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Background: TGF-β is a key modulator in the regulation of cell proliferation and migration, and is also involved in the process of cancer development and progression. Previous studies have indicated that TGF-β responsiveness is determined by TGF-β receptor partitioning between lipid raft/caveolae-mediated and clathrin-mediated endocytosis. Lipid raft/caveolae-mediated endocytosis facilitates TGF-β degradation and thus suppressing TGF-β responsiveness. By contrast, clathrin-mediated endocytosis results in Smad2/3-dependent endosomal signaling, thereby promoting TGF-β responsiveness. Because betulinic acid shares a similar chemical structure with cholesterol and has been reported to insert into the plasma membrane, we speculate that betulinic acid changes the fluidity of the plasma membrane and modulates the signaling pathway associated with membrane microdomains. We propose that betulinic acid modulates TGF-β responsiveness by changing the partitioning of TGF-β receptor between lipid-raft/caveolae and non-caveolae microdomain on plasma membrane. Methods: We employed sucrose-density gradient ultracentrifugation and confocal microscopy to determine membrane localization of TGF-β receptors and used a luciferase assay to examine the effects of betulinic acid in TGF-β-stimulated promoter activation. In addition, we perform western blotting to test TGF-β-induced Smad2 phosphorylation and fibronectin production. Results and conclusions: Betulinic acid induces translocation of TGF-β receptors from lipid raft/caveolae to non-caveolae microdomains without changing total level of TGF-β receptors. The betulinic acid-induced TGF-β receptors translocation is rapid and correlate with the TGF-β-induced PAI-1 reporter gene activation and growth inhibition in Mv1Lu cells. [ABSTRACT FROM AUTHOR]

Background: Almonds can decrease glycemic index of co-consumed foods and are a rich source for oleic acid and a-tocopherol. The aim of the randomized, crossover, controlled feeding trial was to examine whether as compared to NCEP step II diet as control (CON), ~60 g/d almonds (ALM) added to CON would improve glucoregulation and cardiovascular disease (CVD) risk factors in 33 Chinese T2DM patients. Methods: Forty T2DM patients were enrolled and randomly assigned to receive CON or ALM for 12 wks after a 2-wk. run-in period. Blood and urine samples were collected in the beginning and at the end of each dietary intervention phase for the assessment of biomarkers of glucoregulation, lipid profile, inflammation, and oxidative stress. Results: While ALM had a better overall nutritional quality than CON, neither ALM nor CON improved the glycemic status as the primary study outcome and other CVD risk factors, except the circulating nitric oxide being decreased by ALM compared to CON. Among 27 of 33 patients with the baseline HbA1c ≤.8, ALM decreased post-interventional fasting serum glucose and HbA1c by 5.9% and 3.0% as compared to that of CON, respectively (P = 0.01 and 0.04). Mean total and LDL-cholesterol concentrations were not changed by both diets. Conclusions: These results suggest almonds incorporated into healthful diets can improve glycemic status in diabetic patients with a better glycemic control. [ABSTRACT FROM AUTHOR]

Background: Gigantol and syringic acid (SA) have been shown to synergistically prevent formation of diabetic cataract (DC). However, the exact mechanism of this effect is unknown. Here, we investigate the effect of these compounds on the activity of aldose reductase (AR) and cataract formation. Methods: We examined the synergistic anti-cataract efficacy of gigantol and SA in the high glucose- and streptozotocin -induced DC rat model; synergism was evaluated using Jin's formula. We investigated possible mechanisms of action by measuring AR expression and activity and levels of sorbitol using enzyme kinetics, Western blot, and RT-PCR. Finally, we examined binding interaction between AR and both compounds using a combination of site-directed mutagenesis, recombinant expression of wild-type and mutant proteins, and enzyme kinetics. Results: Combination treatment of gigantol and SA synergistically protected both HLECs(human lens epithelial cells) grown in vitro and DC formation in STZ-induced rats in vivo. Synergism was attributed to inhibition of AR activity, downregulation of AR expression via impaired transcription, and decreased sorbitol levels. Enzyme kinetics studies showed that the activity of an AR Asn160Ala mutant protein was significantly decreased compared to wild-type AR, confirming that Asn160 is a key residue for interaction between AR and both compounds. Conclusion: Combined administration of gigantol and SA synergize to enhance anti-cataract efficacy. The synergistic effect is mainly attributed to disruption of the polyol pathway and inhibition of AR activity. [ABSTRACT FROM AUTHOR]

Introduction: Pathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis. Progenitor-like cells derived from adult kidney have been previously used to promote regeneration in acute kidney injury, even though it remained unclear whether the cells could be beneficial in chronic kidney disease (CKD). Methods: In this study, we established a CKD model by five-sixths nephrectomy and mouse kidney progenitor-like cells (MKPCs) were intravenously administered weekly for 5 weeks after establishing CKD. We examined the impact of MKPCs on the progression of renal fibrosis and the potential of MKPCs to preserve the angiogenic process and prevent endothelial mesenchymal transition in vivo and in vitro. Results: Our results demonstrate that the MKPCs delayed interstitial fibrosis and the progression of glomerular sclerosis and ameliorated the decline of kidney function. At 17 weeks, the treated mice exhibited lower blood pressures, higher hematocrit levels, and larger kidney sizes than the control mice. In addition, the MKPC treatment prolonged the survival of the mice with chronic kidney injuries. We observed a decreased recruitment of macrophages and myofibroblasts in the interstitium and the increased tubular proliferation. Notably, MKPC both decreased the level of vascular rarefaction and prevented endothelial mesenchymal transition (EndoMT) in the remnant kidneys. Moreover, the conditioned medium from the MKPCs ameliorated endothelial cell death under hypoxic culture conditions and prevented TGF-β-induced EndoMT through downregulation of phosphorylated Smad 3 in vitro. Conclusions: MKPCs may be a beneficial treatment for kidney diseases characterized by progressive renal fibrosis. The enhanced preservation of angiogenic processes following MKPC injections may be associated with decreased fibrosis in the remnant kidney. These findings provide further understanding of the mechanisms involved in these processes and will help develop new cell-based therapeutic strategies for regenerative medicine in renal fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Almonds reduce cardiovascular disease risk via cholesterol reduction, anti-inflammation, glucoregulation, and antioxidation. The objective of this randomized, controlled, cross-over trial was to determine whether the addition of 85 g almonds daily to a National Cholesterol Education Program (NCEP) Step 1 diet (ALM) for 6 weeks would improve vascular function and inflammation in patients with coronary artery disease (CAD). Research design and methods: A randomized, controlled, crossover trial was conducted in Boston, MA to test whether as compared to a control NCEP Step 1 diet absent nuts (CON), incorporation of almonds (85 g/day) into the CON diet (ALM) would improve vascular function and inflammation. The study duration was 22 weeks including a 6-weeks run-in period, two 6-weeks intervention phases, and a 4-weeks washout period between the intervention phases. A total of 45 CAD patients (27 F/18 M, 45-77 y, BMI = 20-41 kg/m2) completed the study. Drug therapies used by patients were stable throughout the duration of the trial. Results: The addition of almonds to the CON diet increased plasma α-tocopherol status by a mean of 5.8%, reflecting patient compliance (P ≤0.05). However, the ALM diet did not alter vascular function assessed by measures of flow-mediated dilation, peripheral arterial tonometry, and pulse wave velocity. Further, the ALM diet did not significantly modify the serum lipid profile, blood pressure, C-reactive protein, tumor necrosis factor-α or E-selectin. The ALM diet tended to decrease vascular cell adhesion molecule-1 by 5.3% (P = 0.064) and increase urinary nitric oxide by 17.5% (P = 0.112). The ALM intervention improved the overall quality of the diet by increasing calcium, magnesium, choline, and fiber intakes above the Estimated Average Requirement (EAR) or Recommended Dietary Allowance (RDA). Conclusions: Thus, the addition of almonds to a NECP Step 1 diet did not significantly impact vascular function, lipid profile or systematic inflammation in CAD patients receiving good medical care and polypharmacy therapies but did improve diet quality without any untoward effect. Trial registration: The trial was registered with the ClinicalTrials.Gov with the identifier: NCT00782015. [ABSTRACT FROM AUTHOR]

Objective: Almonds reduce cardiovascular disease risk via cholesterol reduction, anti-inflammation, glucoregulation, and antioxidation. The objective of this randomized, controlled, cross-over trial was to determine whether the addition of 85 g almonds daily to a National Cholesterol Education Program (NCEP) Step 1 diet (ALM) for 6 weeks would improve vascular function and inflammation in patients with coronary artery disease (CAD). Research design and methods: A randomized, controlled, crossover trial was conducted in Boston, MA to test whether as compared to a control NCEP Step 1 diet absent nuts (CON), incorporation of almonds (85 g/day) into the CON diet (ALM) would improve vascular function and inflammation. The study duration was 22 weeks including a 6-weeks run-in period, two 6-weeks intervention phases, and a 4-weeks washout period between the intervention phases. A total of 45 CAD patients (27 F/18 M, 45–77 y, BMI = 20-41 kg/m2) completed the study. Drug therapies used by patients were stable throughout the duration of the trial. Results: The addition of almonds to the CON diet increased plasma α-tocopherol status by a mean of 5.8 %, reflecting patient compliance (P ≤0.05). However, the ALM diet did not alter vascular function assessed by measures of flow-mediated dilation, peripheral arterial tonometry, and pulse wave velocity. Further, the ALM diet did not significantly modify the serum lipid profile, blood pressure, C-reactive protein, tumor necrosis factor-α or E-selectin. The ALM diet tended to decrease vascular cell adhesion molecule-1 by 5.3 % (P = 0.064) and increase urinary nitric oxide by 17.5 % (P = 0.112). The ALM intervention improved the overall quality of the diet by increasing calcium, magnesium, choline, and fiber intakes above the Estimated Average Requirement (EAR) or Recommended Dietary Allowance (RDA). Conclusions: Thus, the addition of almonds to a NECP Step 1 diet did not significantly impact vascular function, lipid profile or systematic inflammation in CAD patients receiving good medical care and polypharmacy therapies but did improve diet quality without any untoward effect. [ABSTRACT FROM AUTHOR]

Background: Compared with other common plant foods, walnuts (Juglans regia) are consistently ranked among the highest in antioxidant capacity. In vitro, walnut polyphenols inhibit plasma and LDL oxidation, while in animal models they lower biomarkers of oxidative stress and raise antioxidant capacity. A limited number of human feeding trials indicate that walnuts improve some measures of antioxidant status, but not others. Methods: A 19 wk, randomized crossover trial was conducted in 21 generally healthy men and postmenopausal women ⩾50 y to study the dose-response effects of walnut intake on biomarkers of antioxidant activity, oxidative stress, and nutrient status. Subjects were randomized to receive either 21 or 42 g raw walnuts/d during each 6 wk intervention phase with a 6 wk washout between phases. Subjects were instructed to consume their usual diet, but refrain from eating any other tree nuts, seeds, peanuts, or ellagitannin-rich foods during the entire study, and other polyphenol-rich foods for 2 d prior to each study visit. Results: Compared to baseline levels, red blood cell (RBC) linoleic acid and plasma pyridoxal phosphate (PLP) were significantly higher after 6 wk with 42 g/d walnuts (P < 0.05 for both). Overall, changes in plasma total thiols, and other antioxidant biomarkers, were not significant with either walnut dose. However, when compared to fasting levels, plasma total thiols were elevated within 1 h of walnut consumption with both doses during the baseline and end visits for each intervention phase (P < 0.05 for all). Despite the observed increase in RBC linoleic and linolenic acids associated with walnut consumption, this substrate for lipid peroxidation only minimally affected malondialdehyde (MDA) and antioxidant capacity. The proportional changes in MDA and Oxygen Radical Absorbance Capacity (ORAC) were consistent with a dose-response effect, although no significant within- or between-group differences were observed for these measures. Conclusions: Walnut consumption did not significantly change the plasma antioxidant capacity of healthy, wellnourished older adults in this pilot study. However, improvements in linoleic acid and pyridoxal phosphate were observed with chronic consumption, while total plasma thiols were enhanced acutely. Future studies investigating the antioxidant effects of walnuts in humans are warranted, but should include either a larger sample size or a controlled feeding intervention. Trial Registration: ClinicalTrials.gov: NCT00626691. [ABSTRACT FROM AUTHOR]

Background: Retinal bipolar cells comprise a diverse group of neurons. Cone bipolar cells and rod bipolar cells are so named for their connections with cone and rod photoreceptors, respectively. Morphological criteria have been established that distinguish nine types of cone bipolar cells and one type of rod bipolar cell in mouse and rat. While anatomical and physiological aspects of bipolar types have been actively studied, little is known about the sequence of events that leads to bipolar cell type specification and the potential relationship this process may have with synapse formation in the outer plexiform layer. In this study, we have examined the birth order of rod and cone bipolar cells in the developing mouse and rat in vivo. Results: Using retroviral lineage analysis with the histochemical marker alkaline phosphatase, the percentage of cone and rod bipolar cells born on postnatal day 0 (P0), P4, and P6 were determined, based upon the well characterized morphology of these cells in the adult rat retina. In this in vivo experiment, we have demonstrated that cone bipolar genesis clearly precedes rod bipolar genesis. In addition, in the postnatal mouse retina, using a combination of tritiated-thymidine birthdating and immunohistochemistry to distinguish bipolar types, we have similarly found that cone bipolar genesis precedes rod bipolar genesis. The tritiated-thymidine birthdating studies also included quantification of the birth of all postnatally generated retinal cell types in the mouse. Conclusion: Using two independent in vivo methodologies in rat and mouse retina, we have demonstrated that there are distinct waves of genesis of the two major bipolar cell types, with cone bipolar genesis preceding rod bipolar genesis. These waves of bipolar genesis correspond to the order of genesis of the presynaptic photoreceptor cell types. [ABSTRACT FROM AUTHOR]

An abstract of the article "Therapeutic effects of traditional Chinese medicine in cancer patients undergoing chemotherapy or radiotherapy: randomized, double-blind controlled trial," by L. Lo, C. Chen, C. Chang, T. Lee, M. Hou, T. Cheng, and J. Chiang is presented.

Background: Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), is an important cause of pyogenic skin and soft tissue infections (SSTIs). The aim of present study is to investigate the molecular characteristic of Staphylococcus aureus isolates isolated from the pus samples from the patients with purulent skin and soft tissue infections in Wenzhou, China.Methods: Between December 2002 and June 2008, a total of 111 nonduplicate S. aureus isolates were collected from the pus samples of the patients with SSTIs in a teaching hospital in Wenzhou, China. All the tested isolates were confirmed as S. aureus using a Staph SPA agglutination kit, Gram's stain and a Vitek-60 microbiology analyzer. The homology among the tested isolates was determined by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was used to determine the sequence types (STs) of the selected isolates. The genotypes of SCCmec were determined by a multiplex PCR in the MRSA isolates. Panton-Valentine leukocidin (PVL) genes and mecA were also determined by another multiplex PCR.Results: Among the 111 S. aureus isolates, 48 and 63 isolates were community-acquired and hospital-acquired respectively. Sixty isolates were confirmed as MRSA harboring mecA detected by PCR. A total of 32 PFGE clonal types were obtained by PFGE, with 10 predominant patterns (types A to J). Twenty-five different STs including ST398 and three novel STs were found among 51 selected isolates. The main STs were ST239, ST1018, ST59, ST7 and ST88. Of 60 MRSA isolates, SCCmec II, III, IV and SCCmec V were found in three, 50, three and two isolates, respectively. The positive rates of PVL genes in overall isolates, HA-isolates, CA-isolates, MRSA isolates and MSSA isolates were 23.4% (26/111), 20.6% (13/63), 27.1% (13/48), 21.7% (13/60) and 25.5% (13/51), respectively. Eight (33.3%, 8/24) of 24 CA-MRSA isolates and 5 (13.9%, 5/36) of 36 HA-MRSA isolates were positive for PVL genes. ST239-MRSA-SCCmecIII and ST1018-MRSA-SCCmecIII clones were found to be main clones and spread between community and hospital.Conclusion: S. aureus isolates causing SSTIs showed considerable molecular heterogeneity and harbored high prevalence of PVL genes. Clonal spread was responsible for the dissemination of the isolates of S. aureus associated with SSTIs. [ABSTRACT FROM AUTHOR]

NDRG2 (N-Myc downstream-regulated gene 2) was initially cloned in our laboratory. Previous results have shown that NDRG2 expressed differentially in normal and cancer tissues. Specifically, NDRG2 mRNA was down-regulated or undetectable in several human cancers, and over-expression of NDRG2 inhibited the proliferation of cancer cells. NDRG2 also exerts important functions in cell differentiation and tumor suppression. However, it remains unclear whether NDRG2 participates in carcinogenesis of the thyroid.~Background~Background~In this study, we investigated the expression profile of human NDRG2 in thyroid adenomas and carcinomas, by examining tissues from individuals with thyroid adenomas (n = 40) and carcinomas (n = 35), along with corresponding normal tissues. Immunohistochemistry, quantitative RT-PCR and western blot methods were utilized to determine both the protein and mRNA expression status of Ndrg2 and c-Myc.~Methods~Methods~The immunostaining analysis revealed a decrease of Ndrg2 expression in thyroid carcinomas. When comparing adenomas or carcinomas with adjacent normal tissue from the same individual, the mRNA expression level of NDRG2 was significantly decreased in thyroid carcinoma tissues, while there was little difference in adenoma tissues. This differential expression was confirmed at the protein level by western blotting. However, there were no significant correlations of NDRG2 expression with gender, age, different histotypes of thyroid cancers or distant metastases.~Results~Results~Our data indicates that NDRG2 may participate in thyroid carcinogenesis. This finding provides novel insight into the important role of NDRG2 in the development of thyroid carcinomas. Future studies are needed to address whether the down-regulation of NDRG2 is a cause or a consequence of the progression from a normal thyroid to a carcinoma.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Introduction: Whether double filtration plasmapheresis (DFPP) is effective in the patients who do not response to the initial immunotherapy is uncertain. This retrospective study aimed to evaluate the efficacy and safety of DFPP in the treatment of patients who had no improvement after initial immunotherapy (steroids and/or immunoglobulin (IVIG)), and moreover, to investigate the factors associated with the efficacy of DFPP., Methods: From January 1st, 2014, to December 30th,2018, a total of 26 patients who were diagnosed autoimmune encephalitis (AE) and were received the treatment of DFPP after unsuccessful or incomplete recovery from their early immune therapy (including intravenous high-dose cortisone, IVIG and or immunosuppressant) for at least 21 days were investigated. Their plasmapheresis volume, the course of disease, treatment sessions, and complications were recorded. The efficacy of DFPP within a week were assessed by modified Rankin scale (mRS). These patients were followed until six months after the last session of DFPP treatment., Results: The duration between the onset of symptoms and DFPP administration was 54.5 days (range 21-243 days). The median DFPP sessions for each patient were three (range 2-6 sessions), and the mean volume of plasma exchange was 50.5 ± 11.1 ml/kg/session. Total clinically relevant improvement was observed in 57.7% of the patients. The median mRS was decreased from 5 to 4 within one week after DFPP treatment (P < 0.001). Only one patient relapsed in the following six months after DFPP. The effectiveness of DFPP has no relationship with age, gender, the type of antibody, with or without neoplasm, clinical course and the volume of plasma exchange. Most patients tolerated well, except 2 cases. One encountered mild allergic reaction and the other had a transient hypotension during DFPP treatment, but both were corrected rapidly., Conclusion: DFPP is an effective and safe treatment option for patients who have poor responsiveness to early immunotherapy)., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the Helsinki Declaration. The study protocol was approved by the Human Research and Ethics Committee of Huashan Hospital Affiliated to Fudan University (KY2016-394). Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Despite the increasing use of metagenomic next-generation sequencing (mNGS) in sepsis, identifying clinically relevant pathogens remains challenging. This study was aimed to evaluate the clinical utility of simultaneous plasma and bronchoalveolar lavage fluid (BALF) detection using mNGS., Methods: This retrospective study enrolled 95 patients with pneumonia-derived sepsis (PDS) admitted to the intensive care unit (ICU) between October 2021 and January 2023. Patients were divided into two groups: mNGS group (n = 60) and the non-mNGS group (n = 35), based on whether simultaneous plasma and BALF mNGS were conducted. All patients underwent conventional microbiological tests (CMT), including bacterial/fungal culture of peripheral blood and BALF, as well as sputum culture, detection of 1, 3-beta-D- glucan in BALF and RT-PCR testing. The clinical data of the enrolled patients were collected, and the detection performance and prognosis of plasma mNGS, BALF mNGS and CMT were compared., Results: The mNGS group exhibited a lower mortality rate than the non-mNGS group (35.0% vs. 57.1%, P = 0.034). Simultaneous detection in dual-sample resulted in a higher proportion of microorganisms identified as definite causes of sepsis alert compared to detection in either plasma or BALF alone (55.6% vs. 20.8% vs. 18.8%, P<0.001). Acinetobacter baumannii, Stenotrophomonas maltophilia, Candida albicans, and human mastadenovirus B were the primary strains responsible for infections in PDS patients. Patients with lower white blood cells and neutrophil indices had a greater consistency in dual-sample mNGS. Patients in the mNGS group had more antibiotic adjustments compared to the non-mNGS group (85.71% vs. 33.33%, P<0.001). The percentage of neutrophils was a risk factor for mortality in PDS patients (P = 0.002)., Conclusion: Dual sample mNGS has the advantage of detecting and determining the pathogenicity of more pathogens and has the potential to improve the prognosis of patients with PDS., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Research Ethics Committee of National Hospital of Guangxi Zhuang Autonomous Region (2022-55), which waived the written informed consent requirement. Conducted in accordance with the principles of the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objective: Chronic prostatitis (CP) is a condition markered by persistent prostate inflammation, yet the specific cytokines driving its progression remain largely undefined. This study aims to identify key cytokines involved in CP and investigate their role in driving inflammatory responses through mechanistic and therapeutic exploration., Methods: A 48-cytokine panel test was conducted to compare the plasma cytokine profiles between participants with CP-like symptoms (CP-LS) and healthy controls. Experimental autoimmune prostatitis (EAP) models were used for functional validation, with further mechanistic studies performed through in vivo and in vitro assays. Pharmacological inhibition was applied using maraviroc, and pathway inhibitors to assess therapeutic potential., Results: Our analysis identified CCL5 as one of the most prominently elevated cytokines in CP-LS patients. Further validation in the EAP model mice confirmed elevated CCL5 levels, highlighting its role in driving prostatic inflammation. Mechanistic studies revealed that CCL5 interacts with the CCR5 receptor, promoting M1 macrophage polarization and activating key inflammatory signaling pathways, including Stat1 and NF-κB, as indicated by increased phosphorylation of Stat1 and p65. In vitro, CCL5 combined with LPS stimulation amplified these effects, further promoting M1 polarization. CCL5 also sustained Stat1 activation by inhibiting its dephosphorylation through reduced interaction with SHP2, leading to prolonged inflammatory signaling. Single-cell transcriptomics confirmed high CCR5 expression in macrophages, correlating with inflammatory pathways. Pharmacological inhibition of CCR5, or its downstream signaling, significantly reduced macrophage-driven inflammation both in vivo and in vitro., Conclusion: These findings establish the CCL5/CCR5 axis as a critical driver of persistant prostatic inflammation and present it as a potential therapeutic target for CP., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures involving human participants, including obtaining written informed consent, were conducted in accordance with the principles outlined in the Helsinki Declaration and were approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University on June 10, 2020 (PJ-2020–07-11). Written informed consent was obtained from all participants involved in this study. All animal experiments were conducted in compliance with the guidelines of the Animal Care and Utilization Committee of the Animal Center of Anhui Medical University, with approval (approval no. LLSC20241750). Consent for publication: Informed consent for publication was obtained from all participants involved in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To evaluate the feasibility of intraoperative human papillomavirus (IOP-HPV) testing for the prediction of postoperative treatment failure in patients with high-grade squamous intraepithelial lesion (HSIL) undergoing loop electrosurgical excisional procedure (LEEP)., Methods: A total of 114 women diagnosed with HSIL by biopsy and/or endocervical curettage who underwent LEEP were included in a prospective cohort study. IOP-HPV testing was performed immediately after the procedure. Patients were followed up for 24 months. Logistic regression was used to analyse the factors influencing the residual or recurrent lesions. Further stratified analyses were performed to investigate the differences in prognosis of IOP-HPV positivity in patients of different age and menopausal status., Results: 1. Of the 114 patients, 6 (5.26%) were pathologically upgraded to cervical cancer, and 21 (18.42%) were lost to follow-up. Recurrence or residual HSIL lesions occurred in 9.20% (8/87) of cases. Of the 8 women who developed post-treatment HSIL, 7 (26.92%) were positive for IOP-HPV, and only 1 (1.64%) was negative for IOP-HPV (< 0.01). 2. Transformation zones of type 2 (P = 0.0306) or type 3 (P = 0.0446), diagnosed as LSIL/negative by cervical biopsy (P = 0.0396), margin involvement (P = 0.0233), positive endocervical curettage after conisation (P = 0.0028), intraoperative HPV-positive (P < 0.01), cytological abnormalities (P = 0.0038), DNA ploidy positivity (P = 0.0172), postoperative HPV (P < 0.01) and DNA ploidy (P = 0.0078) positivity at 6 months were associated with higher risk of residual or recurrent lesions.  3. The results of the multivariate regression analysis showed that IOP-HPV positivity was the independent risk factor for residual or recurrent lesions (OR=10.69 , 95% CI:3.41, 33.51, P<0.01). IOP-HPV positivity was strongly associated with the occurrence of residual/recurrent LSIL (OR=6.42 , 95% CI:1.74, 23.70, P=0.0053) and HSIL (OR=32.08 , 95% CI:3.60, 285.64, P=0.0019). 4. Stratified analyses showed that IOP-HPV positive in patients younger than 50 years or premenopausal patients was associated with a significantly higher risk of recurrence or residual lesions (p<0.05)., Conclusions: IOP-HPV positivity is an independent risk factor for residual or recurrent HSIL lesions. In addition, IOP-HPV positivity was more associated with residual or recurrent lesions in those younger than 50 years or premenopausal. IOP-HPV testing may be of critical clinical value in providing the early and accurate prediction of residual or recurrent lesions., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University. Informed consent was obtained for all patients or family members. In addition, all methods were performed in accordance with the relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The microRNA156 (miR156) has been widely studied in plants, however, the characterization of the miR156 family of genes in wheat and their expression patterns under abiotic stress are not completely clear. In this study, a total of 20 miR156 family members, referred to as tae-miR156a to tae-miR156t, were identified in wheat with their loci mapped to various chromosomes. These members were divided into five subgroups: miR156a/b/c/d/e/f, miR156g/h/i, miR156j/k, miR156l/m/n/o/p/q, and miR156r/s/t. They were highly conserved during evolution. The prediction of cis-elements in the tae-MIR156(s) promoter region revealed that the tae-MIR156(s) had diverse cis-acting elements; of these, 15 tae-MIR156(s) and 6 tae-MIR156(s) were found to be drought-responsive elements and cold-responsive elements, respectively. And the prediction target genes of tae-miR156(s) are mainly SPL transcription factor genes. Expression analysis based on quantitative real-time polymerase chain reaction (qRT‒PCR) showed that miR156(s) have different expression levels in the various wheat tissues, and the subgroups' response to abiotic stress varied. Among them, miR156g/h/i were strongly induced in the root of cold and heat stress, and miR156a/b/c/d/e/f were significantly increased in roots after drought stress, whereas miR156r/s/t were highly inhibited in leaves and roots after salt stress. These findings imply that tae-miR156(s) are involved in stress response in wheat, and they provide new fundamental knowledge for further analysis of the function of miR156 and its regulatory mechanism in response to abiotic stress., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Tea plants are economically important woody plants that originated in southwestern China. The Yunnan Province in China is regarded as the central origin of tea plants owing to the abundance and diversity of the tea germplasm present in this region. However, there is a lack of knowledge regarding the genetic diversity and evolutionary relationships among tea plants in this region. Here, a total of 266,397 high-quality single nucleotide polymorphisms were obtained using double digest restriction-site associated DNA sequencing from 468 tea accessions collected from Yunnan. The phylogenetic relationship and population structure of the 468 tea accessions revealed remarkable inter- and intraspecific introgression across different sect. Thea species. We found that Camellia taliensis (W. W. Smith) Melchior is the main genetic donor that greatly contributed to the domestication of C. sinensis (L.) O. Kuntze, as evidenced by the frequent generation of genetic intermediates derived from the hybridization between C. sinensis and C. taliensis in Lincang, Xishuangbanna, and Pu'er. Notable genetic differences were observed across the populations from distinct regions of Yunnan. Additionally, the Lancang River may have attenuated the genetic interflow between Lincang and Pu'er. Finally, a core collection of 50 tea accessions was constructed based on the genetic diversity of the 468 tea accessions. Our results provide novel insights into the evolutionary and domestication history of tea plants in Yunnan Province and can facilitate the development of strategies for the conservation, breeding, and utilization of the core collection., Competing Interests: Declarations. Ethics approval and consent to participate: All the experiments were performed in accordance with relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: As two of the most impactful abiotic stresses, salt and drought strongly affect tomato growth and development, especially at the seedling stage. However, dissection of the genetic basis underlying salt/drought tolerance at seedling stage in tomato remains limited in scope., Results: Here, we reported an analysis of major quantitative trait locus (QTL) and potential causal genetic variations in seedling stage salt/drought tolerance in recombinant inbred lines (n = 201) of S. pimpinellifolium and S. lycopersicum parents by whole genome resequencing. A total of 5 QTLs on chromosome 1, 3, 5, 7 and 12 for salt tolerance (ST) and 15 QTLs on chromosome 1, 3, 4, 8, 9, 10, 12 for drought tolerance (DT) were identified by linkage mapping. The proportion of phenotypic variation explained (PVE%) by these QTLs ranged from 4.91 to 15.86. Two major QTLs qST7 and qDT1-3 were detected in both two years, for which two candidate genes (methionine sulfoxide reductase SlMSRB1 and brassinosteroid insensitive 1-like receptor SlBRL1) and the potential functional variations were further analyzed. Taking advantage of the tomato population resequencing data, the frequency changes of the potential favorable QTL allele for seedling stage ST/DT during tomato breeding were explored., Conclusions: These results will be beneficial for the exploration of salt/drought tolerance genes at seedling stages, laying a foundation for marker-assisted breeding for seedling stage salt/drought tolerance., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: L-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms., Results: Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice., Conclusions: Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental procedures were approved by the Animal Ethics Committee of ShanghaiTech University (Approval No. 20200706002). Consent for publication: Not applicable. Competing interests: The authors have no actual or potential competing interests to declare., (© 2024. The Author(s).)

Background: The immunogenicity of allogeneic mesenchymal stem cells (MSCs) is significantly enhanced after transplantation or differentiation, and these cells can be recognized and cleared by recipient immune cells. Graft rejection has become a major obstacle to improving the therapeutic effect of allogeneic MSCs or, after their differentiation, transplantation in the treatment of diabetes and other diseases. Solving this problem is helpful for prolonging the time that cells play a role in the recipient body and for significantly improving the clinical therapeutic effect., Methods: In this study, canine adipose-derived mesenchymal stem cells (ADSCs) were used as seed cells, and gene editing technology was used to knock out the B2M gene in these cells and cooperate with the overexpression of the PD-L1 gene. Gene-edited ADSCs (GeADSCs), whose biological characteristics and safety are not different from those of normal canine ADSCs, have been obtained., Results: The immunogenicity of GeADSCs is reduced, the immune escape ability of GeADSCs is enhanced, and GeADSCs can remain in the body for a longer time. Using the optimized induction program, the efficiency of the differentiation of GeADSCs into new islet β-cells was increased, and the maturity of the new islet β-cells was increased. The immunogenicity of new islet β-cells decreased, and their immune escape ability was enhanced after the cells were transplanted into diabetic dogs (the graft site was prevascularized by the implantation of a scaffold to form a vascularized pouch). The number of infiltrating immune cells and the content of immune factors were decreased at the graft site., Conclusions: New islet β-cell transplantation, which has low immunogenicity, can reverse diabetes in dogs, and the therapeutic effect of cell transplantation is significantly enhanced. This study provides a new method for prolonging the survival and functional time of cells in transplant recipients and significantly improving the clinical therapeutic effect., Competing Interests: Declarations. Ethics approval and consent to participate: The study is reported in accordance with ARRIVE guidelines ( https://arriveguidelines.org ). All of the dogs were reared, obtained, and housed in accordance with our institute’s laboratory animal requirements. All procedures and the study design were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (Ministry of Science and Technology of China, 2006) and were approved by the Animal Ethical and Welfare Committee of Northwest Agriculture and Forest University (Title of the approved project: Study on anti-graft rejection effect and mechanism of canine gene-edited MSCs and their differentiated cells. Date of approval: September 17, 2022. Approval No: 20220182). No human cells/tissues/samples/cell lines were used in this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Sulfotransferase family 2B member 1 (SULT2B1) is involved in regulating cell proliferation, migration and metabolism. However, there is still dispute regarding whether SULT2B1 acts as an oncogene or a suppressor, and the intrinsic mechanisms in modulating tumor progression need to be further elucidated., Methods: This work aims to reveal the relationship among SULT2B1, AKT, PKM2 signaling and glycolytic pathways, and provided a theoretical basis for SULT2B1 as a potential therapeutic target for CRC.Bioinformatics methods, immunohistochemistry (IHC) and immunoblotting assays were performed to analyze the correlation between SULT2B1 and colorectal cancer (CRC). The effect of SULT2B1 on cell proliferation and migration were investigated by several phenotypic experiments in vitro and animal studies. The SULT2B1 interacting proteins were determined by immunofluorescence, immunoprecipitation and GST-pull down assays. Immunoblotting and mCherry-GFP-LC3 assays were performed to analysis autophagy. Chromatin immunoprecipitation (CHIP) assay was utilized to detect the effect of SULT2B1 in regulating transcription. Small molecule agonist/antagonist was used to modify protein activity and therefore analyze the mutual relationships., Results: SULT2B1 is a predictive biomarker that is abnormally overexpressed in CRC tissues. Overexpression of SULT2B1 promoted cell proliferation and migration, while its knockout suppressed these processes. Furthermore, SULT2B1 could directly interact with the oncogene AKT and thereby enhance the activity of AKT-mTORC1 signaling. Furthermore, PKM2 was found to bind with SULT2B1, and regulated by SULT2B1 at both transcription and degradation levels. Moreover, blocking glycolysis attenuated the promoting effect of OE-SULT2B1., Conclusion: SULT2B1 acts as an oncogene in CRC via modulating the AKT/PKM2 axis, therefore making it a promising diagnostic and therapeutic target for CRC., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with the guidelines of the Animals Administrative Committee of Lanzhou University. Consent for publication: Not applicable. Competing interests: The authors state that there are no conflicts of interest to declare., (© 2024. The Author(s).)

Background: Reports of congenital isolated medial rectus muscle abnormalities are relatively uncommon and are seldom seen. According to our clinical experience, some rare cases of abnormalities could not be detected by clinical examination and imaging before surgical treatment, which brought difficulties to diagnosis and surgery., Case Presentation: In order to provide clinical guidance, we summarized 4 cases with congenital hypoplasia of the medial rectus muscle in our hospital recently. All the patients exhibited exotropia in the primary position. Only one patient (25.0%) exhibited clinically significant limitations of ocular movements. All the patients were identified with congenital hypoplasia of the medial rectus muscle during strabismus surgery; one patient also had hypoplasia of the lateral rectus muscle. However, abnormalities of the rectus muscles were not identified by MRI in three patients (75.0%). In terms of treatment, we enhanced the surgery amount in three patients. Good correction of exotropia was achieved in all patients., Conclusions: Congenital hypoplasia of the medial rectus muscle is extremely rare and some cases are difficult to be detected by clinical examination or imaging. Surgeons should be aware of this condition and should actively but cautiously adjust the surgical parameters based on the patients' intraoperative status., Competing Interests: Declarations. Ethics approval and consent to participate: The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Ethics approval for this study was obtained from the Institutional Review Board of Eye and ENT Hospital, Fudan University. Written informed consent was obtained from the parents of all patients described in this report for the publication of their clinical findings. Consent for publication: Written informed consent was obtained from the parents of all patients described in this report for both study participation and publication of identifying information/images in an online open-access publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: This study aimed to assess the impact of segmental tongue function training on tongue pressure characteristics in nasopharyngeal carcinoma after radiotherapy(NPCR) patients who experience dysphagia. The findings of this research are crucial in understanding the potential benefits of tongue rehabilitation exercises for individuals with NPC patients. Hence, it is essential to explore the effects of this type of training on tongue pressure and its associated characteristics., Methods: A group of eighteen NPCR dysphagia patients underwent a two-week segmental tongue function training. The researchers assessed their tongue motor function by measuring the tongue pressure (P) and endurance time (ET) in three different regions of the tongue-the anterior tongue region (TAR), central tongue region (TCR), and posterior tongue region (TPR). To gather accurate data, a new flexible tongue pressure sensor with 9 measuring sites arranged in a 3 × 3 configuration was used to measure the pressure exerted by the tongue on the palate. The measurements were taken both before and after the segmental tongue function training., Results: The segmental tongue function training resulted in significant improvements in tongue pressure for the anterior(P TAR ) and central(P TCR ) parts of the tongue(P < 0.05). However, there was no significant change in tongue pressure for the posterior(P TPR ) part of the tongue(P > 0.05). Additionally, there were no significant differences in the endurance time for each part of the tongue(P > 0.05)., Conclusions: Segmental tongue function training improved the P TAR and P TCR in NPCR dysphagia patients within 2 weeks, and the improvement gradually decreased from the anterior part of the tongue to the posterior part of the tongue. Meanwhile, there were no significant differences in PTPR and ET of between each part before and after treatment. This suggests that a longer duration weeks of training may be needed to improve the PTPR and ET in these patients, or alternatively, more targeted training programs could be designed., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Third Affiliated Hospital of Sun Yat-sen University (Approval No: CUHK Attached SAN Medical Ethics [2021]02-200-01) and was conducted according to the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. Consent for publication: All participants and/or their legal guardian(s) have given informed consent for their identifying information/images to be published in online open-access publications. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The fibrogenic conversion of satellite cells contributes to the atrophy and fibrosis of skeletal muscle, playing a significant role in the pathogenesis of age-related sarcopenia. Melatonin, a hormone secreted by the pineal gland, exhibits anti-aging and anti-fibrotic effects in various conditions. However, the effect of melatonin on satellite cell fate and age-related sarcopenia remains under-explored. Here, we report that melatonin treatment mitigated the loss of muscle mass and strength in aged mice, replenished the satellite cell pool and curtailed muscle fibrosis. When primary SCs were cultured in vitro and subjected to aging induction via D-galactose, they exhibited a diminished myogenic potential and a conversion from myogenic to fibrogenic lineage. Notably, melatonin treatment effectively restored the myogenic potential and inhibited this lineage conversion. Furthermore, melatonin attenuated the expression of the fibrogenic cytokine, transforming growth factor-β1, and reduced the phosphorylation of its downstream targets Smad2/3 both in vivo and in vitro. In summary, our findings show melatonin's capacity to counteract muscle decline and inhibit fibrogenic conversion in aging SCs and highlight its potential therapeutic value for age-related sarcopenia., Competing Interests: Declarations. Ethics approval and consent to participate: All animal procedures were approved by the Laboratory Animal Care and Use Committee of Nanfang Hospital, Southern Medical University and were conducted in accordance with the guidelines outlined in the National Research Council’s’ Guide for the Care and Use of Laboratory Animals’. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Triple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation., Methods: This study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo., Results: Through the design, synthesis and screening of a series of targeted compounds, we identified YZ-836P as an effective compound that exerted cytotoxic effects and reduced the protein levels of PRMT5 and its key downstream target protein KLF5 in TNBC after 48 h. Its efficacy was significantly superior to the PRMT5 PROTAC degraders that had been reported. YZ-836P induced G1 phase cell cycle arrest and significantly induced apoptosis in TNBC cells. Additionally, we demonstrated that YZ-836P promoted the ubiquitination and degradation of PRMT5 in a cereblon (CRBN)-dependent manner. Notably, YZ-836P exhibited pronounced efficacy in inhibiting the growth of TNBC patient-derived organoids and xenografts in nude mice., Conclusions: These findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC., Trial Registration: Ethics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023., Competing Interests: Declarations. Ethics approval and consent to participate: The animal experiment followed the ARRIVE guidelines and had been approved by the Animal Ethics Committee of the Kunming Medical University (kmmu20240729). Additionally, the patient-derived organoids assays conformed the Declaration of Helsinki and had been approved by the Ethics Committee of Yunnan Cancer Hospital (KYCS2023-078). Consent for publication: All the authors consent for publication. Competing interests: The authors declare no potential conflicts of interest., (© 2024. The Author(s).)

Background: Breast cancer (BC) is caused by the uncontrolled proliferation of breast epithelial cells followed by malignant transformation, and it has the highest incidence among female malignant tumors. The metastasis of BC occurs through direct and lymphatic spread. Although ocular metastasis is relatively rare, it is a good indicator of a worse prognosis. We used machine learning (ML) to establish a model to analyze the risk factors of BC eye metastasis., Methods: The clinical data of 2225 patients with BC from 2003 to 2019 were collected and randomly classified into the training and test sets using a ratio of 7:3. Based on the presence or absence of eye metastasis, the patients with BC were classified into the ocular metastasis (OM) and non-ocular metastasis (NOM) groups. Univariate and multivariate logistic regression analyses and least absolute shrinkage and selection operator (LASSO) were conducted. We used six ML algorithms to establish a predictive BC model and used 10-fold cross-validation for internal verification. The area under the receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of the model. In addition, we established a web hazard calculator depending on the best-performing model to facilitate its clinical application. Shapley additive interpretation (SHAP) was used to determine the risk factors and the interpretability of the black box model., Results: Univariate logistic regression analysis showed that histopathology (other types), axillary lymph node metastasis (ALNM) (> 4), Ca 2+ , total cholesterol (TC), low-density lipoprotein (LDL), apolipoprotein A (ApoA), carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, CA153, CA199, alkaline phosphatase (ALP), and hemoglobin (Hb) were risk factors for BC eye metastasis. Multivariate logistic regression analysis showed that CA153, ApoA, and LDL were hazardous components for BC eye metastasis. LASSO showed that ALNM, LDL, CA125, Hb, ALP, and CA199 were the first six key variables that were useful for the diagnosis of ocular metastasis in breast cancer. Bootstrapped aggregation (BAG) demonstrated the discriminative ability (area under ROC curve [AUC] = 0.992, accuracy = 0.953, sensitivity = 0.987). Based on this, we applied the BAG machine learning model to build an online web computing system to help clinicians assist in determining the risk of BC eye metastasis. In addition, two typical cases are analyzed to determine the interpretability of the model., Conclusion: We used ML to establish a risk prediction model for BC ocular metastasis, and BAG showed the greatest performance. The model can predict the risk of OM in patients with BC, facilitate early and timely diagnosis and treatment, and reduce the burden on society., Competing Interests: Declarations. Ethical approval and consent to participate: The study methods and protocols were approved by the Medical Ethics Committee of the First Affiliated Hospital of Nanchang University (Nanchang, China) and followed the principles of the Declaration of Helsinki. All subjects were notified of the objectives and content of the study and latent risks, and then provided written informed consent to participate. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Radiotherapy sensitivity is associated with the prognosis of patients with tongue squamous cell carcinoma (TSCC). In the present study, we proposed to explore the specific mechanism of interventional radiology (IR) therapy for TSCC in vitro and in vivo. TSCC cells were treated with 6 Gy IR and tumor bearing mice were treated with 20 Gy × 1 IR. DIA quantitative proteomics along with bioinformatics analysis were conducted in TSCC cells to investigate differential proteins related to IR and relation of which involved in TMEM147 and SPHK1 was confirmed by immunoprecipitation. Cell proliferation, apoptosis, autophagy& autophagy flux along with calcium signaling pathway detection were performed in vitro and in vivo. Our results showed that IR induced increasing calcium levels accompanied by up-regulated TMEM147 and down-regulated SPHK1 along with enhancing autophagy together with apoptosis. The effect of calcium overloading induced by IR on autophagy and apoptosis was dependent on increasing TMEM147 and decreasing SPHK1. However, IR-induced autophagy and apoptosis tended to be independent of only increasing calcium levels when down-regulating TMEM147 or up-regulating SPHK1 expression in vitro and in vivo. Our study suggested that calcium-mediated TMEM147/SPHK1 may promote autophagy and apoptosis to improve radiotherapy sensitivity in TSCC., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors have declared that no competing interest exists., (© 2024. The Author(s).)

Background: Thyroid surgeries are intricate operations that carry the risk of damaging the parathyroid glands, which can result in hypocalcemia and potential long-term hypoparathyroidism. Innovative surgical techniques including Intraoperative Nanocarbon Staining (INS), aim to enhance the preservation of parathyroid glands. This study assesses the effectiveness of INS combined with parathyroid autotransplantation in reducing postoperative complications and preserving parathyroid function., Methods: This retrospective cohort study assessed patients aged ≥ 18 who underwent thyroid surgery at a tertiary care hospital from January 2017 to December 2022. We compared the incidence of postoperative parathyroid injury, recovery rates of parathyroid function, and the incidence of permanent hypoparathyroidism between groups. Data on patient demographics, diagnosis, surgical details, parathyroid hormone levels, and calcium levels were collected and analyzed using chi-square tests, t-tests, and logistic regression., Results: The study included 198 patients, with 101 in the intervention group and 97 in the control group. Baseline characteristics such as sex ratio, age, BMI, and preoperative calcium levels showed no significant differences between groups. The intervention group demonstrated a significantly shorter duration of intravenous calcium supplementation (median 2 vs. 3 days, p < 0.001) and higher calcium nadir levels (median 8.36 vs. 7.85 mg/dL, p < 0.001) compared to controls. Furthermore, the incidence of postoperative parathyroid injury and permanent hypoparathyroidism was lower in the intervention group (15.84% vs. 20.62%, p = 0.045 and 4.95% vs. 15.46%, p = 0.003, respectively). Multivariate analysis revealed factors such as Blood iPTH monitoring level (OR 1.053, 95% CI 1.009-1.099, P = 0.018) and surgery type (Near Total Thyroidectomy) (OR 0.447, 95% CI 0.202-0.990, P = 0.047) were positively associated with surgical success. The intervention group also showed higher surgery success rates (OR 2.054, 95% CI 1.017-4.150, P = 0.045)., Conclusion: The application of INS and parathyroid autotransplantation during thyroidectomy significantly improves postoperative parathyroid gland function, reducing the incidence of permanent hypoparathyroidism. These findings support the incorporation of these techniques into standard surgical practice for thyroidectomy., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the People’s Hospital of Suzhou New District (approval number 2024-092), with all procedures performed in accordance with ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. No other ethical statement is required. Due to the retrospective nature of this study, the requirement for informed consent was waived, contingent upon the anonymization of patient data. Clinical trial number not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The gut microbiota of venous thromboembolism (VTE) patients exhibited significant alterations. However, the causal relationship between gut microbiota and VTE has not been fully understood. This study aimed to assess the causal relationship between gut microbiota and the risk of VTE using a two-sample Mendelian Randomization (MR) study., Methods: The gut microbiota and VTE genetic data were collected from the MiBioGen consortium and the UK biobank, respectively. The potential causal relationship between gut microbiota and VTE was investigated using a two-sample MR analysis, including inverse variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode methods. Cochran's Q-test, MR-PRESSO, and MR-Egger regression intercept analysis were utilized to perform sensitivity analysis., Results: At the genus level, the results of MR analysis found that Coprococcus1 (OR: 1.0029, 95% CI: 1.0005-1.0054, p = 0.0202) was suggestively linked with an increased risk of VTE, while Slackia (odds ratio (OR): 0.9977, 95% confidence interval (CI): 0.9957-0.9998, p = 0.0298), Butyricicoccus (OR: 0.9971, 95% CI: 0.9945-0.9997, p = 0.0309), Eubacterium coprostanoligenes group (OR: 0.9972, 95% CI: 0.9946-0.9999, p = 0.0445), and Bacteroides (OR: 0.9964, 95% CI: 0.9932-0.9995, p = 0.0234) were suggestively associated with a reduced risk of VTE. No heterogeneity and horizontal pleiotropy was detected., Conclusion: This study found that there were potential causal relationships between five gut microbiota and VTE. Our findings may provide new insights into the mechanisms of VTE., Competing Interests: Declarations. Ethics approval and consent to participate: The requirement of ethical approval for this was waived by the Institutional Review Board of our Hospital, because this study was a secondary analysis of summary-level data. The need for informed consent was waived. All methods were performed in accordance with the relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Heart failure (HF) is associated with high mortality and rehospitalization rates, highlighting the need for novel therapeutic approaches. Jianxin (JX) granules, a Traditional Chinese Medicine formulation, have been patented for the treatment of HF. However, the specific therapeutic effects and underlying mechanisms of JX granules have not been fully elucidated. This study aimed at investigating the effects and mechanism of JX granules in the treatment of HF based on proteomics and metabolomic profiling., Methods: HF model was established in rats by ligation of left coronary artery. The successfully modeled rats were randomly divided into three groups: the model group, the JX granules group, and Sacubitril/Valsartan (S/V) group. Four weeks after treatment, left ventricular (LV) function was evaluated via echocardiography. LV fibrosis and apoptosis were examined through histological analyses, while mitochondrial morphology was assessed using transmission electron microscopy. Quantitative assessment of oxidative stress was also conducted. Proteomics was used to identify the differentially expressed proteins and potential pathways. Metabolomics was utilized to elucidate the variations in metabolism. Then western blotting and in vitro analyses were performed., Results: A rat model of HF was established, evidenced by a decrease in left ventricular ejection fraction (LVEF), stroke volume (SV), and left ventricular fractional shortening (LVFS), alongside diminished adenosine triphosphate (ATP) content, elevated oxidative stress, augmented apoptosis, and disrupted pyruvate metabolism. Treatment with JX granules ameliorated these effects, improving systolic function, reducing ventricular chamber size, and increasing LVEF, SV, and LVFS, as assessed by echocardiography. Additionally, JX granules attenuated cardiac fibrosis and improved mitochondrial structure, as evidenced by less vacuolation and clearer mitochondrial cristae, when compared to the model group. The treatment also regulated apoptosis-related protein expression, partially reversing the increase in cleaved Caspase-9, cleaved Caspase-3, and Bax and the suppression of Bcl-2 observed in the heart failure rats. All of these effects were similar to S/V. Proteomic and metabolomic analyses identified key differential genes, such as triosephosphate isomerase 1 (TPI1), lactate dehydrogenase B (LDHB), pyruvate kinase M (PKM), protein kinase B (Akt), Pyruvate Dehydrogenase Beta (PDHB) and lactate dehydrogenase A (LDHA), as well as vital pathways including carbon metabolism, the PI3K-Akt signaling pathway, pyruvate metabolism, and HIF-1α signaling pathway. Moreover, JX granules mitigated oxidative stress, inhibited apoptosis, and activated Akt in H9c2 cells exposed to angiotensin II, which could be reversed by the PI3K inhibitor LY294002., Conclusion: JX granules improve HF in parallel to the efficacy of S/V, at least in part, through enhancing pyruvate metabolism, inhibiting oxidative stress and activating PI3K/Akt pathway., Competing Interests: Declarations. Competing interests: The authors declare no competing interests related to this study. All authors have read and agreed to the published version of the manuscript., (© 2024. The Author(s).)

Background: Platelet transfusion therapy has made a great breakthrough in clinical practice, and the differentiation of human embryonic stem cells (hESCs) to produce functional platelets has become a new potential approach, however, efficient generation of functional platelets still faces great challenges. Here, we presented a novel approach to highly and efficiently generate mature megakaryocytes (MKs) and functional platelets from hESCs., Methods: In hypoxic conditions, we successfully replicated the maturation process of MKs and platelets in a controlled in vitro environment by introducing an optimal combination of cytokines at various stages of development. This method led to the generation of MKs and platelets derived from hESCs. Subsequently, mature MKs and functional platelets were further comprehensively investigated and characterized using a variety of methodologies, including flow cytometry analysis, RT-qPCR validation, Giemsa-Wright's staining, immunofluorescent staining, RNA transcriptome analysis, and DNA ploidy analysis. Additionally, the in vivo function of platelets was evaluated through the transplantation using thrombocytopenia model mice., Results: Under our 3D differentiation conditions with four sequential stages, hESCs could be efficiently induced into mature MKs, with 95% expressing CD41aCD42a or 90% expressing CD41aCD42b, and those MKs exhibited polyploid properties, produced filamentous proplatelet structures and further generated platelets. Furthermore, 95% of platelets showed CD42b + CD62p + phenotype upon the stimulation with ADP and TRAP-6, while 50% of platelets exhibited the ability to bind PAC-1, indicating that hESC-derived platelets possessed the in vitro functionality. In mice models of thrombocytopenia, hESC-derived platelets effectively restored hemostasis in a manner comparable to human blood-derived platelets. Further investigation on the mechanism of this sequential differentiation revealed that cellular differentiation and molecular interactions during the generation of hESC-derived MKs and platelets recapitulated the developmental trajectory of the megakaryopoiesis and thrombopoiesis., Conclusions: Thus, our results demonstrated that we successfully established a highly efficient differentiation of hESCs into mature MKs and functional platelets in vitro. The in vivo functionality of hESC-derived platelets closely resembles that of natural human platelets, thus offering a promising avenue for the development of functional platelets suitable for future clinical applications., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Guangzhou First people's Hospital (Approval No.: K-2021–008-01, and approval date: January 17, 2022.) to use umbilical cord blood and human platelets from healthy volunteers for Large-scale Preparation of Functional Platelets from hESCs/iPSCs. The patients or their guardians/legally authorized representatives provided written informed consent for participation in the study with the use of umbilical cord blood and human platelets. All mouse experiments were performed according to our experimental protocols approved by the Guangzhou Committee for the Use and Care of Laboratory Animals, and by the Animal Ethics Committee of South China University of Technology University (Approval number: 2019073, and approval date: December 12, 2019.). WiCell Research Institute has confirmed that there was the ethical approval for collection of human embryonic stem cells (WA01(H1) and WA09(H9)) with NIH Approval NIHhESC-10–0043 and NIH Approval NIHhESC-10–0062, and that the donors had signed informed consent ( www.wicell.org ). Competing  interests: The authors declare that there is no competing  interests., (© 2024. The Author(s).)

Background: Hibiscus syriacus L. is a deciduous shrub with a strong environmental resistance and wide application prospects. The genetic background and ploidy levels of Hibiscus cultivars are complex, and polyploid breeding has long been an important method for developing new Hibiscus cultivars. However, the relationship of ploidy levels with leaf morphology, stomatal characteristics, and leaf anatomy remains unclear., Results: This study analyzed three ploidy levels (triploid, tetraploid, and hexaploid) of Hibiscus syriacus. Flow cytometry confirmed the ploidy levels, and morphological traits were evaluated. Leaf length, leaf width, and petiole length decreased with increasing ploidy. Stomatal length, stomatal width, guard cell length, and guard cell width increased and stomatal number and density decreased with increasing ploidy. The hexaploids exhibited the highest midrib diameter and palisade tissue thickness values. Correlation analyses revealed that stomatal morphology served as a reliable marker for determining ploidy levels., Conclusion: This study highlights the impact of varying ploidy levels on the leaf and stomatal morphologies and leaf anatomy of Hibiscus syriacus. These findings can provide theoretical guidance for improving Hibiscus cultivars in terms of stress resistance, adaptability, and ornamental traits, and for developing new cultivars with enhanced characteristics. Future research should focus on utilizing these morphological markers to optimize breeding strategies for Hibiscus cultivars., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Successful engraftment and localization of mesenchymal stem cells (MSCs) within target tissues are critical factors influencing their therapeutic efficacy for tissue repair and regeneration. However, the relative contributions of biophysical factors like cell size and adhesion capacity in regulating MSC distribution in vivo remain incompletely understood., Methods: Cell adhesion peptides and hanging drop method were used to modify the adhesive capacity and size of MSCs. To quantitatively track the real-time biodistribution of transplanted MSCs with defined size and adhesion profiles in living mice and rats, the non-invasive positron emission tomography (PET) imaging was applied., Results: Surface modification with integrin binding peptides like RGD, GFOGER, and HAVDI reduced MSC adhesion capacity in vitro by up to 43.5% without altering cell size, but did not significantly decrease lung entrapment in vivo. In contrast, culturing MSCs as 3D spheroids for 48 h reduced their cell diameter by 34.6% and markedly enhanced their ability to pass through the lungs and migrate to other organs like the liver after intravenous administration. This size-dependent effect on MSC distribution was more pronounced in rats compared to mice, likely due to differences in pulmonary microvessel diameters between species., Conclusion: Our findings reveal that cell size is a predominant biophysical regulator of MSC localization in vivo compared to adhesion capacity, providing crucial insights to guide optimization of MSC delivery strategies for enhanced therapeutic efficacy., Competing Interests: Declarations. Ethical approval: All applicable international, national, and/or institutional guidelines for the care and welfare of animals were followed. All animal procedures were conducted under a protocol approved by the Institutional Animal Care and Ethics Committee of Jiangsu Institute of Nuclear Medicine (Wuxi, China) (Title of the approved project, Mesenchymal stem cell regulation and PET imaging cell tracking. Approval number, JSINM-2023-100. Date of approval, 2023.7.28.). Human umbilical cord mesenchymal stem cells (hUC-MSCs) were obtained from Nanjing Drum Tower Hospital (Nanjing, China) and manufactured by Jiangsu Renocell Biotech Co., Ltd. (Nanjing, China). It was approved by ethics committee of Nanjing Drum Tower Hospital (Nanjing, China). The ethics approval number is 2020-197-01. Date of approval is 2020.07.06. The cell product has been certified by the National Institutes for Food and Drug Control of China. Consent for publication: All authors confirm their consent for publication. Conflict of interest: All authors except author Jing Wang report no conflict of interest. Author Jing Wang is a deputy director in Jiangsu Renocell Biotech Co., Ltd. Artificial intelligence: The authors declare that artificial intelligence was not used in this study., (© 2024. The Author(s).)