Skeletal muscle involvement in systemic amyloidosis is often overlooked.

AIM: Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. METHODS: We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. RESULTS: Twenty-eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light-chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL-λ, one with AL-κ and two with ATTR. Group 2 included 15 patients with AL-λ and two patients with AL-κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. CONCLUSIONS: Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis.

Investigation of the formation of furfural compounds in apple products treated with pasteurization and high pressure processing.

The thermal treatment carried out in the processing of apple products is very likely to induce Maillard reaction to produce furfurals, which have raised toxicological concerns. This study aimed to elucidate the formation of furfural compounds in apple products treated with pasteurization and high pressure processing (HPP). The method for simultaneous determination of five furfural compounds including 5-hydroxymethyl-2-furfural (5-HMF), furfural (F), 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), 2-acetylfuran (FMC), and 5-Methyl-2-furfural (MF) using high performance liquid chromatography equipped with diode array detector (HPLC-DAD) was successfully developed and validated. All five furfurals exhibited an increasing trend after the pasteurization treatment of apple clear juice, cloudy juice, and puree. 5-HMF, F, FMC, and MF were increased significantly during the precooking of apple puree. Whereas there was no significant change in the furfurals formation after apple products treated with high pressure processing (HPP) with 300 MPa and 15 min. Based on the variation of the fructose, glucose and sucrose detected in apple products after thermal treatment, it revealed that the saccharides and thermal treatment have great effect on the furfural compounds formation. The commercial fruit juice samples with different treatments and fruit puree samples treated with pasteurization were also analyzed. Five furfurals were detected more frequently in the fruit juice samples treated with pasteurization or ultra-high temperature instantaneous sterilization (UHT) than those treated with HPP. 5-HMF and FMC were detected in all fruit puree samples treated with pasteurization, followed by F, MF, and HDMF with the detection rate of 79.31 %, 72.41 %, and 51.72 %. The results could provide a reference for risk assessment of furfural compounds and dietary guidance of fruit products for human, especially for infants and young children. Moreover, moderate HPP treatment with 300 MPa and 15 min would be a worthwhile alternative processing technology in the fruit juice and puree production to reduce the formation of furfural compounds.

Establishment of an induced pluripotent stem cell (iPSC) line (INNDSUi004-A) from a patient with Congenital Nemaline Myopathy.

We used a non-integrated reprogramming approach to establish a human induced pluripotent stem cell (hiPSC) line (INNDSUi004-A) from the skin fibroblasts of a 13-year-old female individual with Congenital Nemaline Myopath. The cells obtained have typical characteristics of embryonic stem cells, show expression of specific pluripotency markers, and can differentiate into three germ layers in vitro. This iPSC cell line has the genetic information of the patient and is a good model for studying disease mechanisms and developing novel therapies.

Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors.

The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors.

Reproductive factors and cardiovascular health in post-menopausal women: a special focus on natural menopause.

Female-specific reproductive factors might contribute to increased risk of cardiovascular disease, and the American Heart Association (AHA) recently proposed Life's Essential 8 (LE8) score to quantify cardiovascular health (CVH). The study aimed to examine the relationships between reproductive factors and the LE8 score among post-menopause women in the United States. We enrolled 3223 post-menopause women from National Health and Nutrition Examination Survey (NHANES). CVH groups based on LE8 score were low (0-49), moderate (50-79), and high good CVH levels (80-100). Multivariate ordinal logistic regressions were applied to estimate the associations between reproductive factors and the LE8 score. In multivariate model, early menarche (OR: 0.69, 95 percent CI: 0.51-0.93) and early menopause (OR: 0.57, 95 percent CI: 0.43-0.77) were associated with LE8 score compared with normal menarche and menopause; Meanwhile, ages at menarche and menopause were positively correlated with LE8 score. The number of pregnancies and full-term pregnancies were negatively associated with LE8 (OR for per pregnancy increase and 95 percent CI, 0.93 (0.88, 0.98), 0.93 (0.87, 0.99), separately). Overall, natural menopausal women with early age at menarche and menopause, and a higher number of pregnancies may have a high risk of lower CVH, and need to focus on their CVH.

EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS.

ABSTRACT: Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 µg/kg for 10 min, followed by a continuous infusion at 0.2 µg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

Advances in the differentiation of pluripotent stem cells into vascular cells.

Blood vessels constitute a closed pipe system distributed throughout the body, transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys. Changes in blood vessels are related to many disorders like stroke, myocardial infarction, aneurysm, and diabetes, which are important causes of death worldwide. Translational research for new approaches to disease modeling and effective treatment is needed due to the huge socio-economic burden on healthcare systems. Although mice or rats have been widely used, applying data from animal studies to human-specific vascular physiology and pathology is difficult. The rise of induced pluripotent stem cells (iPSCs) provides a reliable in vitro resource for disease modeling, regenerative medicine, and drug discovery because they carry all human genetic information and have the ability to directionally differentiate into any type of human cells. This review summarizes the latest progress from the establishment of iPSCs, the strategies for differentiating iPSCs into vascular cells, and the in vivo transplantation of these vascular derivatives. It also introduces the application of these technologies in disease modeling, drug screening, and regenerative medicine. Additionally, the application of high-tech tools, such as omics analysis and high-throughput sequencing, in this field is reviewed.

Establishment of an induced pluripotent stem cell (iPSC) line (INNDSUi005-A) from a healthy female Chinese Han.

We obtained skin fibroblasts from a 34-year-old healthy woman and established a human induced pluripotent stem cell (hiPSC) line (INDSUi005-A) using a non-integrated reprogramming approach. The obtained cells have typical characteristics of embryonic stem cells, can express specific pluripotency markers and have the ability to differentiate into three germ layers in vitro. This iPSC cell line can be used as an in vitro model for studying disease mechanisms and developing novel therapies.

Water, starch, and nuclear behavior in ray parenchyma during heartwood formation of Catalpa bungei 'Jinsi'.

Catalpa bungei 'Jinsi', a cultivar of C. bungei C. A. Mey., is valued for its heartwood with good overall mechanical properties, naturally durable and golden-yellow color. Little is known about heartwood formation in C. bungei 'Jinsi' trees. The behavior of starch, water, and nuclei was studied in the xylem tissue of C. bungei 'Jinsi' concerning aging in ray parenchyma cells. Blocks containing heartwood, golden zone, transition zone, and sapwood were collected from the stems of six C. bungei 'Jinsi' trees. The moisture content of the blocks was measured by oven drying. Changes in starch and nuclei in ray parenchyma were investigated in radial profiles from sapwood to heartwood blocks using microscopy and various staining techniques. The nuclear size and starch content gradually decreased to heartwood. While the horizontal distribution of moisture content of C. bungei 'Jinsi' was very varied, with the heartwood and golden zone being lower than sapwood but slightly higher than the transition zone. Starch grains were rare, but nuclei were still present in some ray parenchyma cells in the heartwood and golden zone. The nuclei showed irregular shape and elongation before disintegration. These results suggest that the most apparent change occurs in the transition zone, the critical location involved in forming C. bungei 'Jinsi' heartwood. Water and starch appear to be actively engaged in heartwood formation. The loss of function of ray parenchyma cells results from heartwood formation.

Residue behaviors of six pesticides during apple juice production and storage.

The residue behaviors of carbendazim, thiamethoxam, imidacloprid, acetamiprid, prochloraz, and difenoconazole during the production and accelerated storage of apple clear and cloudy juice was systemically evaluated. The pesticides were determined by liquid chromatography-mass spectrometry (LC-MS/MS) after each processing step and at different storage times. The results indicated that the different processing steps in the apple clear and cloudy juices production have different effects on the reduction of pesticide residues. The pre-processing steps including washing and pressing reduced the pesticide residues significantly by 36.8 % to 67.9 % and 32.9 % to 89.8 %, respectively, mainly due to the water solubility and log Kow of pesticides. The enzymation step in clear juice production slightly reduced six pesticide residues from 1.9 % to 31.6 %, and the filtration step after clarification and purification decreased the pesticide residues from 14.0 % to 87.5 % with no significance, while prochloraz was not detected. The centrifugation step in cloudy juice production reduced the pesticide residues from 6.3 % to 88.9 %. The pasteurization step in clear and cloudy juice production lowered the pesticide residues slightly on account of the short heating time of 30 s. The accelerated storage of clear and cloudy juices was effective in the reduction of pesticide residue levels. The processing factors (PFs) in the whole process of clear and cloudy juice production were equal to or lower than 0.2, especially for prochloraz and difenoconazole, illustrating that apple juice production could decrease the pesticide residues greatly. The results will provide important references to predict the levels of pesticide residues in apple juice during processing and storage. Meanwhile, the PFs identified in the study could be helpful in the risk assessment of pesticides in apple juice.

Tissue engineering RPE sheet derived from hiPSC-RPE cell spheroids supplemented with Y-27632 and RepSox.

BACKGROUND: Retinal pigment epithelium (RPE) cell therapy is a promising way to treat many retinal diseases. However, obtaining transplantable RPE cells is time-consuming and less effective. This study aimed to develop novel strategies for generating engineered RPE patches with physiological characteristics. RESULTS: Our findings revealed that RPE cells derived from human induced pluripotent stem cells (hiPSCs) successfully self-assembled into spheroids. The RPE spheroids treated with Y27632 and Repsox had increased expression of epithelial markers and RPE-specific genes, along with improved cell viability and barrier function. Transcriptome analysis indicated enhanced cell adhesion and extracellular matrix (ECM) organization in RPE spheroids. These RPE spheroids could be seeded and bioprinted on collagen vitrigel (CV) membranes to construct engineered RPE sheets. Circular RPE patches, obtained by trephining a specific section of the RPE sheet, exhibited abundant microvilli and pigment particles, as well as reduced proliferative capacity and enhanced maturation. CONCLUSIONS: Our study suggests that the supplementation of small molecules and 3D spheroid culture, as well as the bioprinting technique, can be effective methods to promote RPE cultivation and construct engineered RPE sheets, which may support future clinical RPE cell therapy and the development of RPE models for research applications.

BRMS1L confers anticancer activity in non-small cell lung cancer by transcriptionally inducing a redox imbalance in the GPX2-ROS pathway.

Low expression levels of breast cancer metastasis suppressor 1 like (BRMS1L) have been associated with the growth of cancer cells. However, the mechanisms underlying the role of BRMS1L as an antitumour transcription factor in the progression of NSCLC have not been explored. Herein, we reveal that BRMS1L plays a key role as a tumour suppressor in inhibiting NSCLC proliferation and metastasis. Mechanistically, BRMS1L overexpression results in the downregulation of glutathione peroxidase 2 (GPX2) expression and consequently causes abnormal glutathione metabolism and increased levels of reactive oxygen species (ROS) in cells, inducing oxidative stress injury and apoptosis. Furthermore, overexpression of GPX2 enhances the growth advantage and oxidative stress repair conferred by knockdown of BRMS1L. Importantly, we show that low expression of BRMS1L in NSCLC cells causes relatively high levels of antioxidant accumulation to maintain cell redox balance and renders cancer cells more sensitive to treatment with piperlongumine as an ROS inducer both in vitro and in vivo. These findings offer new insights into the role of BRMS1L as a transcriptional repressor in NSCLC and suggest that the BRMS1L expression level may be a potential biomarker for predicting the therapeutic response to small molecule ROS inducers, providing new ideas for targeted therapy.

Forage taste agents manage plant communities through modifying grazing behavior of yak in alpine meadow.

The use of taste agents to regulate the grazing behavior of livestock is a new attempt in pasture management, but the effects on grassland plant communities are not clear at present. Therefore, the following scientific questions need to be addressed: (1) how do different taste agents affected plant community structure by changing feed intake? (2) What was the mechanism of this effect? We proposed the following hypotheses: (1) Salt and sweetener increased feed intake of livestock and decreased the biomass of plant community, while bitters did the opposite. (2) Taste agents can regulate the relationship between plant species, and different taste agents can enhance or weaken the competitiveness of the different plants. In order to test the hypothesis, a grazing experiment with yaks was conducted in the alpine meadows of the Tibetan Plateau. Denatonium benzoate (Bitterant), NaCl (Salt), and sodium cyclamate (Sweetener) were sprayed onto the meadows twice a year, along with a control treatment of tap water. The results showed that (1) Salt increased the feed intake of yak significantly; bitterant decreased the feed intake of livestock and increased the biomass of plant community. (2) Salt increased the Pielou index of the plant community significantly. (3) The stability of plant community ranking from high to low is as follows: Control > Bitterant > Sweetener > Salt. (4) Bitterant and salt improved grazing tolerance of grassland and salt reduced the edibility of grassland. (5) The use of taste agents reduced the correlation between dominant species and led to the fragmentation of the relationship chain. The results of this study will provide a theoretical basis for using taste agents to regulate the community, species biodiversity management, restoration of degraded grassland, promoting utilization of grassland though controlling livestock selectivity.

Meta-analysis of the Relationship between Type 2 Diabetes Mellitus and Renal Cancer Risk.

OBJECTIVE: This study aimed to investigate the relationship between type 2 diabetes mellitus and the risk of renal cancer. METHODS: A search was carried out on PubMed, Embase, Web of Science, China Biology Med-icine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and other data-bases. The search period was from 2000 to 2022. The two authors independently conducted literature screening, extracted literature data, and then conducted a literature quality evaluation. The type of study is a cohort study. Meta-analysis was carried out on the included literature through Stata12.0 software, and the combined value was calculated with RR value and 95% confidence interval. Subgroup analysis was carried out to explore the impact of different factors on the overall results. RESULTS: A total of 10 articles were included. Through cohort study, the meta-analysis on the risk of type 2 diabetes and renal cancer showed that the combined effect value Risk Ratio (RR) = 1.57 with 95% Confidence Intervals (CI) (1.36, 1.82) and P<0.05. The difference had a signif-icant impact, indicating that the risk of renal cancer in type 2 diabetes patients was 1.55 times higher than that in non-type 2 diabetes patients. The subgroup analysis showed that the combined effect value RR and 95% CI for men was 1.49 (1.26, 1.75), and the combined effect value RR and 95% CI for women was 1.60 (1.35, 1.88), which was basically consistent. CONCLUSION: Type 2 diabetes can significantly increase the risk of renal cell carcinoma, and the former is a risk factor for the latter. It is suggested that multi-center studies with larger sample sizes should be conducted in the future, and adjustments should be made according to the type of diabetes, the source of the study population, the pathological type of renal cell carcinoma, the use of hypoglycemic drugs, and other factors, to provide a reliable basis for the study of the relationship between diabetes and renal cell carcinoma. At present, the specific mechanism of diabetes increasing the risk of renal cell carcinoma and whether diabetes increases mortality due to renal cell carcinoma is still unclear and needs further research.

Low-Carbohydrate and Low-Fat Diet with Metabolic-Dysfunction-Associated Fatty Liver Disease.

BACKGROUND: This observational cross-sectional study was designed to explore the effects of a low-carbohydrate diet (LCD) and a low-fat diet (LFD) on metabolic-dysfunction-associated fatty liver disease (MAFLD). METHODS: This study involved 3961 adults. The associations between LCD/LFD scores and MAFLD were evaluated utilizing a multivariable logistic regression model. Additionally, a leave-one-out model was applied to assess the effect of isocaloric substitution of specific macronutrients. RESULTS: Participants within the highest tertile of healthy LCD scores (0.63; 95% confidence interval [CI], 0.45-0.89) or with a healthy LFD score (0.64; 95%CI, 0.48-0.86) faced a lower MAFLD risk. Furthermore, compared with tertile 1, individuals with unhealthy LFD scores in terile 2 or tertile 3 had 49% (95%CI, 1.17-1.90) and 77% (95%CI, 1.19-2.63) higher risk levels for MAFLD, respectively. CONCLUSIONS: Healthy LCD and healthy LFD are protective against MAFLD, while unhealthy LFD can increase the risk of MAFLD. Both the quantity and quality of macronutrients might have significant influences on MAFLD.

Spatiotemporal expression of fibroblast growth factor 4 and 10 during the morphogenesis of deciduous molars in miniature pigs.

OBJECTIVE: Fibroblast growth factors (FGFs) play pivotal roles in mediating interactions between dental epithelium and mesenchyme throughout tooth initiation and morphogenesis. This study aimed to elucidate the roles of FGF4 and FGF10 in the regulation of tooth development. DESIGN: In this study, we investigated spatiotemporal expression patterns of FGF4 and FGF10 in the third deciduous molars (DM3) of miniature pigs at the cap, early bell, and late bell stages. Pregnant miniature pigs were obtained, and the samples were processed for histological staining. Non-radioactive in situ hybridization, immunohistochemistry, and real-time PCR were used to detect mRNA and protein expression levels of FGF4 and FGF10. RESULTS: FGF4 was expressed in the dental epithelium and mesenchyme at the cap stage. At the early bell stage, epithelial expression of FGF4 was reduced while mesenchymal expression got stronger. At the late bell stage, the FGF4 expression was restricted to the inner enamel epithelium (IEE) and differentiating odontoblasts. FGF10 was expressed intensely in both epithelium and mesenchyme at the cap stage. The expression of FGF10 was concentrated in the secondary enamel knots and surrounding mesenchyme at the early bell stage. FGF10 was weakly detected in the IEE by the late bell stage. CONCLUSIONS: Our results indicated that FGF4 and FGF10 might have partially redundant functions in regulating epithelium morphogenesis. FGF4 may be involved in regulatory signaling cascades mediating interactions between the epithelium and mesenchyme. In addition, the downregulation of FGF10 expression may be associated with the cessation of mesenchymal cell proliferation and initiation of preodontoblast polarization.

Preparation of starch-palmitic acid complex nanoparticles and their effect on properties of the starch composite film.

The corn starch-palmitic acid complex nanoparticles and amylose-palmitic acid complex nanoparticles were prepared through complex and nanoprecipitation. Their mean size values were 138.2 nm and 654.7 nm, respectively, while the two kinds of complex nanoparticles were mainly showed V-type crystalline structure, the crystallinity of these complex nanoparticles was 20.86 % and 46.81 %. Then the starch composite films were prepared using the corn starch-palmitic acid complex nanoparticles and amylose-palmitic acid complex nanoparticles as reinforcement phases. The starch composite film reinforced with amylose-palmitic acid complex nanoparticles had the higher tensile strength and a better wettability with the water contact angle of 86.51°. Though the crystalline properties of starch composite films had no significant difference, the thermal stability improved when the amylose-palmitic acid complex nanoparticles used as reinforcement phase, the maximum thermal degradation temperature was 313 °C. This study provides a new type of reinforcement phase to improve the properties of starch composite films.