverse variance weighted (IVW) served as the primary method, complemented by the MR-Egger method, weighted median method (WME), simple mode method (SM), and weighted mode method (WM). Finally, to confirm the robustness of the results, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test were conducted. RESULTS: IVW analysis revealed that 12 specific gut microbial taxa were potentially causally associated with PCa; the genera Victivallis, Akkermansia, Odoribacter, Butyrivibrio, and the families Enterobacteriaceae, Verrucomicrobiaceae, as well as the orders Verrucomicrobiales, Enterobacteriales and the class Verrucomicrobiae, were found to be positively associated with PCa risk. Conversely, the genera Eubacterium ruminantium group, Candidatus Soleaferrea, and RuminococcaceaeUCG003 were negatively associated with PCa risk. CONCLUSIONS: Our MR study's results support a genetically predicted causal relationship between the gut microbiota and PCa, and we identified 12 specific gut microbial taxa. These findings could offer new targets for PCa screening and treatment.

The efficacy and safety of tofacitinib in anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis associated interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: The presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies in dermatomyositis (DM) is associated with an increased risk of developing rapidly progressive interstitial lung disease (RP-ILD) and a poor prognosis. OBJECTIVES: We aimed to explore whether tofacitinib could improve the prognosis of Anti-MDA5 antibody positive DM-interstitial lung disease (ILD). DESIGN: Systematic review and meta-analysis. DATA SOURCES AND METHODS: Studies were included if they compared mortality rate and infection events in patients with anti-MDA5 antibody positive DM-associated ILD who were treated with or without tofacitinib. RESULTS: The systematic review and meta-analysis included a total of 148 patients from four cohort studies. Fifty-eight patients with anti-MDA5 antibody positive DM-ILD who received combined treatment-containing tofacitinib were enrolled in the experimental group. Additionally, 90 DM-ILD patients who did not receive tofacitinib-based therapy were included in the control group. The pooled risk ratio (RR) for all-cause mortality was 0.61 (95% CI, 0.41-0.91, p = 0.02) with I2 = 0 indicating no heterogeneity among the included studies. For virus infection risk, the pooled RR was 1.92 (95% CI, 0.90-4.10, p = 0.09), while bacterial and fungal infection-associated RRs were found to be 1.29 (95% CI, 0.65-2.55, p = 0.47) and 1.15 (95% CI, 0.46-2.89, p = 0.77), respectively. There was no statistically significant difference in infection risk between the two groups, and no heterogeneity was observed. CONCLUSION: Our findings suggest that tofacitinib may reduce the risk of all-cause mortality in patients with anti-MDA5 antibody-positive DM-ILD without an increased risk of additional infections. TRIAL REGISTRATION: PROSPERO: CRD42023445427; https://www.crd.york.ac.uk/prospero/.

Tofacitinib is being utilized in the treatment of a type of dermatomyositis-associated rapidly progressive interstitial lung diseaseWhy was the study conducted? Currently, despite the utilization of conventional treatments for anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM)-associated interstitial lung disease (ILD), the 6-month mortality rate still remains alarmingly high. Therefore, it is imperative for us to explore novel therapeutic approaches aiming at controlling the rapid progression of this disease.What did the researchers do? The research team explored mortality rates and infection events in patients with anti-MDA5 antibody-positive DM­ILD who were treated with or without tofacitinib.What did the researchers find? Our study revealed that tofacitinib resulted in a significant reduction in the risk of all-cause mortality. When considering infection risk, there was no statistically significant difference observed in terms of viral, bacterial, or fungal infections compared with the control group.What do the findings mean? Our study suggests that tofacitinib demonstrates both efficacy and safety in treating anti-MDA5 positive DM-ILD.

Computed tomography image quality in patients with primary hepatocellular carcinoma: intraindividual comparison of contrast agent concentrations.

Objective: This study aimed to assess the impact of the different concentrations of iodine contrast agents used on the quality of computed tomography (CT) images obtained intraindividually in hepatocellular carcinoma patients. Methods: In this retrospective study, data from a cohort of 29 patients diagnosed with primary hepatocellular carcinoma who had undergone two preoperative CT-enhanced examinations within a 3-month timeframe were analyzed. Each patient was randomly assigned to receive either a low-concentration contrast agent (300 mg I/mL iohexol) or a high-concentration contrast agent (350 mg I/mL iohexol) for the first scan and the alternative contrast agent for the second scan. CT images of different liver regions of each patient were compared between low-and high-concentration scans using their before-and-after control design. Subjective image quality scores for portal vein images were also assessed. Results: The findings of this study indicate that patients in the high-concentration group presented significantly elevated CT values across various anatomical regions, including the liver parenchyma, abdominal aorta, and hepatic portal vein, compared to those in the low-concentration group (p < 0.05). Moreover, the high-concentration group demonstrated superior subjective image ratings (p < 0.05). Nevertheless, there was no statistically significant difference in the CT values observed in liver cancer parenchyma scans at different phases between the two groups (p > 0.05). Conclusion: In summary, using a high-concentration iodine contrast agent is efficient in enhancing the visual clarity of the liver parenchyma, the aorta, and the portal vein in individuals diagnosed with primary hepatocellular carcinoma.

Effects of Electrochemical Hydrogen Charging Parameters on the Mechanical Behaviors of High-Strength Steel.

Extended exposure to seawater results in the erosion of the structural high-strength steels utilized in marine equipment, primarily due to the infiltration of hydrogen. Consequently, this erosion leads to a decrease in the mechanical properties of the material. In this investigation, the mechanical responses of Q690 structural high-strength steel specimens were investigated by considering various hydrogen charging parameters, such as the current density, charging duration, and solution concentration values. The findings highlighted the significant impacts of electrochemical hydrogen charging parameters on the mechanical behaviors of Q690 steel samples. Specifically, a linear relationship was observed between the mechanical properties and the hydrogen charging current densities, while the associations with the charging duration and solution concentration were nonlinear. Additionally, the fracture morphology under various hydrogen charging parameters was analyzed and discussed. The results demonstrate that the mechanical properties of the material degrade with increasing hydrogen charging parameters, with tensile strength and yield stress decreasing by approximately 2-4%, and elongation after fracture reducing by about 20%. The findings also reveal that macroscopic fractures exhibit significant necking in uncharged conditions. As hydrogen charging parameters increase, macroscopic necking gradually diminishes, the number of microscopic dimples decreases, and the material ultimately transitions to a fully brittle fracture.

Urolithin B inhibits the differentiation of M1 macrophages and relieves the inflammation around the implants under osteoporosis via down-regulating the phosphorylation of VEGFR2.

The inflammation causes the destroyed osseointegration at the implant-bone interface, significantly increasing the probability of implant loosening in osteoporotic patients. Currently, inhibiting the differentiation of M1 macrophages and the inflammatory response could be a solution to stabilize the microenvironment of implants. Interestingly, some natural products have anti-inflammatory and anti-polarization effects, which could be a promising candidate for stabilizing the implants' microenvironment in osteoporotic patients. This research aims to explore the inhibitory effect of Urolithin B(UB) on macrophage M1 polarization, which ameliorates inflammation, thus alleviating implant instability. We established an osteoporosis mouse model of implant loosening. The mouse tissues were taken out for morphological analysis, staining analysis, and bone metabolic index analysis. In in vitro experiments, RAW264.7 cells were polarized to M1 macrophages using lipopolysaccharide (LPS) and analyzed by immunofluorescence (IF) staining, Western blot (WB), and flow cytometry. The CSP100 plus chip experiments were used to explore the potential mechanisms behind the inhibiting effects of UB. Through observation of these experiments, UB can improve the osseointegration between the implants and femurs in osteoporotic mice and enhance the stability of implants. The UB can inhibit the differentiation of M1 macrophages and local inflammation via inhibiting the phosphorylation of VEGFR2, which can be further proved by the weakened inhibited effects of UB in macrophages with lentivirus-induced overexpression of VEGFR2. Overall, UB can specifically inhibit the activation of VEGFR2, alleviate local inflammation, and improve the stability of implants in osteoporotic mice.

Quantification of Cardiac Iron Overload at 3 T MRI in a Rabbit Model Utilizing ME-GRE T2* Sequence.

BACKGROUND: Myocardial iron overload can lead to myocardial dysfunction, muscle cell injury, and end-stage heart failure. The enhanced signal-to-noise ratio and technical advancements have made 3 T magnetic resonance imaging (MRI) more accessible in clinical settings. However, 3 T assessments for early diagnosis of myocardial iron overload are scarce. PURPOSE: To evaluate the feasibility of myocardial iron quantification using 3 T MRI in a rabbit model of iron overload. STUDY TYPE: Animal model. ANIMAL MODEL: Overall, 40 male New Zealand white rabbits were categorized into control (N = 8; no treatment) and experimental (N = 32; weekly 200 mg/kg iron dextran injections) groups. SEQUENCE: 3 T MRI with multi-echo gradient echo (ME-GRE) T2* sequence. ASSESSMENT: Each week, two experimental rabbits were randomly selected for blood collection to determine serum iron (SI) levels; their tissue was harvested to assess myocardial and hepatic iron deposition. STATISTICAL TESTS: Spearman's rank correlation tests were used to evaluate the correlations among R2*, cardiac iron concentration (CIC), liver iron concentration (LIC), total amount of iron injected, and SI levels. P ≤ 0.05 was considered statistically significant. RESULTS: The myocardial T2* value in the experimental group was significantly lower than that of the control group. An excellent correlation was observed between R2* values and CIC (r = 0.854). CIC moderately correlated with LIC (r = 0.712) and the total amount of iron injected (r = 0.698). A strong correlation was observed between the total amount of iron injected and LIC (r = 0.866). SI levels poorly correlated with the total amount of iron injected (r = 0.205, P = 0.277) and LIC (r = 0.170, P = 0.370) but fairly correlated with CIC (r = 0.415, P = 0.022). DATA CONCLUSION: A 3 T MRI with an ME-GRE sequence may serve as a noninvasive method for evaluating cardiac iron content. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: Stage 1.

Abdominal multi-organ iron content and the risk of Parkinson's disease: a Mendelian randomization study.

Background: To evaluate the causal relationship between abdominal multi-organ iron content and PD risk using publicly available genome-wide association study (GWAS) data. Methods: We conducted MR analysis to assess the effects of iron content in various abdominal organs on PD risk, followed by reverse analysis. Additionally, MVMR analysis evaluated the independent effects of organ-specific iron content on PD. We utilized genetic variation data from the UK Biobank, including liver iron content (n = 32,858), spleen iron content (n = 35,324), and pancreas iron content (n = 25,617), as well as summary-level data for Parkinson's disease from the FinnGen (n = 218,473) and two other large GWAS datasets of European populations (First dataset n = 480,018; Second dataset n = 2,829). The primary MR analysis used the inverse variance-weighted (IVW) method, confirmed by MR-Egger and weighted median methods. Sensitivity analysis was performed to address potential pleiotropy and heterogeneity. Observational cohort results were validated through replication cohort analysis, followed by meta-analysis. Results: IVW analysis revealed a causal relationship between increased liver iron content and elevated risk of PD (OR = 1.27; 95% CI: 1.05-1.53; p = 0.015). No significant causal relationship was observed between spleen (OR = 1.00; 95% CI: 0.76-1.32; p = 0.983) and pancreatic (OR = 0.93; 95% CI: 0.72-1.20; p = 0.573) iron content and increased risk of PD. Meta-analysis of GWAS data for PD from three different sources using the random-effects IVW method showed a statistically significant causal relationship between liver iron content and the occurrence of PD (OR = 1.17, 95% CI: 1.01-1.35; p = 0.012). Conclusion: This study presents evidence from Mendelian randomization (MR) analysis indicating a significant causal link between increased liver iron content and a higher risk of Parkinson's disease (PD). These findings suggest that interventions targeting body iron metabolism, particularly liver iron levels, may be effective in preventing PD.

A comprehensive analysis of TRP-related gene signature, and immune infiltration in patients with colorectal cancer.

BACKGROUND: Transient receptor potential (TRP) channels are involved in the development and progression of tumors. However, their role in colorectal cancer (CRC) remains unclear, and this study aims to investigate the role of TRP-related genes in CRC. METHODS: Data was obtained from The Cancer Genome Atlas (TCGA) database, and analyses were conducted on the GSE14333 and GSE38832 datasets to assess the prognosis and mark TRP-related genes (TRGs). Subsequently, clustering analysis and immune infiltration analysis were performed to explore the relevant TRGs. In vitro validation of key TRGs' gene and protein expression was conducted using human colon cancer cells. RESULTS: Compared to normal tissues, 8 TRGs were significantly upregulated in CRC, while 11 were downregulated. TRPA1 was identified as a protective prognostic factor, whereas TRPM5 (HR = 1.349), TRPV4 (HR = 1.289), and TRPV3 (HR = 1.442) were identified as prognostic risk factors. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analyses yielded similar results. Additionally, lower expression of TRPA1 and higher expression of TRPV4 and TRPM5 were negatively correlated with patient prognosis, and experimental validation confirmed the underexpression of TRPA1 and overexpression of TRPV4 and TRPM5 in CRC cell lines. CONCLUSION: This study identifies a TRP channel-related prognosis in CRC, providing a novel approach to stratifying CRC prognosis.

Left bundle branch pacing in third-degree atrioventricular block following morrow surgery: a case report.

Left bundle branch pacing (LBBP) has proven to be an alternative method for delivering physiological pacing to achieve electrical synchrony of the left ventricle (LV), especially in patients with atrioventricular block and left bundle branch block (LBBB). However, it is unclear whether it still achieved in patients whose left bundle branch (LBB) has had surgery-induced damage. The Morrow operation (Morrow septal myectomy) is regarded as one of the most effective treatments for hypertrophic obstructive cardiomyopathy (HOCM). The surgery resects small sections of muscle tissue in the proximal ventricular septum nearby or contains the LBB, which means that physical damage to the LBB is almost inevitable. Approximately 2%-12% of patients may need pacemaker implanted after Morrow surgery. LBBP is a feasible and effective method for achieving electric resynchronization of LBBB compared to right ventricular pacing (RVB). Nevertheless, there is a dearth of data on LBBP in third-degree atrioventricular block (AVB) following Morrow surgery. We report a case of successful LBBP in those patients.

Inhibition of endoplasmic reticulum stress and excessive autophagy by Jiedu Tongluo Tiaogan Formula via a CaMKKß/AMPK pathway contributes to protect pancreatic ß-cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiedu Tongluo Tiaogan Formula (JTTF), a traditional Chinese herbal decoction, exhibits the potential to treat type 2 diabetes mellitus (T2DM) by inhibiting endoplasmic reticulum stress (ERS) and excessive autophagy, which are the risk factors for the abnormal development and progression of ß cells. AIM OF THE STUDY: We aimed to assess the effect of JTTF on pancreatic glucotoxicity by inhibiting ERS and excessive autophagy, for which db/db mice and INS-1 insulinoma cells were used. MATERIALS AND METHODS: The chemical composition of the JTTF was analyzed by UPLC-Q/TOF-MS. Diabetic (db/db) mice were treated with distilled water or JTTF (2.4 and 7.2 g/kg/day) for 8 weeks. Furthermore, INS-1 cells induced by high glucose (HG) levels were treated with or without JTTF (50, 100, and 200 µg/mL) for 48 h to elucidate the protective mechanism of JTTF on glucose toxicity. The experimental methods included an oral glucose tolerance test, hematoxylin-eosin staining, immunohistochemistry, western blotting, RT-qPCR, and acridine orange staining. RESULT: 28 chemical components of JTTF were identified. Additionally, treatment with JTTF significantly decreased the severity of glycemic symptoms in the db/db mice. Moreover, the treatment partially restored glucose homeostasis in the db/db mice and protected the pancreatic ß-cell function. JTTF protected INS-1 cells from HG injury by upregulating GSIS and PDX1, MafA mRNA expression. Further, treatment with JTTF downregulated GRP78 and ATF6 expression, whereas it inhibited Beclin-1 and LC3 activation. The treatment protected the cells from HG-induced ERS and excessive autophagy by downregulating the CaMKKß/AMPK pathway. CONCLUSIONS: The present study findings show that JTTF may protects ß-cells by inhibiting the CaMKKß/AMPK pathway, which deepens our understanding of the effectiveness of JTTF as a treatment strategy against T2DM.

Association of different domains of physical activity with diabetic kidney disease: a population-based study.

Background: The aim of this cross-sectional study was to elucidate the associations between various domains of physical activity, such as occupation-related (OPA), transportation-related (TPA), leisure-time (LTPA) and overall physical activity (PA), and diabetic kidney disease. Methods: Our study encompassed 2,633 participants, drawn from the cross-sectional surveys of the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018, and employed survey-weighted logistic regression, generalized linear regression, and restricted cubic spline (RCS) analyses to ascertain the relationship between different domains of physical activity and diabetic kidney disease. Results: After controlling for all confounders, multivariate logistic regression analyses revealed a lack of correlation between the various domains of physical activity and the prevalence of diabetic kidney disease. Multiple generalized linear regression analyses showed that durations of PA (ß = 0.05, 95% CI, 0.01-0.09, P = 0.012) and TPA (ß = 0.32, 95% CI, 0.10-0.55, P = 0.006) were positively associated with eGFR levels; and LTPA durations were inversely associated with UACR levels (ß = -5.97, 95% CI, -10.50 - -1.44, P = 0.011). The RCS curves demonstrated a nonlinear relationship between PA, OPA, and eGFR, as well as a nonlinear correlation between PA and ACR. Subgroup and sensitivity analyses largely aligned with the outcomes of the multivariate generalized linear regression, underscoring the robustness of our findings. Conclusion: Our population-based study explored the association between different domains of physical activity and diabetic kidney disease. Contrary to our expectations, we found no significant association between the duration of physical activity across all domains and the prevalence of diabetic nephropathy. Nonetheless, renal function markers, including eGFR and UACR, exhibited significant correlations with the duration of total physical activity (TPA) and leisure-time physical activity (LTPA), respectively, among diabetic patients. Interestingly, our findings suggest that diabetic patients engage in physical activity to preserve renal function, ensuring moderate exercise durations not exceeding 35 hours per week.

Regulating neuronal excitability: The role of S-palmitoylation in NaV1.7 activity and voltage sensitivity.

S-palmitoylation, a reversible lipid post-translational modification, regulates the functions of numerous proteins. Voltage-gated sodium channels (NaVs), pivotal in action potential generation and propagation within cardiac cells and sensory neurons, can be directly or indirectly modulated by S-palmitoylation, impacting channel trafficking and function. However, the role of S-palmitoylation in modulating NaV1.7, a significant contributor to pain pathophysiology, has remained unexplored. Here, we addressed this knowledge gap by investigating if S-palmitoylation influences NaV1.7 channel function. Acyl-biotin exchange assays demonstrated that heterologously expressed NaV1.7 channels are modified by S-palmitoylation. Blocking S-palmitoylation with 2-bromopalmitate resulted in reduced NaV1.7 current density and hyperpolarized steady-state inactivation. We identified two S-palmitoylation sites within NaV1.7, both located in the second intracellular loop, which regulated different properties of the channel. Specifically, S-palmitoylation of cysteine 1126 enhanced NaV1.7 current density, while S-palmitoylation of cysteine 1152 modulated voltage-dependent inactivation. Blocking S-palmitoylation altered excitability of rat dorsal root ganglion neurons. Lastly, in human sensory neurons, NaV1.7 undergoes S-palmitoylation, and the attenuation of this post-translational modification results in alterations in the voltage-dependence of activation, leading to decreased neuronal excitability. Our data show, for the first time, that S-palmitoylation affects NaV1.7 channels, exerting regulatory control over their activity and, consequently, impacting rodent and human sensory neuron excitability. These findings provide a foundation for future pharmacological studies, potentially uncovering novel therapeutic avenues in the modulation of S-palmitoylation for NaV1.7 channels.

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain.

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

Sclerostin Transduced Bone Marrow Mesenchymal Stem Cells Promote Fracture Healing in Rats Through the Wnt/ß-Catenin Signal Pathway.

The prognosis of fracture is directly related to several factors. Due to the limitations of existing treatment strategies, there are still many fractures with poor healing. Bone marrow mesenchymal stem cells (BMSCs) have the potential to differentiate into osteoblasts and chondrocytes. Therefore, BMSC transplantation is promised as an effective method for treating bone fractures. We aim to explore whether silently expressing sclerostin gene (SOST) can promote bone formation through the SOST/Wnt/ß-catenin signal pathway. We isolated rat BMSCs and the target gene (SOST shRNA) was transduced into them for osteogenic induction. The results showed that SOST significantly inhibited the proliferation and osteogenic differentiation of BMSCs during osteogenic induction, whereas silently expressing SOST not only increased the number of surviving BMSCs but also promoted the expression of osteogenesis-related proteins RUNX2, osteoprotegerin, Collagen I (COL-I), and bone morphogenetic protein-2 during osteogenic induction. The results of imaging examination in rats show that downregulating the expression of SOST can promote the formation of bony callus and the transformation of cartilage tissue into normal bone tissue, and then accelerate the healing of osteoporotic fracture. In addition, we also found that SOST silencing can activate the Wnt/ß-catenin pathway to achieve these effects. In conclusion, SOST silencing can promote the proliferation and osteogenic differentiation of BMSCs in situ, and therefore may enhance the therapeutic efficiency of BMSC transplantation in OPF.

Temperature-Induced Variations in Slip Behavior of Single Crystal Aluminum: Microstructural Analysis.

The simultaneous increase in strength and plasticity of aluminum and its alloys at cryogenic temperatures has been shown in previous research, but the deformation mechanism was still unclear. Therefore, the purpose of this investigation was to reveal the relationship between slip behavior and mechanical response at low temperatures. A quasi-in situ scanning electron microscope was used to observe the evolution of slip bands in the selected aluminum single crystals with two typical orientations at 25 °C, -100 °C, and -180 °C. The results showed that irrespective of orientation, the density of the slip plane was increased with the decline in temperature, which inhibited slip localization and significantly improved plasticity and work hardening. In detail, at RT, the slip bands were widening until the micro-cracks were generated, causing early failure during deformation. When the temperature was decreased to -180 °C, the slip plane density was increased, and the deformation was more homogenous. Moreover, the slip mode was influenced by orientation and temperature. In particular, a single slip system was activated in the sample with the [112] orientation at all the temperatures investigated. Multiple slip systems were found to activate at 25 °C and -100 °C, and only the primary slip system was activated in the sample with [114] orientation at -180 °C. These findings deepen the understanding of slip behavior at cryogenic temperatures, providing new insights into the deformation mechanism of aluminum and its alloys.

Mineralization of SF6 and NF3 fluorinated compounds for greenhouse gas abatement by oxalates.

Fluorinated compounds (FCs) such as sulfur hexafluoride (SF6) and nitrogen trifluoride (NF3) have garnered attention due to their environmental impact. This study investigates the mineralization and removal of two potent FCs: SF6 and NF3. The results confirm that utilizing various oxalate salts leads to the formation of corresponding metallic fluorides: lithium fluoride (LiF), sodium fluoride (NaF), and potassium fluoride (KF), validating the occurrence of mineralization reactions. Among the oxalate salts, sodium oxalate demonstrates the highest mineralization efficiency in both SF6 and NF3 removal. Real-time Fourier transform infrared spectroscopy (FT-IR) gas-phase analysis confirms rapid and complete gas removal within a short reaction time using the selected oxalate salts. Meticulous mass balance calculations revealed that oxalates (LiF, NaF, and KF) yielded sulfur (S) at rates of 92.09%, 91.85%, and 84.98% following SF6 mineralization. Additionally, the conversion rates of oxalates to the corresponding metallic fluorides (LiF, NaF, and KF) after SF6 mineralization were 98.18%, 95.82%, and 95.21%, respectively. Similarly, after NF3 mineralization, these conversion rates stood at 92.18%, 90.67%, and 90.02%, respectively. The removal efficiencies for SF6 (1000 ppm) were 4.98, 12.01, and 7.23 L/g, while those for NF3 (1000 ppm) were 14.1, 12.6, and 11.7 L/g, respectively. Notably, sodium oxalate exhibits superior effectiveness, achieving 100% SF6 conversion within 30 min and 100% NF3 conversion within 50 min. This work underscores the potential of oxalate mineralization as a promising strategy for efficient and rapid removal of potent fluorinated compounds, paving the way for environmentally benign FC remediation techniques with broader implications for sustainable gas treatment technologies.

Effect of bariatric surgery on metabolism in diabetes and obesity comorbidity: Insight from recent research.

Obesity is a prevalent cause of diabetes mellitus (DM) and is a serious danger to human health. Type 2 DM (T2DM) mostly occurs along with obesity. Foodborne obesity-induced DM is caused by an excessive long-term diet and surplus energy. Bariatric surgery can improve the symptoms of T2DM in some obese patients. But different types of bariatric surgery may have different effects. There are some models built by researchers to discuss the surgical procedures' effects on metabolism in diabetes animal models and diabetes patients. It is high time to conclude all this effects and recommend procedures that can better improve metabolism.